Interventions to Increase Multivitamin Use Among Women in the Interconception Period: An IMPLICIT Network Study

Maternal and Child Health Journal - Each year, 3% of infants in the Unites States (US) are born with congenital anomalies, including 3000 with neural tube defects. Multivitamins (MVIs) including...     

Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas

In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading‐associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5% (4/266) of all patients, 4% (3/77) of all familial cases and 7% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes.     

SARS-CoV-2 Monitoring in Wastewater Reveals Novel Variants and Biomarkers of Infection

Wastewater-based epidemiology (WBE) is a popular tool for the early indication of community spread of infectious diseases. WBE emerged as an effective tool during the COVID-19 pandemic and has provided meaningful information to minimize the spread of infection. Here, we present a combination of analyses using the correlation of viral gene copies with clinical cases, sequencing of wastewater-derived RNA for the viral mutants, and correlative analyses of the viral gene copies with the bacterial biomarkers. Our study provides a unique platform for potentially using the WBE-derived results to predict the spread of COVID-19 and the emergence of new variants of concern. Further, we observed a strong correlation between the presence of SARS-CoV-2 and changes in the microbial community of wastewater, particularly the significant changes in bacterial genera belonging to the families of Lachnospiraceae and Actinomycetaceae. Our study shows that microbial biomarkers could be utilized as prediction tools for future infectious disease surveillance and outbreak responses. Overall, our comprehensive analyses of viral spread, variants, and novel bacterial biomarkers will add significantly to the growing body of literature on WBE and COVID-19.     

Dose‐dependent effect of impaired renal function on all‐cause mortality in patients following percutaneous coronary intervention

ObjectiveTo determine the risk prediction of various degrees of impaired renal function on all‐cause mortality in patients following percutaneous coronary intervention (PCI).BackgroundPatients with chronic kidney disease (CKD) are at high risk of all‐cause mortality after PCI. However, there are less data of various degrees of impaired renal function to predict those risks.MethodsThis was a subgroup analysis of nationwide PCI registry of 22 045 patients. Patients were classified into six CKD stages according to preprocedure estimated glomerular filtration rate (eGFR) (ml/min/1.73 m²): I (≥90), II (60−89), III (30−59), IV (15−29), or V (<15) without or with dialysis. Baseline clinical and angiographic characteristics were compared among patients in each stage. One‐year all‐cause mortality was reported with risk prediction based on CKD stages and other risk factors.ResultsPatients with CKD stage I−V without and with on dialysis were found in 26.9%, 40.8%, 23.2%, 3.9%, 1.5%, and 3.7%, respectively. PCI procedural success and complication rates ranged from 94.0% to 96.2% and 2.8% to 6.1%, respectively. One‐year overall survival among CKD stages I−V was 96.3%, 93.1%, 84.4%, 65.2%, 68.0%, and 69.4%, respectively (p < .001 by log‐rank test). After adjusting covariables, the hazard ratios of all‐cause mortality for CKD stages II−V as compared to stage I by multivariate Cox regression analysis were 1.5, 2.6, 5.3, 5.9, and 7.0, respectively, (p < .001).ConclusionAmong patients undergoing PCI, lower preprocedure eGFR is associated in a dose‐dependent effect with decreased 1‐year survival. This finding may be useful for risk classification and to guide decision‐making.     

Helicobacter pylori Infection Impairs the Mucin Production Rate and Turnover in the Murine Gastric Mucosa

To protect the surface of the stomach, the epithelial cells secrete a mucus layer, which is mainly comprised of the MUC5AC mucin. Further protection is provided by a thick glycocalyx on the apical surface of the epithelial cell, with the cell surface mucin MUC1 as a major component. Here, we investigate the production rate and turnover of newly synthesized mucin in mice and analyze the effects of early colonization and chronic infection with H. pylori. Metabolic incorporation of an azido GalNAc analog (GalNAz) was used as a nonradioactive method to perform pulse experiments in the whole animal. First, the subcellular movement of newly synthesized mucin and mucin turnover was determined in uninfected mice. Based on the time line for mucin transport and dissemination, 2, 6, and 12 h after GalNAz injection was selected to collect the stomachs from mice infected with H. pylori strain SS1 during early colonization (7 days) and chronic infection (90 days). The results demonstrated that the speed from the start of glycosylation to the final destination is faster for the membrane-bound mucin to reach the glycocalyx (2 h) than for the secretory mucins to become secreted into the mucus layer (5 h). Furthermore, infection with H. pylori reduces the rate of mucin turnover and decreases the levels of Muc1. Since H. pylori colonizes this mucus niche, the decreased turnover rate indicates that H. pylori creates a more stable and favorable environment for itself by impairing the defense mechanism for clearing the mucosal surface of pathogens by mucus flow.     

