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Maleimide and amidine functionalities often appear in medicinal and natural product targets. We describe a catalyst-free, three-component coupling reaction for the synthesis of amidinomaleimides. This one-pot reaction fuses a broad range of secondary amines and aldehydes with azidomaleimides. The conditions are mild, simple, modular, high yielding, and amenable to aqueous solvents. Most reaction products can be sufficiently purified without column chromatography. The synthesis creates complex, multifunctional molecules with four different molecules, including a tripeptide, arrayed around an amidinomaleimide core.
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OBJECTIVE: Patients commonly use physician review websites when choosing a surgeon for an elective procedure. Although data exist regarding other orthopaedic specialties, no study has investigated one-star reviews for pediatric orthopaedic surgeons. The goal of this retrospective study was to classify the factors contributing to one-star reviews of pediatric orthopaedic surgeons to identify which areas contribute to lower patient satisfaction. METHODS: Patient ratings on a 5-star system and comments about pediatric orthopaedic surgeons were collected from the state with the most physicians registered in the "Pediatric Orthopaedic Society of North American" database for each of the 9 geographical regions of the United States as defined by the Association of American Medical Colleges. One-star reviews that included comments were classified as either surgical or nonsurgical. These comments were then further classified based on their content. RESULTS: Three hundred fifty-four one-star reviews with 700 complaints were included in this study. Of these complaints, 481 (68.7%) were from nonsurgical patients and 219 (31.3%) were from surgical patients. Nonsurgical patients were significantly more likely to reference the amount of time spent with the physician (12.9% to 6.6%, P = 0.026), wait time (11.9% to 0.0%, P < 0.001), and bedside manner (41.2% to 22.8%, P < 0.001). Patients who said they had undergone a surgical procedure in their one-star review were significantly more likely to reference a disagreement with the physician's decision or plan (35.3% to 17.5%, P < 0.001), and uncontrolled pain (21.6% to 5.2%, P < 0.001). There was no significant difference in the comments that referenced medical staff or institutional complaints between surgical and nonsurgical patients (13.8% to 11.4%, P = 0.424). CONCLUSION: Most one-star reviews of pediatric orthopaedic surgeons referenced interpersonal skills and other nonclinical aspects of a clinical encounter, with bedside manner being the most frequent complaint. Patients who had undergone surgical procedures were less likely to leave a one-star review, but if they did, their comment was usually about a disagreement with the physician's plan. CLINICAL RELEVANCE: Prognostic studies III.
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Cirurgiões Ortopédicos , Ortopedia , Cirurgiões , Humanos , Estados Unidos , Criança , Estudos Retrospectivos , Satisfação do PacienteRESUMO
Adult Hirschsprung's disease (AHD) is a rare condition characterized by a shortened aganglionic segment in the distal colon or rectum that is diagnosed after the age of 10. Diagnostic challenges stem from its rarity, nonspecific presentation, and often delayed consideration following emergent interventions. This report details the case of a 33-year-old male who presented with chronic constipation and abdominal pain, leading to a severe bowel obstruction attributed to self-reported Hirschsprung's disease (HD). Clinical, radiological, and historical aspects were suggestive of AHD, but definitive diagnostic procedures, including manometry and biopsy, were hindered by the patient's deteriorating condition. Exploratory laparotomy unveiled a secondary small bowel obstruction due to volvulus, necessitating immediate intervention, resulting in the removal of 4000 cc of fecal material. A comprehensive resection involving mid-to-distal transverse colon, left colon, sigmoid colon, and proximal rectum with the creation of Hartman's colostomy was performed due to the patient's worsening clinical status. We present a case of possible ultrashort-segment Hirschsprung's disease (USHD) and sketch a classic presentation of AHD. This endeavor aims to enhance awareness and consideration of AHD and/or USHD within the spectrum of potential diagnoses for chronic constipation when relevant and demonstrate the effectiveness of surgical intervention in this population.
