The treatment effect on peripheral B cell markers in antibody positive myasthenia gravis patients.

B cells play a major role in the pathophysiology of myasthenia gravis (MG) with their ability to produce disease specific, pathogenic antibodies. However, their status during disease development and follow-up stages of the disease in the peripheral blood may need further studies to determine useful markers. In this study, we aimed to detect B cell associated factors concerning immunosuppressive treatment in generalized non-thymomatous MG patients. Although CD19+ B cell distribution did not vary among disease subgroups, expressions of both CD38 and BAFFR were altered on B cells in MG patients under immunosuppressive therapy. Serum levels of BAFF were elevated in untreated MG patients as compared to treated MG patients and healthy controls. B cell activation factors may show profound alterations due to immunosuppression.

Identification of candidate biomarkers in converting and non-converting clinically isolated syndrome by proteomics analysis of cerebrospinal fluid.

Multiple sclerosis (MS) often starts in the form of clinically isolated syndrome (CIS) and only some of the CIS patients progress to relapsing-remitting MS (RRMS). Biomarkers to predict conversion from CIS to MS are thus greatly needed for making correct treatment decisions. To identify a predictive cerebrospinal fluid (CSF) protein, we analyzed the first-attack CSF samples of CIS patients who converted (CIS-MS) (n = 23) and did not convert (CIS-CIS) (n = 19) to RRMS in a follow-up period of 5 years using proteomics analysis by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and verified by ELISA. Label-free differential proteomics analysis of CSF ensured that 637 proteins were identified and 132 of these proteins were found to be statistically significant. Further investigation with the ingenuity pathway analysis (IPA) software led to identification of three pathway networks mostly comprised proteins involved in inflammatory response, cellular growth and tissue proliferation. CSF levels of four of the most differentially expressed proteins belonging to the cellular proliferation network function, chitinase-3-like protein 1 (CHI3L1), tumor necrosis factor receptor superfamily member 21 (TNFRSF21), homeobox protein Hox-B3 (HOXB3) and iduronate 2-sulfatase (IDS), were measured by ELISA. CSF levels of HOXB3 were significantly increased in CIS-MS patients. Our results indicate that cell and tissue proliferation functions are dysregulated in MS as early as the first clinical episode. HOXB3 has emerged as a potential novel biomarker which might be used for prediction of CIS-MS conversion.

Discontinuation of lamivudine treatment in HBeAg-negative chronic hepatitis B: a pilot study with long-term follow-up.

BACKGROUND: Finite treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) with nucleoside/nucleotide analogues (NAs) is important in resource-limited countries. Outcome of treatment discontinuation in patients on long-term lamivudine (LVD) was assessed in a single centre observational pilot study in the current study. METHODS: Non-cirrhotic patients on LVD for at least 5 years with undetectable HBV DNA on at least two consecutive assessments were offered to stop treatment. Biochemical, serological and virological measures were determined at 3-6 month intervals after treatment discontinuation. Serum quantitative hepatitis B surface antigen (HBsAg) was determined at treatment discontinuation and 5-6 years thereafter. NA treatment was re-instituted in patients with confirmed viral rebound defined as HBV DNA >20,000 IU/ml. Relapser patients were no longer followed but were re-assessed 6 years after treatment cessation. RESULTS: LVD was discontinued in 23 patients. 8 patients relapsed within 1 year and NA treatment was restarted; 15 patients (65%) were non-relapsers. Thirteen of them were followed for at least 5 years. Two patients had undetectable HBV DNA throughout the follow-up period. In the rest, HBV DNA fluctuated at low levels. Two patients cleared HBsAg 24 and 36 months after stopping treatment. Quantitative HBsAg levels 5-7 years after treatment discontinuation were lower in non-relapser compared to relapser patients (1.21 IU/ml ±0.98 versus 2.71 ±0.76; P=0.002). Of 8 relapser patients 1 patient had HBsAg levels less than 100 IU/ml compared to 11 out of 13 non-relapser patients (P=0.0022). CONCLUSIONS: These data suggest that cessation of NA treatment is a viable option after a reasonable treatment duration in patients with HBeAg-negative CHB and that HBsAg clearance may become an achievable target in these patients.

