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31366408
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Noted above, rural primary care practices often lack the resources necessary to provide MAT. All MAT, behavioral, and physical health related services delivered within the project service model are reimbursable through Medicaid MCO contracts with providers. Practices recruited to participate in this project are directly connected with billing specialists from their corresponding Medicaid MCOs to instruct on appropriate procedures and available billing codes to ensure adequate reimbursement for services provided to sustain MAT expansion within the clinic.
|
[
"Gerald Cochran",
"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
] |
https://doi.org/10.1186/s13722-019-0154-4
|
OpenAccess
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http://creativecommons.org/licenses/by/4.0/
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en
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The process for supporting the MAT program implementation follows the Framework for Systems Transformation (STF) and encompasses 7 domains, see Table 1 . The domains are: Vision, Leadership, Performance Measurement, Internal Learning, External Learning, Organizational Culture/Behavior, and Organizational Structure. The implementation team uses the STF to understand the organizational health of each implementation site and partnership, which helps determine the amount of resources necessary to ensure the program meets its implementation goals and to support the sites in the development of a common programmatic vision, specification of implementation processes, collection of implementation related data, and application of continuous quality improvement efforts. Table 1 Framework for systems transformation and RAMP project activities undertaken by implementation team Vision Leadership Performance measurement Internal learning External learning Organizational culture/behavior Organizational structure Develop site-specific vision statement that interfaces with RAMP project implementation vision statement, e.g.: [Name of Primary Care Practice] will increase patient access to MAT and addiction specialty services in [the community] by providing the highest quality MAT services to our patients who suffer from opioid use disorder Identify system/site decision makers for collaboration and engagement Identify champions to support implementation at each site Provide ongoing support to site/system leaders throughout the implementation process Develop core set of data components for primary care, care management, and others to collect in the course of delivering the project activities Assist sites in collection of data components, tailoring methods to sites’ capabilities Clean, verify, and report back aggregated data to sites for performance improvement planning Employ Lean principles to support sites to improve implementation Employ Lean Rules in Use to ensure implementation process/roles are accurately specified Update/improve performance management reports continuously to ensure understanding and identification of needed changes Assign/monitor performance benchmarks to metrics to provide sites and RAMP team targets for implementation efforts Develop curriculum and training to provide skills/resources to physicians, advanced practice professionals, care management staff, and other involved staff that these professionals and the Implementation Team identify as important Update/modify curriculum and training topics based on site requests/needs, including attainment buprenorphine prescribing waivers Perform brief organizational health assessments of systems and sites to determine level of implementation difficulty in order to anticipate barriers and required resources to support implementation Facilitate primary care sites to participate in 1 of 4 MAT models to enhance site engagement/sustainability, which include (1) Site performs all aspects of MAT and patient monitoring (2) Site performs all aspects of MAT, and patient monitoring is referred to community partners (3) Site screens patients for potential MAT need and refer patients to “hubs” for induction and monitoring (4) Site screens patient for MAT need and refers to “hub” for induction, monitoring, and primary care services Implementation model involves “concierge technical assistance,” i.e., ongoing quasi real-time individualized assistance aimed at providing sites what they need when they need it determined via regular communication RAMP rural access to MAT in Pennsylvania, MAT medication assisted treatment
|
[
"Gerald Cochran",
"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
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https://doi.org/10.1186/s13722-019-0154-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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Data collected from each participating site are used to ensure that the primary care practice and collaborating partners are implementing the Project RAMP as designed. The data collected from the primary care practices includes SUD screening counts and data related to naltrexone and buprenorphine administration, such as the stage of treatment (initiation versus maintenance) and date of administration. Other collaborating partners, such as the care management teams, collect data related to contact and follow-up with patients, assessment results, and reasons for discharge from treatment. This data is provided via a web-based application system and/or paper-based spreadsheets faxed to the implementation team, which regularly provides aggregated data back to the sites and to the Steering Committee.
|
[
"Gerald Cochran",
"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
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https://doi.org/10.1186/s13722-019-0154-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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To assess outcomes, the Evaluation Team will conduct a retrospective claims-based analysis and a prospective patient-level survey. For the claims-based analysis, the Evaluation Team will use Pennsylvania Medicaid enrollment, claims, and encounter data to assess the extent MAT utilization increased for Medicaid beneficiaries in participating counties and practices following the intervention implementation during the three-year project period, 2016–2018. Using these data, a number of dependent variables will be constructed for analysis (Table 2 ), for instance: MAT provider supply defined as number of unique providers billing Medicaid for MAT, OUD prevalence, and MAT utilization. With these indicators, outcomes will be examined across time to assess whether implementation is correlated with changes in the indicators. Table 2 Claims-based measures and definitions for study outcomes Measure Operational definition Supply measures Percent of physicians certified to prescribe buprenorphine Number of physicians on SAMHSA list of buprenorphine or naltrexone prescribers/# Medicaid-participating physicians in county Percent of primary care practices delivering MAT Number of physicians with any prescribing of buprenorphine or naltrexone/# Medicaid-participating physicians in county measured in claims data Prevalence measures OUD diagnoses OUD ICD-9/ICD-10 code on inpatient, outpatient or professional claims Overdose events Inpatient stays or ED visits with an opioid overdose ICD-9/ICD-10 code OUD diagnoses among those with evidence of misuse of prescription opioids Rate of OUD diagnosis among those with opioid misuse using an algorithm from Sullivan et al. that uses # prescribers, # pharmacies, and # days short- and long-acting opioids Utilization measures Use of MAT Any prescription fill for buprenorphine or IM naltrexone among those with OUD Use of psychosocial supports Any visit with a service code for psychosocial support for OUD Access to counseling for OUD Any visit with a service code for counseling regarding psychosocial and pharmacologic treatment options among those with OUD Duration of MAT Number of months with proportion of days covered > 80% Access to tele-psychiatry Any visit with a service code for a tele-psychiatry visit Outcome measures Likelihood of any and SUD or mental health-related emergency department visit SUD or mental health ICD-9/ICD-10 code as primary diagnosis for an emergency department visit Likelihood of any and SUD or mental health-related inpatient hospitalization SUD or mental health ICD-9/ICD-10 code as primary diagnosis for an inpatient hospitalization SAMHSA Substance Abuse and Mental Health Services Administration, MAT medication assisted treatment, OUD opioid use disorder, ICD international classification of diseases, SUD substance use disorder
|
[
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"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
] |
https://doi.org/10.1186/s13722-019-0154-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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For the prospective patient survey, participants will be recruited at the various clinic sites. The purpose of the survey will be to assess patient’s perceived access to care and level of satisfaction as well as changes in these domains over a 6-month follow up period after patients are recruited into the project. Recruitment of patients is conducted by both the primary care physician and the care management team. Patient survey packets are distributed to eligible individuals, and those interested are asked to mail back a form indicating their willingness to be contacted by the research team. Survey responses cover items from the Consumer Assessment of Healthcare Providers and Systems survey, Primary Care Center Study Patient Satisfaction Questionnaire, and the Client Perception of Coordination Questionnaire. In addition to close-ended survey questions, participants will also be asked a series of open-ended research questions, which will explore perceived satisfaction, quality of care, and stigma. Participants receive a $10 gift card as remuneration for participation.
|
[
"Gerald Cochran",
"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
] |
https://doi.org/10.1186/s13722-019-0154-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
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This project provides a needed response to a major gap in the availability of MAT in rural areas. Results of this project have the potential to advance the field in two important ways. First, this project recognizes opioid-related adverse events, including OUD, are indeed chronic health conditions and delivers MAT following a chronic condition management model of care, which models have demonstrated in previous research to result in important improvements for patient outcomes [ 9 – 13 ]. Specifically, the service model in this project initiates a redesign of the current delivery system into a proactive approach that facilitates care the management professionals working with rural PCPs, so patients may have access to an interdisciplinary team. This project also works with key staff to ensure leadership is invested and motivated to provide the care required for MAT and reimbursement is available to practices, which engagement efforts have been identified as critical aspects for sustainment of new practices within health care settings [ 36 – 38 ]. Efforts within Project RAMP also include providing expert-informed decision support to guide patient care and grow PCPs’ skillsets . Lastly, Project RAMP offers training and expertise to PCPs via webinars and phone and email responses to questions on MAT and patient self-management. In the spirit of self-management, PCPs and care management professionals work to identify and refer patients to beneficial services and resources.
|
[
"Gerald Cochran",
"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
] |
https://doi.org/10.1186/s13722-019-0154-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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The second important contribution this project makes is that it follows an implementation model, the Framework for Systems Transformation , in order to ensure high fidelity for model implementation. Given the gap between real-world public health application and scientific discovery in the field, rigorous monitoring and evaluation of implementation efforts of evidence-based health care models into practice has been increasingly valued in recent years [ 40 – 42 ]. Thus, the chronic care based MAT model of service utilized in this project follows an implementation process designed to iteratively monitor and provide feedback to project leaders and practitioners. Utilization of implementation science has broad support for evidence-based practice implementation and results in service adoption, maintenance, and long-term outcomes [ 40 , 43 – 45 ]. Utilization of such a framework is especially important in rural areas given limited resources available for training and monitoring health and human services.
|
[
"Gerald Cochran",
"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
] |
https://doi.org/10.1186/s13722-019-0154-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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Rural areas in the US have been hit particularly hard by the current OUD and overdose epidemic given the paucity of health and human services resources available . This project has the potential to provide a model for how other states in the US can expand access to MAT. Components of this project may be transferable to other rural counties in the US, including working with payers to identify communities in need, recruiting key staff within PCP practices to help move forward project needs, and leveraging existing community resources to support behavioral and care management needs of patients.
|
[
"Gerald Cochran",
"Evan S. Cole",
"Jack Warwick",
"Julie M. Donohue",
"Adam J. Gordon",
"Walid F. Gellad",
"Todd Bear",
"David Kelley",
"Ellen DiDomenico",
"Jan Pringle"
] |
https://doi.org/10.1186/s13722-019-0154-4
|
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http://creativecommons.org/licenses/by/4.0/
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en
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Rabies is an acute zoonotic infectious disease caused by the rabies virus that severely impacts the central nervous system. Rabies is commonly seen in carnivorous animals such as dogs, wolves, cats, and bats, and the virus is transmitted by a bite from an infected animal . The mortality of rabies is extremely high; an unvaccinated infected person is expected to live for only a maximum of 7 days after the appearance of symptoms if timely and appropriate therapy is not applied. It is estimated that there are at least 55,000 deaths per year worldwide from rabies; about 56% of these deaths occur in Asia and 44% in Africa (particularly in rural areas of both continents), and almost all of these patients missed the narrow window for optimal treatment due to misdiagnosis [ 1 – 3 ].
