Fahr's disease linked to a novel mutation in MYORG variants manifesting as paroxysmal limb stiffness and dysarthria: Case report and literature review.

BACKGROUND: Primary familial brain calcification (PFBC) is a rare hereditary neurodegenerative disorder associated with the MYORG gene; however, the clinical and radiological characteristics of MYORG-PFBC remain unclear. METHODS: We present relevant medical data obtained from a patient affected by PFBC with a novel MYORG variant and conducted a mutational analysis of MYORG in her family members. We reviewed all reported PFBC cases with biallelic MYORG mutations until April 1, 2023, and summarized the associated clinical and radiological features and mutation sites. RESULTS: The patient (22-year-old woman) exhibited paroxysmal limb stiffness and dysarthria for 3 years. Computed tomography revealed calcifications in the paraventricular white matter, basal ganglia, thalamus, and cerebellum. Whole-exome sequencing revealed a novel homozygous frameshift variant (c.743delG: p.G248Afs*32) in exon 2 of the MYORG gene (NM_020702.5). To date, 62 families and 64 mutation sites have been reported. Among the reported biallelic MYORG mutations, 57% were homozygous and 43% were compound heterozygous. Individuals with biallelic MYORG mutations experience more severe brain calcification with approximately 100% clinical penetrance. Ten single heterozygous mutation sites are associated with significant brain calcifications. CONCLUSION: All patients with primary brain calcification, particularly younger patients without a family history of the disease, should be screened for MYORG mutations.

Comparison of Various Ultrasound-Based Malignant Risk Stratification Systems on an Occasion for Assessing Thyroid Nodules in Hashimoto's Thyroiditis.

Purpose: To compare the diagnostic performance and unnecessary ultrasound-guided fine-needle aspiration (US-FNA) biopsy rate of the 2015 American Thyroid Association (ATA), 2016 Korean Society of Thyroid Radiology (KSThR), and 2017 American College of Radiology (ACR) guidelines for patients with and without Hashimoto's thyroiditis (HT). Patients and Methods: This retrospective study included 716 nodules from 696 consecutive patients, which were classified using the categories defined by the three guidelines: ATA, KSThR, and ACR. The malignancy risk in each category was calculated and the diagnostic performance and unnecessary fine-needle aspiration (FNA) rates of the three guidelines were compared. Results: In total, 426 malignant and 290 benign nodules were identified. Patients with malignant nodules had lower total thyroxine levels and higher thyroid-stimulating hormone, thyroid peroxidase antibody, and thyroglobulin antibody levels than those without malignant nodules (all P<0.01). The margin difference was significant in non-HT patients (P<0.01), but comparable in HT patients (P=0.55). The calculated malignancy risks of high and intermediate suspicion nodules in the ATA and KSThR guidelines and moderately suspicious nodules in the ACR guidelines were significantly lower in non-HT patients compared with HT patients (P<0.05). The ACR guidelines showed the lowest sensitivity, highest specificity, and lowest unnecessary FNA rates in patients with and without HT. Compared to non-HT patients, HT patients had significantly lower unnecessary FNA rates (P<0.01). Conclusion: HT was associated with a higher malignancy rate of thyroid nodules with intermediate suspicion according to the ATA, KSThR, and ACR guidelines. The three guidelines, especially ACR, were likely to be more effective and could allow a greater reduction in the percentage of benign nodules biopsied in patients with HT.

Long-term use of probiotics for the management of office and ambulatory blood pressure: A systematic review and meta-analysis of randomized, controlled trials.

