CCR2-64I and CCR5��32 Polymorphisms in Korean Patients with Myasthenia Gravis

Background and purpose

Chemokines participate in the regulation of immune and inflammatory responses by interacting with their receptors, which are primarily expressed on immune and inflammatory cells such as B- and T-lymphocytes and antigen-presenting cells. Chemokines and their receptors are therefore considered to mediate inflammation and tissue damage in autoimmune disorders. Chemokine receptor (CCR) genotypes were recently identified, and the importance of their genetic polymorphisms in some autoimmune and infectious disorders has been demonstrated. To define the roles of the polymorphism of the CCR2 gene at codon 64 (CCR2-64I) and the 32-bp deletion in the coding region of CCR5 (CCR5Δ32) in Korean patients with myasthenia gravis (MG), we compared these genotypes in MG cases and healthy controls and investigated the clinical features associated with these genotypes.

Methods

One hundred and fifteen healthy controls (51 men and 64 women) and 109 MG patients (44 men and 65 women) from three University hospitals were included. We examined each patient for clinical features using electrophysiology tests, laboratory tests, and thymic pathology. The CCR2-64I and CCR5Δ32 polymorphisms were determined by the PCR-RFLP method.

Results

We detected no difference in the frequencies of CCR2-64I polymorphism between MG patients and healthy controls. All of the MG patients and the healthy controls were homozygous for the wild-type CCR5 genotype. The results of electrophysiological tests and thymic pathologies were not influenced by the type of CCR2-64I polymorphism. However, the anti-acetylcholine-receptor (AChR) antibody titer was higher in the CCR2 G/G genotype (13.34±12.71 nmol/L) than in the CCR2 A/A genotype (5.83±2.56 nmol/L).

Conclusions

We found no evidence of an increased risk for MG associated with the CCR2-64I and CCR5Δ32 polymorphisms. However, the increased anti-AChR antibody titer in the patients with the CCR2 G/G genotype suggests that the CCR2 gene play a role in the pathophysiology of MG.     

Clinical and serological study of myasthenia gravis in HuBei Province, China

Background

Ocular and childhood myasthenia gravis (MG) cases seem relatively more common in Oriental than in Caucasian populations, but there have been no comprehensive serological studies on patients from mainland China.

Methods

391 unselected patients with MG attending Tongji Hospital in WuHan (the largest hospital in the province of HuBei, China) were studied during a 15‐month period; most had already received treatment for their condition.

Results

The male to female ratio was 0.8. 50% of the patients were children (<15 years), and age at onset showed a single peak at between 5 and 10 years of age. 64% of the children and 66% of the adults were positive for acetylcholine receptor (AChR) antibodies but the antibody titres were lower than in similar Caucasian studies, although this was partly due to the high incidence of ocular MG. Of the 43 patients with generalised MG without AChR antibodies, only 1 had muscle‐specific kinase antibodies (2.5%) and 2 had voltage‐gated calcium channel antibodies indicating probable Lambert–Eaton myasthenic syndrome. 75% of the children, compared with only 28% of the adults, had ocular MG. Thymoma was evident by MRI in 1.5% of children and in 20% of adults. Despite most patients having received prednisone, very few had obtained full clinical remission.

Conclusion

This study emphasises the frequency of early childhood onset with ocular symptoms and shows that many of these patients have AChR antibodies. By contrast, patients presenting in later age seem to be very uncommon in comparison with recent studies in Caucasian populations.Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. Acetylcholine receptor (AChR) antibodies are present in sera from 80% to 90% of patients with generalised MG, about 50% from those with pure ocular MG and infrequently in healthy people.¹ The remaining 10–20% of generalised patients with MG are AChR antibody negative (seronegative MG, SNMG). IgG autoantibodies to the muscle‐specific kinase (MuSK) were first identified in 70% of patients with generalised SNMG.² However, subsequent reports have found a variable prevalence in different countries, with a low proportion of MuSK antibody‐positive MG in one study from Taiwan³ (reviewed in Vincent and Liete⁴).A number of studies indicate that MG in Oriental populations may be clinically different from that in Caucasians.^5,6,7,8 In particular, paediatric cases are frequent in China, Taiwan and Japan and purely ocular MG is relatively common in children. Since there are also differences in human leucocyte antigen associations between Japanese, Chinese and Caucasian populations,^9,10,11,12 these observations may provide clues to the immunopathogenesis of MG.However, there have been no comprehensive studies of AChR and MuSK antibodies in patients from mainland China. Here, we studied the histories and serology of 391 Chinese patients attending a major hospital in WuHan, China.     