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
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Typical symptoms of rabies include aggression; hydrophobia; anemophobia; progressive paralysis; and hypersensitivity to sound, light, wind, and pain. In the early stage, atypical flu-like symptoms such as fever, loss of appetite, nausea, headache, fatigue, and general malaise may also appear. Moreover, uncommon symptoms and signs reflecting abnormal sexual behaviors, including frequent ejaculation, priapism, hypersexuality, and other abnormal sexual behaviors, may be the representing manifestations of rabies, which may lead to misdiagnosis. Indeed, over the last five decades, more than 50 sporadic cases with atypical early manifestations have been reported worldwide [ 4 – 40 ]; most cases were misdiagnosed or not diagnosed at all, and all resulted in death.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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In 2014, we admitted a male patient presenting with frequent ejaculation, and a diagnosis of rabies was confirmed. Unfortunately, many physicians are not aware of these atypical cases, and do not consider rabies when encountering a patient presenting with a change in sexual behavior in clinical practice. Considering the high mortality and strong infectivity, this paper will systematically analyze and summarize the clinical features of abnormal sexual behaviors as the presenting manifestations in patients with rabies, by first reporting our case and then presenting data derived from a literature search.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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A 32-year-old Chinese man began to have frequent ejaculations on December 7 (day 1), 2014, at a frequency of 5–6 times a day; these reached 20–30 times on day 3. When frequent ejaculation increased to 40–50 times on the morning of day 4, the patient went to a local clinic in Beijing that specialized in traditional Chinese medicine for treatment of “imbalance of Yin and Yang ”. However, symptomatic treatment to rebalance Yin and Yang had no effect. In the same afternoon, he was sent to a community hospital in Beijing with the following symptoms: headache, dizziness, nausea, and malaise; fever of 39 °C; irritability; tachyphrasia; speech difficulty; and hypersalivation. He was subsequently transferred to a tertiary hospital in Beijing for further diagnosis and treatment, but the etiology remained unidentified. At around 10:00 pm on day 4, the patient was sent to the Infectious Disease Department of Peking University Third Hospital, and then transferred to the Emergency Department due to tachycardia and dyspnea. His complaints included high penis sensitivity, painful erections, and ejaculations > 40 times a day triggered by any touch (or ejaculations without erection and release of semen) as well as headache, nausea, chest congestion, and fever. There was no significant improvement after fluid infusion, symptomatic treatment, and other supportive therapies. No diagnosis was made even after consulting urologists, neurologists, and psychiatrists until 5:00 pm on day 5 when rabies was finally considered as typical symptoms such as anemophobia, hydrophobia, and photophobia then emerged. After questioning the patient and his family, he admitted a history of a scratch on the right foot caused by a dog about 4 months earlier. The wound was superficial and left untreated, and neither rabies vaccine nor a passive immune preparation was given. At 10:30 am on day 6, he developed apnea and was intubated, and multiple vasopressors were given at the same time. His condition continued to deteriorate rapidly, and he was declared clinically dead at 12:59 pm the same day.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
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Two days after the death of the patient, positivity of rabies virus neutralizing antibody (the exact titer was not available due to the absence of quantitative analysis) in serum samples, and a positive lyssavirus signal in a polymerase chain reaction targeting the conserved region of the nucleoprotein gene of lyssaviruses in two saliva specimens were reported by Beijing Center for Disease Control and Prevention Thus, the diagnosis of rabies was officially established. The patient’s family refused the recommendation for autopsy.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
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A literature search of papers reporting rabies cases with abnormal sexual behaviors (or abnormal sexual symptoms as the presenting manifestations) was performed on December 31, 2017. Chinese keywords, (“rabies” or “hydrophobia”) and (“abnormal sexual behaviors”, “frequent ejaculation”, “priapism”, or “hypersexuality”) from databases including CNKI, SinoMed, VIP and Wanfang Data, and English keywords, (“rabies”, “canine madness”, “Lyssa”, “rabid”, “lupomania”, “hydrophobia”, “photophobia”, “photopsia”, or “aerophobia”) and (“sexual arousal”, “sexual desire”, “hypersexual behavior”, “orgasm”, “hypersexuality”, “urogenital symptom”, “libido”, “sexual manifestation”, “priapism”, “hyperlibidinism”, “penile hyperexcitability”, “erection”, or “ejaculation”) from databases, including ScienceDirect, ProQuest, OVID and PubMed, were searched. Relevant references of the searched papers were also checked carefully. Then the literature on rabies cases including patient demographic data, medical history, symptoms, signs, diagnosis, treatment, and outcome were identified and analyzed.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
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en
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A total of 47 papers published between 1970 and 2015, including 54 rabies cases, were identified that reported abnormal sexual behaviors as the presenting manifestations [ 4 – 50 ]. These cases, along with the case we present here, were then reviewed. Among these 47 papers, 38 were published in Chinese reporting 45 cases, and nine papers were published in English reporting nine cases (Table 1 ). Table 1 Reported cases of rabies with abnormal sexual behaviors as the presenting manifestations Authors (Reference) Published year Country Case (sex, age) Sexual manifestation Duration of the manifestation Diagnosis methods Gardner 1970 Burma 1 (M, NR) Desperate increase in libido NR Negri bodies were indeed seen on section of this patient’s hippocampus Talaulicar 1977 India 1 (M, 25Y) Persistent priapism # 1.5D Medical history, clinical manifestation, dog was proved rabid. Bhandari & Kumar 1986 India 1 (M, 56Y) Frequent erection and ejaculation > 10 times a day, penile hyperexcitability # 2D Medical history and clinical manifestation Jiang, et al 1986 China 1 (M, 41Y) Urgent urination, urinary endless and spermatorrhea # 4D Medical history and clinical manifestation Wang, et al 1987 China 1 (M, 40Y) Priapism, spermiation # 15D Medical history and clinical manifestation Madhusudana et al 1988 India 1 (M, 34Y) Increased libido, frequent erection and ejaculation > 10 times a day # NR Medical history and clinical manifestation, corneal smears were positive for rabies antigen by fluorescent antibody technique Udwadia et al 1988 India 1 (M, 47Y) Frequent erection and ejaculation > 10 times a day # 2D Medical history, clinical manifestation, Negri bodies in brain tissue by autopsy, and positive result of Swiss albino mouse inoculation test Wang, et al 1989 China 2 (2 M, 32Y & 44Y) Frequent erection and ejaculation > 10 times a day # 5D & 6D Medical history and clinical manifestation Lin, et al 1989 China 1 (M, 52Y) Spermatorrhea > 10 times, painful penis # 3D Medical history and clinical manifestation Liu, et al 1990 China 1 (M, 65Y) Frequent erection and ejaculation > 50 times a day # 4D Medical history and clinical manifestation Xiao, et al 1990 China 1 (M. 41Y) Frequent erection and ejaculation > 50 times a day # 4D Medical history and clinical manifestation Luo, et al 1990 China 1 (M, 35Y) Frequent erection and ejaculation > 10 times a day # 4D Medical history and clinical manifestation Zhang, et al 1990 China 1 (M, 35Y) Frequent erection and ejaculation > 20 times a day # 5D Medical history and clinical manifestation Yang, et al 1990 China 1 (M, 33Y) Frequent spermatorrhea 3D Medical history and clinical manifestation Ma, et al 1991 China 1 (M, 35Y) Frequent erection and ejaculation > 20 times a day 2D Medical history and clinical manifestation Fu, et al 1991 China 1 (M, 28Y) Priapism > 50 times a day 3D Medical history and clinical manifestation Zhan, et al 1991 China 1 (M, 30Y) Priapism and spermatorrhea 5–10 times # 4D Medical history and clinical manifestation Chou et al 1991 China 1 (M, 46Y) Frequent spermatorrhea # 11D Medical history and clinical manifestation Ge, et al 1992 China 2 (2 M, 40Y & 56Y) Frequent erection and ejaculation > 10 times a day # 4D & 6D Medical history and clinical manifestation Xiao, et al 1992 China 1 (M, 62Y) Frequent erection and ejaculation > 10 times a day # 8D Medical history and clinical manifestation Wei, et al 1992 China 1 (M, 61Y) Frequent erection and ejaculation > 50 times a day # 4D Medical history and clinical manifestation Niu, et al 1993 China 1 (M, 68Y) Frequent erection and ejaculation > 20 times a day # 4D Medical history and clinical manifestation Feng, et al 1994 China 1 (F, 45Y) Feeling of ants climb in vagina # 2D Medical history and clinical manifestation Geng, et al 1994 China 1 (M, 59Y) Frequent erection and ejaculation > 10 times a day # 7D Medical history and clinical manifestation Li, et al 1994 China 1 (M, 52Y) Frequent erection and ejaculation < 10 times a day # 7D Medical history and clinical manifestation He, et al 1994 China 1 (M, 65Y) Pain of penis # 6D Medical history and clinical manifestation Li, et al 1994 China 1 (M, 32Y) Priapism and ejaculation > 10 times # 3D Medical history and clinical manifestation Tang, et al 1994 China 1 (M, 27Y) Frequent erection and ejaculation > 10 times a day 5D Medical history and clinical manifestation Zhang, et al 1995 China 1 (M, 34Y) Frequent erection and ejaculation > 10 times a day # 5D Medical history and clinical manifestation Dutta 1996 India 1 (F, 28Y) Hypersexuality # 10D Medical history, clinical manifestation and Negri bodies in brain tissue by autopsy Cai, et al 1997 China 2 (2 M, 29Y & 31Y) Frequent erection and ejaculation > 50 times a day # 8D & 6D Medical history and clinical manifestation Yang, et al 1998 China 1 (M, 40 + Y) Priapism 1D Medical history and clinical manifestation Du, et al 1999 China 1 (M, 26Y) Frequent erection and ejaculation > 20 times a day # 10D Medical history and clinical manifestation Wu, et al 2000 China 5 (5 M, 18-52Y) Frequent erection and ejaculation > 10 times a day # 5-7D Medical history and clinical manifestation Zhong, et al 2000 China 1 (M, 54Y) Frequent erection and Ejaculation > 11 times a day # 7D Medical history and clinical manifestation Li, et al 2000 China 1 (M, 39Y) Frequent erection and ejaculation > 30 times a day # 4D Medical history and clinical manifestation Ou, et al 2005 China 1 (M, 35Y) Frequent erection and ejaculation > 10 times a day # 6D Medical history and clinical manifestation Daher, et al 2005 Brazil 1 (NR, NR) Priapism NR Clinical manifestations, laboratory tests and postmortem findings Tan, et al 2007 China 1 (M, 71Y) Severe pain of scrotum and testicles # 6D Medical history and clinical manifestation Li, et al 2011 China 1 (M, 43Y) Priapism and ejaculation < 10 times a day # 2D Medical history and clinical manifestation Liu, et al 2011 China 1 (M, 8Y) Priapism and ejaculation 0 times # 6D Medical history and clinical manifestation Senthilkumaran et al 2011 India 1 (F, 28Y) Hypersexuality, frequent intercourse and frequent orgasm # 6D Medical history, clinical manifestation, imaging, CSF PCR and skin biopsy Depani & Molyneux 2012 Malawi 1 (M, 6Y) Priapism with pain # 1D Medical history and clinical manifestation Qin, et al 2012 China 1 (M, 52Y) Priapism and ejaculation < 10 times a day # 3D Medical history and clinical manifestation Lei, et al 2012 China 1 (M, 53Y) Priapism 2D Medical history and clinical manifestation Liu, et al 2013 China 1 (M, 48Y) Priapism 2D Medical history and clinical manifestation Gao, et al 2014 China 1 (M, 66Y) Priapism and ejaculation > 5 times a day # 8D Medical history and clinical manifestation Yan, et al. Submitted China 1 (M, 32Y) Frequent erection and ejaculation > 40 times a day # 6D Medical history and clinical manifestation NR Not reported, M Male, F Female, Y Years, D Days # Abnormal sexual behaviors as the initial manifestations
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31370800_p7
|
31370800
|
sec[3]/p[0]
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Analysis of cases
| 4.183594 |
biomedical
|
Study
|
[
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Among the 55 cases, including our case, 51 were male and three were female, with ages ranging from 6 to 71 years for males and 28 to 45 years for females; the gender of one case was not reported. All cases were reported in developing countries; 46 (83.6%) in China, six (10.9%) in India, one (1.8%) in Burma, one (1.8%) in Brazil and one (1.8%) in Malawi. Animal bites were the major source of infection with 51 (92.7%) cases being infected by dogs, one by a cat, one by a mouse, one by a mongoose, and one by an unspecified source. Extremities were the main exposure (bite) sites, accounting for 43 (78.2%) cases: 30 cases suffered bites to the lower extremities (i.e. thighs, legs, ankles, and feet), 12 in the upper extremities (i.e. arms and hands), and one in both upper and lower extremities. Other exposure sites included the face ( n = 1) and unspecified sites ( n = 11) (Table 2 ). Table 2 Summary of clinical features of 55 cases of rabies with abnormal sexual behaviors as the presenting manifestations Variables N (%) Sex Male 51 (92.7%) Female 3 (5.5%) Unknown 1 (1.8%) Age (years) a Range 6–71 Median 40 Source of infection Dog 51 (92.7%) Cat 1 (1.8%) Mouse 1 (1.8%) Mongoose 1 (1.8%) Unknown 1 (1.8%) Exposure site Leg 25 (45.5%) Arm 10 (18.2%) Leg and arm 1 (1.8%) Feet or ankles 5 (9.1%) Hand 2 (3.6%) Close contact 1 (1.8%) Face 1 (1.8%) Unknown 10 (18.2%) Incubation period (months) b Range 1–24 Median 3 Diagnostic methods Animal bite 5 (9.1%) Typical symptoms 1 (1.8%) Animal bite + typical symptoms 42 (76.4%) Animal bite + typical symptoms + virological or other techniques 7 (12.7%) Typical symptoms of rabies Yes 50 (90.9%) No 5 (9.1%) Abnormal sexual behaviors d Male (n = 51) Frequent ejaculation 35 (68.6%) < 10 4 (11.4%) 10–19 20 (57.1%) 20–49 6 (17.1%) ≥ 50 5 (14.3%) Spermatorrhea 6 (11.8%) Pain of penis 3 (5.9%) Pain of scrotum and testicles 1 (2.0%) Priapism or frequent erection 45 (88.2%) Hypersexuality or increased libido 2 (3.9%) Female (n = 3) Hypersexuality, frequent intercourse and frequent orgasm 1 (33.3%) Hypersexuality 1 (33.3%) Feeling of ants climbing in vagina 1 (33.3%) Gender unknown (n = 1) Priapism 1 Abnormal sexual behaviors as initial symptoms Yes 46 (83.6%) No 8 (14.5%) Unknown 1 (1.8%) Duration of abnormal sexual behaviors (days) c Range 1–15 Median 4 Debridement and vaccination after exposure Debridement 1 (1.8%) Vaccination 2 (3.6%) Debridement with vaccination 1 (1.8%) None 49 (89.1%) Unknown 2 (3.6%) Outcome Death 55 (100%) Survival 0 (0%) Data are expressed as the number (%), unless otherwise indicated a , information on the exact ages was available for 48 cases; b , information on the exact incubation period was available for 49 cases; c , information on the exact duration of abnormal sexual behaviors was available for 47 cases; d , One patient may have more than one abnormal sexual behaviors
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
31370800_p8
|
31370800
|
sec[3]/p[1]
|
Analysis of cases
| 3.771484 |
biomedical
|
Study
|
[
0.9853515625,
0.01439666748046875,
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[
0.99609375,
0.0019245147705078125,
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The associated abnormal sexual behaviors are shown in Table 2 . The major presenting manifestations were priapism, ejaculation, and spermatorrhea in male patients and nymphomania, hypersexuality, and other abnormal sexual behavior in female patients. Overall, 46 (83.6%) of the 55 cases had abnormal sexual behaviors as the initial presenting symptoms. The duration of abnormal sexual behaviors ranged from 1 day (2 cases) to 15 days (1 case), with a median of 4 days and a mean of 5.0 days.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31370800_p9
|
31370800
|
sec[3]/p[2]
|
Analysis of cases
| 2.552734 |
biomedical
|
Study
|
[
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0.16357421875,
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[
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No patients received any standardized post-exposure prophylaxis. Among the 53 cases with available information on vaccination after exposure, only one case received debridement and 5-dose rabies vaccine immediately after biting . Moreover, only two cases received rabies vaccination: one received one dose while the other case received three doses , and one unvaccinated case was given debridement immediately after being bitten .
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
31370800_p10
|
31370800
|
sec[3]/p[3]
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Analysis of cases
| 3.826172 |
biomedical
|
Study
|
[
0.99462890625,
0.00539398193359375,
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[
0.99169921875,
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The rabies incubation period ranged from 1 month to 24 months and was mostly between 2 months and 24 months. Among the 54 cases for whom detailed descriptions on the presenting manifestations were available, abnormal sexual behaviors were the initial manifestations in 46 (85.2%), and were the concurrent manifestations in eight (14.8%) cases. All, except for five, cases developed typical symptoms of rabies, including hydrophobia, anemophobia, and photophobia.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31370800_p11
|
31370800
|
sec[3]/p[4]
|
Analysis of cases
| 3.933594 |
biomedical
|
Study
|
[
0.9990234375,
0.0010833740234375,
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[
0.98828125,
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0.0012102127075195312
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Rabies was clinically diagnosed in all, but five , of the cases based on medical history and clinical manifestations; the diagnosis was confirmed by virological or other techniques, such as brain pathology or imaging only for seven cases [ 5 , 6 , 8 , 40 – 43 ]. In the report by Wu et al., all five patients were bitten by dogs and did not receive debridement and vaccination, and priapism and frequent ejaculation were the initial presenting symptoms, without the development of typical manifestations of rabies or abnormal laboratory findings.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p12
|
31370800
|
sec[3]/p[5]
|
Analysis of cases
| 2.197266 |
biomedical
|
Other
|
[
0.962890625,
0.03485107421875,
0.002094268798828125
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[
0.414306640625,
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A rabies diagnosis was immediately made for all cases with typical rabies symptoms and abnormal sexual behaviors being the concurrent presenting manifestations. However, the diagnosis was not made for all cases with abnormal sexual behaviors alone as the initial presenting manifestations (before typical rabies symptoms appeared) and thus these cases were misdiagnosed prior to the appearance of typical symptoms.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
31370800_p13
|
31370800
|
sec[3]/p[6]
|
Analysis of cases
| 2.330078 |
biomedical
|
Study
|
[
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[
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All of the rabies patients died after the appearance of the presenting symptoms, with the survival time (duration between appearance of the presenting symptoms and death) ranging from 1 to 15 days.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p14
|
31370800
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sec[4]/p[0]
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Discussion and conclusions
| 3.175781 |
biomedical
|
Other
|
[
0.99755859375,
0.0015115737915039062,
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[
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Rabies is an uncommon but deadly disease, with aggression, hydrophobia, anemophobia, and progressive paralysis being its typical symptoms . However, in addition to flu-like symptoms, abnormal sexual behaviors such as priapism, frequent ejaculation, and hypersexuality also occasionally appear as initial or concurrent presenting atypical symptoms. Since the first published report from Burma of a male rabies case with greatly increased libido, 54 cases with abnormal sexual behaviors have been reported in the literature worldwide (mainly from China and India).
