A fibroblast-dependent TGFß1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis.

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGFß1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Biopsies from untreated patients showed higher fibroblast TGFß1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGFß1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzle-like receptor protein 2 (sFRP2), an unrecognized TGFß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision cut lung slices (PCLS) from non-diseased donors, we found TGFß1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature Krt5+ basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGFß1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify TGFß1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.

BCL-2 Modulates IRE1α Activation to Attenuate Endoplasmic Reticulum Stress and Pulmonary Fibrosis.

BCL-2 family members are known to be implicated in survival in numerous biological settings. Here, we provide evidence that in injury and repair processes in lungs, BCL-2 mainly acts to attenuate endoplasmic reticulum (ER) stress and limit extracellular matrix accumulation. Days after an intratracheal bleomycin challenge, mice lose a fraction of their alveolar type II epithelium from terminal ER stress driven by activation of the critical ER sensor and stress effector IRE1α. This fraction is dramatically increased by BCL-2 inhibition, because IRE1α activation is dependent on its physical association with the BCL-2-proapoptotic family member BAX, and we found BCL-2 to disrupt this association in vitro. In vivo, navitoclax (a BCL-2/BCL-xL inhibitor) given 15-21 days after bleomycin challenge evoked strong activation of IRE-1α in mesenchymal cells and markers of ER stress, but not apoptosis. Remarkably, after BCL-2 inhibition, bleomycin-exposed mice demonstrated persistent collagen accumulation at Day 42, compared with resolution in controls. Enhanced fibrosis proved to be due to the RNAase activity of IRE1α downregulating MRC2 mRNA and protein, a mediator of collagen turnover. The critical role of MRC2 was confirmed in precision-cut lung slice cultures of Day-42 lungs from bleomycin-exposed wild-type and MRC2 null mice. Soluble and tissue collagen accumulated in precision-cut lung slice cultures from navitoclax-treated, bleomycin-challenged mice compared with controls, in a manner nearly identical to that of challenged but untreated MRC2 null mice. Thus, apart from mitochondrial-based antiapoptosis, BCL-2 functions to attenuate ER stress responses, fostering tissue homeostasis and injury repair.

Reasons for Preoperative Patient Attrition among Bariatric Surgery Candidates: Patients' Point of View.

PURPOSE: Obesity has become a global health concern, associated with decreased quality of life and life expectancy. Although bariatric surgery has many benefits (e.g., substantial and durable weight loss, amelioration of comorbidities, and improvement in functionality), its patient attrition rate is relatively high. Therefore, we aim to assess the causes of withdrawal from our program. MATERIALS AND METHODS: We interviewed patients who dropped out of our bariatric surgery program between January 2016 and December 2021. A total of 1999 patients were eligible for bariatric surgery during this period, and 255 patients withdrew from the program. We interviewed patients over the phone to find out the reason for withdrawal. We divided participants into two groups: dropouts before and during the COVID-19 pandemic. Several options explaining the reason for leaving the program were presented to the patients to choose from. RESULTS: The number of patients who withdrew from the program before and during the COVID-19 pandemic was 135 (8.9%) and 120 (25.2%), respectively. Before the COVID-19 pandemic, most patients (49.1%) stated that the long waiting time was the cause of withdrawal. Even though during the COVID-19 pandemic, the main causes of attrition were the fear of contracting the disease and COVID-19 infection; the most common reason unrelated to COVID-19 was still the long preoperative preparation. CONCLUSION: Long waiting time was the most common cause of patient attrition before bariatric surgery. To reduce the attrition rate, more studies should be conducted to find an optimized waiting time before bariatric surgery.

Predictors of Weight Regain and Insufficient Weight Loss According to Different Definitions After Sleeve Gastrectomy: a Retrospective Analytical Study.

BACKGROUND: Weight regain (WR) and insufficient weight loss (IWL) after sleeve gastrectomy (SG) are challenging issues. This study aimed to evaluate the predictors of WR and IWL after SG. METHODS: In this retrospective analytical study, 568 patients who underwent SG at Hazrat-e Rasool General Hospital, Tehran, Iran, between January 2015 and April 2022 were evaluated. A total of 333 patients were included. WR and IWL were evaluated by multiple criteria such as a BMI of > 35 kg/m2, an increase in BMI of > 5 kg/m2 above nadir, an increase in weight of > 10 kg above nadir, percentage of excess weight loss (%EWL) < 50% at 18 months, an increase in weight of > 25% of EWL from nadir at 36 months, and percentage of total weight loss (%TWL) < 20% at 36 months. All participants were followed up for 36 months. RESULT: The univariate analysis showed that preoperative BMI, obstructive sleep apnea, metformin consumption, and grades 2 and 3 fatty liver disease were associated with WR and IWL (P < 0.05). WR or IWL incidence varied (0-19.3%) based on different definitions. The multivariate analysis showed that a preoperative BMI of > 45 kg/m2 [odds ratioAdjusted (ORAdj) 1.77, 95% CI: 1.12-4.11, P = 0.038] and metformin consumption [ORAdj: 0.48, 95% CI: 0.19-0.78, P = 0.001] were associated with WR and IWL after SG, regardless of the definition of WR or IWL. CONCLUSION: This study showed that preoperative BMI of > 45 kg/m2, obstructive sleep apnea, metformin consumption, and grades 2 and 3 of fatty liver disease were associated with WR or IWL.

Generalized peritonitis secondary to spontaneous rupture of the urinary bladder in a diabetic patient: A case report.

INTRODUCTION AND IMPORTANCE: Spontaneous rupture of the urinary bladder (SRUB) secondary to emphysematous cystitis(EC) in diabetic patients is extremely rare. Clinical presentations are often non-specific and display the signs and symptoms of peritonitis. The diagnosis is usually made after exploratory laparotomy. CASE REPORT: A 70-year-old diabetic woman presented to the emergency department with sudden diffuse abdominal pain and hematuria of six hours duration. Physical examination revealed generalized peritonitis. Multi-slice abdominal and pelvic CT scans showed free air and fluid in the abdominal cavity. After proper resuscitation, the patient was transferred to the operating room for exploratory laparotomy. A 2 cm full-thickness bladder rupture was noted at the dome of the bladder, which was repaired. CLINICAL DISCUSSION: We noticed free air in the urinary bladder wall postoperatively in the CT scan, which is the radiological sign of EC. The Pathology result was in concordance with the diagnosis. CONCLUSIONS: SRUB in patients with poorly controlled diabetes and EC is highlighted in this case study. Urinary bladder rupture secondary to EC should be considered When a diabetic patient with a history of urinary symptoms presents with an acute onset of abdominal pain suggestive of peritonitis. Uneventful recovery from SRUB is dependent on early diagnosis and treatment.