Obturator mononeuropathy due to adenocarcinoma of unknown primary origin.

A 35-year-old woman presented with a three-month history of left groin and thigh pain. Neurological examination and electromyography showed pathological features consistent with obturator nerve involvement. Imaging studies revealed a left retroperitoneal mass, which by pathological examination was shown to be metastatic adenocarcinoma of possible Mullerian origin. Primary tumor could not be detected in a follow-up period of three years. Obturator mononeuropathy can be the first manifestation of cancer. Cancer of unknown primary origin may occasionally be local, well-restricted and carry a good prognosis.

Expression analysis and clinical correlation of aquaporin 1 and 4 genes in human hippocampal sclerosis.

Mesial temporal sclerosis (MTS) is the most frequent cause of drug resistant symptomatic partial epilepsy. The mechanism and genetic background of this unique pathology are not well understood. Aquaporins (AQP) are regulators of water homeostasis in the brain and are expressed in the human hippocampus. We explored the role of AQP genes in the pathogenetic mechanisms of MTS through an evaluation of gene expression in surgically removed human brain tissue. We analyzed AQP1 and 4 mRNA levels by quantitative real-time polymerase chain reaction and normalized to ABL and cyclophilin genes, followed by immunohistochemistry for AQP4. Relative expressions were calculated according to the delta Ct method and the results were compared using the Mann-Whitney U test. Brain specimens of 23 patients with epilepsy who had undergone surgery for MTS and seven control autopsy specimens were investigated. Clinical findings were concordant with previous studies and 61% of the patients were seizure-free in the postoperative period. AQP1 and 4 gene expression levels did not differ between MTS patients and control groups. Immunofluorescence analysis of AQP4 supported the expression results, showing no difference. Previous studies have reported contradictory results about the expression levels of AQP in MTS. To our knowledge, only one study has suggested upregulation whereas the other indicated downregulation of perivascular AQP4. Our study did not support these findings and may rule out the involvement of AQP in human MTS.

Long-term MRI findings in neuromyelitis optica: seropositive versus seronegative patients.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) is a severe demyelinating inflammatory disorder associated with serum antibodies against aquaporin 4 (AQP4-Ab). A significant number of patients with NMO remain seronegative over time. Long-term observational magnetic resonance imaging (MRI) studies of the CNS in patients with NMO are rare or of limited duration. The objective of this study is to determine long-term MRI characteristics of seropositive and seronegative patients, and assess possible overlap with multiple sclerosis (MS). METHODS: Clinical and radiological characteristics of 28 patients with NMO at onset and of 17 patients after an average follow-up time of 9 years were recorded. Fifty percent of patients were seropositive for AQP4-Ab. Onset and final brain/spinal MRI scans were retrospectively analysed and compared. RESULTS: Significantly more patients in the seronegative group had brain lesions at onset. Spinal lesions of seropositive patients were longer and showed increased cord swelling at onset MRI scans. After the follow-up time the differences between both groups disappeared. Patients in the seropositive group tended to develop brain lesions over time. No patient fulfilled Barkhof's or McDonald's radiological criteria for MS at onset or over time. CONCLUSION: Brain MRI features show differences between seropositive and seronegative patients at time of onset in NMO, but differences between groups vanish over time. None of the AQP4-negative patients fulfill radiological MS criteria on a long-term basis, suggesting that seronegative NMO constitutes an independent entity.

Bickerstaff's encephalitis and Miller Fisher syndrome associated with voltage-gated potassium channel and novel anti-neuronal antibodies.

