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Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = – 0.75, – 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = – 0.72, – 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = – 1.00, – 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity. [ABSTRACT FROM AUTHOR]

The anti-paraneoplastic (Ma2/Ta) antibody is related to testicular, lung and ovarian cancers, and might cause paraneoplastic neurological disorders. We present a 25-year-old woman presenting various neurological symptoms of myokymia, chronic widespread pain, tremor, excessive daytime sleepiness, impaired eye of movements, and seizures and autonomic symptoms related to anti-Ma2/Ta antibodies. Needle electromyography showed spontaneous multiplet and myokymic discharges in the left vestus lateralis. Thus, we diagnosed her as Morvan syndrome. After initiation of steroids, plasma exchange and dantrolene, her symptoms partially improved with decreasing intensity of the antigen of anti-Ma2/Ta antibodies, from moderate strong to borderline. The present case expands the clinical spectrum of anti-Ma2/Ta antibodies-related disorders to include the existence of neuroimmune activation and Morvan syndrome. [ABSTRACT FROM AUTHOR]

Aims/Introduction To elucidate the clinical significance of median neuropathy at the wrist ( MN) in patients with diabetes. Materials and Methods In total, 340 patients with diabetes who were hospitalized for glycemic control were enrolled in the present study. The diagnoses of MN and diabetic polyneuropathy ( DPN) were based on electrophysiological criteria. A total of 187 patients were divided into four subgroups: patients without MN or DPN; patients with MN without DPN; patients with MN and DPN; and patients with DPN without MN. Intergroup comparisons of clinical characteristics and results of nerve conduction studies were carried out. Results A total of 71 patients had neither MN nor DPN; 25 had MN, but no DPN; 55 had MN and DPN; and 36 had DPN, but no MN. In comparison with the MN and DPN group, the MN without DPN group included more patients in the early phase of diabetes (diagnosed within the past 5 years) and fewer patients with diabetic microangiopathy. Comparative median nerve conduction studies showed significantly lower motor and sensory nerve conduction velocities, longer F-wave latencies, and smaller sensory nerve action potentials in patients with MN and DPN than in those without DPN. Conclusions MN in patients with diabetes could be attributed to an impairment in axonal function at common entrapment sites, and could be used to identify an early manifestation of diabetic neuropathy. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. Methods: In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN. Results: The ratio of MMN to ALS patients (0-0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population. Conclusions: The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers. Muscle Nerve 49:357-361, 2014 [ABSTRACT FROM AUTHOR]

Objective We carried out a retrospective study to define clinical features in a large series of patients with multifocal motor neuropathy ( MMN) and to assess the diagnostic spectrum of MMN. Methods The study consisted of 46 patients with MMN between 2005 and 2009 from 19 major neuromuscular centers in Japan. The 2006 European Federation of Neurological Societies ( EFNS)/ Peripheral Nerve Society ( PNS) criteria (hereafter, original criteria) and the efficacy of intravenous immunoglobulin ( IVIg) therapy were taken into consideration in the diagnosis of MMN. The main parameters were clinical features and electrophysiological findings. The Japanese MMN Study Group designed a set of recommended criteria to reduce the frequency of underdiagnosis. Furthermore, we verified the diagnostic spectrum of MMN using both the original criteria and the recommended criteria. Results Clinical features were similar to those of previous studies. A total of 25 of the 46 patients (54.3%) showed conduction block ( CB); that is, nearly half of the patients did not satisfy the original criteria. The Japanese MMN Study Group included findings indicative of focal demyelination, namely, activity-dependent CB and asymmetric abnormality of F-waves in the electrophysiological test, in the recommended criteria. By doing so, the diagnostic sensitivity of the recommended criteria was increased by 17.4% compared with that of the original criteria. Conclusions The recommended criteria designed by the Japanese MMN Study Group showed higher diagnostic sensitivity than the original criteria, but no significant difference was found between them. A prospective study using the recommended criteria might reduce the frequency of underdiagnosis in patients with MMN. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the relationship between mitochondrial DNA (mtDNA) alterations and a mitochondrial disease with a distinct combination of characteristic symptoms, namely episodic hyper-creatine kinase (CK)-emia and mild myopathy. Methods: We selected 9 patients with mtDNA np8291 alteration from 586 patients suspected to have a mitochondrial disease, and assessed them clinically, pathologically, and genetically. These 9 patients had undiagnosed mitochondrial myopathy with episodic hyper-CK-emia, all showing similar symptoms and progression. Results: Patients had mild muscle weakness and episodic hyper-CK-emia triggered by infections or drugs. Five of 9 patients were initially diagnosed with other conditions, such as myasthenia gravis, polymyositis, viral myositis, and drug-induced myopathy, because these conditions were acute or subacute, and 9 patients showed the same 16 mtDNA alterations, which have been reported to be nonpathological polymorphisms. Muscle biopsy revealed ragged-red fibers, highly expressed succinate dehydrogenase staining fibers, and cytochrome c oxidase-deficient fibers. Because their mitochondrial sequence data was almost the same, and 9 patients live in widely separated cities in Japan, the alterations may have arisen from a single source. Interpretation: These findings suggest that mild myopathy with episodic hyper-CK-emia associated with some of the 16 mtDNA alterations or at least with their mitochondria, could be a novel mitochondrial disease. Therefore, we propose that this disease be named as 'mitochondrial myopathy with episodic hyper-CK-emia (MIMECK).' These alterations could work concomitantly and probably modify the impact of medications or other environmental factors. We believe these findings provide an insight into a novel aspect of mitochondrial disease pathogenesis. ANN NEUROL 2011;70: 486-492. [ABSTRACT FROM AUTHOR]

