text
stringlengths 11
9.77k
| label
stringlengths 2
104
|
|---|---|
To find potential type III secretion system (T3SS) inhibitors against citrus canker caused by Xanthomonas citri subsp. citri (Xcc), a new series of 5-phenyl-2-furan carboxylic acid derivatives stitched with 2-mercapto-1,3,4-thiadiazole were designed and synthesized. Among the 30 compounds synthesized, 14 compounds significantly inhibited the promoter activity of a harpin gene hpa1. Eight of the 14 compounds did not affect the growth of Xcc, but significantly reduced the hypersensitive response (HR) of tobacco and decreased the pathogenicity of Xcc on citrus plants. Subsequent studies have demonstrated that these inhibitory molecules effectively suppress the T3SS of Xcc and significantly impair the pathogen's ability to subvert citrus immunity, resulting in a reduction in the level of disease progression. As a result, our work has identified a series of potentially attractive agents for the control of citrus canker. | Type III Secretion Systems |
The recent article by Costa and Klein (2006) contains several inaccuracies about the federal drinking water standard for chromium. The federal drinking water standard for chromium is 100 ppb, not 50 ppb as stated by Costa and Klein, and it is based on non-carcinogenic effects, not a one in one million cancer risk level. The question of whether or not hexavalent chromium is carcinogenic via the oral route is the focus of much current interest and has major implications for regulation of chromium in drinking water and soil. The chronic drinking water study of hexavalent chromium currently being conducted by the National Toxicology Program will provide further information that will be useful in addressing this question. | Chromium Compounds |
Marine soft corals are known as a good source of biologically active compounds, among which a large number of steroid compounds are identified. Structures and activities of these compounds have been used in drug discovery and development. From 2015 to 2020, 179 new steroid compounds were isolated from soft corals and structurally characterized. In this review, we report the structural classification and bioactivities of these compounds. The largest group of steroids from soft corals are hydroxysteroids, while the most common biological activity is anticancer. Besides, anticancer hydroxysteroids from soft corals exhibit anti-inflammatory and antibacterial activity. Unlike anticancer and antibacterial activity that can be observed in a number of steroid classes, antioxidant activity and antileishmanial effect were observed only in 19-oxygenated steroids, antiviral activity in pregnane-type steroids and spirosteroids, immunosuppressive activity in epoxy- and epidioxysteroids, and antibacterial activity in two steroid classes, hydroxysteroids and ketosteroids. This systematically analyzed link between the structure and activity of natural marine steroids is a good starting point for future drug design. | Hydroxysteroids |
Although several classic anatomic studies describing the number, location, size, and weight of normal parathyroid glands have been reported, as detailed description of the parathyroid glands in a large series of patients with primary hyperparathyroidism has not been available. Drawings were made of the exact locations of each of the normal and enlarged parathyroid glands identified, immediately following neck explorations in all patients with primary hyperparathyroidism during a 4-year period (1977 to 1981). The enlarged glands were also measured and weighed after excision. The records of 273 patients were reviewed. Single gland enlargement (adenoma) was found in 218 patients (80%). Hyperplasia of all identified parathyroid glands was found in 42 patients (15%). Two adenomas (at least two other glands grossly and microscopically normal) were found in seven patients (2.6%). Seven patients (2.6%) with biochemical evidence of the disease had only normal glands at neck exploration. Adenomas in ectopic locations were frequent. However, their locations, with few exceptions, were predictable. The larger an adenoma, the more likely it was to be ectopic. Right superior gland adenomas (mean size 2.6 cm) were ectopic in 39%. Left superior glands (mean size 2.62 cm) were ectopic in 36%. No superior parathyroid adenomas were intrathyroidal. five of 223 (2%) adenomas were entirely surrounded by thyroid parenchyma in the lower pole. Nearly all inferior gland adenomas within the thymus could be readily excised through the cervical incision. In the seven cases in which only normal parathyroids were identified, no fewer than three glands wer proven in each. Three patients have had subsequent mediastinal exploration and excision of an adenoma. This failure rate of cervical exploration (4%) is attributed to mediastinal adenomas, and a second adenoma, and incorrect diagnosis. An awareness of the frequency of ectopic adenomas and their usual locations is of considerable benefit to the surgeon. Identification of the normal glands is of great importance as the search for a specific missing gland (adenoma) can be conducted in a logical sequence based on anatomic and embryologic knowledge of the parathyroids. | Parathyroid Glands |
Two new sesquiterpenoids, 4,5-epoxy-13-methoxy-1(10)-germacren-12,6-olide and 4,5-epoxy-13-acetoxy-1(10)-germacren-12,6-olide, were isolated from the leaves of Magnolia grandiflora, together with six known compounds, 2alpha-hydroxy-dihydroparthenolide, parthenolide, costunolide, syringaresinol, (+) medioresinol and 6,7-dimethoxycoumarin. The structures of the new compounds were elucidated on the basis of spectroscopic methods and X-ray diffraction. | Magnoliaceae |
Implicit bias and microaggressions are well-known phenomenon and have recently been acknowledged as contributing to health care disparities. Within Hand Surgery, implicit bias and microaggressions occur in patient-surgeon, surgeon-peer, surgeon-staff, and training environment interactions. Although racial and gender biases are well studied, biases can also be based on age, sexual orientation, socioeconomic background, and/or hierarchal rank. Academia has well-documented evidence of implicit bias and microaggressions, contributing to current disparate demographics of trainees, physicians, and leaders within Hand Surgery. Awareness is fundamental to combating bias and microaggressions; however, actions must be taken to minimize negative effects and change culture. | Bias, Implicit |
OBJECTIVES: To evaluate the performance of international medical graduates in the MRCOG Part 1 and Part 2 written examinations. STUDY DESIGN: Using the database of the Royal College of Obstetricians and Gynaecologists, a retrospective analysis was performed of the performance of overseas candidates who appeared for the first time in the Part 1 (n=11,863) and Part 2 written (n=5336) MRCOG examinations between 2000 and 2010. Candidates were grouped according to the RCOG geographical bands. RESULTS: In the Part 1 MRCOG examination the graduates of band E (India and Pakistan) and band B (Australia, New Zealand and Canada) performed well (pass rate 41.2% and 39.3% respectively) but the candidates of band C (East Africa 27.1%) and bands J and A (Europe 29.9%, Ireland 17.9%) underperformed. In the MRCOG Part 2 written examination the medical graduates of band D (Singapore and Hong Kong) and band B (Australia, New Zealand and Canada) performed well (pass rates 65.9% and 54.8%), but the candidates of band H (Middle East, pass rate 8.5%) and band C (Africa West, pass rate 12.7%) performed worse than the remaining cohort. The greatest number of candidates in the Part 2 written examinations appeared from India and Pakistan (n=2999, pass rate 22.2%). CONCLUSION: Our results have shown that there is variation in performance among the IMG from different geographical regions in the Part 1 and Part 2 written MRCOG examinations. | Foreign Medical Graduates |
The evolution of self-fertilization is one of the most commonly traversed transitions in flowering plants, with profound implications for population genetic structure and evolutionary potential. We investigated factors influencing this transition using Witheringia solanacea, a predominantly self-incompatible (SI) species within which self-compatible (SC) genotypes have been identified. We showed that self-compatibility in this species segregates with variation at the S-locus as inherited by plants in F1 and F2 generations. To examine reproductive assurance and the transmission advantage of selfing, we placed SC and SI genotypes in genetically replicated gardens and monitored male and female reproductive success, as well as selfing rates of SC plants. Self-compatibility did not lead to increased fruit or seed set, even under conditions of pollinator scarcity, and the realized selfing rate of SC plants was less than 10%. SC plants had higher fruit abortion rates, consistent with previous evidence showing strong inbreeding depression at the embryonic stage. Although the selfing allele did not provide reproductive assurance under observed conditions, it also did not cause pollen discounting, so the transmission advantage of selfing should promote its spread. Given observed numbers of S-alleles and selfing rates, self-compatibility should spread even under conditions of exceedingly high initial inbreeding depression." | Self-Incompatibility in Flowering Plants |
Daily rhythms for hormonal traits are likely widespread and important aspects of organismal (e.g., life history) adaptation. Yet they remain substantially understudied, especially with respect to variable rhythms within species. The cricket, Gryllus firmus, exhibits a genetically polymorphic circadian rhythm for the blood titer of the key hormone, juvenile hormone (JH). Gryllus firmus is also wing-polymorphic, consisting of a dispersing morph that delays reproduction and a flightless morph with substantially enhanced egg production. JH circadian phenotype strongly covaries with morph type: The blood JH titer is strongly rhythmic in multiple populations artificially-selected for the dispersing morph (LW(f) = long wings with functional flight muscles) and is essentially arrhythmic in populations selected for the SW (short-winged) morph. Association between JH titer cycle and LW(f) morph is also found in natural populations of G. firmus and in several related species in the field. This is one of the very few studies of endocrine titer variation in natural populations of an insect. The morph-specific cycle is underlain by a circadian rhythm in hormone biosynthesis, which in turn is underlain by a rhythm in a brain neuropeptide regulator of JH biosynthesis. The morph-specific JH titer circadian cycle is also strongly correlated with a morph-specific daily rhythm in global gene expression. This is currently the only example of a genetically-variable hormone circadian rhythm in both the laboratory and field that is strongly associated with an ecologically important polymorphism. The extensive information on the underlying causes of the morph-specific JH titer rhythm, coupled with the strong association between the JH circadian rhythm and wing polymorphism makes this system in G. firmus an exceptional experimental model to investigate the mechanisms underlying circadian hormonal adaptations. Genetic polymorphism for the JH titer circadian rhythm in G. firmus is discussed in context of circadian rhythms for endocrine traits reported for vertebrates and insects. Consequences of the failure to identify endocrine circadian rhythms on the accuracy of estimation of quantitative-genetic parameters, such as heritability and correlations between hormonal and fitness-related traits, are also discussed. | Gryllidae |
Injectable antibacterial hydrogels have attracted considerable attention in wound management. However, the development of injectable hydrogels with excellent antibacterial activity, good biocompatibility, and strong tissue adhesion remains a challenge. In this study, an antibacterial tissue-adhesive hydrogel was developed based on a catalyst-free o-phthalaldehyde (OPA)/amine reaction by simply mixing OPA-terminated four-arm poly(ethylene glycol) (4aPEG-OPA) and epsilon-poly-l-lysine (epsilon-PLL) solutions. The hydrogel showed tunable gelation time, storage moduli, and degradation rate depending on the polymer concentration and 4aPEG-OPA/epsilon-PLL mass ratio. The hydrogel exhibited nearly 100% bacterial inhibition rates in-vitro against Gram-negative E. coli and Gram-positive S. aureus, while maintaining good biocompatibility. The hydrogel matched well in shape and tightly adhered to the tissue after in-situ formation at the wound sites. Following the treatment of rat models of full-thickness skin incisions and round wounds, the hydrogel effectively closed the wounds and promoted wound healing. Moreover, after administering to S. aureus infected full-thickness skin wounds, the hydrogel exhibited remarkable efficacy in inhibiting wound infection with a bacterial inhibition rate over 99.94%, achieving a significantly accelerated wound healing compared with the commercially available Prontosan(R) gel. Therefore, the hydrogel exhibits great potential as a wound dressing for infection prevention and promotion of healing. | o-Phthalaldehyde |
Three Influenza A virus (H9N2) isolates obtained from three separate broiler flocks with variable mortality rates were cloned twice in embryonated SPF chicken eggs by limiting dilution. Biological properties of these isolates were examined in 4-week-old SPF chickens and chick embryo fibroblast (CEF) cultures. The isolates neither caused mortality in the inoculated chickens nor produced CPE in cell cultures, indicating low pathogenicity. PCR products of 486 bp containing the sequences for hemagglutinin (HA) cleavage site, which were generated from the isolates, were subjected to nucleotide sequencing. Sequence analysis of the HA region containing the cleavage site of the isolates showed a similar sequence motif (PARSSRG) but different flanking regions. Phylogenetic analysis of deduced amino acid sequences revealed that the isolates were closely related to those isolated earlier, indicating a common source. Moreover. the amino acid sequences of the recent isolates were very similar to those from Saudi Arabia, Germany and Pakistan. It is postulated that, except for some Chinese isolates, the pathogenicity of Iranian isolates seems to be similar to that of other Eurasian isolates. It is possible that an elevation in mortality rate under field condition could be caused by co-infection of recent isolates with the bacteria such as mycoplasma, Escherichia coli, and Ornithobacterium rhinotracheale rather than by an emerging a pathogenic H9N2 subtype of the virus." | Influenza A Virus, H9N2 Subtype |
