Lysosomal dysfunction plays an important role in neurodegenerative diseases, including Parkinson’s disease (PD) and possibly Parkinson-plus syndromes such as progressive supranuclear palsy (PSP). This role is exemplified by the involvement of variants in the GBA1 gene, which results in a deficiency of the lysosomal enzyme glucocerebrosidase and is the most frequently identified genetic factor underlying PD worldwide. Pathogenic variants in the SMPD1 gene are a recessive cause of Niemann–Pick disease types A and B. Here, we provide the first report on an association between a loss-of-function variant in the SMPD1 gene present in a heterozygous state (p.Pro332Arg/p.P332R, which is known to result in reduced lysosomal acid sphingomyelinase activity), with PSP-Richardson syndrome in three unrelated patients of Chinese ancestry.

BACKGROUND/OBJECTIVES: Previous research has shown maternal betaine supplementation alleviates fetal-derived hepatic steatosis. Therefore, this study examined the anti-inflammatory effect of maternal betaine intake in offspring mice and its mechanism.MATERIALS/METHODS: Female C57BL/6J mice and their offspring were randomly divided into 3 groups according to the treatment received during gestation and lactation: control diet (CD), fatty liver disease (FLD), and fatty liver disease + 1% betaine (FLD-BET). The FLD group was given a high-fat diet and streptozotocin (HFD + STZ), and the FLD-BET group was treated with HFD + STZ + 1% betaine. After weaning, the offspring mice were given a normal diet for 5 weeks and then dissected to measure the relevant indexes. RESULTS: Compared to the CD group, the offspring mice in the FLD group revealed obvious hepatic steatosis and increased serum levels of alanine aminotransferase, interleukin (IL)-6, and tumor necrosis factor (TNF)-α; maternal betaine supplementation reversed these changes. The hepatic mRNA expression levels of IL-6, IL-18, and Caspase-1 were significantly higher in the FLD group than in the CD group. Maternal betaine supplementation reduced the expression of IL-1β, IL-6, IL-18, and apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain (ASC). Maternal betaine supplementation also reversed the increasing protein expressions of nitric oxide dioxygenase-like receptor family pyrin domain containing 3 (NLRP3), ASC, Caspase-1, IL-1β, and IL-18 in offspring mice exposed to HFD + STZ. Maternal betaine supplementation decreased the homocysteine (Hcy) and s-adenosine homocysteine (SAH) levels significantly in the livers. Furthermore, the hepatic Hcy concentrations showed significant inverse relationships with the mRNA expression of TNF-α, NLRP3, ASC, and IL-18. The hepatic SAH concentration was inversely associated with the IL-1β mRNA expression. CONCLUSIONS The lipotropic and anti-inflammatory effect of maternal betaine supplementation may be associated with the inhibition of NLRP3 inflammasome in the livers of the offspring mice.

Objective:To investigate the expression of INHBA in colorectal cancer and its relationship with microsatellite status and clinicopathological features.Methods:Bioinformatics analysis was conducted based on Gene Expression Omnibus (GEO) database and Gene Expression Profiling Interaction Analysis (GEPIA) database, and the differentially expressed prognosis-related target genes in colorectal cancer were selected. Wax mass tissues of 107 patients with colorectal cancer who underwent surgery from January 2016 to June 2022 in the Third Affiliated Hospital of Jinzhou Medical University were collected, and the tissue microarrays were prepared. The clinicopathological microsatellite status [positive expressions of the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2 were mismatch repair proficient (pMMR), which represented low microsatellite instability or microsatellite stabilization; if any of these indexes was negative, it was judged to be mismatch repair deficient (dMMR), which represented high microsatellite instability] and INHBA expression in colorectal cancer tissues were detected by immunohistochemistry, data of the patients were retrospectively analyzed. The relationship between INHBA and microsatellite status as well as clinicopathological features was analyzed.Results:Three data sets of colorectal cancer were selected from GEO database: GSE110223 (13 cancer tissues, 13 paracancerous tissues), GSE110224 (17 cancer tissues, 17 paracancerous tissues), GSE113513 (14 cancer tissues, 14 paracancerous tissues), and the top 50 genes that were differentially up-regulated and down-regulated between cancer tissues and paracancerous tissues were screened. Intersection genes of 3 data sets were analyzed by Venn diagram, and 12 up-regulated genes and 17 down-regulated genes were screened out. According to GEPIA database, AQP8, ZG16 and INHBA genes among the up-regulated and down-regulated differential genes were associated with the prognosis of colorectal cancer. INHBA was higher expressed in colorectal cancer tissues than in paracancerous tissues (≥5 cm from the tumor margin) ( P < 0.05), and INHBA gene was selected for analysis. Immunohistochemical detection of collected colorectal cancer wax samples showed that the proportion of patients with high INHBA expression in colorectal cancer tissues was higher than that in paracancerous tissues [85.05% (91/107) vs. 67.29% (72/107), P < 0.05]. The high expression of INHBA in cancer tissues was related to the lesion site [right colon vs. left colon: 94.00% (47/50) vs. 77.19% (44/57)], maximum tumor diameter [>5 cm vs. ≤5 cm: 92.73% (51/55) vs. 76.92% (40/52)] and the depth of invasion [stage T 3-4 vs. stage T 1-2: 96.43% (54/56) vs. 72.55% (37/51)], differentiation degree [low and medium differentiation vs. high differentiation: 91.04% (61/67) vs. 75.00% (30/40)], lymph node metastasis [yes vs. no: 93.02% (40/43) vs. 78.13% (50/64)] (all P < 0.05), but had no correlation with age, sex, thrombus and nerve invasion (all P > 0.05). The proportion of patients with high expression of INHBA in colorectal cancer tissues in pMMR group was higher than that in dMMR group [93.22% (55/59) vs. 75.00% (36/48), χ2 = 6.91, P = 0.008]. Conclusions:INHBA is highly expressed in colorectal cancer tissues, and the highly expressed INHBA is closely related to clinicopathological features and microsatellite status of colorectal cancer. INBHA may be a new target for diagnosis, treatment and prognosis of colorectal cancer.

Purpose: Varicocele is a common problem among infertile men. Varicocele repair (VR) is frequently performed to improve semen parameters and the chances of pregnancy. However, there is a lack of consensus about the diagnosis, indications for VR and its outcomes. The aim of this study was to explore global practice patterns on the management of varicocele in the context of male infertility. Materials and Methods: Sixty practicing urologists/andrologists from 23 countries contributed 382 multiple-choice-questions pertaining to varicocele management. These were condensed into an online questionnaire that was forwarded to clinicians involved in male infertility management through direct invitation. The results were analyzed for disagreement and agreement in practice patterns and, compared with the latest guidelines of international professional societies (American Urological Association [AUA], American Society for Reproductive Medicine [ASRM], and European Association of Urology [EAU]), and with evidence emerging from recent systematic reviews and meta-analyses. Additionally, an expert opinion on each topic was provided based on the consensus of 16 experts in the field. Results: The questionnaire was answered by 574 clinicians from 59 countries. The majority of respondents were urologists/ uro-andrologists. A wide diversity of opinion was seen in every aspect of varicocele diagnosis, indications for repair, choice of technique, management of sub-clinical varicocele and the role of VR in azoospermia. A significant proportion of the responses were at odds with the recommendations of AUA, ASRM, and EAU. A large number of clinical situations were identified where no guidelines are available. Conclusions This study is the largest global survey performed to date on the clinical management of varicocele for male infertility. It demonstrates: 1) a wide disagreement in the approach to varicocele management, 2) large gaps in the clinical practice guidelines from professional societies, and 3) the need for further studies on several aspects of varicocele management in infertile men.

KMT2B-linked dystonia (DYT-KMT2B) is a childhood-onset dystonia syndrome typically beginning in the lower limbs and progressing caudocranially to affect the upper limbs with eventual prominent craniocervical involvement. Despite its recent recognition, it now appears to be one of the more common monogenic causes of dystonia syndromes. Here, we present an atypical case of DYT-KMT2B with oromandibular dystonia as the presenting feature, which remained restricted to this region three decades after symptom onset. This appears to be the first reported case of DYT-KMT2B from Southeast Asia and provides further supporting evidence for the pathogenic impact of the KMT2B c.6210_6213delTGAG variant.

OBJECTIVE: To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients. METHODS: By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup. RESULTS: Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens. CONCLUSIONS There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.
Humans ; Syndrome ; Ischemic Stroke ; Medicine, Chinese Traditional ; Liver ; Phenotype

Objective: To investigate the prevalence of dyslipidemia, and to explore the association between extracurricular physical activity and dyslipidemia among primary, middle and high school students in Guangzhou. Methods: This cross-sectional study selected primary and middle school students in Guangzhou by the stratified cluster sampling method from March to December 2019. Physical examination and blood lipid test were performed. Information about students' basic characteristics and extracurricular physical activity was collected by questionnaire. Multivariate logistic regression analysis was used to determine the association between extracurricular physical activity and dyslipidemia in this cohort. Results: A total of 7 797 participants (mean aged (12.2±2.9) years) were included (4 194 (53.79%) boys and 3 603 (46.21%) girls]. The detection rates of high total cholesterol, high triglycerides, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol and dyslipidemia were 12.49% (974/7 797), 6.44% (502/7 797), 6.62% (516/7 797), 11.31% (882/7 797) and 23.83% (1 858/7 797), respectively. Dyslipidemia rate was lower in the junior school students (21.39% (675/3 156)) than in primary school students (25.96% (896/3 451)) and high-school students (24.12% (287/1 190)) (P<0.001). The dyslipidemia rates of boys and girls were similar (23.15% (971/4 194) vs. 24.62% (887/3 603), P>0.05). Dyslipidemia rate was lower in students with extracurricular physical activity than in students without extracurricular physical activity (22.50% (923/4 102) vs. 25.30% (935/3 695), P<0.05). Multivariate logistic regression analysis showed that extracurricular physical activity was associated with lower risk of dyslipidemia (OR=0.88, 95%CI=0.79-0.99, P=0.033). Among all types of extracurricular physical activities, participating in extracurricular large ball game was associated with 28% lower risk among junior school students (OR=0.72, 95%CI=0.57-0.91, P=0.006). Conclusion: The prevalence of dyslipidemia is high among primary, middle and high school students in Guangzhou. Extracurricular physical activity is associated with reduced risk of dyslipidemia in this cohort.