Increased glycogen synthase kinase-3β mRNA level in the hippocampus of patients with major depression: a study using the stanley neuropathology consortium integrative database

Objective

Glycogen synthase kinase-3β (GSK-3β) has become recognized as a broadly influential enzyme affecting diverse range of biological functions, including gene expression, cellular architecture, and apoptosis. The results of previous studies suggest that GSK-3β activity may be increased in the brain of patients with major depressive disorders (MDD). A recent animal study reported increased GSK-3β messenger ribonucleic acid (mRNA) level in the hippocampus of those with depression. However, few studies have investigated GSK-3β activity in the brain of patients with MDD.

Methods

In order to test whether patients with MDD have an increase in GSK-3β activity in the brain compared to normal controls, we explored GSK-3β expression level in all brain regions by using the Stanley Neuropathology Consortium Integrative Database (SNCID), which is a web-based method of integrating the Stanley Medical Research Institute data sets.

Results

The level of GSK-3β mRNA expression in the hippocampus was significantly increased in the MDD group (n=8) compared with the control group (n=12, p<0.05). Spearman''s test also reveals that GSK-3β mRNA expression levels were significantly correlated with nitric oxide synthase 1 (NOS1)(ρ=0.70, p<0.0001) and stathmin-like 3 (STMN3)(ρ=0.70, p<0.0001) in the hippocampus.

Conclusion

Our results correspond with the results of previous animal studies that reported increased GSK-3β activity in the hippocampus of those with depression. Our findings also suggest that oxidative stress-induced neuronal cell death and abnormal synaptic plasticity in the hippocampus may play important roles in the pathophysiology of major depression.     

Expression of Immune Molecules CD25 and CXCL13 Correlated with Clinical Severity of Myasthenia Gravis

Differential expressions of immune molecules have been shown in the thymi with pathological results, including myasthenia gravis (MG). CD25 is an activation marker expressed on T cells. CXCL13 mediates the homing and motility of B cells in secondary lymphoid tissues. Herein, we investigated the expressions of CD25 and CXCL13 in the thymi of thymic hyperplasia patients with MG or with non-MG. A total of 34 thymic hyperplasia patients with MG (20 generalized MG (GMG) and 14 ocular MG (OMG) and six thymic hyperplasia patients without MG were enrolled and analyzed using immunohistochemical staining and real-time polymerase chain reaction for CD25 and CXCL13. Our study demonstrated a higher expression of both CD25 and CXCL13 in hyperplastic thymi with OMG or GMG compared to those with non-MG. According to the immunohistochemical results, we observed that CD25 expression was significantly lower in atrophic thymi and non-MG hyperplastic thymi, compared with that in infant thymi (P?=?0.002 and 0.005, respectively). In contrast to CD25 expression, we did not observe differential expression of CXCL13 among three control groups. And a similar CD25 mRNA expression was found in real-time polymerase chain reaction (PCR) results. We observed that both hyperplastic thymi with OMG or GMG expressed significantly higher levels of CD25 than those with non-MG (P?=?0.007 and 0.001, respectively). And an increase of CD25 expression was observed in hyperplastic thymi with GMG compared to those with OMG (P?=?0.030). Similarly, CXCL13 expression was significantly higher in hyperplastic thymi with GMG or with OMG than those with non-MG (P?=?0.001 and 0.050, respectively). No significant CXCL13 expression difference was found between hyperplastic thymi with GMG and those with OMG (P?>?0.05). The real-time PCR results showed a similar tendency of CD25 mRNA expression among the thymi of non-MG, OMG, and GMG patients, but the difference did not reach significance (P?>?0.05). An obvious increased expression of CXCL13 was found in hyperplastic thymi with GMG patients, compared to those with non-MG and OMG patients (P?=?0.003 and 0.071, respectively). There was no difference found between hyperplastic thymi with non-MG and with OMG. Regression analysis showed a positive correlation between thymic CD25 level and MG symptom severity (F?=?28.240; P?=?0.000, r?=?0.523). Similarly, a positive correlation was found between thymic CXCL13 expression and MG disease severity (F?=?36.093; P?=?0.000, r?=?0.671). Taken together, our findings suggest CD25 and CXCL13 participate in the pathogenesis of MG and may influence the clinical symptoms of MG.     