Previous studies showed a controversial result on the relationship between probiotics treatment duration and blood pressure (BP). The present meta-analysis is performed to summarize the effects of long-term (≥8 weeks) use of probiotics on office and ambulatory BP using combined evidence from randomized, controlled trials. We searched PubMed, Embase, Cochrane library, and the ClinicalTrials.gov till January, 2021 to identify eligible articles. Primary outcomes were changes in office BP. In the presence of heterogeneity, a random-effects model was used to calculate the combined treatment effect. Begg's funnel plots and Egger's regression test were used to assess the publication bias. Meta-analysis of 26 trials in 1624 participants demonstrated that probiotic consumption significantly decreased office systolic BP by 2.18 mmHg (95% confidence interval [CI], -3.41 to -0.94 mmHg) and diastolic BP by 1.07 mmHg (95% CI, -1.72 to -0.41 mmHg). The analysis on ambulatory BP from three trials showed a similar reduction by -2.35/-1.61 mmHg (p ≤ .052). Subgroup analysis in hypertensive and diabetic patients showed a significant reduction in systolic and diastolic BP (p ≤ .02). The reductions in diabetic and hypertensive patients were comparatively larger than nondiabetic and normotensive patients (p ≥ .052). With the increase of age, baseline body mass index (BMI), treatment duration, and systolic BP, the effects of probiotics on BP did not increase significantly (p trend ≥ .18). The present meta-analysis suggests a beneficial effect of probiotics on BP by a modest degree, especially in the diabetes mellitus and hypertension. Prolonging the treatment duration could not improve the antihypertensive effect.

Hepatic nNOS impaired hepatic insulin sensitivity through the activation of p38 MAPK.

Neuronal nitric oxide synthase (nNOS) interacts with its adaptor protein NOS1AP through its PZD domain in the neurons. Previously, we had reported that NOS1AP enhanced hepatic insulin sensitivity through its PZD-binding domain, which suggested that nNOS might mediate the effect of NOS1AP. This study aimed to examine the role and underlying mechanisms of nNOS in regulating hepatic insulin sensitivity. nNOS co-localized with NOS1AP in mouse liver. The overexpression of NOS1AP in mouse liver decreased the level of phosphorylated nNOS (p-nNOS (Ser1417)), the active form of nNOS. Conversely, the liver-specific deletion of NOS1AP increased the level of p-nNOS (Ser1417). The overexpression of nNOS in the liver of high-fat diet-induced obese mice exacerbated glucose intolerance, enhanced intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRbeta and Akt in the liver. Similarly, nNOS overexpression increased triglyceride production, decreased glucose utilization, and downregulated insulin-induced expression of p-IRbeta, p-Akt, and p-GSK3beta in the HepG2 cells. In contrast, treatment with Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, improved glucose tolerance and upregulated insulin-induced phosphorylation of IRbeta and Akt in the liver of ob/ob mice. Furthermore, overexpression of nNOS increased p38MAPK phosphorylation in the HepG2 cells. In contrast, inhibition of p38MAPK with SB203580 significantly reversed the nNOS-induced inhibition of insulin-signaling activity (all P < 0.05). This indicated that hepatic nNOS inhibited the insulin-signaling pathway through the activation of p38MAPK. These findings suggest that nNOS is involved in the development of hepatic insulin resistance and that nNOS might be a potential therapeutic target for diabetes.

Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain.

BACKGROUND: NOS1AP is an adaptor protein and its SNP rs12742393 was associated with type 2 diabetes (T2D). However, it remains uncertain whether NOS1AP plays a role in regulation of insulin sensitivity. Hepatic insulin resistance contributed to the development of T2D. Here, our investigation was focused on whether NOS1AP is involved in the regulation of hepatic insulin sensitivity and its underlying mechanisms. METHODS: Liver specific NOS1AP condition knockout (CKO) and NOS1AP overexpression mice were generated and given a high fat diet. SNPs of NOS1AP gene were genotyped in 86 human subjects. FINDINGS: NOS1AP protein is expressed in human and mouse liver. CKO mice exhibited impaired pyruvate, glucose and insulin tolerance, and increased lipid deposits in the liver. Conversely, NOS1AP overexpression in livers of obese mice improved pyruvate and/or glucose, and insulin tolerance, and attenuated liver lipid accumulation. Moreover, hepatocytes from CKO mice exhibited an elevated glucose production and mRNA expressions of Pc and Pck1. Overexpression of NOS1AP potentiated insulin-stimulated activation of IR/Akt in livers from obese mice. The insulin sensitizing effect of NOS1AP could be mimicked by overexpression of C-terminal domain of NOS1AP in ob/ob mice. Furthermore, NOS1AP overexpression in liver significantly inhibited p38 MAPK phosphorylation, and maintained ER homeostasis through p-eIF2a-ATF4-CHOP pathway. Subjects with rsl2742393 of NOS1AP have higher risk to develop hepatic steatosis. INTERPRETATION: Our data demonstrate a novel role of NOS1AP in regulating hepatic insulin sensitivity and p38 MAPK inactivation in obese mice, which makes NOS1AP a potential therapeutic target for the prevention and treatment of T2D. FUND: This work was supported by the National Natural Science Foundation of China (81670707, 31340072) (to C. Wang), and National Basic Research Program of China (Nation 973 Program) (2011CB504001) (to W. Jia).

Human urine-derived stem cells play a novel role in the treatment of STZ-induced diabetic mice.

Human urine-derived stem cells (hUSCs) are a potential stem cell source for cell therapy. However, the effect of hUSCs on glucose metabolism regulation in type 1 diabetes was not clear. Therefore, the aim of the study was to evaluate whether hUSCs have protective effect on streptozotocin (STZ)-induced diabetes. hUSCs were extracted and cultivated with a special culture medium. Flow cytometry analysis was applied to detect cell surface markers. BALB/c male nude mice were either injected with high-dose STZ (HD-STZ) or multiple low-dose STZ (MLD-STZ). Serum and pancreatic insulin were measured, islet morphology and its vascularization were investigated. hUSCs highly expressed CD29, CD73, CD90 and CD146, and could differentiate into, at least, bone and fat in vitro. Transplantation of hUSCs into HD-STZ treated mice prolonged the median survival time and improved their blood glucose, and into those with MLD-STZ improved the glucose tolerance, islet morphology and increased the serum and pancreas insulin content. Furthermore, CD31 expression increased significantly in islets of BALB/c nude mice treated with hUSCs compared to those of un-transplanted MLD-STZ mice. hUSCs could improve the median survival time and glucose homeostasis in STZ-treated mice through promoting islet vascular regeneration and pancreatic beta-cell survival.

Impact of body fat percentage change on future diabetes in subjects with normal glucose tolerance.

The aim of the work was to determine the effect of body fat change on risk of diabetes in normal glucose tolerance (NGT) population. A total of 1,857 NGT subjects were included and followed up for an average period of 44.57 months. Body fat percentage (BF%) was measured by bioelectrical impedance analysis. Subjects were grouped based on the BF% and/or body mass index (BMI) state. Among all subjects, 28 developed diabetes after follow-up. Compared with subjects with stable normal BF% (control), subjects who became obesity at follow-up were defects in insulin secretion and had a higher risk of developing diabetes (7.102, 95% confidence intervals [CI] 1.740-28.993), while no difference in diabetic risk could be viewed between subjects with abnormal BF% at baseline but normal at the end of follow-up and control subjects after adjustment of confounding factors. Moreover, compared with those keeping normal BF% and BMI both at baseline and follow-up, subjects who had normal BMI at baseline and follow-up, but abnormal BF% at baseline or/and follow-up still had a higher risk to develop diabetes (4.790, 95% CI 1.061-21.621), while those with normal BF% at baseline and follow-up, but abnormal BMI at baseline or/and follow-up had not. Subjects from normal BF% at baseline to obese at follow-up are associated with an increased risk of diabetes. Maintaining normal body fat is more relevant than BMI in preventing diabetes. © 2017 IUBMB Life, 69(12):947-955, 2017.