Biomedical subjects
Publications and source records attributed to H Kowa.
We report on a Japanese family affected by Emery-Dreifuss muscular dystrophy carrying a novel mutation of the emerin (STA) gene. The cardinal clinical feature of the family was cardiac conduction block and mild myopathy. A deletion of 11 bp with a frameshift was identified in exon 6, causing truncation of the predicted protein. The relationship between mutation and phenotype is discussed.
The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon). Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS score was improved at all points of determination. Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination. The area under the curve (AUC) for levodopa increased by 34% (p = 0.0059) after the administration of tolcapone. The elimination half-life (T1/2) of levodopa was significantly prolonged by 81% (p = 0.0001) after the treatment. The AUC of 3-O-methyldopa, a metabolite of levodopa, was decreased by 79% (p = 0.0001) and the Cmax (maximum concentration) was also decreased by 80%d after the administration (p = 0.0001) of tolcapone. The combination of tolcapone and levodopa was well tolerated. Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients. It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.
A 9-year nationwide study of bromocriptine monotherapy and combination therapy with bromocriptine and levodopa in Parkinson's disease is reported. Eleven patients were on bromocriptine monotherapy, 35 patients were on combined treatment of bromocriptine and levodopa for a certain time during a 9-year period. Maintenance doses of bromocriptine at the end of the 9th year in the two groups were 11.1 mg/day in the monotherapy and 12.7 mg/day in the combination therapy group with levodopa. Changes in Hoehn and Yahr's grading between the time of trial start and the end of 108 months' treatment revealed that 5 of 11 cases in the monotherapy group remained in the same stages, the other 2 cases improved in condition from stage II to I, and another 4 deteriorated compared with pretreatment grade. On the other hand, 20 of 35 cases in the combination-therapy group reached more advanced stages, 3 patients moving to stage V. Four of them, however, improved, and 11 did not change at the end of 9 years of treatment. Although it is difficult to prove the neuroprotective effect of a dopamine receptor agonist, our long-term nation-wide collaborative studies will help us to answer the question of how bromocriptine works in pharmacokinetic aspects.
Autosomal dominant Parkinson's disease in 5 generations of a family living in Sagamihara City is reported. Clinical features of this family did not differ from common PD, however, neuropathological findings were different from PD. In autopsied cases, the loss of melanin-containing cells was mild to moderate, and the number of neurons of the locus ceruleus was maintained. No Lewy bodies were detected at all from any region where Lewy bodies frequently appear in PD.
A 10-year nationwide multicenter prospective study on the long-term efficacy of bromocriptine for Parkinson's disease is reported. Six patients remained on bromocriptine monotherapy for 10 years, while 22 patients achieved good disease control with bromocriptine plus levodopa (added during the course of the study). In the 6 patients on bromocriptine alone, the disease remained in Hoehn and Yahr stage I or II for 10 years. In the other 22 patients on bromocriptine plus levodopa therapy, disease progression was very slow for 7-8 years. None of the 6 patients remaining on bromocriptine monotherapy experienced adverse reactions like the wearing-off phenomenon, dyskinesia, or the on-off phenomenon. Among the 22 patients who started levodopa therapy during the course of the study, these adverse reactions to levodopa were infrequent (10, 3, and 3 patients, respectively). Thus, early introduction and long continuation of bromocriptine therapy with restricted concomitant use of levodopa may have led to very slow disease progression and the suppression of adverse reactions. Although the patients who could be maintained long-term on bromocriptine monotherapy might represent a population who have very slowly progressive disease, their adequate disease control and the low incidence of adverse reactions in the patients who later started concomitant levodopa suggest that the unwanted effects of levodopa may be reduced by early and sustained treatment with bromocriptine. Introduction of bromocriptine monotherapy at an early stage of Parkinson's disease or with restricted use of additional levodopa therapy to bromocriptine when necessary may be a useful strategy for achieving adequate and sustained disease control.
