Evidence of an abnormal intramuscular component of fatigue in multiple sclerosis

The goals of this study were to investigate muscle fatigue in patients with multiple sclerosis (MS), and to determine the relationships between muscle fatigue, clinical status, and perceived fatigue. The fatigability of the anterior tibial muscle was quantitated in patients and controls during 9 min of intermittent stimulation (used to eliminate central sources of muscle fatigue). During exercise, the decline in tetanic force, phosphocreatine, and intracellular pH was greater in patients than in controls. The compound muscle action potential amplitude did not decrease during exercise, indicating that there was no failure of neuromuscular transmission during fatigue. Thus, the excessive fatigue in MS developed from sources beyond the muscle membrane. Following exercise, the recovery of tetanic force was delayed in patients (a pattern that suggests abnormal excitation–contraction coupling), whereas the recovery of metabolites was complete in both groups. Muscular fatigue was correlated with clinical disability but not with perceived fatigue. These results suggests that fatigue in MS has both central (perception, upper motor neuron dysfunction) and peripheral (impaired metabolism and excitation–contraction coupling) components.© 1995 John Wiley &Sons, Inc.     

The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole

1 Cytochrome P450-mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine.
2 Ten healthy male volunteers were given co-trimoxazole (800  mg sulphamethoxazole and 160  mg trimethoprim) alone or 1  h after either fluconazole (150  mg) or ketoconazole (200  mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24  h, and sulphamethoxazole and its metabolites were quantified by electrospray LC-MS.
3 Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly ( P <0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N₄-acetyl sulphamethoxazole, or sulphamethoxazole N₁-glucuronide excreted in urine.
4 The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end-points.     

两种不同抗体双弹头标记物导向治疗肝癌的比较

在动物实验的基础上，比较了抗ＡＦＰ单克隆抗体（ｍＡｂ）和抗ＡＦＰ多克隆抗体（ｐＡｂ）两种不同抗体双弹头标记物在肝癌患者体内的生物代谢情况。结果显示，两种抗体标记物的血浆清除半衰期均在２４ｈ左右，ｍＡｂ标记物的清除较ｐＡｂ标记物略慢。尿清除的半衰期，ｍＡｂ标记物约为１２０ｈ，而ｐＡｂ标记物则约为１８ｈ，表明二者的体内生物代谢不同，疗效可能不一。     

Changes in Neutrophil Oxidative Potential in Patients Undergoing Cardiopulmonary Bypass with Polypropylene Hollow Fiber Oxygenators

Neutrophil oxidative metabolism, C3d and beta 2 microglobulin levels, were assessed in nine consecutive patients undergoing cardiopulmonary bypass surgery with polypropylene hollow fiber oxygenators for open cardiac operations. Generation of oxygen free radicals by neutrophils was measured as luminol-enhanced chemiluminescence after stimulation with opsonized Zymosan and phorbol myristate acetate. A significant increase in light emission was detected by using both of the chemiluminescence stimulators. Moreover, a remarkable and significant increase in C3d levels was found already at 10 min. Conversely minimal changes in levels of beta 2 microglobulin were detected during cardiopulmonary bypass surgery. These data suggest that the impact of the patient blood with the foreign surface of cardiopulmonary bypass results in activation of phagocyte cells with increased potential in oxygen consumption. These effects could be partially complement-mediated.     

实验性糖尿病大鼠肝,肾,心,脑脂肪酸代谢的动态变化

报道对链脲佐菌素（STZ）诱导的实验性糖尿病大鼠几种重要脏器（肝、肾、心、脑）卵磷脂、脑磷脂中脂肪酸构成的变化。不饱和脂肪酸变化的模式（C18：2n-6，C20：3n-6，C22：5n-3，C22：6n-3增加，C20：4n-6降低）基本相同，改变的先后顺序是肝→心、肾→脑。     

镉对肾脏的毒作用

雄性Ｗｉｓｔａｒ大鼠２４只，随机等分为４组，皮下注射不同剂量的ＣｄＭＴ。结果显示镉接触组尿钙和尿蛋白都高于对照组；肾皮质钠泵和钙泵活性低于对照组，体外试验也显示镉能抑制钙泵活性，ＧＳＨ和半胱氨酸对这种抑制有保护作用；肾皮质ＧＳＨ含量低于对照组，ＭＤＡ含量则高于对照组，但肝脏的这两个指标无变化；高剂量组ｃＡＭＰ／ｃＧＭＰ的比值低于对照组。提示脂质过氧化和钙代谢障碍是镉引起肾损害的机理之一。     

Involvement of synthesis of brain cell structural proteins in the action of antitheines on long-term memory

Academician S. V. Anichkov Department of Pharmacology, Research Institute of Experimental Medicine, Academy of Medical Sciences, St. Petersburg. (Presented by Academician of the Academy of Medical Sciences A. N. Klimov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 5, pp. 506–508, May, 1992.     

