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2,336,100
Comparison of the effect of foot reflexology and body massage on physiological indicators and bilirubin levels in neonates under phototherapy.
Hyperbilirubinemia is one of the most common problems in infancy in the world. The aim of this study was to compare the effect of foot therapy and body massage on physiological indicators and bilirubin levels in infants under phototherapy.</AbstractText>This study was a randomized clinical trial that conducted on 51 infants with jaundice at Imam Hussein Pediatrics' Medical Center, Goldis Hospital in Isfahan (Iran). The samples randomly assigned to first intervention (reflexology), second intervention (body massage) and control groups using the block randomization. In the reflexology group, the relevant area on each foot was massaged for 15&#x2009;min in a relaxed position. In the massage body group, the limbs were massaged with circular motion. The massage was performed once a day for 15&#x2009;min and the control group did not receive any intervention. Physiological indicators were monitored using vital sign monitoring tools, and blood bilirubin levels were measured photo metrically (intravenous blood samples from the wrist). Finally, the data were analyzed using descriptive and inferential statistics and SPSS software version 18.</AbstractText>The results showed that before the intervention there was no significant difference in the mean of physiological indicators and bilirubin level between the three groups (p&#x2009;&gt;&#x2009;0.05), but after the intervention the average percentage of arterial oxygen saturation and bilirubin levels were significantly improved in the intervention groups compared to the control group (p&#x2009;&lt;&#x2009;0.05), while the mean of heart rate and respiration rate between the three groups were not significant (p&#x2009;&gt;&#x2009;0.05).</AbstractText>The results showed that reflexology and massage therapy can be effective in improving the condition of physiological indicators and blood bilirubin levels.</AbstractText>Copyright &#xa9; 2021. Published by Elsevier Ltd.</CopyrightInformation>
2,336,101
Apelin ameliorated acute heart failure via inhibiting endoplasmic reticulum stress in rabbits.
This study aimed to investigate whether inhibition of endoplasmic reticulum stress (ERS) mediated the ameliorative effect of apelin on acute heart failure (AHF). Rabbit model of AHF was induced by sodium pentobarbital. Cardiac dysfunction and injury were detected in the rabbit models of AHF, including impaired hemodynamic parameters and increased levels of CK-MB and cTnI. Apelin treatment dramatically improved cardiac impairment caused by AHF. ERS, indexed by increased GRP78, CHOP, and cleaved-caspase12 protein levels, was simultaneously attenuated by apelin. Apelin also could ameliorate increased protein levels of cleaved-caspase3 and Bax, and improved decreased protein levels of Bcl-2. Two common ERS stimulators, tunicamycin (Tm) and dithiothreitol (DTT) blocked the ameliorative effect of apelin on AHF. Phosphorylated Akt levels increased after apelin treatment in the rabbit models of AHF. The Akt signaling inhibitors wortmannin and LY294002 could block the cardioprotective effect of apelin, which could be relieved by ERS inhibitor 4-phenyl butyric acid (4-PBA). The aforementioned beneficial effects of apelin could all be blocked by APJ receptor antagonist F13A. 4-PBA and SC79, an Akt activator, can restore the ameliorative effect of apelin on AHF blocked by F13A. Apelin treatment dramatically ameliorated cardiac impairment caused by AHF, which might be mediated by APJ/Akt/ERS signaling pathway. These results will shed new light on AHF therapy.
2,336,102
Adjuvant chemotherapy in early-stage endometrioid endometrial cancer with &gt;50% myometrial invasion and negative lymph nodes.
The role of adjuvant chemotherapy as an addition or alternative to radiotherapy for early-stage high-risk endometrioid endometrial cancer is controversial. This study aimed to investigate the role of adjuvant chemotherapy in early-stage high-risk endometrioid endometrial cancer.</AbstractText>We identified patients with stage I or II endometrioid grade 2 or 3 endometrial cancer with myometrial invasion &gt;50%&#x2009;and negative lymph nodes after pelvic with or without para-aortic lymphadenectomy at four institutions (USA and Italy). Associations between chemotherapy and cause-specific and recurrence-free survival were assessed with Cox proportional hazards models. Hematogenous, peritoneal, and lymphatic recurrences were defined as 'non-vaginal'.</AbstractText>We identified 329 patients of mean (SD) age 66.4 (9.8) years. The median follow-up among those alive was 84 (IQR 44-133) months. The 5-year cause-specific survival was 86.1% (95% CI 82.0% to 90.4%) and the 5-year recurrence-free survival was 82.2% (95% CI 77.9% to 86.8%). Stage II (vs stage IB) was associated with poorer cause-specific and recurrence-free survival. A total of 58 (90.6%) of 64 patients who had chemotherapy had 4-6 cycles of platinum-based regimen. In adjusted analysis, we did not observe a statistically significant improvement in cause-specific survival (HR 0.34; 95%&#x2009;CI 0.11 to 1.03; p=0.06) or non-vaginal recurrence-free survival (HR 0.36; 95%&#x2009;CI 0.12 to 1.08; p=0.07) with adjuvant chemotherapy. Sixteen of 18 lymphatic recurrences (88.9%; 3/5 pelvic, all 13 para-aortic) were observed in the 265 patients who did not receive adjuvant chemotherapy. Among stage II patients, no deaths (100% 5-year recurrence-free survival) were observed in the eight patients who received adjuvant chemotherapy compared with 66% 5-year recurrence-free survival in the 34 patients who did not.</AbstractText>Although we observed that adjuvant chemotherapy was associated with improved oncologic outcomes in early-stage high-risk endometrioid endometrial cancer, the associations did not meet conventional levels of statistical significance. Further research is warranted in this relatively uncommon subgroup of patients.</AbstractText>&#xa9; IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.</CopyrightInformation>
2,336,103
Anesthetic effect of ultrasound-guided multiple-nerve blockade in modified radical mastectomy in patients with breast cancer.
Routine anesthesia modality for modified radical mastectomy (MRM) includes general anesthesia (GA), epidural blockade-combined GA and nerve blockade-combined GA. However, GA has been associated with postoperative adverse effects such as vertigo, postoperative nausea and vomiting and requirement for postoperative analgesia, which hinders recovery and prognosis. Moreover, combined blockade of thoracic paravertebral nerves or intercostal nerves and adjuvant basic sedation for massive lumpectomy provided perfect anesthesia and reduced opioid consumption, whereas the excision coverage did not attain the target of MRM. Regional anesthesia strategies involving supplementation of analgesics in ultrasound-guided multiple nerve blocks have garnered interests of clinicians. Nevertheless, the precise effects of intercostal nerves, brachial plexus and supraclavicular nerves in MRM in patients with breast cancer remain obscure.</AbstractText>Eighty female patients with breast cancer scheduled for MRM were recruited in the present trial between May, 2019 and Dec., 2019 in our hospital. The patients ranged from 30 to 65&#x200a;years of age and 18&#x223c;30&#x200a;kg/m2 in body-mass index, with the American Society of Anesthesiologists I or II. The patients were randomized to ultrasound-guided multiple nerve blocks group and GA group. The patients in multiple nerve blocks group underwent ultrasound guided multiple intercostal nerve blocks, interscalene brachial plexus and supraclavicular nerve blocks, (local anesthesia with 0.3% ropivacaine: 5&#x200a;ml for each intercostal nerve block, 8&#x200a;ml for brachial plexus block, 7&#x200a;mL for supraclavicular nerve block) and basic sedation and intraoperative mask oxygen inhalation. The variations of hemodynamic parameters such as mean arterial pressure, heart rate (HR) and pulse oxygen saturation were monitored. The visual analog scale scores were recorded at postoperative 0&#x200a;hour, 3&#x200a;hour, 6&#x200a;hour, 12&#x200a;hour and 24&#x200a;hour in resting state. The postoperative adverse effects, including vertigo, postoperative nausea, and vomiting, pruritus, and urinary retention and so on, as well as the analgesic consumption were recorded.</AbstractText>The ultrasound guided multiple intercostal nerve blocks, brachial plexus and supraclavicular nerve blocks could provide favorable anesthesia and analgesia, with noninferiority to GA and the reduced incidence of adverse effects and consumption of postoperative analgesics.</AbstractText>Copyright &#xa9; 2021 the Author(s). Published by Wolters Kluwer Health, Inc.</CopyrightInformation>
2,336,104
A Randomized Observer-Blinded Controlled Trial to Compare Pre-Emptive with Postoperative Ultrasound-Guided Mandibular Nerve Block for Postoperative Analgesia in Mandibular Fracture Surgeries.
Ultrasound-guided (UG) mandibular nerve block is effective for providing postoperative analgesia in mandibular fracture surgeries. The pre-emptive nerve blockade prolongs the duration of postoperative analgesia and reduces the consumption of intraoperative opioids. The aim of this prospective, randomized, single-blinded study was to compare the efficacy of pre-emptive and postoperative UG mandibular nerve block for postoperative analgesia in mandibular fracture surgeries.</AbstractText>Sixty patients scheduled for unilateral mandibular fracture surgeries were randomly divided into two groups by computer-generated random numbers and sealed envelope method: Group A received UG mandibular nerve block before surgical incision and group B received after surgery with ropivacaine 0.5% 10mL. The second anesthesiologist, who was blinded to the group involved, monitored the patient. The patients as well as the statistician were also blinded. The patients were started on patient-controlled analgesia (PCA) morphine with bolus 1mg and a lockout interval of 10min. The morphine consumption for 24h was recorded. The pain was assessed by the VAS score. The additional intraoperative fentanyl consumption and time for a request for rescue analgesic were recorded.</AbstractText>The total morphine consumption was reduced in group A (4.566&#xb1;0.717mg) than group B (5.93&#xb1;0.876mg) with a p-value of &lt;0.0001. The time for a request for rescue analgesic was also prolonged in group A (794.08&#xb1;89.561min) than group B (505.333&#xb1;3.159min). In group A, only four patients required an additional dose of fentanyl as against 11 patients in group B. The heart rate was also lower in group A 30min after the administration of the block and persisted for two hours intraoperatively.</AbstractText>Pre-emptive ultrasound-guided mandibular nerve block reduces morphine consumption, prolongs the time for a request for rescue analgesic, reduces intraoperative fentanyl consumption, provides better control of intraoperative heart rate, and better pain scores postoperatively when compared to the postoperative mandibular nerve block.</AbstractText>&#xa9; 2021 Venkatraman et al.</CopyrightInformation>
2,336,105
Modulation of human T-type calcium channels by synthetic cannabinoid receptor agonists in vitro.
Consumption of Synthetic Cannabinoid Receptor agonists (SCRAs) is associated with severe adverse reactions including seizures, arrhythmias and death, but the molecular mechanisms surrounding SCRA toxicity are not yet established. These disease-like symptoms are also synonymous with altered T-type calcium channel activity which controls rhythmicity in the heart and brain. This study examined whether SCRAs alter T-type activity and whether this represents a possible mechanism of toxicity.</AbstractText>Fluorescence-based and electrophysiology assays were used to screen 16 structurally related synthetic cannabinoids for their ability to inhibit human T-type calcium channels expressed in HEK293&#xa0;cells. The most potent compounds were then further examined using patch clamp electrophysiology.</AbstractText>MDMB-CHMICA and AMB-CHMINACA potently blocked Cav3.2 with IC50 values of 1.5 and 0.74&#xa0;&#x3bc;M respectively. Current inhibition increased from 47 to 80% and 45-87% respectively when the channel was in slow-inactivated state. Both SCRAs had little effect on steady state inactivation, however MDMB-CHMICA significantly shifted the half activation potential by -7mV. Neither drug produced frequency dependent block, in contrast to the phytocannabinoid &#x394;9-THC.</AbstractText>SCRAs are potent agonists of CB1 receptors and can be extremely toxic, but observed toxicity also resembles symptoms associated with altered Cav3.2 activity. Many SCRAs tested were potent modulators of Cav3.2, raising the possibility that SC toxicity may be due in part to Cav3.2 modulation. This potent T-type channel modulation suggests the possibility of SCRAs as a new drug class with potential to treat diseases associated with altered T-type channel activity. This article is part of the special issue on 'Cannabinoids'.</AbstractText>Copyright &#xa9; 2021 Elsevier Ltd. All rights reserved.</CopyrightInformation>
2,336,106
Case series of late lead dislodgement of Medtronic SelectSecure 3830 pacing leads in growing paediatric patients.
The SelectSecure lumenless 3830 pacing lead is often considered to be the pacing lead of choice for transvenous pacing in children because of its small diameter, lead strength, and reliable long-term sensing and pacing characteristics. One of the potential long-term pitfalls of a sturdy pacing lead is relative retraction with growth in children resulting in late lead dislodgement.</AbstractText>We report two cases of late SelectSecure 3830 lead dislodgement at 11.8&#x2009;years (Case 1) and 8.8&#x2009;years (Case 2), respectively, post the initial implantation. Case 1 was diagnosed with congenital complete heart block (CHB) at 9 months old when he presented with unconfirmed diphtheria infection. Case 2 was diagnosed with CHB at 14&#x2009;weeks of age with positive maternal anti-Ro antibodies. Both patients underwent implantation of a transvenous permanent pacemaker implantation with Medtronic SelectSecure 3830 lead due to symptomatic bradycardia. Apart from a pulse generator change at 8.5&#x2009;years (Case 1) and 7&#x2009;years (Case 2), respectively, post-implant due to normal battery depletion, both patients are well in the interim.</AbstractText>As part of the pacemaker follow-up for rapidly growing children, we recommend more frequent surveillance of lead 'tautness' by chest radiography especially in children with CHB with no underlying heart rhythm.</AbstractText>&#xa9; The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.</CopyrightInformation>
2,336,107
Different acupuncture intervention time-points for improving capacity in motor function and activities of daily living after stroke: A protocol for systematic review and network meta-analysis.
The incidence of stroke has been found in an increasing trend worldwide, resulting in significant negative effects and severe impairments to survivors in terms of motor function and activities of daily living. Acupuncture therapy has been widely used in the clinical treatment of stroke for a long time, meanwhile, the efficacy has been confirmed by many studies. However, the optimal intervention time-point of acupuncture in stroke is controversial. Therefore, the purpose of our study is to provide scientific evidence and reasonable suggestions for this issue.</AbstractText>A computer-based retrieval will be employed in 7 electronic databases: EMBASE Database, PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang databases, Chinese Scientific Journals Database (VIP) and China Biological Medicine Database (CBM), from the establishment date of each database throughout October 2020. Only randomized controlled trials of acupuncture for stroke will be recruited and language is limited to English or Chinese. The outcomes we focus on include the Fugl-Meyer Assessment score and the Barthel Index. Additionally, safety assessments such as adverse events and drop-out cases may also be taken into consideration. The network meta-analysis will be performed based on the Bayesian framework and literature selection will be conducted by 2 trained reviewers. All data analysis will be calculated by Revman5.3, WinBUGS 1.4.3, Stata13.0, and R software 3.6.1. The Assessment of heterogeneity, inconsistency, subgroup, sensitivity, and publication bias will also be done under the guidelines of Cochrane Collaboration's tool.</AbstractText>The results of this study will be submitted to a peer-reviewed journal for publication.</AbstractText>This network meta-analysis will provide evidence-based references to evaluate the efficacy of different acupuncture intervention time-points during the treatment of stroke. Furthermore, it will help the clinicians to formulate appropriate medical plans and improve clinical efficacy.</AbstractText>INPLASY2020120060.</AbstractText>Copyright &#xa9; 2021 the Author(s). Published by Wolters Kluwer Health, Inc.</CopyrightInformation>
2,336,108
Association between physical activity and risk of obstructive sleep apnea.
This aim of this&#xa0;study was to investigate the association of physical activity with OSA risk among adult Chinese.</AbstractText>Participants were selected from baseline survey of the Guangzhou Heart Study. OSA was ascertained by using Berlin Questionnaire, and the physical activity, including leisure-time physical activity (LTPA), occupational activity, and transport activity, was measured with modified Global Physical Activity Questionnaire. Principal component analysis was used to extract the patterns of LTPA with varimax orthogonal transformation. Odds ratios (OR) with 95% confidence interval (95% CI) were calculated by using the logistic regression method.</AbstractText>For all 9733&#xa0;participants,&#xa0;aged 35 to 74 years, LTPA (high vs. inactive, OR: 0.81, 95% CI: 0.64-1.03), occupational activity (vigorous vs. retirement, OR:1.28, 95% CI: 0.93-1.75) and transport activity (high vs. retirement, OR: 1.05, 95% CI: 0.69-1.60) were not associated with OSA risk after considering potential confounders. Any specific component of LTPA and two LTPA patterns were also&#xa0;not associated with OSA risk. Stratified analysis yielded similar nonsignificant association of OSA risk with three dimensions of physical activity in both the retirement group and non-retirement group.</AbstractText>This study found that three dimensions of physical activity, including LTPA, transport activity, and occupational activity, were not associated with any risk of OSA. Future studies with longitudinal design are needed.</AbstractText>&#xa9; 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.</CopyrightInformation>
2,336,109
Anesthetic efficacy of single buccal infiltration of 4% articaine compared to routine inferior alveolar nerve block with 2% lidocaine during bilateral extraction of mandibular primary molars: a randomized controlled trial.
Inferior alveolar nerve block (IANB) using lidocaine 2% is commonly used for anesthetizing primary mandibular molars; however, this technique has the highest level of patient discomfort compared to other local anesthesia techniques. Therefore, alternative anesthesia techniques are necessary. The aim of this study was to evaluate the efficacy of a single buccal infiltration of 4% articaine with IANB using 2% lidocaine, for the bilateral extraction of primary mandibular molars.</AbstractText>The present study was conducted on 30 patients aged between 6 and 9 years, who required the extraction of bilateral primary mandibular molars. The patients were randomly divided into two groups as follows: In the first session, Group A received IANB with lidocaine 2% and group B received infiltration with articaine 4%. In the second session, another injection method was performed on the opposite side. The Wong-Baker Facial Pain scale (WBFPS), Face Leg Activity Cry, and Consolability (FLACC), and physiologic parameters were used to assess pain perception.</AbstractText>The independent t-test showed no statistically significant difference in blood pressure and heart rate before and after extraction (P &gt; 0.05). The mean FLACC index in the lidocaine and articaine groups was 0.89 and 1.36, respectively; there was no statistically significant difference between them (P &gt; 0.05). According to the results of the chi-square test, there was no statistically significant difference between the groups for WBFPS (P &gt; 0.05).</AbstractText>The articaine infiltration technique may be an alternative to the IANB for the extraction of primary mandibular molars.</AbstractText>Copyright &#xa9; 2021 Journal of Dental Anesthesia and Pain Medicine.</CopyrightInformation>
2,336,110
Enhanced endothelial barrier function by monoclonal antibody activation of vascular endothelial cadherin.
Excessive vascular permeability occurs in inflammatory disease processes. Vascular endothelial cadherin (VE-cadherin) is an adhesion protein that controls vascular permeability. We identified monoclonal antibodies (mAbs) to human VE-cadherin that activate cell adhesion and inhibit the increased permeability of endothelial cell monolayers induced by thrombin receptor activator peptide-6 (TRAP-6). Two mAbs, 8A12c and 3A5a, reduce permeability, whereas an inhibitory mAb, 2E11d, enhances permeability. Activating mAbs also reduce permeability induced by tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and vascular endothelial cell growth factor (VEGF). The activating mAbs also stabilize the organization of the adherens junctions that are disrupted by TRAP-6, VEGF, or TNF-&#x3b1;. The activating mAbs act directly on the adhesive function of VE-cadherin because they did not block the accumulation of actin filaments stimulated by TRAP-6 and enhance physical cell-cell adhesion of VE-cadherin-expressing tissue culture cells. Therefore, VE-cadherin function can be regulated at the cell surface to control endothelial permeability.<b>NEW &amp; NOTEWORTHY</b> Excessive vascular permeability is a serious complication of many inflammatory disease conditions. We have developed monoclonal antibodies that inhibit increases in endothelial monolayer permeability induced by several signaling factors by activating VE-cadherin mediated adhesion and stabilizing cell junctions. These antibodies and/or the mechanisms they reveal may lead to important therapeutics to treat vascular leakiness and inflammation.
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[Comparative study between electroacupuncture at Neima point and Neiguan (PC 6) and epidural nerve block for preemptive analgesia in patients undergoing thoracic surgery].