We studied the ultrastructural changes in gilts' pineal gland after the oral administration of melatonin in dose 3 mg once daily (in ethanol vehicle) for 46 consecutive days. Appearance of the pinealocytes containing numerous secretory granules and an enlarged Golgi apparatus was the most visible effect of the melatonin administration. The melatonin treatment caused also some differences in the structure of pinealocytes with cytoplasmic dense bodies. The present results suggest that the orally administered melatonin had some effects on pigs' pineal gland. | Epithalamus |
Regional populations and their migrations are analysed as a system of populations. Such a system can be studied by multiregional models constructed on the basis of the multiregional approach. The results thus achieved may substantially differ from those received by the conventional approach. The theoretical formulations are illustrated by empirical studies of the rural and urban population of Bulgaria in 1960-1982." (summary in ENG, RUS)" | Population |
Cued recall with an extralist cue poses a challenge for contemporary memory theory in that there is a need to explain how episodic and semantic information are combined. A parallel activation and intersection approach proposes one such means by assuming that an experimental cue will elicit its preexisting semantic network and a context cue will elicit a list memory. These 2 sources of information are then combined by focusing on information that is common to the 2 sources. Two key predictions of that approach are examined: (a) Combining semantic and episodic information can lead to item interactions and false memories, and (b) these effects are limited to memory tasks that involve an episodic context cue. Five experiments demonstrate such item interactions and false memories in cued recall but not in free association. Links are drawn between the use of context in this setting and in other settings. | Repression, Psychology |
The advance in nursing care for stoma patients is a challenging issue, which will influence the life quality. The quality of life is a major issue in the recovery of stoma patients. The evidence of experimental nursing has not been explored enough. A systematic search and a meta-analysis were performed for the studies of experimental nursing interventions versus routine warming interventions on patients with a stoma. The comparisons between nursing interventions were performed to find which kind of intervention will be superior in improving life quality. After a restricted selection, 10 studies, 460 subjects with experimental nursing intervention, and 478 controls with the routine nursing intervention were enrolled in a variety of causes of the stoma. The focused outcome was the quality of life. The meta-analysis was performed by Review Manager 5.4. Among the stoma patients, the meta-analysis favours the experimental nursing intervention group with higher scores of life quality when compared to the routine nursing intervention group. The meta-analysis results were with positive mean differences, significant tests for overall effect, and significant heterogeneities in the random-effects model. The experimental nursing intervention showed higher positive effects on the quality of life when compared to routine nursing intervention for stoma patients. Experimental nursing intervention might be an option for stoma nursing practitioners to improve stoma care. | Surgical Stomas |
Rhodium/DuanPhos-catalyzed asymmetric hydrogenation of aliphatic alpha-dehydroamino ketones has been achieved and afforded chiral alpha-amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral beta-amino alcohols by LiAlH(tBuO)3 with good yields. This protocol provides a readily accessible route for the synthesis of chiral alpha-amino ketones and chiral beta-amino alcohols. | Rhodium |
Trichoblastoma(s) (TB) are benign neoplasms of follicular differentiation frequently found in nevus sebaceus. Many morphologic features are shared with nodular basal cell carcinoma(s) (BCC), sometimes rendering the differential diagnosis difficult. Because both neoplasms can simulate components of mature hair follicles histologically, we attempted to corroborate this by immunohistochemical examination of cytokeratins and hair keratins differentially expressed in the hair follicle. Trichoblastoma(s) and BCC showed homogenous expression of CK14 and CK17. The innermost cells of the tumor nodules in all TB and in 72% of BCC were positive for CK6hf. Using a specific CK15 antibody, 38% of TB showed a focal labeling and all BCC remained negative; 70% of TB and 22% of BCC expressed CK19. CK8 was expressed by numerous Merkel cells present in all TB but in none of the BCC examined. All type I and II hair keratins tested, (especially hHa1, hHa5, and hHa8) remained negative in all tumors examined. Trichoblastoma(s) and BCC show consistent expression of CK6hf, CK14, and CK17; variable expression of CK15 and CK19; and absence of hair keratins. This indicates a differentiation toward the outer root sheath epithelium or the companion layer and not toward the inner root sheath, matrix, or cortex. | Carcinoma, Basal Cell |
Acute respiratory distress syndrome (ARDS) is characterized by alterations in microvascular permeability. In ARDS secreted phospholipase A(2) (sPLA(2)) IB and IIA are found to be highly upregulated. In this study, we therefore investigated the influence of exogenously added sPLA(2)-IB and sPLA(2)-IIA on the production of chemokines and adhesion molecules in lung microvascular endothelial cells (LMVEC). Treatment of LMVEC with sPLA(2)s resulted in a significant increase in the production of chemokines and adhesion molecules due to an increased expression of their mRNA and in an enhanced release of oleic acid. The upregulation of chemokines and adhesion molecules by LPS was stronger in the presence of sPLA(2). Activation of NF-kappaB occurred upon stimulation with sPLA(2). Moreover the MAPkinase pERK seems to be involved since a specific pERK inhibitor, e.g., U0126, but not a p38Kinase inhibitor, e.g., SB203580 prevented sPLA(2)-induced chemokine upregulation. Our data therefore suggest that LMVEC are a highly sensitive target for the direct action of extracellular sPLA(2)s. | Group I Phospholipases A2 |
The scientific community is fully aware of the importance of heat-related illness and heat stroke syndrome. Numerous guidelines have been recently published and most of them agree on the key role played by the intestine. Likewise, the role of endotoxinemia in the pathophysiology is well established. However, the possibility of bacterial translocation is not mentioned. Our patient illustrates the likelihood of bacterial translocation in heat stroke and consistently the potential need of antibiotic therapy. A 45-year-old man diagnosed with paranoid schizophrenia was confined in a penitentiary center. One summer day in which a temperature of 41 degrees C was observed in the shade, the patient was found in deep coma with an axillary temperature of 42 degrees C. Multiorgan failure was detected in the hospital. Other causes of coma and/or hyperthermia were excluded, and heat stroke was diagnosed. Blood cultures were positive for Pseudomonas aeruginosa and Escherichia coli. Infection site was not identified despite of an exhaustive search. The patient fully recovered after 48 hours. On the basis of review of the literature, we think that bacterial translocation can take part in the pathophysiology of heat stroke. Therefore, antibiotic treatment must be evaluated in heat stroke patients. | Heat Stroke |
In the study, total segment, grey matter and white matter volume values of lumbosacral segment of spinal cord in quails (Coturnix coturnix japonica) were stereologically examined. Regardless of sex, six adult quails were used as material. After the materials were perfused, they were dissected and their spinal cords were uncovered. Tissue samples were taken from each lumbosacral segment of spinal cord. After the tissue fixation process, 6-7 sections having a 5-microm thickness were separated in every 50th section as from the first section, where the tissue was seen, among tissue samples of each segment. These segments were stained with haematoxylin-eosin staining. They were photographed via a microscope. By using the Cavalieri's principle, the volume values of both the total segment, grey matter (GM) and white matter (WM) in each lumbosacral segment were separately calculated. All these calculations were performed by using SHTEREOM 1.5 program. As a result, total volume, grey matter and white matter volume values of lumbosacral segments and white matter/total volume, grey matter/total volume, and grey matter/white matter volume fractions were obtained. | Quail |
It has clearly been demonstrated that cognitive stimulation, physical exercise, and social engagement help counteract age-related cognitive decline. However, several important issues remain to be addressed. Given the wide differences in cognitive impairment found among individuals of the same age, identifying the subjects who will benefit most from late-life interventions is one such issue. Environmental Enrichment (EE) is a particularly valuable approach to do this. In this study, aged (21-month-old) rats were assigned to a better (BL) or a worse (WL) learner group (training phase) and to a non-impaired (NI) or an impaired (I) group (probe phase) by their performance on the Morris Water Maze, using the test performances of adult (12-month-old) rats as the cut-offs. The aged rats were retested after a 12-week EE or standard housing (SH) protocol. After 12 weeks, the performances of SH rats had deteriorated, whereas all rats benefited from EE, albeit in different ways. In particular, the animals assigned to the BL and the NI groups prior to EE still performed as well as the adult rats (performance preservation) whereas, critically, the animals assigned to the WL and the I groups before EE showed such improved performances that they reached the level of the adult rats (performance improvement), despite having aged further. EE seems to induce the preservation in BLs and the improvement in WLs of spatial search strategies and the preservation in NIs and the increase in Is of a focused and protract research of the escape point. Our findings suggest that late-life EE prevents spatial learning and memory decline in still cognitively preserved animals and stimulates residual functional reserve in already cognitively compromised animals. Future research should focus on individually tailored stimulation protocols to improve their effect and afford a better understanding of the underlying processes. | Spatial Learning |
There is a growing interest in precision medicine, where a potentially censored survival time is often the most important outcome of interest. To discover optimal treatment regimens for such an outcome, we propose a semiparametric proportional hazards model by incorporating the interaction between treatment and a single index of covariates through an unknown monotone link function. This model is flexible enough to allow non-linear treatment-covariate interactions and yet provides a clinically interpretable linear rule for treatment decision. We propose a sieve maximum likelihood estimation approach, under which the baseline hazard function is estimated nonparametrically and the unknown link function is estimated via monotone quadratic B-splines. We show that the resulting estimators are consistent and asymptotically normal with a covariance matrix that attains the semiparametric efficiency bound. The optimal treatment rule follows naturally as a linear combination of the maximum likelihood estimators of the model parameters. Through extensive simulation studies and an application to an AIDS clinical trial, we demonstrate that the treatment rule derived from the single-index model outperforms the treatment rule under the standard Cox proportional hazards model. | Models, Statistical |
An extraskeletal osteochondroma is an infrequently encountered benign cartilaginous tumor with a predilection for the hands and feet that usually does not exceed 3 cm in diameter. This diagnosis can be misleading because it bears the same name as the osseous neoplasm more commonly referred to as an exostosis. The authors present an unusual case of a painful enlarging mass in the foot of a 28-year-old man who was later diagnosed as having an extraskeletal osteochondroma measuring in excess of 4 cm. Clinical, radiographic, and magnetic resonance images are provided along with intraoperative and histopathologic figures. There was no sign of recurrence 1 year after surgical excision. A review of the literature regarding this uncommon lesion is also presented. | Osteochondroma |
Phase separation of mixtures of oppositely charged polymers provides a simple and direct route to compartmentalisation via complex coacervation, which may have been important for driving primitive reactions as part of the RNA world hypothesis. However, to date, RNA catalysis has not been reconciled with coacervation. Here we demonstrate that RNA catalysis is viable within coacervate microdroplets and further show that these membrane-free droplets can selectively retain longer length RNAs while permitting transfer of lower molecular weight oligonucleotides. | Cell Compartmentation |
A key step in understanding the genetic basis of different evolutionary outcomes (e.g., adaptation) is to determine the roles played by different mutation types (e.g., SNPs, translocations and inversions). To do this we must simultaneously consider different mutation types in an evolutionary framework. Here, we propose a research framework that directly utilizes the most important characteristics of mutations, their population genetic effects, to determine their relative evolutionary significance in a given scenario. We review known population genetic effects of different mutation types and show how these may be connected to different evolutionary outcomes. We provide examples of how to implement this framework and pinpoint areas where more data, theory and synthesis are needed. Linking experimental and theoretical approaches to examine different mutation types simultaneously is a critical step towards understanding their evolutionary significance. | Sequence Inversion |