Association of estrogen receptor gene polymorphism in patients with degenerative lumbar spondylolisthesise

Objective

The purpose of this study was to investigate the possible association of estrogen receptor alpha (ERα) gene polymorphisms in a cohort of degenerative spondylolisthesis (DS) patients.

Methods

Accordingly, the authors examined the association between DS and ERα gene polymorphisms in 174 patients diagnosed with DS. The Pvu II and Xba I polymorphisms, bone mineral density at the lumbar spine and femoral neck, and biochemical markers were analyzed and compared in the 174 patients with DS and 214 patients with spinal stenosis (SS).

Results

A comparison of genotype frequencies in DS and SS patients revealed a significant difference for the Pvu II polymorphism only (p=0.0452). No significant difference was found between these two groups with respect to the Xba I polymorphism, BMD or biochemical markers. No significant association was found between the Pvu II polymorphism of ERα and BMD, vertebral slip or biochemical markers in patients with DS.

Conclusion

These results suggest that the ERα gene polymorphism using Pvu II restriction enzyme influences the prevalence of DS.     

Complement activation profiles in anti-acetylcholine receptor positive myasthenia gravis

Background and purpose

Complement component 5 (C5) targeting therapies are clinically beneficial in patients with acetylcholine receptor antibody⁺ (AChR-Ab⁺) generalized myasthenia gravis (MG). That clearly implicates antibody-mediated complement activation in MG pathogenesis. Here, classical and alternative complement pathways were profiled in patients from different MG subgroups.

Methods

In a case–control study, concentrations of C3a, C5a and sC5b9 were simultaneously quantified, indicating general activation of the complement system, whether via the classical and lectin pathways (C4a) or the alternative pathway (factors Ba and Bb) in MG patients with AChR or muscle-specific kinase antibodies (MuSK-Abs) or seronegative MG compared to healthy donors.

Results

Treatment-naïve patients with AChR-Ab⁺ MG showed substantially increased plasma levels of cleaved complement components, indicating activation of the classical and alternative as well as the terminal complement pathways. These increases were still present in a validation cohort of AChR-Ab⁺ patients under standard immunosuppressive therapies; notably, they were not evident in patients with MuSK-Abs or seronegative MG. Neither clinical severity parameters (at the time of sampling or 1 year later) nor anti-AChR titres correlated significantly with activated complement levels.

Conclusions

Markers indicative of complement activation are prominently increased in patients with AChR-Ab MG despite standard immunosuppressive therapies. Complement inhibition proximal to C5 cleavage should be explored for its potential therapeutic benefits in AChR-Ab⁺ MG.     

Genetic Polymorphisms in the HTR2C and Peroxisome Proliferator-Activated Receptors Are Not Associated with Metabolic Syndrome in Patients with Schizophrenia Taking Clozapine

Objective

Genetic variation in the serotonin-2C receptor encoded by the HTR2C gene is one of the genetic determinants of antipsychotic-induced weight gain. Peroxisome proliferator-activated receptors are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. In this cross-sectional study, we investigated whether HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T genotypes were associated with metabolic syndrome (MetS) in patients with schizophrenia taking clozapine.

Methods

One hundred forty-six Korean patients using clozapine for more than one year were genotyped for the HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T polymorphisms, and their weight, waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol, total cholesterol, and glucose were measured. We used the criteria for MetS proposed by the National Cholesterol Education Program-adapted Adult Treatment Panel III.

Results

The prevalence of MetS was 47.3% and was similar among men (49%) and women (42.9%). We found no significant differences between patients with and without MetS in terms of genotypes or allele frequencies. Logistic regression analyses also revealed no association between MetS and each genotype.

Conclusion

We did not find significant associations between four polymorphisms (HTR2C-759C/T, HTR2C-697G/C, PPARα V227A, and PPARγ 161C/T) and MetS in patients with schizophrenia taking clozapine.     

Mutation Screening of the γ-Aminobutyric Acid Type-A Receptor Subunit γ2 Gene in Korean Patients with Childhood Absence Epilepsy

Background and Purpose

Since the γ-aminobutyric acid type-A receptor subunit γ2 gene (GABRG2) mutation was discovered in an Australian family with childhood absence epilepsy (CAE) and febrile convulsions, a few screening studies for the GABRG2 mutation have been conducted in sporadic individuals with CAE from other ethnic groups. The aim of this study was to determine whether or not the previously reported genetic mutations and single-nucleotide polymorphisms (SNPs) of GABRG2 can be reproduced in sporadic Korean individuals with CAE, compared to healthy Korean individuals.