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Importance: Improved, efficient, and acceptable treatments are needed for combat-related posttraumatic stress disorder (PTSD). Objective: To determine the efficacy of 2 compressed prolonged exposure (PE) therapy outpatient treatments for combat-related PTSD. Design, Setting, and Participants: This randomized clinical trial was conducted among military personnel and veterans at 4 sites in Texas from 2017 to 2019. Assessors were blinded to conditions. Data were analyzed from November 2020 to October 2022. Interventions: The interventions were massed-PE, which included 15 therapy sessions of 90 minutes each over 3 weeks, vs intensive outpatient program PE (IOP-PE), which included 15 full-day therapy sessions over 3 weeks with 8 treatment augmentations. The IOP-PE intervention was hypothesized to be superior to massed-PE. Main Outcomes and Measures: Coprimary outcomes included the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) (CAPS-5) and the PTSD Checklist for DSM-5 (PCL-5) administered at baseline and posttreatment follow-ups. Measures ranged from 0 to 80, with higher scores indicating greater severity. Diagnostic remission and reliable change were secondary outcomes. Results: Among 319 military personnel and veterans screened, 234 were randomized (mean [SD] age, 39.20 [7.72] years; 182 [78%] male participants), with 117 participants randomized to IOP-PE and 117 participants randomized to massed-PE. A total of 61 participants (26%) were African American, 58 participants (25%) were Hispanic, and 102 participants (44%) were White; 151 participants (65%) were married. Linear mixed-effects models found that CAPS-5 scores decreased in both treatment groups at the 1-month follow-up (IOP-PE: mean difference, -13.85 [95% CI, -16.47 to -11.23]; P < .001; massed-PE: mean difference, -14.13 [95% CI, -16.63 to -11.62]; P < .001). CAPS-5 change scores differed from 1- to 6-month follow-ups (mean difference, 4.44 [95% CI, 0.89 to 8.01]; P = .02). PTSD symptoms increased in massed-PE participants during follow-up (mean difference, 3.21 [95% CI, 0.65 to 5.77]; P = .01), whereas IOP-PE participants maintained treatment gains (mean difference, 1.23 [95% CI, -3.72 to 1.27]; P = .33). PCL-5 scores decreased in both groups from baseline to 1-month follow-up (IOP-PE: mean difference, -21.81 [95% CI, -25.57 to -18.04]; P < .001; massed-PE: mean difference, -19.96 [95% CI, -23.56 to -16.35]; P < .001) and were maintained at 6 months (IOP-PE: mean change, -0.21 [95% CI, -3.47 to 3.06]; P = .90; massed-PE: mean change, 3.02 [95% CI, -0.36 to 6.40]; P = .08). Both groups had notable PTSD diagnostic remission at posttreatment (IOP-PE: 48% [95% CI, 36% to 61%] of participants; massed-PE: 62% [95% CI, 51% to 73%] of participants), which was maintained at 6 months (IOP-PE: 53% [95% CI, 40% to 66%] of participants; massed-PE: 52% [95% CI, 38% to 66%] of participants). Most participants demonstrated reliable change on the CAPS-5 (61% [95% CI, 52% to 69%] of participants) and the PCL-5 (74% [95% CI, 66% to 81%] of participants) at the 1-month follow-up. Conclusions and Relevance: These findings suggest that PE can be adapted into compressed treatment formats that effectively reduce PTSD symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT03529435.
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Militares , Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Masculino , Adulto , Feminino , Transtornos de Estresse Pós-Traumáticos/terapia , Pacientes Ambulatoriais , Resultado do TratamentoRESUMO
Background: Enhancing resiliency and optimizing readiness in military personnel is a high priority for the U.S. Department of Defense. Most military resiliency-enhancement programs are evidence-informed interventions. However, few randomized studies have demonstrated efficacy of any intervention or training program to enhance resiliency and prevent the development of psychological health symptoms in military personnel when exposed to operational stressors. This manuscript provides an overview of the theoretical foundation, research design, and research methods of a preventive intervention trial designed to evaluate the efficacy of a training program to enhance resiliency and prevent psychological health symptoms in military personnel. The resiliency training intervention is based on Acceptance and Commitment Therapy (ACT), an evidence-based intervention with broad empirical support for improving functioning in those living with psychological and medical conditions. Method/design: This study will evaluate the efficacy of a two-day training program based on ACT for fostering psychological flexibility, the central target in ACT, for enhancing resiliency, and for preventing the development of psychological health symptoms. The research participants will be a non-clinical population of active duty military personnel (N = 600). The ACT-based training program (n = 300) will be compared to a military resiliency training as usual, known as Master Resilience Training (n = 300). Assessment measures will be administered at the baseline assessment, after training, prior to a military deployment, and after returning from a deployment. Qualitative interviews will be conducted to provide feedback on the training program.Clinical Trial Registration: NCT05094115.