xial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNA gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD. [ABSTRACT FROM AUTHOR]

16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and −16C>T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C–T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan.Journal of Human Genetics (2009) 54, 377–381; doi:10.1038/jhg.2009.44; published online 15 May 2009 [ABSTRACT FROM AUTHOR]

Background: Recently, human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), encoded from a minus strand mRNA was discovered and was suggested to play an important role in adult T cell leukemia (ATL) development. However, there have been no reports on the role of HBZ in patients with HTLV-1 associated inflammatory diseases. Results: We quantified the HBZ and tax mRNA expression levels in peripheral blood from 56 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 10 ATL patients, 38 healthy asymptomatic carriers (HCs) and 20 normal uninfected controls, as well as human leukemic T-cell lines and HTLV-1-infected T-cell lines, and the data were correlated with clinical parameters. The spliced HBZ gene was transcribed in all HTLV-1-infected individuals examined, whereas tax mRNA was not transcribed in significant numbers of subjects in the same groups. Although the amount of HBZ mRNA expression was highest in ATL, medium in HAM/TSP, and lowest in HCs, with statistical significance, neither tax nor the HBZ mRNA expression per HTLV- 1-infected cell differed significantly between each clinical group. The HTLV-1 HBZ, but not tax mRNA load, positively correlated with disease severity and with neopterin concentration in the cerebrospinal fluid of HAM/TSP patients. Furthermore, HBZ mRNA expression per HTLV-1- infected cell was decreased after successful immunomodulatory treatment for HAM/TSP. Conclusion: These findings suggest that in vivo expression of HBZ plays a role in HAM/TSP pathogenesis. [ABSTRACT FROM AUTHOR]

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive, inflammatory disease of the central nervous system (CNS). We report a patient with transverse myelitis, who exhibited acute onset and rapid progression of the disease and whose symptoms resembled those observed in multiple sclerosis with spinal cord presentation. During neurological exacerbation of the condition, the HTLV-I proviral load in the cerebrospinal fluid (CSF) increased to 10 times that in the peripheral blood. This suggests that the accumulation of HTLV-I-infected cells in the CNS contributes to neurological exacerbation. Based on the increased proviral load in the CSF, we diagnosed the disease as acute progressive HAM/TSP. The measurement of the HTLV-I proviral load in the CSF is useful for the diagnosis of HAM/TSP and for monitoring its progression. [ABSTRACT FROM AUTHOR]

