Search

Although renal failure can be a life-threatening complication even in neuromuscular disorders (NMDs), renal dysfunction is easily overlooked because muscle atrophy decreases the serum creatinine level. Renal function was retrospectively assessed using cystatin C (CysC) in various NMDs to clarify the differences among diseases. As is in the general population, age was correlated to CysC, and female patients showed lower CysC levels. Although elevated CysC was frequent in myotonic dystrophy 1 (DM1: MIM 160900) and motor neuron disorders, an inter-disease comparison by sex adjusted for age showed that only DM1 had a higher CysC compared to other diseases. Multivariate linear regression with the stepwise method also suggested that the number of CTG repeats had an impact on CysC levels. In two autopsy DM1 cases, nephrosclerotic changes were observed even though they were in their forties. These facts suggested a disease-specific pathomechanism for renal dysfunction in DM1. Although further study is required, renal function should be carefully monitored in patients with DM1., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In addition to the underlying shallow acetabular deformity, a patient with hip dysplasia has a greater risk of development of a labral tear, a cam lesion, and capsular laxity. This combination of abnormalities exacerbates joint instability, ultimately leading to osteoarthritis. Unsurprisingly, only repairing the acetabular labrum remains controversial, and the outcome is unpredictable. In this technical note, with video, we demonstrate an entirely endoscopic approach for simultaneously repairing the most common mechanical abnormalities found in moderate hip dysplasia: labral repair, cam osteochondroplasty, capsular plication, and shelf acetabuloplasty using an autologous iliac bone graft.

Purpose: The purpose of this study is to elucidate the criteria and limitations for selecting a sagittal split ramus osteotomy (SSRO) alone for patients with skeletal mandibular prognathism and open bite., Study Design: The relationship between the mandibular relapse after 1 year and the extent of vertical movement following SSRO alone was investigated for patients with skeletal mandibular prognathism and open bite and the criteria were determined., Results: The limitation in SSRO alone was found to be 3-mm vertical movement at the gonion. There was a significant difference in the mandibular relapse between the patients with >3-mm change and <3-mm change., Conclusions: For patients with skeletal mandibular prognathism and open bite, if the vertical movement at the gonion is <3 mm, SSRO alone could be an effective treatment. However, if the movement is >3 mm, SSRO alone should be avoided and bimaxillary osteotomies may be a preferable treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We report an extremely rare case of epidermal choristoma in the midline of the maxillary gingiva. A 2-month-old Japanese boy presented with a polypoid mass in the midline of the maxillary gingiva. The initial clinical diagnosis was congenital epulis. Microscopic examination revealed a granular cell layer and melanin pigmentation within the basal cell layer. Furthermore, sebaceous glands and hair follicles were observed within the connective tissue. The histological diagnosis was therefore epidermal choristoma, based on clinical microscopic observations., (Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Objectives: To examine the relationship between the anatomical position and the bone quality of the inferior alveolar nerve (IFAN) canal and long-term neurosensory disturbance (NSD) of the IFAN after a sagittal split ramus osteotomy (SSRO)., Material and Methods: CT images were taken of patients with mandibular prognathism. The location of the IFAN and the bone density around the IFAN were measured on CT images. Whether NSD at 6 months and 1 year after SSRO was related to the position and bone quality of the IFAN canal was analyzed., Results: Significant correlations were found between the anatomical position and the bone quality of the IFAN canal and the period to the resolution of NSD of the IFAN from 3 months to 1 year after SSRO. If the HU values around the IFAN were greater than 300 HU and/or the distance from the buccal aspect of the IFAN canal to the outer buccal cortical margin was less than 6 mm, NSD of the IFAN at 1 year after SSRO was significantly increased., Conclusion: It is important to pay particular attention to the anatomical position of the IFAN and the bone quality around the IFAN to predict long-term NSD of the IFAN after SSRO., (Copyright © 2011 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Mutations in the pore-forming subunit of the skeletal muscle sodium channel (SCN4A) are responsible for hyperkalemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are classified based on their cardinal symptoms, myotonia and/or paralysis. We report the case of a Japanese boy with a novel mutation of SCN4A, p.I693L, who exhibited severe episodic myotonia from infancy and later onset mild paralytic attack. He started to have apneic episodes with generalized hypertonia at age of 11 months, then developed severe episodic myotonia since 2 years of age. He presented characteristic generalized features which resembled Schwarz-Jampel syndrome. After 7 years old, paralytic episodes occurred several times a year. The compound muscle action potential did not change during short and long exercise tests. Functional analysis of the mutant channel expressed in cultured cell revealed enhancement of the activation and disruption of the slow inactivation, which were consistent with myotonia and paralytic attack. The severe clinical features in his infancy may correspond to myotonia permanence, however, he subsequently experienced paralytic attacks. This case provides an example of the complexity and overlap of the clinical features of sodium channel myotonic disorders., (Copyright © 2011 Elsevier B.V. All rights reserved.)