Methods

Thirty-five children with CAE in Chonnam National University Hospital and healthy controls (n=207) were enrolled, and the medical records of patients with CAE were reviewed. CAE was diagnosed according to the Classification and Terminology of the International League Against Epilepsy. All nine exons of GABRG2 were directly sequenced. In addition, the two SNPs found in our CAE patients were analyzed: C315T in exon 3 (E3) and C588T in exon 5 (E5). The frequencies of the two SNPs in the CAE patients were compared with data from healthy controls (for E3 and E5) and from previously reported Korean population data (only for E3).

Results

No mutation of GABRG2 was found in our CAE patients. In addition, the allele and genotype frequencies of the two polymorphisms did not differ significantly between CAE patients, healthy controls, and the Korean general population (p>0.05).

Conclusions

Our study of sporadic Korean individuals with CAE found no evidence that GABRG2 contributes to the genetic basis of CAE.     

Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis

In myasthenia gravis (MG), extraocular muscle (EOM) weakness is often an initial and persisting symptom. It has been proposed that acetylcholine receptor (AChR) from EOM is antigenically different from AChR of other innervated muscles and that the presence of antibodies to fetal AChR expressed in EOM causes their weakness. We have (1) studied mRNA expression for each of the AChR subunits (α, β, γ, δ, and ?) in human muscle, including EOM, and (2) compared the binding of sera from ocular myasthenia gravis (OMG) patients with fetal (α₂βγδ) and adult (α₂β?δ) human AChRs. RNase protection assays showed that expression of the AChR γ-subunit (fetal-type) mRNA in EOM was comparable with that in other innervated muscle types. By contrast, ?-subunit (adult-type) mRNA was expressed at much higher levels in EOM than in other muscles studied. Moreover, some OMG sera bound specifically to adult AChR. These results do not support the contention that susceptibility of EOM in MG results from expression of fetal AChR and indicate that the inclusion of antigen from a source rich in adult AChR in the MG diagnostic assay will increase the yield of positive results in OMG patients.     

Event-related potentials and changes of brain rhythm oscillations during working memory activation in patients with first-episode psychosis

Background

Earlier contributions have documented significant changes in sensory, attention-related endogenous event-related potential (ERP) components and θ band oscillatory responses during working memory activation in patients with schizophrenia. In patients with first-episode psychosis, such studies are still scarce and mostly focused on auditory sensory processing. The present study aimed to explore whether subtle deficits of cortical activation are present in these patients before the decline of working memory performance.

Methods

We assessed exogenous and endogenous ERPs and frontal θ event-related synchronization (ERS) in patients with first-episode psychosis and healthy controls who successfully performed an adapted 2-back working memory task, including 2 visual n-back working memory tasks as well as oddball detection and passive fixation tasks.

Results

We included 15 patients with first-episode psychosis and 18 controls in this study. Compared with controls, patients with first-episode psychosis displayed increased latencies of early visual ERPs and phasic θ ERS culmination peak in all conditions. However, they also showed a rapid recruitment of working memory–related neural generators, even in pure attention tasks, as indicated by the decreased N200 latency and increased amplitude of sustained θ ERS in detection compared with controls.

Limitations

Owing to the limited sample size, no distinction was made between patients with first-episode psychosis with positive and negative symptoms. Although we controlled for the global load of neuroleptics, medication effect cannot be totally ruled out.

Conclusion

The present findings support the concept of a blunted electroencephalographic response in patients with first-episode psychosis who recruit the maximum neural generators in simple attention conditions without being able to modulate their brain activation with increased complexity of working memory tasks.     

Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer

Background

The clinical and immunological profiles of patients with paraneoplastic cerebellar degeneration (PCD) and non‐small‐cell lung cancer (NSCLC) are not well known.

Objective

To review the clinical and immunological features of patients with PCD, NSCLC and without well‐characterised onconeural antibodies.

Methods

The clinical features of nine patients with the diagnosis of classical PCD and NSCLC, included in our archives, were retrospectively reviewed. The presence of antibodies to cerebellar components was determined by immunohistochemistry and immunoblot of rat cerebellum. A cDNA library of human cerebellum was screened with the positive sera to identify the antigen.

