Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study.

Muscular dystrophies (MDs) are inherited disorders characterized by progressive muscle weakness. Previously, we have shown that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and an activator of the protein deacetylase SIRT1, decreases muscular and cardiac oxidative damage and improves pathophysiological conditions in animal MD models. To determine whether resveratrol provides therapeutic benefits to patients with MDs, an open-label, single-arm, phase IIa trial of resveratrol was conducted in 11 patients with Duchenne, Becker or Fukuyama MD. The daily dose of resveratrol was 500 mg/day, which was increased every 8 weeks to 1000 and then 1500 mg/day. Primary outcomes were motor function, evaluated by a motor function measure (MFM) scale, muscular strength, monitored with quantitative muscle testing (QMT), and serum creatine kinase (CK) levels. Adverse effects and tolerability were evaluated as secondary outcomes. Despite the advanced medical conditions of the patients, the mean MFM scores increased significantly from 34.6 to 38.4 after 24 weeks of medication. A twofold increase was found in the mean QMT scores of scapula elevation and shoulder abduction. Mean CK levels decreased considerably by 34%. Diarrhoea and abdominal pain was noted in six and three patients, respectively. Resveratrol may provide some benefit to MD patients.

The acid-sensing ion channel 2 (ASIC2) of ciliated cells in the developing rat nasal septum.

The airway epithelium is exposed to an acidic environment in certain conditions. The acid-sensing ion channel 2 (ASIC2) belongs to the epithelial amiloride-sensitive sodium channel and degenerin (ENaC/DEG) family and is expressed on cilia of the respiratory epithelium. The aim of this study was to detect the expression of ASIC2 in the nasal septum in the embryonic stage of the rat. ASIC2 expression was not observed in the primary cilium but was found in some cilia on embryonic day 17 (E17). After E18, all cilia showed ASIC2 immunoreactivity. RT-PCR analysis revealed that ASIC2b, a subtype of ASIC2, was expressed in the nasal septum while ASIC2a was not. Quantitative Real-time RT-PCR studies indicated that the expression level of ASIC2 mRNA was highest on E21, just before birth. These results imply that ASIC2 plays little part in the development of the nasal septum epithelium. On the other hand, ASIC2, especially ASIC2b, may function for the survival and retention of ciliated cells of the nasal septum against dynamic changes in the pH environment at birth.

The Change of Grip Strength in a Patient with Congenital Myotonic Dystrophy Over a 4-year Period.

Myotonic dystrophy (MyD) is a neuromuscular disease that is autosomal dominant and the most common form of muscular dystrophy affecting adults. The clinical features of MyD include a multisystemic disorder characterized by myotonia, progressive muscle weakness and wasting, cataracts, premature balding and mental retardation. The most severe type of MyD is classified as congenital MyD (CMyD). The muscle weakness in CMyD is very severe, but muscle development can be observed in the period of growth. However, no clinical case of this type has been reported yet. Therefore, we report on a girl with CMyD who had an increase in muscle strength over a four-year period. The girl with CMyD participated in this study from the age of 9 to the age of 12. The measurement of muscle strength was recorded as the maximum score of grip strength with the use of dynamometers. Grip strength was assessed once a year by the same two physical therapists. Grip strength of CMyD for each year was markedly weak when compared with the normal controls, but muscle strength changed within some specific growth areas. The muscle weakness in CMyD was remarkable, but the result showed that specific muscle strength of CMyD in childhood was actually increased.

Carbamazepine-induced hemolytic and aplastic crises associated with reduced glutathione peroxidase activity of erythrocytes.

Although pure red cell aplasia is a well-known side effect of carbamazepine treatment, intravascular hemolytic anemia is rare. We describe a 5-year-old boy who developed concurrent intravascular hemolytic anemia and erythroblastopenia, probably due to carbamazepine. Carbamazepine treatment was subsequently discontinued, and the patient was treated with red blood cell transfusions, haptoglobin, and methylprednisolone. His hematologic abnormalities were almost fully recovered within 2 weeks. Examination of the patient's and mother's erythrocyte enzyme activities revealed mildly decreased erythrocyte glutathione peroxidase (GSH-Px) activity. We speculate that patients with reduced GSH-Px activity are at a high risk of developing carbamazepine-induced hemolytic crisis and/or aplastic crisis.

New mutation of the PTCH gene in nevoid basal-cell carcinoma syndrome with West syndrome.