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
31370800_p15
|
31370800
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sec[4]/p[1]
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Discussion and conclusions
| 3.951172 |
biomedical
|
Review
|
[
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[
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In the present review, we added one more case with frequent ejaculation as the initial presenting symptom of rabies. All of these cases, with abnormal sexual behaviors as the initial symptoms, were misdiagnosed in the early phase. Among these cases, 46 (85.2%) patients had abnormal sexual behaviors as the initial symptoms. The correct diagnosis was made only in the later stage of all cases when typical rabies symptoms appeared through medical history and clinical manifestations; however, the diagnosis was confirmed by virological, postmortem pathological testing and/or imaging examination only in a few cases.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31370800_p16
|
31370800
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sec[4]/p[2]
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Discussion and conclusions
| 2.859375 |
biomedical
|
Study
|
[
0.998046875,
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[
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It is noticeable that among the 53 cases with abnormal sexual behaviors of rabies and reported ages, 51 (96.2%) were 18 or older and two (3.8%) under 10 (they were 6 and 8 years old respectively). Also, among the 54 cases whose gender was reported, 51 (94.4%) were males and only three (5.6%) were females. These findings suggest that abnormal sexual behaviors of rabies mostly occur in adult males; however, the symptoms can occasionally occurs in boys under 10 and in adult females.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31370800_p17
|
31370800
|
sec[4]/p[3]
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Discussion and conclusions
| 3.916016 |
biomedical
|
Review
|
[
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[
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After examining the cases in the literature and in this review, we identified the following reasons as likely for the misdiagnoses: (1) rabies with abnormal sexual behaviors as the initial symptoms is clinically rare, and many physicians in general medicine, emergency medicine, urology and even psychiatry have insufficient knowledge or lack of awareness about abnormal sexual manifestations of rabies; (2) inability to remember details or avoidance by patients and their family to provide medical history may influence the initial establishment of diagnosis; (3) physicians fail to strictly follow treatment guidelines; they neither carefully elicit a medical history and course of disease nor seriously analyze the correlation between symptoms; and (4) rabies is not considered, simply because some physicians falsely believe that rabies is extremely rare clinically, or has already been eradicated in developing countries (it has only been eradicated in some developed countries) .
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p18
|
31370800
|
sec[4]/p[4]
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Discussion and conclusions
| 4.273438 |
biomedical
|
Review
|
[
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[
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Once exposure occurs, timely post-exposure prophylaxis, including correct wound care and appropriate vaccination, is believed to effectively prevent the progression to clinical disease . However, rabies continues to cause about 61,000 human deaths every year globally , indicating that this disease remains to be underestimated and the true burden of this disease has not been captured . The primary reason for these miserable deaths is that a large number of victims do not receive rabies vaccination at all, and some of those who do do not complete the full course. Noticeably, while rabies used to be considered certainly fatal, several rabies survivors have been increasingly reported over the past two decades worldwide, particularly in recent years [ 53 – 61 ]. Excellent intensive care facilities and aggressive management approaches with appropriate supportive care are believed to contribute to the increase of human rabies survivors . For example, in India, although public health facilities may be lacking (especially in rural areas), several private and some public medical institutes provide world-class medical care, thus likely playing an important role in the prolonged survival of human rabies patients . Most recently, Mani et al. reported two cases whose lives were saved after receiving both rabies vaccine and immunoglobulin and intensive care. However, the patients progressed to clinical disease with typical symptoms of rabies, probably due to multiple exposures or bites on highly innervated areas .
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p19
|
31370800
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sec[4]/p[5]
|
Discussion and conclusions
| 3.992188 |
biomedical
|
Other
|
[
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[
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Therefore, we believe that if the treating physicians try to confirm the intra vitam diagnosis, and antemortem laboratory facilities such as virological test, imaging examination, or other techniques are readily available, then the rabies diagnosis can be made in the early stage, and timely aggressive treatment and care would significantly increase the chance for the patient to survive. Indeed, in 2005, Willoughby et al. reported that a 15-year-old girl almost completely recovered from rabies after being in an induced coma while the native immune response matured but rabies vaccine was not administered ; this has provided an impetus for physicians to attempt aggressive management and given hope for rabies patients to survive. Therefore, better awareness among physicians that rabies patients may present with abnormal sexual symptoms as initial presenting manifestations and the fact that rabies patients with atypical manifestations may recover prior to the appearance of typical symptoms is clinically important for those working in general medicine, emergency medicine, urology, and psychiatry.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p20
|
31370800
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sec[4]/p[6]
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Discussion and conclusions
| 3.910156 |
biomedical
|
Study
|
[
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[
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Nevertheless, it must be emphasized that most of the reported human rabies survivors did not achieve a complete recovery and they developed various neurological sequelae. Mani et al. reported eight patients with laboratory-confirmed rabies who were managed with supportive care in intensive care units and finally survived . Unfortunately, all except for one case had moderate to severe neurological sequelae with poor functional outcomes . Moreover, many efforts have been made to replicate the expensive and intensive “Milwaukee protocol” , but generally been unsuccessful. In a tertiary care hospital in South India, Manesh et al. reported that the attempts to treat three patients of canine-acquired rabies encephalitis using similar protocol all turned out to be failed . Hence it is urgent to find novel antiviral drugs and innovative therapeutic strategies to improve the outcomes, particularly in relation to neurological sequelae.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p21
|
31370800
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sec[4]/p[7]
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Discussion and conclusions
| 4.53125 |
biomedical
|
Study
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[
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[
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The pathogenesis of abnormal sexual behaviors in patients with rabies has not been fully elucidated. The following mechanisms have been proposed. After exposure, the strongly neurotropic rabies virus stays and replicates in the invasion site as well as in the nerve fibers of muscle spindle receptor in nearby striated muscle cells. Then the virus travels centrally along peripheral nerves and massively proliferates at dorsal root ganglia. When the rabies virus invades lumbosacral cord segments, nerve irritation impulses lead to penile erection in males. Nerve impulses travel in the smooth muscles of ductus deferens, seminal vesicle, prostate, and ischiocavernosus muscle and through the hypogastric nerve and sympathetic nerve of the hypogastric plexus thus causing rhythmic contraction of this muscle group, which may result in ejaculation . In females, nymphomania or hypersexuality may be present due to the influence of nerve impulses from involved lumbosacral cord segments on sexual organs . In addition to the effect on the spinal cord that may produce sexual excitement, the rabies virus can also interfere with the function of the hypothalamus, amygdaloid nucleus, and limbic system, resulting in hypersexuality which may present earlier than other typical symptoms such as hydrophobia and anemophobia .
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p22
|
31370800
|
sec[4]/p[8]
|
Discussion and conclusions
| 3.896484 |
biomedical
|
Other
|
[
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[
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Physicians should be mindful that many diseases can present with abnormal sexual behaviors, especially priapism which can be seen in leukemia, infection, central nervous system diseases, spinal injury, penis injury, or tumor metastasis, and may be related to antipsychotic drugs, sickle cell anemia, and penile dorsal vein embolization . However, the absence of ejaculation and psychiatric symptoms in most non-rabies cases is a useful feature for the differential diagnosis. Finally, we should remember that in addition to flu-like symptoms and abnormal sexual behaviors, patients with rabies may also present other atypical clinical symptoms, such as acute disseminated encephalomyelitis, impaired vagus ganglion, sympathetic ganglia, and cardiac ganglion, which can lead to dysfunction of the heart and cardiovascular system, and even sudden death .
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31370800_p23
|
31370800
|
sec[4]/p[9]
|
Discussion and conclusions
| 3.646484 |
biomedical
|
Other
|
[
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[
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In conclusion, patients with abnormal sexual behaviors as presenting manifestations have unique clinical features. It is important to improve the level of awareness of rabies with abnormal sexual behaviors as presenting manifestations, as delayed diagnosis or misdiagnosis leads to the critical treatment window being missed. Therefore, unexplained abnormal sexual behaviors should raise clinical suspicion for rabies although they are uncommon manifestations of this deadly disease.
|
[
"Zhaoxing Tian",
"Yingyu Chen",
"Wei Yan"
] |
https://doi.org/10.1186/s12879-019-4252-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p0
|
31366407
|
sec[0]/p[0]
|
Background
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biomedical
|
Study
|
[
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[
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Primary Sjögren’s syndrome (pSS) is a systemic rheumatic autoimmune disease that is characterised by chronic inflammation, autoantibody production and destruction of exocrine glands through mononuclear cell infiltration. The primary target organs are the lacrimal and salivary glands , resulting in reduced secretion of tears and saliva . The main classification criteria used today for pSS are the American-European Consensus Group (AECG) criteria from 2002 and the American College of Rheumatology (ACR) criteria from 2012 . In addition to evaluating symptoms of ocular and oral dryness, assessing the secretory ability of exocrine glands, and screening for anti-Ro and anti-La autoantibodies, minor salivary gland biopsies are evaluated for mononuclear cell infiltration, also known as focus scoring . This routine histological assessment has been employed to describe salivary gland involvement in SS , where a biopsy of focus score ≥ 1 (i.e., ≥ 1 foci per 4 mm 2 ) is considered positive. In some cases, subjects may display sicca symptoms and may show some mild infiltration of mononuclear cells in their exocrine glands, yet serologically no autoantibody production is detected . Hence, these underexplored non-SS sicca subjects represent an interesting study group when compared to both pSS patients and healthy individuals, since they lack the characteristic features for attaining the pSS diagnosis, yet possess the symptomatic characteristics of ocular and oral dryness nonetheless. Whether these alterations are the result of a different disease course stands to be determined.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
31366407_p1
|
31366407
|
sec[0]/p[1]
|
Background
| 4.132813 |
biomedical
|
Study
|
[
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] |
[
0.98779296875,
0.0006337165832519531,
0.0115203857421875,
0.0001590251922607422
] |
Interestingly, the destruction of salivary gland tissue through the deregulated infiltration and proliferation of lymphocytes may also lead to the formation of ectopic germinal centre (GC)-like structures in approximately 20% of pSS patients [ 11 – 14 ]. It is also commonly accompanied by the development of both adipose (fatty) tissue and fibrosis . The presence of adipose tissue replacement has also been observed in non-SS sicca subjects, yet to a lesser degree . Hence, evaluating the degree of adipose tissue replacement as part of routine salivary gland assessment has been suggested as an additional helpful tool when classifying pSS patients .
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p2
|
31366407
|
sec[0]/p[2]
|
Background
| 4.234375 |
biomedical
|
Study
|
[
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[
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] |
In view of currently available diagnostic tools for pSS, there is an unmet need for the incorporation of non-invasive, more accurate diagnostics. Studying the proteome of biological fluids and screening for disease-specific biomarkers through liquid chromatography-mass spectrometry (LC-MS) has therefore been in focus over the last decades. Both saliva [ 18 , 21 – 27 ] and tear fluid have previously been analysed to identify potential biomarkers for SS. Moreover, salivary and tear fluid samples can easily be obtained using a simple, non-invasive, and fairly safe procedure that also permits repetition and multiple collections. The majority of proteomic studies of SS have chosen saliva as the ideal biological fluid for performing LC-MS analyses, under both stimulated and unstimulated conditions. As a result, several common biomarkers for SS have been identified, including highly abundant immune-system-related molecules, secretory proteins, enzymes, and cytokines . Examples of such biomarkers include β-2 microglobulin (B2MG), Neutrophil gelatinase-associated lipocalin (LCN2), Lymphocyte-specific protein 1 (LSP1), interleukin-4 (IL-4), IL-5, and Clusterin (CLU), displaying molecules active in both innate and adaptive immunity.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p3
|
31366407
|
sec[0]/p[3]
|
Background
| 4.257813 |
biomedical
|
Study
|
[
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[
0.97119140625,
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0.00016379356384277344
] |
Various separation techniques can also be coupled with proteomic analyses, in order to isolate cellular components of interest when screening for disease biomarkers. Extracellular vesicles (EVs) are an example of such cellular components, comprising of exosomes (size < 100 nm), microvesicles , and apoptotic bodies . Interestingly, EVs can be separated and purified through different approaches, including size-exclusion chromatography [ 32 – 34 ]. They are regarded as important mediators of intercellular communication that can influence recipient cell functions [ 35 – 37 ]. For instance, EVs can act as inducers of pro-inflammatory signals on the innate immune system during infections . Patients with autoimmune diseases have also displayed increased levels of EVs associated with inflammation and complement activation . Consequently, various cell types of the innate immune system are known to release EVs, including natural killer (NK) cells , macrophages , monocytes and dendritic cells .
