Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation

BACKGROUND Arachidyl amido cholanoic acid(Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1(SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis(NASH), 52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an indicator of glycemic control.AIM To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model [induced with a 0.1% methionine and choline deficient diet(0.1 MCD)] after treatment with Aramchol.METHODS Isolated primary mouse hepatocytes were incubated with 20 μmol/L Aramchol or vehicle for 48 h. Subsequently, analyses were performed including Western blot, proteomics by mass spectrometry, and fluxomic analysis with ~(13)C-uniformly labeled glucose. For the in vivo part of the study, male C57 BL/6 J mice were randomly fed a control or 0.1 MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites.RESULTS Combination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes. This translated into changes in the content of their downstream targets including proteins involved in fatty acid(FA) synthesis and oxidation [PACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative phosphorylation(NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2), tricarboxylic acid(TCA) cycle(MDH2, SUCLA2, and SUCLG2), and ribosome(P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with ~(13)C uniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes, as indicated by the increase in the number of rounds that malate remained in the TCA cycle. Finally, liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1 MCD fed mice in a dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose, and Rbl5 P/Xyl5 P.CONCLUSION Aramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1, which in turn activate FA β-oxidation and oxidative phosphorylation.     

Prediction of incident type 2 diabetes mellitus based on a twenty-year follow-up of the Ventimiglia heart study

A novel algorithm to predict incident type 2 diabetes mellitus (iT2DM) is presented considering data from a 20-year prospective study in a Southern Italy population. Eight hundred and fifty-eight out of 1,351 subjects (24?C85?years range of age) were selected. Incident type 2 diabetes was diagnosed in 103 patients in a 20-year follow-up. The Finnish Diabetes Risk Score (FINDRISC) and the Framingham Offspring Study simple clinical model (FOS) have been used as reference algorithms. Two custom algorithms have been created using Cox parametric hazard models followed by PROBIT analyses: the first one (VHSRISK) includes all the study subjects and the second one (VHS95RISK) evaluates separately subjects with baseline fasting blood glucose (FBG) above/below 5.2?mmol/L (95?mg/dL). The 44 iT2DM cases below 5.2?mmol/L of baseline FBG were predicted by high LDL cholesterol, metabolic syndrome (ATPIII criteria), BMI?>?30?kg/m², and high factor VII activity. The 59 cases above the FBG threshold were predicted by FBG classes, hypertension, and age. ROC areas for iT2DM prediction were: FINDRISC?=?0.759, FOS?=?0.762, VHSRISK?=?0.789, and VHS95RISK?=?0.803. In a Mediterranean population, the use of a custom generated algorithm evaluating separately low/high FBG subjects improves the prediction of iT2DM in subjects classified at lower risk by common estimation algorithms.     

Ophthalmic manifestations in the COVID-19 clinical spectrum

Purpose:The aim of this study was to determine the frequency and various types of ophthalmic manifestation of patients with COVID-19.Methods:This is a prospective observational study conducted on patients with SARS-Co-V-2 infection, at a dedicated tertiary COVID-19 hospital in South India from April 1 to July 31, 2020. At the time of their admission to the COVID hospital, demographic data such as name, age, sex was recorded. A thorough history regarding the onset, duration, progression, nature of symptoms and its associated factors, medication history, treatment history were elicited and documented. Ocular examination was performed under torchlight by an ophthalmologist posted for COVID duty. Further investigations including imaging were sought for, depending on clinical indications. Serial follow-up examinations of all patients were carried out every 72 hours or when patients complained of any ocular symptoms whichever earlier, until discharge. All relevant data were compiled and statistically analyzed.Results:A total of 2742 patients were examined. Of them, 1461 (53.28%) were males and 1281 (46.72%) were females. The mean age (±SD) was 39.46 ± 17.63 years. None of the patients in our study had any ocular symptoms or signs as the presenting complaint at the time of their admission. On subsequent follow-up, only 20 (0.72%) developed ocular manifestations, of which 19 (95%) had features suggestive of Bilateral viral conjunctivitis. However, 1 (5%) patient had orbital cellulitis secondary to pansinusitis.Conclusion:Ophthalmic manifestations in the clinical spectrum of COVID-19 infection are uncommon and unlikely to be the presenting clinical impression. However, it has broadened our view to a wider spectrum of COVID-19 presentations enhancing our clinical acumen for staunch detection of COVID-19 suspects in our daily practice, augmenting early diagnosis and management and also break the chain of transmission for the greater good of humanity.     

Salient haptic skills trainer: initial validation of a novel simulator for training force-based laparoscopic surgical skills

Background

There is an increasing need for efficient training simulators to teach advanced laparoscopic skills beyond those imparted by a box trainer. In particular, force-based or haptic skills must be addressed in simulators, especially because a large percentage of surgical errors are caused by the over-application of force. In this work, the efficacy of a novel, salient haptic skills simulator is tested as a training tool for force-based laparoscopic skills.

Methods

Thirty novices with no previous laparoscopic experience trained on the simulator using a pre-test–feedback–post-test experiment model. Ten participants were randomly assigned to each of the three salient haptic skills—grasping, probing, and sweeping—on the simulator. Performance was assessed by comparing force performance metrics before and after training on the simulator.

Results

Data analysis indicated that absolute error decreased significantly for all three salient skills after training. Participants also generally decreased applied forces after training, especially at lower force levels. Overall, standard deviations also decreased after training, suggesting that participants improved their variability of applied forces.

Conclusions

The novel, salient haptic skills simulator improved the precision and accuracy of participants when applying forces with the simulator. These results suggest that the simulator may be a viable tool for laparoscopic force skill training. However, further work must be undertaken to establish full validity. Nevertheless, this work presents important results toward addressing simulator-based force-skills training specifically and surgical skills training in general.     

Impact of aging on cardiac sympathetic innervation measured by <Superscript>123</Superscript>I-mIBG imaging in patients with systolic heart failure

Purpose

Sympathetic nervous system (SNS) hyperactivity is a salient characteristic of chronic heart failure (HF) and contributes to the progression of the disease. Iodine-123 meta-iodobenzylguanidine (¹²³I-mIBG) imaging has been successfully used to assess cardiac SNS activity in HF patients and to predict prognosis. Importantly, SNS hyperactivity characterizes also physiological ageing, and there is conflicting evidence on cardiac ¹²³I-mIBG uptake in healthy elderly subjects compared to adults. However, little data are available on the impact of ageing on cardiac sympathetic nerve activity assessed by ¹²³I-mIBG scintigraphy, in patients with HF.

Methods and results

We studied 180 HF patients (age?=?66.1?±?10.5 years [yrs]), left ventricular ejection fraction (LVEF?=?30.6?±?6.3 %) undergoing cardiac ¹²³I-mIBG imaging. Early and late heart to mediastinum (H/M) ratios and washout rate were calculated in all patients. Demographic, clinical, and echocardiographic data were also collected. Our study population consisted of 53 patients aged >75 years (age?=?77.7?±?4.0 year), 67 patients aged 62–72 years (age?=?67.9?±?3.2 years) and 60 patients aged ≤61 year (age?=?53.9?±?5.6 years). In elderly patients, both early and late H/M ratios were significantly lower compared to younger patients (p?<?0.05). By multivariate analysis, H/M ratios (both early and late) and washout rate were significantly correlated with LVEF and age.

Conclusions

Our data indicate that, in a population of HF patients, there is an independent age-related effect on cardiac SNS innervation assessed by ¹²³I-mIBG imaging. This finding suggests that cardiac ¹²³I-mIBG uptake in patients with HF might be affected by patient age.