We studied relationships between anti-ganglioside antibodies and the clinical characteristics of Guillain-Barré syndrome (GBS) using multivariate analysis. Serum anti-ganglioside antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in 42 GBS patients and 47 controls. Relationships between antibodies and 15 clinical characteristics were analyzed using a logistic model. Anti-GM1 antibodies were significantly infrequent in patients with objective sensory disturbance (immunoglobulin G (IgG), p < 0.05, odds ratio = 0.094; immunoglobulin M (IgM), p < 0.01, odds ratio = 0.032) and frequent in patients with prodromal diarrhea (IgG, p < 0.05, odds ratio = 5.759; IgM, p < 0.05, odds ratio = 16.28). The combination of anti-GM1 and anti-GD1b antibodies was frequent in patients with prodromal diarrhea (IgG, p < 0.01, odds ratio = 9.667; IgM, p < 0.01, odds ratio = 14.50). IgG anti-GQ1b antibodies were extremely frequent in patients with ophthalmoplegia (p < 0.01, odds ratio = 102.3), and infrequent in patients with objective sensory disturbance (p < 0.05, odds ratio = 0.023).
We report an 84-year-old man with marked dropped head from 80 years of age. On neurologic examination, weakness was restricted to the neck extensor muscle, and the range of motility (ROM) of cervical spine was limited. He also had vascular parkinsonism. Needle electromyography indicated myogenic changes localized in the cervical paraspinal and trapezius muscles. CT and MRI of the cervical region demonstrated neck extensor muscle atrophy. Cervical paraspinal muscle biopsy revealed decreased numbers of muscle fibers which were embedded in markedly increased connective tissue. There was neither cellular infiltration nor specific changes. These findings were identical to those seen in isolated neck extensor myopathy recently proposed by Katz et al. (1996). In addition, pathological finding of the biceps muscle of the left arm suggested subclinical general myopathy because of mild fiber-size variability with moth-eaten appearance on NADH-TR straining. Neck extensor muscle weakness and limitation of ROM improved by physical therapy, and gait disturbance also improved simultaneously. To our knowledge, this is the first report isolated neck extensor myopathy in Japanese.
It was one of the great pleasures to have fulfilled my long-held dream in 1986, newly opened the Kitasato University East Hospital (KUEH). In 1965, I served at chronic ward of Baltimore City Hospitals as a resident of neurology, where most of the patients were relaxed and enjoyed their hospital life. Since then, my dream had been growing that chronic ward for neurological diseases was necessary in Japan, good for chronic cares as well as clinical research. KUEH include 89 beds for neurological diseases, uniquely enough, of which 15 beds specially prepared for the patients with respiratory distress suffering from intractable neurological diseases. KUEH gave us a lot of medical informations, developed to clinical research. Some of them will be introduced briefly as follows; firstly, in three patients with Guillain-Barré syndrome (GBS) we found high titers of serum IgM and IgG antibodies associated with acute cytomegalovirus (CMV) infections. They also had high titers of IgM and IgG anti-GM2 antibodies. The titers of anti-GM2 antibodies decreased on absorption with CMV-infected cells. These new findings suggested that anti-GM2 antibodies are associated with acute CMV infections in GBS patients. Secondly, we have patients with autosomal dominant familial Parkinsonism in Sagamihara, Kanagawa. Their clinical features are not essentially different from solitary Parkinson disease, and they respond well to levodopa treatment. Three autopsied cases, however, revealed neuropathological findings much different from those of classical Parkinson disease, such as rather mild to moderate loss of melanin-containing cells, well-maintained locus ceruleus neurons in number and no Lewy bodies detected at all. There are no reports in literatures of familial Parkinsonism from clinical and neuropathological points of view. Thirty-eight years have passed since establishment of the Japan Neurological Society, meanwhile the expertise neurologists come out. Neurology is, however, still minor in medical practice. This is my opinion that neurologist should take leadership in clinical medicine as well as in academic fields. We need tell people our work, how our neurologic expertise can help them treat various disorders such as stroke, pain, sleep, and headache, epilepsy as well as physical and mental rehabilitation for the establishment of our identity.
We examined serum anti-cytomegalovirus (CMV) and anti-ganglioside antibodies by ELISA in 51 patients with Guillain-Barré syndrome (GBS), and titers were compared with those from 47 normal and 74 disease controls. Three GBS patients with IgM anti-CMV antibodies had high titers of IgM and IgG anti-GM2 antibodies. The other GBS patients without IgM anti-CMV antibodies, and the normal and disease controls except one of 6 non-GBS patients with acute CMV infections had no anti-GM2 antibodies. The titers of anti-GM2 antibodies decreased on absorption with CMV-infected cells. These findings suggest that anti-GM2 antibodies are associated with acute CMV infections in GBS patients.