BACKGROUND: GQ1b antibody (GQ1b-Ab) is detected in approximately two-thirds of sera of patients with Bickerstaffs encephalitis (BE). Whilst some of the remaining patients have antibodies to other gangliosides, many patients with BE are reported to be seronegative. METHODS AND RESULTS: Voltage-gated potassium channel antibody (VGKC-Ab) at high titer was detected during the diagnostic work-up of one patient with BE. Sera of an additional patient with BE and nine patients with Miller Fisher syndrome (MF) (all GQ1b-Ab positive) were investigated for VGKC-Ab and other anti-neuronal antibodies by radioimmunoprecipitation using 125I-dendrotoxin-VGKC and immunohistochemistry, respectively. Two patients with MF exhibited moderate titer VGKC-Abs. Regardless of positivity for VGKC or GQ1b antibodies, serum IgG of all patients with BE and MF reacted with the molecular layer and Purkinje cells of the cerebellum in a distinctive pattern. CONCLUSION: Voltage-gated potassium channel antibodies might be involved in some cases of BE or MF. The common staining pattern despite different antibody results suggests that there might be other, as yet unidentified, antibodies associated with BE and MF.

High interleukin-10 production is associated with anti-acetylcholine receptor antibody production and treatment response in juvenile myasthenia gravis.

To investigate the significance of humoral immunological factors in juvenile myasthenia gravis (JMG) patients, 11 children with JMG (age of onset between 2 and 13 years) and 8 healthy controls were enrolled. Plasma IL-2, IL-10, IFN-gamma, TNF-alpha, complement factor C3, C4, and C1q levels were measured by ELISA. IL-2, IL-10, TNF-alpha, C3, and C4 levels were significantly elevated in the patient group. Moreover, plasma IL-10 levels were associated with the presence of anti-AChR antibody and response to treatment suggesting a critical role for IL-10 in JMG pathogenesis.

Acceptability, reliability, validity and responsiveness of the Turkish version of WOMAC osteoarthritis index.

OBJECTIVE: To evaluate the acceptability, reliability, validity and responsiveness of the Turkish version of Western Ontario and McMaster Universities (WOMAC) osteoarthritis (OA) index in physiotherapy outpatient practice in Turkey. METHOD: Data were obtained from 72 patients with OA of the knee. They were asked to answer two disease-specific questionnaires (WOMAC LK 3.1 and Lequesne-Algofunctional Index of Severity for the knee) and one generic instrument (Medical Outcomes study SF-36 Survey-SF-36). Acceptability was assessed in terms of refusal rate, rates of missing responses, and administration time. Reliability was assessed using Cronbach's alpha. Content validity was assessed by examining the floor and ceiling effects, and skew of the distributions. Convergent and divergent validity was assessed by examining the Pearson's correlation coefficients. Responsiveness was determined by examining effect size (ES), standardized response means (SRM) and P values generated using Wilcoxon's test. RESULTS: The overall response rate was 100%. Alpha values for all WOMAC subscales exceeded the value of 0.70 at both baseline and follow-up assessments. Frequency distributions of scores were symmetrical. Subscales had negligible floor and ceiling effects. Both pain and physical function subscales were fairly correlated with the subscales measuring similar constructs of SF-36, whereas they were weakly correlated with other dimensions of SF-36. A good correlation was obtained between WOMAC total and Lequesne index. The pain and physical function subscales of WOMAC index were the most responsive subscales. CONCLUSION: The Turkish WOMAC OA index is acceptable, valid, reliable and responsive for use in Turkish patients with knee OA.

Etanercept treatment in corticosteroid-dependent myasthenia gravis.

The authors report a prospective pilot trial of etanercept in corticosteroid-dependent autoimmune myasthenia gravis. Eleven patients were enrolled, with eight completing the 6-month trial. Two patients were withdrawn owing to disease worsening, and one patient was withdrawn because of an erythematous skin rash. Six of the eight patients who completed the trial improved, based on quantitative measures of muscle strength and lowering of corticosteroid requirement.

The inversely proportional relation between nitric oxide and lipid peroxidation in atherosclerotic plaque formation in human.

It is known that in the presence of oxygen radicals, anti-atherogenic nitric oxide is converted into pro-atherogenic products, which increase lipid peroxidation. In this study, plaque-free atherosclerotic tissues (n=26), atherosclerotic plaques (n=26) and fetal tissues (n=2; as control) were evaluated. High nitrite, but low malondialdehyde, levels in non-atherosclerotic tissues may show the protective role of nitric oxide from atherosclerosis. In plaque-developed tissues nitrite levels were three times, and lipid peroxidation levels were 10 times, higher than non-plaque developed tissues. In the atherosclerotic plaque forming process, the role of nitric oxide can be discovered according to the lipid peroxidation of tissues. In conclusion, the results of this study show an inversely proportional relation between pro- and anti-atherogenic effects of nitric oxide in the pathogenesis of atherosclerotic vascular diseases.

