Shiho Okuda

Steroid Myopathy: Pathogenesis and Effects of Growth Hormone and Insulin-Like Growth Factor-I Administration

Glucocorticoids have been widely used in the treatment of autoimmune and other diseases. Chronic steroid use, however, could cause proximal muscle weakness and atrophy, termed steroid myopathy. The onset of steroid myopathy is usually insidious and there are no specific laboratory findings except for elevated urinary creatine excretion. Muscle biopsy reveals non-specific type II fiber atrophy. There are many reports showing preventive effects of either growth hormone (GH) or insulin-like growth factor (IGF)-I on steroid myopathy. The pathogenesis of steroid myopathy is not fully understood. Recently, glutamine synthetase has been reported to play a key role in steroid myopathy. GH as well as IGF-I decreased the steroid-induced glutamine synthetase activity in skeletal muscle.

Preventive effects of insulinlike growth factor-I on steroid-induced muscle atrophy

We examined the effects of simultaneous administration of recombinant insulinlike growth factor‐I (IGF‐I) and glucocorticoid on the diameter of muscle fibers in rats. The steroid group received subcutaneous injection of triamcinolone, the IGF‐treated group received IGF‐I alone, and the steroid plus IGF group received both triamcinolone and IGF‐I. After 14 days, each rat was subjected to muscle biopsy of the extensor digitorum longus and soleus. Glucocorticoid treatment caused significant reduction in diameter of muscle fibers, compared to controls. Simultaneous administration of IGF‐I significantly attenuated glucocorticoid‐induced muscle atrophy. Glucocorticoid increased both urinary concentration of 3‐methylhistidine and urinary creatine/creatinine ratio. IGF‐I reduced those changes in the urine. We conclude that IGF‐I administration prevents, at least partially, the development of steroid myopathy.

Human Herpes Virus 6 Encephalitis in Allopurinol-induced Hypersensitivity Syndrome

Hypersensitivity syndrome is one of the most severe forms of drug eruption, and is characterized by a severe, potentially lethal, multiorgan involvement. Recently, reactivation of human herpesvirus 6 (HHV-6) has been suggested to be involved in this syndrome, although the exact role of HHV-6 remains elusive. In addition to exanthem subitum, neurological illnesses, such as infantile febrile illness without rash and encephalitis in immunocompromised patients have been attributed to HHV-6. A 51-year-old man developed a generalized erythematous eruption during treatment with allopurinol. Prednisolone improved his condition, but after the dose of prednisolone was reduced neurological abnormalities such as mental deterioration and positive meningeal signs developed. HHV-6 DNA in his blood by PCR analysis was positive. Furthermore, we detected HHV-6 DNA in the cerebrospinal fluid. The titers of anti-HHV-6-IgG increased during the course. His neurological symptoms gradually improved and no neurological sequelae were noted. Neurological abnormalities associated with hypersensitivity syndrome are very rare. However, the detection of HHV-6 DNA in the cerebrospinal fluid strongly indicates an involvement of reactivated HHV-6 in encephalitis.

Hyperkalemic periodic paralysis and paramyotonia congenita – A novel sodium channel mutation –

Sirs: The group of hereditary sodium channel diseases, also termed sodium channelopathies, comprises hyperkalemic periodic paralysis (HyperPP), some forms of hypokalemic periodic paralysis, paramyotonia congenita (PC) and potassium aggravated myotonia [1, 4, 5, 7, 8]. They occur by autosomal dominant inheritance caused by point mutations in the gene encoding the α-subunit of the adult human skeletal muscle sodium channel (SCN4A) [1, 7, 8]. Here we report a case of HyperPP and PC with novel point mutation on the SCN4A gene. A 23-year-old man was admitted to our hospital for periodic muscle weakness in his lower extremities. One morning 7 years previously, he noticed muscle soreness and weakness in the lower extremities, which completely disappeared within one week. The same attack was repeated nearly every 6 months (especially the next morning after overeating). He also noticed muscle stiffness in his face and fingers during exercise in the cold. Serum creatine kinase (CK) on admission was 2264 IU/l (normal range:35–169) and potassium was 5.4 mEq/l (3.5–4.7), both levels soon normalized. Electromyography (EMG) showed myotonic discharges in all extremities (Fig. 1B upper). Immediately after a provocative test with potassium infusion had induced muscle weakness in the lower extremities, a biopsy from the gastocnemius muscle was performed that revealed mild variability in fiber size without vacuolar changes and an increase in the number of central nuclei. He did not have grip myotonia, but we discovered that myotonia of the face and fingers induced by cold water or inside a cold room (4 °C) could be increased with repeated contraction (paradoxical myotonia). Based on these findings, we diagnosed overlapping syndromes of HyperPP and PC (Table 1). The patient’s father had experienced periodic paralysis (PP) that gradually faded with age and still had muscle stiffness during exercise in the cold (Fig. 1A). His younger sister had muscle stiffness but not PP, and his younger brother had both. Their EMGs showed myotonic discharges (Fig. 1B middle and lower). A molecular analysis of the SCN4A gene revealed an A-to-G transition at nucleotide 4,108, causing the substitution of valine for methionine at codon 1370 (Fig. 1C). Up to date, approximately 20 point mutations have been detected in the SCN4A gene that can cause sodium channelopathy [1, 7]. As the present patient and symptomatic family members had the same point mutation in SCN4A and neither asymptomatic family members nor 30 healthy subjects had this point mutation, we concluded this mutation could be pathogenic. This is a novel sodium channel mutation at methionine 1370 of the SCN4A gene. This mutation, Met1370Val, produces clinical symptom of only PC in females (in LETTER TO THE EDITORS

