Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation.

BACKGROUND & AIMS: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH. METHODS: We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B12 (B12) and folate (Fol) to reverse NASH features in mice and cell culture. RESULTS: Serum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B12/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated ß -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH. CONCLUSIONS: HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B12/folate also may represent a novel first-line therapy for NASH. LAY SUMMARY: The incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B12 and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis.

Use of prefrontal cortex activity as a measure of learning curve in surgical novices: results of a single blind randomised controlled trial.

BACKGROUND: Neurobiological feedback in surgical training could translate to better educational outcomes such as measures of learning curve. This work examined the variation in brain activation of medical students when performing laparoscopic tasks before and after a training workshop, using functional near-infrared spectroscopy (fNIRS). METHODS AND PROCEDURES: This single blind randomised controlled trial examined the prefrontal cortex activity (PFCA) differences in two groups of novice medical students during the acquisition of four laparoscopic tasks. Both groups were shown a basic tutorial video, with the "Trained-group" receiving an additional standardised one-to-one training on the tasks. The PFCA was measured pre- and post-intervention using a portable fNIRS device and reported as mean total oxygenated hemoglobin (HbOµm). Primary outcome of the study is the difference in HbOµm between post- and pre-intervention readings for each of the four laparoscopic tasks. The pre- and post-intervention laparoscopic tasks were recorded and assessed by two blinded individual assessors for objective scores of the performance. RESULTS: 16 Trained and 16 Untrained, right-handed medical students with an equal sex distribution and comparable age distribution were recruited. Trained group had an attenuated left PFCA in the "Precision cutting" (p = 0.007) task compared to the Untrained group. Subgroup analysis by sex revealed attenuation in left PFCA in Trained females compared to Untrained females across two laparoscopic tasks: "Peg transfer" (p = 0.005) and "Precision cutting" (p = 0.003). No significant PFCA attenuation was found in male students who underwent training compared to Untrained males. CONCLUSION: A standardised laparoscopic training workshop promoted greater PFCA attenuation in female medical students compared to males. This suggests that female and male students respond differently to the same instructional approach. Implications include a greater focus on one-to-one surgical training for female students and use of PFCA attenuation as a form of neurobiological feedback in surgical training.

Decision-making for early major amputation in selected diabetic foot ulcer patients with peripheral vascular disease.

Objective: To estimate the costs from delaying major amputation in patients with concurrent diabetic foot ulcer and peripheral vascular disease. We seek to model economic benefits from saved costs from promoting timely major amputations among these patients. Methods: Retrospective modeling using data from National University Hospital, Singapore. We identified patients who might have delayed major amputations by applying a hierarchical clustering algorithm. We then modeled the transitions of all patients over time with a Markov process using a number of relevant health states to enable estimation of cost outcomes. We next summarized the expected changes to the bed days used and cost outcomes arising from reassigning some patients who may have had a delayed amputation to timely amputation. The findings from the sample were scaled to reflect national incidence rates for this disease for the years 2014-2019 in Singapore. Results and Conclusions: Nine of the 137 patients (6.57%) would be suitable for a major amputation at 3 months, yet in reality, their amputation was delayed. Based on this, and assuming a timely amputation is done for the entire population of patients in Singapore we expect annual savings of 264,791 bed days and $211 million in costs. These findings are preliminary and uncertain. The value of this paper is to show a method for estimating outcomes, report the findings from a small sample, and stimulate future research. New cohort studies might be designed to capture a wider range of outcomes and recruit a larger sample of individuals.

Early and late outcomes in Hong Kong Chinese patients undergoing carotid endarterectomy / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To determine the benefit of carotid endarterectomy (CEA) for stroke prevention by reviewing the early and late outcomes of Hong Kong Chinese patients undergoing CEA who have a high reported incidence of intracranial atherosclerotic disease (IAD).</p><p><b>METHODS</b>Fifty-nine Chinese patients underwent 62 CEA. There were 48 males and 11 females, with a mean age of 70 +/- 7 years (range: 52 - 86 years). Twenty-one CEA (34%) were performed for asymptomatic disease. Duplex scan was the primary tool of evaluation prior to surgery. Preoperative angiography was done in 36 instances (58%). All CEA were performed under general anaesthesia with routine intraoperative shunting. The arteriotomy was closed primarily in all patients except three. Patients were followed up regularly with six-monthly Duplex scan surveillance.</p><p><b>RESULTS</b>There were 2 perioperative neurological events consisting of one transient ischemic attack and one minor stroke. There was no operative mortality or major morbidity such as bleeding or cranial nerve injury. Mean hospital stay was 6.5 +/- 4 days (range: 3 - 26 days). The patients were followed up for a mean interval of 24 +/- 17 months (range: 1 - 57 months). Seven patients died during follow-up and subsequent neurological events occurred in 5 patients, including 2 fatal strokes. The 3-year survival, freedom from stroke and stroke free survival were 86%, 87% and 83%, respectively. One recurrent stenosis of 80% was detected on follow-up Duplex scan.</p><p><b>CONCLUSIONS</b>Despite a high incidence of IAD, CEA in Hong Kong Chinese patients is associated with acceptable perioperative morbidity and mortality with satisfactory long-term efficacy in stroke prevention.</p>