Results

Nine patients with PCD and NSCLC were identified. Six patients were men, and the median age at diagnosis of PCD was 63 (range 47–73) years. PCD was completely reversed in two patients, and partially in one, after treatment of the tumour. The serum of one of the patients with PCD showed a unique reactivity with Purkinje cells. The screening of a cerebellar‐expression library resulted in the isolation of protein kinase Cγ (PKCγ). PKCγ immunoreactivity was not observed in the serum of 170 patients with non‐paraneoplastic neurological syndromes, 27 patients with PCD, no onconeural antibodies and small‐cell lung cancer, and 52 patients with NSCLC without paraneoplastic neurological syndromes. The NSCLC from 11 patients without PCD did not express PKCγ at either the RNA or protein level. However, many cells of the NSCLC of the patient with PKCγ antibodies expressed PKCγ.

Conclusion

PCD occurs in patients with NSCLC without typical onconeural antibodies and is associated with immune reactions against key proteins of the Purkinje cells.Paraneoplastic cerebellar degeneration (PCD) is characterised by selective damage to the Purkinje cells of the cerebellum, which usually causes a severe pancerebellar syndrome.¹ In patients with lung cancer, PCD is almost always associated with small‐cell lung cancer (SCLC).² Patients with non‐small‐cell lung cancer (NSCLC) and PCD usually harbour onconeural antibodies typically associated with SCLC in the serum and cerebrospinal fluid, which probably indicate a common immune‐mediated mechanism of neuronal damage.^3,4 Although a few studies have indicated the occurrence of PCD in patients with NSCLC and no onconeural antibodies, these patients were usually included in larger series of patients with PCD with different tumours^2,5,6,7 or were reported as single observations.⁸In this study, we describe the clinical and immunological findings of a series of patients without previously characterised onconeural antibodies who presented with PCD associated with NSCLC.     

Elevated Levels of α-Synuclein Oligomer in the Cerebrospinal Fluid of Drug-Na?ve Patients with Parkinson's Disease

Background and Purpose

The detection of α-synuclein in the body fluids of patients with synucleinopathy has yielded promising but inconclusive results, in part because of conformational changes of α-synuclein in response to environmental conditions. The aim of this study was to determine the feasibility of using α-synuclein as a biological marker for Parkinson''s disease (PD).

Methods

Twenty-three drug-naïve patients with PD (age 62.4±12.7 years, mean±SD; 11 males) and 29 age- and sex-matched neurologic control subjects (age 60.1±16.2 years; 16 males) were recruited. The levels of oligomeric and total α-synuclein in the cerebrospinal fluid (CSF) and plasma were measured using two simultaneous enzyme-linked immunosorbent assays.

Results

The level of α-synuclein oligomer in the CSF of PD patients was significantly higher in PD patients than in neurological controls, but other findings (plasma α-synuclein oligomer and total α-synuclein in CSF and plasma) did not differ significantly between the two groups. When the control subjects were divided into a symptomatic control group (11 patients who complained of parkinsonian symptoms and were diagnosed with hydrocephalus and drug-induced or vascular parkinsonism) and a neurologic control group (10 normal subjects and 8 patients with diabetic ophthalmoplegia), the level of α-synuclein oligomer in the CSF was still significantly higher in PD patients than in both of the control subgroups.

Conclusions

These findings provide further evidence for a pathogenic role of the α-synuclein oligomer and suggest that CSF levels of α-synuclein oligomer can be a reliable marker for PD.     

A Study of the Reliability and Validity of the Korean Version of the Penn Alcohol Craving Scale for Alcohol-Dependent Patients

Objective

The Penn Alcohol Craving Scale (PACS) is a stronger predictor of subsequent drinking and relapse of alcohol dependence that can be administered more quickly and easily than other craving scales. The goal of this study was to develop the Korean version of the Penn Alcohol Craving Scale (PACS-K).

Methods

To examine the psychometric properties of the PACS-K, responses were chosen from 80 patients admitted to a treatment facility for alcohol dependence.

Results

The PACS-K possesses good psychometric properties, as assessed by Cronbach''s α estimates (Cronbach''s α=0.91). The test-retest reliability of the PACS-K showed high correlation (p<0.01) when the retest interval was 1 day. When the validity of the PACS-K was investigated using correlation analysis with two other craving scales (the Obsessive Compulsive Drinking Scale (OCDS) and the Visual Analogue Scale (VAS), high correlations were obtained between total PACS scores and total OCDS scores, and between total PACS scores and VAS scores (p<0.01, respectively).