An 8-year nationwide study of bromocriptine monotherapy and combination therapy with bromocriptine and levodopa in Parkinson's disease is reported. Fifteen patients were on bromocriptine monotherapy, and 44 patients on bromocriptine combined with levodopa for a certain time during an 8-year period. By judging from Hoehn and Yahr's grading, 4 of the 15 patients in the monotherapy group were in a better condition than before treatment, while 7 cases remained in the same grading, and only 4 showed deterioration. On the other hand, 26 of 44 patients on combination therapy showed more advanced grading at the end of 8 years compared to the stage at the onset of the trial. Maintenance doses of bromocriptine in the two groups were 12-13 mg per day, and levodopa doses were kept at a relatively low level (310-370 mg per day) during this study period. Whether dopamine receptor agonists have neuroprotective effect or not is extremely difficult to prove in human subjects, but this type of long-term follow-up study might give some clues as to these important questions.
Paraneoplastic syndrome(PS) associated anti-neuronal autoantibodies are characterized by their antigen molecular weight determined by Western blot and immunostaining pattern recognized through immunohistochemistry. We investigated immunohistochemical fixatives for their sensitivity in the detection of anti-neuronal nuclear antibody(Hu). Serum used for this study was taken from a patient with anti-Hu antibody seropositivity, which was ascertained by recombinant Hu protein. Western blot analysis produced 37kDa band. We examined six fixative conditions: immersion fixed with acetone, Bouin's solution, Sakura rapid fixative("Ufix'), and perfusion fixed with 2%, 4%, 8% paraformaldehyde (PFA) on the basis of each immunoreactivity in a rat cerebellum, brain stem and liver. The optimal fixation for detecting anti-Hu antibody was perfusion fixed with 2% PFA, that reacted conspicuously with nucleus but not nucleolus of neurons. The perfusion method proved superior to immersion in immunostaining intensity. With immersion fixation, specific immunostaining pattern lessened and differentiation from cytoplasm decreased. With various concentrations of PFA, immuno-reactivity with nucleus at 2% PFA was similar to 4%, although serum optimal dilution at 2% was slightly greater than 4%. The variety of staining patterns of anti-Hu antibody is closely related to the vulnerability of neuronal antigens to the fixatives. The detection of anti-neuronal antibodies is important for early diagnosis and treatment of occult tumors. The immunostaining method is a useful and sensitive way to research these antibodies. Therefore, it is essential to consider the selection of fixation and the preservation of the antigenicity in evaluating immunohistochemical hallmarks.
Usefulness of needle electromyography (EMG) in the thoracic paraspinal muscles was investigated in 22 patients with amyotrophic lateral sclerosis (ALS). All patients revealed denervation changes in the thoracic paraspinal muscles, though the EMG findings were insufficient to fulfill the WFN criteria of lower motor neuron sign. We could not diagnose three patients as having ALS at their first visits by conventional EMG. One patient had restricted neurogenic change within one limb and two patients had cervical spondylosis causing difficulty to diagnose anterior horn cell involvement at the cervical level. In these patients, however, we believed to having ALS because of the neurogenic findings of EMG in the thoracic paraspinal muscles. Afterwards, they became clinically definite ALS. On relation to respiratory function, patients with acute denervation potentials (fibrillation potentials) in upper thoracic paraspinal muscles innervated by Th1 approximately Th4 had respiratory dysfunction (% VC is less than 80). Two patients had the acute denervation potentials in the upper thoracic paraspinal muscles before the decrease in % VC. We conclude that needle EMG testing in thoracic paraspinal muscle is useful to diagnose ALS in early stage and to predict respiratory failure in ALS patients.
We report a 54-year-old man with X-linked bulbospinal muscular atrophy (BSMA) with bilateral abductor vocal cord paralysis. He noticed distal weakness in the lower limbs at age 20. In the following 18 years the weakness and atrophy of his leg muscles increased gradually. He has complained of stridors during respiratory tract infection and snored heavily during sleep since his age of 50. He was admitted to our hospital for the progressive stridors during meals. His two brothers were said to have similar complaints. Physical examination showed gynecomastia, hypertension and inspiratory stridor. Neurologic examination revealed distal muscular atrophy in his four extremities, especially more severe in bilateral lower limbs. Deep tendon reflexes were absent in all extremities. His tongue was slightly atrophic with fasciculation. Neurological diagnosis was made by family history, neurological findings, electromyography and a CAG repeat expansion in the androgen receptor gene. Lungs and diaphragm were normal on the chest radiograph. Cranial MRI including brain stem was also normal. Direct laryngoscopy showed a complete paralysis of both vocal cords in paramedian position. Tracheostomy was done right away; his respiratory distress showed prompt improvement after the tracheostomy. No previous report of bilateral vocal cord paralysis in BSMA has been found. Life expectancy in BSMA patients with vocal cord paralysis may be shortened because of respiratory distress or asphyxia. Of clinical importance is a careful assessment of vocal cord function in BSMA patients.
The Modified Norris Scale is a rating scale for amyotrophic lateral sclerosis (ALS), which consists of two parts, the Limb Norris Scale and the Norris Bulbar Scale. The Limb Scale has 21 items to evaluate extremity function and the Bulbar Scale has 13 items to evaluate bulbar function. Each item is rated in 4 ordinal categories. Considering the habitual difference, we translated the English scale into Japanese one with minor modification, and added more detailed explanations for all categories of each item. Then we examined reliability and factorial structure of the translated scale. The subjects were 23 patients with motor disturbance and each subject was rated twice by 2-4 neurologists. As a measure of reliability, the Kappa coefficient proposed by Cohen (1960) and Kraemer (1980) was calculated for each item and the intraclass correlation coefficient (ICC) was evaluated for total scores of each of two scales. To analyze the factorial structure, the factor analysis was carried out. The minimum and the maximum Kappa values were .70 and .97 for intra-rater reliability of the Limb Scale's items, .60 and .83 for inter-rater reliability of the Limb Scale's items, .41 and 1.00 for intra-rater reliability of the Bulbar Scale's items and .26 and .81 for inter-rater reliability of the Bulbar Scale's items, respectively. Concerning the factorial structure, the contribution of the first factor was 83.6% for the Limb Scale and that for the Bulbar Scale was 66.7%. This indicates unidimensionality of both Scales. The ICCs for the total scores were .97 (95%C.I. .95-.99) for the Limb Scale and .86 (.73-.93) for the Bulbar Scale, respectively. On the basis of these results, the Scale has unidimensionality and high reliability enough for practical use.
Explore the source record for details and available documents.
We report a patient with Lambert-Eaton myasthenic syndrome (LEMS) and anti-Hu antibody, which was an important clue in detecting small cell lung cancer (SCLC) at the early stage. This patient had no symptoms of anti-Hu associated paraneoplastic neurological syndrome. In LEMS patients in whom conventional tests fail to detect malignancy, anti-Hu antibody should be evaluated to diagnose SCLC at the early stage.
Familial polyneuropathy mimicking Charcot-Marie-Tooth disease associated with parkinsonism and dementia has been reported in literature. We present with similar peroneal muscular atrophy, rigidity of upper extremities, severe peripheral neuropathy, mental retardation and diabetes mellitus. The patient, a 42-year-old man, developed progressive muscle weakness, mental retardation and difficulty in walking in childhood. Because of his pes cavus, he had three surgical operations. At the age of 20 years, he developed distal muscular atrophy of lower limbs. On neurological examination, all limb muscles were atrophic, especially in lower one third of the thigh. Rigidity was noted in the upper extremities. Deep tendon reflexes were hyperactive in the upper and diminished in the lower extremities. Muscle CT revealed low density areas in all the muscles examined, specially in the gastrocnemius and anterior tibial muscles. Needle EMG showed neurogenic change in the forearm, but not in the lower limbs, because of no voluntary contractions obtained due to severe muscle atrophy. Marked slowing of motor conduction velocity with muscle action potentials of very low amplitude was found in the ulnar nerve. Muscle action potentials were not elicited in the median and peroneal nerves. Sensory action potentials were not elicited from the median, ulnar and sural nerves. These findings were consistent with axonal polyneuropathy. In the sural nerve biopsy, the densities of myelinated fibers were markedly decreased. However, unmyelinated fiber densities were relatively preserved. Onion bulb formation was not found. This patient may be classified into hereditary motor-sensory neuropathy (HMSN) type II based on the clinical findings delayed nerve conduction velocities and axonal degeneration in the sural nerve. He has also diabetes mellitus. CT of the brain revealed nothing particular. He is one of members with familial Parkinson's disease (PD) developed in Sagamihara. Peroneal muscular atrophies are not necessarily associated with PD, though it has been occasionally complicated in various neuro-degenerative diseases including parkinsonism. We are now following the patient to detect the symptom of Parkinson's disease for early treatment.
Explore the source record for details and available documents.