Oxidative stress is a key mechanism in amyloid ␤-peptide (A␤)-mediated neurotoxicity; therefore, the protective roles of 17␤-estradiol (E 2 ) and antioxidants (Trolox and vitamin C) were assayed on hippocampal neurons. Our results show the following: 1) E 2 and Trolox attenuated the neurotoxicity mediated by A␤ and H 2 O 2 as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assays, quantification of apoptotic cells, and morphological studies of the integrity of the neurite network. 2) Vitamin C failed to protect neurons from A␤ toxicity. 3) A␤-mediated endoperoxide production, reported to induce cell damage, was decreased in the presence of E 2 and Trolox. 4) Two key Wnt signaling components were affected by E 2 and Trolox; in fact, the enzyme glycogen synthase kinase 3␤ was inhibited by both E 2 and Trolox, and both compounds were able to stabilize cytoplasmic ␤-catenin. 5) E 2 activated the expression of the Wnt-5a and Wnt-7a ligands, and at the same time, E 2 , through the ␣-estrogen receptor, was able to prevent the excitotoxic A␤-induced rise in bulk-free Ca 2؉as an alternative pathway to increase cell viability. 6) Finally, the Wnt-7a ligand protected against cytoplasmic calcium disturbances induced by A␤ treatment. Our results suggest that control of oxidative stress, regulation of cytoplasmic calcium, and activation of Wnt signaling may prevent A␤ neurotoxicity. Alzheimer disease (AD)1 is a neurodegenerative disease characterized by neuronal cell death, dystrophic neurites, neurofibrillary tangles, and senile plaques (1). Senile plaques are composed by the amyloid ␤-peptide (A␤), a 40 -42-amino acid peptide that originates from the proteolytic cleavage of the amyloid precursor protein (2). There is also evidence relating the etiopathology of AD with oxidative stress induced by A␤ in the brain of AD patients (3-6). A␤ increases the production of intraneuronal reactive oxygen species (ROS) and stimulates hydrogen peroxide (H 2 O 2 ) levels through metal ion reduction (7,8). Free radicals peroxidize membrane lipids (9) and oxidize proteins (10). In vitro experiments also support the observation that the neurotoxic effect of A␤ is mediated by free radical mechanisms (5, 11, 12) and alteration of Ca 2ϩ homeostasis (13). Furthermore, several studies have reported neuroprotection by antioxidants against A␤-mediated cytotoxicity (14 -16). Also, 17␤-estradiol (E 2 ; estrogen) treatment apparently has beneficial effects on AD (17, 18). In addition, E 2 prevents A␤-induced cell death by activation of the ␣-ER (19) and preserves neuronal viability and function in cortical neurons exposed to glutamate toxicity (20). Also, there is evidence that E 2 prevents morphological neurodegenerative changes in hippocampal neurons caused by A␤ deposits (21).On the other hand, neurofibrillary tangles are intracellular aggregates of paired helical filaments produced by hyperphosphorylation of the microtubule-associated protein tau (23). It has been proposed that glycogen synthase kinase-3␤ (GSK-3␤...

ObjectiveIrritable bowel syndrome (IBS) is a common gastrointestinal disorder that is difficult to diagnose and treat due to its inherent heterogeneity and unclear aetiology. Although there is evidence suggesting the importance of the microbiome in IBS, this association remains poorly defined. In the current study, we aimed to characterise a large cross-sectional cohort of patients with self-reported IBS in terms of microbiome composition, demographics, and risk factors.DesignIndividuals who had previously submitted a stool sample for 16S microbiome sequencing were sent a comprehensive survey regarding IBS diagnosis, demographics, health history, comorbidities, family history, and symptoms. Log ratio-transformed abundances of microbial taxa were compared between individuals reporting a diagnosis of IBS without any comorbidities and individuals reporting no health conditions. Univariable testing was followed by a multivariable logistic regression model controlling for relevant confounders.ResultsOut of 6386 respondents, 1692 reported a diagnosis of IBS without comorbidities and 1124 reported no health conditions. We identified 3 phyla, 15 genera, and 19 species as significantly associated with IBS after adjustment for confounding factors. Demographic risk factors include a family history of gut disorders and reported use of antibiotics in the last year.ConclusionThe results of this study confirm important IBS risk factors in a large cohort and support a connection for microbiome compositional changes in IBS pathogenesis. The results also suggest clinical relevance in monitoring and investigating the microbiome in patients with IBS. Further, the exploratory models described here provide a foundation for future studies.

BackgroundHospitalization and antibiotic treatment can put patients at high risk for Clostridium difficile infection, where a disturbance of the gut microbiome allows for Clostridium difficile proliferation and associated symptoms, including mild, moderate, or severe diarrhea. Clostridium difficile infection is challenging to treat, often recurrent, and leads to almost 30,000 annual deaths in the USA alone. Here we present a case where SmartGut™, an at-home, self-administered sequencing-based clinical intestinal screening test, was used to identify the presence of Clostridium difficile in a patient with worsening diarrhea. Identification of this pathogen and subsequent treatment led to a significant improvement in symptoms.Case presentationThe patient is a 29-year-old white woman with a history of severe irritable bowel syndrome with diarrhea, hemorrhoidectomy, and anal sphincterotomy complicated by a perianal fistula and perirectal abscesses that required extended courses of broad-spectrum antibiotics. In June 2016, she developed intermittent Clostridium difficile infections, which required continued antibiotic use. Months later she used an at-home, self-administered, intestinal microbial test, the first of which was negative for the presence of Clostridium difficile, but it detected the relative abundance of microbes associated with irritable bowel syndrome outside the healthy reference ranges. In the subsequent 2 months after the negative Clostridium difficile result, her gastrointestinal symptoms worsened dramatically. A second microbiome test resulted in a positive Clostridium difficile finding and continued abnormal microbial parameters, which led the treating physician to refer her to a gastroenterologist. Additional testing confirmed the presence of Clostridium difficile with a toxin-positive strain. She received treatment immediately and her gastrointestinal symptoms improved significantly over the next week.ConclusionsThis case report suggests that more frequent DNA testing for Clostridium difficile infections may be indicated in patients that are at high-risk for Clostridium difficile infection, especially for patients with irritable bowel syndrome, and those who undergo gastrointestinal surgery and/or an extended antibiotic treatment. This report also shows that such testing could be effectively performed using at-home, self-administered sequencing-based clinical intestinal microbial screening tests. Further research is needed to investigate whether the observations reported here extrapolate to a larger cohort of patients.

No abstract

No abstract