Decreased Angiotensin II -Stimulated Aldosterone Production, but Normal Inositol Phosphate Response in Adrenal Glomerulosa Cells from Streptozotocin-Induced Diabetic Rats: Role of lnsulin

Streptozotocin(SlZ)-induced diabetic rats develop hyporeninemic hypoaldosteronism during the progression of diabetes mellitus. However,the nature and mechanism of aldosterone deficiency in diabetic rats still remain unclear and acute effects of insulin on aldosterone production in-vitro are not known. We evaluated the responses of aldosterone production to angiotensin 11 (AlI), potassium (K+), AClH and insulin in adrenal glomerulosa cells prepared from SlZ-induced diabetic rats with and without insulin treatment 2 weeks after diabetes induction. We also measured inositol phosphate<IP) levels in All-stimulated glomerulosa cells labeled with [3HI myoinositol using standardized anion exchange chromatography. Plasma renin activity and aldosterone level were not different among control rats,untreated and insulin-treated diabetic rats. Basal aldosterone production was similar in cells from the three groups. Cells from untreated diabetic rats showed a significant decrease in the maximal All (to-8M)-stimuiated aldosterone production and a tendency to be low in the maximal K+(8.7 mM)-stimulated aldosterone production, compared with control rats (3.2±2.2 \IS 7.7±2.4, P (0.05 and 4.8±1.8 \IS 8.0±3.2 ng/105 cells/hr, 0.05 (P (0.1, respectively). In contrast, there were no differences in All- and K+-stimulated aldosterone production between control and insulin-treated diabetic rats. AClH (to-8M), however, caused a similar effect on aldosterone production and insulin (I mU /ml for 1 hour) did not alter either basal or agonists-stimulated aldosterone production in cells from the three groups. All (to-8M)-induced IP formation among the three groups was similar and did not change with the addition of insulin u mU / ml), These results indicate that reduced response to All in the early phase of SlZ-induced diabetes in rats may be due to the zona glomerulosa dysfunction secondary to chronic lack of insulin and the main defect responsible for altered All effects may be located at some step(s) mediating All action downstream from IP formation

Prognostic value of low muscle mass at the 12th thoracic vertebral level in multiple myeloma treated with transplantation: CAREMM-2101 study

PURPOSEAutologous hematopoietic stem cell transplantation (ASCT) has been introduced as a standard treatment for newly diagnosed multiple myeloma (NDMM) following novel agent-based induction chemotherapy. This study investigated whether pre-ASCT low muscle mass evaluated using the paraspinal muscle index (PMI) at the 12th thoracic vertebra (T12) level is a reliable prognostic marker in NDMM after chemotherapy.METHODSA multi-center registry database was retrospectively analyzed. Between 2009 and 2020, 190 patients with chest computed tomography images underwent frontline ASCT following induction therapy. The PMI was defined as the value of the paraspinal muscle area at the T12 level divided by the square of the patient’s height. The cut-off value indicating a low muscle mass was sex-specific, using the lowest quintiles.RESULTSOf the 190 patients, 38 (20%) were in the low muscle mass group. The low muscle mass group had a lower 4-year overall survival (OS) rate than the non-low muscle mass group (68.5% vs. 81.2%; P = 0.074). The median progression-free survival (PFS) in the low muscle mass group was significantly shorter compared with the non-low muscle mass group (23.3 months vs. 29.2 months; P = 0.029). The cumulative incidence of transplant-related mortality (TRM) was significantly higher in the low muscle mass group than in the non-low muscle mass group (4-year probability of TRM incidence, 10.6% vs. 0.7%; P < 0.001). In contrast, no significant difference in the cumulative incidence of disease progression was found between the two groups. Multivariate analysis revealed that low muscle mass was associated with significant negative outcomes for OS [(hazard ratio (HR): 2.14; P = 0.047], PFS (HR: 1.78; P = 0.012), and TRM (HR: 12.05; P = 0.025).CONCLUSIONParaspinal muscle mass may have a prognostic role in NDMM patients who undergo ASCT. Patients with low paraspinal muscle mass have lower survival outcomes compared to non-low muscle mass group

Reactive oxygen species and p47phox activation are essential for the Mycobacterium tuberculosis-induced pro-inflammatory response in murine microglia