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In the current paper, we aim to expand the dialogue about applying psychological flexibility processes to moral injury-related spiritual suffering using Acceptance and Commitment Therapy (ACT). Psychological flexibility is the process of practicing present moment awareness and openness to experiences of emotions and thoughts, while also choosing to engage in actions that are consistent with one's values. This open, aware, and engaged approach to life fits well with spiritual endeavors. We provide a framework and a case example illustrating how spiritual care providers and Chaplains can use psychological flexibility processes to target spiritual suffering in the context of moral injury.
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Terapia de Aceitação e Compromisso , Transtornos de Estresse Pós-Traumáticos , Ansiedade , Clero , Humanos , EspiritualidadeRESUMO
OBJECTIVE: Concern about symptom worsening with trauma-focused treatment may be one factor hindering the implementation of evidence-based treatments for PTSD, like cognitive processing therapy (CPT), despite evidence for their efficacy. Previous studies have examined the frequency and effect of symptom exacerbation, or temporary symptom increases, on outcomes, but primarily in randomized clinical trials. METHOD: We examined this issue in a community sample of participants receiving CPT from front-line clinicians learning to deliver CPT in a randomized controlled implementation trial of training strategies. Patient participants (n = 183) completed self-report measures of PTSD symptoms at each session. RESULTS: Most participants (67.3%) experienced at least one temporary symptom increase during CPT (only 1.6% continued to have higher symptoms by the end of treatment). Demographic variables, comorbid conditions (i.e., depression, anxiety, substance use), and baseline PTSD symptom levels did not predict symptom increases. Importantly, symptom increases did not predict treatment noncompletion, posttreatment PTSD symptom levels, or loss of probable PTSD diagnosis. Moreover, growth curve modeling revealed that temporary symptom increases did not predict the trajectory of PTSD symptoms over the course of treatment. CONCLUSIONS: The rates of symptom increases, which were higher than in previous studies, may be attributed to a routine care sample or to the differences in session timing and measurement. These results add to a nascent literature documenting that symptom increases may be a normal, transient part of treatment that do not impact a patient's ability to have symptom improvement during a course of CPT. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Terapia Cognitivo-Comportamental , Transtornos de Estresse Pós-Traumáticos , Veteranos , Ansiedade , Terapia Cognitivo-Comportamental/métodos , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Estresse Pós-Traumáticos/terapia , Exacerbação dos Sintomas , Resultado do Tratamento , Veteranos/psicologiaRESUMO
We have modelled genetic risk for binge-like drinking by selectively breeding High Drinking in the Dark-1 and -2 (HDID-1 and HDID-2) mice for their propensity to reach intoxicating blood alcohol levels (BALs) after binge-like drinking in a single bottle, limited access paradigm. Interestingly, in standard two-bottle choice (2BC) tests for continuously available alcohol versus water, HDID mice show modest levels of preference. This indicates some degree of independence of the genetic contributions to risk for binge-like and sustained, continuous access drinking. We had few data where the drinking in the dark (DID) tests of binge-like drinking had been repeatedly performed, so we serially offered multiple DID tests to see whether binge-like drinking escalated. It did not. We also asked whether HDID mice would escalate their voluntary intake with prolonged exposure to alcohol 2BC. They did not. Lastly, we assessed whether an alcohol deprivation effect (ADE) developed. ADE is a temporary elevation in drinking typically observed after a period of abstinence from sustained access to alcohol choice. With repetition, these periods of ADE sometimes have led to more sustained elevations in drinking. We therefore asked whether repeated ADE episodes would elevate choice drinking in HDID mice. They did not. After nearly 500 days of alcohol access, the intake of HDID mice remained stable. We conclude that a genetically-enhanced high risk for binge-like drinking is not sufficient to yield alterations in long-term alcohol intake.