Ethnic differences in the muscle-relaxing effect of botulinum toxin type B (BTX-B) were examined by means of electrophysiological measurements in Japanese and Caucasian volunteers. This was a randomized, single-blinded, single-center study of 24 Japanese and 24 Caucasian healthy adult male subjects in Japan. BTX-B (20 U, 100 U, or 500 U/0.2 mL) or placebo was administered to the extensor digitorum brevis (EDB) muscle in the left lower limb as a single dose (in each dose group, 6 subjects received the test drug and two received placebo). The inhibitory effect of BTX-B on the M wave amplitude of EDB muscle generated by stimulation of the deep peroneal nerve was measured frequently during 2 weeks after administration, and then at weeks 4 (day 28) and 12 (day 84). The inhibitory effect of BTX-B on the M wave amplitude of EDB muscle was dose-dependent in both Japanese and Caucasian subjects, and the dose-response curves were similar. These findings demonstrate that the muscle-relaxing effect of BTX-B in Japanese subjects is electrophysiologically similar to that in Caucasians. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

We evaluated whether the paralytic attacks in thyrotoxic periodic paralysis (TPP) are primarily due to the abnormal excitability of the muscle membrane caused by a preexisting latent abnormality or to the effects of thyroid hormone. The prolonged exercise (PE) test was used to evaluate muscle membrane excitability in 21 patients with TPP and 11 patients with thyrotoxicosis without paralytic attacks (Tw/oPP) in the hyperthyroid state. The PE tests were compared between the hyperthyroid and euthyroid states in five of the TPP and three of the Tw/oPP patients. Compared to 20 healthy subjects, a significant increase in compound muscle action potential (CMAP) amplitudes immediately after exercise and a significant time-dependent gradual decline in CMAP amplitudes starting from 20 min after exercise were observed in the TPP patients. A significant decline in CMAP amplitudes was also observed in the Tw/oPP patients but only at 50 min after exercise. All of the TPP and Tw/oPP patients had a tendency to improve in the euthyroid state; the PE tests remained abnormal only in the TPP patients. Paralytic attacks in TPP patients are due primarily to a preexisting latent abnormal excitability of the muscle membrane, possibly genetic in origin. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) cleaves the phosphodiester bond between a covalently stalled topoisomerase I (Topo I) and the 3′ end of DNA. Stalling of Topo I at DNA strand breaks is induced by endogenous DNA damage and the Topo I-specific anticancer drug camptothecin (CPT). The H493R mutation of Tdp1 causes the neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy (SCAN1). Contrary to the hypothesis that SCAN1 arises from catalytically inactive Tdp1, Tdp1−/− mice are indistinguishable from wild-type mice, physically, histologically, behaviorally, and electrophysiologically. However, compared to wild-type mice, Tdp1−/− mice are hypersensitive to CPT and bleomycin but not to etoposide. Consistent with earlier in vitro studies, we show that the H493R Tdp1 mutant protein retains residual activity and becomes covalently trapped on the DNA after CPT treatment of SCAN1 cells. This result provides a direct demonstration that Tdp1 repairs Topo I covalent lesions in vivo and suggests that SCAN1 arises from the recessive neomorphic mutation H493R. This is a novel mechanism for disease since neomorphic mutations are generally dominant. [ABSTRACT FROM AUTHOR]

Satoyoshi syndrome is a rare postnatal disorder with muscle spasms, alopecia, and diarrhea of unknown etiology. Nutritional deficiency seems to influence lifespan. We present a patient with this syndrome having a unique 'mesh-like' mucosal change radiographically and white granules endoscopically in the gastrointestinal tract. A common antibody against brain, stomach, and duodenal tissue, according to Western blot analysis, was detected in the sera of two patients with this syndrome. These findings suggest that Satoyoshi syndrome is a systemic autoimmune disease involving the nervous, endocrine, and gastrointestinal systems. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

A postmarketing surveillance study was undertaken to investigate the safety and efficacy of interferon-α for human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM) under routine treatment conditions. A total of 273 cases from 91 medical institutions were registered into the survey. So far, 167 cases had been evaluated for safety and 152 for efficacy. The efficacy evaluation was rated based on clinical symptoms of HAM. Efficacy ratio (rate of patients assessed as "modest to markedly improved" and "mildly improved") at 4 weeks was 66.2%. Factors that significantly affected efficacy ratio at 4 weeks was initial Osame's motor disability score (OMDS) before interferon-α therapy and duration and stage of illness. Sustained improvement of OMDS for at least 5 months after stopping interferon-α was observed in 11 of 30 patients (36.7%). A total of 536 adverse drug reactions (ADRs) occurred in 146 patients, 46 of which were serious. Because some of these ADRs occurred late, it is necessary to watch out for them during long-term treatment. [ABSTRACT FROM AUTHOR]