It is known that intrathecal administration of substance P (SP) induces thermal hyperalgesia, whereas hemokinin-1 (HK-1), a member of the same tachykinin family as SP, hardly induces thermal hyperalgesia; however, the underlying mechanism remains to be elucidated. Therefore, we aimed to clarify which amino acid of these peptides contributes to the induction of thermal hyperalgesia. When two chimera peptides between the N-terminal region of SP and the C-terminal region of HK-1, and vice versa, SP (1-5)/HK-1 and HK-1 (1-5)/SP, were intrathecally administered, SP (1-5)/HK-1 induced thermal hyperalgesia whereas HK-1 (1-5)/SP had hardly any effect; furthermore, thermal hyperalgesia was induced by only C-terminal fragments of HK-1 and SP. These findings indicate that the N-terminal region of HK-1 is involved in the non-induction of thermal hyperalgesia. Next, we synthesized and intrathecally administered these chimera peptides in which part of the N-terminal region of HK-1 was replaced with that of SP, and vice versa, and all synthesized peptides induced thermal hyperalgesia. Both SP (1-2)/HK-1 and HK-1 (1-4)/SP certainly induced thermal hyperalgesia, although HK-1 and HK-1 (1-5)/SP had hardly any effect; therefore, it is probable that Ser at the 2nd position and Arg at the 5th position of HK-1 may be involved in the non-induction of thermal hyperalgesia. Furthermore, peptides in which amino acid at the 3rd and/or 4th positions of HK-1 was replaced with that of SP were synthesized. Intrathecal administration of HK-1 (1-2,4-5)/SP, but not HK-1 (1-2,5)/SP and HK-1 (1-3,5)/SP, hardly induced thermal hyperalgesia. These findings indicate that three amino acids, Ser, Thr and Arg at the 2nd, 4th and 5th positions of HK-1, respectively, regulate the induction of thermal hyperalgesia by HK-1., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS). Anti-aquaporin-4 antibody (AQP4-Ab) is a highly specific serum autoantibody that is detected in patients with NMO. Several lines of evidence indicate that AQP4-Ab not only serves as a disease marker but also plays a pivotal role in the pathogenesis of NMO. Although the pathogenicity of AQP4-Ab in vivo has recently been demonstrated, the presence of CNS antigen-specific T cells is recognized as a prerequisite for the antibody to exert pathogenic effects. Thus, it remains unclear whether AQP4-Ab is the primary cause of the disease or a disease-modifying factor in NMO. Here we report that pre-treatment with complete Freund's adjuvant (CFA) alone is sufficient for AQP4-Ab to induce astrocytic damage in vivo. Our results show the primary pathogenic role of AQP4-Ab in the absence of CNS antigen-specific T cells, and suggest that danger signals provided by nonspecific inflammation can be a trigger for those who harbor the autoantibody to develop NMO., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Oral cancer is one of the most common cancers worldwide, and squamous-cell carcinoma (OSCC) is the most common phenotype of oral cancer. Although patients with OSCC have poor survival rates and a high incidence of metastasis, the molecular mechanisms of OSCC development have not yet been elucidated. This study investigated whether N-myc downstream-regulated gene 2 (NDRG2) contributes to the carcinogenesis of OSCC, as NDRG2 is reported to be a candidate tumor-suppressor gene in a wide variety of cancers. The down-regulation of NDRG2 mRNA, which was dependent on promoter methylation, was seen in the majority of OSCC cases and in several cases of precancerous leukoplakia with dysplasia. Induction of NDRG2 expression in an HSC-3/OSCC cell line significantly inhibited cell proliferation and decreased colony formation ability on soft agar. The majority of OSCC cell lines showed an activation of PI3K/Akt signaling, and enforced expression of NDRG2 in HSC-3 cells decreased the level of phosphorylated Akt at Serine 473 (p-Akt). Immunohistochemical p-Akt staining was detected in 56.5% of the OSCC tumors, and 80.4% of the tumors were negative for NDRG2 staining. Moreover, positive p-Akt staining was inversely correlated with decreased NDRG2 expression in OSCC tumors with moderate to poor differentiation (p<0.005). Therefore, NDRG2 is a candidate tumor-suppressor gene for OSCC development and probably contributes to the tumorigenesis of OSCC partly via the modulation of Akt signaling., (Copyright 2010 Elsevier Inc. All rights reserved.)