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Consumo Excessivo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/genética , Animais , Escuridão , Etanol/sangue , Masculino , Camundongos , Modelos AnimaisRESUMO
Community mental health providers play an essential role in delivering services to veterans who either have limited access to U.S. Department of Veterans Affairs (VA) facilities or who prefer to seek care outside of the VA. However, there are limited training opportunities in evidence-based treatments for posttraumatic stress disorder (PTSD) outside of the VA. In 2017, the STRONG STAR Training Initiative was established to develop competency-based training in two evidence-based therapies for PTSD and to provide that training for mental health providers serving veterans and their families in community settings in Texas. This article describes the program's development and implementation, baseline characteristics of participating clinicians, and lessons learned toward the scale-up and extension of this competency-based training effort to include other interventions and locations.
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Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Saúde Mental , Transtornos de Estresse Pós-Traumáticos/terapia , Texas , Estados Unidos , United States Department of Veterans AffairsRESUMO
BACKGROUND: Chronic alcohol exposure can alter glucocorticoid receptor (GR) function in some brain areas that promotes escalated and compulsive-like alcohol intake. GR antagonism can prevent dependence-induced escalation in drinking, but very little is known about the role of GR in regulating high-risk nondependent alcohol intake. Here, we investigate the role of GR in regulating binge-like drinking and aversive responses to alcohol in the High Drinking in the Dark (HDID-1) mice, which have been selectively bred for high blood ethanol (EtOH) concentrations (BECs) in the Drinking in the Dark (DID) test, and in their founder line, the HS/NPT. METHODS: In separate experiments, male and female HDID-1 mice were administered one of several compounds that inhibited GR or its negative regulator, FKBP51 (mifepristone [12.5, 25, 50, 100 mg/kg], CORT113176 [20, 40, 80 mg/kg], and SAFit2 [10, 20, 40 mg/kg]) during a 2-day DID task. EtOH consumption and BECs were measured. EtOH conditioned taste and place aversion (CTA and CPA, respectively) were measured in separate HDID-1 mice after mifepristone administration to assess GR's role in regulating the conditioned aversive effects of EtOH. Lastly, HS/NPT mice were administered CORT113176 during DID to assess whether dissimilar effects from those of HDID-1 would be observed, which could suggest that selective breeding had altered sensitivity to the effects of GR antagonism on binge-like drinking. RESULTS: GR antagonism (with both mifepristone and CORT113176) selectively reduced binge-like EtOH intake and BECs in the HDID-1 mice, while inhibition of FKBP51 did not alter intake or BECs. In contrast, GR antagonism had no effect on EtOH intake or BECs in the HS/NPT mice. Although HDID-1 mice exhibit attenuated EtOH CTA, mifepristone administration did not enhance the aversive effects of EtOH in either a CTA or CPA task. CONCLUSION: These data suggest that the selection process increased sensitivity to GR antagonism on EtOH intake in the HDID-1 mice, and support a role for the GR as a genetic risk factor for high-risk alcohol intake.
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Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Etanol/administração & dosagem , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/fisiologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/genética , Animais , Agentes Aversivos , Consumo Excessivo de Bebidas Alcoólicas/genética , Consumo Excessivo de Bebidas Alcoólicas/prevenção & controle , Feminino , Isoquinolinas/farmacologia , Masculino , Camundongos , Mifepristona/farmacologia , Pirazóis/farmacologia , Receptores de Glucocorticoides/genética , Proteínas de Ligação a Tacrolimo/antagonistas & inibidoresRESUMO
Alcohol use disorders (AUDs) are prevalent, and are characterized by binge-like drinking, defined by patterns of focused drinking where dosages ingested in 2-4 âh reach intoxicating blood alcohol levels (BALs). Current medications are few and compliance with the relatively rare prescribed usage is low. Hence, novel and more effective medications are needed. We developed a mouse model of genetic risk for binge drinking (HDID: High Drinking in the Dark mice) by selectively breeding for high BALs after binge drinking. A transcriptional analysis of HDID brain tissue with RNA-Seq implicated neuroinflammatory mechanisms, and, more specifically extracellular matrix genes, including those encoding matrix metalloproteinases (MMPs). Prior experiments from other groups have shown that the tetracycline derivatives doxycycline, minocycline, and tigecycline, reduce binge drinking in inbred C57BL/6J mice. We tested these three compounds in female and male HDID mice and found that all three reduced DID and BAL. They had drug-specific effects on intake of water or saccharin in the DID assay. Thus, our results show that the effectiveness of synthetic tetracycline derivatives as potential therapeutic agents for AUDs is not limited to the single C57BL/6J genotype previously targeted, but extends to a mouse model of a population at high risk for AUDs.