Neurologic involvement in nevoid basal-cell carcinoma syndrome includes intracranial calcification, congenital hydrocephalus, intracranial neoplasms, and mental retardation. A few cases of epilepsy with nevoid basal-cell carcinoma syndrome were reported. We report on a patient with nevoid basal-cell carcinoma syndrome and West syndrome. The patient had a heterozygous mutation (insertion of TGGC) in the PTCH gene. This mutation causes a shift of the reading frame, and creates a stop codon predicting the truncation of the PTCH protein. This mutation was not found in previously described patients with nevoid basal-cell carcinoma syndrome.

Clinicopathological and virological analyses of familial human T-lymphotropic virus type I--associated polyneuropathy.

Human T-lymphotropic virus type I (HTLV-I) is known to be the causative agent of the chronic myelopathy, HTLV-I--associated myelopathy (HAM), and on rare occasions infection is also associated with the development of polyneuropathy. Here the authors present an HTLV-I--positive family of whom four members developed a chronic demyelinating polyneuropathy without HAM. Four female patients in a family from Hokkaido in Japan developed distal dominant paresthesia and muscle weakness in the second and third decades of their life. Neurological findings at ages ranging from 50 to 65 years included mild painful sensorimotor disturbances with atrophy of the distal parts of the extremities but without pyramidal signs or hyperactive tendon reflexes. Magnetic resonance imaging (MRI) findings of brain and spinal cord were unremarkable. Serum HTLV-I antibody levels were elevated at 1:8192 to 1:32,768, whereas those in cerebrospinal fluid were low at 1:4 to 1:8. Electrophysiological studies revealed polyphasic compound muscle action potentials with denervation potentials on nerve conduction studies and neurogenic patterns by electromyography, which were consistent with signs of chronic motor dominant demyelinating polyneuropathy. Sural nerve biopsy showed decreased myelinated fibers, occurrence of globule formation, myelin ovoid and remyelinated fibers, and an infiltration of CD68-positive macrophages with occasional CD4-positive T cells in the nerve fascicles. The polyneuropathy was responsive to steroid therapy. Analyses of serological human leukocyte antigen (HLA) types indicated that none of the patients possessed a high-risk HLA type known to be associated with adult T-cell leukemia (ATL), whereas they did have high responsive alleles to HTLV-I env similar to that observed in HAM. Nucleotide sequence analysis of the HTLV-I tax region demonstrated the B subgroup in all patients. This study suggests that HTLV-I infection can result in the development of a familial form of polyneuropathy that is associated with distinct HLA class I alleles, which might possibly involve a distinct virus subtype.

A new mutation of IGHMBP2 gene in spinal muscular atrophy with respiratory distress type 1.

This report presents a new mutation in the first Japanese female infant with spinal muscular atrophy with respiratory distress type 1. She manifested the characteristic clinical features, including early-onset respiratory failure due to diaphragmatic paralysis and severe distal muscle weakness. Muscle biopsy in the femoral muscle indicated massive neurogenic changes. Sural nerve biopsy disclosed a moderate reduction of myelinated fibers, predominantly reduced large fibers. She had a novel homozygous missense mutation 2685 C -->A, leading to a T879K substitution in the immunoglobulin mu-binding protein 2 gene. Both parents were heterozygous for this mutation.

[Non-radioactive PCR southern method for analysis of CTG repeat in myotonic dystrophy].

Myotonic dystrophy (MyD) is a hereditary neuromuscular disorder of an autosomal dominant trait. MyD is caused by an expansion of unstable CTG trinucleotide repeat in the 3' untranslated region of mRNA coding myotonin protein kinase (MT-PK). We analyzed CTG repeat expansion in 10 patients with congenital MyD and their relatives using the non-radioactive PCR Southern method. The region containing the CTG repeat was amplified by PCR using specific primers. The PCR products were electrophoresed on a 1% agarose gel and transferred to a nylon membrane. The CTG repeat expansion was shown using a fluorescein-labelled (CTG) 10 probe. To estimate the number of CTG repeats, we compared the smears obtained on Southern blotting with a picture of PCR products and a DNA size marker (100 bp). We compared our results of radioactive Southern blotting for genomic DNA digested by Eco RI or Bgl I and for PCR products. In congenital MyD patients, heterogeneous smears (3.89-10.22 kb:about 1252-3362 CTG repeat) were observed, whereas in the adult type MyD had heterogeneous smears (0.92-1.82 kb:about 262-562 CTG repeat). In asymptomatic MyD patients, there were heterogeneous smears (0.35-1.16 kb:about 72-342 CTG repeat). These results demonstrated anticipation. We conclude that the non-radioactive PCR Southern method is useful and convenient for the DNA diagnosis of MyD.