Recurrent attacks of optic neuritis and myelitis are the hallmarks of both neuromyelitis optica (NMO) and multiple sclerosis (MS). NMO immunoglobulin G (NMO-IgG), which recognizes astrocytic aquaporin-4 (AQP4) water channels, is a specific serum autoantibody that distinguishes NMO from MS. The pathogenic role of the anti-AQP4 antibody (AQP4-Ab, NMO-IgG) in NMO has been speculated based on several studies in vitro. The aim of this study was to demonstrate the pathogenicity of AQP4-Ab in vivo. We obtained IgG from patients who underwent therapeutic plasmapheresis, and developed an animal model by passive transfer of IgG to rats. The active lesions of the rats exhibited pathological characteristics strikingly similar to those of NMO, marked by astrocytic loss and perivascular deposition of immunoglobulin and complements. These findings provide the first evidence of the pathogenicity of AQP4-Ab in vivo and support the therapeutic efficacy of eliminating the antibodies by plasmapheresis.

We report on a 27-year-old man with Fabry disease who had widespread white-matter lesions (WMLs) despite the absence of renal or cardiac manifestations. Genomic analysis revealed a novel mutation: a GAT deletion at nucleotide position 234-236 in exon 5 of the coding region. After 12 months of enzyme replacement therapy (ERT), most of the WMLs had disappeared. Cell counts and protein levels in the cerebrospinal fluid also decreased. These findings suggest that ERT may play a role in the recovery of WMLs.

Introduction: Tooth movement and alveolar bone reaction after corticotomies have not been thoroughly examined. In this study, the effects of corticotomies on orthodontic tooth movement and alveolar bone reaction were investigated in dogs., Methods: Corticotomies were performed on the cortical bone of the mandibular left third premolar region in 12 male adult beagles. The third premolars on the left experimental side and on the right sham side were moved mesially with a continuous force of 0.5 N., Results: Tooth movement velocities from 0 to 1 week and from 1 to 2 weeks after the corticotomies were significantly faster on the experimental side than on the sham side. Hyalinization of the periodontal ligament appeared only at 1 week after the corticotomies on the experimental sides, whereas it was observed from 1 to 4 weeks after the corticotomies on the sham sides. Tartrate-resistant-acid-phosphatase positive cells of the experimental side tended to work vigorously at an early time on the alveolar wall and in the bone marrow cavities., Conclusions: Orthodontic tooth movement increased for at least 2 weeks after the corticotomies. This might be brought about by rapid alveolar bone reaction in the bone marrow cavities, which leads to less hyalinization of the periodontal ligament on the alveolar wall.

High prevalence of a form of autosomal recessive spastic ataxia with early onset was originally described among French Canadians in the Charlevoix-Saguenay region, in northeastern Quebec. Since the responsible gene (SACS) was identified, mutations in the SACS gene have been described in Tunisia, Italy, Turkey, and Japan. The mutation sites found outside Quebec are different from the ones in Quebec. All patients outside Quebec, except one Italian patient, have been reported to have homozygous mutations. The authors report here identical twin sisters with novel compound heterozygous mutations (c.[2951&#95;2952delAG]+[3922delT]) in the SACS gene.