A clinical trial of Niclofolan on human opisthorchiasis was carried out in 60 patients admitted to the Hospital for Tropical Diseases. Two dosage regimen, 2 mg and 3 mg per kg body weight repeated after a 72 hour interval was administered to 31 and 4 patients respectively. Comparative evaluation with the placebo group of 25 patients was made by the Stoll count on day 20, 40 and 60 after treatment. On day 60 percentage egg reduction of the treated and the placebo groups were similar. Mild and transient side effects such as nausea, anorexia, myalgia and arthralgia were recorded in all 3 groups but more severe in the higher dosage group. In this study, Niclofolan failed in reducing the egg production of Opisthorchis viverrini. | Niclofolan |
Menopausal symptoms, bone loss, changes in lipid profiles and reduction of insulin sensitivity due to an abrupt decrease in circulating estrogen level are well known in women during the menopausal transition. On the other hand, the effect of androgen on women's health has not been fully elucidated. Circulating levels of testosterone and dehydroepiandrosterone sulfate (DHEA-S) gradually decrease with age in postmenopausal women, although transient increases have been observed during the menopausal transition. High testosterone level has been suggested to be associated with increased risk of cardiovascular disease, increased triglyceride, insulin resistance and increase in the risk of developing breast cancer in postmenopausal women. Circulating DHEA-S level does not affect the risk of cardiovascular disease, mortality or lipid profiles in women. Female androgen insufficiency, which is characterized by the presence of reduced androgen level in circulation, leads to an impairment in sexual drive, reduced libido, depressed mood, and signs and symptoms of limited androgen exposure such as decreased muscle mass, reduced bone density and decreased sense of well-being. An appropriate level of androgen may play important roles in metabolic, psychological and sexual functions in women. In addition, the roles of testosterone and DHEA-S in women's health may be different." | Dehydroepiandrosterone Sulfate |
Bacillus subtilis flagella are not only required for locomotion but also act as sensors that monitor environmental changes. Although how the signal transmission takes place is poorly understood, it has been shown that flagella play an important role in surface sensing by transmitting a mechanical signal to control the DegS-DegU two-component system. Here we report a role for flagella in the regulation of the K-state, which enables transformability and antibiotic tolerance (persistence). Mutations impairing flagellar synthesis are inferred to increase DegU-P, which inhibits the expression of ComK, the master regulator for the K-state, and reduces transformability. Tellingly, both deletion of the flagellin gene and straight filament (hag(A233V) ) mutations increased DegU phosphorylation despite the fact that both mutants had wild type numbers of basal bodies and the flagellar motors were functional. We propose that higher viscous loads on flagellar motors result in lower DegU-P levels through an unknown signaling mechanism. This flagellar-load based mechanism ensures that cells in the motile subpopulation have a tenfold enhanced likelihood of entering the K-state and taking up DNA from the environment. Further, our results suggest that the developmental states of motility and competence are related and most commonly occur in the same epigenetic cell type. | Basal Bodies |
Azelastine (4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-p hthalazinone hydrochloride), a novel long-acting antiasthmatic/antiallergic drug has been demonstrated to be effective in the treatment both of asthma and of allergic rhinitis. In this paper some selected properties of azelastine are presented which might contribute to its antiasthmatic and antiallergic effect. Azelastine causes a marked inhibition of generation of oxygen radicals in alveolar macrophages. A bronchosecretolytic activity of azelastine is observed which is based on the secretion of a more liquid mucus. Furthermore, the mucociliary clearance is enhanced as demonstrated in a rabbit model. Also IL-1 generation is inhibited in vitro and in vivo. Finally, the possible tissue and cellular accumulation of azelastine in lung and alveolar macrophages resp. is discussed. | Phthalazines |
This article highlights how a developmental approach to understanding the causes of conduct disorder (CD) could be critical for understanding and preventing delinquent and violent behavior in youth. The approach recognizes that there may be multiple causal pathways leading to CD. It also integrates developmental research and theory with research on antisocial and aggressive behavior to explain how normal developmental mechanisms may be disrupted to place a child at risk for showing problem behavior. The article reviews research outlining several such pathways that differ in the age at which serious conduct problems develop and that differ on the presence or absence of callous-unemotional traits. The presence of these different developmental pathways has important implications for how research is conducted to study CD and interventions are implemented to prevent or treat children who have CD. | Conduct Disorder |
An efficient one-pot sequential hydrogen isotope exchange (HIE)/reductive deuteration approach was developed for the preparation of alpha,beta-deuterated alcohols using ketones as the precursors. The HIE step can also be used for the synthesis of alpha-deuterated ketones. This method has been applied in the synthesis of four deuterated drug and MS internal standards. | Hydrogen |
An effective strategy for personalized medicine requires a major conceptual change in the development and application of therapeutics. In this article, we argue that further advances in this field should be made with reference to another conceptual shift, that of network pharmacology. We examine the intersection of personalized medicine and network pharmacology to identify strategies for the development of personalized therapies that are fully informed by network pharmacology concepts. This provides a framework for discussion of the impact personalized medicine will have on chemistry in terms of drug discovery, formulation and delivery, the adaptations and changes in ideology required and the contribution chemistry is already making. New ways of conceptualizing chemistry's relationship with medicine will lead to new approaches to drug discovery and hold promise of delivering safer and more effective therapies. | Vitamin K Epoxide Reductases |
Physiologic end points for fluid resuscitation in septic shock patients with acute kidney injury (AKI) have been undertaken in randomized studies using the Early Goal-Directed Therapy (EGDT) approach. These studies have demonstrated a beneficial effect on in-hospital mortality with EGDT. The Saline versus Albumin Fluid Evaluation (SAFE) randomized study in critically ill patients demonstrated no difference in survival when saline versus albumin solutions were used for resuscitation. However, a benefit of albumin has been demonstrated in a randomized study on renal function and survival in cirrhotic patients with spontaneous bacterial periotonitis. On the other hand, recent observational studies have shown a correlation between fluid overload and mortality in AKI patients whether or not they necessitated dialysis. Moreover, the Adult Respiratory Distress Syndrome (ARDS) network performed a randomized study in critically ill patients to compare liberal versus conservative fluid administration. The liberal fluid administration group exhibited worse pulmonary function and no protection of renal function. Constancy of central venous pressure (CVP) measurements in the 12-mmHg range were observed in the liberal fluid group despite a mean increase in positive fluid balance of 7 L, thus suggesting increased interstitial fluid accumulation leading to pulmonary congestion. The review presented here discusses these various aspects of fluid administration in critically ill patients, particularly those with AKI, and indicates the potential deleterious effects of fluid overload on lung, heart, and kidney function that could contribute to increased mortality. | Fluid Therapy |
OBJECTIVE: This work described a video information processing scheme for optogenetic forms of visual cortical prosthetics. APPROACH: The architecture is designed to perform a processing sequence: Initially simplifying the scene, followed by a pragmatic visual encoding scheme which assumes that initially optical stimulation will be stimulating bulk neural tissue rather than driving individual phosphenes. We demonstrate an optical encoder, combined with what we called a zero-run length encoding (zRLE) video compression and decompression scheme-to wirelessly transfer information to an implantable unit in an efficient manner. In the final step, we have incorporated an even power distribution driver to prevent excessive power fluctuations in the optogenetic driving. SIGNIFICANCE: The key novelty in this work centres on the completeness of the scheme, the new zRLE compression algorithm and our even power distributor. MAIN RESULTS: Furthermore, although the paper focusses on the algorithm, we confirm that it can be implemented on real time portable processing hardware which we will use for our visual prosthetics. | Phosphenes |
INTRODUCTION: The management of tumors located in the posterior compartment of the knee, whatever the nature of the tumor, remains surgical excision and can be done by open surgery or under arthroscopic control. The objective of this study was to evaluate the arthroscopic management of intra-articular tumors of the posterior compartment of the knee. The hypothesis is that tumors or tumor-like lesions confined to the posterior compartment are accessible by arthroscopy with low iatrogenic risk. MATERIALS AND METHODS: All patients with an intra-articular tumor of the posterior compartment of the knee were enrolled between 2009 and 2013. The surgical management consisted of arthroscopic resection. Patients underwent postoperative MRI, repeated at last follow-up. The outcomes were the occurrence of complications, functional evaluation using the Lysholm Knee Scoring Scale, and the recurrence rate. RESULTS: Fifteen patients were included. All patients had a complete resection. One case of delayed healing of the arthroscopic entry point was observed. At a mean 22months, the mean Lysholm Knee Score increased from 74 (+/-8.5) preoperatively to 92 (+/-7.7) postoperatively, a significant increase of 18 points (P=0.001). One patient had a recurrence of osteochondromatosis, requiring removal of a foreign body. DISCUSSION: Resection of posterior intra-articular tumors of the knee using arthroscopy is possible, subject to a learning curve. | Osteochondromatosis |
OBJECTIVES: Little is known about the molecular details regarding the contribution of different cell types of the salivary gland to the altered gene expression profile seen in Sjogren's syndrome (SS). METHODS: Using laser microdissection, tissue samples enriched in acini, ducts and inflammatory foci in subjects with and without SS were isolated for RNA-seq analysis. Gene expression profiles were analysed and selected enriched genes were further examined using real time PCR and by immunofluorescence. RESULTS: RNA-seq analysis of salivary biopsies from subjects with and without SS revealed marked differences in gene expression occurring in the ductal and infiltrating cells compared to acinar cells. Up-regulated genes in the SS ductal cells included C4A complement and the SLC26A9 ion channel. The inflammatory infiltrate showed the most dramatic differences in gene expression and contained up-regulated genes associated with T-cells, natural killer, dendritic and basophils/mast cells. qPCR with total salivary gland mRNA confirmed the differential mRNA expression of several genes (MMP9, FOL1HB, CCL21, CCR7), thereby validating the approach. Additional immunofluorescence studies demonstrated high expression and co-localisation of CCL21 chemokine and CCR7 chemokine receptor within the SS infiltrates. CONCLUSIONS: Major gene expression changes in the salivary gland of SS were detected in the ductal and inflammatory cells and not in the acinar cells. Two chemokines involved in immune cell trafficking to secondary lymphoid tissue, CCR7 and CCL21, showed markedly increased expression and may contribute to the recruitment of diverse immune cells to the salivary glands, causing inflammation and loss of secretory function. | Chemokine CCL21 |
INTRODUCTION: Primary carcinoma of the Fallopian tube (FTC) is a rare but extremely aggressive neoplasm. It must be expected to cause up to 40% of tumor-related deaths even in Stage I, and up to 57% in Stage II. Due to its rarity, there exist only a few and divergent reports on the value of adjuvant therapy. Therefore the present study aims at evaluating the influence of postoperative adjuvant therapy on FTC by studying the effects of irradiation and chemotherapy on the overall survival of patients in Stages I and II. PATIENTS AND METHODS: We investigated 95 cases of FTC in Stages I (n = 66) and II (n = 29) in a retrospective multicenter study. Group I (n = 32) are patients who underwent a complete irradiation with cobalt or photon energies of 23 MV (administering a daily dose of 2 Gy resulted in a total of 45-52 Gy in the pelvic areas). Group II (n = 31) consists of those cases who received postoperative chemotherapy with platinum. Thirty-two women were excluded from this study because they had other chemotherapies, incomplete irradiation, or no adjuvant therapy at all. RESULTS: Median survival time was 57 months in Group I patients (95% confidence interval 33-81 months), compared to 73 months (95% confidence interval, 68-78 months) in the chemotherapeutically treated Group II. This difference did not prove to be statistically significant (p = 0.476).If primary surgical therapy is included in the evaluation, and patients with total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) are compared to those with additional radical lymphadenectomy (TAH+BSO+lymph nodes), the latter group's overall survival essentially improves but fails to reach statistical significance. Their 5-year survival rate is 83% against 58% in the TAH+BSO group (p = 0.12). CONCLUSION: Chemotherapy and irradiation are two adjuvant therapies that are similarly effective in FTC of Stages I and II, with chemotherapy being preferred at the present time. Primary surgical treatment, however, is of crucial impact on the prognosis of FTC. | Fallopian Tube Neoplasms |