<p>Abstract</p> <p>Background</p> <p>Activated microglia elicits a robust amount of pro-inflammatory cytokines, which are implicated in the pathogenesis of tuberculosis in the central nervous system (CNS). However, little is known about the intracellular signaling mechanisms governing these inflammatory responses in microglia in response to <it>Mycobacterium tuberculosis </it>(Mtb).</p> <p>Methods</p> <p>Murine microglial BV-2 cells and primary mixed glial cells were stimulated with sonicated Mtb (s-Mtb). Intracellular ROS levels were measured by staining with oxidative fluorescent dyes [2',7'-Dichlorodihydrofluorescein diacetate (H₂DCFDA) and dihydroethidium (DHE)]. NADPH oxidase activities were measured by lucigenin chemiluminescence assay. S-Mtb-induced MAPK activation and pro-inflammatory cytokine release in microglial cells were measured using by Western blot analysis and enzyme-linked immunosorbent assay, respectively.</p> <p>Results</p> <p>We demonstrate that s-Mtb promotes the up-regulation of reactive oxygen species (ROS) and the rapid activation of mitogen-activated protein kinases (MAPKs), including p38 and extracellular signal-regulated kinase (ERK) 1/2, as well as the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-12p40 in murine microglial BV-2 cells and primary mixed glial cells. Both NADPH oxidase and mitochondrial electron transfer chain subunit I play an indispensable role in s-Mtb-induced MAPK activation and pro-inflammatory cytokine production in BV-2 cells and mixed glial cells. Furthermore, the activation of cytosolic NADPH oxidase p47phox and MAPKs (p38 and ERK1/2) is mutually dependent on s-Mtb-induced inflammatory signaling in murine microglia. Neither TLR2 nor dectin-1 was involved in s-Mtb-induced inflammatory responses in murine microglia.</p> <p>Conclusion</p> <p>These data collectively demonstrate that s-Mtb actively induces the pro-inflammatory response in microglia through NADPH oxidase-dependent ROS generation, although the specific pattern-recognition receptors involved in these responses remain to be identified.</p

Comparison of the Efficacy of Glimepiride, Metformin, and Rosiglitazone Monotherapy in Korean Drug-Naïve Type 2 Diabetic Patients: The Practical Evidence of Antidiabetic Monotherapy Study

BackgroundAlthough many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated.MethodsWe evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naïve type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels.ResultsHbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group.ConclusionThe efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naïve Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information

Early detection of subclinical ventricular deterioration in aortic stenosis with cardiovascular magnetic resonance and echocardiography

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Severe aortic stenosis (AS) patients with late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) or left ventricular (LV) systolic dysfunction are known to have worse outcome. We aimed to investigate whether LGE on CMR would be useful in early detection of subclinical LV structural and functional derangements in AS patients. Methods: 118 patients with moderate to severe AS were prospectively enrolled. Echocardiography and CMR images were taken and the patients were divided into groups according to the presence/absence of LGE and of LV systolic dysfunction (LV ejection fraction (EF) <50%). The stiffness of LV was calculated based on Doppler and CMR measurements. Results: Patients were grouped into either group 1, no LGE and normal LVEF, group 2, LGE but normal LVEF and group 3, LGE with depressed LVEF. There was a significant trend towards increasing LV volumes, worsening of LV diastolic function (E/e, diastolic elastance), systolic function (end-systolic elastance) and LV hypertrophy between the three groups, which coincided with worsening functional capacity (all p-value < 0.001 for trend). Also, significant differences in the above parameters were noted between group 1 and 2 (E/e, 14.6 ± 4.3 (mean ± standard deviation) in group 1 vs. 18.2 ± 9.4 in group 2; end-systolic elastance, 3.24 ± 2.31 in group 1 vs. 2.38 ± 1.16 in group 2, all p-value < 0.05). The amount of myocardial fibrosis on CMR correlated with parameters of diastolic (diastolic elastance, Spearmans ρ = 0.256, p-value = 0.005) and systolic function (end-systolic elastance, Spearmans ρ = −0.359, p-value < 0.001). Conclusions: These findings demonstrate the usefulness of CMR for early detection of subclinical LV structural and functional deterioration in AS patients.Peer Reviewe