Insulin-like growth factor 1 inhibits glucocorticoid-induced glutamine synthetase activity in cultured L6 rat skeletal muscle cells.

We previously demonstrated the preventive effect of insulin-like growth factor 1 (IGF-1) on steroid myopathy in rats. However, the mechanism by which IGF-1 inhibits steroid myopathy remains unclear. Recent studies have revealed that glutamine synthetase (GS) is induced by glucocorticoid and may be related to the development of steroid myopathy. In this study, we examined whether IGF-1 affected steroid-induced enhancement of GS activity in L6 rat skeletal muscle cells. Dexamethasone (10(-6) M) significantly increased GS activity in L6 cells (P < 0.01). IGF-1 dose-dependently inhibited dexamethasone-induced GS activity. Addition of IGF-1 (750 ng/ml) decreased GS activity to approximately 50% of that with dexamethasone alone (P < 0.01). These results suggest that a decrease in GS activity may be involved in the preventive effect of IGF-1 on steroid myopathy.

Transforming growth factor-β enhances connective tissue growth factor expression in L6 rat skeletal myotubes

Transforming growth factor (TGF)-beta plays an important role in fibrosis of various organs and tissues. TGF-beta1 stimulates fibroblastic cells to form extracellular matrix (ECM), and regulates all critical events in wound healing. Connective tissue growth factor (CTGF), a TGF-beta-inducible molecule, has recently been reported to promote fibroblast proliferation, migration, adhesion and extracellular matrix formation, both in vivo and in vitro. In this study, we demonstrated that TGF-beta1 enhances CTGF mRNA and protein levels in L6 rat skeletal muscle myotubes. TGF-beta might, therefore, play a role in fibrosis of skeletal muscle by stimulating CTGF expression in the muscle tissue itself.

Clinical Features of Late-onset Poststroke Seizures

BACKGROUND Compared to the patients with early-onset seizures (ES), those with late-onset seizures (LS) have a high risk of epilepsy that is a feared complication after stroke. However, few studies have described detailed clinical features of LS in Japanese patients. METHODS To elucidate the clinical features of LS, a series of 448 stroke patients (cerebral infarction n = 286; cerebral hemorrhage n = 162) in our hospital were retrospectively examined in this study. Stroke location was determined by computed tomographic and/or magnetic resonance imaging scans. Lesion size was evaluated using the Alberta Stroke Program Early Computed Tomographic Score. We examined occurrence rate, onset time, and recurrence rate of LS. In addition, clinical features of the infarction of LS and non-LS group were compared on age, gender, laterality, location, and extent, respectively. RESULTS LS occurred in 18 patients (4.0%). Of these, 17 experienced LS within 1.5 years after stroke. While epilepsy developed in none of the patients with ES, it developed in 33% of those with LS. Patients with cortical and a larger infarction involving the middle cerebral artery had at significantly greater risk of LS (P < .05). CONCLUSIONS Patients with cortical and a larger infarction involving the middle cerebral artery should be carefully observed because of a high risk of LS.

A 51-year-old man with intramedullary spinal cord abscess having a patent foramen ovale

The authors report a case of a 51-year-old man with intramedullary spinal cord abscess (ISCA) having a patent foramen ovale (PFO). He developed fever and tetraplegia after a recent dental treatment. MRI showed ISCA with longitudinal swelling from the upper cervical to the lumbar spinal cord. Cerebrospinal fluid (CSF) analysis indicated bacterial meningitis, and the culture of CSF revealed Streptococcus viridans. Transoesophageal echocardiography revealed the existence of a PFO. We suspected another possibility other than systemic bacteraemia, that paradoxical bacteric embolisation through PFO after the dental treatment caused ISCA. While several reports of brain abscess with PFO are available, this is the first report of ISCA with PFO.

Gait analysis of patients with Parkinson's disease using a portable triaxial accelerometer

Gait disturbance is a major problem for Parkinsons disease patients.