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IntroductionWe have previously shown that Environmental Enrichment (EE), a multi-modal psychosocial intervention consisting of increased social interaction, novelty, and open spaces, improved disease presentation, anxiety, and immune-related disturbances in the rat model of endometriosis. However, there is a knowledge gap regarding the effects of EE interventions in patients with this painful, inflammatory chronic disease.AimTo adapt and test the efficacy of an EE intervention on pelvic pain, mental health, perceived stress, quality of life, and systemic inflammation in endometriosis patients through a randomized clinical trial (RCT).Materials and methodsA multidisciplinary team with expertise in physiology, neuroscience, psychology, and women’s health adapted and implemented a two-arm RCT comparing an EE intervention with a wait-list control group. Six EE modules administered on alternate weeks were provided to patients in the intervention (N = 29); controls received education only. Survey data and biospecimens were collected at baseline, end-of-study, and 3-months post-intervention to assess pain (Brief Pain Inventory, BPI), endometriosis-related quality of life-QoL (Endometriosis Health Profile-30, EHP30), anxiety (Generalized Anxiety Disorder 7, GAD7), depression (Patient Health Questionnaire for Depression 8, PHQ8), pain catastrophizing (Pain Catastrophizing Score, PCS), stress (Perceived Stress Scale-14, PSS14), and saliva cortisol levels (AM, PM).ResultsCompared to the wait-list controls, participants in the EE intervention showed significantly decreased GAD-7 scores at the end of the intervention and 3-month follow-up. Depression, perceived stress, and QoL improved at the 3-month follow-up compared to baseline. While pain levels did not improve, they significantly correlated with anxiety, depression, QoL and pain catastrophizing scores.ConclusionThis pilot RCT demonstrated significant improvements in anxiety and depressive symptoms, QoL, and perceived stress, supporting enriched environments as an integrative psychosocial intervention to be used as adjuvant to the standard of care for endometriosis pain.

Abstract Background Skeletomuscular diseases result in significant muscle loss and decreased performance, paralleled by a loss in mitochondrial and oxidative capacity. Insulin and insulin‐like growth factor‐1 (IGF‐1) are two potent anabolic hormones that activate a host of signalling intermediates including the serine/threonine kinase AKT to influence skeletal muscle physiology. Defective AKT signalling is associated with muscle pathology, including cachexia, sarcopenia, and disuse; however, the mechanistic underpinnings remain unresolved. Methods To elucidate the role of AKT signalling in muscle mass and physiology, we generated both congenital and inducible mouse models of skeletal muscle‐specific AKT deficiency. To understand the downstream mechanisms mediating AKT's effects on muscle biology, we generated mice lacking AKT1/2 and FOXO1 (M‐AKTFOXO1TKO and M‐indAKTFOXO1TKO) to inhibit downstream FOXO1 signalling, AKT1/2 and TSC1 (M‐AKTTSCTKO and M‐indAKTTSCTKO) to activate mTORC1, and AKT1/2, FOXO1, and TSC1 (M‐QKO and M‐indQKO) to simultaneously activate mTORC1 and inhibit FOXO1 in AKT‐deficient skeletal muscle. Muscle proteostasis and physiology were assessed using multiple assays including metabolic labelling, mitochondrial function, fibre typing, ex vivo physiology, and exercise performance. Results Here, we show that genetic ablation of skeletal muscle AKT signalling resulted in decreased muscle mass and a loss of oxidative metabolism and muscle performance. Specifically, deletion of muscle AKT activity during development or in adult mice resulted in a significant reduction in muscle growth by 30–40% (P

Background and aimsThere is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood.MethodsMale C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics.ResultsCombined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism.ConclusionsIn our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.

Summary: The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA Gm11967, whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring Gm11967 expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of Gm11967 contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.

Background and aims The pathogenesis of acute cholangitis (AC) occurs with biliary obstruction followed by bacterial growth in the bile duct. The leading cause of AC is obstructing gallstones. There have been conflicting theories about the optimal timing for cholecystectomy following AC. The aim of this study is to assess the impact of early cholecystectomy on the 30-day readmission rate, 30-day mortality, 90-day readmission rate and the length of hospital stay.Methods This retrospective study was performed between January 2015 and January 2021 in a high-volume tertiary referral teaching hospital. Included patients were 18 years or older with a definitive diagnosis of acute gallstone cholangitis who underwent endoscopic retrograde cholangiopancreatography (ERCP) with complete clearance of the bile duct as an index procedure. We divided the patients into two groups: patients who underwent ERCP alone and those who underwent ERCP with laparoscopic cholecystectomy (LC) on the same admission (ERCP+LC). Data were extracted from electronic medical records. The primary endpoint of the study was the 30-day readmission rate.Results A total of 114 patients with AC met the inclusion criteria of the study. The ERCP+LC group had significantly lower rates of 30-day readmission (2.2% vs 42.6%, p

Objective: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but the mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. Methods: We subjected mice lacking FOXO transcription factors in the liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. Results: Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. Conclusions: This study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.

