Morphology of G Cells in Hypergastrinemic Cotton Rats

In a strain of inbred cotton rats, 25-50% of females develop spontaneous gastric hypochlorhydria and  hypergastrinemia. Hypergastrinemic animals develop ECL cell derived gastric carcinomas located in the  oxyntic mucosa, thus being an interesting animal model for studying the role of gastrin in gastric carcinogenesis.  The response to gastric hypoacidity in cotton rats as regards the level of hypergastrinemia is far  more pronounced than in the more commonly used laboratory rat. It is unknown whether the pronounced  hypergastrinemic response in cotton rats is due to a greater population of G cells or a greater capacity of  hormone synthesis in each G cell. The aim of the study was therefore to examine G cell population and  ultrastructure in normogastrinemic and hypergastrinemic cotton rats by the use of immunhistochemical  methods applied on both light- and electron-microscopy. Five hypergastrinemic vs. five normogastrinemic  cotton rats were compared. Cotton rats with gastric hypochlorhydria have a 55-fold increase in serum gastrin levels and a 6-fold  increase in G cell number, but this is not accompanied by significant changes in G cell ultrastructure. The  lack of ultrastructural changes in these activated G cells indicates that previously reported changes in  chronic stimulated G cells are just one of several ways G cells are activated.

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

The Phylogeny and Biological Function of Gastric Juice—Microbiological Consequences of Removing Gastric Acid

Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

Proton pump inhibitors (PPIs) have been increasingly used over the last decades and there are concerns about overuse and the numerous reported side-effects. It is uncertain whether associations between PPI use and potential side effects are causal. However, important evidence from experimental and mechanistic studies that could support a causal relationship may have been underestimated by epidemiologists and meta-analysists. In the current manuscript we review the combined epidemiological and mechanistic evidence of the adverse effects of PPI use