<b>&#x76ee;&#x7684;&#xff1a;</b>&#x6bd4;&#x8f83;&#x7535;&#x9488;&#x5185;&#x9ebb;&#x70b9;&#x548c;&#x5185;&#x5173;&#x7a74;&#x8d85;&#x524d;&#x9547;&#x75db;&#x4e0e;&#x786c;&#x819c;&#x5916;&#x795e;&#x7ecf;&#x963b;&#x6ede;&#x8d85;&#x524d;&#x9547;&#x75db;&#x5728;&#x80f8;&#x79d1;&#x624b;&#x672f;&#x56f4;&#x672f;&#x671f;&#x9547;&#x75db;&#x7684;&#x4e34;&#x5e8a;&#x6548;&#x679c;&#x3002;<b>&#x65b9;&#x6cd5;&#xff1a;</b>&#x5c06;60&#x4f8b;&#x62e9;&#x671f;&#x884c;&#x98df;&#x7ba1;&#x764c;&#x6839;&#x6cbb;&#x672f;&#x7684;&#x60a3;&#x8005;&#x968f;&#x673a;&#x5206;&#x4e3a;&#x89c2;&#x5bdf;1&#x7ec4;&#x3001;&#x89c2;&#x5bdf;2&#x7ec4;&#x548c;&#x5bf9;&#x7167;&#x7ec4;&#xff0c;&#x6bcf;&#x7ec4;20&#x4f8b;&#x3002;&#x89c2;&#x5bdf;1&#x7ec4;&#x4e8e;&#x9ebb;&#x9189;&#x8bf1;&#x5bfc;&#x524d;30 min&#x786c;&#x819c;&#x5916;&#x8154;&#x6ce8;&#x5165;0.375&#xff05;&#x7f57;&#x54cc;&#x5361;&#x56e0;20 mL&#xff0c;&#x672f;&#x4e2d;&#x6b63;&#x5e38;&#x9ebb;&#x9189;&#xff1b;&#x89c2;&#x5bdf;2&#x7ec4;&#x4e8e;&#x9ebb;&#x9189;&#x8bf1;&#x5bfc;&#x524d;&#x7535;&#x9488;&#x53cc;&#x4fa7;&#x5185;&#x9ebb;&#x70b9;&#x3001;&#x5185;&#x5173;&#x7a74;30 min&#xff0c;&#x672f;&#x4e2d;&#x6b63;&#x5e38;&#x9ebb;&#x9189;&#xff1b;&#x5bf9;&#x7167;&#x7ec4;&#x5355;&#x7eaf;&#x884c;&#x5168;&#x8eab;&#x9ebb;&#x9189;&#xff0c;3&#x7ec4;&#x672f;&#x540e;&#x5747;&#x884c;&#x9759;&#x8109;&#x81ea;&#x63a7;&#x9547;&#x75db;&#xff08;PCIA&#xff09;&#x3002;&#x8bb0;&#x5f55;3&#x7ec4;&#x60a3;&#x8005;&#x9488;&#x523a;/ &#x786c;&#x819c;&#x5916;&#x7a7f;&#x523a;&#x524d;&#xff08;T<sub>0</sub>&#xff09;&#x3001;&#x5207;&#x76ae;&#x65f6;&#xff08;T<sub>1</sub>&#xff09;&#x3001;&#x62d4;&#x7ba1;&#x65f6;&#xff08;T<sub>2</sub>&#xff09;&#x3001;&#x672f;&#x540e;2 h&#xff08;T<sub>3</sub>&#xff09;&#x5e73;&#x5747;&#x52a8;&#x8109;&#x538b;&#xff08;MAP&#xff09;&#x548c;&#x5fc3;&#x7387;&#xff08;HR&#xff09;&#xff1b;&#x8bb0;&#x5f55;&#x672f;&#x4e2d;&#x9ebb;&#x9189;&#x836f;&#x7684;&#x7528;&#x91cf;&#x53ca;&#x62d4;&#x7ba1;&#x65f6;&#x95f4;&#xff1b;&#x68c0;&#x6d4b;T<sub>0</sub>&#x3001;T<sub>3</sub>&#xff0c;&#x672f;&#x540e;12 h&#xff08;T<sub>4</sub>&#xff09;&#x3001;24 h&#xff08;T<sub>5</sub>&#xff09;&#x548c;48 h&#xff08;T<sub>6</sub>&#xff09;&#x8840;&#x6d46;&#x3b2;-&#x5185;&#x5561;&#x80bd;&#xff08;&#x3b2;-EP&#xff09;&#x3001;5-&#x7f9f;&#x8272;&#x80fa;&#xff08;5-HT&#xff09;&#x3001;&#x524d;&#x5217;&#x817a;&#x7d20;E<sub>2</sub>&#xff08;PGE<sub>2</sub>&#xff09;&#x7684;&#x542b;&#x91cf;&#xff1b;&#x91c7;&#x7528;&#x89c6;&#x89c9;&#x6a21;&#x62df;&#x91cf;&#x8868;&#xff08;VAS&#xff09;&#x8bc4;&#x4f30;&#x60a3;&#x8005;&#x9547;&#x75db;&#x6548;&#x679c;&#x3002;<b>&#x7ed3;&#x679c;&#xff1a;</b>&#x89c2;&#x5bdf;1&#x7ec4;MAP&#x5728;T<sub>1</sub>&#x3001;T<sub>2</sub>&#x65f6;&#x95f4;&#x70b9;&#x4f4e;&#x4e8e;&#x89c2;&#x5bdf;2&#x7ec4;&#x3001;&#x5bf9;&#x7167;&#x7ec4;&#xff08;<i>P</i>&lt;0.05&#xff09;&#xff0c;HR&#x5728;T<sub>1</sub>&#x3001;T<sub>2</sub>&#x65f6;&#x95f4;&#x70b9;&#x4f4e;&#x4e8e;&#x5bf9;&#x7167;&#x7ec4;&#xff08;<i>P</i>&lt;0.05&#xff09;&#xff1b;&#x89c2;&#x5bdf;2&#x7ec4;MAP&#x548c;HR&#x5728;T<sub>1</sub>&#x3001;T<sub>2</sub>&#x65f6;&#x95f4;&#x70b9;&#x4f4e;&#x4e8e;&#x5bf9;&#x7167;&#x7ec4;&#xff08;<i>P</i>&lt;0.05&#xff09;&#x3002;&#x89c2;&#x5bdf;1&#x7ec4;&#x3001;&#x89c2;&#x5bdf;2&#x7ec4;&#x672f;&#x4e2d;&#x745e;&#x82ac;&#x592a;&#x5c3c;&#x7528;&#x91cf;&#x8f83;&#x5bf9;&#x7167;&#x7ec4;&#x5c11;&#xff08;<i>P</i>&lt;0.05&#xff09;&#xff0c;&#x62d4;&#x7ba1;&#x65f6;&#x95f4;&#x8f83;&#x5bf9;&#x7167;&#x7ec4;&#x65e9;&#xff08;<i>P</i>&lt;0.05&#xff09;&#x3002;&#x89c2;&#x5bdf;2&#x7ec4;&#x3b2;-EP&#x542b;&#x91cf;&#x5728;T<sub>4</sub>&#x3001;T<sub>5</sub>&#x3001;T<sub>6</sub>&#x65f6;&#x95f4;&#x70b9;&#x8f83;&#x89c2;&#x5bdf;1&#x7ec4;&#x3001;&#x5bf9;&#x7167;&#x7ec4;&#x5347;&#x9ad8;&#xff08;<i>P</i>&lt;0.05&#xff09;&#xff1b;&#x89c2;&#x5bdf;1&#x7ec4;&#x3001;&#x89c2;&#x5bdf;2&#x7ec4;5-HT&#x548c;PGE<sub>2</sub>&#x542b;&#x91cf;&#x5728;T<sub>3</sub>&#x3001;T<sub>4</sub>&#x3001;T<sub>5</sub>&#x65f6;&#x95f4;&#x70b9;&#x8f83;&#x5bf9;&#x7167;&#x7ec4;&#x964d;&#x4f4e;&#xff08;<i>P</i>&lt;0.05&#xff09;&#x3002;&#x89c2;&#x5bdf;1&#x7ec4;&#x3001;&#x89c2;&#x5bdf;2&#x7ec4;VAS&#x8bc4;&#x5206;&#x5728;T<sub>3</sub>&#x3001;T<sub>4</sub>&#x3001;T<sub>5</sub>&#x65f6;&#x95f4;&#x70b9;&#x4f4e;&#x4e8e;&#x5bf9;&#x7167;&#x7ec4;&#xff08;<i>P</i>&lt;0.05&#xff09;&#x3002;<b>&#x7ed3;&#x8bba;&#xff1a;</b>&#x7535;&#x9488;&#x5185;&#x9ebb;&#x70b9;&#x548c;&#x5185;&#x5173;&#x7a74;&#x8d85;&#x524d;&#x9547;&#x75db;&#x4e0e;&#x786c;&#x819c;&#x5916;&#x795e;&#x7ecf;&#x963b;&#x6ede;&#x8d85;&#x524d;&#x9547;&#x75db;&#x5747;&#x80fd;&#x4e3a;&#x80f8;&#x90e8;&#x624b;&#x672f;&#x63d0;&#x4f9b;&#x6709;&#x6548;&#x56f4;&#x672f;&#x671f;&#x9547;&#x75db;&#xff0c;&#x524d;&#x8005;&#x5728;&#x7ef4;&#x6301;&#x672f;&#x4e2d;&#x8840;&#x6d41;&#x52a8;&#x529b;&#x5b66;&#x65b9;&#x9762;&#x66f4;&#x5e73;&#x7a33;&#xff0c;&#x5bf9;&#x673a;&#x4f53;&#x7684;&#x751f;&#x7406;&#x5e72;&#x6270;&#x66f4;&#x5c0f;&#x3002;.
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Pharmacokinetic and Tissue Distribution of Orally Administered Cyclosporine A-Loaded poly(ethylene oxide)-block-Poly(&#x3b5;-caprolactone) Micelles versus Sandimmune<sup>&#xae;</sup> in Rats.
We have previously reported on a polymeric micellar formulation of Cyclosporine A (CyA) based on poly(ethylene oxide)-block-poly(&#x3b5;-caprolactone) (PEO5K</sub>-b-PCL13K</sub>) capable of changing drug biodistribution and pharmacokinetic profile following intravenous administration. The objective of the present study was to explore the potential of this formulation in changing the tissue distribution and pharmacokinetics of the encapsulated CyA following oral administration making comparisons with Sandimmune&#xae;.</AbstractText>The in vitro CyA release and stability CyA-loaded PEO-b-PCL micelles (CyA-micelles) were evaluated in biorelevant media. The pharmacokinetics and tissue distribution of orally administered CyA-micelles or Sandimmune&#xae; and tissue distribution of traceable Cyanine-5.5 (Cy5.5)-conjugated PEO-b-PCL micelles were then investigated in healthy rats.</AbstractText>CyA-micelles showed around 60-70% CyA release in simulated intestinal and gastric fluids within 24&#xa0;h, while Sandimmune&#xae; released its entire CyA content in the simulated intestinal fluid. CyA-micelles and Sandimmune&#xae; showed similar pharmacokinetics, but different tissue distribution profile in rats. In particular, the calculated AUC for CyA-micelles was higher in liver, comparable in heart, and lower in spleen, lungs, and kidneys when compared to that for Sandimmune&#xae;.</AbstractText>The results point to the influence of excipients in Sandimmune&#xae; on CyA disposition and more inert nature of PEO-b-PCL micelles in defining CyA biological interactions.</AbstractText>
2,336,113
First trimester combined screening test for aneuploidies in anti-Ro carriers pregnant women.
Anti-Ro/SSA and anti-La/SSB antibodies are associated with neonatal lupus and congenital heart block. Controversial results regarding perinatal outcomes are found and less is known about aneuploidy screening. The hypothesis is that the presence of anti-Ro and/or anti-La antibodies influences the levels of PAPP-A and &#xdf;-HCG, thus interfering in the calculation of risk of aneuploidies.</AbstractText>Fifty-five anti-Ro/SSA positive pregnant women were included. The demographic characteristics and laboratory variables were studied. Data concerning chromosomopaties screening were also recorded.</AbstractText>PAPP-A and &#x3b2;-HCG levels were calculated (as well as NT and CRL) and compared with a healthy cohort of 12971 pregnant women. PAPP-A levels in mg/mL were lower significatively. In anti-La/SS-B cohort, significant differences were found in PAPP-A in mg/mL and in MoM. Combined risks for Down syndrome (DS) in both groups were higher but the differences were due to age.</AbstractText>Serum levels of PAPP-A were significative lower but not confirmed when adjusted to MoM. This will have to be confirmed in studies with a larger number of patients and to check whether there is an impact in the calculation of DS risk or not. They could represent a group of pregnant women with significantly a higher risk of adverse perinatal outcome. Key Points &#x2022; Pregnant patients with anti-Ro/SS-A ant/or anti-La/SS-B antibodies have low PAPP-A levels compared with pregnant women without antibodies. &#x2022; PAPP-A levels are used in obstetrics for aneuploidies screening in the first trimester, so in these patients, there could be more false positive screening. &#x2022; In these findings are verified in trials with a larger number of patients, a correction variable would have to be applied for the aneuploidies screening calculation. &#x2022; Also, low PAPP-A levels are correlated with poor placentation, that is to say, more risk of miscarriages, small fetus for gestational age, and preeclampsia. This is another topic to take into consideration in this population.</AbstractText>
2,336,114
Integrin-directed antibody-based immunotherapy: focus on VLA-4.
One major finding of chronic inflammatory diseases of various origins is the establishment of inflammatory infiltrates, bearing different leukocyte subpopulations, including activated T lymphocytes. Integrins are among the large series of molecular interactions that have been implicated as players in both triggering and maintenance of leukocyte influx from the blood into a given organ parenchyme. Accordingly, blocking the interaction between VLA-6 integrin and laminin, experimentally abrogates heart graft rejection. Many reports have shown that VLA-4 is used by T cells to cross endothelial barriers, as well as to migrate within target tissues. In this respect, a humanized IgG4 anti-VLA-4 monoclonal antibody (specific to the &#x3b1;4-integrin chain of VLA-4) has been successfully applied to treat multiple sclerosis as well as inflammatory bowel disease. Anti-VLA-4 monoclonal antibody has also been applied to block transendothelial passage in other autoimmune diseases, such as rheumatoid arthritis. On this same vein is the action of such a reagent in impairing <i>in vitro</i> transendothial and fibronectin-driven migration of CD4<sup>+</sup> and CD8<sup>+</sup> T cells expressing high densities of VLA-4 from Duchenne muscular dystrophy patients, thus potentially enlarging the use of this strategy to other diseases. Yet, in a small number of patients, the use of Natalizumab has been correlated with the progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus. This issue restricted the use of the reagent. In this respect, the development of smaller and more specific antibody reagents should be envisioned as a next-generation promising strategy.
2,336,115
Combined transverse thoracis plane and pectoral nerve blocks for breast surgery under sedation.
The pectoral nerves 2 (pecs 2) block is widely used as adjunct to general anaesthesia for breast surgery. There are a few case reports and a single case series that describe regional anaesthesia as a single technique or supplemented by light to moderate sedation. Here we describe the management of a 91-year-old ASA physical status 4 patient who presented with a T4 breast malignancy. She was considered unfit for general anaesthesia due to significant valvular heart disease. A wide local excision was successfully performed under a pecs 2 block and a transverse thoracis plane block, supplemented with light sedation. We consider this technique to be a good option for selected patients who are considered unfit for general anaesthesia.
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Unpacking power dynamics in research and evaluation on social accountability for sexual and reproductive health and rights.
Over the past decade, social accountability for health has coalesced into a distinct field of research and practice. Whether explicitly stated or not, changed power relations are at the heart of what social accountability practitioners seek, particularly in the context of sexual and reproductive health. Yet, evaluations of social accountability programs frequently fail to assess important power dynamics. In this commentary, we argue that we must include an examination of power in research and evaluation of social accountability in sexual and reproductive health, and suggest ways to do this. The authors are part of a community of practice on measuring social accountability and health outcomes. We share key lessons from our efforts to conduct power sensitive research using different approaches and methods.First, participatory research and evaluation approaches create space for program participants to engage actively in evaluations by defining success. Participation is also one of the key elements of feminist evaluation, which centers power relations rooted in gender. Participatory approaches can strengthen 'traditional' health evaluation approaches by ensuring that the changes assessed are meaningful to communities.Fields from outside health offer approaches that help to describe and assess changes in power dynamics. For example, realist evaluation analyses the causal processes, or mechanisms, grounded in the interactions between social, political and other structures and human agency; programs try to influence these structures and/or human agency. Process tracing requires describing the mechanisms underlying change in power dymanics in a very detailed way, promoting insight into how changes in power relationships are related to the broader program.Finally, case aggregation and comparison entail the aggregation of data from multiple cases to refine theories about when and how programs work. Case aggregation can allow for nuanced attention to context while still producing lessons that are applicable to inform programming more broadly.We hope this brief discussion encourages other researchers and evaluators to share experiences of analysing power relations as part of evaluation of social accountability interventions for sexual and reproductive health so that together, we improve methodology in this crucial area.
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The Impacts of Temporal Variation and Individual Differences in Driver Cognitive Workload on ECG-Based Detection.
This paper aimed to investigate the robustness of driver cognitive workload detection based on electrocardiogram (ECG) when considering temporal variation and individual differences in cognitive workload.</AbstractText>Cognitive workload is a critical component to be monitored for error prevention in human-machine systems. It may fluctuate instantaneously over time even in the same tasks and differ across individuals.</AbstractText>A driving simulation study was conducted to classify driver cognitive workload underlying four experimental conditions (baseline, N-back, texting, and N-back + texting distraction) in two repeated 1-hr blocks. Heart rate (HR) and heart rate variability (HRV) were compared among the experimental conditions and between the blocks. Random forests were built on HR and HRV to classify cognitive workload in different blocks and for different individuals.</AbstractText>HR and HRV were significantly different between repeated blocks in the study, demonstrating the time-induced variation in cognitive workload. The performance of cognitive workload classification across blocks and across individuals was significantly improved after normalizing HR and HRV in each block by the corresponding baseline.</AbstractText>The temporal variation and individual differences in cognitive workload affects ECG-based cognitive workload detection. But normalization approaches relying on the choice of appropriate baselines help compensate for the effects of temporal variation and individual differences.</AbstractText>The findings provide insight into the value and limitations of ECG-based driver cognitive workload monitoring during prolonged driving for individual drivers.</AbstractText>
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What Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation?
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
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Fever as a predictor of adverse outcomes in COVID-19.
<AbstractText Label="BACKGROUND/INTRODUCTION" NlmCategory="BACKGROUND">There are little data on outcomes of COVID-19 patients with the presence of fever compared to the presence of symptoms.</AbstractText>We examined the associations between symptomology, presence of fever and outcomes of a COVID-19 cohort.</AbstractText>Between 23 January and 30 April 2020, 554 COVID-19 patients were admitted to a tertiary hospital in Singapore. They were allocated into four groups based on symptomology and fever-Group 1: asymptomatic and afebrile, Group 2: symptomatic but afebrile, Group 3: febrile but asymptomatic and Group 4: symptomatic and febrile. The primary outcomes were intensive care unit (ICU) admissions and mortality. The composite end-point included ICU admissions, mortality or any COVID-19 related end-organ involvement.</AbstractText>There were differences in ferritin (P=0.003), C-reactive protein (CRP) levels (P&lt;0.001) and lymphopenia (P=0.033) across all groups, with the most favourable biochemical profile in Group 1, and the least in Group 4. Symptomatic groups (Groups 2 and 4) had higher ICU admissions (1.9% and 6.0%, respectively, P=0.003) than asymptomatic groups (Groups 1 and 3). Composite end-point was highest in Group 4 (24.0%), followed by Group 3 (8.6%), Group 2 (4.8%) and Group 1 (2.4%) (P&lt;0.001). The presence of fever (OR 4.096, 95% CI 1.737-9.656, P=0.001) was associated with the composite end-point after adjusting for age, pulse rate, comorbidities, lymphocyte, ferritin and CRP. Presence of symptoms was not associated with the composite end-point.</AbstractText><AbstractText Label="DISCUSSION/CONCLUSION" NlmCategory="CONCLUSIONS">In this COVID-19 cohort, presence of fever was a predictor of adverse outcomes. This has implications on the management of febrile but asymptomatic COVID-19 patients.</AbstractText>&#xa9; The Author(s) 2021. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: [email protected].</CopyrightInformation>
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Comparison Between the Effects of Bupivacaine and Levobupivacaine for Spinal Anesthesia on QT Dispersion.
Bupivacaine and Levobupivacaine are frequently used local anesthetic drugs in spinal anesthesia practice. Both agents have arrhythmic effects on the heart. However, there is no clear information about which agent is more arrhythmogenic.</AbstractText>The aim of this article is to investigate the effects of bupivacaine and its S (-)-enantiomer, levobupivacaine, on cardiac arrhythmias in patients.</AbstractText>The study included 40 patients scheduled for inguinal hernia surgery. Patients were randomly divided into the following two groups using a sealed envelope method: Group I, the bupivacaine group (n = 20); and Group II, the levobupivacaine group (n = 20). The QT values were taken preoperatively and during the 10th of the spinal block, the 10th of the surgical incision, and the 10th postoperative minute. Additionally, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), oxygen saturation (SO2</sub>), and heart rate (HR) values, in addition to motor block (Bromage scale) levels and durations, were recorded for each patient.</AbstractText>HR values measured at 10 min after spinal block were significantly higher than the baseline values in the levobupivacaine group (p &lt; 0.05). The corrected QT interval (QTc) values increased significantly at 10 minutes after spinal block and at 10 min postoperatively in the bupivacaine group (p &lt; 0.05). QTd and QTcd measurements were taken at the 10th minute of spinal anesthesia, the 10th minute of the incision, and the 10th minute postoperatively. When compared to the levobupivacaine group, a statistically significant increase was found in the bupivacaine group (p &lt; 0.05).</AbstractText>Levobupivacaine allows greater hemodynamic stability, while bupivacaine affects QTc and QTd measurement times more. As such, we believe that levobupivacaine may be a better alternative to bupivacaine during clinical practice, particularly in patients with cardiac problems.</AbstractText>Copyright&#xa9; Bentham Science Publishers; For any queries, please email at [email protected].</CopyrightInformation>
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Excess sarcoplasmic reticulum-mitochondria calcium transport induced by Sphingosine-1-phosphate contributes to cardiomyocyte hypertrophy.
Sphingosine-1-phosphate (S1P) has been shown to possess pro-hypertrophic properties in the heart, but the detailed molecular mechanism that underlies the pathological process is rarely explored. In the present study, we aim to explore the role of S1P-mediated intracellular Ca<sup>2+</sup> signaling, with a focus on sarcoplasmic reticulum (SR)-mitochondria communication, in cardiomyocyte hypertrophy. Cultured neonatal rat ventricular myocytes (NRVMs) displayed significantly hypertrophic growth after treatment with 1&#xa0;&#x3bc;mol/L S1P for 48&#xa0;h, as indicated by the cell surface area or mRNA expressions of hypertrophic marker genes (ANP, BNP and &#x3b2;-MHC). Importantly, mitochondrial Ca<sup>2+</sup> and reactive oxygen species (ROS) levels were dramatically elevated upon S1P stimulation, and pharmacological blockage of which abolished NRVM hypertrophy. 0.5&#xa0;Hz electrical pacing induced similar cytosolic Ca<sup>2+</sup> kinetics to S1P stimulation, but unaffected the peak of mitochondrial [Ca<sup>2+</sup>]. With interference of the expression of type 2 inositol 1,4,5-trisphosphate receptors (IP<sub>3</sub>R2), which are unemployed in electrical paced Ca<sup>2+</sup> activity but may be activated by S1P, alteration in mitochondrial Ca<sup>2+</sup> as well as the hypertrophic effect in NRVMs under S1P stimulation were attenuated. The hypertrophic effect of S1P can also be abolished by pharmacological block of S1PR1 or Gi signaling. Collectively, our study highlights the mechanistic role of IP<sub>3</sub>R2-mediated excess SR-mitochondria Ca<sup>2+</sup> transport in S1P-induced cardiomyocyte hypertrophy.
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Association of OLR1 gene polymorphisms with the risk of coronary artery disease: A systematic review and meta-analysis.
Oxidized LDL receptor 1 (OLR1) encodes LOX-1, LOXIN, and OLR1D4 transcript variants. Up-regulation of LOX-1 and down-regulation of LOXIN have an essential role in causing coronary artery disease (CAD). Discovery of risk single nucleotide polymorphisms (SNPs) in OLR1 gene is clinically important as these polymorphisms could be candidate biomarkers of CAD.</AbstractText>The purpose of this study is quantitative evidence synthesis on how OLR1 polymorphisms in the haplotype block impact the risk of CAD.</AbstractText>First, a systematic keyword-based search in PubMed, Web of Science, and Scopus was conducted. After data extraction, pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for OLR1 polymorphisms and CAD. Twelve case-control studies, including 6,238 cases and 15,773 controls, were concluded in the meta-analysis.</AbstractText>Our findings demonstrate significant association of OLR1 polymorphisms in the haplotype block with CAD risk in all genetic models (allelic model: OR&#xa0;=&#xa0;1.19, 95%CI&#xa0;=&#xa0;1.06-1.34; additive model: OR&#xa0;=&#xa0;1.54, 95%CI&#xa0;=&#xa0;1.16-2.05; recessive model: OR&#xa0;=&#xa0;1.26, 95%CI&#xa0;=&#xa0;1.04-1.53; dominant model: OR&#xa0;=&#xa0;1.28, 95%CI&#xa0;=&#xa0;1.09-1.51). Subgroup analysis based on the type of polymorphism revealed that rs1050283 (3'UTR*188 C&#xa0;&gt;&#xa0;T) and rs3736235 (IVS4-14 A&#xa0;&gt;&#xa0;G) are more significantly associated with the risk of CAD compared to other polymorphisms in the haplotype block.</AbstractText>We found a significant association between OLR1 polymorphisms in the haplotype block, especially rs1050283 and rs3736235, with CAD. We also suggest that precise determination of disease association with polymorphisms in a haplotype requires investigation of all SNPs rather than a single SNP in that specific haplotype.</AbstractText>Copyright &#xa9; 2021 Elsevier Inc. All rights reserved.</CopyrightInformation>
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Autonomic mechanisms of blood pressure alterations during sleep in orexin/hypocretin-deficient narcoleptic mice.
Increase in arterial pressure (AP) during sleep and smaller differences in AP between sleep and wakefulness have been reported in orexin (hypocretin)-deficient mouse models of narcolepsy type 1 (NT1) and confirmed in NT1 patients. We tested whether these alterations are mediated by parasympathetic or sympathetic control of the heart and/or resistance vessels in an orexin-deficient mouse model of NT1.</AbstractText>Thirteen orexin knock-out (ORX-KO) mice were compared with 12 congenic wild-type (WT) mice. The electroencephalogram, electromyogram, and AP of the mice were recorded in the light (rest) period during intraperitoneal infusion of atropine methyl nitrate, atenolol, or prazosin to block muscarinic cholinergic, &#x3b2;&#x200a;1-adrenergic, or &#x3b1;&#x200a;1-adrenergic receptors, respectively, while saline was infused as control.</AbstractText>AP significantly depended on a three-way interaction among the mouse group (ORX-KO vs WT), the wake-sleep state, and the drug or vehicle infused. During the control vehicle infusion, ORX-KO had significantly higher AP values during REM sleep, smaller decreases in AP from wakefulness to either non-rapid-eye-movement (non-REM) sleep or REM sleep, and greater increases in AP from non-REM sleep to REM sleep compared to WT. These differences remained significant with atropine methyl nitrate, whereas they were abolished by prazosin and, except for the smaller AP decrease from wakefulness to REM sleep in ORX-KO, also by atenolol.</AbstractText>Sleep-related alterations of AP due to orexin deficiency significantly depend on alterations in cardiovascular sympathetic control in a mouse model of NT1.</AbstractText>&#xa9; Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: [email protected].</CopyrightInformation>
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Spatial phase discontinuity at the center of moving cardiac spiral waves.