This study investigated the role of human T-cell lymphotropic virus type I HTLV-I infection in 11 patients who developed slowly progressive myelopathy with abnormal spinal cord lesions. The authors performed clinical and neuroradiological examinations and calculated the odds that an HTLV-I-infected individual of a specific genotype, age, and provirus load has HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Anti-HTLV-I antibodies were present in both the serum and cerebrospinal fluid in all of the patients. Abnormal magnetic resonance imaging (MRI) lesions were classified as cervical to thoracic type (CT type), cervical type (C type), and thoracic type (T type). In each type, there was swelling of the spinal cords with high-intensity lesions, which were located mainly in bilateral posterior columns, posterior horns, or lateral columns. Virological and immunological analyses revealed that all patients showed a high risk of developing HAM/TSP. These 11 patients may have developed HAM/TSP, as manifested by spinal cord abnormalities shown on MRI. These MRIs implicate clinical variability of HAM/TSP, which may indicate active-early stages of HAM/TSP lesions. [ABSTRACT FROM AUTHOR]

Mutations of selenoprotein N, 1 gene ( SEPN1) cause rigid spine with muscular dystrophy type 1 (RSMD1), multiminicore disease, and desmin-related myopathy. We found two novel SEPN1 mutations in two Japanese patients with RSMD1. To clarify the pathomechanism of RSMD1, we performed immunohistochemical studies using a newly developed antibody for selenoprotein N. Selenoprotein N was diffusely distributed in the cytoplasm of the control muscle, but was reduced and irregularly expressed in the cytoplasm of a patient with RSMD1. The expression pattern was very similar to that of calnexin, a transmembrane protein of the endoplasmic reticulum. Selenoprotein N seems to be an endoplasmic reticulum glycoprotein, and loss of this protein leads to disturbance of muscular function. One of the families had the SEPN1 homozygous mutation in the initiation codon 1_2 ins T in exon 1 and showed truncated protein expression. The other had a homozygous 20-base duplication mutation at 80 (80_99dup, frameshift at R27) which, in theory, should generate many nonsense mutations including TGA. These nonsense mutations are premature translation termination codons and they degrade immediately by the process of nonsense-mediated decay (NMD). However, truncated selenoprotein N was also expressed. A possible mechanism behind this observation is that SEPN1 mRNAs may be resistant to NMD. We report on the possible molecular mechanism behind these mutations in SEPN1. Our study clarifies molecular mechanisms of this muscular disorder. [ABSTRACT FROM AUTHOR]

The authors have previously developed a logistic regression equation to predict the odds that a human T-cell lymphotropic virus type 1 (HTLV-1)–infected individual of specified genotype, age, and provirus load has HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) in southern Japan. This study evaluated whether this equation is useful predictor for monitoring asymptomatic HTLV-1–seropositive carriers (HCs) in the same population. The authors genotyped 181 HCs for each HAM/TSP-associated gene (tumor necrosis factor [TNF]- α - 863A/C, stromal cell-derived factor 1 (SDF-1) + 801G/A, human leukocyte antigen [HLA]-A * 02, HLA-Cw * 08, HTLV-1 tax subgroup) and measured HTLV-1 provirus load in peripheral blood mononuclear cells using real-time polymerase chain reaction (PCR). Finally, the odds of HAM/TSP for each subject were calculated by using the equation and compared the results with clinical symptoms and laboratory findings. Although no clear difference was seen between the odds of HAM/TSP and either sex, family history of HAM/TSP or adult T-cell lenkemia (ATL), history of blood transfusion, it was found that brisk patellar deep tendon reflexes, which suggest latent central nervous system compromise, and flower cell-like abnormal lymphocytes, which is the morphological characteristic of ATL cells, were associated with a higher odds of HAM/TSP. The best-fit logistic regression equation may be useful for detecting subclinical abnormalities in HCs in southern Japan. Journal of NeuroVirology (2006) 12 , 171–177. [ABSTRACT FROM AUTHOR]