Developing functional insight into the causal molecular drivers of immunological disease is a critical challenge in genomic medicine. Here, we systematically apply Mendelian randomization (MR), genetic colocalization, immune-cell-type enrichment, and phenome-wide association methods to investigate the effects of genetically predicted gene expression on ten immune-associated diseases and four cancer outcomes. Using whole blood-derived estimates for regulatory variants from the eQTLGen consortium (n = 31,684), we constructed genetic risk scores for 10,104 genes. Applying the inverse-variance-weighted MR method transcriptome wide while accounting for linkage disequilibrium structure identified 664 unique genes with evidence of a genetically predicted effect on at least one disease outcome (p < 4.81 x 10(-5)). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci by using gene expression data derived from 18 types of immune cells. This highlighted many cell-type-dependent effects, such as PRKCQ expression and asthma risk (posterior probability = 0.998), which was T cell specific. Phenome-wide analyses on 311 complex traits and endpoints allowed us to explore shared genetic architecture and prioritize key drivers of disease risk, such as CASP10, which provided evidence of an effect on seven cancer-related outcomes. Our atlas of results can be used to characterize known and novel loci in immune-associated disease and cancer susceptibility, both in terms of elucidating cell-type-dependent effects as well as dissecting shared disease pathways and pervasive pleiotropy. As an exemplar, we have highlighted several key findings in this study, although similar evaluations can be conducted via our interactive web platform. | Genomic Medicine |
Body composition of 292 males aged between 18 and 65 years was measured using the deuterium oxide dilution technique. Participants were divided into development (n=146) and cross-validation (n=146) groups. Stature, body weight, skinfold thickness at eight sites, girth at five sites, and bone breadth at four sites were measured and body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-stature ratio (WSR) calculated. Equations were developed using multiple regression analyses with skinfolds, breadth and girth measures, BMI, and other indices as independent variables and percentage body fat (%BF) determined from deuterium dilution technique as the reference. All equations were then tested in the cross-validation group. Results from the reference method were also compared with existing prediction equations by Durnin and Womersley (1974), Davidson et al (2011), and Gurrici et al (1998). The proposed prediction equations were valid in our cross-validation samples with r=0.77- 0.86, bias 0.2-0.5%, and pure error 2.8-3.6%. The strongest was generated from skinfolds with r=0.83, SEE 3.7%, and AIC 377.2. The Durnin and Womersley (1974) and Davidson et al (2011) equations significantly (p<0.001) underestimated %BF by 1.0 and 6.9% respectively, whereas the Gurrici et al (1998) equation significantly (p<0.001) overestimated %BF by 3.3% in our cross-validation samples compared to the reference. Results suggest that the proposed prediction equations are useful in the estimation of %BF in Indonesian men. | Body Weights and Measures |
We report a significant decrease in transcription of the G protein-coupled receptor GPR39 in striatal neurons of Parkinson's disease patients compared to healthy controls, suggesting that a positive modulator of GPR39 may beneficially impact neuroprotection. To test this notion, we developed various structurally diverse tool molecules. While we elaborated on previously reported starting points, we also performed an in silico screen which led to completely novel pharmacophores. In vitro studies indicated that GPR39 agonism does not have a profound effect on neuroprotection. | Pyrimidines |
The cyclic-AMP-dependent protein kinase A (PKA) regulates processes such as cell proliferation and migration following activation of growth factor receptor tyrosine kinases (RTKs), yet the signaling mechanisms that link PKA with growth factor receptors remain largely undefined. Here we report that RTKs can directly modulate the function of the catalytic subunit of PKA (PKA-C) through post-translational modification. In vitro kinase assays revealed that both the epidermal growth factor and platelet derived growth factor receptors (EGFR and PDGFR, respectively) tyrosine phosphorylate PKA-C. Mass spectrometry identified tyrosine 330 (Y330) as a receptor-mediated phosphorylation site and mutation of Y330 to phenylalanine (Y330F) all but abolished the RTK-mediated phosphorylation of PKA-C in vitro. Y330 resides within a conserved region at the C-terminal tail of PKA-C that allosterically regulates enzymatic activity. Therefore, the effect of phosphorylation at Y330 on the activity of PKA-C was investigated. The K(m) for a peptide substrate was markedly decreased when PKA-C subunits were tyrosine phosphorylated by the receptors as compared to un-phosphorylated controls. Importantly, tyrosine-phosphorylated PKA-C subunits were detected in cells stimulated with EGF, PDGF, and Fibroblast growth factor 2 (FGF2) and in fibroblasts undergoing PDGF-mediated chemotaxis. These results demonstrate a direct, functional interaction between RTKs and PKA-C and identify tyrosine phosphorylation as a novel mechanism for regulating PKA activity." | Cyclic AMP-Dependent Protein Kinase Type II |
A recently described factor, interleukin-1 receptor antagonist binding factor (IL-1raBF), in serum of normal individuals is immunologically related to the interleukin-1 receptor type I (IL-1RI). It is presumably a soluble form of the receptor that binds exclusively to interleukin-1 receptor antagonist (IL-1ra). Recombinant soluble human IL-1RI expressed in COS cells (sIL-1RI) consists of the extracellular part of the receptor and binds all three known IL-1 species but preferentially to Il-1ra. We further characterized the sizes and binding of IL-1raBF and sIL-1RI to IL-1ra by polyacrylamide gel electrophoresis in the presence of sodium dodecylsulfate, ligand binding interference analyses, N-glycosidase treatment, concanavalin A affinity chromatography, and with the use of monoclonal antibodies (mAb) to human recombinant IL-1ra. We also evaluated the binding of IL-1ra to cellular IL-1RI on MRC5 fibroblasts and the interference afforded by the soluble receptors. The results show that the protein backbones of IL-1raBF and sIL-1RI are of similar size (approximately 35-40 kDa) and that there are differences in the glycosylation of the two molecules. These carbohydrates were necessary for optimal binding of both molecules to IL-1ra. Both factors blocked binding of IL-1ra to cellular IL-1RI, as did mAb to IL-1ra, but the sites on IL-1ra which bound to the mAb, and to IL-1raBF and sIL-1RI, differed. We conclude that there are important differences between the natural and recombinant forms of soluble IL-1RI and that IL-1ra binds differently to these molecules and to cellular IL-1RI. | Receptors, Interleukin-1 |
In vascular research, clinical samples and samples from animal models are often used together to foster translation of preclinical findings to humans. General concepts of endothelia and murine-specific endothelial phenotypes were discussed in part 1 of this two part series. Here, in part 2, we present a comprehensive overview of human-specific endothelial phenotypes. Pan-endothelial cell markers, organ specific endothelial antigens, and flow cytometric immunophenotyping of blood-borne endothelial cells are reviewed." | Receptor-Like Protein Tyrosine Phosphatases |
OBJECTIVE: to assess alcohol intake in the bariatric surgery pre and postoperative periods. METHODS: Patients were interviewed at Surgery Clinic of the Hospital das Clinicas da Universidade Federal de Pernambuco - HC/UFPE (Brazil) from July 2011 to March 2012. We analyzed socioeconomic, anthropometric and clinical variables. We used the Alcohol Use Disorders Identification Test (AUDIT C). RESULTS: One hundred nineteen patients were enrolled (mean age: 41.23+11.30 years), with a predominance of the female gender (83.2%), non-Caucasian race (55%), married individuals or in a stable union (65.5%), with a high school education (40.3%)and active in the job market (37%). Weight and body mass index (BMI) were 128.77+25.28 Kg and 49.09+9.26 Kg/m2,respectively in the preoperative period (class II obesity) and 87.19+19.16 Kg and 33.04+6.21 Kg/m2, respectively in the postoperative period (class I obesity) (p<0.001). Hypertension was the most frequent disease in the pre (66.6%) and postoperative (36.5%) periods. The prevalence of alcohol use was 26.6% in the preoperative period, of which 2.2% of high risk, and 35.1% in the postoperative period, of which 1.4% of probable dependence; this difference did not achieve statistical significance (p=0.337). CONCLUSION: The prevalence of abusive alcohol intake and/or probable dependence was low in both the pre and postoperative periods, with little evidence of risky consumption among the patients submitted to bariatric surgery. | Perioperative Period |
Oxidative DNA damage is considered to play an important role in pathophysiological processes, ageing and cancer. So far major interest has been on measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG), the preferred methods relying on HPLC or GC-mass spectrometry. The high biological relevance of 8-OHdG is due to its ability to induce G-->T transversions, which are among the most frequent somatic mutations found in human cancers. Effects of workplace exposures on the level of white blood cell 8-OHdG or urinary 8-OHdG have been reported with controversial results. Exposures examined include asbestos, azo-dyes, benzene, fine particulate matter (PM(2.5)), glassworks, polycyclic aromatic hydrocarbons (PAHs), rubber manufacturing, silica, metals, styrene, toluene and xylenes. The available data indicate that there is still a lack of well established dose-response relations between occupational or environmental exposures and the induction of 8-OHdG. Smoking has been most consistently identified as a confounder for 8-OHdG, but various occupational studies did not reveal higher levels of 8-OHdG in smokers. Despite the conflicting results, the reported studies show promise for 8-OHdG as a biomarker of oxidative stress associated with chemical exposure. However, there are critical aspects related to the analytical challenge, artifactual production of 8-OHdG, inter- and intra-individual variation, confounding factors and inter-laboratory differences, implying that further work is needed to reach a consensus on the background level of 8-OHdG. | Deoxyguanosine |
OBJECTIVE: To identify the factors shaping the pattern of removable partial denture (RPD) provision by dentists in England. Design Cross sectional survey of general dental practitioners. METHODS: Details of current practice and provision, influences, attitudes and demographic details were collected using a self-completion questionnaire mailed to general dental practitioners identified through the Dental Practice Board register. RESULTS: Three hundred and eighty-five questionnaires were returned by general dental practitioners from 62 health authorities throughout England. The most important factor reported as influencing both the GDP's decision to provide a partial denture and its subsequent success was patient desire to have a partial denture. Constructing the denture from cobalt chrome, advising the patient on aftercare, making time available to make minor adjustments and being responsible for design were all factors dentists associated with success of a RPD. However, for a number of dentists there was a reported divergence between knowledge and practice. CONCLUSION: Overall it is clear that provision of partial dentures continues to be patient led. However, the decision making process is also influenced by a number of factors including time, cost and the NHS fee structure. | Denture, Partial, Removable |
Although their ssrRNA gene sequences are closely related, the lizard sarcosporidia (Apicomplexa, Sarcocystidae) Sarcocystis lacertae and Sarcocystis gallotiae posses heteroxenous and dihomoxenous life cycles, respectively. When aligned with available sarcosporidian ssrRNA genes, both species constitute a monophyletic clade that is only distantly related with sarcosporidia that have a viperid snake as their definitive host (Sarcocystis sp., Sarcocystis atheridis). To test the phyletic status of the dihomoxenous life style, Sarcocystis rodentifelis and Sarcocystis muris, two dihomoxenous parasites of mammals were included into this study. All studied species group together with former Frenkelia spp., Sarcocystis neurona and related marsupial and bird sarcosporidia in a monophyletic clade. However, the available dataset supports independent appearance of the dihomoxenous life cycle at least twice during the evolution of the Sarcocystidae. | Sarcocystis |
Hysterical neurosis, though infrequently diagnosed in the West, is still one of the commonest mental disorders in India. In this study, 38 women with an index diagnosis of hysterical neurosis were evaluated after a period of 5 years; 63% of the patients remained totally asymptomatic. The premorbid hysterical personality alone showed significant relationship with the outcome. | Dissociative Disorders |
A century ago Thomas G. Lee amassed an unparalleled collection of developmental series of North American rodents such as the thirteen-lined ground squirrel, the Plains pocket gopher and Merriam's kangaroo rat. He was the first to describe the initial attachment of the squirrel blastocyst to the antimesometrial side of the uterus. The full potential of Lee's material was not realized until after his death, when it came into the possession of Mossman. The latter relied heavily on Lee's collection when writing his seminal monograph on the comparative morphogenesis of fetal membranes and much of Lee's material was subsequently described in detail by Mossman and others. It now forms part of the Harland W. Mossman Collection at the University of Wisconsin. | Dipodomys |