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Two independent lines of High Drinking in the Dark (HDID-1, HDID-2) mice have been bred to reach high blood alcohol levels after a short period of binge-like ethanol drinking. Male mice of both lines were shown to have reduced sensitivity to develop a taste aversion to a novel flavor conditioned by ethanol injections as compared with their unselected HS/NPT founder stock. We have subsequently developed inbred variants of each line. The current experiments established that reduced ethanol-conditioned taste aversion is also seen in the inbred variants, in both males and females. In other experiments, we asked whether HDID mice would ingest sufficient doses of ethanol to lead to a conditioned taste aversion upon retest. Different manipulations were used to elevate consumption of ethanol on initial exposure. Access to increased ethanol concentrations, to multiple tubes of ethanol, and fluid restriction to increase thirst motivation all enhanced initial drinking of ethanol. Each condition led to reduced intake the next day, consistent with a mild conditioned taste aversion. These experiments support the conclusion that one reason contributing to the willingness of HDID mice to drink to the point of intoxication is a genetic insensitivity to the aversive effects of ethanol.
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Headspace solid-phase microextraction (HS-SPME) was used in combination with gas chromatography-mass spectrometry (GC-MS) for the analysis of polycyclic aromatic hydrocarbons (PAH) at part per billion levels in fish oil samples collected from menhaden fish. The method was initially developed using fish oil from capsules spiked with a standard PAH mixture. The final HS-SPME-GC-MS method presented a linear range from 3 to 1,500 ng/g, with precision for most analytes <10% relative standard deviation. The limits of detection varied from 1 to 7 ng/g depending on the analyte. Real sample analysis was done on menhaden fish oil extracted from fish collected off the coasts of New Jersey and Louisiana. Naphthalene, fluorene, fluoranthene, pyrene, anthracene were detected at low levels of 70-180 ng/g in the real samples. The concentrations of PAHs detected in the real samples were well below established levels of concern for PAHs in finfish.
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Combat-related posttraumatic stress disorder (PTSD) is the most common psychological health condition in military service members and veterans who have deployed to the combat theater since September 11, 2001. One of the highest research priorities for the Department of Defense and the Department of Veterans Affairs is to develop and evaluate the most efficient and efficacious treatments possible for combat-related PTSD. However, the treatment of combat-related PTSD in military service members and veterans has been significantly more challenging than the treatment of PTSD in civilians. Randomized clinical trials have demonstrated large posttreatment effect sizes for PTSD in civilian populations. However, recent randomized clinical trials of service members and veterans have achieved lesser reductions in PTSD symptoms. These results suggest that combat-related PTSD is unique. Innovative approaches are needed to augment established evidence-based treatments with targeted interventions that address the distinctive elements of combat-related traumas. This paper describes the design, methodology, and protocol of a randomized clinical trial to compare two intensive prolonged exposure therapy treatments for combat-related PTSD in active duty military service members and veterans and that can be administered in an acceptable, efficient manner in this population. Both interventions include intensive daily treatment over a 3-week period and a number of treatment enhancements hypothesized to result in greater reductions in combat-related PTSD symptoms. The study is designed to advance the delivery of care for combat-related PTSD by developing and evaluating the most potent treatments possible to reduce PTSD symptomatology and improve psychological, social, and occupational functioning.
