Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice.

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

Impaired skeletal health in patients with chronic atrophic gastritis.

OBJECTIVE: In chronic atrophic gastritis (CAG), destruction of gastric parietal cells causes anacidity and hypergastrinemia. Use of proton pump inhibitors, which also induces gastric anacidity, is associated with increased fracture rates. Our objectives were to study possible differences in bone mineral density (BMD) and bone quality in patients with CAG compared to controls. MATERIAL AND METHODS: We performed a cross-sectional study on 17 CAG patients aged 54 ± 13 years and 41 sex- and age-matched controls. Lumbar and femoral BMD and bone quality assessed by lumbar trabecular bone score (TBS) were measured by DXA, and bone material strength (BMS) by microindentation of the tibia. Serum bone markers (CTX, P1NP, sclerostin, osteocalcin, OPG, RANKL) were analyzed. RESULTS: We found lower lumbar BMD Z-score (-0.324 ± 1.096 versus 0.456 ± 1.262, p = 0.030), as well as a higher frequency of osteoporosis at the lumbar spine (p = 0.046) and osteopenia at total hip (p = 0.019) in patients compared to controls. In a post hoc subgroup analysis, we observed that the differences were confined to the male patients. TBS also tended to be lower in male patients (p = 0.059), while BMS did not differ between the groups. Osteocalcin, sclerostin, OPG, and OPG/RANKL ratio were lower in patients compared to controls, while CTX and P1NP did not differ between the groups. CONCLUSIONS: We observed lower lumbar BMD, increased frequency of osteopenia and osteoporosis in male, but not female patients with CAG. Bone markers suggest a decrease in bone formation and increased bone resorption in CAG patients compared to controls.

The Effect of Roux-en-Y Gastric Bypass on Non-Alcoholic Fatty Liver Disease Fibrosis Assessed by FIB-4 and NFS Scores-An 11.6-Year Follow-Up Study.

Severe obesity is a strong risk factor for non-alcoholic fatty liver disease (NAFLD). Roux-en-Y gastric bypass (RYGB) surgery effectively induces weight loss, but few studies have described the long-term effects of RYGB on NAFLD-related fibrosis. Data from 220 patients with severe obesity operated by RYGB in Central Norway were analysed. Variables incorporated in NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4) index and anthropometric data were collected before surgery and a mean of 11.6 years postoperatively. FIB-4 > 1.3 or NFS > 0.675 were used as cut-off values for advanced fibrosis. Proportions with advanced fibrosis decreased from 24% to 14% assessed by FIB-4 and from 8.6% to 2.3% using NFS, with resolution rates of advanced fibrosis of 42% and 73%, respectively. The shift towards lower fibrosis categories was significant (NFS p < 0.0001; FIB-4 p = 0.002). NFS decreased from −1.32 (IQR −2.33−−0.39) to −1.71 (IQR −2.49−−0.95, p < 0.001) 11.6 years after surgery, whereas FIB-4 did not change: 0.81 (IQR 0.59−1.25) to 0.89 (IQR 0.69−1.16, p = 0.556). There were weak correlations between change in fibrosis scores and weight loss. In conclusion, the majority of patients with advanced fibrosis at baseline had improvement after 11.6 years. Factors associated with reduction in fibrosis were not identified.

Increased prescribing of ursodeoxycholic acid in Norway.

Background Ursodeoxycholic acid is a hydrophilic bile acid prescribed for a variety of cholestatic liver disorders, although with variable clinical evidence with regards to efficacy. Objective The aim of this study was to investigate the prescription pattern of ursodeoxycholic acid in Norway over the last 13 years. Method Information on the prescribing of ursodeoxycholic acid was extracted from the Norwegian Prescription Database. Data was obtained on the number of individuals who had at least one prescription of ursodeoxycholic acid for any indication dispensed per year in the period 2004-2017. Results The period 2004-2017 witnessed an overall rise in the prevalence of ursodeoxycholic acid prescribing of 237%. With regards to development in prescribing across different age cohorts there is an increase in prescribing in all age groups, although the trend seems to be levelling off in some cohorts. Conclusion Considering the variable clinical evidence of the efficacy of ursodeoxycholic acid, the increase in prescribing is interesting and should prompt vigilance and further research with regards to its long term effects on clinical outcomes.

Adiponectin Reduces Bone Stiffness: Verified in a Three-Dimensional Artificial Human Bone Model In Vitro.

Primary human osteoblasts and osteoclasts incubated in a rotating coculture system without any scaffolding material, form bone-like tissue that may be used to evaluate effects of various compounds on mechanical strength. Circulating adiponectin has been found to be negatively associated with BMD and strength and was therefore assessed in this system. Osteospheres of human osteoblasts and osteoclasts were generated with and without adiponectin. The osteospheres were scanned using micro-computed tomography, the mechanical properties were tested by flat punch compression using nanoindentation equipment, and the cellular morphology characterized by microscopy. The association between autologously produced adiponectin and biomechanical properties was further evaluated by quantitation of adiponectin levels using quantitative polymerase chain reaction (qPCR) and immunoassays, and identification of stiffness by bending test of rat femurs. The molecular mechanisms were examined in vitro using human bone cells. Mechanical testing revealed that adiponectin induced a more compliant osteosphere compared with control. The osteospheres had a round, lobulated appearance with morphologically different areas; inner regions containing few cells embedded in a bone-like material surrounded by an external area with a higher cell quantity. The expression of adiponectin was found to correlate positively to ultimate bending moment and ultimate energy absorption and deflection, on the other hand, it correlated negatively to bending stiffness, indicating autocrine and/or paracrine effects of adiponectin in bone. Adiponectin enhanced proliferation and expression of collagen, leptin, and tumor necrosis factor-alpha in osteoblasts and stimulated proliferation, but not the functional activity of osteoclasts. Our results indicate that both administration of adiponectin during osteosphere production and in situ elevated levels of adiponectin in rat femurs, reduced stiffness of the bone tissues. An increase in undifferentiated cells and extracellular matrix proteins, such as collagen, may explain the reduced bone stiffness seen in the osteospheres treated with adiponectin.

Adiponectin prevents orthodontic tooth movement in rats.

OBJECTIVE: The objective was to examine the effects of repetitive local administration of adiponectin on experimental tooth movement in rats. MATERIALS AND METHODS: The maxillary right first molar of male Wistar rats (n=24) was moved mesially for 14days, with local adiponectin injections (0.2 or 2µg) every third day. Micro-computed tomography was performed at days 0, 6 and 14 and molar movement, bone density and bone volume fraction were calculated from the scans. Changes in extracellular matrix collagen and cell numbers in the periodontal ligament were analyzed histologically, and levels of circulating cytokines were measured by Luminex and ELISA. RESULTS: Adiponectin injections induced a reduction in tooth movement after 12 and 14days compared to controls. No tooth movement was observed between days 3 and 14 in the group receiving the highest dosage (2µg) of adiponectin. Differences in bone density and bone volume fractions between treatment and control groups were not identified. Relative size and morphology of collagen fibrils, and cell number in the periodontal region after adiponectin injections were unchanged compared to controls. Levels of circulating adiponectin or other selected factors in plasma were not influenced by the adiponectin injections. CONCLUSIONS: Submucosal injections of adiponectin prevented experimental tooth movement in rats. The effect was dosage-dependent and local. Adiponectin injections caused no detectable changes in bone density, periodontal cell number or collagen content.