BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

Objective:To explore the genetic characteristics of a child with comorbid 16p11.2 microdeletion syndrome and Rett syndrome (RTT).Methods:A male infant who was admitted to Gansu Provincial Maternity and Child Health Care Hospital in May 2020 was selected as the study subject. Clinical data of the infant was collected. Genomic DNA was extracted from peripheral blood samples from the infant and his parents, and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing.Result:The patient, a 4-day-old male infant, had presented with poor response, poor intake, feeding difficulties, and deceased at 8 months after birth. WES revealed that he has harbored a 0.643 Mb deletion in the 16p11.2 region, which encompassed key genes of the 16p11.2 microdeletion syndrome such as ALDOA, CORO1A, KIFF22, PRRT2 and TBX6. His father has carried the same deletion, but was phenotypically normal. The deletion was predicted to be pathogenic. The child was also found to harbor a maternally derived c. 763C>T (p.R255X) hemizygous variant of the MECP2 gene, which was also predicted to be pathogenic (PVS1+ PS4+ PM2_Supporting). Conclusion:The 16p11.2 deletion and the MECP2: c.763C>T (p.R255X) variant probably underlay the pathogenesis in this infant.

The cranial suture complex is made up of fibrous tissue with mesenchyme,an osteogenic front,the dura mater beneath,and an overlying periosteum.The dura mater is a layer of fibrous connective tissue that protects the brain and spinal cord,containing blood and lymphatic vessels.It is important for the progression of cranial osteo-genesis during early development,as well as the cranial morphology and the state of the cranial suture later in life.Cranial suture mesenchymal stem cells are primarily found in the cranial suture and can proliferate,differentiate in-to osteoblasts,generate cranial bone,and aid in the repair of cranial bone after injury.Understanding how cranial suture mesenchymal stem cells interact with the dura mater is critical for cranial growth and development,as well as the treatment of cranial diseases.This article reviews the roles of dura mater and cranial suture mesenchymal stem cells in cranial bone formation.

Objective To explore the effects of exposure to lipopolysaccharides in late pregnancy on age-related cognitive changes in offspring of mice,and to investigate whether there is a gender specific genetic effect.Methods Institute of cancer research(ICR)CD-1 mice during gestational days 15-17 were injected with lipopolysaccha-ride daily(LPS group,50 μg/kg),or equal volume of normal saline(CON group).At the age of 2 months after their delivery,LPS treated offspring mice(F1-LPS,male and female)were randomly selected and hybridized with age-matched wild-type CD-1 mice.F1-LPS males and females with different littermates,and F1-CON males and fe-males were hybridized to obtain F2 generations of different lineages.Similarly,F2-LPS mice were mated with wild-type mice to conceive the F3 generation.At the age of 3 and 18 months old,F1,F2,and F3 mice(n=8 in each group)were randomly selected to complete the Morris maze experiment in order to test their cognitive abilities.Re-sults Compared with 3-month-old CON mice,18-month-old CON mice showed poorer learning and memory abili-ties,especially in females.For Fl generation,the learning and memory abilities of the 3-month-old and 18-month-old F1-LPS mice were inferior to those of the same aged CON mice.For F2 generation,the 3-month-old F2-LPS-parental mice had poorer learning and memory compared to the same aged CON mice,while the F2-LPS-paternal mice only had poorer memory compared to the same aged CON group.The learning and memory abilities of 18-month-old F2-LPS paternal and F2-LPS-parental mice were inferior to those of the same aged CON mice.The learn-ing and memory abilities of F2-LPS maternal male mice were inferior to those of CON male mice,and the memory abilities of F2-LPS maternal mice were stronger than those of F2-LPS-parental mice.With regards to the F3 genera-tion,the memory of the 3-month-old F3-LPS-parental mice was poorer than that of the same aged CON mice.The learning and memory abilities of F3-LPS paternal and F3-LPS-parental mice at 18 months old were inferior to those of CON mice of the same age.The 18-month-old F3-LPS maternal and paternal male mice had better memory than F3-LPS-parental male mice.Conclusion Exposure to lipopolysaccharides in late pregnancy can accelerate age-re-lated cognitive decline in offspring mice,and it has a cross generational genetic effect and gender differences,mainly in paternal inheritance.

Objective To explore the effect of virtual reality treadmill training on balance and gait in stroke patients. Methods From March,2022,to March,2023,40 stroke patients in Beijing Tiantan Hospital,Capital Medical University were randomly divided into control group(n = 20)and experimental group(n = 20).Both groups received rou-tine rehabilitation training.The control group received ordinary treadmill walking training,and the experimental group received treadmill walking training with virtual reality,for two weeks.They were assessed with Berg Bal-ance Scale(BBS)and Timed Up and Go Test(TUGT),and the envelope ellipse area,center of pressure(COP)av-erage speed of movement,step length,stride length and stride width were compared between two groups before and after treatment. Results After treatment,the scores of BBS and time of TUGT improved in both groups(|t|>3.508,P<0.01),and they were better in the experimental group than in the control group(|t|>3.019,P<0.01);there was no significant dif-ference in the envelope ellipse area,COP average speed,and stride width between two groups(P>0.05);howev-er,the step length and stride width improved in the experimental group(|t|>4.008,P<0.01). Conclusion Treadmill training with virtual reality can improve the balance and walking ability of stroke patients.

Objective To observe the abnormal brain activity in patients with migraine without aura(MwoA)with MRI.Methods Fifty MwoA patients(MwoA group)and 46 healthy volunteers(control group)were prospectively enrolled.Functional MRI(fMRI)was performed to observe the dynamic regional homogeneity(dReHo)of brain regions,then brain regions with differences of dReHo value between groups were extracted,and correlations with clinical scales were analyzed.Results Compared with control group,dReHo values of surrounding cortex of bilateral calcarine fissure and right middle occipital gyrus increased,of right middle temporal gyrus,right middle frontal gyrus and left cuneus decreased in MwoA group(GRF correction,voxel level all P＜0.005,cluster level all P＜0.05).The weight analysis showed that brain regions with top 3 absolute weight values were surrounding cortex of right calcarine fissure,left cuneus and right middle occipital gyrus.dReHo value of surrounding cortex of left calcarine fissure in MwoA patients was negative correlated with self-rating depression scale(SDS)(r=-0.28,P=0.04).Conclusion Abnormalities in the upward transmission pathway of visual information existed in MwoA patient,especially in surrounding cortex of right calcarine fissure,left cuneus and right middle occipital gyrus.

BACKGROUND:The dura mater and skull are physically and functionally related,although there have been few investigations on primary extraction of dura mater and cranial cells,as well as co-culture of the two.The use of primary cells to investigate the influence of the dura mater on the skull is novel,and it is hoped that it may give a theoretical foundation for therapeutic therapy. OBJECTIVE:Rat dura mater and cranial bone cells were retrieved in situ to observe the influence of dura mater on cranial bone proliferation and differentiation,as well as to get a basic knowledge of the involvement of Twist1 in this process. METHODS:The enzyme digestion method was used in conjunction with the tissue block method to extract dural cells and cranial osteoblasts from rats within three days of birth.Immunofluorescence staining was used to identify the extracted cells,and alizarin red staining was used to identify and evaluate cranial osteoblasts and their mineralization ability.After co-culturing dural cells and cranial osteoblasts,real-time PCR was utilized to identify the expression of genes associated to cranial osteoblast proliferation and osteogenesis,as well as Twist1. RESULTS AND CONCLUSION:(1)Morphology:The retrieved dural cells had morphological traits similar to fibroblasts,while the osteoblasts were spindle-shaped.(2)Cell identification:immunofluorescence staining revealed that extracted dural cells expressed high levels of vimentin and cranial osteoblasts expressed high levels of alkaline phosphatase;cranial osteoblasts were stained with alizarin red 28 days after osteogenic induction,and obvious mineralized nodules were observed.(3)Real time PCR detection showed that the co-culture group had higher levels of PCNA,alkaline phosphatase,and RUNX2 mRNA expression than the control group(P＜0.01);however,Twist1 mRNA expression was lower(P＜0.01).(4)The findings showed that the primary extracted cranial osteoblasts had a high mineralization capacity,and that the dura mater was a key factor in promoting cranial growth and development and osteogenic differentiation,with Twist1 playing a key role in this process.

The hippocampus and its circuits play crucial roles in human learning, memory, and emotional regulation. Whether it is vascular cognitive impairment (VCI) or Alzheimer's disease (AD), damage to the hippocampus is a prominent pathological feature. This review summarizes the recent advance in multimodal magnetic resonance imaging in anatomy, blood supply, structure and function of the hippocampus and the circuits related to VCI and AD in recent years, aiming to provide help in early recognizing and differentially diagnosing VCI and AD.

Background The substantial health damage attributed to heat waves, along with their increasing intensity and frequency in the context of global warming, highlights the importance of exploring the health effects of heat waves. Objective To calculate the excess heat stroke cases during heat waves in the summer of 2013—2023 in Shanghai, analyze the association between heat waves and heat stroke, and to further explore the modifying effects of heat wave characteristics on heat stroke. Methods Using a retrospective ecological study design, data on heat stroke cases were collected from the heat stroke case reporting system of the Chinese Center for Disease Control and Prevention, and concurrent meteorological data from Xujiahui Meteorological Station. A heat wave was defined as at least 3 consecutive days with daily maximum temperature meeting or exceeding 35 ℃ in this study, excess heat stroke cases related to heat waves were assessed as the difference between the numbers of heat stroke cases observed on a given day and the corresponding 31 d (15 d before and after that day) moving average, and statistical analyses using generalized linear model based on time series study were performed to assess the impact of heat waves on heat stroke. Results Overall 25 heat waves during the study period were observed, leading to a total of estimated 792.6 extra heat stroke cases. The risk of heat stroke significantly increased during heat waves (RR=2.60, 95%CI: 2.08, 3.26), but no statistically significant differences in heat wave effects were observed among different genders, ages, or regions. In terms of the timing of heat waves, the risk of heat stroke was highest during the first heat wave (RR=3.58, 95%CI: 2.82, 4.55), which was significantly higher than that during the second heat wave (RR=2.19, 95%CI: 1.66, 2.90), and no significant effect was observed during the third or subsequent heat waves. The impact of heat waves on heat stroke persisted for more than 4 d, with the risk higher on the fourth day and beyond (RR=2.95, 95%CI: 2.28, 3.83), significantly higher than on the first day of heat wave (RR=1.74, 95%CI: 1.18, 2.56). Conclusion Heat waves had a substantial effect on heat stroke in Shanghai from 2013 to 2023, and special attention need to be paid to heat waves with early onset and long duration.

Cerebral small vascular disease (CSVD) is an important risk factor for stroke, cognitive impairment, and death, but its exact pathogenesis is not yet fully understood. Recent studies have shown that as an important part of pathophysiological mechanisms of CSVD, immunoinflammation may affect the progression and prognosis of CSVD. This article reviews the role of immunoinflammation in CSVD.