Cnaphalocrocis medinalis is a major pest of rice in South and South-East Asia. Insecticides are the major means farmers use for management. A naturally occurring baculovirus, C. medinalis granulovirus (CnmeGV), has been isolated from the larvae and this has the potential for use as microbial agent. Here, we described the complete genome sequence of CnmeGV and compared it to other baculovirus genomes. The genome of CnmeGV is 112,060 base pairs in length, has a G+C content of 35.2%. It contains 133 putative open reading frames (ORFs) of at least 150 nucleotides. A hundred and one (101) of these ORFs are homologous to other baculovirus genes including 37 baculovirus core genes. Thirty-two (32) ORFs are unique to CnmeGV with no homologues detected in the GeneBank and 53 tandem repeats (TRs) with sequence length from 25 to 551 nt intersperse throughout the genome of CnmeGV. Six (6) homologous regions (hrs) were identified interspersed throughout the genome. Hr2 contains 11 imperfect palindromes and a high content of AT sequence (about 73%). The unique ORF28 contains a coiled-coil region and a zinc finger-like domain of 4-50 residues specialized by two C2C2 zinc finger motifs that putatively bound two atoms of zinc. ORF21 encoding a chit-1 protein suggesting a horizontal gene transfer from alphabaculovirus. The putative protein presents two carbohydrate-binding module family 14 (CBM_14) domains rather than other homologues detected from betabaculovirus that only contains one chit-binding region. Gene synteny maps showed the colinearity of sequenced betabaculovirus. Phylogenetic analysis indicated that CnmeGV grouped in the betabaculovirus, with a close relation to AdorGV. The cladogram obtained in this work grouped the 17 complete GV genomes in one monophyletic clade. CnmeGV represents a new crambidae host-isolated virus species from the genus Betabaculovirus and is most closely relative of AdorGV. The analyses and information derived from this study will provide a better understanding of the pathological symptoms caused by this virus and its potential use as a microbial pesticide. | Granulovirus |
Leukotriene receptor antagonists (LTRA) are widely used drugs for treating allergic asthma, and they have recently been suggested to have a suppressive effect on carcinogenesis and cancer cell proliferation. Aberrant crypt foci (ACF) are considered a reliable surrogate biomarker of colorectal cancer. This prospective study explored the chemopreventive effect of an LTRA on colonic ACF formation and the safety of the medicine in patients as a pilot trial leading to a colorectal cancer chemoprevention trial. This was a nonrandomized, open-label, controlled trial in patients with colorectal ACFs. The participants were allocated to LTRA or observation groups. Patients in the LTRA group received 10 mg of montelukast orally daily for 8 weeks. After the intervention, colonoscopy was performed to evaluate the changes in the number of ACFs. From November 2017 to March 2020, 40 patients were enrolled. The first 30 were assigned to the LTRA group, and the remaining 10 were assigned to the observation group. In the LTRA group, the mean change in the number of ACFs per patient at 8 weeks from baseline was -2.4 +/- 2.2, while the mean change in the observation group was 0.4 +/- 2.3 (P = 0.002). There were no severe adverse events. This is the first study to explore the effect of LTRAs against colorectal ACF formation in humans. LTRAs are potential candidates for chemoprevention in colorectal cancer. PREVENTION RELEVANCE: We conducted the first LTRA chemoprevention trial for human rectal ACFs, which is considered a surrogate marker of colorectal carcinogenesis. 8-week treatment with LTRA suppressed ACF formation and cell proliferation in colonic epithelium. LTRAs are possible candidates for chemoprevention in colorectal cancer. See related Spotlight, p. 637. | Aberrant Crypt Foci |
The aim of the present study was to develop a self-emulsifying drug delivery system (SEDDS) containing the extract of S oleraceus Linn (SOL) with improved intestinal stability in order to increase oral bio-potency. SOL was effectively incorporated into emulsions, which showed resistance to in vitro digestion without any destruction of its phenolic acids, glycosides and aglycone. SEDDS and SOL were also prepared for the comparison of in vivo anti-diabetic effects. Four weeks of daily treatments of SEDDS dramatically improved the quality of life for diabetic rats. Streptozotocin (STZ) caused body weight reduction, which was reversed by SEDDS at a low dose (100 mg kg-1), and it was more effective than SOL at a high dose (200 mg kg-1). SEDDS also improved the response to glucose tolerance, which was significantly higher than that of SOL. On the basis of these findings, the SEDDS approach might be an efficacious dosage option to enhance the nutraceutical properties of SOL. | Sonchus |
Two papers in this special issue of Cold Spring Harbor Molecular Case Studies on Mosaicism throw light on an interesting conundrum in mosaic disorders. This conundrum centers on thresholds for the definition of mosaic disorders and how to reconcile the incredible inter- and intrapatient variability of mosaic disorders with the clinical imperative to have clear and distinct categorical diagnoses. | Mosaicism |
In skilled hands, multiplane TEE provides a comprehensive assessment of the anatomy and function of the mitral and tricuspid valves. TEE is uniquely effective in the evaluation of the diverse pathophysiologic processes that cause valvular heart disease. | Tricuspid Valve Prolapse |
The effects of trazodone on sleep were compared with those of placebo and the sedating tricyclic antidepressant trimipramine in a double-blind crossover study in six healthy young men. Only trazodone significantly increased deep sleep without otherwise altering the normal architecture of sleep. The alpha-adrenergic receptor-blocking property of trazodone and a relative lack of noradrenergic reuptake blocking and the lack of anticholinergic effects are hypothesized to be responsible for the effects on sleep. | Trimipramine |
RATIONALE: We report the unsolved molecular structure of the complex biopolymer sporopollenin exine extracted from Lycopodium clavatum pollen grains. METHODS: TOF-SIMS and CID-MS/MS, MALDI-TOF-MS and CID-TOF/TOF-MS/MS were used for the analysis of this complex biopolymer sporopollenin exine extracted from Lycopodium clavatum pollen grains. Solid-state (1) H- and (13) C-NMR, 2D (1) H-(1) H NOESY, Rotor-synchronized (13) C(1) H HSQC, and (13) C(1) H multi CP-MAS NMR experiments were used to confirm the structural assigments revealed by MS and MS/MS studies. Finally, high-resolution XPS was used to check for the presence of aromatic components in sporopollenin. RESULTS: The combined MS and NMR analyses showed that sporopollenin contained poly(hydroxy acid) dendrimer-like networks with glycerol as a core unit, which accounted for the sporopollenin empirical formula. In addition, these analyses showed that the hydroxy acid monomers forming this network contained a beta-diketone moiety. Moreover, MALDI-TOF-MS and MS/MS allowed us to identify a unique macrocyclic oligomeric unit composed of polyhydroxylated tetraketide-like monomers. Lastly, high-resolution X-ray photoelectron spectroscopy (HR-XPS) showed the absence of aromaticity in sporopollenin. CONCLUSIONS: We report for the first time the two main building units that form the Lycopodium clavatum sporopollenin exine. The first building unit is a macrocyclic oligomer and/or polymer composed of polyhydroxylated tetraketide-like monomeric units, which represents the main rigid backbone of the sporopollenin biopolymer. The second building unit is the poly(hydroxy acid) network in which the hydroxyl end groups can be covalently attached by ether links to the hydroxylated macrocyclic backbone to form the sporopollenin biopolymer, a spherical dendrimer. Such spherical dendrimers are a typical type of microcapsule that have been used for drug delivery applications. Finally, HR-XPS indicated the total absence of aromaticity in the sporopollenin exine. | Lycopodiaceae |
The problems of etiology, pathogenesis, pathological anatomy, classification, and incidence of congenital hypotrophy in newborn babies are considered. Reduction in body weight and height of the newborns with congenital hypotrophy, weight of internal organs, developmental retardation, as well as dysplastic, atropic, and compensatory-adaptative processes are regularly observed. The intensity of these manifestations of congenital hypotrophy in newborn babies depends on the duration and potency of the prenatal effect of the pathogenic factors. | Infant, Newborn, Diseases |
Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects. | Chloroacetates |
OBJECTIVE: To analyze evolution of the health technology assessment (HTA) at the national level in South Korea. METHODS: Analysis of public documents, personal communication, and literative review. RESULTS: HTA in South Korea has been developed since 1990s, first introduced by academia and institutionalized within the National Health Insurance (NHI). Rapidly increasing expenditure had been a challenge of the NHI, which considered health technology management as a cost controlling measure. An amendment was made to the NHI Law in 2000, and provision was made to regulate the process of determining new insurance benefits including procedures, drugs, and equipment. This requirement made the NHI agencies to promote HTA approaches in connection with the government and professional organizations. Also the Healthcare Act was revised in October 2006 ruling that HTA focusing on safety and effectiveness be responsible for new health technologies. Currently, the HTA process is governed by a governmental committee comprising twenty members and technically supported by the HTA center created in the NHI structure. CONCLUSIONS: Institutionalized HTA in Korea has been driven mainly by the requirements of the NHI and manifested strengths as well as weaknesses. The government is establishing a new organization for HTA, independent from the NHI." | Technology Assessment, Biomedical |
Three coryneform strains from clinical specimens were studied. They belonged to the genus Corynebacterium, since they had type IV cell walls containing corynemycolic acids. They had phenotypic characteristics that included alpha-glucosidase, pyrazinamidase and alkaline phosphatase activities and fermentation of glucose, ribose, maltose and sucrose. These are the characteristics of Corynebacterium xerosis. Since this species is very rare in human pathology, the strains were studied in more detail by comparing the 16S-23S intergenic spacers, rDNA sequences and levels of DNA similarity of these three strains and those of the reference strains C. xerosis ATCC 373T and Corynebacterium amycolatum CIP 103452T. According to DNA-DNA hybridization data, the three novel strains are members of the same species (level of DNA similarity >72%). Phylogenetic analysis revealed that these strains are closely related to C. xerosis and C. amycolatum, but DNA-relatedness experiments showed clearly that they constitute a distinct new species, with levels of DNA relatedness of less than 23% to C. xerosis ATCC 373T and less than 5% to C. amycolatum CIP 103452T. Two other alpha-glucosidase-positive strains presenting the same biochemical characteristics were included in the study and proved to be C. amycolatum. This new species can be differentiated from C. xerosis and C. amycolatum strains by carbon source utilization, intergenic spacer region length profiles and some biochemical characteristics such as glucose fermentation at 42 degrees C and growth at 20 degrees C. The name Corynebacterium freneyi sp. nov. is proposed with the type strain ISPB 6695110T (= CIP 106767T = DSM 44506T). | Corynebacterium |
The protein C anticoagulant pathway provides many new insights into control mechanisms for regulating coagulation. The observation that protein C deficiency is associated with thrombotic tendencies in the heterozygote (106-109) and early, lethal thrombosis in the homozygote (110, 111) points to the importance of the system as a major regulatory pathway. The complexity of the system has only recently begun to emerge. Thrombin activation of protein C at the endothelial cell surface requires not only the synthesis of thrombomodulin but the coupling of the receptor to a protein C binding site. It is reasonable to assume that an inherited or acquired deficiency in thrombomodulin might lead to thrombotic tendencies. This aspect of the system may explain, in part, the association between vascular disease and thrombosis. Once activated, protein C has an almost total dependence on protein S to express anticoagulant activity. (98) This suggests that deficiencies of protein S may also be associated with thrombotic tendencies. Protein S offers an additional intriguing property. Protein S, a regulatory protein of the coagulation system, is found both free and associated with C4BP, a regulatory protein of the complement system. The high affinity, very stable interaction between these components (85) suggests that the interaction is likely to be involved in regulation. (89) The importance of the interaction remains to be demonstrated, but clearly this is a potential direct link between major control proteins of the coagulation and complement system. Clinical studies suggest that protein C and/or thrombomodulin might be effective therapeutically. Certainly, protein C supplementation during the onset of oral anticoagulant therapy would be expected to circumvent the transient rapid decrease in protein C levels that may influence the early effectiveness of oral anticoagulants. (119) In addition to the systems clinical importance, protein C, its activation, and its function offer a variety of intriguing biochemical problems. For instance, how does thrombomodulin alter the specificity of thrombin? What is the protein C binding site on the cell surface, and what role does Factor Va or its degradation products play in the formation and regulation of this site? How does protein S facilitate activated protein C anticoagulant activity and what roles do membrane surfaces play in this system? What role does beta-hydroxyaspartic acid play in protein C activation and function? How does activated protein C influence fibrinolytic activity? The answers to these questions will undoubtedly add to our understanding of the fundamental mechanisms involved in regulating blood coagulation.(ABSTRACT TRUNCATED AT 400 WORDS) | Factor VIIIa |