Conclusion

The PACS-K is a reliable and valid measure of alcohol cravings, and it could be useful for predicting which individuals are at risk for subsequent relapse.     

The effect of radiofrequency neurotomy of lower cervical medial branches on cervicogenic headache

Objective

Cervicogenic headache (CGH) is known to be mainly related with upper cervical problems. In this study, the effect of radiofrequency neurotomy (RFN) for lower cervical (C4-7) medial branches on CGH was evaluated.

Methods

Eleven patients with neck pain and headache, who were treated with lower cervical RFN due to supposed lower cervical zygapophysial joint pain without symptomatic intervertebral disc problem or stenosis, were enrolled in this study. CGH was diagnosed according to the diagnostic criteria of the cervicogenic headache international study group. Visual analogue scale (VAS) score and degree of VAS improvement (VASi) (%) were checked for evaluation of the effect of lower cervical RFN on CGH.

Results

The VAS score at 6 months after RFN was 2.7±1.3, which were significantly decreased comparing to the VAS score before RFN, 8.1±1.1 (p<0.001). The VASi at 6 months after RFN was 63.8±17.1%. There was no serious complication.

Conclusion

Our data suggest that lower cervical disorders can play a role in the genesis of headache in addition to the upper cervical disorders or independently.     

ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype

Background

Apolipoprotein E (apoE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between apoE and cholesterol levels and the APOE genotype.

Methods

We obtained dorsolateral prefrontal grey and white matter from the Stanley Medical Research Institute Brain Collection (schizophrenia n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were quantified using high-pressure liquid chromatography, whereas apoE was measured by enzyme-linked immunosorbent assay.

Results

We found no significant differences in cholesterol or apoE levels among the groups. ApoE levels were higher in grey matter than in white matter in all groups; conversely, levels of cholesterol were higher in white matter than in grey matter. We observed a significant inverse correlation between apoE and cholesterol levels in both grey and white matter. Furthermore, in grey matter, apoE levels were significantly higher in APOE ɛ2 carriers compared with APOE ɛ3 or APOE ɛ4 carriers, with cholesterol levels following the opposite trend.

Limitations

Limitations of our study include our inability to control for potential confounding variables and the small numbers of APOE ɛ2 and ɛ4 carriers in each group.

Conclusion

Although large amounts of cholesterol are present in white matter, apoE expression is limited. The APOE genotype may play a role in the regulation of both cholesterol and apoE levels in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people with psychiatric disorders warrants further investigation.     

放射免疫法定量检测乙酰胆碱受体抗体与重症肌无力患者临床特征的相关性

目的探讨乙酰胆碱受体抗体(AChR-Ab)与重症肌无力(MG)临床特征的相关性。方法采用放射免疫法检测115例MG患者及92例对照组(非MG神经系统疾病患者42例,健康体检者50名)血清AChRAb浓度,应用临床绝对评分记录MG患者病情严重程度。分析各组血清AChR-Ab浓度的差异,以及AChR-Ab浓度与MG患者临床特征的相关性。采用ROC工作特征曲线探讨AChR-Ab诊断MG的敏感度和特异度。结果MG患者血清AChR-Ab浓度中位数(四分位数间距,下同)为3.45(39.38)nmol/L,较非MG神经系统疾病患者[0(0)nmol/L]和健康体检者[0(0)nmol/L]增高(P0.01)。全身型MG(GMG)患者AChR-Ab浓度[25.45(46.14)nmol/L]较眼肌型MG(OMG)患者[0.58(3.56)nmol/L]增高(P0.01)。用ROC曲线法分析显示,以血清AChR-Ab浓度≥0.50nmol/L作为诊断MG界值时灵敏度为72.17%,特异度为100%,曲线下面积(AUC)=0.895(95%CI:0.849~0.941)。AChR-Ab浓度与发病年龄、病程及改良Osserman分型呈正相关(r=0.220,P0.05;r=0.184,P0.05;r=0.382,P0.01),但相关性较弱(均r0.5),与临床绝对记分无相关性(r=0.147,P0.05)。结论用放射免疫法检测血清AChR-Ab浓度诊断MG的灵敏度和特异度均高,有助于减少MG的漏诊率及误诊率,值得临床推广。     

Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder

Background

In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention. Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its patho-physiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed.

