A nongenomic mechanism for progesterone-mediated immunosuppression: Inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes

The mechanism by which progesterone causes localized suppression of the immune response during pregnancy has remained elusive. Using human T lymphocytes and T cell lines, we show that progesterone, at concentrations found in the placenta, rapidly and reversibly blocks voltage-gated and calcium-activated K+ channels (KV and KCa, respectively), resulting in depolarization of the membrane potential. As a result, Ca2+ signaling and nuclear factor of activated T cells (NF-AT)-driven gene expression are inhibited. Progesterone acts distally to the initial steps of T cell receptor (TCR)-mediated signal transduction, since it blocks sustained Ca2+ signals after thapsigargin stimulation, as well as oscillatory Ca2+ signals, but not the Ca2+ transient after TCR stimulation. K+ channel blockade by progesterone is specific; other steroid hormones had little or no effect, although the progesterone antagonist RU 486 also blocked KV and KCa channels. Progesterone effectively blocked a broad spectrum of K+ channels, reducing both Kv1.3 and charybdotoxin-resistant components of KV current and KCa current in T cells, as well as blocking several cloned KV channels expressed in cell lines. Progesterone had little or no effect on a cloned voltage-gated Na+ channel, an inward rectifier K+ channel, or on lymphocyte Ca2+ and Cl- channels. We propose that direct inhibition of K+ channels in T cells by progesterone contributes to progesterone-induced immunosuppression

Progressive wound necrosis associated with postoperative thrombocytosis in mastectomy and immediate breast reconstruction surgery: report of a case.

A 37-year-old who underwent splenectomy for motor vehicle accident-related injuries was diagnosed with stage IIA carcinoma of left breast 12 years later. She underwent bilateral mastectomy and bilateral immediate unipedicle TRAM flap reconstruction. Her preoperative platelet counts ranged from 332 to 424 K/cmm. Intraoperative fluorescein confirmed mastectomy flap viability. On postoperative day 1, platelet count was 374 K/cmm and all suture lines appeared benign. The patient was discharged 3 days later with healthy appearing tram flaps and slight epidermolysis in the abdominal region. Over the next 2 weeks, both the mastectomy flaps and the abdominal region underwent progressive necrosis as the platelet count increased to 1390 K/cmm. Aspirin therapy was instituted at this time. The TRAM flaps remained completely viable. Eighteen days later, the patient required wound debridement with secondary closure of the breast wounds. Platelet count peaked at 1689 K/cmm 2 days later (postoperative day 38). The wounds deteriorated again and were managed conservatively. Two months after mastectomy, the first area of spontaneous healing was documented (platelet count 758 K/cmm). Ultimately, wounds healed as platelet count reached its preoperative baseline. We hypothesize that an abnormal secondary thrombocytosis at subdermal plexus level caused problematic healing in this patient\u27s mastectomy and abdominal flaps

The Effect of Bevel on Fracture Resistance of GIC Restorations in Primary Molars: In Vitro Study Rôle du Biseau dans la Résistance à la Fracture des Restaurations aux Ciments Verres-Ionomères des Molaires Temporaires : Étude In Vitro