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p4
|
31366407
|
sec[0]/p[4]
|
Background
| 4.207031 |
biomedical
|
Study
|
[
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] |
[
0.9990234375,
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] |
We have previously applied LC-MS using samples of stimulated whole saliva and tear fluid from patients with pSS and healthy controls, in combination with EV isolation, which resulted in the detection of potential novel disease biomarkers . To date, non-SS sicca subjects remain understudied within the field of proteomics. Still, they represent an interesting analytical group, in relation to pSS, that displays the common symptoms of dry eyes and dry mouth, and may also show mild signs of inflammation in their salivary gland tissue, yet remain serologically autoantibody-negative. Whether these discrepancies are the result of a different disease trajectory remains to be explored. Hence, we wished to further investigate patterns of chronic inflammation in the salivary gland tissue, tear fluid and saliva of these non-SS sicca subjects. By applying histopathological assessment of minor salivary gland biopsies, in combination with LC-MS on tear fluid and saliva, coupled with EV isolation, we aimed to gain insight into the cellular processes propagating disease and delineate whether this underexplored group of non-SS subjects behaves more like pSS patients or healthy controls on a glandular and protein level. Accordingly, additional biomarkers may also be identified, and in turn implemented as potential non-invasive diagnostic tools that can aid in increasing diagnostic accuracy when evaluating non-SS sicca subjects and patients with pSS, in accordance with the AECG and ACR criteria.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
31366407_p5
|
31366407
|
sec[1]/sec[0]/p[0]
|
Study population
| 4.136719 |
biomedical
|
Study
|
[
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[
0.99951171875,
0.000286102294921875,
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Fifteen non-SS sicca subjects, 10 pSS patients that fulfilled the AECG classification criteria from 2002 and 10 age- and gender-matched healthy controls participated in the current study. The subjects in the non-SS group possessed dry eye and dry mouth symptoms, yet did not fulfil the classification criteria for pSS due to negative anti-SSA/SSB serology and a focus score < 1 in their evaluated salivary gland biopsies. These biopsies were collected at the Department of Oral Surgery and Oral Medicine, University of Oslo (JLJ), and evaluated at the Gade Laboratory for Pathology, University of Bergen (KS). Following recruitment at the Department of Rheumatology, Oslo University Hospital, the pSS patients, along with the non-SS sicca subjects and volunteering healthy controls, were all referred to the Norwegian Dry Eye Clinic, Oslo, and the Dry Mouth Clinic, Oslo. At these clinics, participants underwent a thorough ocular and oral examination, followed by tear fluid and stimulated saliva sample collection, as described below. A detailed explanation of the study aim and protocols was provided to the recruited subjects upon enrolment. Written informed consent was also obtained from the participants, and the Regional Medical Ethical Committee of South-East Norway approved the study . Medical records and clinical data of the pSS patients were attained from the Department of Rheumatology, Oslo University Hospital. The demographics of the non-SS and pSS subjects participating in the current study are presented in Tables 1 and 2 . Table 1 Clinical characteristics of non-SS subjects included in the proteomics analysis Patient no. Age Gender Anti-SSA* Anti-SSB* Focus score** FI score*** Schirmer test**** Saliva secretion ***** Dry mouth Dry eyes 1 71 F – – < 1 1 + + + + 2 33 F – – 0 1 + NT + + 3 48 F – – 0 0 + + + + 4 65 F – – 0 2 + + + + 5 39 F – – 0 0 + + + + 6 44 F – – 0 0 – + + + 7 30 F – – 0 0 – + + + 8 56 F – – 0 1 + + + + 9 41 F – – 0 0 + + + + 10 50 F – – 0 0 + + + + 11 47 F – – 0 1 + – + + 12 64 F – – < 1 0 + + + + 13 73 F – – 0 2 + + + + 14 59 F – – < 1 0 + + + + 15 51 F – – < 1 – + + + + F female, FI fatty infiltration, NT not tested *Autoantibody production was assessed by ELISA **Values are the number of focal infiltrates/4mm 2 tissue area containing > 50 mononuclear cells ***The degree of fatty infiltration was assessed and the sections were scored blindly, where no or little fatty infiltration = 0, moderate = 1, and prominent = 2 ****Values are in mm/5 min; normal flow > 5 mm/5 min. ‘+’ indicates dryness and tear secretion ≤ 5 mm/5 min *****Values are in ml/15 min; normal flow > 1.5 ml/15 min. ‘+’ indicates dryness and unstimulated whole saliva secretion ≤ 1.5 ml/15 min Table 2 Clinical characteristics of pSS patients included in the study Patient no. Age Gender Anti-SSA* Anti-SSB* Focus score** GC FI score*** Schirmer test**** Saliva secretion ***** Dry mouth Dry eyes 1 48 F + + – – – + + + + 2 59 F + + – – – + + + + 3 52 F + + 8 + 1 + + + + 4 54 F + – 1 – 2 + + – + 5 60 F + + 3 + 1 + + – – 6 64 F + – 0 – 1 + + + + 7 55 F + – 0 – 2 + + + + 8 50 F + + – – – + – + + 9 35 F + + 3 + 0 + + – – 10 75 F + + – – – + – + + F female, GC germinal centres, FI fatty infiltration *Autoantibody production was assessed by ELISA **Values are the number of focal infiltrates/4mm 2 tissue area containing > 50 mononuclear cells ***The degree of fatty infiltration was assessed and the sections were scored blindly, where no or little fatty infiltration = 0, moderate = 1, and prominent = 2 ****Values are in mm/5 min; normal flow > 5 mm/5 min. ‘+’ indicates dryness and tear secretion ≤ 5 mm/5 min *****Values are in ml/15 min; normal flow > 1.5 ml/15 min. ‘+’ indicates dryness and unstimulated whole saliva secretion ≤ 1.5 ml/15 min
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p6
|
31366407
|
sec[1]/sec[1]/p[0]
|
Histopathological evaluation of minor salivary gland biopsies
| 4.105469 |
biomedical
|
Study
|
[
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[
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] |
Routine haematoxylin and eosin-stained sections from minor salivary gland biopsies of the non-SS and pSS subjects included in the study were evaluated using a light microscope (Leica, DMLB, Leica Microsystems Wetzlar, Germany). Both mononuclear cells in focal infiltrates and those located interstitially, i.e., in close proximity to the acinar or ductal epithelium, were analysed. Additionally, other forms of tissue damage, including fibrosis, in the same area were also investigated. Furthermore, these salivary gland sections were scored blindly for the presence of fatty infiltration, as previously described . Depending on the degree of fat deposition either numbers 0, 1 or 2 was assigned for each category during the assessment, where 0 was regarded negative to little, while 1 was considered moderate, and 2 signified prominent fatty infiltration .
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366407_p7
|
31366407
|
sec[1]/sec[2]/p[0]
|
Tear fluid and saliva collection
| 4.117188 |
biomedical
|
Study
|
[
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] |
[
0.9990234375,
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] |
Participants underwent a thorough ocular surface examination at the Norwegian Dry Eye Clinic, and a detailed oral examination at the Dry Mouth Clinic, where tear fluid and stimulated whole saliva were collected, respectively, as previously described . In brief, the tear fluid was collected from both eyes using a Schirmer tear test strip (HAAG-STREIT, Essex, UK) to produce a minimum combined total of 10 mm of tear volume, that was then transferred to 500 μl of 0.1 μm filtered phosphate-buffered saline (PBS) (Gibco, pH 7.4, ThermoFisher Scientific, Oslo, Norway). Additionally, stimulated whole saliva was collected on ice from all participants, while chewing on a paraffin block (Paraffin Pellets, Ivoclor Vivadent, Shaen, Lichtenstein) for 5 min. Only patients producing ≥ 800 μl of stimulated whole saliva were included in the study. All tear fluid and saliva samples were then stored at − 80 °C.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p8
|
31366407
|
sec[1]/sec[3]/p[0]
|
Extraction of EVs from tear fluid and saliva
| 4.164063 |
biomedical
|
Study
|
[
0.99951171875,
0.00031566619873046875,
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] |
[
0.9990234375,
0.00035190582275390625,
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0.00007838010787963867
] |
EVs were isolated from tear fluid and stimulated whole saliva using size-exclusion chromatography, as described previously . In brief, due to the low volume of tear fluid collected from the individual pSS patients, tear fluid of Schirmer strips from all non-SS subjects, pSS patients and healthy controls were pooled into three groups, respectively, concentrated to 200 μl using Amicon Ultra-4 columns, and then adjusted to a volume of 1 ml with 0.1 μm filtered PBS. Saliva samples from all participants were centrifuged at 300 rpm for 10 min to remove debris, and then diluted 1:2 with 0.1 μm filtered PBS. A qEV size-exclusion chromatography column (iZON Science, Oxford, UK) was equilibrated by washing the column with 15 ml of 0.1 μm filtered PBS. Samples were then added to the equilibrated qEV size-exclusion chromatography column, and 16 fractions, each 500 μl in volume, were collected by continuously adding 0.1 μm filtered PBS to the column. A new column was used for each sample. The eluted fractions 8–10 (containing the majority of microvesicles and exosomes present in the samples) were concentrated for 80 min at 30 °C in an Eppendorph concentrator 5301 (Eppendorph AG, Hamburg, Germany) and collected into a joint fraction. The protein concentration was then determined using Qubit Fluorometric Quantitation (ThermoFisher Scientific, Oslo, Norway). A volume of the tear fluid, the diluted stimulated whole saliva (100 μl), the joint fractions from the pooled tear samples, and from each saliva sample were then sent for proteomic analysis while preserved on dry ice.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
31366407_p9
|
31366407
|
sec[1]/sec[4]/p[0]
|
Characterisation of EVs
| 4.21875 |
biomedical
|
Study
|
[
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0.000308990478515625,
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] |
[
0.99951171875,
0.00022721290588378906,
0.0003933906555175781,
0.0000776052474975586
] |
In order to characterise the isolated EVs, nanoparticle tracking analysis and immunoaffinity capture for detection of CD9 positive EVs were conducted on joint fractions from saliva and tears as previously described . In brief, the nanoparticle tracking analysis determined the size distribution and concentration of the respective EVs using a NanoSight NS500 instrument (Malvern Instruments Ltd., Malvern, UK) . The hydrodynamic diameter of the particles in each sample was calculated by the NTA 3.0 software (Malvern Instruments, Malvern, UK). Additionally, immunoaffinity capture for detection of CD9 positive EVs was performed using the Exosome Human CD9 Flow Detection Kit (Dynal®, ThermoFisher Scientific, Oslo, Norway) and flow cytometry with BD Accuri™ C6 Cytometer (BD Biosciences, Oslo, Norway). Median fluorescence intensity (MFI) was reported as a signal to noise (S/N) ratio to isotype control from a total of 300 singlet events. A summary of the measurements obtained from the nanoparticle tracking analysis and the flow cytometry analyses in tear fluid and saliva is presented in Table 3 . Table 3 Characterisation of EVs in saliva and tears Mean particle size* (nm) Particles/mL* CD9 + EVs** S/N ratio MFI Tear fluid Pool of patients with pSS ( n = 9) 255 ± 40 5.0 E+08 1.04 Pool of patients with non-SS ( n = 14) 204 ± 8 1.2 E+09 1.22 Pool of controls ( n = 10) 215 ± 9 7.1 E+08 1.20 Saliva Patients with pSS ( n = 9) 233 ± 17 1.9 E+10 ± 0.7E+9 4.32 ± 1.19 Patients with non-SS ( n = 14) 231 ± 13 1.0 E+10 ± 1.6E+9 3.98 ± 0.57 Controls ( n = 10) 264 ± 6 7.9 E+9 ± 1.6E+9 3.22 ± 0.98 *Nanoparticle tracking analysis was conducted on EV joint fractions from pooled tear fluid ( n = 9 pSS, n = 14 non-SS and n = 10 controls) and whole saliva ( n = 9 pSS, n = 14 non-SS and n = 10 controls), to determine mean particle size of microvesicles and exosomes (nm ± SEM), in addition to concentrations of EVs (particles/ml ± SEM) **Detection of CD9+ EVs from joint fractions of pooled tear fluid ( n = 9 pSS, n = 14 non-SS and n = 10 controls), and whole saliva ( n = 9 pSS, n = 14 non-SS and n = 10 controls) was performed by immunoaffinity capture using anti-CD9 coated magnetic beads followed by flow cytometry analysis. The results were reported as signal to noise (S/N) ratios of median fluorescence intensity (MFI)
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366407_p10
|
31366407
|
sec[1]/sec[5]/p[0]
|
Protein profiling by LC-MS
| 4.125 |
biomedical
|
Study
|
[
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0.0002359151840209961,
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[
0.9990234375,
0.0003230571746826172,
0.0003452301025390625,
0.00006973743438720703
] |
Proteomics analysis was performed on saliva and tears from non-SS sicca subjects, pSS patients, and healthy controls before and after isolation of EVs, as previously described . In brief, samples were diluted with ice-cold acetone, vortexed, precipitated overnight at − 20 °C, centrifuged at 16000 g for 20 min at 4 °C , and then re-dissolved in 50 μl of a mixture of 6 M urea and 100 mM ammonium bicarbonate (pH 7.8), followed by reduction and alkylation of cysteines. The alkylation reaction was quenched, and the proteins were digested with 10 μg of trypsin for 16 h at 37 °C to generated peptides that were then purified using an OMIX C18-micro SPE (Agilent, Santa Clara, CA, USA) and dried using a Speed Vac concentrator (Concentrator Plus, Eppendorf, Hamburg, Germany). These tryptic peptides were analysed using an Ultimate 3000 RSLCnano-UHPLC system connected to a Q Exactive mass spectrometer (Thermo Fisher Scientific, Bremen, Germany) and a nano electrospray ion source.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p11
|
31366407
|
sec[1]/sec[5]/p[1]
|
Protein profiling by LC-MS
| 4.027344 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.9677734375,
0.031219482421875,
0.0007634162902832031,
0.00044274330139160156
] |
For liquid chromatography separation, an Acclaim PepMap 100 column (C18, 2 μm beads, 100 Å, 75 μm inner diameter, 50 cm length) (Dionex, Sunnyvale CA, USA) was used. A flow rate of 300 nL/min was employed with a solvent gradient of 4–35% B in 60 min. Solvent A was 0.1% formic acid, and solvent B was 0.1% formic acid/90% acetonitrile.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366407_p12
|
31366407
|
sec[1]/sec[5]/p[2]
|
Protein profiling by LC-MS
| 4.21875 |
biomedical
|
Study
|
[
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[
0.98828125,
0.01041412353515625,
0.0008516311645507812,
0.00047850608825683594
] |
The mass spectrometer was operated in the data-dependent mode to automatically switch between MS and MS/MS acquisition. Survey full-scan MS spectra were acquired with the resolution R = 70,000 at m/z 200, after accumulation to a target of 1e6. The maximum allowed ion accumulation times were 60 ms. The method used allowed sequential isolation of up to the ten most intense ions, depending on signal intensity (intensity threshold 1.7e4), for fragmentation using higher-energy collisional induced dissociation (HCD) at a target value of 1e5 charges, NCE 28, and a resolution R = 17,500. Target ions already selected for MS/MS were dynamically excluded for 30 s. The isolation window was m/z = 2 without offset. For accurate mass measurements, the lock mass option was enabled in MS mode.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366407_p13
|
31366407
|
sec[1]/sec[5]/p[3]
|
Protein profiling by LC-MS
| 4.050781 |
biomedical
|
Study
|
[
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[
0.99609375,
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0.00010395050048828125
] |
Finally, data were acquired using Xcalibur v2.5.5, and raw files were processed to generate peak lists in Mascot generic format (*.mgf) using ProteoWizard release version 3.0.331. Database searches were performed using Mascot in-house version 2.4.0 to search the SwissProt database (Human, 20,279 proteins), as before .