Summary: Brown adipose tissue (BAT) activity protects animals against hypothermia and represents a potential therapeutic target to combat obesity. The transcription factor early B cell factor-2 (EBF2) promotes brown adipocyte differentiation, but its roles in maintaining brown adipocyte fate and in stimulating BAT recruitment during cold exposure were unknown. We find that the deletion of Ebf2 in adipocytes of mice ablates BAT character and function, resulting in cold intolerance. Unexpectedly, prolonged exposure to cold restores the thermogenic profile and function of Ebf2 mutant BAT. Enhancer profiling and genetic assays identified EBF1 as a candidate regulator of the cold response in BAT. Adipocyte-specific deletion of both Ebf1 and Ebf2 abolishes BAT recruitment during chronic cold exposure. Mechanistically, EBF1 and EBF2 promote thermogenic gene transcription through increasing the expression and activity of ERRα and PGC1α. Together, these studies demonstrate that EBF proteins specify the developmental fate and control the adaptive cold response of brown adipocytes. : Angueira et al. show that early B cell factors (EBFs) control both basal and cold-induced thermogenic activity in brown adipocytes. EBF2 is required to maintain BAT fate under basal conditions, ensuring a capacity for thermogenesis upon cold challenge. BAT recruitment during chronic cold exposure requires EBF1 or EBF2 activity. Keywords: brown adipocyte, UCP1, EBF1, EBF2, thermogenesis, brown fat, ERR, cold exposure, PGC1

Extraintestinal Clostridium difficile infection (CDI) is extremely uncommon. High mortality and poor outcomes have been observed among individuals with this rare medical condition. Empyema is one of the extraintestinal manifestations of CDI. Possible mechanisms to develop this parapneumonic effusion are aspiration and contamination of the chest tube. We present a 42-year-old Hispanic male with C. difficile empyema without any prior history of CDI.

Heterotopic pancreas (HP) is a congenital abnormality that represents ectopic pancreatic tissue that does not have anatomic, vascular, or ductal continuity. The prevalence of HP is 0.55% to 13.7% on autopsy, 0.2% to 0.5% of abdominal operations, and 0.9% of gastrectomies. It is commonly found in the stomach, duodenum, and proximal jejunum. Only 15 cases have been reported in the medical literature regarding involvement of the esophagus. Treatment depends on symptoms and location. In asymptomatic patients, simple observation may be sufficient; however, in those who are symptomatic, surgery may be warranted. We present a case of a 70-year-old male with heartburn, nausea, and abdominal bloating who underwent a diagnostic esophagogastroduodenoscopy (EGD) and was found to have HP on histology in the distal esophagus. In our case, symptoms were treated conservatively and successfully with a proton pump inhibitor (PPI).

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Autoimmune hepatitis has been associated with chronic HCV infection, but there are only few cases reported of HBV infection as a possible trigger. We present a case of a young male who was diagnosed with acute autoimmune hepatitis superimposed on existent chronic HBV infection. A 30-year-old Hispanic male with no past medical history presented to the hospital with complaints of few days of generalized weakness. Laboratory findings were significant for elevated liver enzymes: AST, 1164 U/L; ALT, 1461 U/L; total bilirubin, 2 MG/DL; and alkaline phosphatase, 75 IU/L. Extensive workup was done to find the etiology for elevated liver enzymes. Only blood work that came back positive was for chronic HBV infection and elevated immunoglobulin G (IgG) level 1937 mg/dL. HBV viral load was 42,900,000 IU/mL. The patient was started on tenofovir 300 mg daily. Liver biopsy was done which was consistent with autoimmune hepatitis. Prednisone 60 mg daily was started. Six months later, blood work showed completely normal liver enzymes and total IgG. Hepatotropic viruses have been proposed as triggering factors for several autoimmune diseases. There are theories suggesting that similarity in viral epitope and self-proteins expression on liver cells’ surface causes a cross-reactive immunologic response and possible viral-induced autoimmune hepatitis.

Technological advances of early humans occurred slowly over long periods of time. For the first humans, the transition from nomadic hunters and gatherers living in caves to a people who [...]

INTRODUCTION The compilers and redactors of the Books of Samuel fundamentally present an idealized David. (1) To realize that the biblical narrative is pro-David, however, is also to realize that [...]