Composites, in which two or more material elements are combined to provide properties unattainable by single components, have a historical record dating to ancient times. Few include a living microbial community as a key design element. A logical basis for enabling bioelectronic composites stems from the phenomenon that certain microorganisms transfer electrons to external surfaces, such as an electrode. A bioelectronic composite that allows cells to be addressed beyond the confines of an electrode surface can impact bioelectrochemical technologies, including microbial fuel cells for power production and bioelectrosynthesis platforms where microbes produce desired chemicals. It is shown that the conjugated polyelectrolyte CPE-K functions as a conductive matrix to electronically connect a three-dimensional network of Shewanella oneidensis MR-1 to a gold electrode, thereby increasing biocurrent approximately 150-fold over control biofilms. These biocomposites spontaneously assemble from solution into an intricate arrangement of cells within a conductive polymer matrix. While increased biocurrent is due to more cells in communication with the electrode, the current extracted per cell is also enhanced, indicating efficient long-range electron transport. Further, the biocomposites show almost an order-of-magnitude lower charge transfer resistance than CPE-K alone, supporting the idea that the electroactive bacteria and the conjugated polyelectrolyte work synergistically toward an effective bioelectronic composite. | Shewanella |
Hunter syndrome is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. In the absence of sufficient enzyme activity, glycosaminoglycans accumulate in the lysosomes of many tissues and organs and contribute to the multisystem, progressive pathologies seen in Hunter syndrome. The nervous, cardiovascular, respiratory, and musculoskeletal systems can be involved in individuals with Hunter syndrome. Although the management of some clinical problems associated with the disease may seem routine, the management is typically complex and requires the physician to be aware of the special issues surrounding the patient with Hunter syndrome, and a multidisciplinary approach should be taken. Subspecialties such as otorhinolaryngology, neurosurgery, orthopedics, cardiology, anesthesiology, pulmonology, and neurodevelopment will all have a role in management, as will specialty areas such as physiotherapy, audiology, and others. The important management topics are discussed in this review, and the use of enzyme-replacement therapy with recombinant human iduronate-2-sulfatase as a specific treatment for Hunter syndrome is presented. | Iduronate Sulfatase |
Senecavirus A (SVA) is the only member of genus Senecavirus that causes vesicular lesions in pigs. We have characterized seven SVA isolates from different swine farms in Guangdong, China. The most variable isolate, CH-DL-01-2016, contained a single amino acid insertion at position 219-220 and a 16 amino acid insertion at position 250-251. The VP1 protein also had four nucleotide changes when compared to 31 other SVA VP1 sequences obtained from GenBank. These mutations have not been identified before. Phylogenetic trees demonstrated that the new SVA isolates were clustered into two different clades and shared 96.3%-97.1% similarity with US strains and 97.9%-98.3% similarity with Brazilian stains on nucleotide level, respectively. Prediction of antigenic epitope indicated that SVA VP1 protein contained both potential B-cell and potential T-cell epitopes. This report provides information about variation analysis in SVA in southern China. | Picornaviridae |
This paper presents findings from a national study of the Irish public health nursing service and focuses, in particular, on issues relating to service configuration. The findings are drawn mainly from a national questionnaire of public health nurses (PHNs) working with families with infants (n=613; response rate 54 per cent) and the data were gathered in 1999/2000. The average ratio of public health nurse (PHN) to population size was found to be 1:3997 with a range between 500 and 16,500. The vast majority of respondents (85 per cent) had responsibility for five or more client groups including the elderly, those requiring clinical nursing care, terminal nursing care, psychiatric care, school nursing and the organisation of the home help service. Statistically significant differences between and within health board areas in the extent to which other nurses were available to the service led to a conclusion that in these circumstances a standardised service across individual PHN areas is not possible. The findings highlight the importance of the principle of vertical equity where service configuration is determined by population composition and need. | Child Health Services |
The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1-3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome. | Leupeptins |
Dimethoate, bromophos, naled or trichlorophon were applied i.p. or p.o. to rats in 3 doses each differing by the factor 10. In the urine of 24 h gas chromatographic determination of dimethylphosphate (DM), O.O-dimethylthiophosphate (TP), and/or O.O-dimethyldithiophosphate (DT) were carried out. After i.p. application of dimethoate the excretion rate of DT calculated from the dates found with the lowest dosage differed significantly from those found with the two other doses (t-test; p = 0.01). The excretion rates of DM and TP, in the same way, or those of DM, TP, and DT after oral intake of dimethoate did not show any significant differences. The excretion rates of TP after bromophos and of DM after naled or trichlorophon did not differ significantly after the same way of application. The findings make evident that under the given test conditions the excretion rate of DM, TP, or DT is practically independent on the dose. | Naled |
The aerial parts of the Lamiaceae Hedeoma drummondii (Benth.) are used in Mexico to prepare a herbal tea and by North American Amerindians as a spice. The methanolic extract of the aerial parts exhibited a strong antioxidant effect measured by the scavenging of the free diphenyl picrylhydrazyl (DPPH) radical. Assay-guided fractionation of the crude methanolic extract allowed the identification of three major active constituents, chlorogenic, caffeic and rosmarinic acid, as well as sideritoflavone derivatives and simple phenolics. The TEAC, FRAP, total phenolic and flavonoid content were determined. The high content of caffeic acid and rosmarinic acid relates to the antioxidant activity of H. drummondii. | Hedeoma |
A 49-year-old man presented with shortness of breath on exertion, orthopnea, and chest pain. On transthoracic echocardiography, a myxomatous mass was seen in the left atrium. A diagnosis of atrial myxoma was made and the patient underwent urgent surgical intervention. At operation, the mass, which extended into the anterior leaflet of the mitral valve, was excised. Histopathologic examination showed a primary cardiac sarcoma arising within a preexisting atrial myxoma. The patient received no further treatment and died 7 months postoperatively. We report the first case of a malignant transformation of an atrial myxoma to a cardiac sarcoma." | Preexisting Condition Coverage |
This study analyzes the Children's Embedded Figures Test by examining its internal consistency, test-retest reliability, the order of difficulty of the items, and the change of scores with age. Among the sample 337 boys and 287 girls who were between the ages of 6 and 11 years and in the first five grades of primary school scores increased significantly. The test presented moderate internal consistency (.86), and the test-retest reliability after one year was .63. The order of difficulty of the items did not coincide with the order proposed by the test's authors and varied from grade to grade, i.e., in the Tent series Item 4 and in the House series Item 5 were among the most difficult. | Personality Tests |
Prodrugs are ingenious derivatives of therapeutic agents designed to improve the pharmacokinetic profile of the drug. Here, we report an efficient and regioselective solid phase approach for obtaining new prodrugs of 9''-silybins conjugated with 3'-ribonucleotide units (uridine and adenosine) as pro-moieties. Uridine and adenosine conjugates were obtained in good yields (41-50%), beginning with silibinin and its diastereomers (silybin A and silybin B), using a NovaSyn(R) support functionalized with an ad hoc linker, which allowed selective detachment of only the desired products. As expected, the solubility of both uridine and adenosine conjugates was higher than that of the parental natural product (5 mg/mL and 3 mg/mL for uridine and adenosine, respectively). Our investigations revealed that uridine conjugates were quickly cleaved by RNase A, releasing silybin drugs, even at low enzyme concentrations. No toxic effects were found for any ribonucleotide conjugate on differentiated neuroblastoma SH-SY5Y cells when tested at increasing concentrations. All results strongly encourage further investigations of uridine-silybin prodrugs as potential therapeutic agents for both oral and intravenous administration. The present synthetic approach represents a valuable strategy to the future design of new prodrugs with modified nucleoside pro-moieties to modulate the pharmacokinetics of silybins or different natural products with strong pharmacological activities but poor bioavailability. | Flavonolignans |
Lymphocyte enhancer factor 1 (LEF1), a member of the LEF/T-cell-specific factor (TCF) family of the high mobility group domain transcription factors, acts downstream in canonical Wnt signaling. Aberrant transactivation of LEF1 contributes to the tumorigenesis of colonic neoplasms, sebaceous skin tumors, and lymphoblastic leukemia. LEF1-associated proteins are crucial for regulating its transcriptional activity. In this study, glutathione-S-transferase pull-down assay and mass spectrometry enabled identification of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a novel interaction partner for LEF1. The interaction between LEF1 and DNA-PKcs was confirmed using in vivo co-immunoprecipitation. Furthermore, double immunofluorescence observations showed that LEF1 and DNA-PKcs colocalized in the nuclei of colon adenocarcinoma cell lines. Identification of the interaction between LEF1 and DNA-PKcs may provide clues for a novel therapy for cancer treatment as well as for understanding LEF1-mediated transcriptional regulation. | DNA-Activated Protein Kinase |
The mechanism of the vasodilator action of pinacidil has been studied in rat mesenteric small arteries. The results show, first, that the use of flux studies to make measurements of ion permeability requires knowledge of the membrane potential, especially as regards K+ permeability. Second, the results confirm that the vasodilator effect of pinacidil is due to an increase in K+ permeability. Lastly, the results suggest that the K+ channels involved are sensitive to glibenclamide. | Cell Membrane Permeability |
The design and operation of a modular, bacteriological continuous-flow culture system have been adapted for the growth of Trypanosoma cruzi epimastigotes in simple monophasic media. The system was designed to achieve a minimum of 200 days of continuous culture and provision was made for the continuous supply of medium and collection of parasites under sterile conditions. The system provides large quantities of epimastigotes with homogeneous morphology and uniform viability. The system also lends itself to the analysis of the factors which affect parasite growth. We examined the effects of changes in environmental parameters on epimastigote growth rate. Optimal growth was observed at 27 degrees C. The rate of stirring of the culture had a small but definable effect on the growth rate, which was greatest at 80 rp.m. Growth was only slightly affected by the level of dissolved oxygen between 10 and 50% saturation, but was inhibited at higher concentrations. Growth was slower at extreme values of pH but showed a broad optimum around pH 7.4. | Parasitology |
An increasing interest has been developed in the past 15 years in the relationship between trace elements and cell functioning. In the present work the possibility of transgenerational effects of Te was investigated in rats. F(1) generation exposed to K(2)TeO(3) (1.55nM) from day 1 of pregnancy until litters were 30 day old, these animals with no other treatment than tap water and food were let to reach 60-70 day old. At this age, female rats were mated with normal untreated male rats. The F(2) generation also without any Te treatment was allowed to grow until 30 days of age. At this age, behavioral tests measuring exploration induced by novelty, lateralized exploration, social interaction and survival behavior were applied. Results showed that head-dipping, rearing, lateralized exploration, social interaction, and survival behaviors, affected by Te treatment in F(1) generation, also were modified in the same manner in F(2) generation. These data show that Te effects on coping behavior in rats are preserved epigenetically in the next generation. | Tellurium |
