[My history of study on child neurology].
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History, 20th Century↗
Biomedical subjects
Teruhisa Miike
Publications and source records attributed to Teruhisa Miike.
Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice.
Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Therapeutic options for DMD are limited because the pathogenetic mechanism by which dystrophin deficiency produces the clinical phenotype remains obscure. Recent reports of abnormal alpha-adrenergic vasoregulation in the exercising muscles of DMD patients and in the mdx mouse, an animal model of DMD, prompted us to hypothesize that the dystrophin-deficient smooth muscle contributes to the vascular and dystrophic phenotypes of DMD. To test this, we generated transgenic mdx mice that express dystrophin only in smooth muscle (SMTg/mdx). We found that alpha-adrenergic vasoconstriction was markedly attenuated in the contracting hindlimbs of C57BL/10 wild-type mice, an effect that was mediated by nitric oxide (NO) and was severely impaired in the mdx mice. SMTg/mdx mice showed an intermediate phenotype, with partial restoration of the NO-dependent modulation of alpha-adrenergic vasoconstriction in active muscle. In addition, the elevated serum creatine kinase levels observed in mdx mice were significantly reduced in SMTg/mdx mice. This is the first report of a functional role of dystrophin in vascular smooth muscle.
Animals↗
Adenoviral mediated MyoD gene transfer into fibroblasts: myogenic disease diagnosis.
MyoD, a master regulatory gene for myogenesis, converts mesoderm derived cells to the skeletal muscle phenotype MyoD gene transfer into skin fibroblasts has been attempted in an effort to diagnose genetic muscle diseases. Although the gene transduction efficiency of adenoviral gene delivery systems is higher than that of various other systems, the rate of myo-conversion is insignificant. Since high adenovirus doses are cytotoxic and exogenous MyoD expression is insufficient for skin fibroblasts to re-differentiate into muscle cells, we constructed the novel adeno-MyoD vector, Ad.CAGMyoD using the recombinant CAG promoter. Even at a lower multiplicities of infection most skin fibroblasts infected with Ad.CAGMyoD could convert into myotubes without vector-induced cytotoxicity. The converted cells expressed muscle-specific desmin and full-length dystrophin, both of which were detected by Western blotting. Genetic and immunohistochemical analyses using skin fibroblasts and our vector system are reliable and useful for the clinical diagnosis of genetic muscle diseases.
Adenoviridae↗
[Brain science, education and living environment].
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Adolescent↗
Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder.
In recent years, circadian rhythm sleep disorders in humans have been increasing. Clinical features characteristic of this disorder are well known, but the specific causes remain unknown. However, various derangements of circadian expression of the clock gene are a probable cause of this disease. We have attempted to elucidate the relationship between the expression of the clock genes in whole blood cells and the clinical features characteristic of this disorder. In this study, we indicate the daily expression of clock genes period (Per) 1, 2, 3, Bmal1, and Clock in whole blood cells in 12 healthy male subjects. The peak phase of Per1, Per2, and Per3 appeared in the early morning, whereas that of Bmal1 and Clock appeared in the midnight hours. Furthermore, in one patient case with circadian rhythm sleep disorder, we observed variations of the peak phase in clock genes by treatments such as light therapy, exercise therapy, and medicinal therapy. This study suggested that the monitoring of human clock genes in whole blood cells, which may be functionally important for the molecular control of the circadian pacemaker as well as in suprachiasmatic nucleus, might be useful to evaluate internal synchronization.
ARNTL Transcription Factors↗
Cytokine production and modulation: comparison of patients with chronic fatigue syndrome and normal controls.
We studied cytokine production in 15 patients with chronic fatigue syndrome (CFS) and 23 controls. CFS patients' peripheral blood mononuclear cells were cultured with lipopolysaccharide or phytohemagglutinin. Enzymatic immunoassay indicated cytokine concentration in culture supernatants. CFS patients showed significantly lower mRNA levels and transforming growth factor-beta1 (TGF-beta1) production. Cytokine dysregulation affects CFS pathogenesis. TGF-beta1 may aid treatment because it affects CFS inflammatory characteristics.
Adult↗
Research on promotion of management of children with psychosomatic and psychosocial disorders in Japan.
