Whole-exome sequencing detected a novel AIFM1 variant in a Han-Chinese family with Cowchock syndrome.

Charcot-Marie-Tooth disease(CMT) is a hereditary peripheral neuropathy, characterized by progressive distal hypoesthesia and amyotrophia. CMT is characterized by an X- linked recessive inheritance pattern. The apoptosis-inducing factor mitochondria associated-1 (AIFM1) is the main pathogenic gene of the X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4), also known as Cowchock syndrome. In this study, we enrolled a family with CMTX from the southeast region of China and identified a novel AIFM1 variant (NM_004208.3: c.931C>G; p.L311V) using whole exon sequencing technology. The results of our study may also be useful for genetic counseling, embryo screening of in vitro fertilization embryos, and prenatal genetic diagnosis.

Time and Influencing Factors to Chronic Subdural Hematoma Resolution After Middle Meningeal Artery Embolization.

OBJECTIVE: We sought to describe the resolution time of chronic subdural hematoma (CSDH) after middle meningeal artery embolization (MMAE) and potential variables that may affect hematoma resolution. METHODS: A retrospective analysis was performed on CSDH patients between December 2018 and December 2021. Patient characteristics, radiologic manifestations, and data of hematoma resolution were recorded. Univariate and multivariate analyses were conducted to identify predictors of CSDH resolution time. RESULTS: A total of 53 patients were enrolled including 53 hematomas. Only 1 participant relapsed and did not require surgical evacuation. Hematoma resolution was observed in 27 (50.9%) at 4 months and 48 (90.6%) cases at the last radiologic follow-up. The median MMAE-to-resolution time was 19 weeks (interquartile range: 8-24). The burr-hole irrigation + MMAE group showed faster hematoma resolution than MMAE alone during early follow-up periods, but no significant difference was found at 6 months. Increased thickness of residual hematoma, excessive postoperative midline shift, high-density hematoma, mixed-density hematoma, separated hematoma, and anticoagulant or antiplatelet agents used were predictive of nonresolution at 4 months as determined by univariate analysis, whereas anticoagulant or antiplatelet agents used and high-density hematoma were not significant on multivariate analysis. No significant association was noted between hematoma resolution and comorbidities or other hematoma radiologic features. CONCLUSIONS: MMAE is an effective and minimally invasive treatment for CSDH with a lower recurrence rate. The median resolution time of CSDH following MMAE was 19 weeks (interquartile range: 8-24). Burr-hole irrigation contributed to early hematoma resolution but had no significant effect at 6 months. In addition, residual hematoma thickness, postoperative midline shift, and specific type of hematoma were associated with delayed hematoma resolution at 4 months.

Identification of immune-related features involved in Duchenne muscular dystrophy: A bidirectional transcriptome and proteome-driven analysis.

Background: We aimed to investigate the biological mechanism and feature genes of Duchenne muscular dystrophy (DMD) by multi-omics and experimental verification strategy. Methods: We integrated the transcriptomic and proteomic methods to find the differentially expressed mRNAs (DEMs) and proteins (DEPs) between DMD and Control groups. Weighted gene co-expression network analysis (WGCNA) was then used to identify modules of highly correlated genes and hub genes. In the following steps, the immune and stromal cells infiltrations were accomplished by xCELL algorithm. Furthermore, TF and miRNA prediction were performed with Networkanalyst. ELISA, western blot and external datasets were performed to verify the key proteins/mRNAs in DMD patient and mouse. Finally, a nomogram model was established based on the potential biomarkers. Results: 4515 DEMs and 56 DEPs were obtained from the transcriptomic and proteomic study respectively. 14 common genes were identified, which is enriched in muscle contraction and inflammation-related pathways. Meanwhile, we observed 33 significant differences in the infiltration of cells in DMD. Afterwards, a total of 22 miRNAs and 23 TF genes interacted with the common genes, including TFAP2C, MAX, MYC, NFKB1, RELA, hsa-miR-1255a, hsa-miR-130a, hsa-miR-130b, hsa-miR-152, and hsa-miR-17. In addition, three genes (ATP6AP2, CTSS, and VIM) showed excellent diagnostic performance on discriminating DMD in GSE1004, GSE3307, GSE6011 and GSE38417 datasets (all AUC > 0.8), which is validated in patients (10 DMD vs. 10 controls), DMD with exon 55 mutations, mdx mouse, and nomogram model. Conclusion: Taken together, ATP6AP2, CTSS, and VIM play important roles in the inflammatory response in DMD, which may serve as diagnostic biomarkers and therapeutic targets.

Case report: A novel APTX p.Ser168GlufsTer19 mutation in a Chinese family with ataxia with oculomotor apraxia type 1.

Ataxia with oculomotor apraxia type 1 (AOA1) is a rare genetic disorder and is inherited in an autosomal recessive manner. It is mainly characterized by childhood-onset progressive cerebellar ataxia, with dysarthria and gait disturbance being the two most common and typical manifestations. Axonal sensorimotor peripheral neuropathy, dystonia, chorea, and cognitive impairment are common associated symptoms, as are hypoalbuminemia and hypercholesterolemia. Oculomotor apraxia (OMA)has been reported to be a feature often, although not exclusively, associated with AOA1. The Aprataxin gene, APTX, is ubiquitously expressed, and numerous APTX mutations are associated with different clinical phenotypes have been found. In the present study, we enrolled a 14-year-old boy who developed ataxia with staggering gait from the age of 4 years. Early-onset cerebellar ataxia, peripheral axonal neuropathy, cognitive impairment and hypoalbuminemia, hypercholesterolemia were presented in this patient, except for OMA. We applied ataxia-related genes filtering strategies and whole-exome sequencing (WES) to discover the genetic factors in a Chinese family. Sanger sequencing was used in the co segregation analysis in the family members. A compound heterozygous mutation in APTX gene (c.739C>T and c.501dupG) was identified. This is the first description of a genetically confirmed patient of AOA1 in a Chinese family in addition to a novel mutation of c.501dupG in APTX.

Whole-Exome Sequencing Identified a Novel Homozygous Frameshift Mutation of HPS3 in a Consanguineous Family with Hermansky-Pudlak Syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder with an autosomal recessive inherited pattern. It is mainly characterized by deficiencies in lysosome-related organelles, such as melanosomes and platelet-dense granules, and leads to albinism, visual impairment, nystagmus, and bleeding diathesis. A small number of patients will present with granulomatous colitis or fatal pulmonary fibrosis. At present, mutations in ten known genetic loci (HPS1-11) have been identified to be the genetic cause of HPS. In this study, we enrolled a consanguineous family who presented with typical HPS phenotypes, such as albinism, visual impairment, nystagmus, and bleeding diathesis. Whole-exome sequencing and Sanger sequencing were applied to explore the genetic lesions of the patient. A novel homozygous frameshift mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 was identified and cosegregated in the family members. Furthermore, real-time PCR confirmed that the mutation decreased the expression of HPS3, which has been identified as the disease-causing gene of HPS type 3. According to ACMG guidelines, the novel mutation, resulting in a premature stop codon at amino acid 442, is a pathogenic variant. In summary, we identified a novel mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 in a family with HPS. Our study expanded the variant spectrum of the HPS3 gene and contributed to genetic counseling and prenatal genetic diagnosis of the family.

Microglial TREM2 Mitigates Inflammatory Responses and Neuronal Apoptosis in Angiotensin II-Induced Hypertension in Middle-Aged Mice.

Growing evidence suggests that hypertension and aging are prominent risk factors for the development of late-onset Alzheimer's disease (LOAD) by inducement of neuroinflammation. Recent study showed that neuroinflammation via activated microglia induces reactive astrocytes, termed A1 astrocytes, that highly upregulate numerous classical complement cascade genes that are destructive to neurons in neurodegeneration diseases. Moreover, triggering receptor expressed on myeloid cells 2 (TREM2) is considered as one of the strongest single-allele genetic risk factors and plays important roles in neuroinflammation for LOAD. However, the mechanisms of microglia in the regulation of A1 astrocytic activation are still not clear. We introduced angiotensin II-induced hypertension in middle-aged mice and found that hypertension-upregulated TREM2 expression and A1 astrocytic activation were involved in neuroinflammation in the animal models used in this study. The in vitro results revealed that overexpression of microglial TREM2 not only mitigated microglial inflammatory response but also had salutary effects on reverse A1 astrocytic activation and neuronal toxicity.

Incidental Unruptured Intracranial Aneurysms Do Not Impact Outcome in Patients With Acute Cerebral Infarction.

Background: This study was to examine the patients with acute cerebral infarction (ACI) treated at a single center over 9 years and who underwent Unruptured intracranial aneurysm (UIA) screening by three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA), and to explore the factors associated with outcomes. Methods: The outcome was the modified Rankin scale (mRS) score at 90 days after stroke onset. The outcome was classified into a good outcome (mRS score of 0-2 points) and poor outcome (mRS score of 3-6 points). Results: UIAs were found in 260 (6.5%) of 4,033 patients with ACI; 2,543 (63.1%) had a good outcome, and 1,490 (36.9%) had a poor outcome. There was no difference in outcomes between the two groups (P = 0.785). The multivariable analysis showed that age (OR = 1.009, 95%CI: 1.003-1.014, P = 0.003), diabetes (OR = 1.179, 95%CI: 1.035-1.342, P = 0.013), ischemic stroke history (OR = 1.451, 95%CI: 1.256-1.677, P < 0.001), and baseline NIHSS score (OR = 1.034, 95%CI: 1.018-1.050, P < 0.001) were independently associated with the 90-day outcomes in patients with ACI. The presence of incidental UIA was not associated with outcomes after ACI. Conclusions: Age, diabetes, ischemic stroke history, and baseline NIHSS score were independently associated with the early outcomes of patients with ACI.

Restored microRNA-326-5p Inhibits Neuronal Apoptosis and Attenuates Mitochondrial Damage via Suppressing STAT3 in Cerebral Ischemia/Reperfusion Injury.

Studies have greatly explored the role of microRNAs (miRNAs) in cerebral ischemia/reperfusion injury (CI/RI). But the specific mechanism of miR-326-5p in CI/RI is still elusive. Hence, this study was to unmask the mechanism of miR-326-5p/signal transducer and activator of transcription-3 (STAT3) axis in CI/RI. Two models (oxygen and glucose deprivation [OGD] in primary rat cortical neurons and middle cerebral artery occlusion [MCAO] in Sprague-Dawley rats) were established to mimic CI/RI in vitro and in vivo, respectively. Loss- and gain-of function assays were performed with OGD-treated neurons and with MCAO rats. Afterward, viability, apoptosis, oxidative stress and mitochondrial membrane potential in OGD-treated neurons were tested, as well as pathological changes, apoptosis and mitochondrial membrane potential in brain tissues of MCAO rats. Mitofusin-2 (Mfn2), miR-326-5p and STAT3 expression in OGD-treated neurons and in brain tissues of MCAO rats were detected. Mfn2 and miR-326-5p were reduced, and STAT3 was elevated in OGD-treated neurons and brain tissues of MCAO rats. miR-326-5p targeted and negatively regulated STAT3 expression. Restoring miR-326-5p or reducing STAT3 reinforced viability, inhibited apoptosis and oxidative stress, increased mitochondrial membrane potential and increased Mfn2 expression in OGD-treated neurons. Up-regulating miR-326-5p or down-regulating STAT3 relieved pathological changes, inhibited apoptosis and elevated mitochondrial membrane potential and Mfn2 expression in brain tissues of rats with MCAO. This study elucidates that up-regulated miR-326-5p or down-regulated STAT3 protects against CI/RI by elevating Mfn2 expression.

Acute in-hospital blood pressure variability predicts early neurological deterioration in acute minor stroke or transient ischemic attack with steno-occlusive arterial disease.

It is generally known that acute minor stroke and transient ischemic attack (TIA) seem to be benign. However, their occurrence in patients with steno-occlusive arterial disease may result in early neurological deterioration (END). We aimed to elucidate the effect of blood pressure variability (BPV) on the development of END. Consecutive acute minor stroke and TIA patients within 24 hours of onset were prospectively recruited from the Affiliated Hospital of Yangzhou University between Aug 2015 and Feb 2019. END was defined as an NIHSS score increased ≥1 during the first 72 hours compared with the initial NIHSS score. During this period, the mean, maximum (max), the difference between the maximum and minimum (max-min), the SD, and coefficient of variation of BP (BPCV ) were calculated. Of the 160 total patients enrolled in the study (mean age, 68.01 ± 9.33 years; 50.6% female), 52 (32.5%) patients occurred END during the first 72h after admission. To express the BPV as a categorical variable, we classified the subjects into one of four groups, representing four quartiles of BPV. In the multivariable analyses, the lowest quartiles were considered as reference groups. The results showed that patients who fell in the fourth quartile (SBPmax-min :OR = 3.289, 95% CI 1.147-9.430; SBPSD :OR = 3.313, 95% CI 1.041-10.547; SBPCV :OR = 3.425, 95% CI 1.164-10.077; DBPSD :OR = 3.124, 95% CI 1.065-9.158) had a significantly higher risk of END after adjusting the variables (age, female, diabetes mellitus, atrial fibrillation, and CRP with P values <.1 in univariate analyses). Our study demonstrated that the acute in-hospital BPV was associated with the development of END in acute minor stroke and TIA with steno-occlusive arterial disease.

Relationship between high-sensitivity C-reactive protein and early neurological deterioration in stroke patients with and without atrial fibrillation.

BACKGROUND AND PURPOSE: The association of high-sensitivity C-reactive protein (hsCRP) with early neurological deterioration (END) is unclear, especially in stroke patients with atrial fibrillation (AF). In this study, we aimed to assess the association of baseline hsCRP levels with END in acute ischemic stroke with and without AF. METHODS: Consecutive acute ischemic stroke patients prospectively recruited from the Affiliated Hospital of Yangzhou University were analyzed and divided into two groups: AF related stroke (AF-S) and non-AF related stroke (Non-AF-S) groups. Plasma hsCRP levels on admission were categorized into three risk groups: low (<1.0 mg/L), average (1-3 mg/L) and high (>3 mg/L). RESULTS: A total of 655 consecutive patients diagnosed acute ischemic stroke were prospectively registered from our department in 2015-2018, which included 168 AF-S and 487 Non-AF-S cases. After standard therapy, 62 AF-S and 155 Non-AF-S cases developed END within 72 h of hospitalization. In AF-S cases, statistical differences between END and Non-END patients were found in age, gender, baseline National Institute of Health Stroke Scale (NIHSS) score, fasting blood glucose, responsible artery occlusion, CHA2DS2-VASc score and hsCRP level (p < 0.05). When variates showing p ≤ 0.1 in univariate analysis were adjusted, logistics regression analysis revealed following indexes as independent risk factors for END in AF-S patients: female (OR = 2.396, 95%CI:1.062-5.405, P = 0.035), fasting blood glucose (OR = 1.192, 95%CI:1.026-1.385, P = 0.022), responsible artery occlusion (OR = 3.589, 95%CI 1.425-9.036, P = 0.007), and high risk hsCRP (OR = 2.780, 95%CI 1.067-7.240, P = 0.036). In the Non-AF group, any level of hsCRP was not independently related to END after adjustment for age, sex, diabetes mellitus, smoking, baseline NIHSS, lesion size and responsible artery occlusion. CONCLUSION: High hsCRP level was independently correlated with END in patients with AF-S.

Pterostilbene reduces endothelial cell injury in vascular arterial walls by regulating the Nrf2-mediated AMPK/STAT3 pathway in an atherosclerosis rat model.

Endothelial cell injury in vascular arterial walls is a hallmark of atherosclerosis. Pterostilbene (Pts) has been shown to have an anti-oxidative and anti-apoptotic effect in numerous diseases via regulation of intracellular metabolism. The purpose of this study was to investigate the protective effect and possible mechanism of Pts against endothelial cell apoptosis in an atherosclerotic rat model. An atherosclerotic rat model was established using a high-fat, high glucose and high cholesterol diet. The effects of Pts on apoptosis and oxidative stress injury were measured using atherosclerotic lesion analysis, western blot analysis, hematoxylin and eosin straining, TUNEL assay and immunohistochemistry. In vivo results in an atherosclerosis rat model showed that Pts administration decreased the inflammatory response. Pts administration attenuated atherogenesis, reduced aortic plaque size, reduced macrophage infiltration, and suppressed oxidative stress and apoptosis of vascular arterial walls. In vitro assays using cultured human endothelial cells showed that Pts administration decreased hydrogen peroxide-induced cytotoxicity, oxidative stress injury and apoptosis via nuclear factor erythroid 2-related factor 2 (Nrf2) activation in endothelial cells. Additionally, Pts administration increased the expression level of Nrf2 and 5' adenosine monophosphate-activated protein kinase (AMPK), and the phosphorylation level of AMPK and decreased signal transducer and activator of transcription 3 (STAT3) expression in these cells. Furthermore, knockdown of Nrf2 prevented Pts-decrease oxidative stress injury and apoptosis. In conclusion, these data suggest that Pts can protect endothelial cells in the vascular arterial walls against atherosclerosis-induced injury through regulation of the Nrf2-mediated AMPK/STAT3 pathway.

Investigation of Nonmotor Symptoms in First-Degree Relatives of Patients with Different Clinical Types of Parkinson's Disease.

BACKGROUND: Nonmotor symptoms (NMS) are prodromal characteristics of Parkinson's disease (PD). The first-degree relatives (FDR) of PD patients had a higher risk of PD and also had more NMS. OBJECTIVE: To delineate NMS in FDR of patients with different clinical types of PD. METHODS: A total of 98 PD probands were recruited; 256 siblings of them were enrolled in the FDR group. Various scales were used to assess NMS, including depression, anxiety, cognitive impairment, insomnia, constipation, excessive daytime sleepiness, rapid eye movement sleep behavior disorder (RBD), and restless legs syndrome (RLS). The incidences of NMS were further compared between the FDR groups of PD with different types. RESULTS: The FDR of early-onset PD (EOP) showed a higher incidence of moderate to severe depression (OR = 4.08; 95% CI: 1.12-14.92; P=0.033), anxiety (OR = 4.22; 95% CI: 1.87-9.52; P=0.001), and excessive daytime sleepiness (OR = 3.40; 95% CI: 1.00-11.48; P=0.049) than the FDR of late-onset PD (LOP). It was also found that RBD (OR = 11.65; 95% CI: 3.82-35.54; P < 0.001), constipation (OR = 4.94; 95% CI: 1.85-13.21; P=0.001), sleep disorders (OR = 4.51; 95% CI: 1.73-11.78; P=0.002), cognitive impairment (OR = 3.55; 95% CI: 1.62-7.77; P=0.002), and anxiety (OR = 2.49; 95% CI: 1.32-4.71; P=0.005) were more frequent in FDR of tremor-dominant PD (TDP) than in FDR of non-tremor-dominant PD (NTDP). CONCLUSIONS: The siblings of patients with EOP and TDP have more NMS, presuming that they have a higher risk in the PD prodromal stage. Whether they have a greater possibility to progress into PD requires further investigation.

Effect of blood pressure variability on early neurological deterioration in single small subcortical infarction with parental arterial disease.

BACKGROUND AND PURPOSE: Early neurological deterioration (END) is not uncommon in acute single small subcortical infarct (SSSI), especially in those with parental arterial disease (PAD). The purpose of this study was to elucidate the effect of BP variability on the development of END as well as functional outcome at 90 days in SSSI and to determine whether the effect is linked to the status of parent artery. METHODS: Consecutive patients with acute SSSI were prospectively recruited from the First People's Hospital of Yangzhou between Aug 2013 and Jul 2016. END was defined as an NIHSS score increased ≥ 2 during the first 72 h compared with the initial NIHSS score. Functional outcome at 90 days after onset was assessed using the modified Rankin Score (mRS) and dichotomized as good (0-2) and poor (≥ 3). During this period, the parameters of BP variability such as BPmax-min, BPSD, and BPCV (equal to [SD × 100] / mean) were calculated. RESULTS: A total of 296 patients were included in the analysis. Of these, 30 (38.5%) SSSI associated with PAD and 53 (24.3%) without developed END respectively. Logistic regression analysis demonstrated that SBPmax (OR 1.036, 95% CI 1.005-1.069), SBPSD (OR 1.177, 95% CI 1.021-1.356), SBPcv (OR 1.306, 95% CI 1.049-1.626), DBPmax (OR 1.141, 95% CI 1.042-1.250), DBPmax-min (OR 1.085, 95% CI 1.015-1.160), DBPSD (OR 1.369, 95% CI 1.032-1.816), and DBPCV (OR 1.281, 95% CI 1.028-1.597) were all the independent predictors of END after acute SSSI associated with PAD. However, for those without PAD, none of the BP parameters was found significantly associated with END. Also, BP parameters were not related to the poor outcome at 90 days after onset. CONCLUSIONS: Our study demonstrated that the acute in-hospital BP variability was associated with the development of END in patients with acute SSSI. However, its impact varies depending on the status of parent artery.

Lesion patterns of single small subcortical infarct and its association with early neurological deterioration.

Early neurological deterioration (END), happening in the acute phase of infarct, is not rare in patients with single small subcortical infarction (SSSI). The aim of this study was to investigate the lesion patterns of SSSI and its association with END as well as functional outcome at 90 days after onset. 227 patients with acute SSSI in the perforator territory of MCA were prospectively recruited from Yangzhou No.1 People's Hospital between May 2010 and Jan 2014 and divided into proximal SSSI (pSSSI) and distal SSSI (dSSSI) according to the lesion patterns. END was defined as a change in National Institutes of Health Stroke Scale score ≥2 points in the first 72 h after admission. Functional outcome at 90 days after onset was assessed using the modified Rankin Score (mRS) and dichotomized as good (0-2) and poor (≥3). Of them, 93 (40.97%) patients had pSSSI and 134 (59.03%) patients had dSSSI. Univariate analysis found that the risk factors profiles differ significantly between patients with pSSSI and those with dSSSI (P < 0.05). During hospitalization, 60 (26.43%) patients experienced END during the first 72 h after admission, and 46 (22.01%) patients had poor outcome at 90 days after onset. After adjusting for potential confounders, pSSSI pattern (OR 2.242, 95% CI 1.165-4.313, P = 0.016) was an independent predictor of END and that the END (OR 2.637, 95% CI 1.208-5.759, P = 0.015) independently predicted the poor outcome at 90 days after onset. The pSSSI patterns might predict END for patients with SSSI in the MCA perforating territory.