Osteoarthritis is a chronic degenerative joint disease affecting millions of people worldwide, with no disease-modifying drugs currently available to treat the disease. Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a potential therapeutic target in osteoarthritis because of its ability to inhibit the catabolic metalloproteinases that drive joint damage by degrading the cartilage extracellular matrix. We previously found that suramin inhibits cartilage degradation through its ability to block endocytosis and intracellular degradation of TIMP-3 by low-density lipoprotein receptor-related protein 1 (LRP1), and analysis of commercially available suramin analogues indicated the importance of the 1,3,5-trisulfonic acid substitutions on the terminal naphthalene rings for this activity. Here we describe synthesis and structure-activity relationship analysis of additional suramin analogues using ex vivo models of TIMP-3 trafficking and cartilage degradation. This showed that 1,3,6-trisulfonic acid substitution of the terminal naphthalene rings was also effective, and that the protective activity of suramin analogues depended on the presence of a rigid phenyl-containing central region, with para/para substitution of these phenyl rings being most favourable. Truncated analogues lost protective activity. The physicochemical characteristics of suramin and its analogues indicate that approaches such as intra-articular injection would be required to develop them for therapeutic use." | Tissue Inhibitor of Metalloproteinase-3 |
Vernakalant is a new antiarrhythmic agent recently approved in Europe for the rapid cardioversion of recent-onset atrial fibrillation. It works by blocking early-activating K+ atrial channels and frequency-dependent atrial Na+ channels, prolonging atrial refractory periods and rate-dependent slowing atrial conduction, without promoting ventricular arrhythmia. Preclinical and clinical trials showed good toleration of this drug. The main purpose of our review is to describe all the trials that led to the incorporation of vernakalant into the current European atrial fibrillation guidelines. | Anisoles |
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed protein that contains both an ion channel and an active kinase. TRPM7 has involved in a variety of cellular functions and critically participates in various diseases mainly including cancer and neurodegenerative disorders. However, the theme trends and knowledge structures for TRPM7 have not yet been studied bibliometrically. The main purposes of this research are to compare the scientific production in the research field of TRPM7 among countries and to evaluate the publication trend between 2004 and 2019. All publications were extracted from the Web of Science Core Collection (WoSCC) database from 2004 to 2019. Microsoft Excel 2018, Prism 6, and CiteSpace V were applied to analyze the scientific research outputs including journals, countries, territories, institutions, authors, and research hotspots. In this report, a total of 860 publications related to TRPM7 were analyzed. Biophysical Journal ranked top for publishing 31 papers. The United States of America had the largest number of publications (320) with a high citation frequency (11,298) and H-index (58). Chubanov V (38 publications) and Gudermann T (38 citations), who from Ludwig Maximilian University of Munich, were the most productive authors and had the greatest co-citation counts. Our study also combined the bibliometric study with a systematic review on TRPM7, highlighting the four research frontiers of TRPM7. This is the first study that demonstrated the trends and future development in TRPM7 publications, providing a clear and intuitive profile for the contributions in this field. | TRPM Cation Channels |
INTRODUCTION: Pathogen Inactivation allows to overcome microbial contamination and growth related to storage of platelets concentrates (PC) at room temperature. The aim of our study was to evaluate the platelet storage lesion extending the storage period of pathogen inactivated platelet concentrates over 7 days using an automated cytometry assay panel. METHODS: We analyzed 43 concentrates subjected to pathogen inactivation (CPPI) at 3, 5 and 7 days evaluating: platelet count, mean platelet volume, platelets at low optical density, platelets at high density, GPIIb-IIIa glycoprotein, platelet microparticles, lactate dehydrogenase. The collection bags (Fenwal) and the IBS kit made in PL2410/PL2411 are approved for the conservation of PC up to 7 days. Data analysis was performed with anova test. RESULTS: All the parameters except small platelets and PMP were statistically different among day 7 vs. 3 and day 7 vs. 5. CONCLUSIONS: Our study showed a progressive modification of pathogen inactivated platelet concentrates observed up to 7 days. The persistence of the secretory pool and the presence of the platelet membrane fibrinogen receptor suggest the persistence of a potential hemostatic efficacy. Clinical studies are necessary to directly correlate this type of analysis to 24 h recovery or survival of transfused platelets in humans." | Platelet Membrane Glycoprotein IIb |
The removal of initiating primers from the 5'-ends of each Okazaki fragment, required for the generation of contiguous daughter strands, can be catalyzed by the combined action of DNA polymerase delta and Fen1. When the flaps generated by displacement of DNA synthesis activity of polymerase delta become long enough to bind replication protein A or form hairpin structures, the helicase/endonuclease enzyme, Dna2, becomes critical because of its ability to remove replication protein A-coated or secondary structure flaps. In this study, we show that the N-terminal 45-kDa domain of Dna2 binds hairpin structures, allowing the enzyme to target secondary structure flap DNA. We found that this activity was essential for the efficient removal of hairpin flaps by the endonuclease activity of Dna2 with the aid of its helicase activity. Thus, the efficient removal of hairpin structure flaps requires the coordinated action of all three functional domains of Dna2. We also found that deletion of the N-terminal 45-kDa domain of Dna2 led to a partial loss of the intra-S-phase checkpoint function and an increased rate of homologous recombination in yeast. We discuss the potential roles of the N-terminal domain of Dna2 in the maintenance of genomic stability. | DNA Helicases |
A reversed-phase high performance liquid chromatographic (RP-HPLC) method was established for the determination of arsanilic acid and sulfanilic acid as adulterant in the feed additives. The separation was carried out on a Waters Bondapak C18 column, and methanol-water (pH 2.9 adjusted by 0.01 mol/L phosphoric acid) (1 : 4, v/v) was used as the mobile phase with a flow rate of 1.0 mL/min. A diode array detector was used at 244 nm as the detection wavelength. Arsanilic acid and sulfanilic acid were separated within 3 min. The linear ranges all were 5 - 200 mg/L and the detection limits (S/N = 3) were 0.20 and 0.15 mg/L for arsanilic acid and sulfanilic acid, respectively. This method is simple and rapid, and suitable for the simultaneous determination of arsanilic acid and sulfanilic acid in feed additives. | Sulfanilic Acids |
In a protozoan (Tetrahymena) model system, insulin treatment produced a long-term imprinting which upon re-exposure to the hormone resulted in an enhanced binding of the hormone. Insulin pretreatment produced similar effect with regard to the binding of concanavalin-A. Concanavalin-A could only induce a short-term imprinting for itself and was not capable at all of inducing imprinting for insulin. Based on the results of this study it appears that the binding of the sugar component of the receptor, which can be achieved also by lectin, is not sufficient to induce imprinting but the whole (hormone) molecule is needed. | Receptors, Concanavalin A |
In isolated rat liver single pass perfused via both the hepatic artery (80 mmHg, 30% flow) and the portal vein (10 mmHg, 70% flow), norepinephrine (NE) was infused either singly or jointly via the hepatic artery or the portal vein in the absence or presence of the alpha 1-blocker prazosin or the beta 2-blocker butoxamine. Arterial NE caused an increase in glucose output and a shift from lactate uptake to release that was slower in onset and smaller in peak height but longer in duration than the alterations affected by portal NE. The sum of the metabolic changes by arterial and portal NE was not equal to the changes by jointly applied arterial plus portal NE. The metabolic alterations by arterial NE were mediated via alpha 1-receptors, with beta 2-receptors probably having a permissive function, but those by portal NE were transmitted only via alpha 1-receptors. Arterial NE caused a strong decrease in arterial flow and contralaterally also a smaller reduction of portal flow. Portal NE decreased portal flow but did not significantly influence arterial flow. The sum of the alterations in flow by arterial and portal NE was not equal to the changes by jointly applied NE. The hemodynamic alterations in the artery by arterial NE were the results of actions via alpha 1-receptors and counteractions via beta 2-receptors, whereas the changes in the portal vein by arterial NE and portal NE were mediated via alpha 1-receptors. About 65% of arterial and only 30% of portal NE was extracted during a single path. The results indicate that the hepatic artery and the portal vein can function as independent sites of hormonal signal input, which interact by complex but still undefined mechanisms in the regulation of metabolism and hemodynamics. | Butoxamine |
Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (> 99% at 0.1 microM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site-directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8-Tetrahydronaphthalene 2-O-sulfamate (7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 microM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) were prepared to extend this series of nonsteroidal inhibitors, and COUMATE reduces the E1-STS activity in placental microsomes by > 90% at 10 microM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) were also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4-dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 nM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed. | Sulfatases |
Lipoprotein lipase (LPL) interaction with membrane-associated polyanions is a critical component of normal catalytic function. Two strong candidate binding regions, rich in arginine and lysine residues, have been defined in the N-terminal domain (aa279-282 and aa292-304) that show homology to the heparin-binding consensus sequences -X-B-B-X-B-X- and -X-B-B-B-X-X-B-X-, respectively. Additional candidate regions appear in the C-terminal domain, (residues 390-393), which are homologous to the thrombospondin heparin-binding repeat, and the positively charged terminal decapeptide (residues 439-448). To determine residues and domains critical to heparin binding, we have generated different LPL mutants that have alanine substitutions of single arginine and lysine residues and sequence interchanges with the homologous hepatic (HL) and pancreatic (PL) lipases. The mutant cDNAs were expressed in COS-1 cells and catalytically active mutants were assessed for binding to heparin-Sepharose. All the alanine substitutions within the two regions homologous to the heparin-binding consensus sequences in the N-terminal domain either abolished activity or produced a lowering of heparin binding affinity. None of the mutants in the C-terminal domain of LPL showed a loss of activity or a reduction in heparin binding affinity. These data demonstrate that charged residues at positions 279-282 and 292-304 of LPL are important for heparin binding affinity whereas the residues 390-393 and 439-448 in the C-terminal domain are not involved in heparin binding. | Lipoprotein Lipase |
Food distribution (FD) is a part of the public social and care service in Sweden aiming to prevent improper food intake for persons that they are unable to do their own shopping, and prepare their own meals, and in that way ensure reasonable standard of living. Before a person can be granted the FD service, from any municipality, an assessment of their individual requirements has to be made by a public home care officer. The aim of this study was to explore how public home care officers reason when they make a needs assessment for homebound elderly people. The data was collected through individual interviews (n=18). The transcribed interview material was analysed by means of the grounded theory method. The findings showed that the public home care officers were confronted with many challenges when making an assessment of a person's individual needs. They are influenced by their subjective feelings related to their personal views as to what should be the right solution for the individual. However, they remained aware that they needed to be guided by the legal requirements. Further, they described that the level of an individual's living standard is a leading concept in the governing laws that they need to interpret. Interpretation of this concept is very subjective with the possible consequence that an assessment result may lead to inefficient support. In conclusion, the concept of a reasonable standard of living needs to be clearly defined, decision regarding FD should not take long time, need assessment and decision should be based on the whole picture behind each individual case and there are needs to develop general guidelines for making needs assessment. The findings in this study have implications for public administration, nursing and gerontology. | Needs Assessment |
Liver fibrosis is a global health problem currently without clinically approved drugs. It is characterized by the excessive accumulation of extracellular matrix (ECM) mainly produced by activated hepatic stellate cells (HSCs). Uncovering the mechanisms underlying the fibrogenic responses in HSCs may have profound translational implications. Erythropoietin-producing hepatocellular receptor B2 (EphB2) is a receptor tyrosine kinase that has been indicated to be a novel profibrotic factor involved in liver fibrogenesis. In the present study, we investigated the effects of miR-451 and miR-185 on the expression of EphB2 and their roles in liver fibrogenesis both in vitro and in vivo. We found that EphB2 upregulation is a direct downstream molecular event of decreased expression of miR-451 and miR-185 in the process of liver fibrosis. Moreover, miR-451 was unexpectedly found to upregulate miR-185 expression at the post-transcriptional level by directly targeting the nuclear export receptor exportin 1 (XPO-1) and synergistically suppress HSCs activation with miR-185. To investigate the clinical potential of these miRNAs, miR-451/miR-185 agomirs were injected individually or jointly into CCl(4)-treated mice. The results showed that coadministration of these agomirs synergistically alleviated liver fibrosis in vivo. These findings indicate that miR-451 and miR-451/XPO-1/miR-185 axis play important and synergistic regulatory roles in hepatic fibrosis partly through co-targeting EphB2, which provides a novel therapeutic strategy for the treatment of hepatic fibrosis. | Receptor, EphB2 |
Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in both men and women. Because most PC patients are initially diagnosed at an advanced stage of disease, effective diagnostic tests for earlier diagnosis of PC are needed. Several studies have investigated the utility of nanoparticle for both diagnosis and therapy of PC. This review discusses the various engineered nanoparticles currently in use for imaging and therapy. Although nanoparticles have shown considerable clinical promise, complete translation of nanoparticle-based molecular imaging and oncotherapeutic agents has been the challenge. | Pancreatic Neoplasms |
It is difficult to predict, on first contact with patients with AN, whether a compulsory admission to hospital may become necessary to protect their lives and health. There are only tentative pointers so far to an entrenched avoidance of treatment: (1) components of a disordered personality associated with a history of childhood physical or sexual abuse or previous episodes of self-harm and (2) the presence of a more severe illness, suggested by numerous previous admissions. An involuntary admission is likely to be beneficial at least in the short term, as shown by a gratifying weight gain, although a longer period of inpatient stay may be necessary. Patients who have required compulsory detention are at a considerable risk in the long-term as shown by their high mortality rates. It is, therefore, essential to organize long-term observation for all patients who required involuntary admission for AN. A compulsory admission for AN does not require compulsory treatment, such as forced feeding by NGT or other intrusive methods. Clinicians who contemplate a compulsory admission for a seriously ill anorexic patient might therefore question the advantages provided by the detention. First, clinicians can be assured that it should be possible to induce a satisfactory weight gain through persistent nursing methods without running the risk of these patients discharging themselves. With inpatients, the goals are nearly always attained, although the admission may be longer than average. Not only do these patients' nutrition improve vastly, but also they are likely to show improvements in their mental state. Secondly, these patients are likely to learn that the professional staff, their families, and outside agencies take their illness very seriously, even if patients themselves do not seem to. This is particularly evident when patients appeal to a Mental Health Review Tribunal for release. They attend the proceedings and hear the evidence presented by their psychiatrists, the nursing staff, and their nearest relatives. The tribunal usually sustains the compulsory admission: the patient may be initially distressed, but in the long run the experience is generally therapeutic. Finally, compulsory admission permits more stringent forms of supervision. For example, patients who vomit may have legitimately restricted access to bathrooms. Patients addicted to exercise may be rationed to sensibly short periods of walking daily. Patients who are extremely anxious or overactive may be required to take appropriate tranquilizing or sedating drugs, such as one of the benzodiazepine drugs. Clinicians sometimes are reluctant to resort to compulsory admission because of a fear of damaging the therapeutic relationship with their patients. Clinical observations, however, point to the converse being the case, as shown in several studies. Tiller et al maintain: Compulsory treatment may be an act of compassion: it shows that professionals recognize the severity of the illness and that they are prepared to contain the anxieties provoked by weight gain. Often the patients and their families are immensely relieved to hand over the responsibility, temporarily, to the professional team."" | Treatment Refusal |
The aim of the study was the evaluation of myorelaxant action of bee venom (BV) ointment compared to placebo. Parallel group, randomized double blinded trial was performed. Experimental group patients were applying BV for 14 days, locally over masseter muscles, during 3-minute massage. Placebo group patients used vaseline for massage. Muscle tension was measured twice (TON1 and TON2) in rest muscle tonus (RMT) and maximal muscle contraction (MMC) on both sides, right and left, with Easy Train Myo EMG (Schwa-medico, Version 3.1). Reduction of muscle tonus was statistically relevant in BV group and irrelevant in placebo group. VAS scale reduction was statistically relevant in both groups: BV and placebo. Physiotherapy is an effective method for myofascial pain treatment, but 0,0005% BV ointment gets better relief in muscle tension reduction and analgesic effect. This trial is registered with Clinicaltrials.gov NCT02101632. | Muscle Tonus |
This review covers the recent marine chemical ecology literature for macroalgae, sponges, octocorals and other benthic invertebrates; 332 references are cited. | Invertebrates |
Klebsiella variicola is an emerging pathogen responsible for causing blood-stream infections, urinary and respiratory tract related diseases in humans. In this report, we describe the genome sequence data and phenotypic characterization of K. variicola strain KV093 isolated from India. Comparative genome sequence analysis revealed the presence of genes linked with virulence, iron acquisition and transport, type 1 and type 3 pili, secretion systems including the capsular gene cluster. The plant-associated genes such as nitrogen fixation, growth and defense mechanisms against oxidative stress were also identified. On performing antibiotic susceptibility testing, growth inhibition, and stress challenge assays it was observed that the drug resistant K. variicola KV093 exhibited cross resistance to various antibiotics, antiseptics, including disinfectants. This report highlights the arsenal of virulence and antibiotic resistance determinants in K. variicola KV093, an effort emphasizing the current pressing need for regular surveillance of K. variicola strains especially in India. | Klebsiella |
Introduction. Mean platelet volume (MPV) has been thought as a useful index of platelet activation. It is supposed that MPV is also associated with several inflammatory and infectious diseases. Korea still has a high incidence of tuberculosis (TB). The aim of this study was to investigate MPV as an inflammatory marker in TB patients. Materials and Methods. MPV were determined in 221 patients with TB and 143 individuals for control group. MPV was estimated by an Advia 2120 (Siemens Healthcare Diagnostics, Tarrytown, NY, USA). Results. In the TB patient group, a positive correlation was found between CRP and MPV. Age and MPV had a positive correlation in TB patient group. Conclusions. We conclude that there is a significant relation between MPV and inflammatory conditions. MPV can be an inflammatory marker to determine the disease activity in TB patients. | Mean Platelet Volume |
The p53 tumour suppressor protein is subject to many levels of control, including modification with ubiquitin and related proteins such as SUMO and NEDD8. These modifications regulate p53 at a number of levels, including control of protein turnover, alterations in sub-cellular localization and changes in the ability to regulate gene expression. Numerous E3 ligases that can mediate these modifications of p53 have been described, some of which promote conjugation with more than one ubiquitin-like protein. Understanding the complexity of this mechanism of p53 regulation will help in the development of therapeutic drugs that function to modulate these events. | NEDD8 Protein |
A retinal pigment epithelial (RPE) tear is a well-known complication of retinal pigment epithelial detachments (PED) and may cause a significant visual impairment. The most common cause is a vascularized PED in patients with exudative age-related macular degeneration (AMD). The development of diagnostic imaging techniques brings us closer to the etiology and pathophysiological mechanisms of this entity, offering us new strategies for treatment and follow-up. The advent of intravitreal antiangiogenic treatment (anti-VEGF) has led to an increase in the number of reported cases of RPE tears, which are an important vision-limiting factor during treatment. However, RPE tears may occur spontaneously or as a consequence of thermal laser treatment, photodynamic therapy or anti-VEGF therapy. It is accepted that the mechanism of RPE tears is multifactorial. The optimization of the functional outcome of this complication has been described with continuous treatment with antiangiogenic drugs. The goal of the present review is to evaluate the incidence, risk factors and treatment of RPE tears. | Rupture, Spontaneous |
The emergence and convergence of cancer genomics, targeted therapies, and network oncology have significantly expanded the landscape of protein-protein interaction (PPI) networks in cancer for therapeutic discovery. Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintenance of characteristics of cancer essential for cell transformation. Such cancer-enabling PPIs have become promising therapeutic targets. With technological advances in PPI modulator discovery and validation of PPI-targeting agents in clinical settings, targeting of PPI interfaces as an anticancer strategy has become a reality. Future research directed at genomics-based PPI target discovery, PPI interface characterization, PPI-focused chemical library design, and patient-genomic subpopulation-driven clinical studies is expected to accelerate the development of the next generation of PPI-based anticancer agents for personalized precision medicine. Here we briefly review prominent PPIs that mediate cancer-acquired properties, highlight recognized challenges and promising clinical results in targeting PPIs, and outline emerging opportunities. | Neoplasm Proteins |
In a previous study [(1987) J. Mol. Biol. 194, 663-673], we isolated ten insertion/deletion mutants (indels) of the maltose binding protein for which the maltose binding constant was only a little or not at all affected. In this paper, we have localized these mutations in the recently solved three-dimensional structure. Contrary to the general expectation, most of the insertion/deletion modifications occurred within elements of secondary structure. An analysis of the inserted residues for three indels found within alpha helices allowed an interpretation regarding protein structure accommodation to such modifications. | Maltose-Binding Proteins |
Glucosamine synthase (GlmS) converts fructose-6-phosphate to glucosamine-6-phosphate. Overexpression of GlmS in Escherichia coli increased synthesis of glucosamine-6-P, which was dephosphorylated and secreted as glucosamine into the growth medium. The E. coli glmS gene was improved through error-prone polymerase chain reaction (PCR) in order to develop microbial strains for fermentation production of glucosamine. Mutants producing higher levels of glucosamine were identified by a plate cross-feeding assay and confirmed in shake flask cultures. Over 10 mutants were characterized and all showed significantly reduced sensitivity to inhibition by glucosamine-6-phosphate. Ki of mutants ranged from 1.4 to 4.0 mM as compared to 0.56 mM for the wild type enzyme. Product resistance resulted from single mutations (L468P, G471S) and/or combinations of mutations in the sugar isomerase domain. Most overexpressed GlmS protein was found in the form of inclusion bodies. Cell lysate from mutant 2123-72 contained twice as much soluble GlmS protein and enzyme activity as the strain overexpressing the wild type gene. Using the product-resistant mutant, glucosamine production was increased 60-fold." | Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) |
BACKGROUND: Desensitization and downregulation of myocardial beta-adrenergic receptors (betaARs) are initiated by the increase in betaAR kinase 1 (betaARK1) levels. By interacting with betaARK1 through the phosphoinositide kinase (PIK) domain, phosphoinositide 3-kinase (PI3K) is targeted to agonist-stimulated betaARs, where it regulates endocytosis. We tested the hypothesis that inhibition of receptor-targeted PI3K activity would alter receptor trafficking and ameliorate betaAR signaling, ultimately improving contractility of failing cardiomyocytes. METHODS AND RESULTS: To competitively displace PI3K from betaARK1, we generated mice with cardiac-specific overexpression of the PIK domain. Seven-day isoproterenol administration in wild-type mice induced desensitization of betaARs and their redistribution from the plasma membrane to early and late endosomes. In contrast, transgenic PIK overexpression prevented the redistribution of betaARs away from the plasma membrane and preserved their responsiveness to agonist. We further tested whether PIK overexpression could normalize already established betaAR abnormalities and ameliorate contractile dysfunction in a large animal model of heart failure induced by rapid ventricular pacing in pigs. Failing porcine hearts showed increased betaARK1-associated PI3K activity and marked desensitization and redistribution of betaARs to endosomal compartments. Importantly, adenoviral gene transfer of the PIK domain in failing pig myocytes resulted in reduced receptor-localized PI3K activity and restored to nearly normal agonist-stimulated cardiomyocyte contractility. CONCLUSIONS: These data indicate that the heart failure state is associated with a maladaptive redistribution of betaARs away from the plasma membrane that can be counteracted through a strategy that targets the betaARK1/PI3K complex." | beta-Adrenergic Receptor Kinases |
In contrast to mammalian erythrocytes, chicken erythrocytes contain fructose 2,6-bisphosphate at levels (0.5 nmol/10(9) cells) similar to those of 2,3-bisphosphoglycerate (1.2 nmol/10(9) cells) and slightly lower than those of glucose 1,6-bisphosphate (5.2 nmol/10(9) cells). In chick embryo erythrocytes the levels of both fructose 2,6-bisphosphate and glucose 1,6-bisphosphate are much lower. They begin to increase at hatching and reach the levels in chicken in a few days. | Fructosediphosphates |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.