A novel MRPS34 gene mutation with combined OXPHOS deficiency in an adult patient with Leigh syndrome.

We report a novel pathogenic variant (c.223G > C; p.Gly75Arg) in the gene encoding the small mitoribosomal subunit protein mS34 in a long-surviving patient with Leigh Syndrome who was genetically diagnosed at age 34 years. The patient presented with delayed motor milestones and a stepwise motor deterioration during life, along with brain MRI alterations involving the subcortical white matter, deep grey nuclei and in particular the internal globi pallidi, that appeared calcified on CT scan. The novel variant is associated with a reduction of mS34 protein levels and of the OXPHOS complex I and IV subunits in peripheral blood mononuclear cells of the case. This study expands the number of variants that, by affecting the stability of the mitoribosome, may cause an OXPHOS deficiency in Leigh Syndrome and reports, for the first time, an unusual long survival in a patient with a homozygous MRPS34 pathogenic variant.

Prevalence of hepatic steatosis in patients with type 2 diabetes and response to glucose-lowering treatments. A multicenter retrospective study in Italian specialist care.

AIM: Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI. METHODS: We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs. RESULTS: MAFLD (defined by HSI > 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI < 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was > threefold higher among subjects with HSI > 36 than among those with HSI < 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide. CONCLUSION: About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D.

SARS CoV2 infection in a young subject affected by arginosuccinate synthase deficiency: A case report of epilepsy worsening.

We describe a case of a 21 years old woman affected by Citrullinemia type 1- Arginosuccinate Synthase deficiency (ASSD)-who underwent a SARS CoV2 infection during the first phase of pandemic burst in Italy. She had no symptoms of infection nor a metabolic crisis. After recovery from SARS CoV2, she experienced a worsening in their epilepsy despite therapy, with one/two crisis a week.

Metabolic alterations in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a rare, X-linked neuromuscular disease characterised by lower motor neurons degeneration, slowly progressive myopathy and multisystem involvement. SBMA is caused by trinucleotide repeat expansion in the first exon of the androgen receptor (AR) gene on chromosome X that encodes a polyglutamine (polyQ) tract in the AR protein. Disease onset occurs between 30-60 years of age with easy fatigability, muscle cramps, and weakness in the limbs. In addition to neuromuscular involvement, in SBMA phenotype, many non-neural manifestations are present. Recently, some studies have reported a high prevalence of metabolic and liver disorders in patients with SBMA. Particularly, fatty liver and insulin resistance (IR) have been found in many SBMA patients. The alteration of AR function and the androgen insensitivity can be involved in both fatty liver and IR. In turn, IR and liver alterations can influence neuromuscular damage through different mechanisms. These data lead to consider SBMA as a metabolic as well as a neuromuscular disease. The mechanism of metabolic alterations, their link with the neuromuscular damage, the effects on the course of disease and their treatment will have to be yet fully clarified.

One-year caloric restriction and 12-week exercise training intervention in obese adults with type 2 diabetes: emphasis on metabolic control and resting metabolic rate.

PURPOSE: The effect of combined lifestyle interventions (LSI) including dietary and physical activity on metabolic health, energy metabolism and VO2max in diabetic patients has provided mixed results. We evaluated the impact of 1-year caloric restriction (CR), and 12-week supervised structured exercise training (SSET) on metabolic health, RMR and VO2max in obese adults with type 2 diabetes. METHODS: After 1-month education for LSI, 33 participants had anthropometric, biochemical and metabolic assessments. They then started CR based on RMR, and 3-month SSET during the months 1-3 (Early-SSET) or 4-6 (Late-SSET). Reassessments were planned after 3, 6 and 12 months. Using a per-protocol analysis, we evaluated parameter changes from baseline and their associations for the 23 participants (11 Early-SSET, 12 Late-SSET) who completed the study. RMR was adjusted (adjRMR) for age, sex, fat-free mass (FFM) and fat mass (FM). RESULTS: Compared with baseline, after 6 months we found significant increases in VO2max (+ 14%) and HDL-cholesterol (+ 13%), and reduction in body mass index (- 3%), FM (- 8%) and glycated hemoglobin (HbA1c, - 7%). Training-related caloric expenditure negatively correlated with changes in body weight (p < 0.001), FM (p < 0.001) and HbA1c (p = 0.006). These results were confirmed at the 12-month follow-up. Pooling together all follow-up data, adjRMR changes correlated with changes in glycemia (r = 0.29, p = 0.02), total-cholesterol (r = 0.29, p = 0.02) and VO2max (r = - 0.26,p = 0.02). No significant differences emerged between the Early- and Late-SSET groups. CONCLUSIONS: Combined intervention with SSET and CR improved metabolic control. Changes in metabolic health and fitness correlated with changes of adjRMR, which was reduced improving fitness, glycemia and cholesterolemia. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03785379. URL of registration: http://clinicaltrials.gov .

Vitamin D status and non-alcoholic fatty liver disease in patients with type 1 diabetes.

