Increased intestinal bile acid absorption contributes to age-related cognitive impairment.

Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.

Salivary metabolite signatures of oral cancer and leukoplakia.

Oral cancer, one of the six most common human cancers with an overall 5-year survival rate of <50%, is often not diagnosed until it has reached an advanced stage. The aim of the current study is to explore salivary metabolomics as a disease diagnostic and stratification tool for oral cancer and leukoplakia and evaluate the potential of salivary metabolome for detection of oral squamous cell carcinoma (OSCC). Saliva metabolite profiling for a group of 37 OSCC patients, 32 oral leukoplakia (OLK) patients and 34 healthy subjects was performed using ultraperformance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry in conjunction with multivariate statistical analysis. The OSCC, OLK and healthy control groups demonstrate characteristic salivary metabolic signatures. A panel of five salivary metabolites including γ-aminobutyric acid, phenylalanine, valine, n-eicosanoic acid and lactic acid were selected using OPLS-DA model with S-plot. The predictive power of each of the five salivary metabolites was evaluated by receiver operating characteristic curves for OSCC. Valine, lactic acid and phenylalanine in combination yielded satisfactory accuracy (0.89, 0.97), sensitivity (86.5% and 94.6%), specificity (82.4% and 84.4%) and positive predictive value (81.6% and 87.5%) in distinguishing OSCC from the controls or OLK, respectively. The utility of salivary metabolome diagnostics for oral cancer is successfully demonstrated in this study and these results suggest that metabolomics approach complements the clinical detection of OSCC and stratifies the two types of lesions, leading to an improved disease diagnosis and prognosis.

Sex-dependent effects on gut microbiota regulate hepatic carcinogenic outcomes.

Emerging evidence points to a strong association between sex and gut microbiota, bile acids (BAs), and gastrointestinal cancers. Here, we investigated the mechanistic link between microbiota and hepatocellular carcinogenesis using a streptozotocin-high fat diet (STZ-HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) murine model and compared results for both sexes. STZ-HFD feeding induced a much higher incidence of HCC in male mice with substantially increased intrahepatic retention of hydrophobic BAs and decreased hepatic expression of tumor-suppressive microRNAs. Metagenomic analysis showed differences in gut microbiota involved in BA metabolism between normal male and female mice, and such differences were amplified when mice of both sexes were exposed to STZ-HFD. Treating STZ-HFD male mice with 2% cholestyramine led to significant improvement of hepatic BA retention, tumor-suppressive microRNA expressions, microbial gut communities, and prevention of HCC. Additionally the sex-dependent differences in BA profiles in the murine model can be correlated to the differential BA profiles between men and women during the development of HCC. These results uncover distinct male and female profiles for gut microbiota, BAs, and microRNAs that may contribute to sex-based disparity in liver carcinogenesis, and suggest new possibilities for preventing and controlling human obesity-related gastrointestinal cancers that often exhibit sex differences.

Clinical anatomical study and evaluation of the use of the free anteromedial thigh perforator flaps in reconstructions of the head and neck.

The anteromedial thigh (AMT) perforator flap is usually thin, pliable, and nearly hairless, making it particularly suitable to repair defects of the head and neck. We studied the topography and outcomes of AMT perforator flaps in such defects after excision of tumours. We retrospectively reviewed the casenotes of 11 consecutive patients who had had reconstructions of the head and neck with the initial intent of using an AMT perforator flap from January 2010 to July 2011. For each patient we recorded the size and thickness of the flap; the length of the pedicle; and the number, external diameters, anatomical types, source vessels, and sites of the sizeable perforators. Of the 11 patients, 10 had successful reconstruction using AMT perforator flaps, but one had no AMT perforator big enough. The mean (range) number of sizeable perforators/flap was 1.3 (1-2), length of pedicle 10.6 (7-13) cm, and diameter of the artery 1.1(1.0-1.5) mm. Of the 13 sizeable perforators, 3 were direct and septocutaneous. The remaining ones were all musculocutaneous. Most of them were located in the middle third of the thigh. Primary closure of the donor site was achieved in all patients. One flap was successfully revised after compression of the perforator. All flaps survived with good functional and aesthetic outcomes. The free AMT perforator flap is suitable for reconstructions of the head and neck if a sizeable perforator can be found. The AMT flap may be used as a primary flap rather than as an alternative to the anterolateral thigh flap or a component of a chimeric flap.