BACKGROUND: The number of children with psychosomatic and psychosocial disorders has been increasing in Japan. There are, however, few trained pediatricians who have adequate knowledge of the treatment needed. The Research Group on the Promotion of Management of Children with Psychosomatic and Psychosocial Disorders carried out the present study to (i) disseminate knowledge about psychosomatic and psychosocial disorders of children; and (ii) establish a community-based network model to ensure effective communication among relevant institutions. METHODS: To disseminate knowledge of the psychosocial and psychosomatic disorders, the Research Group compiled the Handbook for Psychosomatic Disorders of Children and distributed it to pediatricians throughout Japan. A follow-up questionnaire survey was then carried out. Also, in order to examine the current status of the communication network between pediatricians and the related institutions, the Research Group conducted a questionnaire survey on general pediatricians. RESULTS: Sixty-five percent of the respondents indicated that they were actually using the Handbook. The topics in the Handbook that were most frequently referred to by the respondents were attention deficit hyperactivity disorders, school refusal, eating disorders, and orthostatic dysregulation. Thirty-seven percent of the participants indicated changes in their behavior towards psychosomatic and psychosocial problems. The results of the survey on communication networks found that the pediatricians generally collaborated with different institutions depending on the nature of the problems, such as school refusal and bullying, developmental disorders, child abuse and maltreatment, and others. CONCLUSION: Promotion of the Handbook would greatly contribute to improving the management of children with psychosomatic and psychosocial disorders, together with the construction of the basic network model for management of these children.
Adult↗
A novel approach to identify Duchenne muscular dystrophy patients for aminoglycoside antibiotics therapy.
Aminoglycoside antibiotics have been found to suppress nonsense mutations located in the defective dystophin gene in mdx mice, suggesting a possible treatment for Duchenne muscular dystrophy (DMD). However, it is very difficult to find patients that are applicable for this therapy, because: (1) only 5-13% of DMD patients have nonsense mutations in the dystrophin gene, (2) it is challenging to find nonsense mutations in the gene because dystrophin cDNA is very long (14 kb), and (3) the efficiency of aminoglycoside-induced read-through is dependent on the kind of nonsense mutation. In order to develop a system for identifying candidates that qualify for aminoglycoside therapy, fibroblasts from nine DMD patients with nonsense mutation of dystrophin gene were isolated, induced to differentiate to myogenic lineage by AdMyoD, and exposed with gentamicin. The dystrophin expression in gentamicin-exposed myotubes was monitored by in vitro dystrophin staining and western blotting analysis. The results showed that gentamicin was able to induce dystrophin expression in the differentiated myotubes by the read-through of the nonsense mutation TGA in the gene; a read-through of the nonsense mutations TAA and TAG did not occur and consequently did not lead to dystrophin expression. Therefore, it is speculated that the aminoglycoside treatment is far more effective for DMD patients that have nonsense mutation TGA than for patients that have nonsense mutation TAA and TAG. In this study, we introduce an easy system to identify patients for this therapy and report for the first time, that dystrophin expression was detected in myotubes of DMD patients using gentamicin.
Anti-Bacterial Agents↗
Ex vivo gene transfer to mature skeletal muscle by using adenovirus helper cells.
BACKGROUND: Adenoviral gene transfer to adult skeletal muscle is hindered by several major limitations, including host immune responses and maturation-dependent loss of myofiber infectivity. Ex vivo gene delivery is more efficient than direct viral injection in surmounting maturation-dependent adenoviral transduction. Here we investigated the use of helper cells to improve the efficiency of ex vivo gene transfer to adult mouse skeletal muscle. METHODS: New producer cells carrying the E1 gene of adenovirus type 5 (E32 cells) were developed using primary myoblasts from mdx mice. The E32 cells and 293 cells were infected with an E1-deleted first-generation adenovirus carrying the LacZ gene. These transduced helper cells were injected into the skeletal muscle of adult mdx and SCID mice. RESULTS: LacZ-positive mature myofibers were detected in the skeletal muscle of adult mice sacrificed 5 days post-injection. The gene transfer efficiency using 293 cells and E32 cells was 6.2 and 3.6 times higher than myoblast-mediated gene transfer, respectively. Ex vivo gene transfer of these cell types led to a better outcome than did direct adenoviral injection. CONCLUSIONS: We achieved more efficient adenoviral gene transduction by using 293 and E32 helper cells than by myoblast-mediated gene transfer and direct viral injection. These helper cells also enabled adenoviral gene transfer to mature myofibers. The mechanisms by which this method facilitated adenoviral gene transfer to mature myofibers remains unclear; however, we hypothesize that the in vivo occurrence of cytopathic effects (CPE) in the transduced 293 and E32 helper cell populations facilitated the improved adenoviral transduction of myofibers.