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Distúrbios de Guerra/terapia , Terapia Implosiva/métodos , Militares , Transtornos de Estresse Pós-Traumáticos/terapia , Veteranos , Assistência Ambulatorial , Terapia Cognitivo-Comportamental/métodos , HumanosRESUMO
AIMS: Glutamate decarboxylase (GAD) antibodies are the most widely used predictive marker for Type 1 diabetes, but many individuals currently found to be GAD antibody-positive are unlikely to develop diabetes. We have shown previously that radioimmunoassays using N-terminally truncated 35 S-GAD65 (96-585) offer better disease specificity with similar sensitivity to full-length 35 S-GAD65 (1-585). To determine whether assay performance could be improved further, we evaluated a more radically truncated 35 S-GAD65 (143-585) radiolabel. METHODS: Samples from people with recent-onset Type 1 diabetes (n = 157) and their first-degree relatives (n = 745) from the Bart's-Oxford family study of childhood diabetes were measured for GAD antibodies using 35 S-labelled GAD65 (143-585). These were screened previously using a local radioimmunoassay with 35 S-GAD65 (1-585). A subset was also tested by enzyme-linked immunosorbent assay (ELISA), which performs well in international workshops, but requires 10 times more serum. Results were compared with GAD antibody measurements using 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). RESULTS: Sensitivity of GAD antibody measurement was maintained using 35 S-GAD65 (143-585) compared with 35 S-GAD65 (1-585) and 35 S-GAD65 (96-585). Specificity for Type 1 diabetes was improved compared with 35 S-GAD65 (1-585), but was similar to 35 S-GAD65 (96-585). Relatives found to be GAD antibody-positive using these truncated labels were at increased risk of diabetes progression within 15 years, compared with those positive for GAD(1-585) antibody only, and at similar risk to those found GAD antibody-positive by ELISA. CONCLUSIONS: The first 142 amino acids of GAD65 do not contribute to epitopes recognized by Type 1 diabetes-associated GAD antibodies. Low-volume radioimmunoassays using N-terminally truncated 35 S-GAD65 are more specific than those using full-length GAD65 and offer practical alternatives to the GAD antibody ELISA for identifying children at increased risk of Type 1 diabetes.
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Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Glutamato Descarboxilase/imunologia , Fragmentos de Peptídeos/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Família , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Radioimunoensaio , Sensibilidade e Especificidade , Adulto JovemRESUMO
Individuals with type 1 diabetes (T1D) are at increased risk of coeliac disease (CD), autoimmune thyroiditis and autoimmune gastritis, but the absolute risks are unclear. The aim of this study was to investigate the prevalence of autoantibodies to tissue transglutaminase (TGA), thyroid peroxidase (TPOA) and gastric H+ /K+ -ATPase (ATPA) and their genetic associations in a well-characterized population-based cohort of individuals with T1D from the Bart's-Oxford family study for whom islet autoantibody prevalence data were already available. Autoantibodies in sera from 1072 patients (males/females 604/468; median age 11·8 years, median T1D duration 2·7 months) were measured by radioimmunoassays; HLA class II risk genotype was analysed in 973 (91%) using polymerase chain reaction with sequence specific primers (PCR-SSP). The prevalence of TGA (and/or history of CD), TPOA and ATPA in patients was 9·0, 9·6 and 8·2%, respectively; 3·1% had two or more autoantibodies. Females were at higher risk of multiple autoimmunity; TGA/CD were associated with younger age and TPOA with older age. ATPA were uncommon in patients under 5 years, and more common in older patients. Anti-glutamate decarboxylase autoantibodies were predictive of co-existing TPOA/ATPA. TGA/CD were associated with human leucocyte antigen (HLA) DR3-DQ2, with the DR3-DQ2/DR3-DQ2 genotype conferring the highest risk, followed by DR4-DQ8/DR4-DQ8. ATPA were associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype. TPOA were associated with the DR3-DQ2/DR3-DQ2 genotype. Almost one-quarter of patients diagnosed with T1D aged under 21 years have at least one other organ-specific autoantibody. HLA class II genetic profiling may be useful in identifying those at risk of multiple autoimmunity.