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p14
|
31366407
|
sec[1]/sec[6]/p[0]
|
LC-MS data processing and statistical analysis
| 4.144531 |
biomedical
|
Study
|
[
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[
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0.00007480382919311523
] |
In order to validate MS/MS-based peptide and protein identifications, Scaffold (version Scaffold_4.4, Proteome Software Inc., Portland, OR) was used, as before . Here, peptide identifications were accepted if they could be established at greater than 95.0% probability by the Scaffold Local FDR algorithm, while protein identifications were accepted if they could be established at greater than 99.0% probability. For label-free quantification, the entire MS2 total ion current (TIC) across all biological replicates was evaluated using t-test ( p < 0.05). For functional analysis of the proteomics data, Database for Annotation, Visualization and Integrated Discovery (DAVID) (v 6.7, https://david.ncifcrf.gov ) and Functional Enrichment Analysis Tool (FunRich) ( http://www.funrich.org/ ) were applied. Tear fluid, stimulated whole saliva, and EVs (joint fractions) were analysed individually, comparing pSS patients with the non-SS sicca subjects and the healthy controls, correspondingly. DAVID was applied, using a False Discovery Rate (FDR) with a maximum 5% cut-off, in order to delineate specific cellular pathways involving these upregulated proteins in the pSS patients, while FunRich was used to visualise the percentage of proteins involved in each of these upregulated signalling pathways.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
31366407_p15
|
31366407
|
sec[2]/sec[0]/p[0]
|
Histopathological evaluation of minor salivary gland biopsies shows patterns of chronic inflammation in the target organ of non-SS sicca subjects
| 4.179688 |
biomedical
|
Study
|
[
0.9990234375,
0.000537872314453125,
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[
0.99951171875,
0.00020015239715576172,
0.00037169456481933594,
0.00009989738464355469
] |
In order to account for the morphological patterns of chronic inflammation in minor salivary gland biopsies of the non-SS and pSS subjects included in the study, the sections were evaluated for mononuclear cell infiltration, other form of tissue damage including fibrosis, and for the presence of fatty infiltration . Interestingly, 27% of the non-SS subjects showed some focal chronic inflammation in their salivary gland tissue and had a focus score value of < 1. Also, 67% of those pSS patients that have had their biopsies taken had a positive focus score, ranging from 1 to 8, and 50% of these biopsies were also GC positive. Additionally, 83% of pSS patients had a positive fatty infiltration score in their salivary glands; where 17% had a fatty infiltration score of 0, 50% had a score of 1, and 33% had a score of 2. Meanwhile, 40% of the non-SS sicca participants also showed fatty infiltration in their biopsies (Tables 1 and 2 ). An illustration of such focal chronic inflammation and fibrosis detected in the non-SS subjects, as compared to pSS patients, is presented in Fig. 1 . Fig. 1 Histopathological evaluation of minor salivary gland biopsies shows implications of inflammation in the target organ of non-SS sicca subjects. Haematoxylin and eosin staining of minor salivary gland biopsies taken from the non-SS and pSS subjects included in the study allowed the evaluation for mononuclear cell infiltration, fibrosis, and the presence of fatty infiltration in their salivary gland tissue. a Non-SS subject with normal salivary gland morphology. b Non-SS individual with fibrosis in the salivary gland tissue. c Non-SS participant with mild focal inflammation in the salivary gland and a focus score < 1. d Salivary gland biopsy of a pSS patient with a focus score value of 3 and GC-like structure within the focal infiltrate. Areas of inflammation are indicated by black arrow
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p16
|
31366407
|
sec[2]/sec[1]/p[0]
|
Upregulation of proinflammatory pathways and proteins involved in ubiquitination and B cell differentiation detected in tear fluid of pSS patients, as compared to both non-SS sicca subjects and healthy controls
| 4.253906 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.9990234375,
0.0002105236053466797,
0.0005345344543457031,
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] |
Performing LC-MS on tear fluid from 15 non-SS sicca subjects, 10 pSS patients, and 10 healthy controls helped identify significantly upregulated proteins with p values < 0.05 that were distinguished using spectral counts (Additional file 4 : Table S1 and Additional file 5 : Table S2). These upregulated proteins were further analysed using DAVID, and cellular processes for the upregulated proteins in the pSS patients were detected. Upregulated signalling pathways identified in the pSS patients, as compared to non-SS sicca controls, included Wnt receptor signalling (20.6%), MAP kinase cascade, ubiquitination, tumour necrosis factor (TNF)-mediated signalling, T cell receptor signalling, Fc receptor signalling, NF-kappa B cascade, MHC class I antigen processing and presentation, IL-1 mediated signalling, in addition to general innate immune responses, apoptotic processes, and inflammatory responses, in descending order, as indicated by the percent values of the upregulated proteins involved in each cellular process . Similarly, when comparing these pSS patients to the healthy controls, the same cellular processes were observed as a result of upregulated proteins in the patients, with the addition of MHC class II antigen processing and presentation, and catabolic processes . Fig. 2 Upregulation of proinflammatory pathways detected in tear fluid of pSS patients. For functional analysis of the proteomics data, DAVID (v 6.7, https://david.ncifcrf.gov ) was applied using a FDR with a maximum 5% cut-off, and cellular processes for the upregulated proteins in the pSS patients were identified. FunRich ( http://www.funrich.org/ ) was then used to visualise the fraction of proteins involved in each of these upregulated signalling pathways. a Upregulated signalling pathways identified in the pSS patients, as compared to non-SS sicca controls. b Comparing pSS patients to healthy controls helped detect similar cellular processes as with the non-SS subjects, affecting both innate and adaptive immunological processes. Percentage values indicate the amount of overexpressed proteins involved in upregulating each of the cellular processes identified
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366407_p17
|
31366407
|
sec[2]/sec[1]/p[1]
|
Upregulation of proinflammatory pathways and proteins involved in ubiquitination and B cell differentiation detected in tear fluid of pSS patients, as compared to both non-SS sicca subjects and healthy controls
| 4.222656 |
biomedical
|
Study
|
[
0.99951171875,
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[
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] |
Since proteins found upregulated in the pSS patient group could be the most promising candidates for potential disease biomarkers, we also considered the number of spectral counts in our analyses. Accordingly, the three most upregulated proteins in pSS patients that are involved in immunological reactions, when compared to both non-SS subjects and healthy controls, were LIM domain only protein 7 (LMO7), E3 ubiquitin-protein ligase HUWE1 (HUWE1) and Tumour protein D52 (TPD52), in descending order. The most upregulated protein in tear fluid of patients with pSS, namely LMO7, is involved in ubiquitination and cell adhesion. Moreover, HUWE1, also mediates ubiquitination, in addition to neutrophil degranulation and cell differentiation. Lastly, TPD52 plays a central role in regulating B cell differentiation . Table 4 Highly upregulated proteins in tear fluid of pSS patients Number Gene Related protein* Classification and function** Non-SS vs. pSS 1 LMO7 LIM domain only protein 7 Ubiquitination, cell signalling, cell adhesion 2 HUWE1 E3 ubiquitin-protein ligase HUWE1 Mediates ubiquitination, neutrophil degranulation, cell differentiation 3 TPD52 Tumour protein D52 B cell differentiation, cell proliferation, Ca 2+ -signalling Controls vs. pSS 1 LMO7 LIM domain only protein 7 Ubiquitination, cell signalling, cell adhesion 2 HUWE1 E3 ubiquitin-protein ligase HUWE1 Mediates ubiquitination, neutrophil degranulation, cell differentiation 3 TPD52 Tumour protein D52 B cell differentiation, cell proliferation, Ca 2+ -signalling *The three most upregulated immunological proteins in whole saliva of pSS patients deviating in replicates, i.e. number of individuals (frequency), and spectral counts, as identified by proteomics analysis and Scaffold (v 4.4.6, http://www.proteomesoftware.com/products/scaffold/ ) **The classification and functions of the proteins presented were identified using publicly available databases, such as UniProt ( http://www.uniprot.org )
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p18
|
31366407
|
sec[2]/sec[2]/p[0]
|
Overexpression of proteins regulating cellular innate and adaptive immunological pathways detected in EVs from tear fluid of pSS patients, utilising non-SS sicca subjects and healthy individuals as controls
| 4.214844 |
biomedical
|
Study
|
[
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[
0.9990234375,
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The DAVID analysis of the pooled tear sample from 15 non-SS subjects and 10 pSS patients, respectively, revealed upregulated cellular pathways in pSS patients involved in retina homeostasis (83.3%), metabolic processes, regulation of NF-kappaB import, erythrocyte homeostasis, MAP kinase cascade, removal of superoxide radicals, regulation of programmed cell death, natural killer cell cytotoxicity and activation, response to oxidative stress, as well as regulation of cell proliferation and apoptotic processes, in downward order, as determined by the percent values of the upregulated proteins contributing to each cellular process . Similarly, the most upregulated cellular processes in the pSS patient group when compared to the healthy controls was retina homeostasis (77.8%), followed by other central innate and adaptive immune responses . Fig. 3 Overexpression of proteins regulating cellular innate and adaptive immunological pathways detected in EVs from tear fluid of pSS patients. Following LC-MS of EVs extracted from tear fluid, DAVID analysis (v 6.7, https://david.ncifcrf.gov ) was applied using a FDR with a maximum cut-off of 5%. Cellular processes for the upregulated proteins in the pSS patients were identified, and FunRich ( http://www.funrich.org/ ) was then used to visualise the segment of proteins involved. a Upregulated signalling pathways distinguished in EVs isolated from tears of pSS patients, as compared to non-SS subjects. b Comparing pSS patients to healthy controls, the most upregulated of cellular processes in the pSS patient group was again retina homeostasis, followed by other central innate and adaptive immune responses. Percentage values represent the fraction of overexpressed proteins contributing to the upregulation of each cellular process
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
31366407_p19
|
31366407
|
sec[2]/sec[2]/p[1]
|
Overexpression of proteins regulating cellular innate and adaptive immunological pathways detected in EVs from tear fluid of pSS patients, utilising non-SS sicca subjects and healthy individuals as controls
| 4.113281 |
biomedical
|
Study
|
[
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[
0.99951171875,
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0.0003762245178222656,
0.000057697296142578125
] |
When comparing non-SS participants to pSS patients, no significant proteins were found to be significantly upregulated in the patients. However, proteins expressed significantly more in the pSS patient group compared to the healthy controls were erythrocyte band 7 integral membrane protein (STOM), Annexin A4 (ANXA4) and Annexin A11 (ANXA11). STOM is involved in neutrophil degranulation and regulation of viral genome replication, while ANXA4 affects NF-kappaB binding, apoptosis, and interleukin-8 secretion. Finally, ANXA11 regulates MHC class II protein complex binding and phagocytosis.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p20
|
31366407
|
sec[2]/sec[3]/p[0]
|
Whole saliva and EVs isolated from whole saliva revealed proteins vital for innate MHC class I cellular regulation and T cell activation in pSS patients
| 4.078125 |
biomedical
|
Study
|
[
0.99951171875,
0.00028014183044433594,
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] |
[
0.99951171875,
0.00014960765838623047,
0.0002994537353515625,
0.00006473064422607422
] |
The LC-MS conducted on stimulated whole saliva from 15 non-SS sicca subjects, 10 pSS patients and 10 healthy controls aided in the identification of significantly upregulated proteins in the patient group when compared to non-SS sicca subjects and healthy controls, respectively (Additional file 6 : Table S3 and Additional file 7 : Table S4). Furthermore, significantly upregulated proteins for pSS patients found in EVs of whole saliva were distinguished in a similar manner (Additional file 8 : Table S5 and Additional file 9 : Table S6). However, the DAVID analysis performed on these highly expressed proteins did not reveal any signalling pathways involving cellular processes to be significantly affected in the patient group.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p21
|
31366407
|
sec[2]/sec[3]/p[1]
|
Whole saliva and EVs isolated from whole saliva revealed proteins vital for innate MHC class I cellular regulation and T cell activation in pSS patients
| 4.273438 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.9990234375,
0.00028324127197265625,
0.00055694580078125,
0.00007593631744384766
] |
Considering the number of spectral counts, the three most overexpressed proteins in the pSS patient group when compared to the non-SS sicca participants were peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A), CD44 antigen (CD44) and B2MG. The most upregulated of these proteins, FKBP1A, plays a role in T cell activation in FOXP3 expression and regulatory T cell suppression, in addition to promoting tumour growth and progression. Meanwhile, B2MG mediates antigen processing and presentation on MHC class I, and innate immunity. When comparing patients with pSS to healthy controls, proteins Secreted Ly-6/uPAR-related protein 1 (SLUR1), B2MG, and Clusterin (CLUS) were highly expressed in the patient group, in declining order. SLUR1 affects acetylcholine receptor activity, cell migration and proliferation, while CLUS plays modulates NF-kappa-B activity and TNF production . Table 5 Highly upregulated proteins in stimulated whole saliva of pSS patients Number Gene Related protein* Classification and function** Non-SS vs. pSS 1 FKBP1A Peptidyl-prolyl cis-trans isomerase FKBP1A T cell activation and proliferation, upregulation of NF-kappa-B signalling 2 CD44 CD44 antigen FOXP3 expression and regulatory T cell suppression, promotes tumour growth 3 B2MG Beta-2-microglobulin Antigen processing and presentation on MHC class I, innate immunity Controls vs. pSS 1 SLUR1 Secreted Ly-6/uPAR-related protein 1 Acetylcholine receptor activity, cell migration and proliferation 2 B2MG Beta-2-microglobulin Antigen processing and presentation on MHC class I, innate immunity 3 CLUS Clusterin Innate immunity, modulates NF-kappa-B activity and TNF production *The three most upregulated immunological proteins in whole saliva of pSS patients deviating in replicates, i.e. number of individuals (frequency), and spectral counts, as identified by proteomics analysis and Scaffold (v 4.4.6, http://www.proteomesoftware.com/products/scaffold/ ) **The classification and functions of the proteins presented were identified using publicly available databases, such as UniProt ( http://www.uniprot.org )
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p22
|
31366407
|
sec[2]/sec[3]/p[2]
|
Whole saliva and EVs isolated from whole saliva revealed proteins vital for innate MHC class I cellular regulation and T cell activation in pSS patients
| 4.304688 |
biomedical
|
Study
|
[
0.99951171875,
0.0002574920654296875,
0.0001863241195678711
] |
[
0.99853515625,
0.00032019615173339844,
0.0009007453918457031,
0.00008386373519897461
] |
Viewing the spectral counts of proteins identified in EVs of whole saliva, the three most upregulated proteins in patients with pSS, as related to non-SS sicca participants, included CD44, Major vault protein (MVP), and Neutrophil gelatinase-associated lipocalin (NGAL), also referred to as LCN2. MVP promotes IFNγ-mediated signalling, MAP kinase activity and neutrophil degranulation, while NGAL is a tumour-associated antigen involved in cell adhesion and innate immunity. Comparing the pSS patient group with healthy controls helped distinguish proteins Ficolin-1 (FCN1), CD44 and ANXA4 as upregulated in the patient group, in descending order. The most changed of these proteins in EVs from whole saliva, FCN1, is a pattern-recognition receptor involved in innate immunity and complement activation . Table 6 Highly upregulated proteins in EVs isolated from stimulated whole saliva of pSS patients Number Gene Related protein* Classification and function** Non-SS vs. pSS 1 CD44 CD44 antigen FOXP3 expression and regulatory T-cell suppression, promotes tumour growth 2 MVP Major vault protein IFNγ-mediated signalling, MAP kinase activity, neutrophil degranulation 3 NGAL Neutrophil gelatinase-associated lipocalin Innate immunity, tumour-associated antigen, cell adhesion Controls vs. pSS 1 FCN1 Ficolin-1 Pattern-recognition receptor in innate immunity, complement activation 2 CD44 CD44 antigen FOXP3 expression and regulatory T-cell suppression, promotes tumour growth 3 ANXA4 Annexin A4 NF-kappaB binding, apoptosis, IL-8 secretion *The three most upregulated immunological proteins in whole saliva of pSS patients deviating in replicates i.e. number of individuals (frequency), and spectral counts, as identified by proteomics analysis and Scaffold (v 4.4.6, http://www.proteomesoftware.com/products/scaffold/ ) **The classification and functions of the proteins presented were identified using publicly available databases, such as UniProt ( http://www.uniprot.org )
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p23
|
31366407
|
sec[3]/p[0]
|
Discussion
| 4.28125 |
biomedical
|
Study
|
[
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[
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Non-SS sicca subjects represent an interesting group, in relation to pSS, since they display the common symptoms of dry eyes and dry mouth, and may also display mild signs of chronic inflammation in their salivary gland tissue. Still, they serologically are autoantibody negative, and their evaluated salivary gland biopsies usually have a focus score value of 0 or < 1. To date, it remains undetermined whether these discrepancies are a result of an alternate disease trajectory, and these subjects remain understudied within the field of proteomics. By investigating morphological patterns of chronic inflammation in the salivary gland tissue of these non-SS sicca subjects, and studying the proteome of their biological fluids through LC-MS, in combination with size-exclusion chromatographic extraction of EVs, we aimed to delineate the cellular pathways propagating disease. By doing so, we may gain further insight into whether these subjects behave more like pSS patients or healthy controls on glandular and protein levels. Thus, additional biomarkers could also be identified and implemented as potential non-invasive diagnostic tools, encompassing both lacrimal and salivary disease target organs. Together, these findings may aid in increasing diagnostic accuracy when evaluating non-SS subjects and patients with pSS and monitoring disease progression.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p24
|
31366407
|
sec[3]/p[1]
|
Discussion
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biomedical
|
Study
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[
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[
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In order to assess the level of chronic inflammation in minor salivary gland biopsies of the non-SS subjects included in this study, in relation to patients with pSS, the sections were evaluated for mononuclear cells infiltration, tissue damage and fatty replacement . Interestingly, 27% of these non-SS subjects showed some focal chronic inflammation in their salivary gland tissue, which resulted in a slightly positive focus score of < 1, and fatty infiltration in 40% of the cases (Table 1 ). Meanwhile, 67% of pSS patients had a positive focus score, where 50% of these biopsies were also GC positive, and 83% also had a positive fatty infiltration score (Table 2 ). Hence, our histopathological evaluation of minor salivary gland biopsies showed clear implications of chronic inflammation in the target organ of non-SS sicca controls, in the form of focal inflammation, fibrosis and fatty infiltration, although to a lesser degree than pSS patients .