The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia

Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR‐ABL down‐regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non‐canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR‐ABL silencing reduced full‐length NOTCH1 (NOTCH1‐FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1‐ICD), resulting in decreased expression of the NOTCH1 targets c‐MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3 (rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1‐ICD, p < 0.05). Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR‐ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Histological observations on the anterior olfactory nucleus in human

Aim: Localization of isolated clusters of anterior olfactory nucleus (AON) in a human olfactory bulb and tract. Materials and methods: This investigation was done on human olfactory bulbs and their tracts, collected from the freshly donated cadavers, before embalming, in the Department of Anatomy, IPGMER, Kolkata. H&E stained histological slides were prepared along the whole length of specimens and examined under a Leica DM 2000 microscope and with a Leica Quin image analyzer. Results: The anterior olfactory nucleus was detected in the form of a major cluster and in two smaller clusters of neurons. The major cluster was located at the caudal pole of the bulb and was composed of medium-sized triangular cells which had an average diameter of 13.92 ± 3.43 μm. Out of the two minor clusters, one was detected at the beginning and another at the middle of the olfactory tract. Here neurons were little larger in size and their diameter ranged approximately 15–17 μm. Olfactory striae also accommodated some neurons in a scattered manner. Conclusion: This observation will be helpful in exploration of the complex role of AON in the organization and function of the olfactory system and its clinical significance in human.     

Recent progress in therapeutic strategies for microglia-mediated neuroinflammation in neuropathologies

Introduction: Chronic activation of microglia is the hallmark of numerous neuropathologies such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. The activated microglia perpetuate inflammation by releasing an array of pro-inflammatory and neurotoxic factors, which eventually exacerbate neurotoxicity and neurodegeneration upon chronic activation of these cells. However, under acute conditions, activated microglia elicit pro-inflammatory as well as anti-inflammatory responses that are associated with neuroprotection. Given the role of microglia in neuroinflammation, recent studies have attempted to unravel the mechanisms that aid to establish microglial cell-based therapy.

Areas covered: While total suppression of microglial activation may compromise its beneficial role in tissue repair in the aftermath of an insult, the benefits of modulating microglial activation and promoting microglia polarization to a neuroprotective phenotype have been highlighted recently.

Expert opinion: So far, the therapeutic strategy focussed on neutralizing microglia-mediated neuroinflammation using drugs that block the release of pro-inflammatory mediators has limitations, such as unwarranted side effects. Recent advances reveal several alternative molecular targets and potential epi-drugs that are capable of modulating microglial function and promoting neuroprotection. This review discusses the recent progress made in understanding the mechanisms of microglia-mediated neuroinflammation in various neuropathologies, and the emerging anti-inflammatory therapeutic strategies in this field.     

Immune checkpoint blockade and biomarkers of clinical response in non–small cell lung cancer

Immunotherapy with PD-1 and PD-L1 inhibitors has revolutionized the treatment for patients with NSCLC the last years with increased overall survival and in particular increased number of long-time survivors in patients with metastatic disease. It is now a treatment of choice for patients with distant metastases (stage IV) and in conjunction with chemoradiotherapy for patients with limited spread confined to the chest (stage III). PD-1 inhibition has been proven to be superior to standard chemotherapy, both as a single treatment and when combined with either chemotherapy or CTLA-4 inhibition. Despite the success of immunotherapy, the majority of patients do not respond or relapse within a short time frame. Biomarkers that would help to properly select patients with a high likelihood of clinical response to PD-1 and PD-L1 inhibitors are scarce and far from optimal, and only one (PD-L1 expression) has reached clinical practice. Thus for immunotherapy to be effective, the discovery and validation of additional biomarkers is critical for patient selection and prediction of clinical response. In this mini-review, we give an overview of current clinical management of NSCLC including treatment landscape with regard to immunotherapy, as well as discuss the current genetic and immune cell biomarker studies and their potential for introduction into clinical practice.