Precise analysis of cardiac spiral wave (SW) dynamics is essential for effective arrhythmia treatment. Although the phase singularity (PS) point in the spatial phase map has been used to determine the cardiac SW center for decades, quantitative detection algorithms that assume PS as a point fail to trace complex and rapid PS dynamics. Through a detailed analysis of numerical simulations, we examined our hypothesis that a boundary of spatial phase discontinuity induced by a focal conduction block exists around the moving SW center in the phase map.</AbstractText>In a numerical simulation model of a 2D cardiac sheet, three different types of SWs (short wavelength; long wavelength; and low excitability) were induced by regulating ion channels. Discontinuities of all boundaries among adjacent cells at each instance were evaluated by calculating the phase bipolarity (PB). The total amount of phase transition (PTA) in each cell during the study period was evaluated.</AbstractText>Pivoting, drifting, and shifting SWs were observed in the short-wavelength, low-excitability, and long-wavelength models, respectively. For both the drifting and shifting cases, long high-PB edges were observed on the SW trajectories. In all cases, the conduction block (CB) was observed at the same boundaries. These were also identical to the boundaries in the PTA maps.</AbstractText>The analysis of the simulations revealed that the conduction block at the center of a moving SW induces discontinuous boundaries in spatial phase maps that represent a more appropriate model of the SW center than the PS point.</AbstractText>Copyright &#xa9; 2021 Elsevier Ltd. All rights reserved.</CopyrightInformation>
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Improving care coordination for patients with cardiac disease: Study protocol of the randomised controlled new healthcare programme (Cardiolotse).
A lack of effective coordination and communication between ambulatory care physicians and hospitals, including the lack of follow-up care, poses a challenge to the recovery process of patients suffering from cardiac disease, often resulting in rehospitalisation and adverse outcomes. This innovative care programme aims to bridge the gap between ambulatory and hospital care. A key element of this programme is specifically trained care managers (Cardiolotse) who provide post-discharge support, access to additional resources and help the patient to navigate successfully through the healthcare system.</AbstractText>The study is set up as a prospective, randomised, controlled trial. Allocation to intervention group (support of care managers) and control group (usual care) follows an allocation ratio of 1:1 using block randomisation. Sample size calculations resulted in 1454patients per group after adjusting for potential non-compliance. All participants are surveyed at discharge, after 3 and 12&#xa0;months. The primary outcome of the study is the 12-month rehospitalisation rate. Secondary outcomes include differences in length of hospital stay, mortality, quality-adjusted life years, costs and patient satisfaction. Statistical analysis and economic evaluation will be complemented by a process evaluation.</AbstractText>The new healthcare programme is designed to support patients when leaving hospital with cardiac conditions by easing the transition between sectors through access to Cardiolotses and individualised care plans. We hypothesise that the programme reduces rehospitalisation and improves clinically relevant patient outcomes.</AbstractText>German Clinical Trial Register, DRKS00020424. Registered 2020-06-18, http://www.drks.de/DRKS00020424.</AbstractText>Copyright &#xa9; 2021 The Authors. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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Cardiovascular protective properties of oxytocin against COVID-19.
SARS-CoV-2 infection or COVID-19 has become a worldwide pandemic; however, effective treatment for COVID-19 remains to be established. Along with acute respiratory distress syndrome (ARDS), new and old cardiovascular injuries are important causes of significant morbidity and mortality in COVID-19. Exploring new approaches managing cardiovascular complications is essential in controlling the disease progression and preventing long-term complications. Oxytocin (OXT), an immune-regulating neuropeptide, has recently emerged as a strong candidate for treatment and prevention of COVID-19 pandemic. OXT carries special functions in immunologic defense, homeostasis and surveillance. It suppresses neutrophil infiltration and inflammatory cytokine release, activates T-lymphocytes, and antagonizes negative effects of angiotensin II and other key pathological events of COVID-19. Additionally, OXT can promote &#x3b3;-interferon expression to inhibit cathepsin L and increases superoxide dismutase expression to reduce heparin and heparan sulphate fragmentation. Through these mechanisms, OXT can block viral invasion, suppress cytokine storm, reverse lymphocytopenia, and prevent progression to ARDS and multiple organ failures. Importantly, besides prevention of metabolic disorders associated with atherosclerosis and diabetes mellitus, OXT can protect the heart and vasculature through suppressing hypertension and brain-heart syndrome, and promoting regeneration of injured cardiomyocytes. Unlike other therapeutic agents, exogenous OXT can be used safely without the side-effects seen in remdesivir and corticosteroid. Importantly, OXT can be mobilized endogenously to prevent pathogenesis of COVID-19. This article summarizes our current understandings of cardiovascular pathogenesis caused by COVID-19, explores the protective potentials of OXT against COVID-19-associated cardiovascular diseases, and discusses challenges in applying OXT in treatment and prevention of COVID-19. CHEMICAL COMPOUNDS: Angiotensin-converting enzyme 2 (ACE2); atrial natriuretic peptide (ANP); cathepsin L; heparan sulphate proteoglycans (HSPGs); interferon; interleukin; oxytocin; superoxide dismutase; transmembrane serine protease isoform 2 (TMPRSS2).
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Serratus Anterior Plane Block and Erector Spinae Plane Block Versus Thoracic Epidural Analgesia for Perioperative Thoracotomy Pain Control: A Randomized Controlled Study.
This study was designed to evaluate the safety and efficacy of erector spinae plane block and serratus anterior plane block versus thoracic epidural in perioperative pain control for patients with cancer undergoing lung surgeries.</AbstractText>Single blinded, randomized, controlled trial.</AbstractText>The study was carried out at the National Cancer Institute in Cairo, Egypt.</AbstractText>Fifty-one patients with cancer.</AbstractText>Patients were allocated randomly into three groups: thoracic epidural analgesia (TEA) group, serratus anterior plane block (SAPB) group, and erector spinae plane block (ESPB) group.</AbstractText>Outcome measures were 24 hours postoperative visual analog scale (VAS), intraoperative rescue fentanyl consumption, perioperative heart rate, mean blood pressure (mean arterial pressure [MAP]), and total postoperative morphine consumption. VAS scores at rest were significantly lower in the TEA group at the postanesthesia care unit and 24 hours. VAS scores with cough were significantly higher in the SAPB group at eight and 24 hours. The first time to receive morphine was significantly longer in the TEA group. No patients in the TEA group required postoperative morphine, whereas 88.2% and 47.1% required morphine in the SAPB and ESPB groups, respectively, p &lt; 0.001. In the TEA group, intraoperative MAP values were lower than the other two groups, p &lt; 0.05.</AbstractText>Erector spinae plane block can be used as an effective and safe alternative to thoracic epidural analgesia and shows superior analgesic profile to serratus anterior plane block for patients with lung cancer undergoing posterolateral thoracotomy.</AbstractText>Copyright &#xa9; 2021 Elsevier Inc. All rights reserved.</CopyrightInformation>
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Iron Deficiency Anemia in Nigerians with Heart Failure (IDAN-HF): Therapeutic efficacy of iron replacement: An interventional study.
Recent evidence has reported significant improvement in clinical profile, quality of life, and prognosis of heart failure subjects with iron replacement.</AbstractText>This study aimed to determine the safety and outcome of parenteral iron replacement among heart failure subjects in Nigeria.</AbstractText>A randomized interventional study was done at the Cardiology Clinic of LAUTECH Teaching Hospital, Ogbomoso, Nigeria. One hundred and forty subjects with heart failure were recruited. Iron deficiency and anemia were determined according to standardized criteria. Parenteral iron dextran was administered to a block randomized group of 30 of those identified with iron deficiency and compared with controls. The primary outcome was the six minutes' walk test (6 MWT) after 8 weeks while the Kansas City Cardiomyopathy Questionnaire (KCCQ) score was used to assess the quality of life as a secondary outcome. Statistical analysis was done with the SPSS 20.0. P value &lt;0.05 was taken as statistically significant.</AbstractText>Iron deficiency was present in 84 (60.0%) of all study participants. Iron dextran was fairly tolerated with mild to moderate adverse reactions reported in 7 (23.3%) subjects who had an iron infusion. Improvement in the 6 MWT distance (390.1 &#xb1; 92.6 vs. 156.9 &#xb1; 72.5 meters, P &lt; 0.05) and the KCCQ score (84.5 &#xb1; 3.7 vs. 64.2 &#xb1; 12.5%, P &lt; 0.05) among iron-deficient heart failure subjects who received iron dextran was significantly higher than those who did not receive the iron replacement. Functional classification according to the New York Heart Association (NYHA) profile and heart rate were also much improved after the iron replacement than those who did not receive it.</AbstractText>Parenteral iron dextran therapy was fairly tolerated among heart failure subjects. Iron replacement is associated with improved quality of life, better temporal clinical profile, and functional classification among Nigerians with heart failure. Iron replacement therapy can be an additional therapeutic option in heart failure management among Africans to improve prognosis.</AbstractText>
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Awake fiberoptic orotracheal intubation: a protocol feasibility study.
To assess the feasibility of an awake fiberoptic intubation (AFOI) protocol.</AbstractText>We enrolled 40 patients with simulated difficult intubation. The protocol consisted of conscious sedation (midazolam, 0.03&#x2009;mg/kg and sufentanil, 0.1 &#xb5;g/kg), regional anesthesia, and intubation. The time, first-attempt intubation success rate, hemodynamic parameters, blood oxygen saturation (SpO2</sub>), intubation amnesia rate, patient satisfaction, and relative complications were recorded.</AbstractText>AFOI was completed in all patients. The average total AFOI time was 14.17&#x2009;&#xb1;&#x2009;1.47 minutes, and the time to placing the landmark-guided bilateral superior laryngeal nerve block was 1.24&#x2009;&#xb1;&#x2009;0.42 minutes. The first-attempt intubation success rate was 97.5%, and patient satisfaction was 90%. Blood pressure changed (&lt;20%) briefly after administering conscious sedation. Heart rates did not change significantly, and SpO2</sub> remained stable and &#x2265;95%. Three patients had a sore throat, which resolved on postoperative day 1 without other complications. On postoperative day 1, 82.5% (33/40) of the patients had no recall of AFOI, and 17.5% (7/40) had only an indistinct memory.</AbstractText>The protocol was feasible with a high first-attempt intubation success rate and low complications rate. Hemodynamic parameters and respiration remained stable, with high patient satisfaction and effective amnesia.</AbstractText>
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Role of platelets in regulating activated coagulation factor XI activity.
Factor XI (FXI) has been shown to bind platelets, but the functional significance of this observation remains unknown. Platelets are essential for hemostasis and play a critical role in thrombosis, whereas FXI is not essential for hemostasis but promotes thrombosis. An apparent functional contradiction, platelets are known to support thrombin generation, yet platelet granules release protease inhibitors, including those of activated FXI (FXIa). We aim to investigate the secretory and binding mechanisms by which platelets could support or inhibit FXIa activity. The presence of platelets enhanced FXIa activity in a purified system and increased coagulation Factor IX (FIX) activation by FXIa and fibrin generation in human plasma. In contrast, platelets reduced the activation of FXI by activated coagulation factor XII (FXIIa) and the activation of FXII by kallikrein (PKa). Incubation of FXIa with the platelet secretome, which contains FXIa inhibitors, such as protease nexin-II, abolished FXIa activity, yet in the presence of activated platelets, the secretome was not able to block the activity of FXIa. FXIa variants lacking the anion-binding sites did not alter the effect of platelets on FXIa activity or interaction. Western blot analysis of bound FXIa [by FXIa-platelet membrane immunoprecipitation] showed that the interaction with platelets is zinc dependent and, unlike FXI binding to platelets, not dependent on glycoprotein Ib. FXIa binding to the platelet membrane increases its capacity to activate FIX in plasma likely by protecting it from inhibition by inhibitors secreted by activated platelets. Our findings suggest that an interaction of FXIa with the platelet surface may induce an allosteric modulation of FXIa.
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Reversible complete heart block due to hypercalcaemia.
A 65-year-old woman presented to the emergency room with a syncope. An ECG done revealed complete heart block with a narrow QRS escape rhythm and a normal QT interval. Further investigation revealed severe hypercalcaemia and elevated parathormone levels. Her heart block disappeared on correction of the hypercalcaemia. A right inferior parathyroid adenoma was found and surgically removed. Thus, hypercalcaemia may lead to reversible complete heart block without QT interval shortening.
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Health-related quality of life among Chinese primary care patients with different lower urinary tract symptoms: a latent class analysis.
No previous study has used a data-driven approach to explore symptom subclasses among patients with lower urinary tract symptoms (LUTS). The objectives of this study were to use latent class analysis (LCA) to identify distinct classes of LUTS among primary care patients and to assess the class differences in health-related quality of life (HRQOL).</AbstractText>In this cross-sectional study, 500 patients were randomly recruited, and 18 symptoms according to the International Continence Society 2002 criteria were assessed. Classes were identified by LCA. Patient HRQOL was measured using the 12-item Short Form Health Survey (version 2), the modified Incontinence Impact Questionnaire-Short Form and the HRQOL item from the International Prostate Symptom Score.</AbstractText>Six distinct LUTS classes were identified: "asymptomatic" (26.0%), "mild symptoms" (22.6%), "moderate multiple symptoms" (17.0%), "urgency symptoms" (13.8%), "urinary incontinence" (12.0%) and "severe multiple symptoms" (8.6%). Multinomial regression analysis found differences in the gender distribution and prevalence of heart diseases across classes, and multiple linear regression found that patients with "severe multiple symptoms" and "urinary incontinence" had the poorest HRQOL.</AbstractText>Almost three quarters of the primary care patients in this study were suffering from varying degrees of LUTS. The poor HRQOL in "severe multiple symptoms" and "urinary incontinence" implies that patients in these classes require additional attention and treatments.</AbstractText>
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Bioprinting 3D human cardiac tissue chips using the pin type printer 'microscopic painting device' and analysis for cardiotoxicity.
In this study, three-dimensional (3D) cardiac tissue constructed using the pin type bioprinter 'microscopic painting device' and layer-by-layer cell coating technique was confirmed to have drug responsiveness by three different analytical methods for cardiotoxicity assay. Recently, increasing attention has been focused on biofabrication to create biomimetic 3D tissue. Although various tissues can be produced in vitro, there are many issues surrounding the stability and reproducibility of the preparation of 3D tissues. Thus, although many bioprinters have been developed, none can efficiently, reproducibly and precisely produce small 3D tissues (&#x3bc;m-mm order) such as spheroids, which are most commonly used in drug development. The 3D cardiac tissue chips were successfully constructed with a similar number of cells as conventional 2D tissue using a pin type bioprinter, and corresponding drug-induced cardiotoxicities were obtained with known compounds that induce cardiotoxicity. The 3D cardiac tissue chips displayed uniform cell density and completely synchronized electrophysiological properties as compared to 2D tissue. The 3D tissues constructed using a pin type bioprinter as a biofabrication device would be promising tools for cardiotoxicity assay as they are capable of obtaining stable and reproducible data, which cannot be obtained by 2D tissue.
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Globally defining the effects of mutations in a picornavirus capsid.
The capsids of non-enveloped viruses are highly multimeric and multifunctional protein assemblies that play key roles in viral biology and pathogenesis. Despite their importance, a comprehensive understanding of how mutations affect viral fitness across different structural and functional attributes of the capsid is lacking. To address this limitation, we globally define the effects of mutations across the capsid of a human picornavirus. Using this resource, we identify structural and sequence determinants that accurately predict mutational fitness effects, refine evolutionary analyses, and define the sequence specificity of key capsid-encoded motifs. Furthermore, capitalizing on the derived sequence requirements for capsid-encoded protease cleavage sites, we implement a bioinformatic approach for identifying novel host proteins targeted by viral proteases. Our findings represent the most comprehensive investigation of mutational fitness effects in a picornavirus capsid to date and illuminate important aspects of viral biology, evolution, and host interactions.<CopyrightInformation>&#xa9; 2021, Mattenberger et al.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mattenberger</LastName><ForeName>Florian</ForeName><Initials>F</Initials><Identifier Source="ORCID">0000-0002-2727-0284</Identifier><AffiliationInfo><Affiliation>Institute for Integrative Systems Biology, I2SysBio (Universitat de Val&#xe8;ncia-CSIC), Paterna, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Latorre</LastName><ForeName>Victor</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute for Integrative Systems Biology, I2SysBio (Universitat de Val&#xe8;ncia-CSIC), Paterna, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tirosh</LastName><ForeName>Omer</ForeName><Initials>O</Initials><Identifier Source="ORCID">0000-0001-8139-9866</Identifier><AffiliationInfo><Affiliation>The Shmunis School of Biomedicine and Cancer Research, Tel-Aviv University, Tel-Aviv, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stern</LastName><ForeName>Adi</ForeName><Initials>A</Initials><Identifier Source="ORCID">0000-0002-2919-3542</Identifier><AffiliationInfo><Affiliation>The Shmunis School of Biomedicine and Cancer Research, Tel-Aviv University, Tel-Aviv, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Geller</LastName><ForeName>Ron</ForeName><Initials>R</Initials><Identifier Source="ORCID">0000-0002-7612-4611</Identifier><AffiliationInfo><Affiliation>Institute for Integrative Systems Biology, I2SysBio (Universitat de Val&#xe8;ncia-CSIC), Paterna, Spain.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2021</Year><Month>01</Month><Day>12</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Elife</MedlineTA><NlmUniqueID>101579614</NlmUniqueID><ISSNLinking>2050-084X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D036022">Capsid Proteins</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D002213" MajorTopicYN="N">Capsid</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D036022" MajorTopicYN="N">Capsid Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="Y">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010849" MajorTopicYN="N">Picornaviridae</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList><OtherAbstract Type="plain-language-summary" Language="eng">A virus is made up of genetic material that is encased with a protective protein coat called the capsid. The capsid also helps the virus to infect host cells by binding to the host receptor proteins and releasing its genetic material. Inside the cell, the virus hitchhikes the infected cell&#x2019;s machinery to grow or replicate its own genetic material. Viral capsids are the main target of the host&#x2019;s defence system, and therefore, continuously change in an attempt to escape the immune system by introducing alterations (known as mutations) into the genes encoding viral capsid proteins. Mutations occur randomly, and so while some changes to the viral capsid might confer an advantage, others may have no effect at all, or even weaken the virus. To better understand the effect of capsid mutations on the virus&#x2019; ability to infect host cells, Mattenberger et al. studied the Coxsackievirus B3, which is linked to heart problems and acute heart failure in humans. The researchers analysed around 90% of possible amino acid mutations (over 14,800 mutations) and correlated each mutation to how it influenced the virus&#x2019; ability to replicate in human cells grown in the laboratory. Based on these results, Mattenberger et al. developed a computer model to predict how a particular mutation might affect the virus. The analysis also identified specific amino acid sequences of capsid proteins that are essential for certain tasks, such as building the capsid. It also included an analysis of sequences in the capsid that allow it to be recognized by another viral protein, which cuts the capsid proteins into the right size from a larger precursor. By looking for similar sequences in human genes, the researchers identified several ones that the virus may attack and inactivate to support its own replication. These findings may help identify potential drug targets to develop new antiviral therapies. For example, proteins of the capsid that are less likely to mutate will provide a better target as they lower the possibility of the virus to become resistant to the treatment. They also highlight new proteins in human cells that could potentially block the virus in cells.
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ECPR-extracorporeal cardiopulmonary resuscitation.
Extracorporeal cardiopulmonary resuscitation (ECPR) is a salvage procedure in which extracorporeal membrane oxygenation (ECMO) is initiated emergently on patients who have had cardiac arrest (CA) and on whom the conventional cardiopulmonary resuscitation (CCPR) has failed. Awareness and usage of ECPR are increasing all over the world. Significant advancements have taken place in the ECPR initiation techniques, in its device and in its post-procedure care. ECPR is a team work requiring multidisciplinary experts, highly skilled health care workers and adequate infrastructure with appropriate devices. Perfect coordination and communication among team members play a vital role in the outcome of the ECPR patients. Ethical, legal and financial issues need to be considered before initiation of ECPR and while withdrawing the support when the ECPR is futile. Numerous studies about ECPR are being published more frequently in the last few years. Hence, keeping updated about the ECPR is very important for proper selection of cases and its management. This article reviews various aspects of ECPR and relevant literature to date.
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Dexamethasone blunts postspinal hypotension in geriatric patients undergoing orthopedic surgery: a double blind, placebo-controlled study.
Post-spinal anesthesia (PSA) hypotension in elderly patients is challenging. Correction of PSA hypotension by fluids either colloids or crystalloids or by vasoconstrictors pose the risk of volume overload or compromising cardiac conditions. Dexamethasone is used to treat conditions manifested by decrease of peripheral vascular resistance. The research team was the first to test the hypothesis of its role in preventing or decreasing the incidence of PSA hypotension.</AbstractText>One hundred ten patients, aged 60&#x2009;years or more were recruited to receive a single preoperative dose of dexamethasone 8&#x2009;mg IVI in 100&#x2009;ml normal saline (D group) (55 patients) 2&#x2009;h preoperatively, and 55 patients were given placebo (C group) in a randomized, double-blind trial. Variations in blood pressure and heart rate in addition to the needs of ephedrine and/or atropine following spinal anesthesia (SA) were recorded. SA was achieved using subarachnoid injection of 3&#x2009;ml hyperbaric bupivacaine 0.5%.</AbstractText>Demographic data and the quality of sensory and motor block were comparable between groups. At 5th, 10th minutes post SA; systolic, diastolic and mean arterial pressures were statistically significant higher in D group. At 20th minutes post SA; the obtained blood pressure readings and heart rate changes didn't show any statistically significance between groups. The need for ephedrine and side effects were statistically significant lower in D group than C group.</AbstractText>Post-spinal anesthesia hypotension, nausea, vomiting and shivering in elderly patients were less common after receiving a single preoperative dose of dexamethasone 8&#x2009;mg IVI than control.</AbstractText>ClinicalTrials.gov Identifier: NCT03664037 , Registered 17 September 2018 - Retrospectively registered, http://www.ClinicalTrial.gov.</AbstractText>
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A study on the bio-applicability of aqueous-dispersed van der Waals 1-D material Nb<sub>2</sub>Se<sub>9</sub> using poloxamer.
In this research, dispersion of a new type of one-dimensional inorganic material Nb<sub>2</sub>Se<sub>9</sub>, composed of van der Waals bonds, in aqueous solution for bio-application study were studied. To disperse Nb<sub>2</sub>Se<sub>9</sub>, which exhibits hydrophobic properties in water, experiments were carried out using a block copolymer (poloxamer) as a dispersant. It was confirmed that PPO, the hydrophobic portion of Poloxamer, was adsorbed onto the surface of Nb<sub>2</sub>Se<sub>9</sub>, and PEO, the hydrophilic portion, induced steric hinderance to disperse Nb<sub>2</sub>Se<sub>9</sub> to a size of 10&#xa0;nm or less. To confirm the adaptability of muscle cells C2C12 to the dispersed Nb<sub>2</sub>Se<sub>9</sub> using poloxamer 188 as dispersant, a MTT assay and a live/dead assay were performed, demonstrating improvement in the viability and proliferation of C2C12 cells.
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Metagenomics survey unravels diversity of biogas microbiomes with potential to enhance productivity in Kenya.
The obstacle to optimal utilization of biogas technology is poor understanding of biogas microbiomes diversities over a wide geographical coverage. We performed random shotgun sequencing on twelve environmental samples. Randomized complete block design was utilized to assign the twelve treatments to four blocks, within eastern and central regions of Kenya. We obtained 42 million paired-end reads that were annotated against sixteen reference databases using two ENVO ontologies, prior to &#x3b2;-diversity studies. We identified 37 phyla, 65 classes and 132 orders. Bacteria dominated and comprised 28 phyla, 42 classes and 92 orders, conveying substrate's versatility in the treatments. Though, Fungi and Archaea comprised 5 phyla, the Fungi were richer; suggesting the importance of hydrolysis and fermentation in biogas production. High &#x3b2;-diversity within the taxa was largely linked to communities' metabolic capabilities. Clostridiales and Bacteroidales, the most prevalent guilds, metabolize organic macromolecules. The identified Cytophagales, Alteromonadales, Flavobacteriales, Fusobacteriales, Deferribacterales, Elusimicrobiales, Chlamydiales, Synergistales to mention but few, also catabolize macromolecules into smaller substrates to conserve energy. Furthermore, &#x3b4;-Proteobacteria, Gloeobacteria and Clostridia affiliates syntrophically regulate PH2 and reduce metal to provide reducing equivalents. Methanomicrobiales and other Methanomicrobia species were the most prevalence Archaea, converting formate, CO2(g), acetate and methylated substrates into CH4(g). Thermococci, Thermoplasmata and Thermoprotei were among the sulfur and other metal reducing Archaea that contributed to redox balancing and other metabolism within treatments. Eukaryotes, mainly fungi were the least abundant guild, comprising largely Ascomycota and Basidiomycota species. Chytridiomycetes, Blastocladiomycetes and Mortierellomycetes were among the rare species, suggesting their metabolic and substrates limitations. Generally, we observed that environmental and treatment perturbations influenced communities' abundance, &#x3b2;-diversity and reactor performance largely through stochastic effect. Understanding diversity of biogas microbiomes over wide environmental variables and its' productivity provided insights into better management strategies that ameliorate biochemical limitations to effective biogas production.
