Abnormalities of serotonin metabolism and their relation to symptoms in untreated celiac disease.

BACKGROUND AND AIMS: Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut function that in excess causes nausea, vomiting, and diarrhea. We recently showed that patients with post-infective irritable bowel syndrome have increased postprandial release of 5-HT associated with low-grade T-cell mediated inflammation. Celiac disease is another common disease in which a T-cell enteropathy is associated with increased mucosal 5-HT levels. Our aim was to determine how this inflammatory lesion influenced 5-HT bioavailability and how changes in 5-HT related to the symptoms of nausea, vomiting, and diarrhea seen in untreated celiac patients. METHODS: Fasting plasma and platelet 5-HT and postprandial plasma 5-HT levels were measured after a high-carbohydrate meal in celiac patients (n = 18) and healthy controls (n = 18) using high-pressure liquid chromatography. Dyspepsia was assessed during the postprandial period using a questionnaire. Finally, we compared the histology and mucosal 5-HT levels in duodenal biopsy specimens from celiac patients and controls. RESULTS: Celiac patients had increased 5-HT-containing enterochromaffin cell numbers and significantly higher peak plasma 5-HT levels (P = .0002), postprandial area under the curve (P = .0006), and platelet 5-HT stores (P = .031) than controls. Peak 5-HT levels correlated significantly with postprandial dyspepsia scores (P = .005). Celiac patients had higher duodenal 5-HT levels (P = .007) than controls. CONCLUSIONS: Celiac disease is associated with increased mucosal 5-HT content and enhanced 5-HT release from the upper small bowel, which correlates with postprandial dyspepsia. Serotonin excess may mediate dyspeptic symptoms in untreated celiac disease.     

Learning Curve of Speech Recognition

Speech recognition (SR) speeds patient care processes by reducing report turnaround times. However, concerns have emerged about prolonged training and an added secretarial burden for radiologists. We assessed how much proofing radiologists who have years of experience with SR and radiologists new to SR must perform, and estimated how quickly the new users become as skilled as the experienced users. We studied SR log entries for 0.25 million reports from 154 radiologists and after careful exclusions, defined a group of 11 experienced radiologists and 71 radiologists new to SR (24,833 and 122,093 reports, respectively). Data were analyzed for sound file and report lengths, character-based error rates, and words unknown to the SR’s dictionary. Experienced radiologists corrected 6 characters for each report and for new users, 11. Some users presented a very unfavorable learning curve, with error rates not declining as expected. New users’ reports were longer, and data for the experienced users indicates that their reports, initially equally lengthy, shortened over a period of several years. For most radiologists, only minor corrections of dictated reports were necessary. While new users adopted SR quickly, with a subset outperforming experienced users from the start, identification of users struggling with SR will help facilitate troubleshooting and support.     

Influence of MRE11, RAD50 and NIBRIN protein expression on survival in pancreatic carcinoma after curative resection

The MRE11/RAD50/NIBRIN complex, a protein complex that repairs DNA double-strand breaks, could serve as an early marker for new lesions in pancreatic cancer. We determined the expression of MRE11, RAD50 and NIBRIN, and their possible prognostic value regarding survival.     

Assessing Adolescent Personality Disorders With the Shedler–Westen Assessment Procedure for Adolescents

This two‐part study describes the development and validation of a method for quantifying adolescent personality pathology using the latest edition of the Shedler–Westen Assessment Procedure for Adolescents (SWAP‐II‐A), an instrument designed to be used by clinically experienced observers. In Study 1, experienced psychologists and psychiatrists described a normative clinical sample of 950 North American patients. Study 2 applied the SWAP‐II‐A in a day treatment setting. Results indicated that SWAP‐II‐A personality disorder (PD) scales evidenced high internal consistency, construct validity with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) symptoms and diagnoses, and concurrent validity with Child Behavior Checklist (CBCL) ratings. Independent observers saw patients similarly, and PD assessments were significantly associated with CBCL scale scores and ward behavior.     

Differential effects of estradiol and progesterone on human T cell activation in vitro

Estradiol (E2) and progesterone (P4) are steroid hormones important for the regulation of immune responses during pregnancy. Their increasing levels coincide with an improvement of T cell-mediated diseases such as multiple sclerosis (MS). Although immune-endocrine interactions are involved in this phenomenon, the relative contribution of hormones is not known. We here report a direct comparison of E2- and P4-mediated effects on human CD4⁺ T cells, key cells in immune regulation. T cells were stimulated to obtain different activation levels and exposed to a broad range of hormone concentrations. Activation level was assessed by CD69/CD25 expression by flow cytometry, and secreted proteins (n = 196) were measured in culture supernatants using proximity extension assay and electrochemiluminescence immunoassay. We found that in low activated cells, pregnancy-relevant E2 concentrations increased activation and the secretion of several immune- and inflammation-related proteins. P4, on the other hand, showed a biphasic pattern, where serum-related concentrations upregulated activation and protein secretion while placenta-relevant concentrations induced a prominent dampening irrespective of the initial activation level. Our results demonstrate the importance of P4 as a major hormone in the immune modulation of T cells during pregnancy and emphasize the need to further evaluate its potency in the treatment of diseases like MS.     

Neuroplasticity in Corticolimbic Brain Regions in Patients After Anterior Cruciate Ligament Reconstruction

ContextFear has been cited as the primary barrier to return to sport (RTS) by athletes after anterior cruciate ligament reconstruction (ACLR). Understanding the neural factors that contribute to fear after ACLR may help us to identify interventions for this population.ObjectiveTo characterize the underlying neural substrate of injury-related fear in patients after ACLR versus healthy matched control individuals during a picture imagination task (PIT) consisting of sport-specific images and images of activities of daily living (ADL).DesignCase-control study.SettingResearch laboratory.Patients or Other ParticipantsA total of 24 right-hand–dominant participants (12 with left-sided ACLR and 12 control individuals) were enrolled. Participants underwent full-brain functional magnetic resonance imaging.Main Outcome Measure(s)Functional data were acquired using blood oxygen level–dependent (BOLD) echoplanar imaging. Independent t tests were conducted to identify between-groups differences in BOLD signal changes during all images of the PIT. Paired t tests were computed to examine differences in BOLD signal change between sport-specific and ADL images in the ACLR group.ResultsIncreased activation in the inferior parietal lobule and the mediodorsal thalamus was observed during PIT in the ACLR group. An inability to suppress the default mode network in the ACLR group was noted. The ACLR group exhibited increased activation in the cerebellum and inferior occipital regions during the sport-specific images versus the ADL images, but no other regions of interest demonstrated differences.ConclusionAfter ACLR, patients may be more predisposed to fear, anxiety, and pain during sport-specific activities and ADLs. Psychosocial interventions may be warranted after ACLR to reduce injury-related fear and mitigate potentially maladaptive neuroplasticity.     

Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions

Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five‐class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align‐Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], MutPred, PolyPhen‐2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen‐2.1 provided the best‐combined model (R² = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen‐2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.