Fat metabolism and its response to infusion of insulin and glucose in patients with advanced chronic obstructive pulmonary disease

Summary. In order to investigate fat metabolism and the regulation of lipolysis and blood fuel metabolites by insulin, nine patients with chronic obstructive pulmonary disease (COPD) with chronic hypoxaemia and seven healthy control subjects of similar age were investigated by determination of the turnover rate of free fatty acids (TOR), using 1-¹⁴C-oleic acid as a tracer, and arterial concentrations of FFA, glycerol and 3-hydroxybutyrate. The measurements were performed in the basal state and during insulin and glucose infusion, aiming at euglycaemia at insulin levels of 50 and 100 mU l^-1. The subjects' ages were 64±2.7 and 66±1.1 (mean±SEM) years in the COPD and control groups, respectively. TOR was 0.73±0.06 and 0.52±0.02 mmol min^-1 (P<0.05) in the basal state, 0.33±0.04 and 0.30±0.02 at an insulin level of 50 mU I^-1 and 0.32±0.08 and 0.24±0.02 at an insulin level of 100 mU I^-1, in the COPD and control groups, respectively. Arterial FFA concentration was 0.98±0.08 and 0.75±0.06 mmol 1^-1 (P<0.05) in the basal state in the COPD and control groups, respectively. During the clamp, the decrease in FFA mirrored that in TOR. The results show that the state of lipolysis is increased in severe COPD patients with chronic hypoxaemia. Furthermore, the results suggest a reduced effect of insulin in lipolysis.     

Carbohydrate metabolism in children receiving growth hormone for 5 years

Carbohydrate metabolism was evaluated by fasting and postprandial glucose, insulin, and hemoglobin (Hb)A_1c levels in children with chronic renal insufficiency and various other growth disorders treated with growth hormone. Mean fasting and postprandial glucose remained unchanged throughout the 5-year study period in all four study groups. Median fasting insulin levels rose from lownormal levels into the normal range after 5 years of growth hormone. Average fasting insulin level after 5 years was 10 mU/l. Median postprandial insulin values also rose, yet remained within the normal range at the 5-year mark. Mean Hb A_1c levels remained within low to middle end of the normal range in the patients with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Mean Hb A_1c levels at the 5 years were slightly elevated to 6.3% for the patients with chronic renal insufficiency.     

Effect of KB-2796, a new diphenylpiperazine Ca antagonist, on voltage-dependent Ca currents and oxidative metabolism in dissociated mammalian CNS neurons

The effects of KB-2796, 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine-2HCl, on the low- and high-voltage activated Ca²⁺ currents (LVA and HVA I_Ca, respectively) and on oxidative metabolism were studied in neurons freshly dissociated from rat brain. KB-2796 reduced the peak amplitude of LVA I_Ca in a concentration-dependent manner with a threshold concentration of 10⁻⁷ M when the LVA I_Ca was elicited every 30 s in the external solution with 10 mM Ca²⁺. The concentration for half-maximum inhibition (IC₅₀) was 1.9 × 10⁻⁶M. At 10⁻⁵ M or more of KB-2796, a complete suppression of the LVA I_Ca was observed in the majority of neurons tested. There was no apparent effect on the current-voltage (I-V) relationship and the current kinetics. KB-2796 delayed the reactivation and enhanced the inactivation of the Ca²⁺ channel for LVA I_Ca voltage- and time-dependently, suggesting that KB-2796 preferentially binds to the inactivated Ca²⁺ channel. KB-2796 at a concentration of3.0 × 10⁻⁶M also decreased the peak amplitude of the HVA I_Ca without shifting the I-V relationship. In addition, KB-2796 reduced the oxidative metabolism (the formation of reactive oxygen species) of the neuron in a concentration-dependent manner with a threshold concentration of3 × 10⁻⁶M. It is suggested that the inhibitory action of KB-2796 on the neuronal Ca²⁺ influx and the oxidative metabolism, in combination with a cerebral vasodilatory action, may reduce ischemic brain damage.