Does k-11706 enhance performance and why?

Erythropoietin gene expression is stimulated by hypoxia-inducible factor 1 and inhibited by GATA. Thus, drugs that attenuate the action of GATA and/or potentiate the action of HIF-1 may increase Epo production and hemoglobin concentration. The effects of such drugs on endurance performance and the potential mechanisms by which they may exert effects are unclear. In Hep3B cells, we showed that K-11706 inhibits GATA binding activity, but enhances HIF-1 binding activity. However, the expression levels of GATA and HIF-1 protein were not changed by the addition of K-11706. We investigated the effects of K-11706 on Epo and Hb concentrations, hematocrit and endurance performance of mice (total number of mice = 40). K-11706 was dissolved in polyethylene glycol and administered via oral tube feeding to mice for either five or eight days. Endurance performance was assessed using a treadmill. Muscle fibers from the quadriceps muscles of mice were stained with ATPase. Administration of 3 mg/kg K-11706 for five or eight days significantly increased erythropoietin concentrations, hemoglobin concentrations, hematocrit and endurance performance, but the diameters of cross-sections and ratios of type I, IIA and IIB muscle fibers were not affected.

Effects of exercise on adiponectin and adiponectin receptor levels in rats.

Adiponectin reportedly reduces insulin-resistance. Exercise has also been shown to lessen insulin-resistance, though it is not known whether exercise increases levels of adiponectin and/or its receptors or whether its effects are dependent on exercise intensity and/or frequency. Catecholamine levels have been shown to increase during exercise and to fluctuate based on exercise intensity and duration. In light of this information, we examined the effects of exercise on catecholamine, adiponectin, and adiponectin receptor levels in rats. Our data showed that blood adiponectin levels increased by 150% in animals that exercised at a rate of 30 m/min for 60 min 2 days per week, but not 5 days, per week; no such increase was observed in rats that exercised at a rate of 25 m/min for 30 min. The effects of exercise on adiponectin receptor mRNA were variable, with adiponectin receptor 1 (AdipoR1) levels in muscle increasing up to 4 times while adiponectin receptor 2 (AdipoR2) levels in liver fell to below half in response to exercise at a rate of 25 m/min for 30 min 5 days per week. We also observed that urinary epinephrine levels and plasma lipids were elevated by exercise at a rate of 25 m/min for 30 min 2 days per week. Exercise frequency at a rate of 25 m/min for 30 min correlated with AdipoR1 and AdipoR2 mRNA expression in the muscle and liver, respectively (r=0.640, p<0.05 and r=-0.808, p<0.0005, respectively). Urinary epinephrine levels correlated with AdipoR2 mRNA expression in liver tissues (r=-0.664, p<0.05) in rats that exercised at a rate of 25 m/min for 30 min. Thus, exercise may regulate adiponectin receptor mRNA expression in tissues, which might cause increases in glucose uptake and fatty acid oxidation in the muscle. The effect of exercise on adiponectin levels depends on the specific conditions of the exercise.

The evaluation of autonomic nervous function in a patient with hereditary sensory and autonomic neuropathy type IV with novel mutations of the TRKA gene.

We report on a 10-year-old girl with anhidrosis and insensibility to pain, but no severe mental retardation or self-mutilation, diagnosed as hereditary sensory and autonomic neuropathy type IV (HSAN IV). Genetic analysis of her TRKA gene, which is responsible for HSAN IV, revealed two novel missense mutations in the tyrosine kinase domain. Cardiovascular autonomic nervous system function tests showed normal muscle sympathetic nerve activity associated with arterial baroreflex, reduced skin sympathetic nerve activity in the second and fifth fingers and palms, and abnormal circadian rhythm of cardiovascular autonomic nervous system. These findings have never before been reported in HSAN IV and may provide a clue to the neurological pathophysiology of this disease.

Acute flank pain, an unusual first symptom of a spinal arteriovenous malformation.

This case report describes a 46-year-old man whose first symptom was an attack of acute flank pain, followed by the gradual onset neurological symptoms. We demonstrated a small nidus and serpentine signal-void area in the spinal cord by MRI and diagnosed a glomus type of spinal arteriovenous malformation (AVM). Flank pain is a rare initial finding in an adult with spinal AVM. In cases with acute flank pain, neurologists should consider spinal AVM as a differential diagnosis.

Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant.

Study of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE) revealed that almost all cases of distal myopathy with rimmed vacuoles were caused by GNE mutations. Seven new mutations were identified, including M712T, which is the most common mutation in Jewish hereditary inclusion body myopathy. In addition, a splice-variant characteristic of the skeletal muscle was found, whereas the difference of the expression level between GNE-mutated and -nonmutated patients was not apparent.