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Clinical Efficacy of Pulsed Radiofrequency Treatment Targeting the Mid-cervical Medial Branches for Intractable Cervicogenic Headache.
Cervicogenic headache has been known to originate from the convergence of the upper 3 cervical and trigeminal afferents. The administration of conservative treatments, interventional procedures, and more recently, pulsed radiofrequency, has been used to relieve cervicogenic headache. In this study, the authors evaluated the clinical efficacy and safety of pulsed radiofrequency targeting the mid-cervical medial branches.</AbstractText>From September 2012 until December 2017, 395 patients were diagnosed with cervicogenic headache based on the third edition of the International Classification of Headache Disorders. The authors treated them conservatively at first, and those patients with nonresolution of pain were treated with mid-cervical medial branches block applied from C3 to C5 twice. Subsequently, if any patient continued to experience persistent pain, the authors classified them as having intractable cervicogenic headache and performed pulsed radiofrequency treatment targeting the mid-cervical medial branches from C3 to C5 bilaterally. The authors analyzed their demographics and used a Visual Analogue Scale to assess their pain for 12 months.</AbstractText>Fifty-seven patients were enrolled in this study. The mean age was 49.8 years, and the mean duration of symptoms was 47.7 months. The mean Visual Analogue Scale score was 6.21 before pulsed radiofrequency treatment, and it improved to 1.54 immediately after the procedure without the symptoms recurring for a minimum of 12 months. There were no severe complications, such as vascular or nerve injuries.</AbstractText>In patients with intractable cervicogenic headache, pulsed radiofrequency treatment targeting the mid-cervical medial branches resulted in a satisfactory, long-lasting outcome without serious complications.</AbstractText>Copyright &#xa9; 2021 The Author(s). Published by Wolters Kluwer Health, Inc.</CopyrightInformation>
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Potent Trivalent Inhibitors of Thrombin through Hybridization of Salivary Sulfopeptides from Hematophagous Arthropods.
Blood feeding arthropods, such as leeches, ticks, flies and mosquitoes, provide a privileged source of peptidic anticoagulant molecules. These primarily operate through inhibition of the central coagulation protease thrombin by binding to the active site and either exosite I or exosite II. Herein, we describe the rational design of a novel class of trivalent thrombin inhibitors that simultaneously block both exosites as well as the active site. These engineered hybrids were synthesized using tandem diselenide-selenoester ligation (DSL) and native chemical ligation (NCL) reactions in one-pot. The most potent trivalent inhibitors possessed femtomolar inhibition constants against &#x3b1;-thrombin and were selective over related coagulation proteases. A lead hybrid inhibitor possessed potent anticoagulant activity, blockade of both thrombin generation and platelet aggregation in vitro and efficacy in a murine thrombosis model at 1&#x2005;mg&#x2009;kg<sup>-1</sup> . The rational engineering approach described here lays the foundation for the development of potent and selective inhibitors for a range of other enzymatic targets that possess multiple sites for the disruption of protein-protein interactions, in addition to an active site.
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Reactivity of 3-nitroindoles with electron-rich species.
The indol(in)e building block is one of the "privileged-structures" for the pharmaceutical industry since this fragment plays a central role in drug discovery. While the electron-rich character of the indole motif has been investigated for decades, exploiting the electrophilic reactivity of 3-nitroindole derivatives has recently been put at the heart of a wide range of new, albeit challenging, chemical reactions. In particular, dearomatization processes have considerably enriched the scope of C2[double bond, length as m-dash]C3 functionalizations of these scaffolds. This feature article showcases this remarkable electrophilic reactivity of 3-nitroindoles with electron-rich species and highlights their value in generating diversely substituted indol(in)es. This compilation underlines how these heteroaromatic templates have gradually become model substrates for electron-poor aromatic compounds in dearomatization strategies.
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Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6.
The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells <i>in vitro</i> and mice <i>in vivo,</i> we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. <i>In vitro</i> airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-&#x3ba;B-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-&#x3ba;B promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-&#x3ba;B-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-&#x3ba;B activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.
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Investigating the Influences of Task Demand and Reward on Cardiac Pre-Ejection Period Reactivity During a Speech-in-Noise Task.
Effort investment during listening varies as a function of task demand and motivation. Several studies have manipulated both these factors to elicit and measure changes in effort associated with listening. The cardiac pre-ejection period (PEP) is a relatively novel measure in the field of cognitive hearing science. This measure, which reflects sympathetic nervous system activity on the heart, has previously been implemented during a tone discrimination task but not during a speech-in-noise task. Therefore, the primary goal of this study was to explore the influences of signal to noise ratio (SNR) and monetary reward level on PEP reactivity during a speech-in-noise task.</AbstractText>Thirty-two participants with normal hearing (mean age = 22.22 years, SD = 3.03) were recruited at VU University Medical Center. Participants completed a Dutch speech-in-noise test with a single-interfering-talker masking noise. Six fixed SNRs, selected to span the entire psychometric performance curve, were presented in a block-wise fashion. Participants could earn a low (&#x20ac;0.20) or high (&#x20ac;5.00) reward by obtaining a score of &#x2265;70% of words correct in each block. The authors analyzed PEP reactivity: the change in PEP measured during the task, relative to the baseline during rest. Two separate methods of PEP analysis were used, one including data from the whole task block and the other including data obtained during presentation of the target sentences only. After each block, participants rated their effort investment, performance, tendency to give up, and the perceived difficulty of the task. They also completed the need for recovery questionnaire and the reading span test, which are indices of additional factors (fatigue and working memory capacity, respectively) that are known to influence listening effort.</AbstractText>Average sentence perception scores ranged from 2.73 to 91.62%, revealing a significant effect of SNR. In addition, an improvement in performance was elicited by the high, compared to the low reward level. A linear relationship between SNR and PEP reactivity was demonstrated: at the lower SNRs PEP reactivity was the most negative, indicating greater effort investment compared to the higher SNRs. The target stimuli method of PEP analysis was more sensitive to this effect than the block-wise method. Contrary to expectations, no significant impact of reward on PEP reactivity was found in the present dataset. Also, there was no physiological evidence that participants were disengaged, even when performance was poor. A significant correlation between need for recovery scores and average PEP reactivity was demonstrated, indicating that a lower need for recovery was associated with less effort investment.</AbstractText>This study successfully implemented the measurement of PEP during a standard speech-in-noise test and included two distinct methods of PEP analysis. The results revealed for the first time that PEP reactivity varies linearly with task demand during a speech-in-noise task, although the effect size was small. No effect of reward on PEP was demonstrated. Finally, participants with a higher need for recovery score invested more effort, as shown by average PEP reactivity, than those with a lower need for recovery score.</AbstractText>Copyright &#xa9; 2020 The Authors. Ear &amp; Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.</CopyrightInformation>
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The inter-rater reliability and individual reviewer performance of the 2012 world heart federation guidelines for the echocardiographic diagnosis of latent rheumatic heart disease.<Pagination><StartPage>146</StartPage><EndPage>151</EndPage><MedlinePgn>146-151</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ijcard.2020.11.013</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0167-5273(20)34087-0</ELocationID><Abstract><AbstractText Label="BACKGROUND">In 2012, the World Heart Federation (WHF) published guidelines for the echocardiographic diagnosis of rheumatic heart disease (RHD). This study assesses individual reviewer performance and inter-rater agreement and reliability on the presence of any RHD, as well classification of RHD based on the 2012 WHF criteria.</AbstractText><AbstractText Label="METHODS">Four cardiologists individually reviewed echocardiograms in the context of a randomized clinical trial (ClinicalTrials.gov:NCT03346525) and participated in a blinded adjudication panel. Panel decision was the reference standard for diagnosis. Performance of individual reviewers to panel adjudication was compared through sensitivity and specificity analyses and inter-rater reliability was assessed between individual panelists using Fleiss free marginal multirater kappa.</AbstractText><AbstractText Label="RESULTS">Echocardiograms from 784 children had two independent reports and panel adjudication. The accuracy of independent reviewers for any RHD had high sensitivity (94%, 95% CI 93-95%) and moderate specificity (62%, 95% CI 53-70%). Sensitivity and specificity for definite RHD was 61.3 (95% CI, 55.3-67.1) and 93.1 (95% CI, 91.6-94.4), with 86.8 (84.7-88.7) and 65.8 (61.0-70.4) for borderline RHD. There was moderate inter-rater agreement (&#x3ba;&#xa0;=&#xa0;0.66) on the presence of any RHD while agreement for specific 2012 WHF classification was only fair (&#x3ba;&#xa0;=&#xa0;0.51).</AbstractText><AbstractText Label="CONCLUSIONS">The 2012 WHF guidelines are moderately reproducible when used by expert cardiologists. More cases of RHD were diagnosed by an consensus panel than by individual reviewers. A revision to the criteria is now warranted to further increase the reliability of the WHF criteria.</AbstractText><CopyrightInformation>Copyright &#xa9; 2020 Elsevier B.V. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Scheel</LastName><ForeName>Amy</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30329, USA. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mirabel</LastName><ForeName>Mariana</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Universit&#xe9; de Paris, Paris Cardiovascular Research Center PARCC, INSERM, 56 Rue Leblanc, 75015 Paris, France; Cardio-oncology unit, AP-HP, H&#xf4;pital Europ&#xe9;en Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nunes</LastName><ForeName>Maria Carmo Pereira</ForeName><Initials>MCP</Initials><AffiliationInfo><Affiliation>School of Medicine of the Federal University of Minas Gerais, Av. Prof. Alfredo Balena, 190 - Santa Efig&#xea;nia, Belo Horizonte, MG 30130-100, Brazil. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Okello</LastName><ForeName>Emmy</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>The Uganda Heart Institute, Block C, Mulago Hospital Complex, Kampala, Uganda.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sarnacki</LastName><ForeName>Rachel</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Children's National Hospital, 111 Michigan Ave, NW, Washington, DC, 20010, USA. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steer</LastName><ForeName>Andrew C</ForeName><Initials>AC</Initials><AffiliationInfo><Affiliation>Tropical Diseases, Murdoch Children's Research Institute, Flemington Road, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, 50 Flemington Road Parkville, Victoria, Australia. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Engelman</LastName><ForeName>Daniel</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Tropical Diseases, Murdoch Children's Research Institute, Flemington Road, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, 50 Flemington Road Parkville, Victoria, Australia. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zimmerman</LastName><ForeName>Meghan</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Dartmouth Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03766, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Z&#xfc;hlke</LastName><ForeName>Liesl</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Rd, Rondebosch, Cape Town 7700, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sable</LastName><ForeName>Craig</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Children's National Hospital, 111 Michigan Ave, NW, Washington, DC, 20010, USA. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Beaton</LastName><ForeName>Andrea</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Cincinnati Children's Hospital Medical Center, The Heart Institute, 3333 Burnet Ave, Cincinnati, 45229, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Ave, Cincinnati, OH 45229, USA. Electronic address: [email protected].</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>ClinicalTrials.gov</DataBankName><AccessionNumberList><AccessionNumber>NCT03346525</AccessionNumber></AccessionNumberList></DataBank></DataBankList><GrantList CompleteYN="Y"><Grant><GrantID>MR/S005242/1</GrantID><Acronym>MRC_</Acronym><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>11</Month><Day>10</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Int J Cardiol</MedlineTA><NlmUniqueID>8200291</NlmUniqueID><ISSNLinking>0167-5273</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>Int J Cardiol. 2021 Apr 1;328:163-164</RefSource><PMID Version="1">33359287</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D002648" MajorTopicYN="N">Child</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004452" MajorTopicYN="N">Echocardiography</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008403" MajorTopicYN="N">Mass Screening</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015995" MajorTopicYN="N">Prevalence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015203" MajorTopicYN="N">Reproducibility of Results</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012214" MajorTopicYN="Y">Rheumatic Heart Disease</DescriptorName><QualifierName UI="Q000000981" MajorTopicYN="N">diagnostic imaging</QualifierName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012680" MajorTopicYN="N">Sensitivity and Specificity</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Echocardiography</Keyword><Keyword MajorTopicYN="N">Rheumatic heart disease</Keyword></KeywordList><CoiStatement>Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>5</Month><Day>20</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2020</Year><Month>10</Month><Day>29</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>11</Month><Day>4</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>11</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2021</Year><Month>5</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>11</Month><Day>13</Day><Hour>20</Hour><Minute>8</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">33186665</ArticleId><ArticleId IdType="doi">10.1016/j.ijcard.2020.11.013</ArticleId><ArticleId IdType="pii">S0167-5273(20)34087-0</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">33186308</PMID><DateRevised><Year>2021</Year><Month>09</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1365-2346</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2021</Year><Month>Sep</Month><Day>09</Day></PubDate></JournalIssue><Title>European journal of anaesthesiology</Title><ISOAbbreviation>Eur J Anaesthesiol</ISOAbbreviation></Journal>Opioid-sparing effect of modified intercostal nerve block during single-port thoracoscopic lobectomy: Retraction: A randomised controlled trial.
In 2012, the World Heart Federation (WHF) published guidelines for the echocardiographic diagnosis of rheumatic heart disease (RHD). This study assesses individual reviewer performance and inter-rater agreement and reliability on the presence of any RHD, as well classification of RHD based on the 2012 WHF criteria.</AbstractText>Four cardiologists individually reviewed echocardiograms in the context of a randomized clinical trial (ClinicalTrials.gov:NCT03346525) and participated in a blinded adjudication panel. Panel decision was the reference standard for diagnosis. Performance of individual reviewers to panel adjudication was compared through sensitivity and specificity analyses and inter-rater reliability was assessed between individual panelists using Fleiss free marginal multirater kappa.</AbstractText>Echocardiograms from 784 children had two independent reports and panel adjudication. The accuracy of independent reviewers for any RHD had high sensitivity (94%, 95% CI 93-95%) and moderate specificity (62%, 95% CI 53-70%). Sensitivity and specificity for definite RHD was 61.3 (95% CI, 55.3-67.1) and 93.1 (95% CI, 91.6-94.4), with 86.8 (84.7-88.7) and 65.8 (61.0-70.4) for borderline RHD. There was moderate inter-rater agreement (&#x3ba;&#xa0;=&#xa0;0.66) on the presence of any RHD while agreement for specific 2012 WHF classification was only fair (&#x3ba;&#xa0;=&#xa0;0.51).</AbstractText>The 2012 WHF guidelines are moderately reproducible when used by expert cardiologists. More cases of RHD were diagnosed by an consensus panel than by individual reviewers. A revision to the criteria is now warranted to further increase the reliability of the WHF criteria.</AbstractText>Copyright &#xa9; 2020 Elsevier B.V. All rights reserved.</CopyrightInformation>
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Rationale and Design of the Genotype-Blinded Trial of Torasemide for the Treatment of Hypertension (BHF UMOD).
Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy.</AbstractText>The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (&#x2265;18 years) with uncontrolled BP, on &#x2265;1 antihypertensive agent for &#x2265;3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) &gt;135 mmHg and/or diastolic BP &gt;85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160).</AbstractText>The study should conclude August 2021.</AbstractText>If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension.</AbstractText>https://clinicaltrials.gov/ct2/show/NCT03354897.</AbstractText>&#xa9; The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.</CopyrightInformation>
2,336,146
Influence of Levobupivacaine Regional Scalp Block on Hemodynamic Stability, Intra- and Postoperative Opioid Consumption in Supratentorial Craniotomies: A Randomized Controlled Trial.
The anesthetic management of supratentorial craniotomy (CR) necessitates tight intraoperative hemodynamic control. This type of surgery may also be associated with substantial postoperative pain. We aimed at evaluating the influence of regional scalp block (SB) on hemodynamic stability during the noxious events of supratentorial craniotomies and total intravenous anesthesia, its influence on intraoperative anesthetic agents' consumption, and its effect on postoperative pain control.</AbstractText>Sixty patients scheduled for elective CR were prospectively enrolled. Patient, anesthesiologist, and neurosurgeon were blind to the random performance of SB with either levobupivacaine 0.33% (intervention group [group SB], n = 30) or the same volume of saline (control group [group CO], placebo group, n = 30). General anesthesia was induced and maintained using target-controlled infusions of remifentanil and propofol that were adjusted according to hemodynamic parameters and state entropy of the electroencephalogram (SE), respectively. Mean arterial blood pressure (MAP), heart rate (HR), SE, and propofol and remifentanil effect-site concentrations (Ce) were recorded at the time of scalp block performance (Baseline), and 0, 1, 3, and 5 minutes after skull-pin fixation (SP), skin incision (SI), CR, and dura-mater incision (DM). Morphine consumption and postoperative pain intensity (0-10 visual analog scale [VAS]) were recorded 1, 3, 6, 24, and 48 hours after surgery. Propofol and remifentanil overall infusion rates were also recorded. Data were analyzed using 2-tailed Student unpaired t tests, 2-way mixed-design analysis of variance (ANOVA), and Tukey's honestly significant difference (HSD) tests for post hoc comparisons as appropriate.</AbstractText>Demographics and length of anesthetic procedure of group CO and SB were comparable. SP, SI, and CR were associated with a significantly higher MAP in group CO than in group SB, at least at one of the time points of recording surrounding those noxious events. This was not the case at DM. Similarly, HR was significantly higher in group CO than in group SB during SP and SI, at least at 1 of the points of recording, but not during CR and DM. Propofol and remifentanil Ce and overall infusion rates were significantly higher in group CO than in group SB, except for propofol Ce during SP. Postoperative pain VAS and cumulative morphine consumption were significantly higher in group CO than in group SB.</AbstractText>In supratentorial craniotomies, SB improves hemodynamic control during noxious events and provides adequate and prolonged postoperative pain control as compared to placebo.</AbstractText>Copyright &#xa9; 2020 International Anesthesia Research Society.</CopyrightInformation>
2,336,147
Cognitive Function After Lung Transplantation.
Cognitive functioning after transplantation, which could influence medication compliance and independence, has not been well studied. This study investigated cognitive impairment after lung transplantation. Patients undergoing bilateral transplant between March 2013 and October 2015 underwent comprehensive neuropsychological assessment at 60.1&#xa0;&#xb1;&#xa0;44.1&#xa0;months post-transplantation: verbal memory (Auditory-Verbal Learning Test, digit span forward), visual memory (Corsi Block-Tapping Test forward, Benton Visual Retention Test), concentration/speed of processing/attention (D2 Test of Attention, Trail Making Test (TMT) A, Grooved Pegboard), and executive functioning (TMT B, Stroop Color-Word Test, semantic and phonematic verbal fluency, digit span backward, Corsi Block-Tapping Test backward). Mean scores were compared with a normative dataset using a one-sample t-test. A cognitive domain was judged impaired if the score on two or more domain-specific tests was greater than one standard deviation below the normative dataset age range mean. Of 124 lung transplant recipients (51% male, 54.3&#xa0;&#xb1;&#xa0;9.0&#xa0;years), 70% showed cognitive impairment in one or more domains. Executive function was most often impaired (78% of recipients not within the age range) followed by verbal memory impairment (72% not within the age range). Cognitive function reductions were largely independent of age, gender, education, immunosuppressive medications, and time since transplantation. The findings show that cognitive impairment is common after lung transplantation and should be subject to rehabilitation and psychological resilience strategies.
2,336,148
Low-pass whole genome bisulfite sequencing of neonatal dried blood spots identifies a role for RUNX1 in Down syndrome DNA methylation profiles.
Neonatal dried blood spots (NDBS) are a widely banked sample source that enables retrospective investigation into early life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early life Down syndrome (DS) DNA methylation profiles. DS represents an example of genetics shaping epigenetics, as multiple array-based studies have demonstrated that trisomy 21 is characterized by genome-wide alterations to DNA methylation. By assaying over 24 million CpG sites, thousands of genome-wide significant (q&#xa0;&lt;&#x2009;0.05) differentially methylated regions (DMRs) that distinguished DS from typical development and idiopathic developmental delay were identified. Machine learning feature selection refined these DMRs to 22 loci. The DS DMRs mapped to genes involved in neurodevelopment, metabolism, and transcriptional regulation. Based on comparisons with previous DS methylation studies and reference epigenomes, the hypermethylated DS DMRs were significantly (q&#xa0;&lt;&#x2009;0.05) enriched across tissues while the hypomethylated DS DMRs were significantly (q&#xa0;&lt;&#x2009;0.05) enriched for blood-specific chromatin states. A ~28&#xa0;kb block of hypermethylation was observed on chromosome 21 in the RUNX1 locus, which encodes a hematopoietic transcription factor whose binding motif was the most significantly enriched (q&#xa0;&lt;&#x2009;0.05) overall and specifically within the hypomethylated DMRs. Finally, we also identified DMRs that distinguished DS NDBS based on the presence or absence of congenital heart disease (CHD). Together, these results not only demonstrate the utility of low-pass WGBS on NDBS samples for epigenome-wide association studies, but also provide new insights into the early life mechanisms of epigenomic dysregulation resulting from trisomy 21.
2,336,149
Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD.
Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.
2,336,150
The Effectiveness of Combat Tactical Breathing as Compared with Prolonged Exhalation.
Tactical breathing (TB) is used by military and law enforcement personnel to reduce stress and maintain psychomotor and cognitive performance in dangerous situations (Grossman and Christensen, in On combat: the psychology and physiology of deadly conflict in war and in peace, PPCT Research Publications, Belleville, 2008). So far, empirical evidence on the effectiveness of TB is limited and there are breathing techniques that are easier to learn and to apply. This study compared the effectiveness of tactical breathing and prolonged exhalation (ProlEx) under laboratory conditions. Thirty healthy participants performed a Stroop interference task under time pressure and noise distraction. Time pressure was induced with short inter-trial intervals of 350&#xa0;ms and short trial durations of 1500&#xa0;ms. Acoustic distraction was realised with white noise with intensity increasing from 77 to 89&#xa0;dB SPL over the course of an experimental block. In a counterbalanced repeated-measures design, participants used either TB or ProlEx to reduce the induced psychological and physiological arousal. Stress reactions were assessed on the subjective level (Steyer et al., in Multidimensional mood questionnaire (MDMQ), Hogrefe, G&#xf6;ttingen, 1997) and on the physiological level (heart rate, heart rate variability, electrodermal activity). Results showed no significant differences between breathing techniques on the subjective level. While participants showed a lower physiological arousal in the TB condition, better performance was achieved in the ProlEx condition. Results indicate that TB may be superior in passive coping conditions, while ProlEx is more effective when active coping is required.
2,336,151
Low-dose Btk inhibitors selectively block platelet activation by CLEC-2.
Inhibitors of the tyrosine kinase Btk have been proposed as novel antiplatelet agents. In this study we show that low concentrations of the Btk inhibitor ibrutinib block CLEC-2-mediated activation and tyrosine phosphorylation including Syk and PLC&#x3b3;2 in human platelets. Activation is also blocked in patients with X-linked agammaglobulinemia (XLA) caused by a deficiency or absence of Btk. In contrast, the response to GPVI is delayed in the presence of low concentrations of ibrutinib or in patients with XLA, and tyrosine phosphorylation of Syk is preserved. A similar set of results is seen with the second-generation inhibitor, acalabrutinib. The differential effect of Btk inhibition in CLEC-2 relative to GPVI signalling is explained by the positive feedback role involving Btk itself, as well as ADP and thromboxane A2 mediated activation of P2Y12 and TP receptors, respectively. This feedback role is not seen in mouse platelets and, consistent with this, CLEC-2-mediated activation is blocked by high but not by low concentrations of ibrutinib. Nevertheless, thrombosis was absent in 8 out of 13 mice treated with ibrutinib. These results show that Btk inhibitors selectively block activation of human platelets by CLEC-2 relative to GPVI suggesting that they can be used at 'low dose' in patients to target CLEC-2 in thrombo-inflammatory disease.
2,336,152
Endothelial Vasodilation After a High-Volume Training Load and Tapered Training in Collegiate Female Swimmers.