A multicentre study of abdominal aorta diameters in a Turkish population.

The aim of this study was to determine the normal values for aortic diameters and the prevalence of aortic dilatation in a mixed Turkish population. Between March 1998 and May 2000, patients who were undergoing abdominal ultrasonography examination for pathologies not involving the aorta, in three different cities, were enrolled into the study prospectively. The anterior posterior aortic diameters were measured at the subdiaphragmatic and aortic bifurcation levels using ultrasonography. A total of 596 patients were included (302 females, 294 males). The mean age was 48 +/- 16 years (range, 6-88 years). The mean aortic diameter in the whole group was 19.0 +/- 3.9 mm (10-45 mm) at the subdiaphragmatic level and 15.7 +/- 3.6 mm (9-65 mm) at the aortic bifurcation level. The mean subdiaphragmatic aortic diameter was 18 +/- 3 mm in females and 19 +/- 4 mm in males. The mean aortic diameters at the bifurcation level was 15 +/- 3 mm in females and 16 +/- 4 mm in males. An aortic bifurcation diameter > 30 mm was encountered in 0.67% of the population. This ratio increased to 1.8% in patients over 55 years of age, regardless of sex. A subdiaphragmatic aorta diameter above 30 mm was observed in 1.2% of the population. In patients over the age of 55 years, this ratio increased to 2.7% (3.6% in males and 1.9% in females). In this national study, the subdiaphragmatic aortic diameters were similar to mean values reported in the world literature. The mean aortic bifurcation diameters were generally lower when compared with the literature, which may be due to difficulties in standardization of the measurements. Aneurysmal dilatation rates in this study also conform to those reported in studies conducted in other countries. Considering the significant number of patients with aneurysmal dilatation of the aorta in the elderly population, we believe it would be prudent to evaluate the aorta in all patients undergoing abdominal ultrasonographic examination.

F wave parameters and F tacheodispersion in mild diabetic neuropathy.

F tacheodispersion and some F wave parameters have previously been suggested to be useful in the detection of peripheral nerve involvement in diabetic patients with normal nerve conduction studies. In this study, ulnar and tibial F wave parameters of diabetic cases with normal motor and sensory nerve conduction studies (Group 1) were calculated, F tacheodispersion histograms were constructed and compared with the same parameters obtained from the normal controls (Control group) and diabetic cases with abnormal motor and sensory nerve conduction examinations (Group 2). There was a tendency towards lower conduction velocities in ulnar and tibial tacheodispersion histograms of Group 1 and Group 2, as compared to Control group. Most of the F wave values were significantly abnormal in Group 2 in comparison to other two groups, whereas statistically significant differences between Group 1 cases and Control group were found in minimum ulnar F wave conduction velocity (FCVmin), mean ulnar FCV (FCVmean), tibial FCVmin and tibial FCVmean values. Unlike other methods, F waves give information about the entire length of the motor nerve fiber. In mild neuropathies, in which nerve fibers are damaged uniformly, testing the whole length of a nerve with this method may be beneficial in detection of a mild conduction abnormality.

Potassium channel antibodies in two patients with reversible limbic encephalitis.

Limbic encephalitis (LE) is often associated with lung, thymic, or testicular tumours and antibodies to Hu, CV2, or Ma2 (Ta) antigens. In these cases, it generally has a poor prognosis. Here we describe two patients with symptoms of LE, negative for typical paraneoplastic antibodies, in whom antibodies to voltage-gated potassium channels (VGKC) were detected retrospectively in serial serum samples. Patient 1 had a thymoma recurrence, but in patient 2 no tumour has been detected in the years following presentation. Plasma exchange was effective in reducing VGKC antibody levels, with substantial improvement in mental symptoms in patient 1. In patient 2, the VGKC antibodies fell spontaneously over two years, with almost complete recovery of mental function. Although neither patient had obvious neuromyotonia at presentation, both showed excessive secretions. We suggest that patients with limbic symptoms and excessive secretions should be tested for VGKC antibodies, and, if they are present, prompt and effective immunosuppressive treatment should be considered.

Divergent origins and concerted expansion of two segmental duplications on chromosome 16.

An unexpected finding of the human genome was the large fraction of the genome organized as blocks of interspersed duplicated sequence. We provide a comparative and phylogenetic analysis of a highly duplicated region of 16p12.2, which is composed of at least four different segmental duplications spanning in excess of 160 kb. We contrast the dispersal of two different segmental duplications (LCR16a and LCR16u). LCR16a, a 20 kb low-copy repeat sequence A from chromosome 16, was shown previously to contain a rapidly evolving novel hominoid gene family (morpheus) that had expanded within the last 10 million years of great ape/human evolution. We compare the dispersal of this genomic segment with a second adjacent duplication called LCR16u. The duplication contains a second putative gene family (KIAA0220/SMG1) that is represented approximately eight times within the human genome. A high degree of sequence identity (approximately 98%) was observed among the various copies of LCR16u. Comparative analyses with Old World monkey species show that LCR16a and LCR16u originated from two distinct ancestral loci. Within the human genome, at least 70% of the LCR16u copies were duplicated in concert with the LCR16a duplication. In contrast, only 30% of the chimpanzee loci show an association between LCR16a and LCR16u duplications. The data suggest that the two copies of genomic sequence were brought together during the chimpanzee/human divergence and were subsequently duplicated as a larger cassette specifically within the human lineage. The evolutionary history of these two chromosome-specific duplications supports a model of rapid expansion and evolutionary turnover among the genomes of man and the great apes.

Paroxysmal attacks in multiple sclerosis.

Paroxysmal attacks are short, frequent and stereotyped symptoms that can be observed in multiple sclerosis (MS) patients. We evaluated retrospectively the clinical and neuroradiological findings of patients, who developed any paroxysmal attacks during the course of their disease. EDSS scores, MS clinical types and disease durations of 59 patients with paroxysmal attacks (Group 1) were compared to 586 consecutive patients without paroxysmal attacks recorded in our MS database (Group 2). Anatomical and clinical correlation was attempted in 31 of the patients who had MRI examinations performed within 6 months of the paroxysmal attacks. EDSS scores of patients in Group 1 at the time of the paroxysmal attacks were significantly lower than the scores at their last clinic visit whereas there were no significant differences for other parameters. Our results demonstrate that paroxysmal attacks occur early in the course of the disease, when there is little or no neurologic disability and associated tissue damage.

Longterm follow-up of electroencephalographic and clinical findings of a case with Gaucher's disease type 3a.

Among three recognised clinical phenotypes, type 3a Gaucher's disease is characterised by mild to severe systemic disease, neurological manifestations and myoclonic seizures. We report the long term clinical and electrophysiological follow-up of a 27-year old man with a diagnosis of type 3a Gaucher's disease, which was confirmed by bone marrow biopsy examination and leukocyte glucocerebrosidase level measurement. His neurological examination was normal throughout the follow-up period. EEG examination, recorded five days after the first seizure, revealed generalised nonrhythmic paroxysmal rapid spikes with occipital predominance increased by photic stimulation and normal background activity. The frequency of seizures increased from 3-4/year to 1-2/month within a follow-up period of 12 years and a repeat EEG examination on the eight year of diagnosis revealed additional background slowing. A giant potential was obtained in somatosensory evoked potential (SEP) examination. EEG findings of this case demonstrate a specific pattern with rapid spike activity, photosensitivity, eye closure sensitivity and gradual background slowing.

Possible role of gangliosides in salivary gland complications of diabetes.

Gangliosides have previously been considered to be possible antigenic sites in Type 1 diabetes. Lymphocytic infiltration of Langerhans islands is the pathologic hallmark of autoimmune diabetes and may also be observed in salivary glands in experimental diabetes. Diabetic complications of parotid and submaxillary glands may therefore be related with an autoimmune process against sialoglycoconjugates of salivary gland tissue.