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p25
|
31366407
|
sec[3]/p[2]
|
Discussion
| 4.300781 |
biomedical
|
Study
|
[
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[
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To delineate cellular pathways involving the upregulated proteins identified with LC-MS in the tear fluid samples from pSS patients, in relation to non-SS sicca controls and healthy individuals, GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway overrepresentation analyses were performed using DAVID. Our results demonstrated pathways in the pSS patients involving inflammatory innate immune responses, such as MHC class I antigen processing and presentation, TNF-mediated signalling and IL-1 mediated signalling. Additional T cell receptor signalling of the adaptive immune response, and apoptotic processes through MAP kinase cascade, were also detected . Interestingly, similar cellular processes were observed as a result of upregulated proteins in the pSS patients, when compared to both non-SS sicca subjects and healthy individuals. Moreover, the three most upregulated proteins identified in tear fluid of pSS patients were similar, when compared to both non-SS subjects and healthy controls, namely LMO7, HUWE1 and TPD52 . Here, LMO7 and HUWE1 are both involved in the post-translational modification processes of ubiquitination , similar to the SS autoantigen Ro52 , also known as E3 ubiquitin ligase. Meanwhile, TPD52 plays a central role in adaptive immunity by regulating B cell differentiation . Taken together, these identified cellular pathways and proteins in tear fluid of pSS patients imply the involvement of innate and adaptive immune systems, where non-SS sicca subjects showed similar behavioural tendencies as healthy controls on a protein level.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p26
|
31366407
|
sec[3]/p[3]
|
Discussion
| 4.351563 |
biomedical
|
Study
|
[
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[
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Our proteomic analysis of EVs extracted from pooled tear samples revealed upregulated cellular pathways in pSS patients, as compared to non-SS sicca subjects, involving retina homeostasis, regulation of metabolic processes, programmed cell death, natural killer cell cytotoxicity and cell proliferation. Correspondingly, the most upregulated of cellular processes in the patient group when compared to the healthy controls was also retina homeostasis, in addition to other adaptive and innate immune responses . Still, no significant proteins were found to be upregulated in the patients when compared to non-SS sicca subjects. This could be a consequence of pooling the tear samples from individuals in each of the study groups prior to EV extraction, due to the compromised tear production in pSS and non-SS subjects, resulting in loss of insight into variability between the samples. Nonetheless, the most upregulated protein in pSS patients as related to healthy controls, STOM, involves neutrophil degranulation and regulation of viral genome replication , suggesting the involvement of viral infection in SS pathogenesis, as previously reported . Meanwhile, ANXA4 and ANXA11 involve innate immune responses and phagocytosis , implying interplay between innate and adaptive immunity, both as a consequence of disease pathogenesis and probably also as part of the healing process.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p27
|
31366407
|
sec[3]/p[4]
|
Discussion
| 4.207031 |
biomedical
|
Study
|
[
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[
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The DAVID analysis performed on highly expressed proteins identified in whole saliva, and EVs separated from whole saliva, did not disclose significantly affected signalling pathways in the pSS patient group. Nevertheless, when considering the number of spectral counts, we managed to identify the three most overexpressed proteins in the whole saliva of pSS patients . When compared to non-SS sicca subjects, the two most upregulated of these proteins in pSS patients, FKBP1A and CD44, play a role in adaptive immunity through T-cell activation and proliferation , in addition to promoting tumour growth and progression. Concurrently, B2MG is central in innate immunity by mediating antigen processing and presentation on MHC class I . Comparing patients with pSS to healthy controls, CD44 was again identified, in addition to SLUR1, affecting acetylcholine receptor activity, cell migration and proliferation, and CLUS, playing a key role in innate immunity by modulating NF-kappa-B activity and TNF production .
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366407_p28
|
31366407
|
sec[3]/p[5]
|
Discussion
| 4.203125 |
biomedical
|
Study
|
[
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[
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Highly upregulated proteins identified in EVs of whole saliva in patients with pSS, as related to non-SS sicca participants, also included CD44, in addition to MVP, and NGAL (LCN2) . We have previously demonstrated NGAL to be upregulated in the proteome of patients with pSS . Being a protein involved in the activation of neutrophils further strengthens the notion of a role for viral infection in the pathogenesis of SS. Hence, NGAL could be viewed as a potential biomarker for SS, whereby screening for NGAL in whole saliva from patients with pSS could provide additional diagnostic accuracy. Interestingly, NGAL has also been reported as a possible disease biomarker in systemic lupus erythematosus (SLE) . Furthermore, CD44 could also be viewed as a potential salivary biomarker for SS, as it was shown to be highly upregulated in both whole saliva and EVs isolated from whole saliva of pSS patients.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366407_p29
|
31366407
|
sec[4]/p[0]
|
Conclusions
| 4.34375 |
biomedical
|
Study
|
[
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[
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In conclusion, non-SS sicca subjects may demonstrate chronic inflammation in their glandular tissue, in the form of mild mononuclear cell infiltration, along with sicca oral and ocular symptoms, yet lack the characteristic feature of autoantibody production. However, studying the proteome of their biological fluids through LC-MS, in combination with size-exclusion chromatographic extraction of EVs, revealed upregulated cellular pathways propagating disease, where these non-SS sicca subjects showed tendencies similar to healthy controls rather than to pSS patients. Thus, this analysis confirms that pSS patients displaying focal sialadenitis in the salivary gland with focus score ≥ 1 and/or serum autoantibodies represent a distinct entity with an alternate disease trajectory from non-SS subjects that have focus score values of 0 or < 1 in their glandular tissue. Furthermore, the additional panels of biomarkers identified in this study, such as LMO7, HUWE1, NGAL and CD44, could be implemented in future potential non-invasive diagnostics. Together, these findings may aid in increasing diagnostic accuracy when evaluating non-SS subjects and patients with pSS, and monitoring disease progression. Future follow-up studies are necessary in order to validate these biomarkers in larger pSS cohorts, in addition to studying the role and expression pattern of these cellular components immunologically.
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366407_p30
|
31366407
|
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|
Untitled Section
| 4.230469 |
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Study
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[
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[
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Additional file 1: Figure S1. Upregulated protein expression of potential disease biomarkers identified in tear fluid of pSS patients. Considering the mean number of spectral counts for the proteins detected in the study groups included in our LC-MS analyses, the three most upregulated proteins in pSS patients (black) that are involved in immunological reactions, when compared to both non-SS subjects (grey) and healthy controls (white), were LMO7, HUWE1, and TPD52, in descending order. Statistical significance where p < 0.01 is indicated by (*), and p < 0.001 is highlighted by (**). Additional file 2: Figure S2. Upregulation of potential disease biomarkers detected in stimulated whole saliva of pSS patients. In view of the mean number of spectral counts of the proteins identified when performing LC-MS analyses, the three most overexpressed proteins in the pSS patient group (black) when compared to the non-SS sicca participants (grey) were FKBP1A, CD44, and B2MG. Meanwhile, when comparing patients with pSS (black) to healthy controls (white), proteins SLUR1, B2MG, and CLUS were highly expressed in the patient group, in declining order. Statistical significance where p < 0.01 is indicated by (*), and p < 0.001 is highlighted by (**). Additional file 3: Figure S3. Overexpression of proteins and potential disease biomarkers found in EVs isolated from stimulated whole saliva in pSS patients. Viewing the mean spectral counts of proteins identified in EVs of whole saliva, the three most upregulated proteins in patients with pSS (black), as related to non-SS sicca participants (grey), included CD44, MVP, and NGAL, also referred to as LCN2. Comparing the pSS patient group (black) with healthy controls (white) helped distinguish proteins FCN1, CD44 and ANXA4 as upregulated in the patient group, in decreasing order. Statistical significance where p < 0.01 is indicated by (*). Additional file 4: Table S1. Upregulated proteins in tear fluid of non-SS subjects vs. pSS patients. (PDF 277 kb) Additional file 5: Table S2. Upregulated proteins in tear fluid of controls vs. pSS patients. (PDF 262 kb) Additional file 6: Table S3. Upregulated proteins in whole saliva of non-SS subjects vs. pSS patients. (PDF 177 kb) Additional file 7: Table S4. Upregulated proteins in whole saliva of controls vs. pSS patients. (PDF 40 kb) Additional file 8: Table S5. Upregulated proteins in EVs isolated from whole saliva of non-SS subjects vs. pSS patients. (PDF 206 kb) Additional file 9: Table S6. Upregulated proteins in EVs isolated from whole saliva of controls vs. pSS patients. (PDF 211 kb)
|
[
"Lara A. Aqrawi",
"Hilde Kanli Galtung",
"Eduarda M. Guerreiro",
"Reidun Øvstebø",
"Bernd Thiede",
"Tor Paaske Utheim",
"Xiangjun Chen",
"Øygunn Aass Utheim",
"Øyvind Palm",
"Kathrine Skarstein",
"Janicke Liaaen Jensen"
] |
https://doi.org/10.1186/s13075-019-1961-4
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366342_p0
|
31366342
|
sec[0]/p[0]
|
Background
| 3.917969 |
biomedical
|
Review
|
[
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[
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0.78125,
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Oral lichen planus (OLP) is a chronic immune-related condition of the oral mucosa of unknown exact etiology . Current data suggest a prevalence of 1.27–2.0% in the general population . Although OLP is considered as the oral manifestation or oral counter part of cutaneous LP, there are essential differences in the biological behavior of these two conditions, especially regarding the protracted course and possible association with malignant transformation of OLP. A diagnosis of OLP with no dermal manifestation is quite popular in the clinical setting of oral medicine with only 20% of the OLP patients having cutaneous LP .
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366342_p1
|
31366342
|
sec[0]/p[1]
|
Background
| 3.996094 |
biomedical
|
Review
|
[
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[
0.0643310546875,
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The immune dysregulation is probably associated with T cell- and cytokine-mediated mechanisms [ 1 – 3 ], but mechanisms of humoral auto-immunity were also suggested . The incapability to define the exact etiology of OLP can raise the possibility that OLP represents an immune response to different and varying causative triggers in inherently susceptible individuals . Irrespective of the etiology, three main clinical forms of OLP are well recognized, reticular/keratotic, atrophic, and erosive. They differ in their appearance, symptomatology, management and prognosis .
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p2
|
31366342
|
sec[0]/p[2]
|
Background
| 4.199219 |
biomedical
|
Study
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[
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[
0.98779296875,
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A possible association between OLP and thyroid gland diseases (TGDs), especially hypothyroidism, has been reported [ 8 – 10 ], which can be partially supported by the observation that several autoimmune conditions tend to be “clustered” with autoimmune TGDs. Since OLP is considered by some as an immune-mediated disease, it is reasonable to assume that it may be associated with other immune-mediated diseases, including autoimmune TGDs [ 10 – 12 ]. The prevalence of TGDs in OLP patients ranges between 6.2 to 15.3% compared to a lower prevalence of 1.6–8% in control groups, with odds ratio ranging between 1.47 and 3.01 . A more recent investigation reported a prevalence of 72.4% of TGDs in OLP patients and of 49.4% in controls . An increased level of auto-antibodies to the thyroid gland in OLP patients was also reported . Furthermore, an association was found between OLP patients treated with Levothyroxine Sodium due to a diagnosis of hypothyroidism and the clinical course of OLP .