Weihl, FM and Van Guilder, GP. Endothelial vasodilation after a high-volume training load and tapered training in collegiate female swimmers. J Strength Cond Res 35(3): 811-818, 2021-High-volume endurance training loads have been linked to adverse remodeling of the heart and large arteries; yet, data on the vascular endothelial function are unclear. Moreover, although collegiate-level endurance athletes often perform high-volumes of vigorous endurance training and resistance training as part of their strength and conditioning programs, it is unknown whether they also experience vascular abnormalities, particularly changes in endothelial function. The aim of this study was to verify the impact of a high-volume training load phase followed by low-volume tapered training on endothelial vasodilator function in National Collegiate Athletic Association (NCAA) Division I competitive female swimmers. Microvascular endothelial vasodilation was assessed by pulse arterial tonometry that provides a reactive hyperemia index in 10 female NCAA Division 1 swimmers after 4 weeks of a high-volume training load, and subsequently, after 3 weeks of low-volume tapered training as part of preparation for annual conference championships. The reactive hyperemia index was calculated as the ratio of the pulse volume amplitude after 5 minutes of left-arm brachial artery ischemia to the baseline amplitude, divided by same ratio in the contralateral arm. The high-volume training load included a 4-week block of dual-day sessions (120 minutes per practice) consisting of vigorous intensity endurance and high-intensity interval/sprint swim training, coupled with 5K running, resistance training, and Olympic weightlifting. Tapered training consisted of 3 weeks of 3-5 swims per week at &#x223c;50% V&#x307;o2max for 60 minutes per practice (&#x223c;4,000 minutes per practice). The reactive hyperemia index (1.73 &#xb1; 0.50) was low in athletes after the high-volume training load with 8 athletes demonstrating endothelial dysfunction. However, after tapered training, the reactive hyperemia index was &#x223c;33% higher (2.29 &#xb1; 0.43; 95% confidence interval [CI]: 1.98-2.60, p = 0.0223 vs. the high-volume training load). Effect size, as expressed by the partial eta2 (0.46) and Cohen's dz (1.1923; 95% CI: 0.1687-2.4643) with tapered training, was large. These results demonstrate distinct differences in endothelial vasodilation after 4 weeks of a high-volume training load compared with a 3-week taper in NCAA Division I female swimmers.
2,336,153
Characterization of rainbow trout cell lines using microsatellite DNA profiling.
Ten microsatellite loci (Omy27DU,Omy325(A3)UoG, OmyFGT5TUF,OmyFGT14TUF, OmyFGT15TUF,OmyFGT23TUF, Omy77DU,Ssa20.19NUIG, Ots1BML, andOne18ASC) were amplified using the polymerase chain reaction to create genetic profiles for nine cell lines (RTG-2, RTH-149,RTL-W1,RTgill-W1, RTS-11, RTS-34st, RTP-2, RTP-91E and RTP-91F) from rainbow trout(Oncorhynchus mykiss) and one cell line (CHSE-214) from Chinook salmon (O. tschawytscha). A cell line (PHL) from anon-salmonid, the Pacific herring (Clupea harengus pallasi), was included as a control. The ten loci clearly revealed the uniqueness of each cell line, except for two cell lines (RTP-91E andRTP-91F) from the same fish. RTP-91E and RTP-91F were identical at all loci except Ssa20.19NUIG. The most useful locus for demonstrating uniqueness was Ots1BML. The information was used to demonstrate that an uncharacterized rainbow trout cell line (Clone 1A)was in fact CHSE-214, illustrating the usefulness of multiplexed microsatellites for the creation of genetic profiles for salmonid cell lines and for the testing of cell line cross-contamination.
2,336,154
Fusiform rust of southern pines: a major success for forest disease management.
ABSTRACT The effective management of fusiform rust in slash and loblolly pine plantations is a major success story for disease management scientists and practitioners in the southeastern United States. This disease, which reached epidemic proportions by the 1960s, resulted from anthropogenic causes associated with intensive pine culture and greatly inhibited the optimum management of slash and loblolly pine throughout extensive areas of the southern pine region. Successful management of this disease was made possible by the combined resources and personnel of federal and state agencies, universities, and the forest industry. Chief among these personnel were research pathologists, geneticists, and silviculturalists. Following early studies on the biology of the fusiform rust pathosystem, research on epidemiology, host resistance, and pathogen variability slowly but steadily progressed. Testing of pine selections for resistance was facilitated by the establishment of a rust screening center. Fortunately, genetic rust resistance is relatively abundant in both slash and loblolly pines and has become the foundation for the management of the disease. Rust resistant half- and full-sib progeny from resistant parents established in seed orchards are routinely planted, especially in high-rust-hazard areas. Several important lessons in disease management have been learned or remembered during the progress of this research. Perhaps the ecologically fit fusiform rust pathogen will have additional instructions for us in the future, but for now resistance is an effective management strategy.
2,336,155
Spatial and Genetic Analysis of a Flag Shoot Subpopulation of Erysiphe necator in Italy.
ABSTRACT Erysiphe necator overwinters as ascospores in cleistothecia and mycelium in dormant buds of grapevines. Shoots developing from infected buds early in the growing season are covered with dense mycelium and are known as "flag shoots". Combining epidemiological and genetic analyses, the objective of this study was to analyze the spatial and genetic structure of a flag shoot subpopulation of E. necator as a way to assess the contribution of flag shoots as primary inoculum, and to determine if flag shoot subpopulations are clonal with only one mating type. One vineyard in Tuscany, Italy was surveyed intensively for flag shoots for 8 years; isolations of E. necator were made from flag shoots for 5 years. We observed distinct disease foci developing around flag shoots early in epidemics, demonstrating a steep dispersal gradient of conidia and the importance of flag shoots as primary inoculum sources. Flag shoots were spatially aggregated within and between years, most likely as a result of short-distance dispersal of conidia from flags early in the season when dormant buds for the next year's shoots are formed and are susceptible to infection. The two mating types were found in 1:1 ratios in this flag shoot subpopulation. Genotypic diversity, based on inter-simple sequence repeat markers, was high in all years with only two haplotypes occurring twice, and subpopulations were genetically differentiated between years. Similarities between haplotypes were not spatially autocorrelated. One multilocus analysis of population structure is consistent with the hypothesis of random mating but another is not. These results are not consistent with expectations for a strictly clonal or strictly randomly mating flag shoot subpopulation. Instead, the hypothesis that the flag shoot subpopulation of E. necator may reproduce clonally and sexually needs further testing.
2,336,156
Molecular mapping of the leaf rust resistance gene rph6 in barley and its linkage relationships with rph5 and rph7.<Pagination><StartPage>604</StartPage><EndPage>609</EndPage><MedlinePgn>604-9</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1094/PHYTO.2003.93.5.604</ELocationID><Abstract><AbstractText>ABSTRACT The barley cv. Bolivia carries two leaf rust (Puccinia hordei) resistance genes, Rph2 and Rph6, and is the only known source of the latter gene. A resistant line (Bolivia-Rph6) carrying Rph6 only was obtained in the F(4) generation of a cross between cv. Bolivia and the susceptible cv. Bowman via progeny testing with differential isolates of the leaf rust pathogen. Genetic analyses and bulk segregant analysis using amplified fragment length polymorphism (AFLP) and restriction fragment length polymorphism (RFLP) markers localized Rph6 on the short arm of barley chromosome 3H at a distance of 4.4 centimorgans (cM) distal from RFLP marker MWG2021 and 1.2 cM proximal from RFLP marker BCD907. The allelic relationship of Rph6 to other leaf rust resistance genes mapping to this region of chromosome 3H (namely Rph5 and Rph7) were tested using crosses among cvs. Magnif 102 (carrying Rph5), Bolivia-Rph6 (Rph6), and Cebada Capa (Rph7). Segregation analyses indicated that Rph6 is allelic to Rph5 and closely linked to Rph7. The data generated from this study will facilitate breeding for leaf rust resistance via marker-assisted selection and provide a starting point for positional gene cloning.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zhong</LastName><ForeName>Shaobin</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Effertz</LastName><ForeName>Roger J</ForeName><Initials>RJ</Initials></Author><Author ValidYN="Y"><LastName>Jin</LastName><ForeName>Yue</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Franckowiak</LastName><ForeName>Jerome D</ForeName><Initials>JD</Initials></Author><Author ValidYN="Y"><LastName>Steffenson</LastName><ForeName>Brian J</ForeName><Initials>BJ</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Phytopathology</MedlineTA><NlmUniqueID>9427222</NlmUniqueID><ISSNLinking>0031-949X</ISSNLinking></MedlineJournalInfo></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2008</Year><Month>10</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2008</Year><Month>10</Month><Day>24</Day><Hour>9</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2008</Year><Month>10</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">18942983</ArticleId><ArticleId IdType="doi">10.1094/PHYTO.2003.93.5.604</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">18784764</PMID><DateCompleted><Year>2008</Year><Month>12</Month><Day>31</Day></DateCompleted><DateRevised><Year>2022</Year><Month>03</Month><Day>27</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1556-5246</ISSN><JournalIssue CitedMedium="Internet"><Issue>4</Issue><PubDate><Year>2005</Year><Month>Oct</Month></PubDate></JournalIssue><Title>National Toxicology Program genetically modified model report</Title><ISOAbbreviation>Natl Toxicol Program Genet Modif Model Rep</ISOAbbreviation></Journal>Toxicology studies of pentaerythritol triacrylate (technical grade) (CAS No. 3524-68-3) in F344/N rats, B6C3F1 mice, and genetically modified (FVB Tg.AC hemizygous) mice (dermal studies).<Pagination><StartPage>1</StartPage><EndPage>190</EndPage><MedlinePgn>1-190</MedlinePgn></Pagination><Abstract><AbstractText Label="UNLABELLED">Pentaerythritol triacrylate is used in the production of ultraviolet-curable inks and coatings, electron beam irradiation- curable coatings, and radiation-cured and photocurable coatings of urethanes and epoxy resins; as a component of photopolymer and flexographic printing inks and plates and photoresists; as an ingredient of acrylic glues, adhesives, and anaerobic sealants; and as a modifier for polyester and fiberglass. It is also used in colloidal dispersions for industrial baked coatings, waterborne and solvent-based alkyds, vinyl/acrylic nonwoven binders, paper and wood impregnates, wire and cable extrusion, polymer-impregnated concrete, and polymer concrete structural composites. Pentaerythritol triacrylate was nominated by the National Cancer Institute for testing based on its high production volume and use, its potential for human exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were administered technical grade pentaerythritol triacrylate (it is reactive and therefore not available as pure pentaerythritol triacrylate) in acetone dermally for 2 weeks or 3 months. Male and female Tg.AC hemizygous mice were administered technical grade pentaerythritol acrylate in acetone for 6 months. Genetic toxicology was evaluated in Salmonella typhimurium and in B6C3F(1) and Tg.AC hemizygous mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All rats survived to the end of the study; mean body weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Irritation at the site of application occurred in all dosed groups except 12.5 mg/kg females. Epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation occurred at the site of application in most dosed groups of rats. 2-WEEK STUDY IN B6C3F(1) MICE: Groups of five male and five female B6C3F(1) mice were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All mice survived to the end of the study. The final mean body weight and body weight gain of 25 mg/kg males were significantly greater than those of the vehicle controls, as was the mean body weight gain of 50 mg/kg males. All dosed groups had irritation at the site of application. Thymus weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Most dosed groups of mice had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation at the site of application. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of 12 mg/kg males were significantly less than those of the vehicle controls. Irritation at the site of application occurred in 12 mg/kg rats. Thymus weights of males administered 3 mg/kg or greater were significantly less than those of the vehicle controls. Hematology results indicated that pentaerythritol triacrylate induced a neutrophil count increase that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Epidermal hyperplasia, hyperkeratosis, epidermal degeneration and necrosis, chronic active inflammation, and sebaceous gland hyperplasia generally occurred at the application site in male and female groups administered 1.5 mg/kg or greater. 3-MONTH STUDY IN B6C3F(1) MICE: Groups of 10 male and 10 female B6C3F(1) mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. One female vehicle control mouse was sacrificed during the first week of the study due to ataxia and one 1.5 mg/kg female died during week 8. Mean body weights of dosed groups were similar to those of the vehicle control groups. Irritation at the site of application occurred in the 6 and 12 mg/kg male groups. Hematology results indicated an increased neutrophil count consistent with an inflammatory response related to the dermatitis observed histopathologically. There also was a minimal decrease in the erythron (hematocrit, hemoglobin concentration, and erythrocyte count) likely secondary to the inflammatory skin process. Males and females administered 1.5 mg/kg or greater generally had increased incidences of epidermal hyperplasia, degeneration, and necrosis; dermal chronic active inflammation, sebaceous gland hyperplasia, and hyperkeratosis at the site of application. 6-MONTH STUDY IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate per kg body weight in acetone 5 days per week for 27 weeks. Additional groups of 15 male and 15 female mice maintained as positive controls received dermal applications of 1.25 mug 12-O-tetradecanoylphorbol-13-acetate per 100 mL acetone 3 days per week for 28 weeks. Survival of all dosed groups of mice was similar to that of the vehicle controls. With the exception of the 3 mg/kg group, body weights of male mice were less than those of the vehicle controls during the last 3 to 6 weeks of the study. Females administered 3 mg/kg had generally reduced body weights during the last month of the study. Treatment-related clinical findings included papillomas at the site of application in males and females receiving 3 mg/kg or more; papillomas were also observed in one 1.5 mg/kg male. Heart and liver weights of 12 mg/kg males were significantly greater than those of the vehicle controls. Lung weights of 6 and 12 mg/kg males and females were significantly decreased, as were thymus weights of 6 and 12 mg/kg females. Squamous cell neoplasms at the site of application were associated with dermal application of pentaerythritol triacrylate. At 6 months, all 3 and 6 mg/kg males had squamous cell papilloma at the site of application, and the incidences of this neoplasm were significantly increased in males and females receiving 3 mg/kg or more. Squamous cell carcinomas at the site of application occurred in two 3 mg/kg males, three 12 mg/kg males, and one 12 mg/kg female. Nonneoplastic lesions noted at the site of application in dosed mice included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. Incidences of hematopoietic cell proliferation were increased in various organs, including the liver of 12 mg/kg females, the spleen of 6 and 12 mg/kg males and females, and the mandibular lymph node of 12 mg/kg females. A hematopoietic disorder (myelodysplasia) occurred in 12 mg/kg males.</AbstractText><AbstractText Label="GENETIC TOXICOLOGY" NlmCategory="RESULTS">Pentaerythritol triacrylate was not mutagenic in several strains of S. typhimurium, with or without hamster or rat liver S9 activation enzymes. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from B6C3F(1) mice treated with pentaerythritol triacrylate by skin painting for 3 months. In contrast, similar treatment of female Tg.AC hemizygous mice for 6 months induced a significant increase in micronucleated erythrocytes; the increase in micronuclei seen in male Tg.AC hemizygous mice was judged to be equivocal.</AbstractText><AbstractText Label="CONTACT HYPERSENSITIVITY STUDIES" NlmCategory="UNASSIGNED">Studies were conducted with female BALB/c mice to evaluate the potential for pentaerythritol triacrylate to induce contact hypersensitization. In an irritancy study in which formulations of pentaerythritol triacrylate (approximately 10% or 45% pure) in acetone were applied to the ear, the maximal nonirritating concentration was 0.1% and the minimal irritating concentration was 0.25% for both mixtures. A mouse ear swelling test yielded negative results for pentaerythritol triacrylate as a potential contact sensitizer using the 10% mixture and positive results with the 45% mixture. Positive responses were seen in local lymph node assays at concentrations of 0.05%, 0.1%, and 0.25% pentaerythritol triacrylate when the approximately 10% pentaerythritol triacrylate mixture was used and at a concentration of 0.25% pentaerythritol triacrylate when the approximately 45% pentaerythritol triacrylate mixture was used.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">Male and female Tg.AC hemizygous mice dosed with pentaerythritol triacrylate for 6 months had significantly increased incidences of squamous cell papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in male mice. Nonneoplastic lesions noted at the site of application included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. A hematopoietic disorder (myelodysplasia) occurred in dosed male mice.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><CollectiveName>National Toxicology Program</CollectiveName></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Natl Toxicol Program Genet Modif Model Rep</MedlineTA><NlmUniqueID>101469988</NlmUniqueID><ISSNLinking>1556-522X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000179">Acrylates</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002273">Carcinogens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011409">Propylene Glycols</NameOfSubstance></Chemical><Chemical><RegistryNumber>PJJ1161ULF</RegistryNumber><NameOfSubstance UI="C027992">pentaerythrityl triacrylate</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000179" MajorTopicYN="N">Acrylates</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="Y">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000279" MajorTopicYN="N">Administration, Cutaneous</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002273" MajorTopicYN="N">Carcinogens</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="Y">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011905" MajorTopicYN="N">Genes, ras</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008822" MajorTopicYN="N">Mice, Transgenic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009190" MajorTopicYN="N">Myelodysplastic Syndromes</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="N">chemically induced</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010212" MajorTopicYN="N">Papilloma</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="Y">chemically induced</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011409" MajorTopicYN="N">Propylene Glycols</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="Y">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011916" MajorTopicYN="N">Rats, Inbred F344</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012878" MajorTopicYN="N">Skin Neoplasms</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="Y">chemically induced</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2008</Year><Month>9</Month><Day>12</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2009</Year><Month>1</Month><Day>1</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2008</Year><Month>9</Month><Day>12</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">18784764</ArticleId><ArticleId IdType="pmc">PMC8950436</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">18784763</PMID><DateCompleted><Year>2008</Year><Month>12</Month><Day>31</Day></DateCompleted><DateRevised><Year>2022</Year><Month>03</Month><Day>23</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1556-5246</ISSN><JournalIssue CitedMedium="Internet"><Issue>3</Issue><PubDate><Year>2005</Year><Month>Oct</Month></PubDate></JournalIssue><Title>National Toxicology Program genetically modified model report</Title><ISOAbbreviation>Natl Toxicol Program Genet Modif Model Rep</ISOAbbreviation></Journal>Toxicology studies of trimethylolpropane triacrylate (technical grade) (CAS No. 15625-89-5) in F344/N rats, B6C3F1 mice, and genetically modified (FVB Tg.AC hemizygous) mice (dermal studies).