Association between catechol-O-methyltransferase gene polymorphisms and wearing-off and dyskinesia in Parkinson's disease.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates catecholamines, including levodopa. An amino acid change (Val-108-Met) in the COMT protein has been found to result in a change from high to low enzyme activity. In the present study, we genotyped 121 Japanese patients with Parkinson's disease (PD) and 100 controls. Comparison of the allele frequencies revealed that homozygosity for the low-activity allele was significantly more common among PD patients than the controls (p = 0.047, odds ratio = 3.23). In addition, homozygosity for the low-activity allele was overrepresented in PD patients that exhibited the 'wearing-off' phenomenon (p = 0.045, odds ratio = 3.82) or dyskinesia (p = 0.030, odds ratio = 4.80) compared with controls, although these differences were not significant after Bonferroni's correction. Our results may help understand the mechanism that cause complications of levodopa therapy in PD patients.

Corticosteroid- responsive asymmetric neuropathy with a myelin protein zero gene mutation.

A patient with hereditary neuropathy presented with asymmetric distal weakness. On nerve biopsy, there was demyelination and onion-bulb formation, and molecular analysis revealed that the patient was heterozygous for an MPZ mutation. The patient improved with corticosteroid treatment.

Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene.

The authors present three novel missense mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the causative gene for hereditary inclusion body myopathy, in Japanese patients with distal myopathy with rimmed vacuoles. Seven out of nine patients had homozygous V572L mutation, one was a compound heterozygote with C303V and V572L mutations, and the remaining patient bore homozygous A631V mutation.

An association between idiopathic Parkinson's disease and polymorphisms of phase II detoxification enzymes: glutathione S-transferase M1 and quinone oxidoreductase 1 and 2.

Individual vulnerability to reactive intermediates and oxidative stress accompanying metabolism of endogenous toxic compounds in the brain may promote the development of PD. Phase II detoxification enzymes such as glutathione S-transferase M1 (GSTM1), NAD(P)H:quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH):quinone oxidoreductase 2 (NQO2) are important as cellular defenses against catecholamine-derived quinones and the oxidative stress that arises as a consequence of their metabolism. We conducted a study of the potential association between idiopathic Parkinson's disease and polymorphisms of GSTM1, NQO1, and NQO2. DNA samples from 111 unrelated outpatients with idiopathic PD and 100 unrelated healthy volunteers were analyzed. GSTM1 deletion polymorphism exhibited no positive association with PD (P = 0.596, odds ratio: 1.135), although GSTM1 were grouped into three genotypes (deletion/deletion, deletion/nondeletion, and nondeletion/nondeletion). In addition, polymorphism of the NQO1 gene caused by a C to T substitution in exon 3 presented no association with PD (P = 0.194, odds ratio: 1.31). However, polymorphism in the form of an insertion/deletion (I/D) of 29 base pairs (bp) nucleotides in the promoter region of the NQO2 gene, which contains four repeats of the putative core sequence (GGGCGGG) of the Sp1-binding cis-element, did associate with PD. The frequency of the D allele was significantly higher in patients with PD than in controls (P < 0.0001, odds ratio: 3.463). Our data suggested that the deletion of 29-bp nucleotides in the promoter region of the NQO2 gene associates with the development of PD.

The expression of dystrophin and alpha1-syntrophin during skeletal muscle regeneration.

The expression of dystrophin and alpha1-syntrophin in rat tibialis anterior muscles were evaluated during a cycle of regeneration after myonecrosis induced by the injection of cardiotoxin. Immunohistochemical studies were performed in cryosections of muscles on days 1, 3, 5, 7, 10, 14, 21 and 28 after injection of cardiotoxin. Western blot analysis was also examined in muscle on days 1, 3, 5, 7, 10, 14, 21 and 28. In immunohistochemical studies, dystrophin was stained weakly at the sarcolemma of some regenerating muscle fibers on day 3, and by day 10 it was stained strongly on almost all regenerating muscle fibers. Alpha1-syntrophin was stained weakly at the sarcolemma of some regenerating fibers on day 5, and by day 14 it was detected on all regenerating muscle fibers. In Western blot analysis, dystrophin (DYS1) and alpha1-syntrophin (alpha1S) were completely absent on day 1. Re-expression of DYS1 and alpha1S was visible by day 5 and accelerated thereafter. The Western blots of DYS1 and alpha1S were densitometrically analyzed on each day. The protein levels on each day were converted to the percentage of the protein level on day 28, which was taken as 100%. From the sequential line based on these data, the following results were obtained on the chronological course of DYS1 and alpha1S. DYS1: 25% of the protein level on day 28 was reached by 3.5 days, 50% was reached by 5.3 days, and 90% was reached by 6.9 days. Alpha1S: 25% of the protein level on day 28 was reached by 4.6 days, 50% was reached by 6.0 days, and 90% was reached by 12.5 days. In this study, DYS1 regenerated earlier than alpha1S at the sarcolemma of regenerating muscle fibers.