Background: Glass ionomer cements (GICs) are commonly used for restorations in primary molars due to their adhesive, hydrophilic, and bioactive properties. However, their low mechanical resistance may limit their use in proximal cavities. Recent advancements in GICs, such as the high viscosity GIC EQUIA Forte®, have improved their mechanical properties. The effect of a Cavo superficial bevel on the mechanical strength of GIC restorations has been previously studied. Objectives: To investigate the effect of a Cavo superficial bevel on fracture resistance and the type of fracture (adhesive, cohesive, or catastrophic) in EQUIA Forte® GIC restorations in primary molars. Methods: 56 standardized proximal cavities were created on 51 temporary molars. The cavities were randomly divided into two groups: group I without a Cavo superficial bevel (n=28) and group II with a 45° Cavo superficial bevel (n=28). The cavities were restored with EQUIA Forte®. The samples were subjected to thermocycling and artificial aging, then, an axial speed loading of 1 mm/min was applied until fracture. Fracture toughness was recorded, and the type of fracture was observed under an optical microscope. A Mann-Whitney U test was used to compare the average fracture resistance between the groups. All tests were two-tailed and the level of significance was set at 5%. Results: The average fracture resistance for group I was (237.57 ± 139.97 N) and for group II was (294.89 ± 171.07 N). There was no statistically significant difference in fracture resistance between the two groups (p\u3e0.05). Mixed fractures were observed in all samples, with adhesive fractures only present in group I and cohesive fractures only present in group II. Conclusion: The Cavo superficial bevel does not significantly affect the fracture resistance of GIC restorations in primary molars. However, the bevel design may prevent adhesive and catastrophic fractures. Contexte : Les ciments verres-Ionomères (CVI) sont couramment utilisés pour les restaurations des molaires temporaires grâce à leurs propriétés adhésives, hydrophiles et bioactives. Cependant, leur faible résistance mécanique limite leur utilisation dans les cavités proximales. Avec les récents progrès de cette classe de matériaux, un CVI à haute viscosité a été introduit : EQUIA Forte®, visant à améliorer leurs propriétés mécaniques. Le rôle du biseau cavo-superficiel sur la résistance mécanique des restaurations au CVI a déjà été étudié. Objectifs : Tester le rôle du biseau dans l’amélioration de la résistance à la fracture et d’étudier la nature du trait de fracture adhésif, cohésif, ou catastrophique des restaurations aux CVI EQUIA Forte® des molaires temporaires. Méthodes : 56 cavités proximales standardisées ont été réalisées sur 51 molaires temporaires. Ces cavités ont été divisées aléatoirement en deux groupes : groupe I sans biseau cavo-superficiel (n=28) et groupe II avec biseau cavo-superficiel de 45° (n=28). Les cavités ont été restaurées par EQUIA Forte®. Les échantillons ont été soumis à un thermocyclage et à un vieillissement artificiel, puis une vitesse axiale de chargement de 1 mm/min a été appliquée jusqu\u27à la fracture. La résistance à la fracture a été enregistrée et le type de fracture a été observé au microscope optique. Le test de Mann-Whitney U a été utilisé pour comparer la résistance moyenne à la fracture entre les groupes. Tous les tests étaient bilatéraux et le niveau de signification a été fixé à 5 %. Résultats : La résistance moyenne à la fracture pour le groupe I était de (237,57 ± 139,97 N) et pour le groupe II était de (294,89 ± 171,07 N). Il n\u27y avait pas de différence statistiquement significative en termes de résistance à la fracture entre les deux groupes (p \u3e 0,05). Cependant, des fractures mixtes ont été observées dans tous les échantillons, les fractures adhésives étant uniquement présentes dans le groupe I et les fractures cohésives présentes uniquement dans le groupe II. Conclusion : Le biseau cavo-superficiel n\u27influence pas de manière significative la résistance à la fracture des restaurations CVI des molaires temporaires. Cependant, il s’est avéré que la conception du biseau empêche les fractures adhésives et catastrophiques d’avoir lieu. Mots clés : Biseau, CVI, Classe II, Molaires Temporaires, Restauration, Type de fractur

A Comparative Analysis of Anterior & Lateral Cranial Base CSF Leaks

Introduction The optimal strategy for management of Idiopathic Intracranial Hypertension (IIH) in anterior and lateral cranial base meningoencephaloceles remains debated. The purpose of this study is to present a comparison of the surgical management of anterior and lateral cranial base meningoencephalocele and a treatment algorithm for the diagnosis and management of IIH in this patient population. Methods Retrospective study of 109 patients who underwent anterior or lateral CSF leak repair at TJU from 2004-2020. Epic & RedCap were utilized to record data. Patient demographics, presenting symptoms, imaging, Beta-2 Transferring testing, surgery, repair, and post-op data were collected. Two-sided Chi-squared tests and Independent t-test were performed via SPSS Statistics 26. Results 49 anterior cranial base (ACB) and 60 lateral cranial base (LCB) defects were included. Anterior cohort had significantly more women (N=77, 85.7%, p=0.02). Anterior cohort presented with significantly higher multiple leak sites (24.5% vs 15.0%, p=0.036). Six patients, 3 in each cohort, none of whom received Ventriculoperitoneal shunts (VPS) developed recurrence. VPS were placed for long-term CSF diversion in 23 ACB cases (46.9%) and 10 LCB cases (16.7%), (p\u3c0.01). Discussion ACB cases had a higher incidence of females, multiple site leaks, and more likely to undergo VPS placement. No patients developed recurrence after placement of a VPS. Long-term CSF diversion via VPS, in addition to surgical repair, should be considered in patients with elevated intracranial pressure and other high-risk factors to prevent recurrence of CSF leaks