ABSTRACT The barley cv. Bolivia carries two leaf rust (Puccinia hordei) resistance genes, Rph2 and Rph6, and is the only known source of the latter gene. A resistant line (Bolivia-Rph6) carrying Rph6 only was obtained in the F(4) generation of a cross between cv. Bolivia and the susceptible cv. Bowman via progeny testing with differential isolates of the leaf rust pathogen. Genetic analyses and bulk segregant analysis using amplified fragment length polymorphism (AFLP) and restriction fragment length polymorphism (RFLP) markers localized Rph6 on the short arm of barley chromosome 3H at a distance of 4.4 centimorgans (cM) distal from RFLP marker MWG2021 and 1.2 cM proximal from RFLP marker BCD907. The allelic relationship of Rph6 to other leaf rust resistance genes mapping to this region of chromosome 3H (namely Rph5 and Rph7) were tested using crosses among cvs. Magnif 102 (carrying Rph5), Bolivia-Rph6 (Rph6), and Cebada Capa (Rph7). Segregation analyses indicated that Rph6 is allelic to Rph5 and closely linked to Rph7. The data generated from this study will facilitate breeding for leaf rust resistance via marker-assisted selection and provide a starting point for positional gene cloning.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zhong</LastName><ForeName>Shaobin</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Effertz</LastName><ForeName>Roger J</ForeName><Initials>RJ</Initials></Author><Author ValidYN="Y"><LastName>Jin</LastName><ForeName>Yue</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Franckowiak</LastName><ForeName>Jerome D</ForeName><Initials>JD</Initials></Author><Author ValidYN="Y"><LastName>Steffenson</LastName><ForeName>Brian J</ForeName><Initials>BJ</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Phytopathology</MedlineTA><NlmUniqueID>9427222</NlmUniqueID><ISSNLinking>0031-949X</ISSNLinking></MedlineJournalInfo></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2008</Year><Month>10</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2008</Year><Month>10</Month><Day>24</Day><Hour>9</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2008</Year><Month>10</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">18942983</ArticleId><ArticleId IdType="doi">10.1094/PHYTO.2003.93.5.604</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">18784764</PMID><DateCompleted><Year>2008</Year><Month>12</Month><Day>31</Day></DateCompleted><DateRevised><Year>2022</Year><Month>03</Month><Day>27</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1556-5246</ISSN><JournalIssue CitedMedium="Internet"><Issue>4</Issue><PubDate><Year>2005</Year><Month>Oct</Month></PubDate></JournalIssue><Title>National Toxicology Program genetically modified model report</Title><ISOAbbreviation>Natl Toxicol Program Genet Modif Model Rep</ISOAbbreviation></Journal><ArticleTitle>Toxicology studies of pentaerythritol triacrylate (technical grade) (CAS No. 3524-68-3) in F344/N rats, B6C3F1 mice, and genetically modified (FVB Tg.AC hemizygous) mice (dermal studies).</ArticleTitle><Pagination><StartPage>1</StartPage><EndPage>190</EndPage><MedlinePgn>1-190</MedlinePgn></Pagination><Abstract><AbstractText Label="UNLABELLED">Pentaerythritol triacrylate is used in the production of ultraviolet-curable inks and coatings, electron beam irradiation- curable coatings, and radiation-cured and photocurable coatings of urethanes and epoxy resins; as a component of photopolymer and flexographic printing inks and plates and photoresists; as an ingredient of acrylic glues, adhesives, and anaerobic sealants; and as a modifier for polyester and fiberglass. It is also used in colloidal dispersions for industrial baked coatings, waterborne and solvent-based alkyds, vinyl/acrylic nonwoven binders, paper and wood impregnates, wire and cable extrusion, polymer-impregnated concrete, and polymer concrete structural composites. Pentaerythritol triacrylate was nominated by the National Cancer Institute for testing based on its high production volume and use, its potential for human exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were administered technical grade pentaerythritol triacrylate (it is reactive and therefore not available as pure pentaerythritol triacrylate) in acetone dermally for 2 weeks or 3 months. Male and female Tg.AC hemizygous mice were administered technical grade pentaerythritol acrylate in acetone for 6 months. Genetic toxicology was evaluated in Salmonella typhimurium and in B6C3F(1) and Tg.AC hemizygous mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All rats survived to the end of the study; mean body weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Irritation at the site of application occurred in all dosed groups except 12.5 mg/kg females. Epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation occurred at the site of application in most dosed groups of rats. 2-WEEK STUDY IN B6C3F(1) MICE: Groups of five male and five female B6C3F(1) mice were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All mice survived to the end of the study. The final mean body weight and body weight gain of 25 mg/kg males were significantly greater than those of the vehicle controls, as was the mean body weight gain of 50 mg/kg males. All dosed groups had irritation at the site of application. Thymus weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Most dosed groups of mice had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation at the site of application. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of 12 mg/kg males were significantly less than those of the vehicle controls. Irritation at the site of application occurred in 12 mg/kg rats. Thymus weights of males administered 3 mg/kg or greater were significantly less than those of the vehicle controls. Hematology results indicated that pentaerythritol triacrylate induced a neutrophil count increase that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Epidermal hyperplasia, hyperkeratosis, epidermal degeneration and necrosis, chronic active inflammation, and sebaceous gland hyperplasia generally occurred at the application site in male and female groups administered 1.5 mg/kg or greater. 3-MONTH STUDY IN B6C3F(1) MICE: Groups of 10 male and 10 female B6C3F(1) mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. One female vehicle control mouse was sacrificed during the first week of the study due to ataxia and one 1.5 mg/kg female died during week 8. Mean body weights of dosed groups were similar to those of the vehicle control groups. Irritation at the site of application occurred in the 6 and 12 mg/kg male groups. Hematology results indicated an increased neutrophil count consistent with an inflammatory response related to the dermatitis observed histopathologically. There also was a minimal decrease in the erythron (hematocrit, hemoglobin concentration, and erythrocyte count) likely secondary to the inflammatory skin process. Males and females administered 1.5 mg/kg or greater generally had increased incidences of epidermal hyperplasia, degeneration, and necrosis; dermal chronic active inflammation, sebaceous gland hyperplasia, and hyperkeratosis at the site of application. 6-MONTH STUDY IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate per kg body weight in acetone 5 days per week for 27 weeks. Additional groups of 15 male and 15 female mice maintained as positive controls received dermal applications of 1.25 mug 12-O-tetradecanoylphorbol-13-acetate per 100 mL acetone 3 days per week for 28 weeks. Survival of all dosed groups of mice was similar to that of the vehicle controls. With the exception of the 3 mg/kg group, body weights of male mice were less than those of the vehicle controls during the last 3 to 6 weeks of the study. Females administered 3 mg/kg had generally reduced body weights during the last month of the study. Treatment-related clinical findings included papillomas at the site of application in males and females receiving 3 mg/kg or more; papillomas were also observed in one 1.5 mg/kg male. Heart and liver weights of 12 mg/kg males were significantly greater than those of the vehicle controls. Lung weights of 6 and 12 mg/kg males and females were significantly decreased, as were thymus weights of 6 and 12 mg/kg females. Squamous cell neoplasms at the site of application were associated with dermal application of pentaerythritol triacrylate. At 6 months, all 3 and 6 mg/kg males had squamous cell papilloma at the site of application, and the incidences of this neoplasm were significantly increased in males and females receiving 3 mg/kg or more. Squamous cell carcinomas at the site of application occurred in two 3 mg/kg males, three 12 mg/kg males, and one 12 mg/kg female. Nonneoplastic lesions noted at the site of application in dosed mice included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. Incidences of hematopoietic cell proliferation were increased in various organs, including the liver of 12 mg/kg females, the spleen of 6 and 12 mg/kg males and females, and the mandibular lymph node of 12 mg/kg females. A hematopoietic disorder (myelodysplasia) occurred in 12 mg/kg males.<AbstractText Label="GENETIC TOXICOLOGY" NlmCategory="RESULTS">Pentaerythritol triacrylate was not mutagenic in several strains of S. typhimurium, with or without hamster or rat liver S9 activation enzymes. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from B6C3F(1) mice treated with pentaerythritol triacrylate by skin painting for 3 months. In contrast, similar treatment of female Tg.AC hemizygous mice for 6 months induced a significant increase in micronucleated erythrocytes; the increase in micronuclei seen in male Tg.AC hemizygous mice was judged to be equivocal.<AbstractText Label="CONTACT HYPERSENSITIVITY STUDIES" NlmCategory="UNASSIGNED">Studies were conducted with female BALB/c mice to evaluate the potential for pentaerythritol triacrylate to induce contact hypersensitization. In an irritancy study in which formulations of pentaerythritol triacrylate (approximately 10% or 45% pure) in acetone were applied to the ear, the maximal nonirritating concentration was 0.1% and the minimal irritating concentration was 0.25% for both mixtures. A mouse ear swelling test yielded negative results for pentaerythritol triacrylate as a potential contact sensitizer using the 10% mixture and positive results with the 45% mixture. Positive responses were seen in local lymph node assays at concentrations of 0.05%, 0.1%, and 0.25% pentaerythritol triacrylate when the approximately 10% pentaerythritol triacrylate mixture was used and at a concentration of 0.25% pentaerythritol triacrylate when the approximately 45% pentaerythritol triacrylate mixture was used.<AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">Male and female Tg.AC hemizygous mice dosed with pentaerythritol triacrylate for 6 months had significantly increased incidences of squamous cell papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in male mice. Nonneoplastic lesions noted at the site of application included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. A hematopoietic disorder (myelodysplasia) occurred in dosed male mice.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><CollectiveName>National Toxicology Program</CollectiveName></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Natl Toxicol Program Genet Modif Model Rep</MedlineTA><NlmUniqueID>101469988</NlmUniqueID><ISSNLinking>1556-522X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000179">Acrylates</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002273">Carcinogens</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011409">Propylene Glycols</NameOfSubstance></Chemical><Chemical><RegistryNumber>PJJ1161ULF</RegistryNumber><NameOfSubstance UI="C027992">pentaerythrityl triacrylate</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000179" MajorTopicYN="N">Acrylates</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="Y">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000279" MajorTopicYN="N">Administration, Cutaneous</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002273" MajorTopicYN="N">Carcinogens</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="Y">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011905" MajorTopicYN="N">Genes, ras</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008822" MajorTopicYN="N">Mice, Transgenic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009190" MajorTopicYN="N">Myelodysplastic Syndromes</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="N">chemically induced</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010212" MajorTopicYN="N">Papilloma</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="Y">chemically induced</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011409" MajorTopicYN="N">Propylene Glycols</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="Y">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011916" MajorTopicYN="N">Rats, Inbred F344</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012878" MajorTopicYN="N">Skin Neoplasms</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="Y">chemically induced</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2008</Year><Month>9</Month><Day>12</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2009</Year><Month>1</Month><Day>1</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2008</Year><Month>9</Month><Day>12</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">18784764</ArticleId><ArticleId IdType="pmc">PMC8950436</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">18784763</PMID><DateCompleted><Year>2008</Year><Month>12</Month><Day>31</Day></DateCompleted><DateRevised><Year>2022</Year><Month>03</Month><Day>23</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1556-5246</ISSN><JournalIssue CitedMedium="Internet"><Issue>3</Issue><PubDate><Year>2005</Year><Month>Oct</Month></PubDate></JournalIssue><Title>National Toxicology Program genetically modified model report</Title><ISOAbbreviation>Natl Toxicol Program Genet Modif Model Rep</ISOAbbreviation></Journal><ArticleTitle>Toxicology studies of trimethylolpropane triacrylate (technical grade) (CAS No. 15625-89-5) in F344/N rats, B6C3F1 mice, and genetically modified (FVB Tg.AC hemizygous) mice (dermal studies).</ArticleTitle><Pagination><StartPage>1</StartPage><EndPage>195</EndPage><MedlinePgn>1-195</MedlinePgn></Pagination><Abstract><AbstractText Label="UNLABELLED">Trimethylolpropane triacrylate is a multifunctional monomer with a wide range of industrial applications. It is used in the production of ultraviolet-curable inks, electron beam irradiation-curable coatings, and polymers and resins; as a component of photopolymer and flexographic printing plates and photoresists; and as an ingredient in acrylic glues and anaerobic sealants. The chemical is also used in paper and wood impregnates, wire and cable extrusion, polymer-impregnated concrete, and polymer concrete structural composites. Trimethylolpropane triacrylate was nominated by the National Cancer Institute for testing due to its high production volume and use, its potential for consumer exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were administered technical grade trimethylolpropane triacrylate (it is reactive and therefore not available as pure trimethylolpropane triacrylate) in acetone dermally for 2 weeks or 3 months. Male and female Tg.AC hemizygous mice were administered technical grade trimethylolpropane triacrylate in acetone for 6 months. Genetic toxicology studies were conducted in B6C3F(1) and Tg.AC hemizygous mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of dosed groups were similar to those of the vehicle controls. Dosed rats had irritation at the site of application; this clinical finding was most commonly seen in rats administered 50 mg/kg or greater. Male and female rats had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, inflammation of the epidermis and dermis, ulceration, epidermal degeneration, and parakeratosis at the site of application. 2-WEEK STUDY IN B6C3F(1) MICE: Groups of five male and five female B6C3F(1) mice were administered 0, 12.5, 25, 50, 100, or 200 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 16 days. All mice survived to the end of the study. The final mean body weight gain of 200 mg/kg males was less than that of the vehicle controls; 100 and 200 mg/kg females had significantly increased final mean body weights. Irritation at the site of application occurred in all dosed males, all 100 and 200 mg/kg females, and one 50 mg/kg female. Thymus weights of males administered 50 mg/kg or greater were significantly decreased. Dosed male and female mice had epidermal hyperplasia, hyperkeratosis, chronic active inflammation of the dermis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, and/or suppurative inflammation of the epidermis at the site of application. Atrophy of the thymus occurred in 100 and 200 mg/kg male mice. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 0.75, 1.5, 3, 6, or 12 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All rats survived to the end of the study, and mean body weights of dosed groups were similar to those of the vehicle controls. Irritation at the site of application was noted in five males and all females administered 12 mg/kg. Hematology results indicated that trimethylolpropane triacrylate at the doses selected induced a neutrophil count increase at 12 mg/kg that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Thymus weights of 12 mg/kg males and 0.75 and 12 mg/kg females were decreased. Incidences of epidermal hyperplasia, degeneration, and necrosis (females only); chronic active inflammation of the dermis, hyperkeratosis, and sebaceous gland hyperplasia were generally increased at the site of application in 1.5 mg/kg or greater males and in 3 mg/kg or greater females. 3-MONTH STUDY IN B6C3F(1) MICE: Groups of 10 male and 10 female B6C3F(1) mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All animals survived to the end of the study; mean body weights of dosed groups were similar to those of the vehicle controls. Irritation at the site of application occurred in male and female mice administered 12 mg/kg. Hematology results indicated that trimethylolpropane triacrylate induced a neutrophil count increase at 12 mg/kg that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Increased incidences of several nonneoplastic lesions occurred at the site of application in 3 mg/kg and greater males and females, including hyperplasia of the epidermis, hyperkeratosis, epidermal degeneration (except 3 mg/kg females) and necrosis, chronic active inflammation of the dermis, and sebaceous gland hyperplasia. Epidermal suppurative inflammation and necrosis and dermal fibrosis occurred in 12 mg/kg males and females. 6-MONTH STUDY IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg trimethylolpropane triacrylate/kg body weight in acetone 5 days per week for 28 weeks. Additional groups of 15 male and 15 female mice maintained as positive controls received dermal applications of 1.25 microg 12-O-tetradecanoylphorbol-13-acetate per 100 mL acetone 3 days per week for 28 weeks; the dosing volume was held constant at 100 microL. Survival and mean body weights of dosed groups were similar to those of the vehicle controls throughout the study. Treatment-related clinical findings included papillomas at the site of application in 3 mg/kg and greater males and 6 and 12 mg/kg females. The heart weights of males and females administered 12 mg/kg and the kidney and lung weights of 12 mg/kg females were significantly increased. The lung weights of 6 and 12 mg/kg males and females were decreased. Squamous cell neoplasms at the site of application were associated with dermal application of trimethylolpropane triacrylate. At 6 months, the incidences of squamous cell papilloma were significantly increased in 6 and 12 mg/kg males and females. One female in each of the 1.5, 6, and 12 mg/kg groups also had squamous cell carcinoma. The incidence of squamous cell papilloma of the forestomach in 12 mg/kg females was significantly greater than that in the vehicle control group. Nonneoplastic skin lesions at the site of application in dosed mice included epidermal hyperplasia, hyperkeratosis, and chronic active inflammation. A hematopoietic disorder (myelodysplasia) also occurred in some 12 mg/kg males and females.<AbstractText Label="GENETIC TOXICOLOGY" NlmCategory="RESULTS">No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from male or female B6C3F(1) mice treated with trimethlylolpropane triacrylate by skin painting for 3 months. Similarly, no increase in micronucleus frequency was seen in male or female Tg.AC hemizygous mice administered trimethylolpropane triacrylate by skin painting for 6 months.<AbstractText Label="CONTACT HYPERSENSITIVITY STUDIES" NlmCategory="UNASSIGNED">Studies were conducted with female BALB/c mice to evaluate the potential for trimethylolpropane triacrylate to induce contact hypersensitization. In an irritancy study in which the chemical, in acetone, was applied to the ear, the maximal nonirritating and minimal irritating doses were 0.1% and 0.25% trimethylolpropane triacrylate. No significant differences in the percentage of ear swelling occurred between trimethylolpropane triacrylate-sensitized and -challenged mice and background controls at 24 or 48 hours after dosing. The local lymph node assay indicated no significant increase in lymph node cell proliferation in mice administered trimethylolpropane triacrylate compared to that in the vehicle controls. Testing for sensitizing potential using the mouse ear swelling test and local lymph node assay failed to indicate trimethylolpropane triacrylate as a potential contact sensitizer.<AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">Male and female Tg.AC hemizygous mice dosed with trimethylolpropane triacrylate for 6 months had significantly increased incidences and multiplicity of papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in dosed female mice. Increased incidences of forestomach squamous cell papilloma in female mice may have been related to chemical administration. Increased incidences of minimal to moderate (mostly mild) hyperplasia of the epidermis, hyperkeratosis, and chronic active inflammation also occurred at the site of application. A hematopoietic disorder (myelodysplasia) also occurred in exposed male and female mice.
2,336,157
Genomics and ethics: the case of cloned and/or transgenic animals.
The point of the present study is to illustrate and, if possible, promote the existing link between genomics and ethics, taking the example of cloned and transgenic animals. These 'new animals' raise theoretical and practical problems that concern applied ethics. We will explore more particularly an original strategy showing that it is possible, starting from philosophical questioning about the nature of identity, to use a genomic approach, based on amplification fragment length polymorphism (AFLP) and methylation-sensitive amplification polymorphism (MSAP) detection, to provide useful tools to define more rigorously what cloned animals are, by testing their genetic and epigenetic identity. We expect from the future results of this combined approach to stimulate the creativity of the philosophical and ethical reflection about the impact of biotechnology on animals, and to increase scientific involvement in such issues.
2,336,158
Dietary supplements and sports performance: introduction and vitamins.
Sports success is dependent primarily on genetic endowment in athletes with morphologic, psychologic, physiologic and metabolic traits specific to performance characteristics vital to their sport. Such genetically-endowed athletes must also receive optimal training to increase physical power, enhance mental strength, and provide a mechanical advantage. However, athletes often attempt to go beyond training and use substances and techniques, often referred to as ergogenics, in attempts to gain a competitive advantage. Pharmacological agents, such as anabolic steroids and amphetamines, have been used in the past, but such practices by athletes have led to the establishment of anti-doping legislation and effective testing protocols to help deter their use. Thus, many athletes have turned to various dietary strategies, including the use of various dietary supplements (sports supplements), which they presume to be effective, safe and legal.
2,336,159
Pedigree Analysis of the Sika Deer (Cervus nippon) using Microsatellite Markers.
The usefulness of microsatellite markers in pedigree analysis of the sika deer (Cervus nippon) was tested in a herd in which the maternal lineages were recorded. Eighteen sets of microsatellite primers originally designed for bovine, ovine, and cervine loci successfully amplified polymorphic DNA in the deer. The numbers of alleles per locus ranged from two to seven, and the observed heterozygosity ranged from 0.350 to 0.900. The resolution power of the markers in paternity testing was then determined by calculating exclusion probabilities and paternity indices. Parentages of the study population were efficiently discriminated by genotyping 17 microsatellite loci. The microsatellite data were also used to calculate the genetic relatedness between individuals, which significantly correlated with coancestry coefficients for the pairs. Our results demonstrate that the microsatellite markers are efficient tools in studying the social structure and behavior of the sika deer, as well as in monitoring the inbreeding status.
2,336,160
The TRAMP mouse as a model for prostate cancer.
The transgenic adenocarcinoma of the mouse prostate (TRAMP) model closely mirrors the pathogenesis of human prostate cancer. Male TRAMP mice uniformly and spontaneously develop autochthonous (orthotopic) prostate tumors following the onset of puberty. Prostate cancer occurs consequent to the expression of SV40 T antigen. The versatility of the TRAMP model has been extended by establishment of several TRAMP-derived prostate tumor cells lines that can be injected into syngeneic male nontransgenic C57BL/6 hosts to induce ectopic prostate tumorigenesis. Subcutaneous tumor induction using the TRAMP-C cell lines has provided the basis for two additional murine models, the first of which can be used for rapid screening of experimental therapies for the treatment of primary prostate tumors and the second for testing the effectiveness of adjunctive therapies targeting prostate cancer metastases. Detailed descriptions for the harvesting and microdissection of TRAMP prostates and tumors, and the evaluation and scoring of tumors are also provided.
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Adjuvant arthritis in the rat.
Adjuvant arthritis (AA) is an induced form of (sub)chronic arthritis. Strains of rats have a varying genetic susceptibility to AA, whereas mice generally are not susceptible. AA is most easily induced with mycobacteria suspended in oil, although in some strains of rats it can be induced with oily adjuvants in the absence of mycobacteria. The disease is a T cell-mediated autoimmune arthritis that is frequently used to study immunological aspects of rheumatoid arthritis (RA) and other arthritic or inflammatory diseases in humans. Furthermore, it is used as a model for developing and testing antiinflammatory drugs. There are no particularly well-defined autoantigens in AA; in this respect, the model resembles spontaneous arthritic diseases in humans. In all susceptible rat strains, the inflammatory process of AA is self remitting, although usually the disease is severe and leads to permanent joint malformations, including ankylosis; a time line for AA development is presented. This unit describes the induction and evaluation of AA and the preparation of adjuvant used to induce AA.
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Fear-potentiated startle in mice.
Pavlovian fear conditioning is frequently used to assess the behavioral, physiological, genetic and molecular correlates of learning and memory. In the typical Pavlovian conditioned fear procedure a neutral stimulus, such as a tone, is paired with a mildly aversive stimulus such as a foot shock. The tone conditioned stimulus (CS) comes to elicit a variety of behaviors that are indicative of learned fear. One of the more prominent of these behaviors is a potentiated acoustic startle response. While fear-potentiated startle in mice is qualitatively similar to that in rats, the stimulus parameters and procedures for producing optimum fear-potentiated startle in mice differ considerably from those used in rats. Procedures outlined in this unit include initial assessment of startle, fear conditioning and fear-potentiated startle testing. Special attention is paid to the parameters that affect the magnitude of fear-potentiated startle and procedures designed to systematically examine these parameters are included.
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Clinical validity and clinical utility of genetic tests.
In considering the appropriate use of new genetic tests, clinicians and health care policymakers must consider the accuracy with which a test identifies a patient's clinical status (clinical validity) and the risks and benefits resulting from test use (clinical utility). Genetic tests in current use vary in accuracy and potential to improve health outcomes, and these test properties may be influenced by the clinical setting in which the test is used. In addition, the relative importance of clinical validity and utility varies according to the proposed use of the test. This unit defines clinical validity and clinical utility, provides examples, and considers the implications of these test properties for clinical practice.
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Genetic algorithm-based neural fuzzy decision tree for mixed scheduling in ATM networks.
Future broadband integrated services networks based on asynchronous transfer mode (ATM) technology are expected to support multiple types of multimedia information with diverse statistical characteristics and quality of service (QoS) requirements. To meet these requirements, efficient scheduling methods are important for traffic control in ATM networks. Among general scheduling schemes, the rate monotonic algorithm is simple enough to be used in high-speed networks, but does not attain the high system utilization of the deadline driven algorithm. However, the deadline driven scheme is computationally complex and hard to implement in hardware. The mixed scheduling algorithm is a combination of the rate monotonic algorithm and the deadline driven algorithm; thus it can provide most of the benefits of these two algorithms. In this paper, we use the mixed scheduling algorithm to achieve high system utilization under the hardware constraint. Because there is no analytic method for schedulability testing of mixed scheduling, we propose a genetic algorithm-based neural fuzzy decision tree (GANFDT) to realize it in a real-time environment. The GANFDT combines a GA and a neural fuzzy network into a binary classification tree. This approach also exploits the power of the classification tree. Simulation results show that the GANFDT provides an efficient way of carrying out mixed scheduling in ATM networks.
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The laboratory diagnosis of Haemophilus ducreyi.
Chancroid is a sexually transmitted infection caused by Haemophilus ducreyi. This fastidious, Gram-negative coccobacilli dies rapidly outside the human host, making diagnostic testing using culture methods difficult. This genital ulcer infection is not common in Canada and, therefore, can often be misdiagnosed. The objective of the present paper is to provide practical approaches for the diagnosis of chancroid in Canadian patients where the prevalence of this infection is low. Issues related to sample collection, sample transport and available diagnostic tests are reviewed, and several alternative approaches are outlined. Although antigen detection, serology and genetic amplification methods have all been reported for H ducreyi, none are commercially available. Culture is still the primary method available to most laboratories. However, the special media necessary for direct bedside inoculation is often not available; therefore, communication with the diagnostic laboratory and rapid specimen transport are essential when chancroid is suspected.
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Diagnosis and analysis of a recent case of human rabies in Canada.
On September 30, 2000, staff at the Canadian Food Inspection Agency's Centre of Expertise for Rabies, located at the Animal Diseases Research Institute in Ottawa, Ontario, diagnosed rabies in a child from Quebec. This was the first case of rabies in a human in Canada in 15 years and in 36 years in the province of Quebec. After spending a week in intensive care in a Montreal hospital, the nine-year-old boy succumbed to this nearly always fatal disease. The boy had been exposed to a bat in late August 2000, while vacationing with his family in the Quebec countryside.</AbstractText>Antemortem specimens taken from the patient were sent to the Canadian Food Inspection Agency laboratory for rabies diagnosis. Samples included saliva, eye secretions, corneal impressions, cerebral spinal fluid and skin. Specimens were examined by direct immunofluorescence microscopy, and results were confirmed using molecular biological techniques. Virus strain identification was performed by both genetic methods and phenotypic analysis with monoclonal antibodies.</AbstractText>Initial results from direct immunofluorescence staining indicated that rabies virus was present in the skin biopsy specimen but not in the corneal impressions. This diagnosis of rabies was confirmed by polymerase chain reaction product analysis from several of the submitted specimens. Virus isolation from postmortem samples was not possible because fresh brain tissue was not available. Rabies virus was isolated from saliva and was determined to be similar to a variant that circulates in populations of silver-haired bats.</AbstractText>Intravitam diagnosis of rabies in humans is very dependent on the samples submitted for diagnosis and the method used for testing. Upon first examination, only skin specimens were positive for rabies virus antigen; using polymerase chain reaction analysis, only saliva yielded positive results for rabies virus genome. Extensive testing and retesting of specimens submitted for rabies diagnosis in humans must be done to avoid false negative results.</AbstractText>
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Diagnosis of primary hyperoxaluria type 1 by determination of peritoneal dialysate glycolic acid using standard organic-acids analysis method.
Hyperglycolic hyperoxaluria is an important biochemical diagnostic hallmark for primary hyperoxaluria type 1 (PH1). Biochemical work-up on urinary specimens becomes impossible after the development end-stage renal failure and anuria. We studied the diagnostic value of determining glycolic acid content in peritoneal dialysate effluent in PH1.</AbstractText>We performed a comparative study on an anuric continuous ambulatory peritoneal dialysis (CAPD) patient whose PH1 was confirmed by genetic study and on 5 anuric CAPD controls. Specimens were taken from each bag of peritoneal dialysate effluent over a 24-hour period, and the corresponding drainage volume was noted. The specimens were then processed using standard procedures for organic-acid analysis. They underwent ethyl acetate extraction, followed by semiquantitative analysis of organic acids by gas chromatography mass spectrometry (GCMS). The daily output of glycolic acid in peritoneal dialysate for each individual was then estimated.</AbstractText>All 6 patients were receiving four 2-L CAPD exchanges daily. The estimated daily glycolic acid output for the PH1 patient was 48.3 micromol daily. The mean glycolic acid output for the 5 controls was estimated to be much lower at 19.6 micromol daily (range: 15.1 - 27.5 micromol daily).</AbstractText>Standard organic-acid analysis for glycolic acid in peritoneal dialysate could be a useful initial screening tool before invasive or sophisticated testing is done in CAPD patients with suspected PH1.</AbstractText>
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Clinical use of cord blood for stem cell transplantation.
Allogeneic bone marrow transplantations (BMT) from HLA-matched siblings have been successfully used for treatment of patients with high-risk hematological malignancies, genetic immunodeficiencies, metabolic disorders, or marrow failure syndromes. Unfortunately, most of patients lack matched related donors. Over the past decade clinicians have explored the suitability of umbilical cord blood (CB) as an alternative source for hematopoietic stem cell transplantation. Since the first related cord blood transplantation (CBT) was performed successfully for a child with Fanconi Anemia in 1988, there have been many children undergoing CBT from related donors. The further experience suggests that CB donation is a safe procedure for both mother and newborn. Subsequently, several quality CB banks were established worldwide with requirement of specific issues including donor recruitment, CB collection and processing, histocompatibility testing, infectious and genetic disease testing, transportation of CB, and protection of confidentiality of donors and recipients. The clinical data showed that unrelated donor CBT had comparable survival results to unrelated donor BMT CB offers many potential advantages such as it is readily available, its collection causes no harm to the donor and minimal HLA-disparity is acceptable. However there are some disadvantages due to the volume and cell dose of each collected CB is limited, thus methods to enhance the number or quality of stem cells in CB are needed. At present the world's experiences suggest that CB is an acceptable alternative to bone marrow.
