Gut Commensal Bacteria and Regional Wnt Gene Expression in the Proximal Versus Distal Colon

Regional expression of Wingless/Int (Wnt) genes plays a central role in regulating intestinal development and homeostasis. However, our knowledge of such regional Wnt proteins in the colon remains limited. To understand further the effect of Wnt signaling components in controlling intestinal epithelial homeostasis, we investigated whether the physiological heterogeneity of the proximal and distal colon can be explained by differential Wnt signaling. With the use of a Wnt signaling-specific PCR array, expression of 84 Wnt-mediated signal transduction genes was analyzed, and a differential signature of Wnt-related genes in the proximal versus distal murine colon was identified. Several Wnt agonists (Wnt5a, Wnt8b, and Wnt11), the Wnt receptor frizzled family receptor 3, and the Wnt inhibitory factor 1 were differentially expressed along the colon length. These Wnt signatures were associated with differential epithelial cell proliferation and migration in the proximal versus distal colon. Furthermore, reduced Wnt/β-catenin activity and decreased Wnt5a and Wnt11 expression were observed in mice lacking commensal bacteria, an effect that was reversed by conventionalization of germ-free mice. Interestingly, myeloid differentiation primary response gene 88 knockout mice showed decreased Wnt5a levels, indicating a role for Toll-like receptor signaling in regulating Wnt5a expression. Our results suggest that the morphological and physiological heterogeneity within the colon is in part facilitated by the differential expression of Wnt signaling components and influenced by colonization with bacteria

Educational Inequalities in Perinatal Outcomes: The Mediating Effect of Smoking and Environmental Tobacco Exposure

OBJECTIVE: Socioeconomic status (SES) is adversely associated with perinatal outcomes. This association is likely to be mediated by tobacco exposure. However, previous studies were limited to single perinatal outcomes and devoted no attention to environmental tobacco exposure. Therefore, this study aimed firstly to explain the role of maternal smoking in the association between maternal education and preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA), and secondly to explain whether environmental tobacco smoke mediates these associations further. STUDY DESIGN: This study was nested in a population-based cohort study in the Netherlands, the Amsterdam Born Children and their Development (ABCD) study. Analyses were done in a sample of 3821 pregnant women of Dutch origin, using logistic regression analysis. RESULTS: Least educated women, who were more often smoking and exposed to environmental tobacco smoke, had a significantly higher risk of PTB (OR 1.95 [95% CI: 1.19-3.20]), LBW (OR 2.41 [95% CI: 1.36-4.27]) and SGA (OR 1.90 [95% CI 1.32-2.74]) than highly educated women. The mediating effect of smoking in the least educated women was 43% for PTB, 55% for LBW and 66% for SGA. Environmental tobacco smoke did not explain these associations further. After adjustment for maternal smoking, the association between lower maternal education and pregnancy outcomes was no longer significant. CONCLUSIONS: Smoking explains to a considerable extent the association between lower maternal education and adverse perinatal outcomes. Therefore, tobacco-interventions in lower educated women should be primarily focussed on maternal smoking to reduce PTB, LBW, and SGA. Additional attention to environmental tobacco exposure does not seem to reduce educational inequalities in perinatal outcomes

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

The CD34+CD38neg population is significantly increased in haemopoietic cell expansion cultures in serum-free compared to serum-replete conditions: Dissociation of phenotype and function

Expansion of haemopoietic stem cells is proposed to combat graft failure in adult recipients following cord blood (CB) transplantation. Cultures are traditionally performed in medium containing FCS, but to transfer expansion to the clinic, 'good manufacturing practice' (GMP) standards are required. This study evaluated expansion cultures in culture bags and serum-free (SF) conditions, to comply with GMP, by analysing subpopulations of CD34+ cells, colony-forming cells (CFC) and long-term culture initiating cells (LTC-IC). CD34+ cell analysis has previously been used to measure clonogenic capacity and the CD34+CD38neg surface pheno-type to measure primitive cell numbers. In this study, comparison of expansion in serum-replete medium with that in SF conditions demonstrated a lack of expression of CD38 on CD34+ cells in the absence of serum. These findings must be considered in clinical studies using in vitro expansion in SF conditions, and the CD34+CD38neg phenotype should not be used to confirm maintenance, or expansion, of primitive progenitor cells