A novel approach to simulate gene-environment interactions in complex diseases

Background: Complex diseases are multifactorial traits caused by both genetic and environmental factors. They represent the major part of human diseases and include those with largest prevalence and mortality (cancer, heart disease, obesity, etc.). Despite a large amount of information that has been collected about both genetic and environmental risk factors, there are few examples of studies on their interactions in epidemiological literature. One reason can be the incomplete knowledge of the power of statistical methods designed to search for risk factors and their interactions in these data sets. An improvement in this direction would lead to a better understanding and description of gene-environment interactions. To this aim, a possible strategy is to challenge the different statistical methods against data sets where the underlying phenomenon is completely known and fully controllable, for example simulated ones. Results: We present a mathematical approach that models gene-environment interactions. By this method it is possible to generate simulated populations having gene-environment interactions of any form, involving any number of genetic and environmental factors and also allowing non-linear interactions as epistasis. In particular, we implemented a simple version of this model in a Gene-Environment iNteraction Simulator (GENS), a tool designed to simulate case-control data sets where a one gene-one environment interaction influences the disease risk. The main aim has been to allow the input of population characteristics by using standard epidemiological measures and to implement constraints to make the simulator behaviour biologically meaningful. Conclusions: By the multi-logistic model implemented in GENS it is possible to simulate case-control samples of complex disease where gene-environment interactions influence the disease risk. The user has full control of the main characteristics of the simulated population and a Monte Carlo process allows random variability. A knowledge-based approach reduces the complexity of the mathematical model by using reasonable biological constraints and makes the simulation more understandable in biological terms. Simulated data sets can be used for the assessment of novel statistical methods or for the evaluation of the statistical power when designing a study

Sample size requirements to detect the effect of a group of genetic variants in case-control studies

<p>Abstract</p> <p>Background</p> <p>Because common diseases are caused by complex interactions among many genetic variants along with environmental risk factors, very large sample sizes are usually needed to detect such effects in case-control studies. Nevertheless, many genetic variants act in well defined biologic systems or metabolic pathways. Therefore, a reasonable first step may be to detect the effect of a group of genetic variants before assessing specific variants.</p> <p>Methods</p> <p>We present a simple method for determining approximate sample sizes required to detect the average joint effect of a group of genetic variants in a case-control study for multiplicative models.</p> <p>Results</p> <p>For a range of reasonable numbers of genetic variants, the sample size requirements for the test statistic proposed here are generally not larger than those needed for assessing marginal effects of individual variants and actually decline with increasing number of genetic variants in many situations considered in the group.</p> <p>Conclusion</p> <p>When a significant effect of the group of genetic variants is detected, subsequent multiple tests could be conducted to detect which individual genetic variants and their combinations are associated with disease risk. When testing for an effect size in a group of genetic variants, one can use our global test described in this paper, because the sample size required to detect an effect size in the group is comparatively small. Our method could be viewed as a screening tool for assessing groups of genetic variants involved in pathogenesis and etiology of common complex human diseases.</p

Dietary soy and meat proteins induce distinct physiological and gene expression changes in rats

This study reports on a comprehensive comparison of the effects of soy and meat proteins given at the recommended level on physiological markers of metabolic syndrome and the hepatic transcriptome. Male rats were fed semi-synthetic diets for 1 wk that differed only regarding protein source, with casein serving as reference. Body weight gain and adipose tissue mass were significantly reduced by soy but not meat proteins. The insulin resistance index was improved by soy, and to a lesser extent by meat proteins. Liver triacylglycerol contents were reduced by both protein sources, which coincided with increased plasma triacylglycerol concentrations. Both soy and meat proteins changed plasma amino acid patterns. The expression of 1571 and 1369 genes were altered by soy and meat proteins respectively. Functional classification revealed that lipid, energy and amino acid metabolic pathways, as well as insulin signaling pathways were regulated differently by soy and meat proteins. Several transcriptional regulators, including NFE2L2, ATF4, Srebf1 and Rictor were identified as potential key upstream regulators. These results suggest that soy and meat proteins induce distinct physiological and gene expression responses in rats and provide novel evidence and suggestions for the health effects of different protein sources in human diets

Mindfulness-based interventions for young offenders: a scoping review

Youth offending is a problem worldwide. Young people in the criminal justice system have frequently experienced adverse childhood circumstances, mental health problems, difficulties regulating emotions and poor quality of life. Mindfulness-based interventions can help people manage problems resulting from these experiences, but their usefulness for youth offending populations is not clear. This review evaluated existing evidence for mindfulness-based interventions among such populations. To be included, each study used an intervention with at least one of the three core components of mindfulness-based stress reduction (breath awareness, body awareness, mindful movement) that was delivered to young people in prison or community rehabilitation programs. No restrictions were placed on methods used. Thirteen studies were included: three randomized controlled trials, one controlled trial, three pre-post study designs, three mixed-methods approaches and three qualitative studies. Pooled numbers (n = 842) comprised 99% males aged between 14 and 23. Interventions varied so it was not possible to identify an optimal approach in terms of content, dose or intensity. Studies found some improvement in various measures of mental health, self-regulation, problematic behaviour, substance use, quality of life and criminal propensity. In those studies measuring mindfulness, changes did not reach statistical significance. Qualitative studies reported participants feeling less stressed, better able to concentrate, manage emotions and behaviour, improved social skills and that the interventions were acceptable. Generally low study quality limits the generalizability of these findings. Greater clarity on intervention components and robust mixed-methods evaluation would improve clarity of reporting and better guide future youth offending prevention programs

The Surgical Infection Society revised guidelines on the management of intra-abdominal infection

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. Methods: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. Results: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. Summary: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline