Oncostatin M:a love-hate relationship in neuroinflammation

<正>Oncostatin M and multiple sclerosis:Every 5minutes,someone in the world is diagnosed with multiple sclerosis(MS),a chronic inflammatory and degenerative disease of the central nervous system(CNS).MS appears in unpredictable episodes of symptoms,which are highly patient-dependent,but often include visual impairment,muscle weakness/spasms,fatigue,cognitive difficulties,and bladder.bowel.or sexual dysfunction.     

Optical coherence tomography and T cell gene expression analysis in patients with benign multiple sclerosis

Benign multiple sclerosis is a retrospective diagnosis based primarily on a lack of motor symptom progres-sion. Recent findings that suggest patients with benign multiple sclerosis experience non-motor symptoms highlight the need for a more prospective means to diagnose benign multiple sclerosis early in order to help direct patient care. In this study, we present optical coherence tomography and T cell neurotrophin gene analysis findings in a small number of patients with benign multiple sclerosis. Our results demonstrated that retinal nerve fiber layer was mildly thinned, and T cells had a distinct gene expression profile that in-cluded upregulation of interleukin 10 and leukemia inhibitory factor, downregulation of interleukin 6 and neurotensin high affinity receptor 1 (a novel neurotrophin receptor). These findings add evidence for fur-ther investigation into optical coherence tomography and mRNA profiling in larger cohorts as a potential means to diagnose benign multiple sclerosis in a more prospective manner.     

Short-chain fatty acids in the context of Parkinson’s disease

Research on neurodegenerative diseases such as Alzheimer’s disease,Parkinson′s disease(PD),Huntington’s disease or amyotrophic lateral sclerosis is becoming increasingly important in our society.Due to the ageing of the population,the prevalence of these diseases continue to rise worldwide,and causal cures are not yet available(Erkkinen et al.,2018).This Perspective focusses on PD,a movement disorder of the central nervous system with an estimated prevalence between 65 and 1250/100,000 in Europe,affecting about 1 percent of the population older than 60 years.The clinical symptoms include motor symptoms like bradykinesia,tremor or rigidity which are associated with loss of dopaminergic neurons in the substantia nigra and their innervating axonal fibers to the striatum.Additional non-motor symptoms may consist in depression,hyposmia,cognitive decline or constipation due to impaired motility of the gastrointestinal tract.     

Ultra-early amplitude decrement after repetitive nerve stimulation supports early neuromuscular junction injury in amyotrophic lateral sclerosis: a prospective cross-sectional study

The dying-back hypothesis holds that the damage to neuromuscular junctions and distal axons in amyotrophic lateral sclerosis occurs at the earliest stage of the disease.Previous basic studies have confirmed early damage to neuromuscular junctions,but it is difficult to obtain such evidence directly in clinical practice.In this prospective cross-sectional study,we recruited 22 patients with early amyotrophic lateral sclerosis with disease duration < 12 months and with clinical symptoms limited to the upper limbs.We also recruited 32 healthy controls.Repetitive nerve stimulation was performed,and patients were followed for 12 months.We found a significant change in the response to repetitive nerve stimulation in amyotrophic lateral sclerosis patients without spontaneous electromyographic activity.Patients that were prone to denervation had an increased decrement response of target muscles after repetitive nerve stimulation.These results suggest that changes in response to repetitive nerve stimulation may occur before denervation in amyotrophic lateral sclerosis patients.The damage to lower motor neurons is more obvious in patients with a higher percentage of repetitive never stimulation-related amplitude decrements.This study was approved by the Institutional Ethics Committee of Peking University Third Hospital(approval No.M2017198) on August 24,2017.     

Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis

正The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis(ALS):ALS is a progressive neurological disease characterized primarily by the development of limb paralysis,which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years.Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested.Since its original discovery,ALS has been associated with pathological alterations in motor neurons located     

MAPT as a predisposing gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population

A previous study of European Caucasian patients with sporadic amyotrophic lateral sclerosis demonstrated that a polymorphism in the microtubule-associated protein Tau （MAPT） gene was significantly associated with sporadic amyotrophic lateral sclerosis pathogenesis. Here, we tested this association in 107 sporadic amyotrophic lateral sclerosis patients and 100 healthy controls from the Chinese Han population. We screened the mutation-susceptible regions of MAPT- the 3＇ and 5＇ untranslated regions as well as introns 9, 10, 11, and 12 - by direct sequencing, and identified 33 genetic variations. Two of these, 105788 A 〉 G in intron 9 and 123972 T 〉 A in intron 11, were not present in the control group. The age of onset in patients with the 105788 A 〉 G and/or the 123972 T 〉 A variant was younger than that in patients without either genetic variation. Moreover, the pa- tients with a genetic variation were more prone to bulbar palsy and breathing difficulties than those with the wild-type genotype. This led to a shorter survival period in patients with a MAPT genetic variant. Our study suggests that the MAPT gene is a potential risk gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population.     

Synaptopathy in CHMP2B frontotemporal dementia highlights the synaptic vesicle cycle as a therapeutic target

<正>Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both devastating neurodegenerative conditions.Despite affecting different regions of the nervous system (FTD affecting primarily the frontal and temporal lobes,whilst ALS presents with motor neuron loss),there is significant overlap between these conditions in terms of genetics,pathology,and disease mechanisms,and they are therefore often grouped as a spectrum of symptoms under the heading FTD/ALS (Abramzon et al....     

The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder.Consequently,the norepinephrine transporter gene is an attractive candidate in major depressive disorder research.In the present study,we evaluated the depression symptoms of subjects with major depressive disorder,who were all from the North of China and of Han Chinese origin,using the Hamilton Depression Scale.We examined the rela-tionship between two single nucleotide polymorphisms in the norepinephrine transporter,rs2242446 and rs5569,and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program.rs5569 was associated with depressed mood,and the GG genotype may be a risk factor for this;rs2242446 was associated with work and interest,and the TT genotype may be a risk factor for loss of interest.Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Han Chinese population.     

Safety of intrathecal injection of Wharton's jellyderived mesenchymal stem cells in amyotrophic lateral sclerosis therapy

Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.     

Activities of daily living and lesion position among multiple sclerosis patients by Bayes network

Magnetic resonance imaging is a highly sensitive approach for diagnosis of multiple sclerosis,and T2-weighted images can reveal lesions in the cerebral white matter,gray matter,and spinal cord.However,the lesions have a poor correlation with measurable clinical disability.In this study,we performed a large-scale epidemiological survey of 238 patients with multiple sclerosis in eleven districts by network member hospitals in Shanghai,China within 1 year.The involved patients were scanned for position and size of lesions by MRI.Results showed that lesions in the cerebrum,spinal cord,or supratentorial position had an impact on the activities of daily living in multiple sclerosis patients,as assessed by the Bayes network.On the other hand,brainstem lesions were very unlikely to influence the activities of daily living,and were not associated with the position of lesion,patient’s gender,and patient’s living place.     

Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample

OBJECTIVE: Previous research has shown high prevalence rates of depression in multiple sclerosis patients seen in specialty clinics. The relationships among depressive symptoms and severity, duration, and course of multiple sclerosis are controversial. METHOD: A survey was mailed to members of the Multiple Sclerosis Association of King County (Wash.). Of the 1,374 eligible participants, 739 returned the survey, a response rate of 53.8%. Data about demographic characteristics, employment, and duration and course of multiple sclerosis were collected. Severity of multiple sclerosis was determined by the Expanded Disability Status Scale, self-report version. Severity of depressive symptoms was evaluated with the Center for Epidemiologic Studies Depression Scale (CES-D Scale). Analysis of covariance was used to compare mean CES-D Scale scores across categories of multiple sclerosis, and logistic regression was used to identify variables associated with clinically significant depression. RESULTS: Clinically significant depressive symptoms (CES-D Scale score > or =16) were found in 41.8% of the subjects, and 29.1% of the subjects had moderate to severe depression (score > or =21). Subjects with advanced multiple sclerosis were much more likely to experience clinically significant depressive symptoms than subjects with minimal disease. Shorter duration of multiple sclerosis was associated with a greater likelihood of significant depressive symptoms, but the pattern of illness progression was not. CONCLUSIONS: In this large community sample, the severity of multiple sclerosis was more strongly associated with depressive symptoms than was pattern of illness. Clinicians should evaluate depression in patients with recent diagnoses of multiple sclerosis, major changes in functioning, or limited social support.     

Psychiatric aspects of multiple sclerosis

A patient who presented with depressive and hysterical symptoms of several years' duration and who proved to have multiple sclerosis is presented. Two further cases whose initial symptoms of dissociation and major depression were prodromes of multiple sclerosis are also presented. A discussion of the factors leading to the correct diagnosis in these cases and reference to relevant literature on psychiatric presentations of multiple sclerosis are presented to illustrate the need for psychiatrists' awareness of multiple sclerosis as a causative factor in patients with a wide variety of psychiatric syndromes.     

Cerebral magnetic resonance imaging findings in multiple sclerosis. Relation to disturbance of affect, drive, and cognition

Forty-six patients with multiple sclerosis were rated with respect to their psychologic symptoms, and magnetic resonance imaging was performed. A significant correlation between the cerebral multiple sclerosis manifestations and the psychologic scores was found. The periventricular and frontal lesions seem to be the most important lesions for the psychologic symptoms of patients with multiple sclerosis.     

Multiple sclerosis and affective disorders

Affective disorders occurring in association with multiple sclerosis have been attributed both to the psychosocial impact of a chronic disabling illness and to the structural lesions of cerebral demyelination. A review of research evidence suggests that while there is a correlation between chronic depressive symptoms and both progressive disability and lack of social support, acute major depressive and manic episodes may be psychiatric manifestations of demyelinating lesions and may be the initial presenting symptoms of multiple sclerosis. Anti-inflammatory agents may be required in the management of acute psychiatric symptoms despite the fact that these agents have a propensity to precipitate psychotic episodes. Two case reports are presented to illustrate the clinical challenge of distinguishing between organic and functional affective illness in patients with multiple sclerosis. The interplay between biological and psychological aspects of multiple sclerosis in precipitating affective disorders is discussed, with implications for patient assessment and management.     

Effect of digitalis on clinical symptoms and conduction variables in patients with multiple sclerosis

Digitalis has been shown to reverse conduction block in demyelinated nerve fibers in experimental animals. In the search for a symptomatic treatment of multiple sclerosis, digoxin (0.02 mg per kilogram of body weight) was given intravenously to 7 patients with probable or clinically definite multiple sclerosis. All of these patients had temperature-dependent symptoms. In 3 patients, improvement of clinical deficits was observed concurrent with significant changes in evoked potential findings. Digitalis derivatives may be useful in ameliorating symptoms in selected patients with multiple sclerosis.     

Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups

Sexual dysfunction is a very important but often overlooked symptom of multiple sclerosis. To investigate the type and frequency of symptoms of sexual dysfunction in patients suffering from multiple sclerosis, we performed a case-control study comparing 108 unselected patients with definite multiple sclerosis, 97 patients with chronic disease and 110 healthy individuals with regard to sexual function, sphincteric function, physical disorders impeding sexual activity and the impact of sexual dysfunction on social life. Information has been collected from a face-to-face structured interview performed by a doctor of the same gender as the patient. The disability, the cognitive performances, the psychiatric conditions and the psychological profile of patients and controls have been assessed. Sexual dysfunction was present in 73.1% of cases, in 39.2% of chronic disease controls and in 12.7% of healthy controls (P<0.0001). Male cases reported symptoms of sexual dysfunction more frequently than female cases (P<0.002). Symptoms of sexual dysfunction more commonly reported in patients with multiple sclerosis were anorgasmia or hyporgasmia (37.1%), decreased vaginal lubrication (35.7%) and reduced libido (31.4%) in women, and impotence or erectile dysfunction (63.2%), ejaculatory dysfunction and/or orgasmic dysfunction (50%) and reduced libido (39.5%) in men. Seventy-five per cent of cases, 51.5% of chronic disease controls and 28.2% of healthy controls (P<0.0001) experienced symptoms of sphincteric dysfunction. In conclusion, a substantial part of our sample of patients with multiple sclerosis reported symptoms of sexual and sphincteric dysfunction. Both sexual and sphincteric dysfunction were significantly more common in patients with multiple sclerosis than in either control group. Our findings suggest that a peculiar damage of the structures involved in sexual function is responsible for the dysfunction in patients with multiple sclerosis, but the highly significant lower frequency of symptoms of depression and anxiety in healthy controls may also imply a possible causative role of psychological factors.     

Management of acute exacerbations in multiple sclerosis

A key component of multiple sclerosis is the occurrence of episodes of clinical worsening with either new symptoms or an increase in older symptoms over a few days or weeks. These are known as exacerbations of multiple sclerosis. In this review, we summarize the pathophysiology and treatment of exacerbations and describe how they are related to the overall management of this disease.     

Lead poisoning from complementary and alternative medicine in multiple sclerosis

A patient with multiple sclerosis is described who was treated for neurological symptoms thought to be a progression of his disease but subsequently found to be caused by lead poisoning secondary to the use of alternative medicine. His clinical signs improved with oral chelation therapy. Neurologists should consider asking about the use of complementary and alternative medicine before simply attributing symptoms and signs to exacerbation of multiple sclerosis.     

OPTIC NEURITIS: STUDIES ON THE CEREBROSPINAL FLUID IN RELATION TO CLINICAL COURSE IN 61 PATIENTS

A prospective study on 61 previously healthy patients with acute mono-symptomatic optic neuritis is reported. Interest was focused on changes in the cerebrospinal fluid and the clinical course with possible development of multiple sclerosis. At the beginning of the disease, a mononuclear pleocytosis was noted in 51 per cent of the patients, an elevated IgG level in 18 per cent, and an oligoclonal IgG distribution in 41 per cent. These results are in sharp contrast to those in multiple sclerosis. Eleven patients have so far developed definite multiple sclerosis. At onset only five of these had cerebrospinal fluid findings indistinguishable from those in multiple sclerosis, with pleocytosis and bands on electrophoresis. In five more patients, who subsequently developed multiple sclerosis, the cerebrospinal fluid IgG was normal at onset, but an oligoclonal IgG appeared during the follow-up; there was no correlation in time between the appearance of new symptoms and cerebrospinal fluid changes. In six patients with normal cerebrospinal fluid and four patients with only mononuclear pleocytosis at the onset of disease, the IgG pattern became oligoclonal on electrophoresis during the follow-up period, although the patients had no further symptoms or signs of disease. It was concluded, therefore, that the cerebrospinal fluid was often normal in the first attack of what later proved to be multiple sclerosis, and that a normal fluid did not preclude a development into definite multiple sclerosis. Sometimes IgG bands appeared in previously normal cerebrospinal fluid, although the patients had not experienced new symptoms.     

The management of multiple sclerosis patients

The management of individuals with multiple sclerosis must be considered under the following headings: administration and follow-up of adequate disease-modifying treatment, symptomatic relief and neurorehabilitation. Neurorehabilitation deserves a four-step strategy: multidisciplinary assessment, identification of areas of potential functional improvement, setting of goals of short/long-term duration, and measurement of outcomes. The patient's perspective is important to evaluate through questionnaires about quality of life. Well organized disability services with multidisciplinary specialists are probably cost effective and efficient. Determining the actual economic impact of multiple sclerosis and defining the most cost-effective type of care for persons with multiple sclerosis is a need in all countries faced with the limitation of healthcare resources. In persons with multiple sclerosis the range of main symptoms includes the loss of mobility and spasticity, pain, tremor, abnormal eye movements, paroxysmal symptoms, bladder and bowel dysfunction, sexual disturbances, fatigue and depression. Current palliative treatments, which are reviewed, are partly successful depending on the type of symptoms under consideration.