Aggrecan, which is a well-known proteoglycan in joint cartilage, also exists in the spinal cord and plays an important role in maintaining water content in the extracellular matrix structure. In this study, we first examined the variable number of tandem repeat (VNTR) polymorphism of the aggrecan gene in 227 HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in 217 HTLV-I-infected healthy carriers (HCs), and in 85 normal controls. The VNTR allele 28 (1,630 bp) was more frequently observed in HAM/TSP patients than in HCs ( χ 2=12.02, p=0.0005, odds ratio 1.79, 95% C.I. 1.29–2.50) and in controls ( χ 2=13.43, p=0.0002, odds ratio 2.54, 95% C.I. 1.52–4.25), although this allele was not related to disease progression or to HTLV-I provirus load. We also found that the aggrecan concentration in cerebrospinal fluid (CSF) from rapidly progressive HAM/TSP patients was significantly higher than in slowly progressive patients (corrected p=0.0145) but not in infected non-inflammatory neurological other disease controls (OND) (corrected p=0.078). We then analyzed this aggrecan VNTR polymorphism in the different set of patients with HAM/TSP ( n=58) and healthy carriers ( n=70). This analysis, again, revealed that allele 28 was detected more frequently in HAM/TSP group than in HCs ( χ 2=11.03, p=0.0009, odd ratio 3.04, 95% C.I. 1.55–5.97). The reproducibility of our study was regarded as a second- or third-class association by comparing combined p values and the Better Associations for Disease and GEnes (BADGE) system. Our results suggest that aggrecan polymorphism can be a novel genetic risk factor for developing HAM/TSP. [ABSTRACT FROM AUTHOR]

The article focuses on a clinical study that was conducted to find the effects of Omega-3 polyunsaturated fatty acids (PUFAs) on inflammatory markers in chronic obstructive pulmonary disease (COPD). The COPD is characterized by chronic inflammation and is considered to be the fifth leading cause of death worldwide. However, no effective agents are available to cure this inflammation. A dietary supplement containing PUFAs has anti-inflammatory effects. Therefore, a clinical study was conducted to find out the effects of omega-3 PUFAs in COPD. The study suggested nutritional support with an omega-3 PUFA-rich diet as a safe and practical method for treating COPD.

The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. To date, at least 11 genes and 13 additional loci have been identified in ADCAs. Despite phenotypic differences, spinocerebellar ataxia 4 (SCA4) and Japanese 16q-linked ADCA type III map to the same region of 16q22.1. We report four Japanese families with pure cerebellar ataxia and a disease locus at 16q22.1. Our families yielded a peak lod score of 6.01 at marker D16S3141. To refine the candidate region, we carried out genetic linkage studies in four pedigrees with a high density set of DNA markers from chromosome 16q22.1. Our linkage data suggest that the disease locus for 16q-ADCA type III is within the 1.25-Mb interval delineated by markers 17msm and CTTT01. We screened for mutations in 36 genes within the critical region. Our critical region lies within the linkage interval reported for SCA4 and for Japanese 16q-ADCA type III. These data suggest that the ADCA that we have characterized is allelic with SCA4 and Japanese 16q-linked ADCA type III. [ABSTRACT FROM AUTHOR]

To investigate non-human leukocyte antigen candidate genes that influence the outcome of human T cell lymphotropic virus (HTLV) type I infection, we analyzed 6 single-nucleotide polymorphisms in the interleukin (IL)-10 promoter region in 280 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/ TSP) and 255 HTLV-I-seropositive asymptomatic carriers from an area where HTLV-I is endemic. The IL-b -592 A allele, which shows lower HTLV-I Tax-induced transcriptional activity than the C allele in the Jurkat T cell line, was associated with a >2-fold reduction in the odds of developing HAM/TSP (P = .011; odds ratio [OR], 0.50 [95% confidence interval, 0.30-0.86]) by reducing the provirus load in the whole cohort (P = .009, analysis of variance). Given the OR and the observed frequency of IL-b -592 A, we demonstrate that this allele prevents ∼44.7% (standard deviation, ± 13.1%) of potential cases of HAM/TSP, which indicates that it defines one component of the genetic susceptibility to HAM/TSP in the cohort. [ABSTRACT FROM AUTHOR]