Methods

We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar disorder type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system.

Results

The mean interleukin (IL)-1β level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respectively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10).

Limitations

All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out.

Conclusion

Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1β in bipolar disorder.     

A structural model of stress, motivation, and academic performance in medical students

Objective

The purpose of the present study was 1) to identify factors that may influence academic stress in medical students and 2) to investigate the causal relationships among these variables with path analysis.

Methods

One hundred sixty medical students participated in the present study. Psychological parameters were assessed with the Medical Stress Scale, Minnesota Multiphasic Personality Inventory, Hamilton Depression Scale, Beck Depression Inventory, and Academic Motivation Scale. Linear regression and path analysis were used to examine the relationships among variables.

Results

Significant correlations were noted between several factors and Medical Stress scores. Specifically, Hamilton Depression Scale scores (β=0.26, p=0.03) and amotivation (β=0.20, p=0.01) and extrinsically identified regulation (β=0.27, p<0.01) response categories on the Academic Motivation Scale had independent and significant influences on Medical Stress Scale scores. A path analysis model indicated that stress, motivation, and academic performance formed a triangular feedback loop. Moreover, depression was associated with both stress and motivation, and personality was associated with motivation.

Conclusion

The triangular feedback-loop structure in the present study indicated that actions that promote motivation benefit from interventions against stress and depression. Moreover, stress management increases motivation in students. Therefore, strategies designed to reduce academic pressures in medical students should consider these factors. Additional studies should focus on the relationship between motivation and depression.     

Serial expression of hypoxia inducible factor-1α and neuronal apoptosis in hippocampus of rats with chronic ischemic brain

Objective

The purpose of this study is to investigate serial changes of hypoxia-inducible factor 1α (HIF-1α), as a key regulator of hypoxic ischemia, and apoptosis of hippocampus induced by bilateral carotid arteries occlusion (BCAO) in rats.

Methods

Adult male Wistar rats were subjected to the permanent BCAO. The time points studied were 1, 2, 4, 8, and 12 weeks after occlusions, with n=6 animals subjected to BCAO, and n=2 to sham operation at each time point, and brains were fixed by intracardiac perfusion fixation with 4% neutral-buffered praraformaldehyde for brain section preparation. Immunohistochemistry (IHC), western blot and terminal uridine deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were performed to evaluate HIF-1α expression and apoptosis.

Results

In IHC and western blot, HIF-1α levels were found to reach the peak at the 2nd week in the hippocampus, while apoptotic neurons, in TUNEL assay, were maximal at the 4th week in the hippocampus, especially in the cornu ammonis 1 (CA1) region. HIF-1α levels and apoptosis were found to fluctuate during the time course.

Conclusion

This study showed that BCAO induces acute ischemic responses for about 4 weeks then chronic ischemia in the hippocampus. These in vivo data are the first to show the temporal sequence of apoptosis and HIF-1α expression.     

Antibody profile may predict outcome in ocular myasthenia gravis

An unsolved issue remains whether there are clinical and immunological features to predict in a single patient the risk of conversion from ocular Myasthenia Gravis (OMG) to generalized disease (GMG) as 50–60% of patients may progress within 1–2 years since onset. Anti-acetylcholine receptor antibodies (AChR Abs) are found in up to 50% of OMG patients; muscle-specific tyrosine kinase antibodies (MuSK-Abs) are present in about 70% of the whole seronegative (SN), who usually develop a severe disease with bulbar involvement. We surveyed a cohort of 175 OMG patients with purely ocular symptoms and we compare the outcome of patients with antibodies to AChR or to MuSK with those seronegative for both Abs (DSN). All patients had purely ocular signs for at least 24 months. Gender, age at onset, time to generalization or to worsening in quantitative ocular QMG scores, electrophysiological results were analyzed. Males were 58.9%, females 41.1%. Patients with late onset of symptoms after 50 years (LOMG) were 78.3%. We assayed anti-MuSK-Abs in 4.7%, anti-AChR Abs in 38.5%; 57.3% were defined DSN. Thirty-seven patients (21.1%) progressed to GMG during the observational time: 23 were females, 62% of the whole group of the generalized subjects, 75% of MuSK-positive OMG converted to GMG versus the 26.2% of AChR positive and 13.7% of DSN. Statistical analysis showed that gender and presence of antibodies either to AChR or to MuSK were independent predictors of worse outcome; the DSN subjects had lower risk of conversion to GMG.