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Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoimunidade/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Proteínas de Ligação ao GTP/imunologia , Glutamato Descarboxilase/imunologia , ATPase Trocadora de Hidrogênio-Potássio/imunologia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Transglutaminases/imunologia , Adolescente , Adulto , Doença Celíaca/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Antígenos HLA-DQ/genética , Antígeno HLA-DR3/genética , Humanos , Lactente , Masculino , Proteína 2 Glutamina gama-Glutamiltransferase , Radioimunoensaio , Gastropatias/genética , Doenças da Glândula Tireoide/genética , Reino Unido , Adulto JovemRESUMO
Despite acceptance that risk for alcohol-use disorder (AUD) has a large genetic component, the identification of genes underlying various components of risk for AUD has been hampered in humans, in part by the heterogeneity of expression of the phenotype. One aspect of AUD is physical dependence. Alcohol withdrawal is a serious consequence of alcohol dependence with multiple symptoms, many of which are seen in multiple species, and can be experienced over a wide-ranging time course. In the present three studies, we developed a battery of withdrawal tests in mice, examining behavioral symptoms from multiple domains that could be measured over time. To permit eventual use of the battery in different strains of mice, we used male and female mice of a genetically heterogeneous stock developed from intercrossing eight inbred strains. Withdrawal symptoms were assessed using commonly used tests after administration of ethanol in vapor for 72 continuous hours. We found significant effects of ethanol withdrawal versus air-breathing controls on nearly all symptoms, spanning 4 days following ethanol vapor inhalation. Withdrawal produced hypothermia, greater neurohyperexcitability (seizures and tremor), anxiety-like behaviors using an apparatus (such as reduced transitions between light and dark compartments), anhedonia (reduced sucrose preference), Straub tail, backward walking, and reductions in activity; however, there were no changes in thermal pain sensitivity, hyper-reactivity to handling, or anxiety-like emergence behaviors in other apparatus. Using these data, we constructed a refined battery of withdrawal tests. Individual differences in severity of withdrawal among different tests were weakly correlated at best. This battery should be useful for identifying genetic influences on particular withdrawal behaviors, which should reflect the influences of different constellations of genes.
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Comportamento Animal , Depressores do Sistema Nervoso Central , Etanol , Síndrome de Abstinência a Substâncias/psicologia , Administração por Inalação , Convulsões por Abstinência de Álcool/genética , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Ataxia/induzido quimicamente , Ataxia/psicologia , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/sangue , Depressão/psicologia , Etanol/administração & dosagem , Etanol/sangue , Feminino , Individualidade , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Especificidade da Espécie , Síndrome de Abstinência a Substâncias/genéticaRESUMO
OBJECTIVE: Potentially morally injurious events (PMIEs)-violations (perpetrated or witnessed) of one's deeply held beliefs or values-have been associated with several forms of psychological distress. The values violated by PMIEs are often influenced by one's religion/spirituality (r/s). Struggles with one's r/s beliefs and/or practices may also contribute to elevated psychological distress. To further develop a framework for understanding and treating the sequelae of PMIE exposure, we examined the role of r/s struggles in the relation between PMIE exposure and psychological distress. METHOD: A diverse sample of 155 veterans at a large Veterans Affairs medical center completed questionnaires assessing PMIE exposure, r/s struggles, and psychological distress. RESULTS: Findings revealed greater PMIE exposure predicted elevated r/s struggles as well as elevated symptoms of anxiety and posttraumatic stress disorder (PTSD). Likewise, greater r/s struggles predicted elevated anxiety, PTSD, and depression symptoms. Regression analyses revealed r/s struggles fully mediated the relation between PMIE exposure and anxiety as well as PTSD, and a significant indirect effect of PMIE exposure on depression symptoms through r/s struggles was observed. Follow-up analyses revealed that no specific domain of r/s struggles accounted for the relation between PMIE exposure and psychological distress; rather, the overarching construct of r/s struggles accounted for this relation. CONCLUSION: These findings advance the evolving theoretical framework of moral injury, elucidating the salience of r/s struggles in the development of distress. Implications for moral injury intervention call for attention to potential dissonance between actions (witnessed or perpetrated) and r/s underpinnings of the individual's moral framework. (PsycINFO Database Record