Adenoviridae↗
Learning and memorization impairment in childhood chronic fatigue syndrome manifesting as school phobia in Japan.
For the last 15 years, we have tried to understand the pathophysiology of childhood chronic fatigue syndrome (CCFS) in Japan. In this condition, two major symptoms are important: easy fatigability and disturbed learning and memorization. In CCFS patients we clinically evaluated autonomic nervous system function, circadian rhythm of hormonal secretion (melatonin, cortisol and 3-endorphin), core body temperature, and sleep-wake pattern. Most patients showed autonomic nervous system dysfunction and circadian rhythm disturbances, similar to those observed in jet lag. Radiological imaging studies (SPECT, Xe-CT, and MRS) revealed decreased blood flow in the frontal and thalamic areas, and accumulation of choline in the frontal lobe. We analyzed the relationship between the laboratory data and clinical symptoms in CCFS.
Adolescent↗
[Therapy for myopathies: from management to genetic treatment: introductory remarks].
Despite a wealth of recent information about the molecular basis of Duchenne muscular dystrophy (DMD), there is no effective treatment for this condition because the mechanism how dystrophin deficiency produces the muscle fiber degradation is unknown. Much effort has been made to develop a new treatment for DMD on clinical and molecular bases. This symposium consist of reports on recent advance of the gene, molecular and clinical therapies for DMD. It also discusses recent topics of therapeutic trial for glycogen storage diseases, featuring recombinant human acid alpha-glucosidase GAA enzyme therapy for fatal glycogen storage disease type II.
Genetic Therapy↗
Dystrophin delivery in dystrophin-deficient DMDmdx skeletal muscle by isogenic muscle-derived stem cell transplantation.
Duchenne's muscular dystrophy (DMD) is a lethal muscle disease caused by a lack of dystrophin expression at the sarcolemma of muscle fibers. We investigated retroviral vector delivery of dystrophin in dystrophin-deficient DMD(mdx) (hereafter referred to as mdx) mice via an ex vivo approach using mdx muscle-derived stem cells (MDSCs). We generated a retrovirus carrying a functional human mini-dystrophin (RetroDys3999) and used it to stably transduce mdx MDSCs obtained by the preplate technique (MD3999). These MD3999 cells expressed dystrophin and continued to express stem cell markers, including CD34 and Sca-1. MD3999 cells injected into mdx mouse skeletal muscle were able to deliver dystrophin. Though a relatively low number of dystrophin-positive myofibers was generated within the gastrocnemius muscle, these fibers persisted for up to 24 weeks postinjection. The injection of cells from additional MDSC/Dys3999 clones into mdx skeletal muscle resulted in varying numbers of dystrophin-positive myofibers, suggesting a differential regenerating capacity among the clones. At 2 and 4 weeks postinjection, the infiltration of CD4- and CD8-positive lymphocytes and a variety of cytokines was detected within the injected site. These data suggest that the transplantation of retrovirally transduced mdx MDSCs can enable persistent dystrophin restoration in mdx skeletal muscle; however, the differential regenerating capacity observed among the MDSC/Dys3999 clones and the postinjection immune response are potential challenges facing this technology.
Animals↗
Trial of intraventricular ribavirin therapy for subacute sclerosing panencephalitis in Japan.
Ten patients with SSPE were surveyed during the last 4 years from the viewpoint of clinical safety for use of ribavirin therapy. Although effectiveness varied among cases, they were all treated safely with intraventricular ribavirin. This study suggests that treatment is safe and well-tolerated.
Adolescent↗
Case study: differences in human Per2 gene expression, body temperature, cortisol, and melatonin parameters in remission and hypersomnia in a patient with recurrent hypersomnia.
Recurrent hypersomnia is characterized by recurring episodes of hypersomnia of 18 h or more per day lasting from several days to several weeks. We report the case of a 17-year-old male subject with recurrent hypersomnia who displayed change in the 24 h expression of the hPer2 gene in whole red and white blood cells as well as markers [deep body temperature (DBT) and cortisol] of the circadian time structure during an episode of hypersomnia compared to remission. The patient was studied for the temporal characteristics of hPer2 gene, DBT, cortisol, and melatonin expression during a single 24 h span during an episode of hypersomnia and again during a single 24 h span in the following remission. The approximation of a 24 h cosine curve to the time series data revealed circadian rhythmicity (P < 0.05) only in DBT in the two stages of the disease with differences in amplitude and acrophase. Cortisol circadian rhythmicity was detected during remission, but not during hypersomnia. Statistically significant differences were detected by ANOVA between the remission and active disease stages in the 24 h mean level of hPer2 gene expression (P < 0.05), cortisol (P < 0.05), and DBT (P < 0.05). The findings of this case study suggest the expression of hPer2 gene and alterations in circadian time structure might play an important role in the pathogenesis of recurrent hypersomnia, although additional study is required.
Adolescent↗
[Brain and education].
Students with school phobia have two major clinical problems in common: 1) easy fatigability and 2) disturbed learning and memory functions. In the last 15 years, we studied these cases using various medical and physiological methods, by evaluating clinical autonomic nervous system functions, circadian rhythms such as hormonal secretion, deep body temperature, and sleep-wake. Most of them showed autonomic nervous system dysfunction and circadian rhythm disturbances quite similar to "jet lag". We suggest that this kind of circadian rhythm disturbances are quite prevalent among children in the world and cause memory and learning disabilities.
Adolescent↗
[Trial of intraventricular ribavirin and interferon-alpha combination therapy for subacute sclerosing panencephalitis (SSPE) in Japan].
A survey was made on 10 patients with subacute sclerosing panencephalitis (SSPE) during the last four years from the viewpoint of clinical safety of ribavirin therapy in Japan. Although the age of onset, latent period, and effectiveness were variable among the cases, they were treated safely with intraventricular ribavirin combined with high doses of interferon (IFN). Their clinical stages on admission ranged from the first to fourth of Jabbour's classification, and those on the beginning of ribavirin therapy also ranged from the first to fourth. Seven of them were first treated with intraventricular IFN-alpha monotherapy, however, the combination of intraventricular IFN-alpha and ribavirin was started after clinical worsening. Although 5 patients showed slow progression, seven responded to the therapy with clinical improvement or decreased measles antibody titers in the CSF. Especially, one patient showed improvement to Jabbour's first stage and no further progression during the following 3 years. Ribavirin therapy caused no severe effects. Lip swelling (50%), sleepiness (40%), and headache (30%) were noted. Although we were unable to perform a double-blinded clinical study for ethical reasons, our results suggest that treatment with intraventricular ribavirin and high doses of IFN may be effective for SSPE. Early administration of intraventricular ribavirin and IFN might be considered especially to IFN in non-responders. To establish this combination therapy as a safe and effective treatment of SSPE, further studies are necessary on the role of ribavirin in the pathogenesis as well as its effects in the central nervous system.
Adolescent↗
[Spinal cord stimulation for complex regional pain syndrome: report of 2 cases].
Two adolescents with complex regional pain syndrome (CRPS) were treated safely and effectively by spinal cord stimulation (SCS). They complained of intractable pain resistant to conservative therapies. Whereas continuous epidural anesthesia temporarily reduced pain, SCS was more effective in alleviating chronic severe pain and improving the quality of life. With careful selection of patients, SCS therapy might be recommended even in young cases.
Adolescent↗
Selective binding of trisamine-modified phosphorothioate antisense DNA to target mRNA improves antisense activity and reduces toxicity.
Antisense activity in living cells has been thought to occur via a mechanism involving both DNA-mediated hybridization arrest of target mRNA and RNase H-mediated mRNA digestion. Therefore an ideal antisense agent should be permeable to the cell and possess capacities (1) to form a thermally stable duplex in vivo with its target, (2) to discriminate between mRNAs with different degrees of complementarity, and (3) to form antisense/RNA complexes that are susceptible to RNase H hydrolysis. A trisamine-modified deoxyuridine derivative of a novel phosphorothioate DNA 15-mer that meets all these criteria is described here. Compared with the unmodified phosphorothioate oligomer, the phosphorothioate derivative exhibits a higher antisense activity as well as reduced cytotoxicity in cells infected with HIV-1. Our data suggest that the melting temperature (T(m)) between antisense DNA and the target mRNA is not only one of the factors contributing to this derivative's improved antisense activity. Also important are an enhanced ability to discriminate between sequences and an increased susceptibility of the DNA/mRNA complex to RNase H hydrolysis. These results will be useful in designing more active, clinically useful antisense drugs.
Anti-HIV Agents↗