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Screening of the Bruton Tyrosine Kinase (BTK) Gene Mutations in 13 Iranian Patients with Presumed X-Linked Agammaglobulinemia.
X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the Bruton tyrosine kinase (Btk) gene. In order to identify the mutations in Btk gene in Iranian patients with antibody deficiency, 13 male patients with an XLA phenotype from 11 unrelated families were enrolled as the subjects of investigation for Btk mutation analysis using PCR-SSCP followed by sequencing. Five different mutations were identified in 5 patients from 5 unrelated families. Three mutations had been reported previously including TTTG deletion in intron 15 (4 bps upstream of exon 16 boundary), nonsense point mutation (1896G&gt;A) that resulted in a premature stop codon (W588X) in kinase domain, and nucleotide alteration in invariant splice donor site of exon12 (IVS12+1G&gt;A). While 2 novel missense mutations (2084A&gt;G, 1783T&gt;C) were identified leading to amino acid changes (I651T, Y551H). The results of this study further support the notion that molecular genetic testing represents an important tool for definitive and early diagnosis of XLA and may allow accurate carrier detection and prenatal diagnosis.
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Wrongful life and wrongful birth: legal aspects of failed genetic testing in oocyte donation.
The field of reproductive medicine has all but exploded in recent years, allowing more people access to novel treatments. New technologies have been introduced so rapidly that ethics and the law have been unable to respond appropriately. A particularly promising reproductive therapy, oocyte donation, and the wide variety of prenatal genetic tests already available, will theoretically present the legal world with a variety of new challenges. How should the law respond to potential wrongful birth and wrongful life suits resulting from failed genetic testing, if the child in question was conceived using a donor egg? Under what circumstances should the physician be held liable? Under what circumstances might the donor be culpable? This paper reviews scholarly opinions and existing case law in order to answer these questions.
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Contact-based Simulated Annealing Protein Sequence Alignment Method.
Protein sequence alignments reveal the evolutionary information between homologous sequences. Traditional sequence alignment methods only use sequence information and the structure information from template is ignored. Recently, Kleinjung et al. developed a contact-based sequence alignment method that used the structural information from side-chain contacts. Alignment scores are provided by the CAO (Contact Accepted mutatiOn) substitution matrices. Kleinjung et al. devised an approximate dynamic programming algorithm for protein sequence alignment, on the assumption that the distance between the contacting residues during evolution has been conserved. However, such assumption is not suitable for insertion/deletion events during evolution. In this paper, the contact-based simulated annealing alignment method has been proposed, which can find the optimal alignment solution between two protein sequences without any restriction. The alignment score is calculated by the sequence-based scores and the weighted contact-based scores. A new parameter, the contact-penalty r, has been introduced. When the contacting residue in the template aligns with gap in the query sequence, the total alignment score is decreased by a contact-penalty. All the parameters including relative weight w of CAO scores versus Blosum62 scores, matrix constant c for CAO scores, gap-open penalty p, gap-extension penalty q and contact-penalty r are re-optimized by genetic algorithm. Testing on the Homstrad database shows that the accuracy of this method is 85.4%, which is higher than that of Kleinjung's method by about 3.6 percent. Such method can be useful in many biological problems such as protein remote homology detection, comparative modeling and fold recognition.
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Integrated microfluidic biochips for immunoassay and DNA bioassays.
Bioassays involve multi-stage sample processing and fluidic handling, which are generally labor-intensive and time-consuming. Using microfluidic technology to integrate and automate all these steps in a single chip device is highly desirable in many practical applications such as clinical diagnostic and in-field environmental testing. We have developed self-contained and fully integrated biochip systems for immunoassay and DNA analysis. These microfluidic biochip devices can perform detection of multiple bioagents (including antigens and DNA) using electrochemical detection methods. Microfluidic mixer, valves, pumps, channels, chambers, and Combimatrix microelectrode array are integrated to perform parallel immunoassays to detect infectious particles (viruses and bacteria) from complex biological samples in a single, fully automated biochip device. All microfluidic components use very simple and inexpensive approaches in order to reduce chip complexity. Back-end detection is accomplished using an enzyme-based electrochemical detection method that has many advantages including high sensitivity ( approximately fM) and simple apparatus. The sensor is a miniaturized array of individually addressable microelectrodes controlled by active CMOS circuitry. Pathogenic bacteria and DNA detections are both demonstrated. The devices with capabilities of on-chip sample processing and detection provide a cost-effective solution to direct sample-to-answer biological analysis for point-of-care genetic analysis, disease diagnosis, and in-field bio-threat detection.
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Prediction of aqueous solubility based on large datasets using several QSPR models utilizing topological structure representation.
Several QSPR models were developed for predicting intrinsic aqueous solubility, S(o). A data set of 5,964 neutral compounds was sub-divided into two classes, aromatic and non-aromatic compounds. Three models were created with different methods on both data sets: two regression models (multiple linear regression and partial least squares) and an artificial neural network model. These models were based on 3343 aromatic and 1674 non-aromatic compounds for training sets; 938 compounds were used in external validation testing. The range in -log S(o) is -1.6 to 10. Topological structure descriptors were used with all models. A genetic algorithm was used for descriptor selection for regression models. For the artificial neural network (ANN) model, descriptor selection was done with a backward elimination process. All models performed well with r2 values ranging 0.72 to 0.84 in external validation testing. The mean absolute errors in validation ranged from 0.44 to 0.80 for the classes of compounds for all the models. These statistical results indicate a sound ANN model. Furthermore, in a comparison with eight other available models, based on predictions using a validation test set (442 compounds), the artificial neural network model presented in this work (CSLogWS) was clearly superior based on both the mean absolute error and the percentage of residuals less than one log unit. In the ANN model both E-State and hydrogen E-State descriptors were found to be important.
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Presence of potential allergy-related linear epitopes in novel proteins from conventional crops and the implication for the safety assessment of these crops with respect to the current testing of genetically modified crops.
Mitochondria of cytoplasmic male sterile crop plants contain novel, chimeric open reading frames. In addition, a number of crops carry endogenous double-stranded ribonucleic acid (dsRNA). In this study, the novel proteins encoded by these genetic components were screened for the presence of potential binding sites (epitopes) of allergy-associated IgE antibodies, as was previously done with transgenic proteins from genetically modified crops. The procedure entails the identification of stretches of at least six contiguous amino acids that are shared by novel proteins and known allergenic proteins. These stretches are further checked for potential linear IgE-binding epitopes. Of the 16 novel protein sequences screened in this study, nine contained stretches of six or seven amino acids that were also present in allergenic proteins. Four cases of similarity are of special interest, given the predicted antigenicity of the identical stretch within the allergenic and novel protein, the IgE-binding by a peptide containing an identical stretch reported in literature, or the multiple incidence of identical stretches of the same allergen within a novel protein. These selected stretches are present in novel proteins derived from oilseed rape and radish (ORF138), rice (dsRNA), and fava bean (dsRNA), and warrant further clinical testing. The frequency of positive outcomes and the sizes of the identical stretches were comparable to those previously found for transgenic proteins in genetically modified crops. It is discussed whether novel proteins from conventional crops should be subject to an assessment of potential allergenicity, a procedure which is currently mandatory for transgenic proteins from genetically modified crops.
2,336,175
Internal and external factors affecting the development of neuropathic pain in rodents. Is it all about pain?<Pagination><StartPage>326</StartPage><EndPage>342</EndPage><MedlinePgn>326-42</MedlinePgn></Pagination><Abstract><AbstractText>It is important to know the factors that will influence animal models of neuropathic pain. A good reproducibility and predictability in different strains of animals for a given test increases the clinical relevance and possible targeting. An obligatory requirement for enabling comparisons of results of different origin is a meticulous definition of the specific sensitivities of a model for neuropathic pain and a description of the test conditions. Factors influencing neuropathic pain behavior can be subdivided in external and internal factors. The most important external factors are; timing of the measurement of pain after induction of neuropathy, circadian rhythms, seasonal influences, air humidity, influence of order of testing, diet, social variables, housing and manipulation, cage density, sexual activity, external stress factors, and influences of the experimenter. The internal factors are related to the type of animal, its genetic background, gender, age, and the presence of homeostatic adaptation mechanisms to specific situations or stress. In practice, the behavioral presentations to pain depend on the combination of genetic and environmental factors such as accepted social behavior. It also depends on the use of genetic manipulation of the animals such as in transgenic animals. These make the interpretation of data even more difficult. Differences of pain behavior between in- and outbred animals will be better understood by using modern analysis techniques. Substrains of animals with a high likelihood for developing neuropathic pain make the unraveling of specific pathophysiological mechanisms possible. Concerning the effect of stress on pain, it is important to differentiate between external and internal stress such as social coping behavior. The individual dealing with this stress is species sensitive, and depends on the genotype and the social learning. In the future, histo-immunological and genetic analysis will highlight similarities of the different pathophysiological mechanisms of pain between different species and human subjects. The final objective for the study of pain is to describe the genetics of the eliciting pain mechanisms in humans and to look for correlations with the knowledge from basic research. Therefore, it is necessary to know the genetic evolution of the different mechanisms in chronic pain. In order to be able to control the clinical predictability of a putative treatment the evolutionary pharmacogenomic structure of specific transmitters and receptors must be clarified.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Vissers</LastName><ForeName>K</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Multidisciplinary Pain Center, Ziekenhuis Oost-Limburg, Genk, Belgium. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Jongh</LastName><ForeName>R</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Hoffmann</LastName><ForeName>V</ForeName><Initials>V</Initials></Author><Author ValidYN="Y"><LastName>Heylen</LastName><ForeName>R</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Crul</LastName><ForeName>B</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Meert</LastName><ForeName>T</ForeName><Initials>T</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Pain Pract</MedlineTA><NlmUniqueID>101130835</NlmUniqueID><ISSNLinking>1530-7085</ISSNLinking></MedlineJournalInfo></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>12</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>12</Month><Day>15</Day><Hour>9</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>12</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">17166129</ArticleId><ArticleId IdType="doi">10.1111/j.1530-7085.2003.03037.x</ArticleId><ArticleId IdType="pii">PPR3037</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">17150527</PMID><DateCompleted><Year>2007</Year><Month>07</Month><Day>19</Day></DateCompleted><DateRevised><Year>2022</Year><Month>12</Month><Day>07</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1746-8272</ISSN><JournalIssue CitedMedium="Internet"><Issue>48</Issue><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Nucleic acids symposium series (2004)</Title><ISOAbbreviation>Nucleic Acids Symp Ser (Oxf)</ISOAbbreviation></Journal>Molecular scanning of susceptibility genes for the development of coronary heart disease in Japanese.
It is important to know the factors that will influence animal models of neuropathic pain. A good reproducibility and predictability in different strains of animals for a given test increases the clinical relevance and possible targeting. An obligatory requirement for enabling comparisons of results of different origin is a meticulous definition of the specific sensitivities of a model for neuropathic pain and a description of the test conditions. Factors influencing neuropathic pain behavior can be subdivided in external and internal factors. The most important external factors are; timing of the measurement of pain after induction of neuropathy, circadian rhythms, seasonal influences, air humidity, influence of order of testing, diet, social variables, housing and manipulation, cage density, sexual activity, external stress factors, and influences of the experimenter. The internal factors are related to the type of animal, its genetic background, gender, age, and the presence of homeostatic adaptation mechanisms to specific situations or stress. In practice, the behavioral presentations to pain depend on the combination of genetic and environmental factors such as accepted social behavior. It also depends on the use of genetic manipulation of the animals such as in transgenic animals. These make the interpretation of data even more difficult. Differences of pain behavior between in- and outbred animals will be better understood by using modern analysis techniques. Substrains of animals with a high likelihood for developing neuropathic pain make the unraveling of specific pathophysiological mechanisms possible. Concerning the effect of stress on pain, it is important to differentiate between external and internal stress such as social coping behavior. The individual dealing with this stress is species sensitive, and depends on the genotype and the social learning. In the future, histo-immunological and genetic analysis will highlight similarities of the different pathophysiological mechanisms of pain between different species and human subjects. The final objective for the study of pain is to describe the genetics of the eliciting pain mechanisms in humans and to look for correlations with the knowledge from basic research. Therefore, it is necessary to know the genetic evolution of the different mechanisms in chronic pain. In order to be able to control the clinical predictability of a putative treatment the evolutionary pharmacogenomic structure of specific transmitters and receptors must be clarified.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Vissers</LastName><ForeName>K</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Multidisciplinary Pain Center, Ziekenhuis Oost-Limburg, Genk, Belgium. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Jongh</LastName><ForeName>R</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Hoffmann</LastName><ForeName>V</ForeName><Initials>V</Initials></Author><Author ValidYN="Y"><LastName>Heylen</LastName><ForeName>R</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Crul</LastName><ForeName>B</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Meert</LastName><ForeName>T</ForeName><Initials>T</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Pain Pract</MedlineTA><NlmUniqueID>101130835</NlmUniqueID><ISSNLinking>1530-7085</ISSNLinking></MedlineJournalInfo></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>12</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>12</Month><Day>15</Day><Hour>9</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>12</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">17166129</ArticleId><ArticleId IdType="doi">10.1111/j.1530-7085.2003.03037.x</ArticleId><ArticleId IdType="pii">PPR3037</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">17150527</PMID><DateCompleted><Year>2007</Year><Month>07</Month><Day>19</Day></DateCompleted><DateRevised><Year>2022</Year><Month>12</Month><Day>07</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1746-8272</ISSN><JournalIssue CitedMedium="Internet"><Issue>48</Issue><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Nucleic acids symposium series (2004)</Title><ISOAbbreviation>Nucleic Acids Symp Ser (Oxf)</ISOAbbreviation></Journal><ArticleTitle>Molecular scanning of susceptibility genes for the development of coronary heart disease in Japanese.</ArticleTitle><Pagination><StartPage>159</StartPage><EndPage>160</EndPage><MedlinePgn>159-60</MedlinePgn></Pagination><Abstract>Genetic predisposition has been implicated in the development of coronary heart disease (CHD). We made a molecular scanning of several genetic polymorphisms to see whether they are associated with CHD in Japanese patients with type 2 diabetes mellitus. Among several polymorphisms, only a polymorphism of paraoxonase gene was confirmed to be associated with CHD in this population. This polymorphism seems to be important in the development of CHD in Japanese as well as in Caucasian population.
2,336,176
Discovering gene networks with a neural-genetic hybrid.
Recent advances in biology (namely, DNA arrays) allow an unprecedented view of the biochemical mechanisms contained within a cell. However, this technology raises new challenges for computer scientists and biologists alike, as the data created by these arrays is often highly complex. One of the challenges is the elucidation of the regulatory connections and interactions between genes, proteins and other gene products. In this paper, a novel method is described for determining gene interactions in temporal gene expression data using genetic algorithms combined with a neural network component. Experiments conducted on real-world temporal gene expression data sets confirm that the approach is capable of finding gene networks that fit the data. A further repeated approach shows that those genes significantly involved in interaction with other genes can be highlighted and hypothetical gene networks and circuits proposed for further laboratory testing.
2,336,177
Recent developments in celiac disease.
Celiac disease is a common disorder associated with a substantially increased standardized mortality ratio if it is left untreated or if the diagnosis is delayed. Diagnostic sensitivity of serologic testing is improved by the addition of IgG-based testing to standard IgA-based serologic testing for endomysial or transglutaminase autoantibodies. The role of intestinal permeability testing as an additional tool for screening and for monitoring the response to a gluten-free diet is discussed. The importance of diagnosing celiac disease in two clinical situations is considered: first, before immune-stimulating therapy with interferon for viral hepatitis is begun and second, in pregnancy when not only maternal but also paternal celiac disease may affect fetal outcome. The strong genetic component of the etiology of celiac disease is illustrated by a monozygotic twin concordance of nearly 90%, with susceptibility conveyed by human leukocyte antigen (HLA) genotypes DQ2 or DQ8 and one or more non-HLA genes. Progress toward identifying these genes from large linkage and association studies is reviewed.
2,336,178
Pediatric inflammatory bowel disease: clinical and therapeutic aspects.
Epidemiologic data suggest that the incidences of pediatric ulcerative colitis and Crohn disease continue to evolve with geographic variations. One study suggests that children with autism have a unique inflammatory bowel disorder that is associated with gastrointestinal symptoms. The appropriate use of new diagnostic tests and novel treatments for inflammatory bowel disease (IBD) needs to be clarified in the pediatric population. Because of concerns regarding sensitivity and specificity, serologic markers measuring anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies cannot yet replace conventional diagnostic testing for screening or diagnosis of pediatric IBD. Large, prospective, pediatric population-based studies still need to be performed to ascertain their use as a noninvasive screening tool. Genetic studies using thiopurine methyl transferase and measurement of 6-mercaptopurine metabolites appear to be valuable for management of pediatric patients with IBD, in assisting clinicians in optimizing therapeutic response to 6-mercaptopurine, and in identifying individuals at increased risk for drug-induced toxicity. Newer immunomodulatory agents also are being explored in pediatric IBD. Open pilot trials of infliximab (Remicade; Centocor, Malvern, PA) for the treatment of children with Crohn disease that does not respond to conventional management have demonstrated short-term efficacy and safety. Trials of tacrolimus for treatment of fulminant colitis in children have been disappointing.
2,336,179
[Interest in breast cancer genetic testing among Icelandic women.].
It is estimated that 6-10% of all breast cancers in Iceland can be attributed to inherited mutations in newly identified breast cancer susceptibility genes (BRCA1 and BRCA2). Before genetic testing becomes widely available in Iceland it is important to understand what motivates women s interest in undergoing testing as that will provide the data necessary for designing effective counseling interventions. Therefore, the aim of this population-based study was to examine interest in and predictors of interest in genetic testing among Icelandic women.</AbstractText>A randomly selected sample of 534 Icelandic women, who had not been previously diagnosed with breast cancer, completed questionnaires assessing, demographic/medical variables, interest in genetic testing, perceived risk of carrying mutations in BRCA1/2 genes, cancer-specific distress and perceived benefits and barriers of genetic testing. The mean age was 53.8 years and 197 of the women had at least one first degree-relative that had been diagnosed with breast cancer.</AbstractText>Interest in testing was high with 74% of the women indicating that they were interested in testing. Family history of breast cancer was unrelated to interest in testing whereas perceived risk of being a mutation carrier was significantly and positively related to interest in testing. Interest in testing was also significantly higher among younger women and among women with higher levels of cancer-specific distress. The most commonly cited reasons for wanting to be tested were to increase use of mammography screening and to learn if one s children were at risk for developing cancer. The most commonly citied reasons against being tested were fear of being mutation carrier and worry that test results would not stay confidential.</AbstractText>These results suggest that demand for genetic testing, once it becomes commercially available, among Icelandic women may be high even among women without family history of breast cancer. The results also suggest that genetic counseling needs to address women s breast cancer worries as that may increase the probability that the decision to undergo testing is based on knowledge rather than driven by breast cancer fear and distress.</AbstractText>
2,336,180
Perioperative management of a common disorder: hereditary haemochromatosis.
Hereditary haemochromatosis is the commonest autosomal recessive disorder affecting Caucasian populations, and is readily diagnosed on the basis of elevated total body iron stores and genetic testing. Increased awareness of this disease in the community will hopefully prompt earlier testing and diagnosis. Treatment with regular phlebotomy is simple and effective and can prevent significant morbidity and mortality. Preoperative evaluation of patients with this disorder should consider the potential multisystem involvement in iron overload.
2,336,181
Genotoxicity screening: the slow march to the future.
Genetic toxicology testing in drug discovery and development is slowly moving into the age of high-throughput screening (HTS). This has been helped by the development of new tools, as well as validation studies and data analysis to support their use in hit-to-lead or lead optimisation decisions. This review provides an overview of the current genetic toxicology methodologies and a few HTS methodologies. Comparisons are made between the predictivity of carcinogenesis that can be achieved in screening strategies as well as by the battery of regulatory tests. The importance of false-positive and false-negative calls at different stages in development is considered. There is a good prospect that in genetic toxicology, as in other areas of ADME-Tox, HTS will reduce the growing costs of carrying compounds with undesirable characteristics too far along the drug development process.
2,336,182
[How to improve the screening and diagnosis of fetal aneuploidy?].
In France, prenatal screening for fetal aneuploidies is legally regulated and is based on second-trimester maternal serum screening at 15-18 weeks. In 2000, 15% of all pregnant women in the Yvelines district of Greater Paris underwent amniocentesis, for a background risk of 11300. This high rate of invasive testing is unacceptable, given the risk of miscarriage and the financial cost. Between 2001 and 2003 we prospectively studied the acceptability and efficacy of screening for fetal aneuploidy in a large unselected population, using a risk calculation approach based on maternal age and serum markers, together with nuchal translucency at 11-14 weeks. A total of 14909 women with a mean age of 30.7 years [18-46] years were included. Pregnancy outcome was known in 93% of cases. The prevalence of trisomy 21 was 1/292 (51/14 909). Using a cut-off risk of 11250, the detection rate was 40/51 (78.4%). The combined risk was &gt; or = 1/250 in 422 women (2.9%). Thus, one case of trisomy was diagnosed per 10.6 invasive tests. The detection rate would be 85% for a 5% false-positive rate. Eleven cases of trisomy were not diagnosed in the first trimester, and five of these were detected at 20-24 weeks by ultrasound examination. There were 50 miscarriages, five of which (1%) followed CVS or amniocentesis. These results confirm those published over the past 12 years by authors using the same methodology and quality controls. Although the French national screening policy has successfully contained a trend towards more invasive testing (which now reaches nearly 50% in some parts of Italy), our results suggests that second-trimester screening has become obsolete and should be replaced by first-trimester screening and diagnosis. This approach would require appropriate quality controls and should be implemented at the regional level.
2,336,183
Nanostructured calcium phosphates for biomedical applications: novel synthesis and characterization.
Materials play a key role in several biomedical applications, and it is imperative that both the materials and biological aspects are clearly understood for attaining a successful biological outcome. This paper illustrates our approach to implement calcium phosphates as gene delivery agents. Calcium phosphates (CaP) belong to the family of biocompatible apatites and there are several CaP phases, the most ubiquitous being hydroxyapatite (HAp, Ca(10)(PO(4))(6)(OH)(2). Other CaP structures include brushite (B, CaHPO(4).2H(2)O) and tricalcium phosphate (TCP, Ca(3)(PO(4))(2)). Several low and high temperature approaches have been reported for synthesizing HAp and brushite, while TCP is primarily synthesized using high temperature methods. Novel low temperature chemical methods have been developed by us to synthesize nanostructured HAp, brushite and TCP phases. The new low temperature approach results in the formation of stoichiometric and nanosized HAp under physiological conditions. Moreover, the synthesis methods were designed to be biocompatible with biological systems such as cells, DNA and proteins so that the CaP structures can be studied for gene delivery. The use of HAp type CaP phases for gene delivery is well known but to our knowledge, other forms of CaP have not been studied for gene delivery due to the lack of a biocompatible synthesis method. In addition to the biocompatible synthesis of CaP structures, we have also performed ion substitution that would provide us the appropriate tools to study the DNA-to-particle interactions and assess how these ionic substitutions would affect the level of DNA uptake by the cell and then its release to the cell nucleus. Substitution of calcium by 14% magnesium results in the formation of crystalline ( approximately 20 mum) brushite platelets that remains stable at pH 7.5. Further substitution results in unique nanostructured spherical morphologies of brushite from which rosette shaped high specific surface area ( approximately 200 m(2)/g) nanocrystals ( approximately 80 nm) of beta-TCMP phase can be grown. The novelty lies in the formation of stable phases of HAp, brushite and beta-TCMP under physiological conditions making them potential candidates for use as carriers for non-viral gene delivery or more generally in biological systems. The resultant nanocrystalline phosphates have been characterized for their structure, morphology, thermal stability, and composition. Results of the in vitro transfection are also described.
2,336,184
Vicious circles: positive feedback in major evolutionary and ecological transitions.
Evolutionary biologists and ecologists often focus on equilibrium states that are subject to forms of negative feedback, such as optima for phenotypic traits or regulation of population sizes. However, recent theoretical and empirical studies show how positive feedback can be instrumental in driving many of the most important and spectacular processes in evolutionary ecology, including the evolution of sex and genetic systems, mating systems, life histories, complex cooperation in insects and humans, ecological specialization, species diversity, species ranges, speciation and extinction. Taken together, this work suggests that positive feedback is more common than is generally appreciated, and that its self-reinforcing dynamics generate the conditions for changes that might otherwise be difficult or impossible for selection or other mechanisms to achieve. Testing for positive feedback requires analysing each causal link in feedback loops, tracking genetic, character and population-dynamic changes across generations, and elucidating the conditions that can result in self-reinforcing change.