We examined the capillaries in muscle biopsy specimens from two patients with Ullrich's disease with collagen VI deficiency by light and electron microscopy. Collagen VI plays an important role in platelet aggregation for binding von Willebrand factor. Using immunohistochemistry, collagen VI was shown to be absent on capillaries from patients with Ullrich's disease, while von Willebrand factor, collagen IV, and vascular endothelial growth factor were normally expressed. Electron microscopy revealed narrow lumens, large nuclei in endothelial cells, and fenestration of a capillary. The number of pinocytotic vesicles per unit endothelial cytoplasm was increased. The cytoplasm of endothelial cells was strongly stained with uranyl acetate and lead citrate. Replication of the capillary basement membrane was observed. On the other hand, easy bleeding and coagulation were not observed in the two patients. These findings suggested that the collagen VI deficiency might have caused the electron microscopic changes of capillaries, while the function of the capillaries is apparently retained. [ABSTRACT FROM AUTHOR]

We report two patients with dystonia aged 53 and 27 years. One patient was diagnosed as a sporadic case of primary dystonia. The other patient was diagnosed as having secondary dystonia following head injury. Skeletal muscle specimens were obtained by open biopsy from the two patients. The muscle biopsy specimens showed lobulated fibers, ring fibers, and type 1 fiber atrophy. Dystonia comprises involuntary movement and causes abnormal muscle tone. We considered that the abnormal muscle tone caused by dystonia might be involved in the pathogenesis of these histochemical changes in skeletal muscle. [ABSTRACT FROM AUTHOR]

By electron microscopy, we examined the skeletal muscle from two patients with Ullrich's disease. One patient had a deletion in the collagen VI alpha 2 gene. The muscle biopsy specimens showed no collagen VI immunoreaction, while the expression of collagen IV was increased. Collagen VI is a microfibrillar protein in the extracellular matrix with cell adhesive properties, and collagen IV is a principal component of the basal lamina. Electron microscopy revealed unevenness, extension, and folding of the muscle plasma membrane, and showed thickening and overproduction of the basal lamina. The data show that type VI collagen is certainly one of the important extracellular matrix components maintaining the structural integrity of skeletal muscle, and a defect of the collagen VI protein causes abnormalities of the muscle plasma membrane, dystrophic muscle changes, and up-regulation of collagen IV. [ABSTRACT FROM AUTHOR]

Summary The purpose of this study was to investigate the cellular source and significance of vascular endothelial growth factor (VEGF) which, as reported previously, is elevated in the sera of pulmonary tuberculous patients. We obtained peripheral blood mononuclear cells (PBMCs) from 28 patients with active pulmonary tuberculosis, from 11 healthy controls who were positive for purified protein derivative of tuberculin (PPD), and from eight healthy individuals who were negative for PPD. We incubated the PBMCs with PPD in the presence or absence of major histocompatibility (MHC) class I or class II antibody in vitro , and measured the VEGF levels of culture supernatants. We also analysed the source of cells that secrete VEGF by using flow cytometry with intracellular staining. The T lymphocytes of active tuberculous patients secreted a higher level of VEGF than those of healthy controls. This production of VEGF was inhibited by adding MHC class II antibody. The addition of MHC class I antibody, however, did not inhibit. We propose that CD4+ T lymphocytes are almost certainly the cells that produce VEGF in response to PPD. VEGF production might be associated with an antigen-specific immune reaction via CD4+ T lymphocytes in tuberculosis. [ABSTRACT FROM AUTHOR]

To clarify clinical and laboratory findings that may be related to the pathomechanism of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we analyzed these findings in 239 patients with HAM/TSP, including 64 patients followed up for 10 years after their first examinations, with special interest in the HTLV-I proviral load in peripheral blood mononuclear cells (PBMCs). The proviral load in PBMCs did not differ in terms of modes of HTLV-I transmission. However, the proviral load in patients with age of disease onset greater than 65 years tended to be higher than those with a younger age of onset. In the 64 patients followed up for 10 years, the clinical symptoms deteriorated in 36 patients (56%), unchanged in 26 patients (41%), and improved in 2 patients (3%). HTLV-I proviral load also appeared to be related to the deterioration of motor disability in these patients. To our knowledge, the present study is the first longitudinal study concerning the relationship between the clinical course of HAM/TSP and HTLV-I proviral load. It is suggested that HTLV-I proviral load is related to the progression of motor disability and is an important factor to predict prognosis of patients with HAM/TSP. [ABSTRACT FROM AUTHOR]

We found a microvascular endothelial abnormality in a biopsy specimen from the gastrocnemius muscle of a patient with gastric cancer, who had severe myalgia and angialgia in the calf region with the symptoms of thrombophlebitis. There were no definite findings of inflammatory myopathy in histochemical and immunohistochemical studies. Electron microscopic examination revealed the accumulation of abnormal mitochondria in the subsarcolemmal area, and a fair number of degenerating capillaries. Immunohistochemical analysis of procoagulant or anticoagulant factors revealed marked reduction of thrombomodulin (TM) expression on small vessels and capillaries. Although a reduction of TM on small vessels has been observed around perifascicular atrophic fibers in patients with dermatomyositis, histochemical findings of the present patient showed no perifascicular atrophy or severely degenerating fibers. These pathological findings in the patient may be related to a malignant neoplasm and may be one of the causes of disseminated intravascular coagulation (DIC), which is the main complication of malignant neoplasms. Further studies are necessary to determine whether the reduction of TM on the small vessels and capillaries in skeletal muscle is a predictor of some severe condition such as DIC or a rare pathological finding in some special condition such as scirrhous carcinoma with thrombophlebitis. [ABSTRACT FROM AUTHOR]

Study Objective: In lung cancer, vascular endothelial growth factor (VEGF) is an important cytokine and is correlated with tumor vessel density, malignant pleural effusions, and coagulation-fibrinolysis factors in vitro. We investigated the correlation between serum VEGF level and stage progression in lung cancer to study the predicted value of VEGF level. We also studied whether coagulation-fibrinolysis factors and PaO(2) levels, which are also important factors for the prediction of the clinical course, are correlated with VEGF.Methods: Forty-nine patients with lung cancer were investigated prospectively. VEGF levels of sera and malignant effusions, and plasma concentrations of coagulation-fibrinolysis factors were measured by enzyme-linked immunosorbent assay. We measured PaO(2) levels in all patients at rest.Results: Serum levels of VEGF were increased significantly according to stage progression. Additionally, plasma concentrations of D dimer, thrombin-antithrombin complex (TAT), and tissue plasminogen activator/plasminogen activator inhibitor type I complex were elevated significantly according to stage progression. The serum VEGF level had a significant positive correlation with the TAT and D dimer levels. Serum VEGF levels had a significant negative correlation with PaO(2) levels. The incidence of cerebral vascular disorder was significantly higher in the patients with systemic hypoxemia than in those without (p<0.05). Mean VEGF levels in malignant effusions in eight patients (five with pleural effusions, two with pericardial effusions, and one with both) were extremely high, especially in pericardial effusions ([mean +/- SD] pleural effusions, 531.9+/-285.4 pg/mL; pericardial effusion, 3,071.6+/-81.3 pg/mL).Conclusion: We predict that in lung cancer, VEGF production and the abnormality of the coagulation-fibrinolysis system differ depending on the stage of progression of disease. Serum VEGF levels would be affected by PaO(2) levels in lung cancer. [ABSTRACT FROM AUTHOR]

To evaluate the possible involvement of vascular endothelial growth factor (VEGF) in the pathogenesis of Castleman's disease, we studied VEGF levels in sera and supernatants of cultured lymph nodes from two patients with the plasma cell type of Castleman's disease, and analysed the expression of VEGF immunohistochemically in the lymph nodes. Clinically, one patient was classified as the localized type and the other as the multicentric type. Histologically, mature plasma cells and hyalinized vessels were prominent in the interfollicular region. The VEGF levels of the sera and the supernatants of cultured lymph nodes of both patients were higher than those of normal controls. VEGF was strongly expressed in plasma cells in the interfollicular region of the lymph nodes of both patients, but rarely in normal lymph nodes. Our results suggest that VEGF may be involved in the marked vascular proliferation in the interfollicular region of the lymph nodes of the plasma cell type of Castleman's disease. [ABSTRACT FROM AUTHOR]