Sleep disorders are common in the general population and occur more frequently with advancing age. However, patients with Parkinson's disease (PD) have been known to have various sleep disturbances beyond those to be expected from the effect of aging alone. We tried to quantify the various aspects of nocturnal sleep problems in PD using the PD sleep scale (PDSS). 64 patients with PD and 60 age- and sex-matched controls completed the PDSS. After neurological examinations, we assessed the degree of sleep disorder by the PDSS. We evaluated the severity of PD by the Hoehn and Yahr Scale and the unified PD rating scale (UPDRS). To compare the various aspects of nocturnal sleep problems in PD between in Japan and in the United Kingdom (UK), we referenced and compared our results with those by Chaudhui et al. The PDSS scores in PD group were significantly different from those in controls. Individual items of the scale showed good discriminatory power between PD and controls. Overall tendencies were the same in Japan and in the UK, but there were some different points, especially absence of refreshing quality of sleep in Japan. We believe that the PDSS provides an objective method for targeted therapeutic approaches for the treatment of disturbed sleep in PD even among countries with different cultures, such as Japan and the UK.

To determine the amount of iron deposits in the basal ganglia, we examined 13 healthy volunteers with a 1.5 T MRI system using three transverse relaxation rates measured with two sequences. The transverse relaxation rates comprise the reversible contribution (R2') and irreversible contribution (R2) to a phase-reversal 180 degrees -pulse sequence. The transverse relaxation rates with the estimated iron indicated that both R2 and R2' had a robust relationship with brain iron level as determined from published post mortem data. This was the case only when the analyses are limited to the subcortical gray matter regions, however. R2' was affected by macroscopic magnetic field inhomogeneity arising from the skull bases, so that it was less robust for estimating the amount of iron deposits in the basal ganglia.

In this study, a mouse genomic region is identified that undergoes DNA rearrangement and yields circular DNA in brain during embryogenesis. External region-directed inverse polymerase chain reaction on circular DNA extracted from late embryonic brain tissue repeatedly detected DNA of this region containing recombination joints. Wide-range genomic PCR and digestion-circularization PCR analysis showed this region underwent recombination accompanied with deletion of intervening sequences, including the circularized regions. This region was mapped by fluorescence in situ hybridization to C1 on mouse chromosome 16, where no gene and no physiological DNA rearrangement had been identified. DNA sequence in the region has segmental homology to an orthologous region on human chromosome 3q.13. These observations demonstrated somatic DNA recombination yielding genomic deletions in brain during embryogenesis.

To develop a new measurement tool for quantitatively detecting the finger movement of a patient with Parkinson's disease (PD), we designed a magnetic sensing system consisting of a magnetic induction coil, a sensing coil, and a circuit unit. The sensing coil detects the inducted magnetic field that varies with the distance between the two coils, and the detected signals are demodulated in the circuit unit in order to obtain the variation voltage from the oscillation frequency. To obtain a coefficient for converting voltage to distance, we measured the output voltages for seven fixed finger positions of 12 normal volunteers. The voltage differences corresponding to the finger movement in 20 PD patients, six age-matched controls, and 12 normal volunteers were then recorded for 30s. To investigate the velocity and acceleration of the finger movement, we calculated their waveforms from the measured displacement waveform. We also detected the main frequency of the tapping rhythm by using a fast Fourier transform (FFT). The averaged amplitude of each waveform decreased with the disorder in the Hoehn-Yahr (HY) stage, while the averaged tapping frequency of PD patients did not have any correlation with this stage. It can be concluded that this magnetic sensing system can assess finger movement quantitatively.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of patients are sporadic cases, while 5-10% of the patients have a family history of ALS (fALS). Mutations in the gene that encodes cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 25% of fALS cases. Although the precise pathogenesis of ALS is still unknown, experimental studies including animal models suggest that fALS is caused by the toxic gain-of-function of the SOD1 mutant. We have analyzed not only SOD1 gene mutation by genomic sequencing, but also SOD1 mutant protein by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). We analyzed 33 fALS patients and found 10 mutations in SOD1 gene, in which two were novel: Asp101His substitution in exon 4 and Gly141Glu substitution in exon 5. Here, we present their mass spectrometric protein analyses and clinical features.

We determined cabergoline and L-dopa in human plasma using liquid chromatography-mass spectrometry with tandem mass spectrometry (LC-MS-MS). The deproteinized plasma samples with organic solvent or acid were analyzed directly by reversed-phase liquid chromatography. Using multiple reaction monitoring (MRM, product ions m/z 381 of m/z 452 for cabergoline and m/z 152 of m/z 198 for L-dopa) on LC-MS-MS with electrospray ionization (ESI), cabergoline and L-dopa in human plasma were determined. Calibration curves of the method showed a good linearity in the range 5-250 pg/ml for cabergoline and 1-200 ng/ml for L-dopa, respectively. The limit of determination was estimated to be approximately 2 pg/ml for cabergoline and approximately 0.1 ng/ml for L-dopa, respectively. The method was applied to the analysis of cabergoline and L-dopa in plasma samples from patients treated with these drugs. The precision of analysis showed coefficients of variation ranging from 3.8% to 10.5% at cabergoline concentration of 13.8-26.2 pg/ml and from 2.9% to 8.9% at an L-dopa concentration of 302.5-522.1 ng/ml in patient plasma. As a result, the procedure proved to be very suitable for routine analysis.

Conventional immunoassays for haptens such as steroids and synthetic drugs are dependent on the competitive reaction between an unlabeled antigen (analyte) and a labeled antigen against a limited amount of anti-hapten antibody. Although noncompetitive immunoassay procedures such as two-site immunometric assays offer a much higher sensitivity, direct application of this principle to haptens has been difficult due to their small molecular mass precluding simultaneous binding by two antibody molecules. Here, we have attempted to develop a noncompetitive immunoassay system based on anti-idiotype or anti-metatype antibodies. Ursodeoxycholic acid 7-N-acetylglucosaminide (UDCA 7-NAG), which is a bile acid metabolite (molecular weight, 595.8), was selected as the model hapten. A/J mice were immunized with a monoclonal antibody against UDCA 7-NAG, which had been affinity-labeled with a relevant hapten derivative. The fusion between the immune spleen cells and P3/NS1/1-Ag4-1 myeloma cells yielded four kinds of alpha-type and two kinds of beta-type monoclonal anti-idiotype antibodies, each recognizing the framework region and paratope of the anti-hapten antibody. The use of a selected combination between alpha-type and beta-type antibodies together with the anti-hapten antibody provided a noncompetitive assay system with a subfemtomole order sensitivity (detection limit, 118 amol) and a practical specificity.

A therapy aimed at blocking the Fas/Fas ligand (FasL) system was investigated using a relapsing form of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis (MS). Intracisternal administration of neutralizing antibody against FasL during the progression phase of EAE significantly reduced the severity of the disease with milder inflammation and myelin breakdown in the central nervous system (CNS). These results raised the possibility that the Fas/FasL system might contribute to tissue destruction in the CNS in the acute phase of EAE and that the intrathecal administration of neutralizing antibody against FasL may be beneficial for suppression of the acute phase of MS., (Copyright 2000 Academic Press.)

We report a patient with HTLV-I-associated myelopathy (HAM), who developed symptoms of myelopathy 4 years after cadaveric renal transplantation. Since he was seronegative before the transplantation, it is suggested that HTLV-I infection was transmitted via renal graft transplantation. He has been treated with immunosuppressive agents such as cyclosporin A (CsA), mycophenolate mofetil (MMF), and prednisolone (PSL) to prevent graft rejection. This case suggested that these immunosuppressive agents are poorly effective in suppressing either the onset or progression of HAM/TSP.

The effect of apoptosis inhibitors on experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, was investigated by intraperitoneal or intracisternal administration of apoptosis inhibitors Ac-YVAD-cmk and zVAD-fmk. After onset of the disease, these agents had no suppressive effect on EAE and resulted in impaired recovery or earlier relapse. Histological examination revealed that administration of zVAD-fmk suppressed the apoptotic death of inflammatory cells in the central nervous system (CNS) of mice with EAE. The results indicated that the apoptotic elimination of infiltrated cells in the CNS might be one of the recovery mechanisms in EAE., (Copyright 2000 Academic Press.)

A cephalometric study was conducted on 12 patients with repaired cleft palate to evaluate the stability in level and length of the base attachment of the velopharyngeal complex following pharyngeal flap surgery by a modified velopharyngoplasty. Complete velopharyngeal closure and normal articulation with a speech appliance were confirmed in all patients prior to pharyngeal flap surgery, which was performed on patients 10 years of age and above. Cephalometric radiographs were taken immediately, 1 year, 2 years and 3 years postoperatively. Cephalometric analysis revealed that although the level and length of the base of the velopharyngeal complex showed changes during the first postoperative year, they remained stable when compared with the palatal plane during the last two years. This indicated therefore that the base of a velopharyngoplasty should be attached at the same level of the palatal plane, namely the level of velopharyngeal closure, and that the procedure appeared useful in producing a stable velopharyngeal complex.

We measured cerebrospinal fluid (CSF) levels of dehydroepiandrosterone sulfate (DHEAS) by radioimmunoassay in seven patients with multi-infarct dementia (MID), fourteen age- and gender-matched non-demented patients with a history of cerebral infarction and fifteen age- and gender-matched patients without neurological disorders. The levels of DHEAS in CSF of patients with MID were significantly lower than those in non-demented patients with a history of cerebral infarction or those in patients without neurological disorders. Daily intravenous administration of 200 mg DHEAS for 4 weeks markedly increased serum and CSF levels of DHEAS in seven MID patients, improved decrease of daily activities and emotional disturbances in three patients and EEG abnormalities in two patients. The DHEAS therapy may provide a beneficial effect on MID patients.

To clarify the characteristics of growth of the nasopharynx, comparison of the cephalometric growth of bones surrounding nasopharynx between 61 patients with complete unilateral cleft lip and palate (UCLP group) and 82 non-cleft controls (NCC group) was carried out. All of the subjects were divided into four developmental stages (i.e. stage 1 at 4 years of age, stage 2 at 8 years of age, stage 3 at 12 years of age and stage 4 at 17 years of age). Measurements on the antero-posterior and the vertical dimensions were derived from a coordinate system and points on bones surrounding the nasopharynx on lateral X-ray cephalograms, and results were analyzed by multivariate analysis and t-test. The results showed that (a) the posterior maxillary point (PMP) in the UCLP group was located more postero-superiorly than that in the NCC group, and this was the main factor that allows discrimination between the two groups and (b) the cranial base, posterior maxilla and the cervical vertebrae were found to be in independent in growth, however, the nasopharyngeal triangle connecting three points on these three bones (Ho: cranial base; PMP: posterior maxillary point; At: atlas) showed harmonious growth in both the UCLP and NCC groups.

Rho-associated kinase (Rho-kinase), the putative target of the small GTP-binding protein Rho, phosphorylated neurofilament protein (NF-L) in vitro with approximately 1 mole phosphate per mole NF-L. Phosphorylated NF-L no longer formed the 10 nm filaments, and NF-L filaments were phosphorylated with a result of nearly complete disassembly. NF-L phosphorylated by Rho-kinase was digested with trypsin, and digested fragments were assigned by MALDI/TOF. Unique phosphorylation sites were found at Ser-26 and Ser-57 in the head domain of NF-L. These results indicate that domain- and site-specific phosphorylation by Rho-kinase may regulate the assembly-disassembly of NF-L filaments.

We analyzed mutant superoxide dismutase-1 (SOD-1) in erythrocytes from patients with familial amyotrophic lateral sclerosis (FALS) by using ion exchange chromatography and HPLC/electrospray ionization mass spectrometry and were able to divide mutant SOD-1 proteins into a stable form including G37R and H46R, and an unstable form including I149T and a two base pair deletion mutant. Each mutant sample showed abnormal copper peaks in different chromatographic fractions without relation to SOD-1 activities. In addition, thioredoxin, known as an antioxidant molecule, was markedly increased in the stable form but not in the unstable form. These results suggest the presence of different pathways leading to motor neuron death between stable and unstable mutants.

Cognitive function in patients with amyotrophic lateral sclerosis (ALS) has drawn recent attention. However, the pathogenesis of cognitive dysfunction in patients with ALS remains uncertain. To explore the underlying mechanism for cognitive dysfunction further, we studied 26 patients with ALS (15 male and 11 female; age from 36 to 67 years) by using neuropsychological batteries, magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). We also evaluated these patients and an additional 26 age- and sex-matched normal controls using neuropsychological batteries with special attention to the frontal lobe function. On the basis of neuropsychological examination, we classified patients into three groups using cluster analysis. Age, education level and severity were comparable across these subgroups. Neuropathologic examination was subsequently carried out in six patients. Patients in Group 1 and 2 had low scores on all measures compared to patients in Group 3 and normal controls. Patients in Group 1 and 2 had frontal atrophy on MRI and reduced isotope uptake in the frontal region on SPECT, which was more evident in patients in Group 1. On neuropathologic examination, patients in Group 1 showed spongy degeneration and neuronal loss in the frontal lobe. Patients in Group 3 showed no notable pathology in the frontal region. The gradient distribution of the scores for attention and executive function, as well as SPECT findings suggested the presence of a continuum of cognitive disability in patients with ALS corresponding to the pathologic process in the frontal lobe ranging from significant impairment to normality. We, therefore, believe that inattention and executive dysfunction alternatives may evolve in patients with ALS corresponding to the pathologic process in the frontal lobe.

Two siblings who exhibited hereditary parkinsonism with pyramidal signs and cerebellar ataxia are reported. Anticholinergics had a dramatic beneficial effect in both cases, but levodopa did not. This responsiveness, which is similar to that reported in patients with Joseph's disease, suggests dysfunction of an "indirect pathway" involving the globus pallidus and the subthalamic nucleus, in addition to that of the nigrostriatal system. We propose a new hereditary variant of early onset Parkinson's disease distinct from the levodopa sensitive forms of juvenile Parkinson's disease.

In order to investigate the role of "neurosteroids" in the central nervous system (CNS), cerebrospinal fluid (CSF) levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were determined by radioimmunoassay in 57 patients with various neurologic disorders and 26 patients with non-neurologic disorders. The content of CSF DHEA and DHEAS in patients with Guillain-Barré syndrome (GBS), and the content of CSF DHEAS in patients with carcinomatous meningitis were significantly higher as compared to non-neurological control patients. These changes may be explained by the breakdown of blood-nerve barrier in these disorders. A significant positive correlation was observed between DHEAS and total protein in CSF. In males but not females, a negative correlation was observed between CSF DHEAS and aging. The level of CSF DHEAS, but not DHEA, was significantly higher in males than in females.

X-linked spinal and bulbar muscular atrophy (SBMA), an adult-onset form of motor neuron disease, was recently reported to be caused by amplification of the CAG repeats in the androgen receptor gene. We report here a simple and rapid strategy to detect the precise number of the CAGs. After the DNA fragment containing the CAG repeats is amplified by the polymerase chain reaction, a primer extension is carried out; the extension of the end-labelled reverse primer adjacent to 3' end of CAG repeats stops at the first T after CAG repeats with the incorporation of dideoxy ATP in the reaction mixture. The resultant primer products are analysed by denaturing polyacrylamide gel electrophoresis and autoradiography. This method could be quite useful to detect not only CAG repeats in SBMA but also other polymorphic dinucleotide and trinucleotide repeats.

This is a report of 3 cases of cardiac sarcoidosis. None of the 3 patients had other overt systemic involvement. Multinucleated giant cells and non-caseating epithelial cell granulomas with small lymphocytic infiltrations were detected in the endomyocardial biopsy specimen. Some focal left ventricular wall motion abnormalities were detected by echocardiography and angiography in all 3 patients. Paroxysmal ventricular tachycardia and multifocal ventricular premature complexes were observed by Holter 24-hour electrocardiography in all 3 patients. Two of the 3 patients did not receive corticosteroids, but remaining patient is on a regimen of corticosteroid.

Evaluation of hepatic venous flow patterns was attempted by pulsed Doppler echocardiography. Subjects were 80 patients including those with dilated cardiomyopathy, old myocardial infarction, angina pectoris, pulmonary hypertension, constrictive pericarditis, tricuspid regurgitation (TR), lone atrial fibrillation, and post-cardiac surgery. Eleven normal subjects served as controls. The mean age was 53.0 +/- 12.4 years. Most of the TR patients had atrial fibrillation. Patients with aortic regurgitation and significant mitral regurgitation were excluded. Afterload stress by angiotensin II infusion was performed in 51 subjects, mainly for those with ischemic heart disease, cardiomyopathy and the normal controls. Hepatic venous flow patterns included double-peaked flow signals toward the right atrium, and the relationship between systolic (S) and diastolic flow velocities (D) was expressed as the velocity ratio [S/(S+D)]. A reversed flow during atrial systole was expressed as an "A wave" and that between the S and D waves, as an "O wave". Systolic flow velocity was less than diastolic flow velocity in cases with atrial fibrillation and the post-surgical cases. The velocity ratio was greater than 0.5 in nearly all patients with normal sinus rhythm, and less than 0.5 in cases with atrial fibrillation and the post-surgical cases. In the former, systolic flow velocity was less than diastolic flow velocity after defibrillation, in spite of restoration of normal sinus rhythm. These findings indicate that systolic flow velocity was influenced by atrial relaxation; diastolic flow velocity, by ventricular diastolic function. The A wave was increased in cases with pulmonary hypertension and A wave velocity in the hepatic vein correlated with systolic pulmonary artery pressure. In cases with tricuspid regurgitation, reversed flows were detected during ventricular systole both in normal sinus rhythm and in atrial fibrillation. After infusions of angiotensin II the velocity ratio increased in cases with dilated cardiomyopathy and in normal controls (p less than 0.01). The hepatic venous flow pattern after infusion in the former was characterized by dominant systolic and diminished diastolic flow velocities with a consequent increase in the velocity ratio toward 1.0, while a change in the ratio was less marked in normal controls. In conclusion, analysis of the hepatic venous flow pattern by pulsed Doppler echocardiography is very useful for evaluating cardiac function. A marked increase in the velocity ratio after angiotensin II infusion suggests decreased cardiac function.

The kinetics of stable isotope-labelled L-threo-3, 4-dihydroxyphenylserine(L-threo-DOPS), an immediate precursor of (-)-norepinephrine, was studied to investigate the pharmacologic mechanism of its therapeutic effect on orthostatic hypotension in familial amyloid polyneuropathy(FAP) and on akinesia and freezing in parkinsonism. [13C,D]-L-threo-DOPS was synthesized, and 100 mg of the compound was infused for 2 h into two normal subjects, two FAP patients and two patients with the degenerative diseases of the central nervous system. Labelled and endogenous norepinephrine in urine and plasma was assayed simultaneously by gas chromatography/mass spectrometry. The results indicate that the increase in norepinephrine in biological fluids after administration of L-threo-DOPS is attributable mostly to norepinephrine derived from L-threo-DOPS, not to pre-formed endogenous norepinephrine released by L-threo-DOPS.

alpha 2-Adrenergic receptor binding has been studied in platelet membranes from 16 patients with type 1 familial amyloidotic polyneuropathy (FAP) at various clinical stages and 15 normal subjects. Binding of the radioligand [3H]yohimbine to platelet membranes was used to examine alpha 2-adrenergic receptors. The number of alpha 2-adrenergic receptors were significantly lower in patients of the early stage than in normal subjects. Then, the numbers tended to be higher than those of normal subjects in the intermediate stage, and they were higher in the single advanced-stage patient studied. The reduction in alpha 2-adrenergic receptor numbers in platelet membranes from patients of the early stage might be explained by the down-regulation of the receptors in vascular smooth muscle, but it remains uncertain whether a high number of alpha 2-adrenergic receptors observed in the single advanced-stage patient might be explained by the up-regulation of the receptors.

The capability of diagnosing left ventricular thrombi was compared by scintigraphy using Ga-67-DFO-DAS-fibrinogen (Ga: gallium, DFO: deferoxamine, DAS: dialdehyde starch) and two-dimensional echocardiography. 1. Ga-67-DFO-DAS-fibrinogen scintigraphy and two-dimensional echocardiography were performed in 17 consecutive patients following myocardial infarction. In 11 of the 17 patients, left ventricular thrombi were visualized by Ga-67-DFO-DAS-fibrinogen scintigraphy, but only five of the 11 patients were found to have thrombi by two-dimensional echocardiography. 2. In eight patients with inferior or posterior myocardial infarction, no left ventricular thrombi were detected by two-dimensional echocardiography, while in six of the eight patients, ventricular thrombi were visualized by Ga-67-DFO-DAS-fibrinogen scintigraphy. 3. Among the patients receiving adequate anticoagulants from the episode, only three patients had thrombi. In contrast, the remaining eight patients with thrombi were either receiving no anticoagulants, or were receiving inadequate anticoagulant therapy. Ga-67-DFO-DAS-fibrinogen scintigraphy is a very simple and useful method for detecting thrombi in the left ventricle after myocardial infarction. It is more sensitive for detecting thrombi in the ventricle than was two-dimensional echocardiography. With this method, we can demonstrate the preventive effect of anticoagulants for left ventricular thrombus formation following myocardial infarction.