PURPOSE: In patients with type 1 diabetes (T1D), the prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 10 to 53% and contrasting evidence suggests that vitamin D deficiency may favor liver fat accumulation. Here, we investigated the association between vitamin D status and NAFLD in adults with T1D. METHODS: 220 consecutive adult T1D patients on multiple daily injections or continuous subcutaneous insulin infusion and not taking calcium or vitamin D supplements were included. Patient characteristics, 25(OH)D serum levels, and metabolic parameters were analyzed. Vitamin D status was defined as sufficiency ( ≥ 75 nmol/L; 30 ng/ml), insufficiency (50-75 nmol/L; 20-30 ng/ml), or deficiency ( < 50 nmol/L; 20 ng/ml). NAFLD was diagnosed at ultrasound examination and graded 0-3. RESULTS: NAFLD was present in 57 patients (29.5%): 51 grade 1, 5 grade 2, and 1 grade 3. Median 25(OH)D levels were 53 nmol/L (IQR 38-70) in patients with NAFLD and 50 nmol/L (34-69) in patients without (p = 0.46). At multivariable analysis, NAFLD was not associated with 25(OH)D levels (p = 0.42) or vitamin D deficiency (p = 0.55), while BMI (OR 1.16, 95% CI 1.07-1.27) and serum triglycerides (OR 1.02, 95% CI 1.01-1.03) were independently associated with NAFLD. CONCLUSIONS: Vitamin D status appears to have no link with low-grade NAFLD in patients with type 1 diabetes.

Thoracic ultrasonography: A new method for the work-up of patients with dyspnea().

OBJECTIVE: Differential diagnosis of dyspnea is vital for the management of respiratory failure, where routine parameters can now be integrated with thoracic ultrasound data. The objective of this study was to evaluate the validity and accuracy of this approach in a department of internal medicine. MATERIALS AND METHODS: We enrolled 152 patients consecutively hospitalized with a diagnosis of dyspnea. After clinical evaluation, chest radiography, biochemical assays (NT-proBNP), and emergency treatment, patients underwent ultrasound examination of the lungs. Results were considered positive if the total number of lines B was higher than 8. The ultrasound examination and NT-proBNP assay were repeated after 48 h. The gold standard was the clinical diagnosis of heart failure made by medical experts in accordance with AHA guidelines. RESULTS: The group of patients with positive ultrasound findings had a higher frequency of heart failure diagnoses (X(2) 92.5, p < 0.005) and significantly higher values of NT-proBNP (10,384 ng/l vs 3889 ng/l, p < 0.05). Moreover, the decrease in the number of B lines at 48 h was significantly greater (p < 0.005) among patients treated for heart failure. There were no significant changes in the values of NT-proBNP (p = 0.37). DISCUSSION: In conclusion we have shown that even in a department of internal medicine, lung ultrasonography is a useful tool for diagnosing respiratory insufficiency and monitoring its response to therapy.

US in the evaluation of abdominal pain in a department of internal medicine.

INTRODUCTION: US (US) examination of the abdomen has acquired a growing role in the investigation of abdominal pain; however its role in the diagnosis of some important causes of abdominal pain is still under investigation. The aim of this study was to evaluate the role of US of the abdomen in the diagnosis of abdominal pain in patients referred to a department of internal medicine. MATERIALS AND METHODS: A retrospective analysis was carried out on 248 US examinations performed in our department due to abdominal pain. For each examination the data written on the request form were registered as well as US findings which could be correlated with abdominal pain. RESULTS: In 105 patients (42%), US examination of the abdomen resulted in a relevant clinical finding and was thus considered positive. A high percentage of patients were elderly (>65 years; 52%) and very elderly (>80 years; 24%); these patients showed a significantly higher percentage of positive US scans. The proportion of positive scans was not significantly different between localized and non-localized pain. Specific pain location was associated with US findings such as hepatic masses, ovarian masses and renal stones, whereas non-localized pain was associated with abdominal free fluid and fluid-distended bowel loops. DISCUSSION: A high percentage of US examinations identified conditions that could possibly cause abdominal pain. Diagnostic yield of abdominal US was higher in elderly and very elderly patients. When a US examination is requested, it should always be evaluated within the clinical context. The physician should be aware of the great value of abdominal US in the diagnosis of the various causes of abdominal pain, but also of its possible limitations.

Relevance of hepatic lipase to the metabolism of triacylglycerol-rich lipoproteins.

HL (hepatic lipase) is a glycoprotein that is synthesized and secreted by the liver, and which binds to heparan sulphate proteoglycans on the surface of sinusoidal endothelial cells and on the external surface of parenchymal cells in the space of Disse. HL catalyses the hydrolysis of triacylglycerols and phospholipids in different lipoproteins, contributing to the remodelling of VLDL (very-low-density lipoprotein) remnants, as well as IDL, LDL and HDL (intermediate-, low- and high-density lipoprotein respectively). HL deficiency in humans is associated with diminished conversion of VLDL remnants into IDL and a near-complete absence of IDL-to-LDL conversion. Remnant lipoproteins and IDL are major determinants of coronary artery disease risk, and accumulation of these lipoproteins in the presence of low HL activity might lead to increased atherosclerosis. In addition to and independently of its lipolytic activity, HL participates as a ligand in promoting the hepatic uptake of remnants and IDL particles, and the latter may represent an additional mechanism linking low HL levels to plasma accumulation of these atherogenic lipoproteins. On the other hand, high HL activity may also result in an increased atherosclerotic risk by promoting the formation of atherogenic small, dense LDL particles. Finally, HL is also synthesized by human macrophages, suggesting that, at the arterial wall site, HL may also contribute locally to promote atherosclerosis by enhancing the formation and retention in the subendothelial space of the arterial wall of VLDL remnants, IDL and small, dense LDL. In conclusion, by interfering with the metabolism of apolipoprotein B100-containing lipoproteins, HL may have pro- as well as anti-atherogenic effects. The anti- or pro-atherogenic role of HL is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. LDL-cholesterol levels), as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism.