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ObjectiveTo study the association between early growth of haematoma with biomarkers of endothelial dysfunction such as leukoaraiosis (LA) and the soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK) in patients with intracerebral haemorrhage (ICH).MethodsThis is a retrospective observational study of patients with nontraumatic ICH. Clinical and biochemical parameters were analysed. sTWEAK levels were measured by ELISA. LA was analysed in the hemisphere without haemorrhage to avoid interference with the acute injury. The main endpoint was the haematoma growth evaluated by the difference in volume between the second and the initial neuroimage. Poor functional outcome, defined as a modified Rankin Scale >2 at 3 months, was considered as secondary endpoint. Receiver operating characteristic curve analysis was performed to stablish the best cut-off for sTWEAK levels associated with haematoma growth.ResultsWe included 653 patients with ICH in our analysis (71.1±11.9 years, 44% women). Haematoma growth was observed in 188 patients (28.8%). sTWEAK levels ≥5600 pg/mL predicted ICH growth with a sensitivity of 84% and a specificity of 87%. sTWEAK levels ≥5600 pg/mL and the presence of LA were associated with haematoma growth (OR: 42.46; (CI 95% 22.67 to 79.52) and OR: 2.73 (CI 95% 1.39 to 5.34), respectively). Also, the presence of LA (OR: 4.31 (CI 95% 2.89 to 6.42)) and the interaction between ICH growth and sTWEAK (OR: 2.23 (CI 95% 1.40 to 3.55)) were associated with poor functional outcome at 3 months.ConclusionsTWEAKs, together with the presence and grade of LA, are biomarkers able to predict ICH growth and poor functional outcome in patients with ICH.

Background Intracranial venous hypertension has been associated with a few cases of meningioma secondary to compression of the venous sinus. This is the rare case of small meningioma involving the sigmoid sinus leading to intracranial venous hypertension mimicking venous thrombosis. Case presentation A 39-year-old woman suffered visual dysfunction due to bilateral papilledema. Noncontrast head computed tomography (CT) showed no intracranial space-occupying lesions or hydrocephalus. Cerebrospinal fluid examination revealed high opening pressure. Various image inspections such as three-dimensional CT angiography, magnetic resonance imaging, and cerebral angiography demonstrated a small 2.5-cm lesion causing subtotal occlusion of the dominant right sigmoid sinus. No improvement of clinical manifestations was observed after medical treatment for 6 months, so right presigmoid craniectomy was performed. Operative findings revealed that the tumor was located predominantly involving the sigmoid sinus. The pathological diagnosis was fibrous meningioma. Postoperative fundoscopic examination showed improvement of bilateral papilledema. Conclusions We treated a patient presenting with intracranial hypertension due to a small meningioma involving the sigmoid sinus. This unusual case suggests that early surgical strategies should be undertaken to relieve the sinus obstruction.

Nervous system diseases are associated with complexity and diversity. As a result, the prognosis of patients deeply depends on physicians' clinical experience and their diagnosis and treatment level. With the exponential growth of medical big data and the development of statistical analysis tools, more researchers discover the pathogenesis of diseases and assist clinical process through the mining of big data, so as to improve the diagnosis, treatment, and prognosis of nervous system diseases. This paper elaborates the application of three kinds of medical big data in nervous system diseases, including structured data, radiomics, and bioinformatics. doi：10.3969/j.issn.1672⁃6731.2021.03.002

Resumen: Introducción: La esclerosis múltiple (EM) es una enfermedad crónica del sistema nervioso central que se caracteriza por la existencia de inflamación, desmielinización, gliosis y daño axonal. La introducción de dimetilfumarato y teriflunomida ha supuesto un aumento de las alternativas terapéuticas en la primera línea de tratamiento de la EM. El objetivo de este estudio fue evaluar el impacto económico de la incorporación de estas nuevas terapias orales en la Unidad de Referencia (CSUR) del Hospital Universitario Puerta de Hierro Majadahonda. Material y métodos: Se realizó un estudio observacional retrospectivo en la población de pacientes diagnosticados de EM, en tratamiento con fármacos modificadores de la enfermedad durante el año 2015, y su seguimiento se prolongó hasta obtener un seguimiento medio superior a un año de tratamiento. Los datos se recogieron de la historia clínica electrónica y del programa de dispensación de medicamentos a pacientes externos y ambulantes del Servicio de Farmacia. Resultados: Evaluando el coste del cambio del tratamiento en 125 pacientes desde otros fármacos a dimetilfumarato o teriflunomida y comparando con el coste que habría supuesto el mantenimiento de los tratamientos previos, el ahorro total durante el periodo de observación fue de 169.107,31 €. Conclusiones: Dimetilfumarato y teriflunomida, además de aportar nuevas alternativas terapéuticas, no solo no han supuesto un incremento sino, por el contrario, una disminución en los costes del tratamiento de la EM en nuestro hospital. Abstract: Introduction: Multiple sclerosis (MS) is a chronic disease affecting the central nervous system and is characterised by inflammation, demyelination, gliosis, and axonal damage. The introduction of dimethyl fumarate and teriflunomide has led to an increase in the number of alternative first-line therapies for MS. The objective of this study was to evaluate the economic impact of the incorporation of new oral therapies at the reference unit (CSUR) at Hospital Universitario Puerta de Hierro Majadahonda. Materials and methods: We performed a retrospective observational study including patients diagnosed with MS, who underwent treatment with disease-modifying drugs in 2015 and were followed up for a minimum mean time of one year. Data were collected from patients’ electronic clinical histories and the pharmacy service's programme for dispensing drugs to outpatients. Results: Evaluating the cost of changing 125 patients’ treatment from other drugs to dimethyl fumarate and teriflunomide, and comparing this with the cost that would have resulted from maintaining their previous treatment, demonstrated a total saving of €169,107.31 over the study period. Conclusions: In addition to contributing new therapeutic alternatives, dimethyl fumarate and teriflunomide produced an economic saving in MS treatment at our hospital.

Introduction Intramedullary spinal epidermoid cysts have a reported incidence of less than 1% of intramedullary spinal cord tumors; and out of these, intramedullary epidermoid lesions within the cervical spinal cord are even rarer. Here, we present the case of an adult patient with an infected intramedullary epidermoid cyst, identified on magnetic resonance imaging (MRI) at the C7–D1 level that was successfully excised without any worsening of neurological status. Case Presentation A 23-year-old female patient presented with history of moderate degree intermittent fever followed by gradually progressive right-sided weakness. She had paresthesia below C5 dermatome on the right side. On close inspection of the back, a tiny sinus opening was noted at the D2 level near the midline. MRI of the spine showed an intramedullary lesion at the C6–D1 level with the tract connecting to the subcutaneous lesion. Somatosensory evoked potential (SSEP) monitoring was done during the surgery with near total excision of the lesion. Conclusion Even though the location is rare, a differential diagnosis of the epidermoid should always be considered. A tiny dermal sinus opening helped us in proper diagnosis, along with surgical excision, by providing us a direct path to the intramedullary lesion. An early diagnosis and treatment with neurophysiological monitoring helped us in the maximum safe resection of the lesion without developing any new deficit.

Objective To summarize the clinical phenotypes and genetic mutations of DNAJB6 related myopathies. Methods We retrospectively reviewed the clinical information, laboratory tests, muscle MRIs, electromyography results, muscle pathology examinations and genetic mutations of 2 patients of DNAJB6 related myopathies from one family and reviewed related published literatures of DNAJB6 related myopathies. Results The proband presented with muscle weakness of both proximal and distal limbs, with lower limbs more serious than upper limbs, and proximal more serious than distal. The father of proband presented with abnormal gait, and he could only climb stairs with assistance. Serum creatine kinase (CK) levels of both patients were normal. Muscle MRIs of both patients showed different degrees of fatty infiltration. Muscle biopsies of both patients showed similar changes with dystrophic features, and some muscle fibers with rimmed vacuoles inside, as well as increased internal nuclei and a few regenerating fibers. Genetic tests proved both patients carried the same DNAJB6 gene variant, c.161A ＞ C (p.Glu54Ala), which was the first report in mainland China. The proband was diagnosed as limb ⁃ girdle muscular dystrophy D1 (LGMD⁃D1) type, and the father of proband was diagnosed as distal myopathy. This family was considered as autosomal dominant DNAJB6 related myopathy. Referring to literature, heterogeneities exist in DNAJB6 related myopathies, and different clinical phenotypes could be presented in one single family. Conclusions The phenotypes of DNAJB6 related myopathies include limb ⁃ girdle muscular dystrophy and distal myopathy. Muscle pathology shows similar changes of rimmed vacuoles and dystrophic features. This reported family further expands the spectrum of phenotypes of DNAJB6 related myopathies. doi：10.3969/j.issn.1672⁃6731.2021.03.013

Background Regenerative therapies to mitigate Alzheimer’s disease (AD) neuropathology have shown very limited success. In the recent era, extracellular vesicles (EVs) derived from multipotent and pluripotent stem cells have shown considerable promise for the treatment of dementia and many neurodegenerative conditions. Methods Using the 5xFAD accelerated transgenic mouse model of AD, we now show the regenerative potential of human neural stem cell (hNSC)-derived EVs on the neurocognitive and neuropathologic hallmarks in the AD brain. Two- or 6-month-old 5xFAD mice received single or two intra-venous (retro-orbital vein, RO) injections of hNSC-derived EVs, respectively. Results RO treatment using hNSC-derived EVs restored fear extinction memory consolidation and reduced anxiety-related behaviors 4–6 weeks post-injection. EV treatment also significantly reduced dense core amyloid-beta plaque accumulation and microglial activation in both age groups. These results correlated with partial restoration of homeostatic levels of circulating pro-inflammatory cytokines in the AD mice. Importantly, EV treatment protected against synaptic loss in the AD brain that paralleled improved cognition. MiRNA analysis of the EV cargo revealed promising candidates targeting neuroinflammation and synaptic function. Conclusions Collectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EVs for remediation of behavioral and molecular AD neuropathologies.

[ES] Introducción: El manejo de la enfermedad de Parkinson en la mujer en edad fértil nos plantea como principal reto el manejo de la enfermedad y los fármacos durante el embarazo y lactancia. El aumento de la edad gestacional de la mujer hace más probable que la incidencia de embarazos pueda incrementarse. Objetivo: Definir las características clínicas y los factores que condicionan la vida de la mujer en edad fértil con enfermedad de Parkinson y definir una guía de actuación y manejo del embarazo en estas pacientes. Resultados: Este documento de consenso se ha realizado mediante una búsqueda bibliográfica exhaustiva y discusión de los contenidos realizados por un grupo de expertos en trastornos del movimiento de la Sociedad Española de Neurología. Conclusiones: La enfermedad de Parkinson afecta a todos los aspectos relacionados con la salud sexual y reproductiva de la mujer en edad fértil. Se debe planificar el embarazo en las mujeres con enfermedad de Parkinson para minimizar los riesgos teratogénicos sobre el feto. Se recomienda un abordaje multidisciplinar de estas pacientes para tener en cuenta todos los aspectos implicados., [EN] Introduction: The main challenge of Parkinson's disease in women of childbearing age is managing symptoms and drugs during pregnancy and breastfeeding. The increase in the age at which women are having children makes it likely that these pregnancies will become more common in future. Objectives: This study aims to define the clinical characteristics of women of childbearing age with Parkinson's disease and the factors affecting their lives, and to establish a series of guidelines for managing pregnancy in these patients. Results: This consensus document was developed through an exhaustive literature search and a discussion of the available evidence by a group of movement disorder experts from the Spanish Society of Neurology. Conclusions: Parkinson's disease affects all aspects of sexual and reproductive health in women of childbearing age. Pregnancy should be well planned to minimise teratogenic risk. A multidisciplinary approach should be adopted in the management of these patients in order to take all relevant considerations into account.

Objective To perform a systematic literature review on revision surgeries at the index level after cervical disc arthroplasty (CDA) failure. Methods A systematic literature review was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Prospective studies on patients who required a secondary surgery after CDA failure were included for analysis. The minimum follow-up for these studies was 5 years. Results Out of 864 studies in the original search group, a total of 20 studies were included. From a total of 4,087 patients, 161 patients required a reoperation at the index level. A total of 170 surgeries were performed, as some patients required multiple surgeries. The most common secondary procedures were anterior cervical discectomy and fusion (ACDF) (68%, N = 61) and posterior cervical fusion (15.5%, N = 14), followed by other reoperation (13.3%, N = 12). The associated outcomes for those who required a revision surgery were rarely mentioned in the included literature. Conclusion The long-term revision rate at the index level of failed CDA surgery was 3.9%, with a minimum 5-year follow-up. ACDF was the most commonly performed procedure to salvage a failed CDA. Some patients who required a new surgery after CDA failure may require a more extensive salvage procedure and even subsequent surgeries.

Growth hormone (GH)-secreting pituitary adenomas (PA) make up 15 to 20% of total amount of hormonally active adenomas. In addition to acromegaly and gigantism, these tumors cause deep metabolic disturbances. Its systemic impact leads to increased mortality ratio of 1.32 compared with general population. Surgical removal remains the priority treatment option in controlling acromegaly and provides endocrinologic remission in up to 72% patients. A total of 92 patients were included in the study. All surgeries were performed via microscopic transsphenoidal approach (TSA) by the senior author in our institution between December 2009 and October 2019. Only patients who were followed-up with 75 g oral glucose tolerance tests (OGTTs), GH, and insulin-like growth factor I (IFG-I) measurements preoperatively, 1 week, and every 6 months postoperatively were analyzed. Based on standard preoperative 1.5-T MR imaging with contrast enhancement, the adenomas were identified and distributed according to the size and KNOSP classification. The efficacy depends on KNOSP grade, which is directly correlated with invasiveness to cavernous sinus (CS). Grades 3 and 4 are unfavorable factors influencing prognosis. Excluding grade 0 adenomas, as the surgery was not difficult with the excellent outcomes, we reached 75% (36 out of 48) remission in grade 1 to 2 groups. In contrast, only 17% (2 out of 12) had successful outcomes after surgery alone. In conclusion, the study demonstrates the efficiency of TS surgery in patients with confirmed GH-secreting PA.

Although the etiology of classical trigeminal neuralgia is clearly understood to be neurovascular compression, the exact etiology of trigeminal neuralgia with continuous pain is often unknown. Mild sphenoid sinusitis is not usually considered to induce trigeminal neuralgia, especially when limited to the maxillary nerve. We report a rare case of trigeminal neuralgia of the maxillary nerve caused only by mild sphenoid sinusitis and discuss the significance of the anatomical structure and diagnostic procedures. A 45-year-old woman noticed a sudden onset of temporal pain followed by numbness on her right cheek. Her right gingiva also experienced sensory disturbance. The symptoms gradually subsided after the initial onset, but they persisted. She visited our hospital for further examinations and had no febrile episodes throughout the course. A tingling sensation and sensory disturbance were only identified in the maxillary nerve. No other neurological symptoms were noted. Magnetic resonance imaging revealed mild sphenoid sinusitis on the right side. The absence of the bony boundary between the sphenoid sinus and maxillary nerve was revealed using thin-sliced computed tomography (CT). The patient’s symptoms were diagnosed as maxillary neuropathy caused by mild sinusitis. The bony defect around the maxillary nerve was considered to have affected development of the pathological process. Even mild sphenoid sinusitis can cause inflammation to spread to the maxillary nerve if no bony boundary exists between it and the sphenoid sinus. A coronal CT study is highly beneficial for clarifying the pathophysiological mechanism of trigeminal neuralgia limited to the maxillary nerve.

Objective Kinesin family member 5A (KIF5A) is a molecular motor protein responsible for intracellular transport, specifically in neurons. While abnormalities in the KIF5A gene have been reported in the onset of various neurological diseases, there are no studies demonstrating an association between this gene and West syndrome. Methods In the case presented here, epileptic spasms appeared at 7 months; electroencephalogram (EEG) investigation confirmed hypsarrhythmia, resulting in a diagnosis of West syndrome. The patient exhibited peculiar facies, hypotonia, failure to thrive, and severe global developmental delay. Results Cranial magnetic resonance imaging (MRI) revealed severe delayed myelination. 123I‐iomazenil SPECT image at 7 months demonstrated decreased accumulation in bilateral areas, including the primary somatosensory and motor cortices, and the primary and association visual areas compared to an age‐matched control. Whole exome sequencing analysis demonstrated a novel de novo heterozygous missense variant in KIF5A, (NM_004984.4:c.710A>T: p. Glu237Val). Significance It was concluded that the KIF5A variant impaired the transport of GABAA receptors to the cell membrane surface, thus leading to an imbalance of these receptors between regions of the cerebrum and resulting in the onset of epilepsy.

We have described a 55-year-old woman with the anterior opercular syndrome (Foix-Chavany-Marie syndrome). The clinical presentation included acute onset of bilateral facial palsy and anarthria. Immediate MRI of the brain revealed acute ischemia in the right opercular region and sequelae after a previous infarction involving the left opercular region. The patient was treated with intravenous thrombolysis resulting in full recovery. The anterior opercular syndrome is rare, and the most common reason is sequential stroke. We emphasize the importance of recognizing this syndrome early, and in all cases, consulting a revascularization center immediately.

Na+(K+)/H+exchanger 6 (NHE6) on synaptic vesicle (SV) is critical for the presynaptic regulation of quantal size at the glutamatergic synapses by converting the chemical gradient (ΔpH) into membrane potential (Δψ) across the SV membrane. We recently found that NHE6 directly interacts with secretory carrier membrane protein 5 (SCAMP5), and SCAMP5-dependent recruitment of NHE6 to SVs controls the strength of synaptic transmission by modulation of quantal size of glutamate release at rest. It is, however, unknown whether NHE6 recruitment by SCAMP5 plays a role during synaptic plasticity. Here, we found that the number of NHE6-positive presynaptic boutons was significantly increased by the chemical long-term potentiation (cLTP). Since cLTP involves new synapse formation, our results indicated that NHE6 was recruited not only to the existing presynaptic boutons but also to the newly formed presynaptic boutons. Knock down of SCAMP5 completely abrogated the enhancement of NHE6 recruitment by cLTP. Interestingly, despite an increase in the number of NHE6-positive boutons by cLTP, the quantal size of glutamate release at the presynaptic terminals remained unaltered. Together with our recent results, our findings indicate that SCAMP5-dependent recruitment of NHE6 plays a critical role in manifesting presynaptic efficacy not only at rest but also during synaptic plasticity. Since both are autism candidate genes, reduced presynaptic efficacy by interfering with their interaction may underlie the molecular mechanism of synaptic dysfunction observed in autism.

There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.

Background and purposePrevious studies have reported about inflammation processes (IPs) that play important roles in aneurysm formation and rupture, which could be driven by blood flow. IPs can be identified using aneurysmal wall enhancement (AWE) on high-resolution black-blood MRI (BB-MRI) and blood flow haemodynamics can be demonstrated by four-dimensional-flow MRI (4D-flow MRI). Thus, this study investigated the associations between AWE and haemodynamics in unruptured intracranial aneurysms (IA) by combining 4D-flow MRI and high-resolution BB-MRI.Materials and methodsBetween April 2014 and October 2017, 48 patients with 49 unruptured IA who underwent both 4D-flow MRI and high-resolution BB-MRI were retrospectively included in this study. The haemodynamic parameters demonstrated using 4D-flow MRI were compared between different AWE patterns using the Kruskal-Wallis test and ordinal regression.ResultsThe results of Kruskal-Wallis test showed that the average wall shear stress in the IA (WSSavg-IA), maximum through-plane velocity in the adjacent parent artery, inflow jet patterns and the average vorticity in IA (vorticityavg-IA) were significantly associated with the AWE patterns. Ordinal regression analysis identified WSSavg-IA (p=0.002) and vorticityavg-IA (p=0.033) as independent predictors of AWE patterns.ConclusionA low WSS and low average vorticity were independently associated with a high AWE grade for IAs larger than 4 mm. Therefore, WSS and average vorticity could predict AWE and circumferential AWE.

Background: Children are the group most susceptible to Mycobacterium leprae infection. The proportion of new leprosy cases in children is indicator of successful leprosy elimination program from World Health Organization (WHO), so this study would like to know the epidemiology of pediatric leprosy at Dermatology and Venereology Polyclinic, Dr. Mohammad Hoesin Palembang. Methods: Retrospective study of all new cases of leprosy in children (0-17 years) who came to Dermatology and Venereology Polyclinic, Dr. Mohammad Hoesin Palembang from January 2017 to December 2020. Results: There were 10 pediatric patients (7.58%) from 132 new leprosy cases. Most cases (40%) were in the 15-17 age group. There are more male than female. Most types of leprosy are BL (60%) followed by TT (20%). Manifestations of hyperpigmented skin patches and nervous disorders, grade 1 disability, and type 2 leprosy reactions are mostly found in type BL leprosy. The duration of illness 6-12 months has a grade 1 disability (30%). The history of positive contact came from same household in 3 cases (30%) with 7 people (70%) domiciled in Palembang. All cases received Multidrug Therapy (MDT) treatment according to WHO guidelines. Conclusion: Found 10 new cases of leprosy in children in Dermatology and Venereology Polyclinic Dr. Moh. Hoesin Palembang for four years, especially in the 15-17 age group, with the most cases being type BL leprosy. Household contact still plays an important role in leprosy transmission.

