Effect of bariatric surgery on circulating FGF‐19: A systematic review and meta‐analysis

Fibroblast growth factor‐19 (FGF‐19) is a gut hormone which interacts with metabolism and is depleted in obesity. There is some indication that the hormone undergoes a resurgence following bariatric surgery (BS), an effect which may contribute to the beneficial outcomes of such procedures. This systematic review and meta‐analysis aims to synthesize the available literature on FGF‐19 levels before and after BS. MEDLINE, Scopus and Web of Science databases were searched, and the effect of different surgical procedures and degrees of body mass index (BMI) reduction on FGF‐19 levels was assessed by DerSimonian and Laird random‐effects model in meta‐analysis and dose–response analyses. This meta‐analysis, which included 474 patients from 25 arms undergoing one of five BS procedures, revealed a significant increase in the levels of circulating FGF‐19 following all‐type BS. Vertical sleeve gastrectomy, duodenal‐jejunal bypass liner and Roux‐en‐Y gastric bypass all significantly increased circulating FGF‐19 levels from baseline. However, gastric banding failed to achieve the same, and in fact, biliopancreatic diversion was associated with decreased circulating FGF‐19. Finally, an inverse association between FGF‐19 and the degree of BMI‐reduction post‐operatively was noted. FGF‐19 is increased by BS and may represent a pharmaceutical target in efforts to reproduce the beneficial effects of BS in a medical setting.     

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver‐damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC.     

Intra-night variation in apnea-hypopnea index affects diagnostics and prognostics of obstructive sleep apnea

Sleep and Breathing - Diagnostics of obstructive sleep apnea (OSA) is based on apnea-hypopnea index (AHI) determined as full-night average of occurred events. We investigate our hypothesis that...     

Proteome-Scale Antibody Responses and Outcome of Mycobacterium tuberculosis Infection in Nonhuman Primates and in Tuberculosis Patients

Background.Biomarkers of progression from latent Mycobacterium tuberculosis infection to active tuberculosis are needed. We assessed correlations between infection outcome and antibody responses in macaques and humans by high-throughput, proteome-scale serological studies. Methods.Mycobacterium tuberculosis proteome microarrays were probed with serial sera from macaques representing various infection outcomes and with single-point human sera from tuberculosis suspects. Fluorescence intensity data were analyzed by calculating Z scores and associated P values. Temporal changes in macaque antibody responses were analyzed by polynomial regression. Correlations between human responses and sputum bacillary burden were assessed by quantile and hurdle regression. Results.Macaque outcome groups exhibited distinct antibody profiles: early, transient responses in latent infection and stable antibody increase in active and reactivation disease. In humans, antibody levels and reactive protein numbers increased with bacillary burden. Responses to a subset of 10 proteins were more tightly associated with disease state than reactivity to the broader reactive proteome. Conclusions.Integration of macaque and human data reveals dynamic properties of antibody responses in relation to outcome and leads to actionable findings for translational research. These include the potential of antibody responses to detect acute infection and preclinical tuberculosis and to identify serodiagnostic proteins for the spectrum of bacillary burden in tuberculosis.     

Opposing roles of membrane and soluble forms of the receptor for advanced glycation end products in primary respiratory syncytial virus infection

Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.     

Downregulation of transforming growth factor, beta receptor 2 and Notch signaling pathway in human abdominal aortic aneurysm

ObjectiveMutations in FBN1 and TGFBR2 genes are the main causative mutations identified in Marfan syndrome (MFS). The major vascular complication of MFS is aneurysm formation. Abdominal aortic aneurysm (AAA) is an acquired disease of later life of unknown etiology. The aim of this study was to examine if genetic aberrations in MFS-related genes FBN1 and TGFBR2 are present in patients with AAA.MethodsWe assessed the presence of copy number variation (CNV) in FBN1 and TGFBR2 genes in AAA biopsies from twelve patients. We also analyzed the expression of these genes in AAA biopsies compared to control biopsies from six organ donors. In addition we assessed the expression of two members of the Notch signaling pathway NOTCH3 and HEY2 as well as aortic smooth muscle cell (AoSMC) differentiation marker TAGLN in AAA and control biopsies.ResultsLoss of one copy (deletion) of the FBN1 exon 66 sequence and TGFBR2 exon 8 was identified in 7 (58%) and 11 (92%) of the 12 AAA biopsies. No copy number amplifications (duplications) were detected. Patients carrying TGFBR2 exon 8 deletion showed marked downregulation of this gene in AAA biopsies compared to control biopsies (0.699 vs. 1.765, p = 0.038). Notch signaling components NOTCH3 and HEY2 were markedly downregulated in AAA, while expression of the AoSMC differentiation marker TAGLN did not differ between AAA and control biopsies (0.468 vs. 0.486, p = 0.546).ConclusionThis study suggests an acquired impairment in TGF-β signaling that along with downregulation of the Notch signaling pathway may contribute to the pathogenesis of AAA.