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p3
|
31366342
|
sec[0]/p[3]
|
Background
| 2.632813 |
biomedical
|
Study
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[
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[
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In view of the wide range of reported prevalence of TGDs among OLP patients, we further add our experience and discuss updated insights in the immunologic etiology of TGDs.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p4
|
31366342
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sec[1]/p[0]
|
Methods
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|
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[
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[
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This is a retrospective case-control study that has been independently reviewed and approved by the Institutional Review Board of Tel-Aviv University, July 2012.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366342_p5
|
31366342
|
sec[1]/p[1]
|
Methods
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|
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[
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[
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The study group included 102 patients who have been diagnosed, clinically and histopathologically, with OLP. All OLP patients were diagnosed and managed in the Oral Medicine Clinic of Tel Aviv University, between the years 2002–2012. The final diagnosis of OLP was based on diagnostic criteria proposed by vander Meij and colleagues . Patients with a diagnosis of oral lichenoid lesions were excluded from the study. The findings of the study group were compared to 102 age- and gender-matched control patients who had no OLP. The control group included consecutive patients referred to the same clinic by dentists from the community during the same period of time. The control patients were managed for other oral findings, such as irritation fibromas, papillomas and fissured tongue. The anamnesis of all patients (both study and control groups) included a full report from the family physician comprising all systemic diagnoses and current medications.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p6
|
31366342
|
sec[1]/p[2]
|
Methods
| 3.625 |
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|
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[
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OLP lesions were classified according to the clinical course, type and location. The clinical characterization was made based on the symptomatology: asymptomatic or symptomatic. OLP type was classified as reticular/plaque, atrophic and erosive forms. In case of a combination of different types, the lesions were defined based on the most severe clinical appearance.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366342_p7
|
31366342
|
sec[1]/p[3]
|
Methods
| 3.320313 |
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|
Study
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[
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[
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Based on the information supplied by the family physician regarding the diagnosis of TGD and related medications, patients with TGDs were divided into two main groups, namely hypothyroidism and all other TGDs. TGDs were diagnosed based on routine studies of blood tests, ultrasound and when needed biopsy procedures. All additional relevant data, including concomitant systemic diseases/conditions and habits, like smoking and alcohol consumption, were also obtained from the medical files of the patients.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366342_p8
|
31366342
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sec[1]/p[4]
|
Methods
| 3.335938 |
biomedical
|
Study
|
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[
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Statistical analysis was performed using the SPSS software (Chicago, USA), version 17. Comparison of parameters of age and gender between the OLP and control groups was performed by T-test. Associations between OLP and TGD (i.e., hypothyroidism, TGD-related drugs) were analyzed by Fisher’s exact test. Statistical significance was set at p < 0.05.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p9
|
31366342
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sec[2]/p[0]
|
Results
| 3.556641 |
biomedical
|
Study
|
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[
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One hundred twenty-five medical files of OLP patients were initially examined, out of which only 102 fulfilled the diagnosis of OLP criteria. Females predominated both study and control groups (70.6%). The mean age at diagnosis in the OLP group was 55.7 + 13.2 years and that of the control group was 54.1 + 14.6 years, with no significant difference ( p = 0.393).
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
31366342_p10
|
31366342
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|
Results
| 4.003906 |
biomedical
|
Study
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The most common type of OLP was the reticular (54.9%), followed by erosive (27.5%) and atrophic (17.6%) types. Although the clinical manifestation of OLP was noted at any site of the oral cavity, the most commonly involved was the buccal mucosa (87.6%). Other sites included the gingivae (63.8%), tongue (40.2%), floor of the mouth (7.8%), palate (6.9%) and lip mucosa (5.9%). Symptoms were recorded in 53.9% of the OLP patients. Skin involvement was found in only 6.9%.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p11
|
31366342
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|
Results
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Study
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The most common TGD was hypothyroidism (Table 1 ). A medical history of hypothyroidism was found in 12.7% subjects of the OLP group compared to 9.8% of those in the control group ( p = 0.659). No significant differences were found in the frequency of other TGDs, such as Hashimoto’s thyroiditis, between OLP group and the control group ( p = 0.748). For all TGDs, the frequency was similar in OLP (16.6%) and control (15.7%) groups ( p > 0.05). In addition, no differences were noted between these groups in regard to other co-existence of systemic conditions. Interestingly, smoking habit was significantly less common in the OLP group (11.8%) than in the control (24.5%) ( p = 0.028); no statistically significant differences were found between groups regarding alcohol abuse ( p = 0.621). Table 1 Thyroid gland diseases, other systemic conditions and habits in the OLP and control groups ( N = 102, each) Characteristics OLP Group Control group P value Thyroid gland diseases Hypothyroidism 13 (12.7%) 10 (9.8%) 0.659 Others thyroid gland conditions 4 (3.9%) 6 (5.9%) 0.748 Thyroid gland disease-related medication Levothyroxine Sodium 13 (12.7%) 10 (9.8%) 0.659 Other concomitant systemic diseases Allergic conditions 15 (14.7%) 19 (18.6%) 0.574 Diabetes Mellitus 4 (3.9%) 5 (4.9%) 1 Dyslipidemia 21 (20.6%) 30 (29.4%) 0.196 Habits Smoking 12 (11.8%) 25 (24.5%) 0.028 Alcohol 3 (2.9%) 1 (1.0%) 0.621 Value in bold indicates statistical significance
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
31366342_p12
|
31366342
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sec[2]/p[3]
|
Results
| 4.074219 |
biomedical
|
Study
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Characteristics of OLP, including symptomatology, clinical type (reticular, atrophic and erosive) and oral sites were analyzed for associations with the diagnosis of hypothyroidism (Table 2 ). No significant associations ( p > 0.05) were found. The same characteristics of OLP were also investigated for associations with the diagnoses of other TGDs. These also yielded no statistically significant results (p > 0.05). Table 2 Associations between characteristics of OLP and thyroid gland diseases OLP characteristics (N) Hypothyroidism (N) P value Others Thyroid gland diseases (N) P value Symptoms (55) 6 0.567 2 1.000 OLP type Reticular OLP (56) 8 0.768 2 1.000 Atrophic OLP (18) 3 0.696 0 1.000 Erosive OLP (28) 2 0.506 2 0.302 OLP sites of lesions Tongue (41) 4 0.554 0 0.147 Buccal mucosa (89) 12 1.000 4 1.000 Gingiva (65) 9 0.765 3 1.000 Palate (7) 2 0.218 1 0.251 Floor of mouth (8) 0 0.592 0 1.000
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p13
|
31366342
|
sec[3]/p[0]
|
Discussion
| 4.078125 |
biomedical
|
Study
|
[
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[
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The present study aimed to investigate any possible association between OLP and TGDs based on data documented in an academic dental center. Diagnosis of OLP was supported both clinically and microscopically in all cases. Diagnosis of TGDs was always confirmed by the patients’ records of the Health Maintenance Organization, to which each regular Israeli citizen is registered. In the current study we found that the prevalence of TGDs (all types and specifically hypothyroidism) in OLP patients was not significantly different from that of an age- and gender-matched control group (16.6% versus 15.7% for all TGDs and 12.7% versus 9.8% for hypothyroidism, p > 0.05). In addition, no significant associations were found between the clinical characteristics of OLP and TGDs. Interestingly, we found that smoking habit was significantly less common in the OLP group (11.8%) than in control (24.5%).
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366342_p14
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Discussion
| 3.931641 |
biomedical
|
Study
|
[
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[
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The relationship between OLP and TGDs has been investigated in a large number of studies from different parts of the world, yet the results were controversial. Lack of uniformity in study design and methodology can provide a partial explanation to this controversy. Patients with OLP were not always diagnosed by a specialist in oral medicine and their oral findings were usually not confirmed by histopathological examination, which was limited only to cases of an equivocal clinical impression. There were only a few studies, including the current one, in which it was clearly mentioned whether specialists in oral medicine have been involved in the diagnosis of OLP and whether both clinical and histopathological exams were performed . The selected samples of OLP patients differed in the inclusion and exclusion criteria regarding OLLs, smoking habits and alcohol consumption . Diagnosis of TGDs sometimes relied on patients’ self-reporting data .
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366342_p15
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31366342
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sec[3]/p[2]
|
Discussion
| 4.070313 |
biomedical
|
Study
|
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In general, auto-immune diseases of the thyroid gland show differential geographic prevalence. Hashimoto thyroiditis has an assessed prevalence of 300–2,980 per 100,000 in Europe-North America-Australia-New Zeeland zone (zone 1) and only 350 in Asia-Middle East-Caribbean-South America zone (zone 2) . Likewise, OLP is also geographically related, ranging from 0.38% in Malaysia, 0.5% in Japan, 1.74% in USA, 1.9% in Sweden, and up to 2.6% in India . In line with this, it would have been expected to find associations between OLP and TGDs in geographical areas where both conditions show a similar trend of frequency. However, on practical grounds, it seems that this geographically-related association may not be valid, as even in the same geographical area, contradicting reports were found . In the present study, TGDs were found in 15.7% of the patients in the control group. In studies from Israel, the frequency of hypothyroidism/TGDs has been reported to range from 4.54% to 12.59% and to 14% , irrespective of the levels of iodine in drinking water . This implies that different parameters (e.g., year of study performance, sample size, group age of included patients) could have an impact on the frequency of TGDs. Thus, associations between OLP and TGDs on a geographical basis seem to be inconclusive, so far.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366342_p16
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31366342
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sec[3]/p[3]
|
Discussion
| 4.195313 |
biomedical
|
Study
|
[
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Up to 15% of patients aged 65 years and over may have subclinical hypothyroidism (mild thyroid failure, as reflected by an elevated thyroid stimulating hormone (TSH) above 4.0 μ IU/mL and normal free T4 levels), with only few, if any, symptoms suggestive of hypothyroidism . The rate of progression to overt hypothyroidism is assessed to be about 5% per year, based on a combination of an elevated level of TSH with the presence of thyroid autoantibodies, thyroid peroxidase (TPO) and anti-thyroglobulin (Tg), together with clinical signs and symptoms, such as fatigue, weight gain, increased sensitivity to cold, drowsiness and others . Although the mean age of patients at time of diagnosis of OLP ranges between 36.9 years and 56.7 years , it is still younger than the estimated mean age when subclinical dysfunction in the thyroid gland begins. Since in most of the studies that attempted to show an association between OLP and TGDs there was no possibility to demonstrate a temporal link or sequence between the onset of OLP lesions and the abnormal thyroid-related levels of TSH, T4 and auto-antibodies, it becomes difficult to support such an association. Moreover, there is one study conducted in patients with auto-immune TGDs, which examined also involvement of OLP . In that study, only one patient out of 65 (3%) was diagnosed with both TGD and OLP, which is substantially lower than that expected rate reported in studies that have investigated the frequency of TGDs among patients with OLP.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366342_p17
|
31366342
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sec[3]/p[4]
|
Discussion
| 4.269531 |
biomedical
|
Study
|
[
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[
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Some studies that investigated the association between OLP and TGDs also referred to the levels of thyroid gland hormones or thyroid auto-autoantibodies. In part of these studies, it was found that 84 to 95% of OLP patients had normal TSH levels , with no difference when compared to control patients . In contrast, a recent study has reported that a significant number of patients with OLP without diagnosed TGDs, showed thyroid parameters (e.g., high levels of TSH, low levels of free T4 and expression of TSH receptor in lesions of OLP) compatible with hypothyroidism . In this regard, it should be mentioned that the levels of TSH may be suppressed by a number of medications such as steroids, dopamine, dobutamine, and octreotide . Since OLP is treated by steroids, local or systemic, depending on the clinical severity of the disease , the precise TSH level in OLP patients might be concealed, thus making it difficult to conclude on any possible association between OLP and TGDs based on TSH levels. In addition, levels of auto-antibodies (i.e., anti-TPO and anti-Tg), which are considered more reliable in defining auto-immune TGDs, are known to be expressed in other medical conditions that are not related to thyroid diseases, such as asthma, idiopathic urticaria, rheumatoid arthritis, diabetes mellitus type 1 and others . Furthermore, 10–15% of patients with Hashimoto thyroiditis may be serum antibody negative, while 10% of healthy young subjects and 15% of people > 60 years of age may have circulating anti-Tg . Exogenous factors, such as smoking and alcohol consumption have a protective effect with lowering the risk for TGDs. More specifically, smoking lowers the levels of anti-TPO and anti-Tg . In line with this, the present study as well as another paper reported a lower frequency of smokers among OLP patients compared to controls. In that paper the frequency of alcohol consumers was also lower in OLP patients compared to controls , which again, may influence the establishment of a possible association between OLP and TGDs.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
31366342_p18
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|
Conclusion
| 4.085938 |
biomedical
|
Study
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[
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We have shown no association between OLP patients and TGDs in a group of OLP patients with well-documented medical data and clinical assessment performed by specialists in oral medicine. The present study agrees with some previous similar studies and contradicts the findings of others, further emphasizing the unresolved issue of a possible association between OLP and TGDs. Associations between OLP and TGDs seems to be complex and multifactorial, probably influenced by both endogenous and exogenous factors, some protecting and others promoting their inter-relations. It is necessary to establish multi-centric collaborations with larger study groups and increased inter-disciplinary collaborations between the field of oral medicine with those of endocrinology and epidemiology in an attempt to provide accurate characterization of the associations between OLP and TGDs.
|
[
"Lazar Kats",
"Yuli Goldman",
"Adrian Kahn",
"Victoria Goldman",
"Meir Gorsky"
] |
https://doi.org/10.1186/s12903-019-0859-5
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366352_p0
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sec[0]/p[0]
|
Introduction
| 3.773438 |
biomedical
|
Review
|
[
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[
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High-intensity aerobic training has been shown to suppress leukocyte counts in moderately fit athletes . There are two possible mechanisms explaining the exercise-induced attenuation of leukocyte counts, including increased oxidative stress and stress hormone concentrations (e.g., cortisol and catecholamines [ 2 – 4 ]). Appropriate nutritional supplementation might prevent, or help to offset, those immunosuppressive effects during high-load endurance training, especially when exposed to more extreme environments. Besides, such supplementation could be beneficial to sedentary individuals who perform less-frequent, high-intensity exercise. However, there is currently insufficient research regarding the efficacy of nutritional supplements.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p1
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31366352
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|
Introduction
| 4.132813 |
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Study
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Cashew apple juice (CAJ), a product of cashew manufacturing, has been reported to improve immunological mechanisms by regulating balance between reactive oxygen species and antioxidant concentrations in mice . Previous studies confirmed that four- and 12-week-consumption of CAJ elicited antioxidant effects in both untrained and trained subjects . That effect may have been due to its essential nutritional components, including vitamin C and anacardic acids, which have established antioxidant activity . Moreover, the link between antioxidant supplementation and reductions in plasma cortisol concentration following strenuous exercise have now been established . Indeed, it is possible that CAJ acts to attenuate the immunosuppressive effect following both overload training and a single bout of high-intensity exercise in sedentary individuals. Besides, CAJ supplementation was shown by our previous study to increase endurance and strength performance . The improved performances may be due to the improved immune system, oxidative stress and stress hormone. However, the chronic effect of CAJ ingestion on the exercise-induced leukocyte counts, oxidative stress and circulating cortisol in trained and untrained populations remain unknown.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p2
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31366352
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|
Introduction
| 4.101563 |
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Therefore, we investigated the chronic effects of CAJ supplementation on primarily on leukocyte counts and secondary on oxidative stress and cortisol changes in both endurance-trained and sedentary subjects before, and after, a bout of high-intensity, endurance exercise. Our aim was to explore possible advantageous effects of CAJ supplementation, and, if present, to identify the possible mechanisms underlying those effects. It was hypothesized that CAJ supplementation would enhance leukocyte counts, and that such a change would be associated with an attenuation of oxidative stress and circulating cortisol concentrations. Finally, it was postulated that those effects would be positively influenced by endurance training status.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366352_p3
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31366352
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|
Study design
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A randomized, double-blind, crossover design was used for this experiment, with two treatment arms; CAJ supplementation and placebo (PLA). Ten moderately (endurance) trained and untrained men were randomized to ingest either daily CAJ or a placebo at 3.5 mL/kgBM/day for four weeks, with a four-week wash out period. Before and after each period, they performed 20-min, high-intensity cycling (85% VO 2max ). All subjects were informed both verbally, and in writing, as to the possible risks of the study before signing a consent form. All experimental procedures were approved by the Human Ethical Committee of Khon Kaen University , and followed the ethical guidelines of the most recent Declaration of Helsinki . This study was also retrospectively registered in the Thai Clinical Trials Registry . Based on the observations of Özaslan et al. , in which vitamin C supplementation (4 mg/day for four weeks) increased leukocyte counts by 7.3% compared to a control group, power calculations (80% power and alpha level of 0.05) were used to determine the required sample size to observe a 5% increase in leukocyte counts. Accordingly, the sample size for this study was ten subjects for each of the two experimental groups (endurance-trained and sedentary).