Alpha-pyrrolidinovalerophenone (alpha-PVP) is a designer drug, the mechanism of action of which resembles that of cocaine and amphetamine. New data about the side effects of alpha-PVP are emerging. We present a case report of an acute ischemic stroke following the recreational use of alpha-PVP. The ischemic lesions were located in the middle cerebral artery and deep watershed areas of the left cerebral hemisphere. Occupational therapy and physiotherapy were initiated, and the patient was discharged with only a mild right hemiparesis.

Upper limb intention tremor is a common cause of disability in multiple sclerosis (MS). Transcranial direct current stimulation (tDCS) is an emerging form of brain stimulation used to improve sensorimotor impairments in many neurological disorders. Here, we describe a combined therapeutic approach with botulinum neurotoxin type A (BoNT-A) and tDCS for the treatment of upper limb tremor in a patient with MS. We administered a cathodal tDCS 15 days after the injections of BoNT-A. Both post-injection and post-stimulation evaluation revealed a considerable improvement of the tremor. This approach positively affected the patient’s activities of daily living. Our case report shows a safe and beneficial effect of tDCS in the treatment of action tremor in MS especially as a possible adjunctive synergic treatment with BoNT-A injections.

Spastic paraplegia type 4 (SPG4) is the most common type of hereditary spastic paraplegia (HSP) caused by the mutations in the SPAST gene, which encodes a microtubule-severing protein named spastin. Spastin regulates the number and mobility of microtubules and is essential for axonal outgrowth and neuronal morphogenesis. Herein, we report a patient with SPG4 harboring a novel donor splice site mutation in the SPAST gene (c.1616+1dupG). Although SPG4 usually manifests itself as a pure form of HSP, this patient exhibited a slow progressive cognitive decline and also developed narcolepsy type 2 (narcolepsy without cataplexy) prior to the onset of SPG4. Recently, cognitive decline has attracted attention as a main non-motor symptom of SPG4. However, this is the first reported case of a patient developing both SPG4 and narcolepsy, although it remains unclear whether the manifestation of the two diseases is a coincidence or an association. In this report, we describe the clinical symptoms and genetic background of the patient.

We report 2 cases of probable neuro-Behcet’s disease (NBD) with longitudinally extensive transverse myelitis (LETM). In both cases, the patients presented paraplegia, as well as sensory, bladder, and rectal disturbances. Magnetic resonance imaging (MRI) of patient 1 showed continuous high signal intensity extending from the midbrain to the entire spinal cord in the central part of the cord on T2-weighted imaging (T2WI). Spinal MRI of patient 2 revealed high signal intensity extending from Th2 to Th10 in the central part of the cord on T2WI. Both patients received high-dose methylprednisolone. A continuous lesion from the midbrain to the entire spinal cord as in patient 1 has not been previously reported. Patient 2 dramatically improved by infliximab therapy. The present cases suggest that NBD should be considered as a differential diagnosis in patients with LETM.

A B S T R A C TThe field of hereditary qualities has offered ascend to innovation that will reform thenatural sciences: the amazing quality altering device known as CRISPR-Cas9. Betweenclinical advancement, extreme new age solution for sicknesses and the danger ofmodifying human DNA in an irreversible manner, the lawful difficulties of applyingCRISPR in the wellbeing setting, alongside the administrative and moral issues thatmay emerge should be drawn nearer with expanded duty. A primary objective or anassortment of purposes? Upgrade or quality altering to improve ordinary humancharacteristics, changes from altered genomes that may be acquired - repercussionsof the new quality altering innovation could bring about adjusting human DNA.Current worldwide enactment and understanding, worldwide agreement worthseeking after regarding this matter and future guidelines required.

A B S T R A C T Klippel-Trenaunay syndrome is a rare congenital vascular disease. The pathogenesis of this syndrome is unclear, but it is thought that most cases are the result of somatic mutations that affect genes that play a role in vasculogenesis and angiogenesis. Some patients come with a triad of capillary malformation (hemangioma or port-wine stain), venous varicosities and bony or soft tissue hypertrophy. Clinical presentation of this syndrome can lead to significant morbidities and mortalities due to severe bleeding and emboli. Although the number of cases is low, a doctor must be able to distinguish Klippel-Trenaunay Syndrome from other rare vascular disorders. Parkes Weber syndrome is usually similar to Klippel-Trenaunay syndrome, except in the arterial malformations associated with capillary malformations and soft tissue to skeletal or bone hypertrophy. The diagnosis of Klippel-Trenaunay Syndrome is carried out clinically and is quite difficult to do even with experienced doctors because there is no precise pathognomonic test. There are several options in relation to the management of Klippel-Trenaunay Syndrome and non-invasive procedure is considered to be the most important of therapy modalities. Early diagnoses, progression monitoring, and proper intervention should be carried out for better prognosis and preventing complication.

A B S T R A C TTrials in pre-clinical trials are very complex multidisciplinary studies. Extrapolatingdata from animals to humans requires information from many fields of science. Frompre-clinical trials, more detailed information and data on efficacy and safety wereobtained, especially at doses equivalent to doses in humans, and the presence orabsence of cumulative effects and whether these effects could return to normal(reversible) after the administration of the test material was stopped. This test canbe used to predict the negative impact on humans if he is exposed to the materialfor a long time.

Objective Our goal was to perform detailed clinical and genomic analysis of a large multigenerational Chinese family with 21 individuals showing symptoms of Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE) that we have followed for over 20 years. Methods Patients were subjected to clinical evaluation, routine EEG, and structural magnetic resonance imaging. Whole exome sequencing, repeat‐primed PCR, long‐range PCR, and PacBio sequencing were performed to characterize the disease‐causing mutation in this family. Results All evaluated patients manifested adult‐onset seizures and presented with progressive myoclonic postural tremors starting after the third or fourth decade of life. Seizures typically diminished markedly in frequency with implementation of antiseizure medications but did not completely cease. The electroencephalogram of affected individuals showed generalized or multifocal spikes and slow wave complexes. An expansion of TTTTA motifs with addition of TTTCA motifs in intron 4 of SAMD12 was identified to segregate with the disease phenotype in this family. Furthermore, we found that the mutant allele is unstable and can undergo both contraction and expansion by changes in the number of repeat motifs each time it is passed to the next generation. The size of mutant allele varied from 5 to 5.5 kb with 549‐603 copies of TTTTA and 287‐343 copies of TTTCA repeat motifs in this family. Significance Our study provides a detailed description of clinical progression of FCMTE symptoms and its management with antiseizure medications. Our method of repeat analysis by PacBio sequencing of long‐range PCR products does not require high‐quality DNA and hence can be easily applied to other families to elucidate any correlation between the repeat size and phenotypic variables, such as, age of onset, and severity of symptoms.

Background Although several brain networks play important roles in cervical dystonia (CD) patients, regional homogeneity (ReHo) changes in CD patients have not been clarified. We investigated to explore ReHo in CD patients at rest and analyzed its correlations with symptom severity as measured by Tsui scale. Methods A total of 19 CD patients and 21 gender-, age-, and education-matched healthy controls underwent fMRI scans at rest state. Data were analyzed by ReHo method. Results Patients showed increased ReHo in the right cerebellum crus I and decreased ReHo in the right superior medial prefrontal cortex (MPFC). Moreover, the right precentral gyrus, right insula, and bilateral middle cingulate gyrus also showed increased ReHo values. A significantly positive correlation was observed between ReHo value in the right cerebellum crus I and symptom severity (p Conclusions Our investigation suggested abnormal ReHo existed in brain regions of the “pain matrix” and salience network (the right insula and bilateral middle cingulate gyrus), the motor network (the right precentral gyrus), the cerebellum and MPFC and further highlighted the significance of these networks in the pathology of CD.

Background Astronauts undergoing long-duration spaceflight are exposed to numerous health risks, including Spaceflight-Associated Neuro-Ocular Syndrome (SANS), a spectrum of ophthalmic changes that can result in permanent loss of visual acuity. The etiology of SANS is not well understood but is thought to involve changes in cerebrovascular flow dynamics in response to microgravity. There is a paucity of knowledge in this area; in particular, cerebrospinal fluid (CSF) flow dynamics have not been well characterized under microgravity conditions. Our study was designed to determine the effect of simulated microgravity (head-down tilt [HDT]) on cerebrovascular flow dynamics. We hypothesized that microgravity conditions simulated by acute HDT would result in increases in CSF pulsatile flow. Methods In a prospective cohort study, we measured flow in major cerebral arteries, veins, and CSF spaces in fifteen healthy volunteers using phase contrast magnetic resonance (PCMR) before and during 15° HDT. Results We found a decrease in all CSF flow variables [systolic peak flow (p = 0.009), and peak-to-peak pulse amplitude (p = 0.001)]. Cerebral arterial average flow (p = 0.04), systolic peak flow (p = 0.04), and peak-to-peak pulse amplitude (p = 0.02) all also significantly decreased. We additionally found a decrease in average cerebral arterial flow (p = 0.040). Finally, a significant increase in cerebral venous cross-sectional area under HDT (p = 0.005) was also observed. Conclusions These results collectively demonstrate that acute application of −15° HDT caused a reduction in CSF flow variables (systolic peak flow and peak-to-peak pulse amplitude) which, when coupled with a decrease in average cerebral arterial flow, systolic peak flow, and peak-to-peak pulse amplitude, is consistent with a decrease in cardiac-related pulsatile CSF flow. These results suggest that decreases in cerebral arterial inflow were the principal drivers of decreases in CSF pulsatile flow.

CACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

Background Blister-like aneurysms (BLAs) on the supraclinoid segment of the internal carotid artery (ICA) are an enigma of cerebrovascular disease. Neither has a definite pathogenesis been so far identified, nor have uniform treatment guidelines been established for them. Our aim was to develop a hypothesis regarding the evolution of BLAs according to their macroscopic morphologies and to evaluate the efficacy of microsurgical clipping. Methods The clinical data and morphological features of 15 consecutive patients with 16 BLAs on the supraclinoid ICA were retrospectively reviewed. The treatment strategies were analyzed, and functional outcomes were evaluated using the modified Rankin scale (mRS). Favorable outcomes were defined as a mRS score of 0–2. Results Morphologically, aneurysm growth with expansion of the aneurysm neck before the surgical procedure occurred in two ruptured and one unruptured aneurysm. Daughter bleb formation was observed in two ruptured and five unruptured aneurysms. A varied degree of parent artery sclerosis was observed in nine patients. Thirteen patients were treated with direct surgical clipping, one patient was treated with clipping and wrapping, and the remaining patient was treated with an encircling clipping graft. Favorable and unfavorable outcomes were observed in 13 and two cases, respectively. Follow-up angiograms revealed 4 cases of stenosis with respective degree of mild, 30%, 50%, and 80% without any neurological dysfunction. Conclusions We suggest a hypothesis that BLAs on the supraclinoid ICA may share different evolving mechanisms between ruptured and unruptured lesions. A majority of them can be reliably and safely obliterated by direct clipping technique, except for the aneurysms accompanied with severely atherosclerotic parent walls.

Background In recent years, excellent results have suggested an association between the “brain-gut” axis and Alzheimer’s disease (AD) progression, yet the role of the “brain-gut” axis in AD pathogenesis still remains obscure. Herein, we provided a potential link between the central and peripheral neuroinflammatory disorders in AD progression. Methods The Morris water maze (MWM) test, immunohistochemistry, ELISA, ProcartaPlex Multiplex immunoassay, multiple LC-MS/MS methods, and the V3-V4 regions of 16S rRNA genes were applied to explore potential biomarkers. Results In Tg-APP/PS1 mice, gut dysbiosis and lipid metabolism were highly associated with AD-like neuroinflammation. The combination of inflammatory factors (IL-6 and INF-γ), phosphatidylcholines (PCs) and SCFA-producing bacteria were expected to be early diagnostic biomarkers for AD. Huanglian Jiedu decoction (HLJDD) suppressed gut dysbiosis and the associated Aβ accumulation, harnessed neuroinflammation and reversed cognitive impairment. Conclusion Together, our findings highlighted the roles of neuroinflammation induced by gut dysbiosis and lipid metabolism disorder in AD progression. This integrated metabolomics approach showed its potential to understand the complex mechanisms of HLJDD in the treatment of AD.

Introduction: We have developed the Dementia Elderly Odayaka Scale (DEOS) to evaluate psychosocial aspects in older people. The DEOS can be used to assess well-being, such as personhood and social interaction. Objective: The aim of this study was to apply the 18-item DEOS in participants with dementia and to examine the characteristics and usefulness of this scale. Methods: Facility staff provided care for the participants while taking into consideration each participant’s individuality and strong points. The DEOS was applied at the beginning of the interventions and at 1 and 2 months after the start of the interventions. The changes in the participants’ behaviors and their DEOS scores were then evaluated over time. Results: We examined 13 participants (2 men, 11 women) between the ages of 68 and 91 years. In 60% of the participants the DEOS score increased over time. When care interventions were tailored toward communication and leadership for the 2 men, according to each of their individualities, we observed increases in their scores for “social interaction” at 1 and 2 months thereafter. We also observed increases in the scores for “Expression of emotions” category in 2 of the 5 cases who received an aromatherapy massage. Discussion/Conclusion: The changes in the scores over time and the contents of the field notes were consistent with each other, suggesting that the DEOS can be used both to evaluate the effects of interventions and to plan care that takes advantage of each participant’s positive aspects.

Spontaneous intracerebral hemorrhage (SICH) is a severe subtype of stroke. Hematoma expansion could occur in the short term after symptom onset in most patients, leading to neurological deterioration and mortality. Therefore, early hemostasis treatment is essential to save patients' lives and improve prognosis. Currently, the hemostatic agents used for intracerebral hemorrhage are mainly antifibrinolytic drugs and recombinant activated factor Ⅶ. However, there is no decisive evidence for the clinical benefit of hemostatic drugs in patients with intracerebral hemorrhage. To provide reference for clinical choice of drugs, this article reviews the hematoma expansion mechanism and hemostatic therapy of spontaneous intracerebral hemorrhage. doi：10.3969/j.issn.1672⁃6731.2021.02.006

Acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is an immune mediated neuropathy characterized by progressive weakness and sensory impairment lasting over 2 months. Guillain-Barré-Strohl syndrome (GBS) is an immune mediated polyneuropathy with a similar presentation often over less than 4 weeks. While some have argued for the existence of recurrent GBS, most classify the syndrome as a form of relapsing-remitting CIDP. However, there are cases of GBS with treatment-related fluctuations that must be distinguished from A-CIDP as patients with A-CIDP require long-term immunotherapy. In this case report, we discuss a patient with multiple relapses over 3 years, who is more likely to have A-CIDP. His ganglioside profile, which has rarely been reported in A-CIDP, included high concentrations of anti-GM1, anti-GD1a, and anti-GD1b antibodies, which may account for his severe disease course.

Neurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms. In the present study, we prepared different tau fractions by sedimentation combined with sarkosyl solubility from AD brains and analyzed their biochemical and pathological properties. We found that tau in oligomeric fraction (O-tau), sarkosyl-insoluble fractions 1 and 2 (SI1-tau and SI2-tau) and monomeric heat-stable fraction (HS-tau) showed differences in truncation, hyperphosphorylation, and resistance to proteinase K. O-tau, SI1-tau, and SI2-tau, but not HS-tau, were hyperphosphorylated at multiple sites and contained SDS- and β-mercaptoethanol–resistant high molecular weight aggregates, which lacked the N-terminal portion of tau. O-tau and SI2-tau displayed more truncation and less hyperphosphorylation than SI1-tau. Resistance to proteinase K was increased from O-tau to SI1-tau to SI2-tau. O-tau and SI1-tau, but not SI2-tau or HS-tau, captured tau from cell lysates and seeded tau aggregation in cultured cells. Heat treatment could not kill the prion-like activity of O-tau to capture normal tau. Hippocampal injection of O-tau into 18-month-old FVB mice induced significant tau aggregation in both ipsilateral and contralateral hippocampi, but SI1-tau only induced tau pathology in the ipsilateral hippocampus, and SI2-tau and HS-tau failed to induce any detectable tau aggregation. These findings suggest that O-tau and SI1-tau have prion-like activities and may serve as seeds to recruit tau and template tau to aggregate, resulting in the propagation of tau pathology. Heterogeneity of tau pathology within AD brain results in different fractions with different biological and prion-like properties, which may pose a major challenge in targeting tau for development of effective therapeutic treatments.

Chemical synapses in the brain connect neurons to form neural circuits, providing the structural and functional bases for neural communication. Disrupted synaptic signaling is closely related to a variety of neurological and psychiatric disorders. In the past two decades, proteomics has blossomed as a versatile tool in biological and biomedical research, rendering a wealth of information toward decoding the molecular machinery of life. There is enormous interest in employing proteomic approaches for the study of synapses, and substantial progress has been made. Here, we review the findings of proteomic studies of chemical synapses in the brain, with special attention paid to the key players in synaptic signaling, i.e., the synaptic protein complexes and their post-translational modifications. Looking toward the future, we discuss the technological advances in proteomics such as data-independent acquisition mass spectrometry (DIA-MS), cross-linking in combination with mass spectrometry (CXMS), and proximity proteomics, along with their potential to untangle the mystery of how the brain functions at the molecular level. Last but not least, we introduce the newly developed synaptomic methods. These methods and their successful applications marked the beginnings of the synaptomics era.

Primary brainstem hemorrhage (PBSH) has the worst outcome among all types of spontaneous intracerebral hemorrhage (SICH). There is no standardized criteria to diagnose PBSH. Generally, the diagnosis of PBSH is based on the history of hypertension, the clinical and radiological features after excluding other bleeding etiologies such as aneurysm, arteriovenous malformation, cavernomas and tumor apoplexy within brainstem. The management of PBSH remains controversial. Conservative and supportive treatment is given in most western countries where surgery is considered not to improve consciousness and other neurological functions. However, Asian countries such as China, Korea and Japan make a great contribution in surgical management of PBSH, emphasizing the lifesaving role of surgery. The current study of PBSH progresses very slow due to the lack of high ⁃ level clinical trial. In the future, multicenter cohort or randomized clinical study may guide the best way to deal with PBSH. doi：10.3969/j.issn.1672⁃6731.2021.02.002

Background New Oral Anticoagulants (NOACs) such as Rivaroxaban are introduced as alternatives to conventional vitamin-K antagonists in the long-term treatment of thrombotic events due to their lower bleeding risk. There is a lack of evidence on the effectiveness and safety of Rivaroxaban in Cerebral venous thrombosis (CVT). This study aims to assess the effectiveness and bleeding risk of Rivaroxaban in comparison with Warfarin for the treatment of CVT. Materials and methods 36 patients with diagnosis of CVT were included. Clinical and background information was assessed on admission and patients were followed for at least 12 months. Measured outcomes were modified Rankin Scale (mRS), evidence of recanalization on contrast-enhanced Brain MR venography (MRV) and major or minor bleeding. Patients were divided into two groups according to the type of oral anticoagulant (Rivaroxaban vs Warfarin). Groups were compared in terms of final outcomes and side effects. Result Overall, 13 (36.11%) patients received Warfarin and 23 (63.89%) received Rivaroxaban. Optimal mRS score (0–1) was attained in 9 of 10 (90%) of patients treated with Rivaroxaban and 19 of 22 (86.36%) of patients received Warfarin. MRV showed complete or partial recanalization in 12 of 14 (85.71%) patients treated with Rivaroxaban and all patients in the Warfarin group. There was no significant difference between the two groups in terms of major and minor hemorrhage. Conclusion Rivaroxaban holds promise for the treatment of CVT.

Objective To assess the predictive value of common measures validated to predict falls in other geriatric populations in patients presenting with suspected Normal Pressure Hydrocephalus (NPH). Methods One hundred ninety-five patients over the age of 60 who received the Fall Risk Questionnaire were retrospectively recruited from the CSF Disorders clinic within the departments of Neurosurgery and Neurology. Multiple logistic regression was used to create a model to predict falls for patients with suspected NPH using common measures: Timed Up & Go, Dual Timed Up & Go, 10 Meter Walk, MiniBESTest, 6-Minute Walk, Lower Extremity Function (Mobility), Fall Risk Questionnaire, and Functional Activities Questionnaire. Results The Fall Risk Questionnaire and age were shown to be the best predictors of falls. The model was 95.92% (Positive predictive value: 83.93%) sensitive and 47.92% specific (Negative predictive value: 77.78%). Conclusion Patients presenting with suspected NPH are at an increased fall risk, 75% of the total patients and 89% of patients who responded to a temporary drain of CSF had at least one fall in the past 6 months. The Fall Risk Questionnaire and age were shown to be predictive of falls for patients with suspected NPH. The preliminary evidence indicates measures that have been validated to assess fall risk in other populations may not be valid for patients presenting with suspected NPH.

Sudden-onset bilateral cortical deafness is a very rare symptom of stroke, but must be recognized as stroke, as it is a treatable condition, and the treatment is highly time dependent. We report a 53-year-old man with an acute onset of complete bilateral hearing loss that gradually improved spontaneously over 4 h. The hearing loss was explained by an infarction visualized on magnetic resonance imaging, which showed a subacute temporoparietal ischemic lesion in the left cerebral hemisphere involving the insular cortex and an older infarction in the right temporoparietal region. The location of these kinds of lesions may typically not cause motor deficits, but sensory and cognitive (e.g., aphasia) symptoms, which can be challenging to recognize in a suddenly deaf patient. Taking the possible differential diagnoses into account, immediate stroke workup should always be prioritized in patients with sudden bilateral deafness, as acute revascularizing treatment is possible.

Cholesterol is an essential component for neural physiology. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood⁃brain barrier (BBB). In order to keep brain function well, the content of cholesterol in brain must be accurately maintained through close coordination between astrocyte, neurons and vascular endothelial cell, which are the three main components of neurovascular unit (NVU). Hypercholesterolemia is usually accompanied with increased permeability of BBB, activated astrocytes then upregulate the transcription of a series of cholesterol⁃related genes, leading to high expression of cholesterol transmembrane proteins, which destroy the stability of the cell⁃to⁃cell signal transduction between astrocyte and neuron, together with activated microglia releasing a large number of neuroinflammatory factors, triggering the neuroinflammatory response, and eventually lead to neuronal cell apoptosis. As a result, hypercholesterolemia related cognitive dysfunction is present. Vascular endothelial injury characterized by erythrocyte stasis, is an early manifestation of hypercholesterolemia on brain small vessels and capillaries, the appearance of fribi thrombi is a sign of the late stage of cerebral small vessel disease (CSVD), causing extensive occlusion of brain microvessels, resulting in decreased vascular density and cerebral blood flow. Hypercholesterolemia shows positive correlation with the characteristic features of CSVD on MRI, such as lacunar infarction, periventricular white matter hyperintensity and brain atrophy, but rarely with cerebral microbleeds (CMBs). With the advent of statins and their wide⁃spread application, the risk of stroke and its all⁃cause mortality decreased greatly around the world, which is mainly related to the significant decrease of plasma low density lipoprotein cholesterol (LDL⁃C) level caused by statins. However, there are still a number of controversial reports about the relationship with hypercholesterolemia, statin therapy and the risk of cerebral hemorrhage, thus, further work is needed. doi：10.3969/j.issn.1672⁃6731.2021.02.008

Background/Setting A subject presenting with a unilateral sensorineural hearing loss and with vertigo/imbalance and a lesion of internal acoustic meatus (IAM) most often represents a vestibular schwannoma. Several alternative pathologies involving the region, with clinical and neuroradiological similarities, could lead to an error in judgement and management. Rare tumors of the IAM pose unique diagnostic difficulty. A rare case that we present here had a typical history and imaging findings suggestive of vestibular schwannoma. A primary central nervous system (CNS) lymphoma was diagnosed in later stages of brain involvement warranting a retrospective analysis of the entity. Case Summary An 80-year-old male presented with unilateral sensorineural hearing loss, vertigo, and imbalance. On imaging, he was found to have a lesion in the left internal auditory meatus, reported as a vestibular schwannoma and operated upon. Subject's condition worsened with time and a repeat imaging was suggestive of a CNS lymphoma with lesions involving bilateral cerebellum and subcortical white matrix. Conclusion To conclude, primary CNS lymphoma presenting an isolated lesion in the IAM with no other parenchymal lesions at presentation is a rare incidence; to our knowledge this is the first case of such unique presentation.

The mechanism of occurrence and rupture of intracranial aneurysm is complex and may involve various environmental and genetic factors. Histopathological studies of intracranial aneurysm suggest a possible relationship between intracranial aneurysm and connective tissue diseases. Clinical studies have shown that patients suffering from hereditary connective tissue diseases are at significantly increased risk of multiple cerebrovascular diseases such as intracranial aneurysm. Further studies have found that mutations in associated gene loci involved in these hereditary diseases are closely related to the occurrence and development of intracranial aneurysm. Based on previous literatures, this study aims to review intracranial aneurysm related hereditary connective tissue diseases and important gene loci involved. doi：10.3969/j.issn.1672⁃6731.2021.02.009

After the onset of intracerebral hemorrhage (ICH), the immune storm causes the massive death of neurons and their supporting cells. Cytotoxic substances such as hemoglobin, heme and iron ions released by red blood cells lysis also promote death of neurons. After neurons died, damage⁃associated molecular patterns (DAMP) are released to activate the innate immune response, leading to a vicious circle of "inflammatory response⁃cell death⁃DAMP release⁃inflammatory response", which is an important mechanism of secondary brain injury after ICH. A series of studies have explored the role of DAMP in secondary brain injury after ICH. This review summarizes the research progress and provides references for further basic research and clinical translational research. doi：10.3969/j.issn.1672⁃6731.2021.02.004

Vulvovaginal candidiasis is a common fungal infection caused by Candida Sp, especially Candida albicans. Recurrent vulvovaginal candidiasis was defined as the occurrence of four or more episodes of vulvovaginal candidiasis ​​in 12 months period. As many as 9% of women from various populations have recurrent vulvovaginal candidiasis. Vulvovaginal candidiasis affects the quality of life, mental health, and sexual activity. There are many predisposing factors that caused recurrent vulvovaginal candidiasis, such as genetics, host, habit, idiopathic and non-albican candida microbes. Management of recurrent vulvovaginal candidiasis includes elimination of predisposing factors; mycological culture diagnosis and identification of specific Candida species; followed by microbiological examination to confirm the sensitivity of the azole group to Candida sp. Further, oral, or topical therapy should be continued until the patient is asymptomatic and culture-negative. Patients should receive induction therapy followed by maintenance suppressive therapy for six months.

Background Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) plays an important role in mediating inflammatory responses during ischemic stroke. Bile acid receptor Takeda-G-protein-receptor-5 (TGR5) has been identified as an important component in regulating brain inflammatory responses. In this study, we investigated the mechanism of TGR5 in alleviating neuroinflammation after middle cerebral artery occlusion (MCAO). Methods Sprague-Dawley rats were subjected to MCAO and TGR5 agonist INT777 was administered intranasally 1 h after MCAO. Small interfering RNAs (siRNA) targeting TGR5 and Pellino3 were administered through intracerebroventricular injection 48 h before MCAO. Infarct volumes and neurologic scores were evaluated, and ELISA, flow cytometry, immunofluorescence staining, immunoblotting, and co-immunoprecipitation were used for the evaluations. Results Endogenous TGR5 and Pellino3 levels increased after MCAO. TGR5 activation by INT777 significantly decreased pro-inflammatory cytokine, cleaved caspase-8, and NLRP3 levels, thereby reducing brain infarctions; both short- and long-term neurobehavioral assessments showed improvements. Ischemic damage induced the interaction of TGR5 with Pellino3. Knockdown of either TGR5 or Pellino3 increased the accumulation of cleaved caspase-8 and NLRP3, aggravated cerebral impairments, and abolished the anti-inflammatory effects of INT777 after MCAO. Conclusions TGR5 activation attenuated brain injury by inhibiting neuroinflammation after MCAO, which could be mediated by Pellino3 inhibition of caspase-8/NLRP3.

Background: Transcranial direct current stimulation (tDCS) of the cerebellum dynamically modulates cerebello-thalamo-cortical excitability in a polarity-specific manner during motor, visuo- motor and cognitive tasks. It remains to be established whether tDCS of the cerebellum impact also on resting-state intrinsically connected networks (ICNs). Such impact would open novel research and therapeutical doors for the neuromodulation of ICNs in human. Method: We combined tDCS applied over the right cerebellum and fMRI to investigate tDCS- induced resting-state intrinsic functional reconfiguration, using a randomized, sham-controlled design. fMRI data were recorded both before and after real anodal stimulation (2 mA, 20 min) or sham tDCS in 12 right-handed healthy volunteers. We resorted to a region-of-interest static correlational analysis and to a sliding window analysis to assess temporal variations in resting state FC between the cerebellar lobule VII and nodes of the main ICNs. Results: After real tDCS and compared with sham tDCS, functional changes were observed between the cerebellum and ICNs. Static FC showed enhanced or decreased correlation between cerebellum and brain areas belonging to visual, default-mode (DMN), sensorimotor and salience networks (SN) (p-corrected < 0.05). The temporal variability (TV) of BOLD signal was significantly modified after tDCS displaying in particular a lesser TV between the whole lobule VII and DMN and central executive network and a greater TV between crus 2 and SN. Static and dynamic FC was also modified between cerebellar lobuli. Conclusion: These results demonstrate short- and long-range static and majorly dynamic effects of tDCS stimulation of the cerebellum affecting distinct resting-state ICNs, as well as intracerebellar functional connectivity, so that tDCS of the cerebellum appears as a non-invasive tool reconfigurating the dynamics of ICNs., SCOPUS: ar.j, info:eu-repo/semantics/published

Background The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 μg/0.5 μL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. Results The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 μg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. Conclusions The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

Background Regardless of the cause of the superficial siderosis (SS) disease, which is bleeding, the source of bleeding cannot be found in some cases. Case presentation In this article, we report two cases with idiopathic SS. Case 1 presented with bilateral hearing loss, cognitive impairment, sleep disturbances, and tremors. Case 2 presented with sensory neural hearing loss, ataxia, and spastic paraparesis. In both cases, brain MRI indicated evidence of SS. CT myelogram and SPECT with labeled RBC couldn’t help finding the source of occult bleeding. Conclusion SS is a rare central nervous system disease caused by the deposition of hemosiderin in the brain and spinal cord, which results in the progression of neurological deficits. The cause of this hemorrhage is often subarachnoid haemorrhage, intracranial surgery, carcinoma, arteriovenous malformation, nerve root avulsion, and dural abnormality. The condition progresses slowly and, by the time diagnosis is confirmed, the damage is often irreversible. In our cases, brain MRI clarified the definitive diagnosis, but we could not find the source of bleeding. SS should be considered in cases with ataxia and hearing loss, even if no source of bleeding is found.

Background The pathological process of traumatic spinal cord injury (SCI) involves excessive activation of microglia leading to the overproduction of proinflammatory cytokines and causing neuronal injury. Sphingosine kinase 1 (Sphk1), a key enzyme responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P), plays an important role in mediating inflammation, cell proliferation, survival, and immunity. Methods We aim to investigate the mechanism and pathway of the Sphk1-mediated neuroinflammatory response in a rodent model of SCI. Sixty Sprague-Dawley rats were randomly assigned to sham surgery, SCI, or PF543 (a specific Sphk1 inhibitor) groups. Functional outcomes included blinded hindlimb locomotor rating and inclined plane test. Results We discovered that Sphk1 is upregulated in injured spinal cord tissue of rats after SCI and is associated with production of S1P and subsequent NF-κB p65 activation. PF543 attenuated p65 activation, reduced inflammatory response, and relieved neuronal damage, leading to improved functional recovery. Western blot analysis confirmed that expression of S1P receptor 3 (S1PR3) and phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) are activated in microglia of SCI rats and mitigated by PF543. In vitro, we demonstrated that Bay11-7085 suppressed NF-κB p65 and inhibited amplification of the inflammation cascade by S1P, reducing the release of proinflammatory TNF-α. We further confirmed that phosphorylation of p38 MAPK and activation of NF-κB p65 is inhibited by PF543 and CAY10444. p38 MAPK phosphorylation and NF-κB p65 activation were enhanced by exogenous S1P and inhibited by the specific inhibitor SB204580, ultimately indicating that the S1P/S1PR3/p38 MAPK pathway contributes to the NF-κB p65 inflammatory response. Conclusion Our results demonstrate a critical role of Sphk1 in the post-traumatic SCI inflammatory cascade and present the Sphk1/S1P/S1PR3 axis as a potential target for therapeutic intervention to control neuroinflammation, relieve neuronal damage, and improve functional outcomes in SCI.

The SCN9A gene encodes a voltage gated sodium channel Nav1.7 in which mutations can result in a wide variety of phenotypes ranging from congenital insensitivity to pain to small fiber neuropathy. We report the genotype phenotype analysis in a family carrying a specific mutation, I1739V, in the SCN9A gene. Neurophysiological studies have documented the gain of function impact of this mutation on this sodium channel. Interestingly, there is significant interfamilial phenotypic variability in individuals carrying this mutation. In our family, a father daughter combination had identical genotypes analyzing the SCN9A gene and multiple other genes known to cause neuropathy. Both of them carry the I1739V mutation but exhibit significant phenotypic variability with complaints of decreased sensitivity to discomfort in the father while the daughter has the clinical and laboratory features consistent with a small fiber neuropathy. We hypothesize that there are modifiers of the I1739V mutation that could involve intronic or exonic gene variants which contribute to this intrafamilial phenotypic variability. Our study has implications for genetic counseling, personalized medicine and the development of drugs to treat neuropathic pain.