2,336,185
Genic capture and resolving the lek paradox.
The genic capture hypothesis offers a resolution to the question of how genetic variation in male sexually selected traits is maintained in the face of strong female preferences. The hypothesis is that male display traits are costly to produce and hence depend upon overall condition, which itself is dependent upon genes at many loci. Few attempts have been made to test the assumptions and predictions of the genic capture hypothesis rigorously and, in particular, little attention has been paid to determining the genetic basis of condition. Such tests are crucial to our understanding of the maintenance of genetic variation and in the evaluation of recent models that propose a role for sexual selection in the maintenance of sex. Here, we review approaches to testing the link between genetically determined condition and levels of sexual trait expression and consider the probable importance of deleterious mutations.
2,336,186
Structured antedependence models for functional mapping of multiple longitudinal traits.
In this article, we present a statistical model for mapping quantitative trait loci (QTL) that determine growth trajectories of two correlated traits during ontogenetic development. This model is derived within the maximum likelihood context, incorporated by mathematical aspects of growth processes to model the mean vector and by structured antedependence (SAD) models to approximate time-dependent covariance matrices for longitudinal traits. It provides a quantitative framework for testing the relative importance of two mechanisms, pleiotropy and linkage, in contributing to genetic correlations during ontogeny. This model has been employed to map QTL affecting stem height and diameter growth trajectories in an interspecific hybrid progeny of Populus, leading to the successful discovery of three pleiotropic QTL on different linkage groups. The implications of this model for genetic mapping within a broader context are discussed.
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Telling the difference between frontotemporal dementia and Alzheimer's disease.<Pagination><StartPage>628</StartPage><EndPage>632</EndPage><MedlinePgn>628-32</MedlinePgn></Pagination><Abstract><AbstractText Label="PURPOSE OF REVIEW" NlmCategory="OBJECTIVE">A precise diagnosis of the cause of dementia during life is needed for proper management, in order to explain the symptoms to the patient and to the close relatives, and to give appropriate indications on the prognosis and possibly on the genetic risk. Frontotemporal dementia remains under-diagnosed and often misdiagnosed for Alzheimer's disease, the most common cause of dementia. More and more studies explore the differences between the two syndromes.</AbstractText><AbstractText Label="RECENT FINDINGS" NlmCategory="RESULTS">Progress in neuropsychological testing improves the ability to distinguish between syndromes and knowledge on brain functioning. More attention has been paid over these last months--or years--on emotion, insight, behavior, artistic creativity and quality of responses. Yet, biomarkers do not improve the diagnostic accuracy of trained clinicians, and do not help to distinguish between histological subtypes of frontotemporal dementia.</AbstractText><AbstractText Label="SUMMARY" NlmCategory="CONCLUSIONS">Improvement in knowledge on cognitive and emotional impairment in frontotemporal dementia and Alzheimer's disease is essential for the management of the patient--information can be given to the patients and the families that helps them to understand and to behave in consequence.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pasquier</LastName><ForeName>Florence</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Memory Clinic, Department of Neurology, University Hospital, Lille, France. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Curr Opin Psychiatry</MedlineTA><NlmUniqueID>8809880</NlmUniqueID><ISSNLinking>0951-7367</ISSNLinking></MedlineJournalInfo></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16639086</ArticleId><ArticleId IdType="doi">10.1097/01.yco.0000185988.05741.2a</ArticleId><ArticleId IdType="pii">00001504-200511000-00005</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16628879</PMID><DateCompleted><Year>2006</Year><Month>09</Month><Day>29</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1134-7198</ISSN><JournalIssue CitedMedium="Internet"><Issue>23</Issue><PubDate><Year>2005</Year><Season>Jul-Dec</Season></PubDate></JournalIssue><Title>Revista de derecho y genoma humano = Law and the human genome review</Title><ISOAbbreviation>Rev Derecho Genoma Hum</ISOAbbreviation></Journal>Gene tests and employees in an international comparison.
In this research, Professor J&#xfc;rgen Simon and Christian Ravenstein have highlighted the general existing prohibition, in the labour field, of the undertaking of genetic tests that could mean discrimination for the genetic heritage of the worker. They have made a comparative study of several member States of the EU that have specific regulation on this area.
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Plasmid vaccines and therapeutics: from design to applications.<Pagination><StartPage>41</StartPage><EndPage>92</EndPage><MedlinePgn>41-92</MedlinePgn></Pagination><Abstract><AbstractText>In the late 1980s, Vical and collaborators discovered that the injection into tissues of unformulated plasmid encoding various proteins resulted in the uptake of the plasmid by cells and expression of the encoded proteins. After this discovery, a period of technological improvements in plasmid delivery and expression and in pharmaceutical and manufacturing development was quickly followed by a plethora of human clinical trials testing the ability of injected plasmid to provide therapeutic benefits. In this chapter, we summarize in detail the technologies used in the most recent company-sponsored clinical trials and discuss the potential for future improvements in plasmid design, manufacturing, delivery, formulation and administration. A generic path for the clinical development of plasmid-based products is outlined and then exemplified using a case study on the development of a plasmid vaccine from concept to clinical trial.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Manthorpe</LastName><ForeName>Marston</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Vical Incorporated, San Diego, CA 92121, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hobart</LastName><ForeName>Peter</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Hermanson</LastName><ForeName>Gary</ForeName><Initials>G</Initials></Author><Author ValidYN="Y"><LastName>Ferrari</LastName><ForeName>Marilyn</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Geall</LastName><ForeName>Andrew</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Goff</LastName><ForeName>Blake</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Rolland</LastName><ForeName>Alain</ForeName><Initials>A</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Adv Biochem Eng Biotechnol</MedlineTA><NlmUniqueID>8307733</NlmUniqueID><ISSNLinking>0724-6145</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D022122">Anthrax Vaccines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014614">Vaccines, Synthetic</NameOfSubstance></Chemical><Chemical><RegistryNumber>9007-49-2</RegistryNumber><NameOfSubstance UI="D004247">DNA</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D022122" MajorTopicYN="N">Anthrax Vaccines</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration &amp; dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001483" MajorTopicYN="N">Base Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002986" MajorTopicYN="N">Clinical Trials as Topic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004247" MajorTopicYN="N">DNA</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004742" MajorTopicYN="N">Enhancer Elements, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008969" MajorTopicYN="N">Molecular Sequence Data</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010957" MajorTopicYN="Y">Plasmids</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011401" MajorTopicYN="N">Promoter Regions, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013728" MajorTopicYN="N">Terminator Regions, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014614" MajorTopicYN="N">Vaccines, Synthetic</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration &amp; dosage</QualifierName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading></MeshHeadingList><NumberOfReferences>257</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>3</Month><Day>30</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>6</Month><Day>20</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>3</Month><Day>30</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16568888</ArticleId><ArticleId IdType="doi">10.1007/10_003</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">16562356</PMID><DateCompleted><Year>2006</Year><Month>05</Month><Day>16</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1546-6426</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Genetics and genetic engineering</Title><ISOAbbreviation>Genet Genet Eng</ISOAbbreviation></Journal>Ethical issues and public opinion.<Pagination><StartPage>133</StartPage><EndPage>141</EndPage><MedlinePgn>133-41</MedlinePgn></Pagination><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wexler</LastName><ForeName>Barbara</ForeName><Initials>B</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Genet Genet Eng</MedlineTA><NlmUniqueID>101196690</NlmUniqueID><ISSNLinking>1546-6426</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D001709" MajorTopicYN="N">Biotechnology</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D033041" MajorTopicYN="Y">Embryo Research</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D035082" MajorTopicYN="N">Federal Government</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005380" MajorTopicYN="N">Financing, Government</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005818" MajorTopicYN="N">Genetic Engineering</DescriptorName><QualifierName UI="Q000523" MajorTopicYN="Y">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName><QualifierName UI="Q000523" MajorTopicYN="Y">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016045" MajorTopicYN="N">Human Genome Project</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011639" MajorTopicYN="Y">Public Opinion</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012109" MajorTopicYN="N">Research Support as Topic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018570" MajorTopicYN="N">Risk Assessment</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013234" MajorTopicYN="Y">Stem Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014481" MajorTopicYN="N" Type="Geographic">United States</DescriptorName></MeshHeading></MeshHeadingList><OtherID Source="KIE">125753</OtherID><OtherID Source="NRCBL">QH430.W49 2004</OtherID><KeywordList Owner="KIE"><Keyword MajorTopicYN="N">Biomedical and Behavioral Research</Keyword><Keyword MajorTopicYN="N">Empirical Approach</Keyword><Keyword MajorTopicYN="N">Genetics and Reproduction</Keyword></KeywordList><GeneralNote Owner="KIE">KIE Bib: embryo and fetal research; genetic intervention; genetic screening</GeneralNote></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>3</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>5</Month><Day>17</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>3</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16562356</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">16562354</PMID><DateCompleted><Year>2006</Year><Month>05</Month><Day>16</Day></DateCompleted><DateRevised><Year>2017</Year><Month>11</Month><Day>16</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1546-6426</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year></PubDate></JournalIssue><Title>Genetics and genetic engineering</Title><ISOAbbreviation>Genet Genet Eng</ISOAbbreviation></Journal>Genetic testing.
In the late 1980s, Vical and collaborators discovered that the injection into tissues of unformulated plasmid encoding various proteins resulted in the uptake of the plasmid by cells and expression of the encoded proteins. After this discovery, a period of technological improvements in plasmid delivery and expression and in pharmaceutical and manufacturing development was quickly followed by a plethora of human clinical trials testing the ability of injected plasmid to provide therapeutic benefits. In this chapter, we summarize in detail the technologies used in the most recent company-sponsored clinical trials and discuss the potential for future improvements in plasmid design, manufacturing, delivery, formulation and administration. A generic path for the clinical development of plasmid-based products is outlined and then exemplified using a case study on the development of a plasmid vaccine from concept to clinical trial.
2,336,189
The evolving role of proteomics in the early detection of breast cancer.
There has been emerging interest in the examination of tumor protein expression (proteomics) as a means to identify novel diagnostic and therapeutic targets in women with breast cancer. Specifically, several investigators have examined biological fluids (serum and breast ductal fluid) and breast tissue in an attempt to detect novel proteomic profiles in women with breast carcinoma. The current tools of proteomic research are evolving, but include two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Initial studies have identified several unique biomarkers and proteomic profiles that were able to discriminate between non-cancer and breast cancer patients. In the future, the application of large-scale proteomic technology may provide a means of early detection, surveillance, and identification of potential therapeutic targets.
2,336,190
Identifying genetic variation affecting a complex trait in simulated data: a comparison of meta-analysis with pooled data analysis.
We explored the power and consistency to detect linkage and association with meta-analysis and pooled data analysis using Genetic Analysis Workshop 14 simulated data. The first 10 replicates from Aipotu population were used. Significant linkage and association was found at all 4 regions containing the major loci for Kofendrerd Personality Disorder (KPD) using both combined analyses although no significant linkage and association was found at all these regions in a single replicate. The linkage results from both analyses are consistent in terms of the significance level of linkage test and the estimate of locus location. After correction for multiple-testing, significant associations were detected for the same 8 single-nucleotide polymorphisms (SNP) in both analyses. There were another 2 SNPs for which significant associations with KPD were found only by pooled data analysis. Our study showed that, under homogeneous condition, the results from meta-analysis and pooled data analysis are similar in both linkage and association studies and the loss of power is limited using meta-analysis. Thus, meta-analysis can provide an overall evaluation of linkage and association when the original raw data is not available for combining.
2,336,191
Analysis of binary traits: testing association in the presence of linkage.
Most methods for testing association in the presence of linkage, using family-based studies, have been developed for continuous traits. FBAT (family-based association tests) is one of few methods appropriate for discrete outcomes. In this article we describe a new test of association in the presence of linkage for binary traits. We use a gamma random effects model in which association and linkage are modelled as fixed effects and random effects, respectively. We have compared the gamma random effects model to an FBAT and a generalized estimating equation-based alternative, using two regions in the Genetic Analysis Workshop 14 simulated data. One of these regions contained haplotypes associated with disease, and the other did not.
2,336,192
Identifying susceptibility genes by using joint tests of association and linkage and accounting for epistasis.
Simulated Genetic Analysis Workshop 14 data were analyzed by jointly testing linkage and association and by accounting for epistasis using a candidate gene approach. Our group was unblinded to the "answers." The 48 single-nucleotide polymorphisms (SNPs) within the six disease loci were analyzed in addition to five SNPs from each of two non-disease-related loci. Affected sib-parent data was extracted from the first 10 replicates for populations Aipotu, Kaarangar, and Danacaa, and analyzed separately for each replicate. We developed a likelihood for testing association and/or linkage using data from affected sib pairs and their parents. Identical-by-descent (IBD) allele sharing between sibs was explicitly modeled using a conditional logistic regression approach and incorporating a covariate that represents expected IBD allele sharing given the genotypes of the sibs and their parents. Interactions were accounted for by performing likelihood ratio tests in stages determined by the highest order interaction term in the model. In the first stage, main effects were tested independently, and in subsequent stages, multilocus effects were tested conditional on significant marginal effects. A reduction in the number of tests performed was achieved by prescreening gene combinations with a goodness-of-fit chi square statistic that depended on mating-type frequencies. SNP-specific joint effects of linkage and association were identified for loci D1, D2, D3, and D4 in multiple replicates. The strongest effect was for SNP B03T3056, which had a median p-value of 1.98 x 10(-34). No two- or three-locus effects were found in more than one replicate.
2,336,193
Olfactory function in people with genetic risk of dementia.<Pagination><StartPage>46</StartPage><EndPage>50</EndPage><MedlinePgn>46-50</MedlinePgn></Pagination><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Screening for sensorial impairment is a secondary objective in the context of neurodegenerative diseases, including dementias. For example, olfactory dysfunction is among the first signs of Alzheimer's disease. There has been no study of olfactory function in Irish subjects at risk of dementia.</AbstractText><AbstractText Label="AIM" NlmCategory="OBJECTIVE">To investigate olfactory function in non-demented Irish persons, who carry genetic risk factors for dementia.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">Thirty-eight Irish adult subjects, who are at risk of dementia, were recruited. Cognitive performance and olfactory function were assessed and apolipoprotein E (APOE) genotype determined.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">Three and six subjects had a Mini Mental State Examination (MMSE) and Brief Smell Identification Test (B-SIT) score, respectively, outside the normal range. While five out of the fifteen epsilon-4 allele positive subjects had B-SIT scores outside the normal range, only one out of the twenty-three epsilon-4 allele negative subjects had; the difference in this frequency was significant (P=0.025). There was no significant difference (P=0.266) in the frequency of abnormal MMSE scores between epsilon-4 allele groups.</AbstractText><AbstractText Label="CONCLUSION" NlmCategory="CONCLUSIONS">Further investigation is required to explore the reasons for the higher prevalence of olfactory dysfunction in epsilon-4 allele positive subjects.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Salerno-Kennedy</LastName><ForeName>R</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Dept of Food and Nutritional Sciences, University College, Cork. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cusack</LastName><ForeName>S</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Cashman</LastName><ForeName>K D</ForeName><Initials>KD</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Ireland</Country><MedlineTA>Ir J Med Sci</MedlineTA><NlmUniqueID>7806864</NlmUniqueID><ISSNLinking>0021-1265</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001057">Apolipoproteins E</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D017677" MajorTopicYN="N">Age Distribution</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000483" MajorTopicYN="N">Alleles</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000544" MajorTopicYN="N">Alzheimer Disease</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001057" MajorTopicYN="N">Apolipoproteins E</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003072" MajorTopicYN="N">Cognition Disorders</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015331" MajorTopicYN="N">Cohort Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003704" MajorTopicYN="N">Dementia</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005500" MajorTopicYN="N">Follow-Up Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020022" MajorTopicYN="N">Genetic Predisposition to Disease</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="Y">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015994" MajorTopicYN="N">Incidence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007494" MajorTopicYN="N" Type="Geographic">Ireland</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000857" MajorTopicYN="N">Olfaction Disorders</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018570" MajorTopicYN="N">Risk Assessment</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012720" MajorTopicYN="N">Severity of Illness Index</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017678" MajorTopicYN="N">Sex Distribution</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>2</Month><Day>1</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>3</Month><Day>1</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>2</Month><Day>1</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16445161</ArticleId><ArticleId IdType="doi">10.1007/BF03168982</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>J Geriatr Psychiatry Neurol. 2003 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Khir</ISOAbbreviation></Journal>[The models of hepatic insufficiency and encephalopathy in animals].
The majority of the investigation methods of biochemical, morphological and metabolic disorders in hepatic insufficiency and encephalopathy occurrence are inadequate in use in clinical conditions because their invasiveness frequently creates dangerous situations to the patient life and health. That's why, to characterize the mechanisms, constituting the hepatic and cerebral damages base, for testing of a new medicinal preparations, aprobation of a new theoretical and clinical hypotheses, the models of an acute and chronic hepatic insufficiency are applied on the animals, permitting to unify the age, genetic peculiarities and physiological parameters of the individuals involved in experiments, the pathology character, its severity and longevity. Homogeneity of these indexes permits to estimate molecular, structural and functional disorders, laying in the base of pathological process. We have analyzed the experimental models of hepatic insufficiency, basing on the hepatotoxins usage--acetaminophen (paracetamol), carbon tetrachloride, thioacetamide, D-galactosamine, concanavalin A, lipopolysaccharides. Every existing pharmacological model of hepatic insufficiency and encephalopathy for animals owes its own advantages and faults. The choice of a model depends on tasks of the investigation and of the animal species, involved in the procedures.
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Support versus corroboration.
Numerous metrics have been developed that attempt to assess the reliability of phylogenetic trees. Several of these commonly used measures of tree and tree branch support are described and discussed in the context of their relationship to Popperian corroboration. Claims that measures of support indicate the accuracy of phylogenetic trees or provide information for tree choice are rebutted. Measures of support are viewed as being of heuristic value within a given phylogenetic framework for describing the precision of the data based on perturbations to the data. However, no direct link is observed between the calculation of measures of support and corroboration. Direct measures of support, but not re-sampling or randomization methods, may play a more specific role in phylogenetic inference by providing the tools to search for falsifiers that could be the subject of future rounds of hypothesis testing.
2,336,195
[Hereditary non polyposis colon cancer--basic principle and ethical considerations].
HNPCC is a hereditary cancer syndrome of several organs but more particularly the colon and the uterus. It is characterized by microsatellite instability (MSI) related to mutations of DNA mismatch repair (MMR) genes. The role of the pathologist in the detection of colorectal cancer with MSI phenotype is important. Among the available tests to detect MSI, immunohistochemistry appears being a sensitive, specific and inexpensive test. The detection of HNPCC syndrome by the genetic test among the MSI cancers implies a coordination of the structures of health and requires a follow-up of the patients, during and after the genetic test. Ethical dimension related to these hereditary cancers must be considered without constituting a brake for their detection.
2,336,196
The evolution of genetic architecture. I. Diversification of genetic backgrounds by genetic drift.
The genetic architecture of a phenotype plays a critical role in determining phenotypic evolution through its effects on patterns of genetic variation. Genetic architecture is often considered to be constant in evolutionary quantitative genetic models. However, genetic architecture may be variable and itself evolve when there are dominance and epistatic interactions among alleles at the same and different loci, respectively. The evolution of genetic architecture by genetic drift is examined here by testing the breeding value of four standard inbred mouse strains mated across a set of 26 related recombinant quasi-inbred (RqI) lines generated from the intercross of the Large (LG/J) and Small (SM/J) inbred mouse strains. Phenotypes of interest include age-specific body weights, growth, and adult body composition. If the genetic architecture of these traits has differentiated by genetic drift during the production of the RqI strains, we should observe interactions between tester strain and RqI strain. The breeding values of the tester strains will change relative to one another depending on which RqI strain they are crossed to. The study included an average of 15.1 offspring per cross, over a total of 100 different crosses. Multivariate and univariate analyses of variance indicate that there is strongly significant interaction for all traits. Interaction is more pronounced in males than in females and accounted for an average of about 40% of the explained variation in males and 30% in females. These results indicate that the genetic architecture of these traits has differentiated by genetic drift in the RqI strains since their isolation from a common founder population. Further analysis indicates that this differentiation results in changes in the order of tester strain effects so that common patterns of selection in these differentiated populations could result in the fixation of different alleles.
2,336,197
Identification of amyloid-beta 1-42 binding protein fragments by screening of a human brain cDNA library.
Extracellular and intraneuronal formation of amyloid-beta (Abeta) deposits have been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of Abeta neurotoxicity is not completely understood. Previous studies suggest that binding of Abeta with a number of targets have deleterious effects on cellular functions. It has been shown that Abeta directly interacted with intracellular protein ERAB (endoplasmic reticulum amyloid beta-peptide-binding protein) also known as ABAD (Abeta-binding alcohol dehydrogenase) resulting in mitochondrial dysfunction and cell death. In the present study we have identified another mitochondrial enzyme, ND3 of the human complex I, that binds to Abeta1-42 by the screening of a human brain cDNA library expressed on M13 phage. Our results indicated a strong interaction between Abeta and a phage-displayed 25 amino acid long peptide TTNLPLMVMSSLLLIIILALSLAYE corresponding to C-terminal peptide domain of NADH dehydrogenase, subunit 3 (MTND3) encoded by mitochondrial DNA (mtDNA). This interaction may explain, in part, the inhibition of complex I activity in astrocytes and neurons in the presence of Abeta, described recently. To our knowledge, the present study is the first demonstration of interaction between Abeta and one of the subunits of the human complex I.
2,336,198
Hereditary ataxia and behavior.
Recognizing cognitive deficits and psychiatric disorders in patients with autosomal dominant ataxias is relatively new. At this time, the percentage of patients with these disorders who experience changes in cognition or psychiatric symptoms is unknown. Cognitive impairment, when seen, is often found on tests of executive function, probably reflecting disruption of afferent and efferent pathways of the prefrontal cortex and subcortical structures, including the cerebellum. Widespread global dysfunction does occur in some cases, especially later in the disease course. Psychiatric symptoms including depression, aggression, irritability, and psychosis have all been reported. As these behavioral changes receive further study, one hopes that guidelines for treating these symptoms will emerge. Clinicians should be mindful of the psychosocial effects that genetic testing for the hereditary ataxias may have, especially in cases of predictive testing for those who are asymptomatic but at risk because of family history. Guidelines established for genetic testing in HD may be helpful when approaching these cases.
2,336,199
Hydrogel-beta-TCP scaffolds and stem cells for tissue engineering bone.
Trabecular bone is a material of choice for reconstruction after trauma and tumor resection and for correction of congenital defects. Autologous bone grafts are available in limited shapes and sizes; significant donor site morbidity is another major disadvantage to this approach. To overcome these limitations, we used a tissue engineering approach to create bone replacements in vitro, combining bone-marrow-derived differentiated mesenchymal stem cells (MSCs) suspended in hydrogels and 3-dimensionally printed (3DP) porous scaffolds made of beta-tricalcium-phosphate (beta-TCP). The scaffolds provided support for the formation of bone tissue in collagen I, fibrin, alginate, and pluronic F127 hydrogels during culturing in oscillating and rotating dynamic conditions. Histological evaluation including toluidine blue, alkaline phosphatase, and von Kossa staining was done at 1, 2, 4, and 6 weeks. Radiographic evaluation and high-resolution volumetric CT (VCT) scanning, expression of bone-specific genes and biomechanical compression testing were performed at 6 weeks. Both culture conditions resulted in similar bone tissue formation. Histologically collagen I and fibrin hydrogels specimens had superior bone tissue, although radiopacities were detected only in collagen I samples. VCT scan revealed density values in all but the Pluronic F127 samples, with Houndsfield unit values comparable to native bone in collagen I and fibrin glue samples. Expression of bone-specific genes was significantly higher in the collagen I samples. Pluronic F127 hydrogel did not support formation of bone tissue. All samples cultured in dynamic oscillating conditions had slightly higher mechanical strength than under rotating conditions. Bone tissue can be successfully formed in vitro using constructs comprised of collagen I hydrogel, MSCs, and porous beta-TCP scaffolds.