Effects of exercise on muscle activation and metabolism in multiple sclerosis

We investigated the role of metabolism in muscle fatigue during voluntary exercise in persons with mild multiple sclerosis (MS). Six MS and 8 healthy control subjects performed intermittent, progressive, isometric contractions of the ankle dorsiflexors, during which we measured maximum voluntary force (MVC), inorganic phosphate (Pi), phosphocreatine (PCr), and pH. During exercise. MVC fell sooner in MS, but by the end of exercise the relative decrease in MVC was similar in both groups. In contrast, at the end of exercise Pi/PCr increased to 1.86 ± 0.22 in controls but to only 0.66 ± 0.04 in MS (P < 0.01); likewise, pH was 6.75±0.04 in controls and unchanged (7.06 ± 0.04) in MS (P <0.01). The smaller metabolic change at the same relative exercise intensity suggests a failure of muscle activation that is present even in mild MS. Neurophsyiologic measures of activation indicated some central activation failure and no neuromuscular junction impairment in MS, and suggested that activation failure beyond the muscle membrane(excitation–contraction coupling) may be important in MS. We conclude that metabolic factors do not play a significant role in the development of muscle fatigue during voluntary exercise in mild MS. © 1994 John Wiley & Sons, Inc.     

Term delivery in a woman with severe congenital neutropenia, treated with growth colony stimulating factor

The patient was diagnosed in childhood as having severe congenital neutropenia and had recurrent admissions with severe infections. In 1987, prior to getting married, she was sterilized. She continued to require i.v. antibiotics when she contracted a severe infection. On one occasion, she was treated with growth colony stimulating factor (G- CSF). Her increased neutrophil count was sustained following this treatment. In June 1993, she wished to start a family and underwent in- vitro fertilization (IVF) treatment. G-CSF was given prior to oocyte retrieval. She conceived on her first cycle and an ultrasound scan revealed a singleton pregnancy. Throughout the course of the pregnancy, her white cell count was monitored closely and remained at <1.0x10(9)/l. The pregnancy progressed uneventfully and at 37 weeks gestation she was admitted for G-CSF injections. At 38 weeks she was delivered of a boy weighing 3350 g, by elective Caesarean section. His white cell count was normal. This is the first case of G-CSF being used before conception and during pregnancy in a patient with congenital neutropenia. It shows that advances in cytokine therapy and close interdisciplinary liaison can lead to a successful outcome and help patients, who would otherwise remain childless, to achieve a family.      

Clastogenic effect of fenfluramine in mice bone marrow cells in vivo

Fenfluramine, an amphetamine derivative used in the treatment of obesity, has been evaluated in vivo in the bone marrow cells of Swiss albino mice using two cytogenetic endpoints for assessing its genotoxic and clastogenic potentials. Concentrations of 0.75, 1.5, 3.0, and 5.0 mg/kg b.w. were administered orally for the study of sister chromatid exchange frequencies and chromosome aberrations (CA). SCE frequencies showed a positive dose response; 1.5 mg/kg being the minimum effective concentration. Fen caused a prolongation of cell cycle at all concentrations. Except for the minimum therapeutic dose (0.75 mg), all other doses (1.5, 3.0, and 5.0 mg) showed a significant increase in the percentage of damaged cells over that of the vehicle control. The degree of clastogenicity was directly proportional to the dosage used and inversely related with the duration of treatment. A gradual reduction of the clastogenic potential was observed after 12 and 24 hr of exposure, indicating that the maximum effect occurs at the middle or late synthetic phase of the cell cycle. This study, probably the first detailed screening of the drug for its genotoxicity, shows that Fen is moderately clastogenic and a DNA damaging agent in vivo.     

Nucleoside peptides. 10. Synthesis and T-cell immunostimulatory properties of certain peptide derivatives of 6-azacadeguomycin

Several amino acid and peptide conjugates of 6-azacadeguomycin (6-amino-1-beta-D-ribofuranosyl-4,5-dihydro-4-oxopyrazolo[3,4-d]py rimidine- 3-carboxylic acid, 2) have been prepared in good yields, via a two-step procedure involving 1-hydroxybenzotriazole and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride mediated coupling of 2 with an appropriately protected amino acid or peptide, followed by ammonolysis. Thus, condensation of 2 with L-phenylalanine methyl ester, glycine ethyl ester, and L-glutamic acid diethyl ester gave the corresponding protected linear nucleoside peptides (3, 5 and 7, respectively). Subsequent ammonolysis of 3, 5 and 7 furnished L-phenylalanine amide (4), glycine amide (6) and L-glutamic acid diamide (8) conjugates of 6-azacadeguomycin, respectively. Saponification of 7 gave the corresponding L-glutamic acid derivative 9. A similar coupling of 2 with L-phenylalaninyl-N epsilon-nitro-L-arginine methyl ester trifluoroacetate and subsequent ammonolysis (after catalytic hydrogenation) gave L-phenylalaninyl-L-arginine amide conjugate (12) of 6-azacadeguomycin. Compounds 2, 4, 6, 8, 9, and 12 were evaluated for their ability to potentiate T-cell responses to plant mitogens, in comparison with cadeguomycin (1). Compounds 4, 6, and 9 exhibited an increase in the T-cell proliferation in a dose-dependent manner.     

Preparation and evaluation of 99mTc(V)-DMSA complex: studies in medullary carcinoma of thyroid

Consequent to the promising results reported with 99mTc(V)-DMSA for imaging certain types of soft tissue tumors, we have developed methods to prepare this radiopharmaceutical in three ways: from freshly prepared reagents, through the use of a two component kit and use of the standard renal DMSA kit by a modified recipe. The 99mTc(V)-DMSA complex has been subjected to paper electrophoretic and chromatographic procedures and also biodistribution studies. The distinctly different behaviour of this new product compared to that of the well known renal DMSA complex has been clearly established. Scintiimaging in a preliminary clinical trial in patients with medullary carcinoma of the thyroid has been encouraging.     

Immediate Effect of Verapamil on Pulmonary Functions in Bronchial Asthma

This article describes the immediate effect of verapamil, a calcium antagonist, on pulmonary functions in bronchial asthma. The effect of oral administration of 80 mg of verapamil or placebo was studied in a randomized double-blind manner in 30 extrinsic asthmatic subjects. No significant bronchodilator effect was observed with verapamil administration. There were no significant changes in heart rate and blood pressure after verapamil.