Effect of riluzole on the acquisition and expression of amygdala kindling.

PURPOSE: Riluzole possesses various synaptic effects including an inhibitory action on glutamate release. The drug has been shown to inhibit kindled seizures, while its effect on the acquisition of kindling has not been reported. We investigated effects of riluzole on the kindling development in addition to effects on kindled seizures. METHODS: A bipolar electrode was implanted in the right amygdala of rats. Riluzole was injected intraperitoneally 30 min before kindling stimulation. To investigate effects of riluzole on the kindling development, rats were stimulated once daily for the drug session of 14 days at a current of 200 microA, 60 Hz, 1 ms for 2 s and thereafter stimulated without drugs (drug-free session) until completion of kindling. Seizure ranks and after discharge duration were observed every day. To investigate effects of riluzole on kindled seizures, fully-kindled rats were stimulated at the current of generalized seizure threshold (GST) before and after the administration of riluzole. Seizure ranks and after discharge duration were measured. GST after the treatment was also determined. RESULTS: The number of stimuli required for the first appearance of stage five seizure was significantly larger in rats treated with 8 mg/kg of riluzole than in vehicle controls. Riluzole at a dose of 8 mg/kg significantly retarded the development of seizure stages in the drug session. By comparison, effects on the duration of after discharge was relatively mild, though significantly different from the vehicle control. Riluzole at a dose of either 4 or 8 mg/kg markedly inhibited behavioral seizures and reduced the duration of after discharge in kindled seizures provoked by GST. The drug also significantly increased GST at both doses, suggesting that the anticonvulsant effects were attributed to the increase in GST. CONCLUSION: It was demonstrated that inhibitory effects of riluzole on both kindled seizures and the development of behavioral seizures in kindling acquisition with relatively mild correlation to afterdischarge duration. These effects might be attributed to inhibitory actions of riluzole on glutamate release and NMDA-receptor mediated events.

[Adult Sandhoff disease presented as a motor neuron disease phenotype with slow progression].

A 35-year old Japanese male with adult Sandhoff disease was described, who was presented as a motor neuron disease phenotype with slow progression. At the age of 15, he first noticed weakness in his thigh. At the age of 28, his upper and lower motor neuron disturbances were disclosed. He was diagnosed as atypical amyotrophic lateral sclerosis. At the age of 34, a slight sensory disturbance appeared in the lower extremities. When he was admitted to our hospital, he displayed marked atrophy and weakness in his quadriceps femoris muscles, but no signs of mental deterioration and cerebellar ataxia. Because of the atypical course of motor neuron disease, hexosaminidase activity in peripheral leukocytes was determined. The assay of total hexosaminidase, hexosaminidase A and hexosaminidase B activities demonstrated low levels of these activities (7-15% of controls), leading the diagnosis of Sandoff disease. He was a member of non-consanguineous family, and the abnormal patterns of hexasaminidase activities were different between his father and mother. These data appear to show that he is a compound heterozygote in the locus of the hexosaminidase B gene. This is the first Japanese case of adult Sanhoff disease presented as a motor neuron disease phenotype.

Ataxic form of chronic inflammatory demyelinating polyradiculoneuropathy: clinical features and pathological study of the sural nerves.

We investigated clinical and pathological features of the sural nerves of 5 patients with the ataxic form of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and compared these features with those of chronic ataxic neuropathies due to other causes. The CIDP patients presented with slowly progressive ataxia with deep sensory impairment. The durations of the symptoms from onset were relatively short in CIDP (4-8 months) and cancer (3 and 10 months), but long in chronic idiopathic ataxic neuropathy (24-260 months). Corticosteroid therapy elicited a good response in all the patients with CIDP, but a poor response in the patients with other ataxic neuropathies. Sural nerve biopsy of CIDP patients showed a slight or moderate loss of myelinated fiber. This report suggests that ataxic form of CIDP is a steroid-responsive ataxic neuropathy, and large myelinated fibers of the sural nerves in ataxic form of CIDP were better preserved than those in nerves with other chronic ataxic neuropathies.