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p4
|
31366352
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sec[1]/sec[1]/p[0]
|
Subjects
| 4.171875 |
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Ten moderately trained men and ten untrained men in Khon Kaen province undertook this study (Table 1 ). Subjects were recruited during January 2012–December 2012. Before enrolling, all subjects were examined general health, including blood chemistry, health questionnaires, and physical examinations. This was a single-gender investigation, since gender influences on oxidative stress and the inflammatory response to exercise have been reported. Both population samples were of a similar age and of normal body mass for Thai adults since both factors affect oxidative stress biomarkers and antioxidant responses to exercise . The following inclusion criteria were applied to both groups: 1) an absence of any health-related conditions 2) no use of any nutritional supplements for at least 6 months, but also during this study, c) non-smokers or drinkers. Finally, the untrained subjects had a sedentary lifestyle, and did not perform exercise of any form more than twice per week, while trained subjects performed moderate- to high-intensity endurance exercise at least six days per week for at least the previous two years. Table 1 Baseline physical and physiological characteristics of subjects Untrained group ( n = 10) Trained group ( n = 10) P value Age (yr) 20.4 ± 2.72 21.5 ± 0.97 0.24 Body mass (kg) 62.7 ± 8.30 67.2 ± 10.18 0.29 Height (m) 1.69 ± 0.06 1.70 ± 0.07 0.36 BMI (kg/m 2 ) 21.9 ± 1.73 22.7 ± 2.35 0.38 Waist circumference (cm) 73.6 ± 6.87 75.6 ± 4.27 0.43 Hip circumference (cm) 92.2 ± 5.05 92.3 ± 4.96 0.97 W/H ratio 0.80 ± 0.04 0.80 ± 0.03 0.19 Body fat (%) 21.9 ± 8.09 16.1 ± 6.58 0.10 Fat mass (kg) 14.3 ± 5.61 13.8 ± 8.28 0.88 Fat free mass (kg) 48.9 ± 5.68 50.8 ± 4.95 0.43 V̇O 2,peak (ml/kgBM/min) V̇O 2,max (ml/kgBM/min) 32.2 ± 7.26 45.6 ± 4.12 0.00 V̇O 2,peak (ml/kgFFM/min) V̇O 2,max (ml/kgFFM/min) 42.2 ± 7.69 58.5 ± 4.86 0.00 Work rate max (watts) 136 ± 14.30 177 ± 13.37 0.00 Values are mean ± SD, n = 10 in each group. BM body mass, BMI body mass index, W/H waist to hip circumference, V̇O 2,peak peak oxygen consumption, V̇O 2,max maximal oxygen consumption, FFM fat free mass, Work rate max maximal work rate P value < 0.05, significantly different from the untrained group
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
31366352_p5
|
31366352
|
sec[1]/sec[2]/p[0]
|
Baseline measurements
| 4.027344 |
biomedical
|
Study
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[
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[
0.9990234375,
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Baseline data were collected prior to commencing supplementation (Table 1 ), including routine medical examinations and measurements of body height, mass, body mass index (BMI), and body composition. Fat distribution was estimated from the ratio of waist and hip circumferences. Body composition (excluding cranium) was assessed using dual emission X-ray absorptiometry (DXA; Lunar Prodigy whole-body scanner, GE Medical System, USA).
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p6
|
31366352
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sec[1]/sec[3]/p[0]
|
Supplementation protocol
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biomedical
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Study
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[
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[
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] |
Two treatments were used within each of the population samples: an experimental CAJ supplementation and a control PLA supplementation. The CAJ supplement (Srisupphaluck Orchid Co., Ltd., Phuket, Thailand) was composed of vitamin C (3.36 mg/100 g), branched-chain amino acids of leucine (1.64 mg/100 g), isoleucine (3.04 mg/100 g), and valine (0.19 mg/100 g), and contained a total sugar content of 69.8 g/100 mL) . The PLA was prepared with a total sugar equal to that of the CAJ. Both supplements were provided at a body-mass dependent concentration of 3.5 mL/kg/day.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p7
|
31366352
|
sec[1]/sec[4]/p[0]
|
Randomization
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biomedical
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Other
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[
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[
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Within each of the subject groups (1:1), an electronic randomization procedure was used to assign an equal number of participants into either the experimental or control supplementation groups . Each number was kept in a sealed envelope before the allocation. A researcher who generated the random allocation sequence was different from the one who enrolled participants, and assigned participants to interventions . Fig. 1 Flow chart of the trial protocol
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p8
|
31366352
|
sec[1]/sec[5]/p[0]
|
Study protocol
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biomedical
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Study
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[
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[
0.9970703125,
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] |
Prior to commencing supplementation, all subjects performed an incremental exercise test to volitional exhaustion, thereby permitting the determination of peak oxygen consumption (V̇O 2,peak ) and maximal work rate for every participant (Table 1 ). One week later, they commenced the 12-week nutritional supplementation phase, commencing with four weeks of supplement administration, followed by a washout period (four weeks) before entering the second arm of supplementation. Immediately before and after supplementation, each participant performed a 20-min bout of high-intensity cycling (Corival, Lode B.V., The Netherlands), the intensity of which was set at 85% of each person’s maximal work rate. Expired-gas samples were collected throughout (PowerLab 8/30 AD Instruments, Australia), as were oxygen saturation, heart rate, and electrocardiographic data (Nihon Kohden Monitoring System Network, Japan). Venous blood samples (12 mL) were taken from the antecubital vein and collected into EDTA-treated and lithium heparin-treated tubes. Those samples were collected before and after this exercise bout, and used to analyze leukocyte counts and the concentrations of plasma 8-isoprostane, malondialdehyde, and serum cortisol. Whole blood for leukocyte counts remained capped at an ambient temperature was analysed within four hours. Room temperature was 24 ± 2 °C and humidity during testing was 59 ± 8%. All tests were performed at the same time of the day.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
31366352_p9
|
31366352
|
sec[1]/sec[5]/p[1]
|
Study protocol
| 2.021484 |
biomedical
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Study
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[
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[
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Subjects were instructed not to alter their diets or physical activities all over the course of the entire 12 weeks of this experiment. One week before beginning and finishing the experiment, subjects were asked to record their daily diet and physical activity patterns for three days of that week; two days from the middle of the week and one weekend day.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p10
|
31366352
|
sec[1]/sec[6]/p[0]
|
Analysis of leukocyte counts and serum cortisol concentration
| 3.720703 |
biomedical
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Study
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[
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[
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Whole blood sample for three mL in an EDTA-treated tube was analyzed for the counts of total leukocyte, monocyte, neutrophil, and lymphocyte using the routine hematology laboratory method in Srinagarind hospital, Faculty of medicine, Khon Kaen University. The Automated Hematology Analyzer was calibrated before every measurement.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p11
|
31366352
|
sec[1]/sec[6]/p[1]
|
Analysis of leukocyte counts and serum cortisol concentration
| 4.074219 |
biomedical
|
Study
|
[
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[
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Blood sample for three mL in a lithium heparin-treated tube was analyzed for serum cortisol concentration using the radioimmunoassay technique in Srinagarind hospital, Faculty of medicine, Khon Kaen University. The assay is based on the competition between the labelled cortisol and cortisol contained in calibrators or specimens to be assayed for a fixed and limited number of antibody binding sites bound to the solid phase. After incubation, the unbound tracer is easily removed by a washing step. The amount of labelled cortisol bound to the antibody is inversely related to the amount of unlabelled cortisol initially present in the sample.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p12
|
31366352
|
sec[1]/sec[7]/p[0]
|
Analysis of plasma MDA and 8-isoprostane concentrations
| 4.097656 |
biomedical
|
Study
|
[
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[
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Blood samples (3 mL) in the EDTA-treated tubes were centrifuged at 4 °C and 2,500 g for 15 min to remove red blood cells and to recover plasma. The concentration of plasma MDA was analyzed indirectly from the concentration of Thiobarbituric acid reactive substances using Draper’s method . The basis of the TBA methods is the reaction of MDA with TBA at low pH and high temperature to form a colored complex, the MDA-TBA complex, with an absorption maximum at 532–535 nm that can be measured by visible absorption spectrophotometry.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
31366352_p13
|
31366352
|
sec[1]/sec[7]/p[1]
|
Analysis of plasma MDA and 8-isoprostane concentrations
| 3.978516 |
biomedical
|
Study
|
[
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[
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The concentration of plasma 8-isoprostane was analyzed using 8-isoprostane EIA kit (Cayman Chemical Company, USA). The competition between 8-isoprostane and 8-isoprostane acetylcholinesterase (AChE) conjugate for specific antiserum binding sites. The product of the enzymatic reaction has yellow colour and absorb at 412 nm. The intensity of colour measured by spectrophotometer. The amount of free 8-isoprostane show as inversely proportional with intensity.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
31366352_p14
|
31366352
|
sec[1]/sec[8]/p[0]
|
Statistical analyses
| 4.066406 |
biomedical
|
Study
|
[
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[
0.9990234375,
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Data were tested for normal distribution (Shapiro-Wilks), homogeneity of variance (Levene’s test of equality of error variance), and sphericity (Mauchly’s). Data were then compared between the CAJ and the PLA supplements, and between the trained and untrained subjects using two-way analysis of variance (repeated measures). The data were initially compared prior to commencing the supplements using a one-way analysis of variance (ANOVA) with an alpha level of 0.05 to ensure there was no significant treatment order effect of supplement. A two-way analysis of variance (ANOVA) with an alpha level of 0.05 was run to evaluate the interaction effects of nutritional supplementation and the endurance training status at rest and after exercise, before and after the supplementation. When significant interactions were observed, post hoc analysis was performed using Tukey test comparison. Effect sizes were reported as partial Cohen’s d with the following effect thresholds: small (d = 0.2), medium (d = 0.6) and large (d = 1.2). All data are shown as mean with standard deviations (±). Probabilities at the 5% level were considered as statistically significant. All statistics were evaluated using SPSS Statistics for Windows (IBM Inc., Armonk, NY, USA).
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
31366352_p15
|
31366352
|
sec[2]/sec[0]/p[0]
|
Pre-experimental status
| 4.066406 |
biomedical
|
Study
|
[
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[
0.99951171875,
0.00019025802612304688,
0.000255584716796875,
0.000064849853515625
] |
Prior to commencing this experiment, the aerobic power of the two population samples differed significantly, regardless of fat-free mass or total-body mass ( p < 0.05; Table 1 ). There were no significant differences in baseline anthropometrics, body composition, or physiological characteristics between the subject groups ( p > 0.05; Table 1 ). Similarly, the baseline immunological variables and cell counts did not differ, and were within the reference intervals for people of normal health. Furthermore, we did not find any treatment order effect on all variables in both untrained and trained subjects ( p > 0.05). Furthermore, no harmful effect from the experiment to all subjects.
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p16
|
31366352
|
sec[2]/sec[1]/p[0]
|
Leukocyte counts at rest and immediately after exercise
| 4.132813 |
biomedical
|
Study
|
[
0.9990234375,
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[
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There was a significant main effect of supplementation (F = 6.77, p = 0.02, effect size = 0.29), with the CAJ supplement resulting in a greater total leukocyte counts immediately after exercise . Furthermore, there was a significant supplement effect on the resting neutrophil counts (F = 11.25, p = 0.00, effect size = 0.40). In this case, CAJ significantly produced increased resting neutrophil counts . However, neither CAJ nor PLA modified lymphocyte or monocyte counts in either subject group, either at rest or immediately after exercise. Finally, there was no interaction between supplement and training status over time for the leukocyte counts (total leukocyte: F = 0.27, p = 0.61; neutrophil: F = 0.59, p = 0.45; monocyte: F = 2.07, p = 0.17; lymphocyte: F = 0.00, p = 0.97). Both trained and untrained groups had increased leukocyte, neutrophil, and lymphocyte counts after exercise compared with before exercise in both supplement groups ( p < 0.05). Only monocyte counts before both supplementations in untrained subjects was increased after exercise compared with before exercise ( p < 0.05). Fig. 2 Total leukocyte 1( a ), neutrophil 1( b ), lymphocyte 1( c ), and monocyte 1( d ) counts before and immediately after exercise at 85% V̇O 2,peak or 85% V̇O 2,max after four-week placebo (PLA) and cashew apple juice (CAJ) supplementation. Values are mean ± SE, n = 10 in each group. # significantly different from PLA supplementation at the same condition, p < 0.05, ¶ significantly different from before exercise at the same condition, p < 0.05
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
31366352_p17
|
31366352
|
sec[2]/sec[2]/p[0]
|
Oxidative stress at rest and immediately after exercise
| 4.132813 |
biomedical
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Study
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[
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[
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There was no effect of training status on any of the oxidative stress markers, either before or after supplementation (all p > 0.05). Similarly, there was no interaction between the supplementation and training status of the two groups in oxidative stress markers , either before or following supplementation. Fig. 3 Plasma MDA concentrations before and immediately after exercise at 85% V̇O 2,peak or 85% V̇O 2,max after four-week placebo (PLA) and cashew apple juice (CAJ) supplementation. Values are mean ± SD, n = 10 in each group. MDA, malaondialdehyde. * Significantly different from before supplementation, p < 0.05, # significantly different from PLA supplementation, p < 0.05, @ significantly different from untrained group, p < 0.05. ¶ significantly different from before exercise at the same condition, p < 0.05 Fig. 4 Plasma 8-isoprostane concentrations before and immediately after exercise at 85% V̇O 2,peak or 85% V̇O 2,max after 4-week placebo (PLA) and cashew apple juice (CAJ) supplementation. Values are mean ± SD, n = 10 in each group. * Significantly different from before supplementation, p < 0.05, # significantly different from PLA supplementation, p < 0.05. ¶ significantly different from before exercise at the same condition, p < 0.05
|
[
"Piyapong Prasertsri",
"Thapanee Roengrit",
"Yupaporn Kanpetta",
"Terdthai Tong-un",
"Supaporn Muchimapura",
"Jintanaporn Wattanathorn",
"Naruemon Leelayuwat"
] |
https://doi.org/10.1186/s12970-019-0299-2
|
OpenAccess
|
http://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |