Dihydroisotanshinone I and BMAL-SIRT1 Pathway in an In Vitro 6-OHDA-Induced Model of Parkinson's Disease.

Danshen has been widely used for the treatment of central nervous system diseases. We investigated the effect of dihydroisotanshinone I (DT), a compound extracted from Danshen, as well as the corresponding mechanisms in an in vitro-based 6-OHDA-induced Parkinson's disease (PD) model. SH-SY5Y human neuroblastoma cell lines were pretreated with 6-hydroxydopamine (6-OHDA) and challenged with DT. Subsequently, the cell viability and levels of reactive oxygen species (ROS) and caspase-3 were analyzed. The effect of DT on the 6-OHDA-treated SH-SY5Y cells and the expression of the core circadian clock genes were measured using a real-time quantitative polymerase chain reaction. Our results indicated that DT attenuated the 6-OHDA-induced cell death in the SH-SY5Y cells and suppressed ROS and caspase-3. Moreover, DT reversed both the RNA and protein levels of BMAL1 and SIRT1 in the 6-OHDA-treated SH-SY5Y cells. Additionally, the SIRT1 inhibitor attenuated the effect of DT on BMAL1 and reduced the cell viability. The DT and SIRT1 activators activated SIRT1 and BMAL1, and then reduced the death of the SH-SY5Y cells damaged by 6-OHDA. SIRT1 silencing was enhanced by DT and resulted in a BMAL1 downregulation and a reduction in cell viability. In conclusion, our investigation suggested that DT reduces cell apoptosis, including an antioxidative effect due to a reduction in ROS, and regulates the circadian genes by enhancing SIRT1 and suppressing BMAL1. DT may possess novel therapeutic potential for PD in the future, but further in vivo studies are still needed.

The impact of SARS-CoV-2 on neuromuscular disorders.

The emergence of SARS-CoV-2 has profoundly impacted global society and various aspects of human life. While the pandemic has resulted in disruptions and challenges, it has also accelerated scientific research on viruses and immunology, leading to remarkable progress in vaccine technology and immunization strategies. This review examines the impact of SARS-CoV-2 on pre-existing neuromuscular disorders, and neuromuscular events following SARS-CoV-2 infection, including immune-mediated and critical illness status-related disorders. Furthermore, the review discusses the relationship between SARSCoV- 2 vaccination and neuromuscular complications. The findings highlight the need for further research and understanding to improve patient outcomes. Keywords: SARS-CoV-2, neuromuscular diseases, vaccine.

Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood. CASE PRESENTATION: A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder. CONCLUSIONS: The increase of ß-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.

The significance of myositis autoantibodies in idiopathic inflammatory myopathy concomitant with interstitial lung disease.

AIM: This study identified factors associated with interstitial lung disease (ILD) in patients with idiopathic inflammatory myopathy (IIM) based on the latest classification and recent advances in autoantibody serology. METHODS: We retrospectively analyzed data of 173 patients who underwent complete myositis autoantibody serology examination in a medical center in Taiwan from July 2018 to February 2020. After exclusion of patients who did not receive a final diagnosis of IIM, clinical features, serology data, concomitant diseases, treatment, presence of respiratory failure, and mortality rate of the remaining 97 patients were analyzed. RESULTS: Of IIM patients in our cohort, 47.4% had ILD. ILD was significantly associated with subtypes of IIM, older age of onset, presence of mechanic's hand, and presence of anti-Jo-1 and anti-Ro52 antibodies. Among five IIM subtypes, overlap myositis (OM) and dermatomyositis (DM) were significantly associated with a higher prevalence rate of ILD (67.5% in OM and 53.3% in DM). Among patients with OM, the presence of anti-Jo-1 (100%), anti-PL-7 (100%), and anti-EJ antibodies (77.8%) was most significantly associated with ILD. CONCLUSION: The latest classification of IIM, older age of onset, presence of mechanic's hand, and presence of anti-Jo-1 and anti-Ro52 antibodies were significantly associated with ILD. Among five IIM subtypes, OM and DM had higher prevalence rate of ILD. Among OM patients, the presence of anti-Jo-1, anti-EJ, and anti-PL-7 antibodies was significantly associated with ILD. The study results may help physicians to timely screen and monitor pulmonary function in high-risk groups.

The first two cases of neurotoxocariasis in Taiwan.

Toxocariasis is a zoonosis disease with high sero-prevalence in Southeast Asian. Neurotoxocariasis has never been reported in Taiwan. Herein, we presented 2 cases of neurotoxocariasis. The first case is a 48-year-old man with febrile headache, rapid progressive cognitive problems and later thoracic myelitis. Meningeal enhancements on the corresponding sites were found on magnetic resonance imaging (MRI). Eosinophilic pleocytosis was present in peripheral blood and cerebrospinal fluid (CSF). A positive Toxocara canis larval excretory-secretory antigen (TcES)-based immunoblotting test for CSF confirmed the diagnosis. The second case is a 42-year-old woman of progressive headache with features of increased intracranial pressure. CSF analysis showed lymphocytic pleocytosis initially and eosinophilic pleocytosis later. Her brain MRI was normal. The diagnosis was confirmed by the presence of anti-TcES IgG in CSF. The two cases were soonly cured by mebendazole. Neurotoxocariasis presented a broad spectrum of neurological symptoms and the CSF profile can be non-eosinophilic pleocytosis. The prevalence of neurotoxocariasis may be seriously underestimated due to low awareness of physicians and lack of standard conventional diagnostic test in Taiwan. The two cases of neurotoxocariasis firstly reported in Taiwan will raise physician's awareness in recognizing this curable disease particularly in managing patients with aseptic meningitis or meningoencephalitis of undetermined pathogen.

Cerebral Venous Thrombosis Mimicking Acute Ischemic Stroke in the Emergency Assessment of Thrombolysis Eligibility: Learning from a Misdiagnosed Case.

PURPOSE: Cerebral venous thrombosis (CVT) occasionally presents with acute focal neurologic signs, mimicking arterial stroke syndrome. Diagnosing CVT in the setting of thrombolysis eligibility evaluation is challenging. We reported this case to discuss the promptly recognizing CVT in the setting of thrombolysis eligibility evaluation, and review the literature of thrombolytic therapy in CVT patients. CASE REPORT: A 57-year-old man presented with acute-onset right upper extremity monoparesis, right facial palsy, and aphasia. He underwent emergent thrombolysis with recombinant tissue plasminogen activator according to American Stroke Association guidelines. Subsequently, CVT was identified on multiphase computed tomography (CT) angiography. His symptoms initially improved but subsequently deteriorated because of intracranial hemorrhage. Cryoprecipitate and tranexamic acid were immediately administered. Anticoagulation was started 24 hours after the onset of hemorrhage. His modified Rankin Scale score was 4 at 120 days after the hemorrhage. CONCLUSION: Patients with CVT have a higher risk of thrombolysis-related intracranial hemorrhage than other stroke mimics. A greater focus on noncontrast brain CT and the venous phase of CT angiography help identifying this stroke mimic before thrombolysis.

Smoking Paradox in Stroke Survivors?: Uncovering the Truth by Interpreting 2 Sets of Data.

Background and Purpose- The observation that smokers with stroke could have better outcome than nonsmokers led to the term "smoking paradox." The controversy of such a complex claim has not been fully settled, even though different case mix was noted. Analyses were conducted on 2 independent data sets to evaluate and determine whether such a paradox truly exists. Methods- Taiwan Stroke Registry with 88 925 stroke cases, and MJ cohort with 541 047 adults participating in a medical screening program with 1630 stroke deaths developed during 15 years of follow-up (1994-2008). Primary outcome for stroke registry was functional independence at 3 months by modified Rankin Scale score ≤2, for individuals classified by National Institutes of Health Stroke Scale score at admission. For MJ cohort, mortality risk by smoking status or by stroke history was assessed by hazard ratio. Results- A >11-year age difference in stroke incidence was found between smokers and nonsmokers, with a median age of 60.2 years for current smokers and 71.6 years for nonsmokers. For smokers, favorable outcome in mortality and in functional assessment in 3 months with modified Rankin Scale score ≤2 stratified by the National Institutes of Health Stroke Scale score was present but disappeared when age and sex were matched. Smokers without stroke history had a ≈2-fold increase in stroke deaths (2.05 for ischemic stroke and 1.53 for hemorrhagic stroke) but smokers with stroke history, 7.83-fold increase, overshadowing smoking risk. Quitting smoking at earlier age reversed or improved outcome. Conclusions- "The more you smoke, the earlier you stroke, and the longer sufferings you have to cope." Smokers had 2-fold mortality from stroke but endured stroke disability 11 years longer. Quitting early reduced or reversed the harms.

Initial National Institute of Health Stroke Scale to Early Predict the Improvement of Swallowing in Patients with Acute Ischemic Stroke.

OBJECTIVES: To study the applicability of National Institutes of Health Stroke Scale (NIHSS) in early predicting the prognosis of poststroke dysphagia in an acute ward. METHODS: This is an observational retrospective cohort study including adult patients with ischemic stroke. Patients with various factors affecting swallowing were excluded to obtain a representative sample of 165 patients. The main outcome measure was the improvements of oral intake function. RESULTS: The scores of facial palsy (NIHSS item 4) (odds ratio [OR]: 0.484, 95% confidence interval [CI]: 0.279-0.838, P = .0096] and language/aphasia (NIHSS item 9) (OR: 0.562, 95% CI: 0.321-0.982, P = .0430) demonstrated significantly negative effects on the early improvement of dysphagia. Moreover, the improved patients had a 4.14-fold (95% CI: 2.53-11.23, P = .005) increased odds of returning home compared with nonimproved patients. CONCLUSIONS: Our findings provide evidence that early improvement of poststroke dysphagia was significantly associated with a favorable discharge destination and NIHSS items of facial palsy and language/aphasia can be used at the onset of stroke to identify dysphagic patients at risk of achieving limited improvement. These findings provide valuable prognostic indicators for clinicians to make a precise outcome prediction at very early stage.

Is traumatic brain injury a risk factor for neurodegeneration? A meta-analysis of population-based studies.

BACKGROUND: To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease. METHODS: All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta-analysis was performed by RevMan 5.3. RESULTS: There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47-2.55, p < 0.001), 4.44 (95% CI 3.86-5.10, p < 0.001), and 2.97 (95% CI 1.35-6.53, p < 0.001). However, analyses of individual diagnoses found no evidence that the risk of Alzheimer's disease, and Parkinson's disease in individuals with previous TBI compared to those without TBI. CONCLUSIONS: History of TBI is not associated with the development of subsequent neurodegeneration disease. Care must be taken in extrapolating from these results because no suitable criteria define post TBI neurodegenerative processes. Therefore, further research in this area is needed to confirm these questions and uncover the link between TBI and neurodegeneration disease.

Association of anti-Ro-52 antibodies with occurrence of interstitial lung disease in patients with idiopathic inflammatory myopathy.

BACKGROUND: Anti-Ro-52 antibodies have been associated with interstitial lung disease (ILD) in various autoimmune diseases. However, their role in ILD among patients with idiopathic inflammatory myopathies (IIMs) is relatively underexplored. This study aimed to investigate the association between anti-Ro-52 antibodies and the occurrence of ILD in individuals with IIMs. METHODS: This retrospective observational study included 604 patients who underwent myositis autoantibody testing between July 2018 and January 2021 at our hospital and were diagnosed with either IIMs or IIM-mimics. Comparative analyses were conducted between IIMs and IIM-mimics, as well as within the IIM group between cases with and without ILD. Logistic regression or Firth's logistic regression analyses were employed to assess the risk of ILD development in different IIM subgroups and myositis antibody categories. RESULTS: This study included 190 patients with IIM and 414 patients with IIM-mimics. Patients with IIM demonstrated higher incidence of ILD, concurrent autoimmune disease, and a greater likelihood of various myositis autoantibodies when compared to the IIM-mimics group. Within the IIM patient cohort, those with ILD exhibited a later age of onset of IIM, an increased mortality rate, and a more frequent presence of anti-aminoacyl-tRNA synthetase (ARS) antibodies compared to those without ILD. The presence of any myositis-specific antibody (MSA) was associated with a six-fold increased risk of ILD, while dual positivity for MSA and anti-Ro-52 antibodies conferred a twenty-fold risk. Anti-ARS antibodies carried a 14-fold increased risk of ILD, which escalated to 38-fold in cases of dual positivity for anti-ARS and anti-Ro-52 antibodies. Anti-Ro-52 antibodies alone increased the risk eight-fold. CONCLUSIONS: Among patients with IIM, the presence of ILD was linked to higher mortality. Certain autoantibodies, notably anti-ARS and anti-Ro-52 antibodies, were associated with an increased risk of ILD. The greatest risk of ILD was observed in cases of dual positivity for anti-ARS and anti-Ro-52 antibodies.

Simple coiling of middle meningeal artery embolization for chronic subdural hematoma: An inverse probability of treatment weighting matched cohort study.

BACKGROUND: Middle meningeal artery embolization (MMAE) for chronic subdural hematoma (CSDH) has gained much attention in recent years. However, unintended embolization may occur when employing liquid embolic agents or particles. We present our clinical experience in simple coiling of MMAE to manage CSDH. METHODS: Patients underwent either surgical evacuation or MMAE with simple coiling for CSDH were reviewed. Clinical and radiographic outcomes were assessed at admission, 1-month, and 6-month intervals. Two treatment groups were matched with inverse probability of treatment weighting. RESULTS: One hundred twelve patients were included, with 27 patients in MMAE group and 87 patients in surgery group. In MMAE group, significant reductions were observed in hematoma width (admission vs. 1-month, 2.04 [1.44-2.60] cm vs. 0.62 [0.37-0.95] cm, p < 0.001). The adjusted odds ratio (aOR) of surgical rescue rate (0.77 95%CI 0.13-4.47, p = 0.77), hematoma reduction (>50%) (0.21 95%CI 0.04-1.07, p = 0.06), and midline shift improvement rate (3.22, 95%CI 0.84-12.4, p = 0.09) had no substantial disparities between two groups at 1-month follow-up. In addition, no significant difference was noted between two groups in terms of hematoma reduction (>50%) at 6-month follow-up (aOR 1.09 95%CI 0.32-3.70, p = 0.89). No procedure-related complications were found in MMA embolization group. CONCLUSION: Simple coiling for MMA had comparable outcomes with surgical evacuation for CSDH. Our findings suggest that simple coiling can be an alternative choice for liquid agents or particles in MMA embolization for CSDH with acceptable safety.

Erinacine S, a small active component derived from Hericium erinaceus, protects oligodendrocytes and alleviates mood abnormalities in cuprizone-exposed rodents.

Hericium erinaceus mycelium extract (HEM), containing erinacine A (HeA) and erinacine S (HeS), has shown promise in promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs), crucial for myelin production in the central nervous system (CNS). The main aim of this study was to characterize the protective effects of HEM and its components on OLs and myelin in demyelinating rodents by exposure to cuprizone (CPZ), a copper chelating agent commonly used to induce demyelination in the corpus callosum of the brain. Rats were fed by CPZ-containing diet and simultaneously orally administered HEM, HeA, or HeS on a daily basis for three weeks. We found that HEM and HeS preserved myelin and OLs in the corpus callosum of CPZ-fed rats, along with reduced microglia and astrocyte activation, and downregulated IL-1ß expression. Furthermore, post-treatment with HeS, in mouse models with acute (6 weeks) or chronic (12 weeks) CPZ-induced demyelination demonstrated oral administration during the final 4 weeks (HeS4/6 or HeS4/12) effectively preserved myelin in the corpus callosum. Additionally, HeS4/6 and HeS4/12 inhibited anxious and depressive-like behaviors in CPZ-fed mice. In summary, simultaneous administration of HEM and HeS in rats during short-term CPZ intoxication preserved OLs and myelin. Furthermore, post-administration of HeS not only inhibited demyelination and gliosis but also alleviated anxiety and depression in both acute and chronic CPZ-fed mice. This study presents compelling evidence supporting the potential of HeS as a promising small active compound for protecting OLs and preserving myelin in demyelinating diseases associated with emotional disorders.

Endovascular treatment in bilateral cavernous sinus dural arteriovenous fistulas: a systematic review and meta-analysis.

Few studies have discussed the disease nature and treatment outcomes for bilateral cavernous sinus dural arteriovenous fistula (CSDAVF). This study aimed to investigate the clinical features and treatment outcomes of bilateral CSDAVF. Embase, Medline, and Cochrane library were searched for studies that specified the outcomes of bilateral CSDAVF from inception to April 2022. The classification, clinical presentation, angiographic feature, surgical approach, and treatment outcomes were collected. Meta-analysis was performed using the random effects model. Eight studies reporting 97 patients were included. The clinical presentation was mainly orbital (n = 80), cavernous (n = 52) and cerebral (n = 5) symptoms. The most approached surgical route was inferior petrosal sinus (n = 80), followed by superior orbital vein (n = 10), and alternative approach (n = 7). Clinical symptoms of 88% of the patients (95% CI 80-93%, I2 = 0%) were cured, and 82% (95% CI 70-90%, I2 = 7%) had angiographic complete obliteration of fistulas during follow up. The overall complication rate was 18% (95% CI 11-27%, I2 = 0%). Therefore, endovascular treatment is an effective treatment for bilateral CSDAVF regarding clinical or angiographic outcomes. However, detailed evaluation of preoperative images and comprehensive surgical planning of the approach route are mandatory owing to complexity of the lesions.

K⁺-Cl⁻ cotransport mediates the bactericidal activity of neutrophils by regulating NADPH oxidase activation.

Neutrophilic phagocytosis is an essential component of innate immunity. During phagocytosis, the generation of bactericidal hypochlorous acid(HOCl) requires the substrates, Cl− and superoxide produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to kill the internalized pathogens. Here we show that the neutrophilic K+­Cl− cotransporter (KCC) constitutes aCl− permeation pathway and mediates the bactericidal activity by regulating NADPH oxidase activation. Dihydroindenyloxy alkanoic acid (DIOA), a KCC inhibitor, suppressed the toxin- or chemical-induced efflux of 36Cl− or 86Rb+, and diminished the production of superoxide in human and murine neutrophils. Inhibition of KCC activity or knockdown of KCC expression, in particular KCC3, reduced the phosphorylation as well as the membrane recruitment of oxidase components. Activated neutrophils displayed a significant colocalization of KCC3 and early endosomal marker, indicating that KCC3 could be localized on the phagosomes once neutrophils are activated. The NADPH oxidase activity and the phosphorylation level of oxidase component were 50% lower in the neutrophils isolated from KCC3−/− mice than in the neutrophils isolated from KCC3+/+ mice.Mortality rate after intraperitoneal challenge with Staphylococcus aureus was higher in KCC3−/− mice, and the bacterial clearance was impaired in the survivors.We conclude that, in activated neutrophil, NADPH oxidase complexes are associated with KCC3 at the plasma membrane and are internalized to form phagosomes, where KCC activity and expression level affect the production of oxidants.

Muscle Biopsy: A Requirement for Precision Medicine in Adult-Onset Myopathy.

Muscle biopsy is a fundamental procedure to assist the final diagnosis of myopathy. With the recent advances in molecular diagnosis, serology tests, and mechanism-based classification in myopathy, the précised diagnosis for myopathy required the applications of multiple tools. This study intends to reappraise the benefit of muscle biopsy in adult-onset myopathy under the setting of an optimized muscle biopsy protocol and comprehensive serology tests. A one-group pretest-posttest study design was used. The pre- and post-biopsy diagnoses and treatments in 69 adult patients were compared. Muscle biopsy yielded 85.5% of definitive diagnoses, including changes in pre-biopsy diagnoses (40.6%) and narrowing down the suspicious myopathies (49.3%). The demographic data and clinical parameters between the group "with change" and "without change" after biopsy were not different. Among those with changes in diagnosis, 39.3% also had a corresponding shift in treatment, which benefits the patients significantly. Regarding the most common adult-onset myopathy, idiopathic inflammatory myopathy (IIM), 41% of patients with pre-biopsy diagnosis as IIM had changes in their IIM subtype diagnosis, and 53% was finally not IIM after muscle biopsy. Although there have been advances in molecular diagnosis recently, muscle biopsy still undoubtedly critically guided the diagnosis and treatment of adult-onset myopathy in the era of precision medicine.

Coexistence of Multiple Myositis-Specific Antibodies in Patients with Idiopathic Inflammatory Myopathies.

The mutual exclusivity of myositis-specific antibodies (MSAs) has been reported before, but the coexistence of 2 or more MSAs was still found in a few case reports. This study aims to confirm the existence and prevalence of double MSAs in patients with idiopathic inflammatory myopathy (IIM) and to clarify the clinical features of these patients. One hundred fifty-one patients with IIM diagnosed from 1 July 2018 to 31 July 2022, at National Cheng Kung University Hospital, Taiwan, were enrolled and divided into two groups, patients with ≤1 MSA (n = 128, 84.8%) and those with ≥2 MSAs (n = 23, 15.2%) according to the initial serology results. After being re-examined by ANA-IIF assay, 8 out of 23 patients were confirmed to have ≥2 MSAs. The demographic data and clinical features were presented. The prevalence of double-positive MSAs among IIM was 5.3% in this cohort. The coexistence of two MSAs in an IIM patient does exist but is rare. Patients with two MSAs belonging to two distinct IIM subtypes presented clinical features skewed to one subtype instead of "mixed phenotypes". No apparent difference in clinical severity was found between patients with ≥2 MSAs and ≤1 MSA. Longer follow-ups and more studies are required to characterize the patients of IIM with ≥2 MSAs.

Outcome of acute ischemic stroke in very elderly patients: is intravenous thrombolysis beneficial?

BACKGROUND/AIMS: Intravenous tissue plasminogen activator (tPA) treatment is recommended in acute stroke within 3 h of onset; however, the benefit of its use in the elderly remains uncertain. We assessed the safety and efficacy of tPA treatment in elderly patients. METHODS: We recruited 97 elderly Chinese patients aged ≥80 years with cerebral ischemia presenting within 3 h of onset. Favorable outcomes were defined as discharge to home and modified Rankin Scale (mRS) ≤2 at discharge. RESULTS: For moderate to severe patients (NIHSS ≥6), the baseline characteristics between the tPA (n = 30) and non-tPA (n = 41) group were not different. The proportion of patients discharged home was 56.7 and 61%, respectively (p = 0.72). For patients with baseline mRS ≤2, the frequency of discharged mRS ≤2 was not different (27.3% of the tPA group and 26.9% of the non-tPA group; p = 1.00). Symptomatic intracranial hemorrhage was 6.7 and 2.4%, respectively (p = 0.31). For minor stroke patients (NIHSS ≤5), tPA was not considered and the outcome of those discharged home and mRS ≤2 was 73 and 88%, respectively. CONCLUSION: Elderly patients can be treated safely with intravenous tPA, whereas our data did not support routine thrombolysis. Further randomized trials in the elderly are encouraged.

A Novel Pathogenic HSPG2 Mutation in Schwartz-Jampel Syndrome.

Schwartz-Jampel syndrome is a rare autosomal recessive disease caused by mutation in the heparan sulfate proteoglycan 2 (HSPG2) gene. Its cardinal symptoms are skeletal dysplasia and neuromuscular hyperactivity. Herein, we identified a new pathogenic mutation site (NM_005529.6:c.1125C>G; p.Cys375Trp) of HSPG2 leading to Schwartz-Jampel syndrome by whole-exome sequencing. This mutation carried by the asymptomatic parents was previously registered in a single-nucleotide polymorphism database of the National Institutes of Health as a coding sequence variant rs543805444. The pathogenic nature of this missense mutation was demonstrated by in silico pathogenicity assessment, clinical presentations, and cellular function of primary fibroblast derived from patients. Various in silico software applications predicted the mutation to be pathogenic [Sorting Intolerant From Tolerant (SIFT), 0; Polyphen-2, 1; CADD (Combined Annotation Dependent Depletion), 23.7; MutationTaster, 1; DANN (deleterious annotation of genetic variants using neural networks); 0.9]. Needle electromyography revealed extensive complex repetitive discharges and multiple polyphasic motor unit action potentials in axial and limb muscles at rest. Short exercise test for myotonia showed Fournier pattern I. At cellular levels, mutant primary fibroblasts had reduced levels of secreted perlecan and impaired migration ability but normal capability of proliferation. Patients with this mutation showed more neuromuscular instability and relatively mild skeletal abnormality comparing with previously reported cases.

Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy.

Aims: Diabetes-related cerebral microangiopathy can manifest as cerebral small vessel disease (CSVD) and exhibit cognitive decline. To find the early change of function in advance, this study examined the spatiotemporal dynamics of cerebral vascular permeability (Ktrans) in the progression of type 2 diabetes mellitus (T2DM). Methods: Ktrans was cross-sectionally measured in T2DM and non-diabetes groups with or without CSVD using dynamic contrast-enhanced MRI (DCE-MRI). Results: In all patients with T2DM, the Ktrans of white matter (WM) was increased, whereas the Ktrans of gray matter (GM) was increased only in T2DM with CSVD. The involvement of WM was earlier than GM and was before the CSVD features could be visualized on MRI. Among the commonly available four CSVD items of MRI, microbleeds were the most sensitive, indicating the increased permeability in all patients. Increased Ktrans in T2DM was more associated with moderate WM hyperintensity but less with the presence of lacunae or multiple perivascular spaces, in contrast to patients without diabetes. The differential correlation suggested distinct mechanisms underlying diabetes-related CSVD and other CSVDs. Conclusions: This study highlights the early development of cerebral microangiopathy with increased BBB leakage in T2DM, before the CSVD features can be visualized on MRI. The results may increase the proactivity of clinicians in recognizing the subsequent neurological comorbidities.

Hyperglycemia compromises the ischemia-provoked dedifferentiation of cerebral pericytes through p21-SOX2 signaling in high-fat diet-induced murine model.

AIM: Diabetes-related cerebral small vessel disease (CSVD) causes neurological deficits. Patients with diabetes showed pericyte loss as a hallmark of retinopathy. Cerebral pericytes, which densely localize around brain capillaries, are quiescent stem cells regulating regeneration of brain and may have a role in CSVD development. This study investigated whether diabetes impairs ischemia-provoked dedifferentiation of pericytes. METHODS: A murine high-fat diet (HFD)-induced diabetes model was used. After cerebral ischemia induction in the mice, pericytes were isolated and grown for a sphere formation assay. RESULTS: The sphere counts from the HFD group were lower than those in the chow group. As the spheres formed, pericyte marker levels decreased and SOX2 levels increased gradually in the chow group, but not in the HFD group. Before sphere formation, pericytes from the HFD group showed high p21 levels. The use of a p21 inhibitor rescued the reduction of sphere counts in the HFD group. At cellular level, hyperglycemia-induced ROS increased the level of p21 in cerebral pericytes. The p21-SOX2 signaling was then activated after oxygen-glucose deprivation. CONCLUSION: HFD-induced diabetes compromises the stemness of cerebral pericytes by altering p21-SOX2 signaling. These results provide evidence supporting the role of pericytes in diabetes-related CSVD and subsequent cerebral dysfunction.