Beta-adrenergic blockade and training in healthy men—effects on central circulation

The effect of chronic β-adrenergic blockade on central circulatory adaptations to physical training was investigated. 16 healthy sedentary males (20–31 yrs) trained on cycle ergometers 40 min/day, 4 days a week for 8 weeks at a work load that during the last 5 weeks corresponded to 75% of the pretraining VO₂ max. In a single blind way, 8 subjects were during the training period treated with the β-adrenergic receptor blocker propranolol (160 mg/day), while the remaining 8 received placebo tablets. Pretraining tests were performed before the start of medication and posttraining tests were performed 6 days after the last day of training and medication. The training program resulted in a similar increase (8%) in VO₂ max in both groups (p<0.01). The resting heart rate (-4 beats/min; p<0.05) as well as the exercise heart rate at a moderate work load (120 W: -11 beats/min; p<0.01) decreased with training, and no significant difference was seen between the 2 groups. At a high work load (180 W), however, the heart rate decreased significantly more with training in the placebo group as compared with the β-blockade group (-19 vs.-7 beats/min; p<0.05). The oxygen pulse (VO₂/HR) increased in both groups at 120 W (+6%; p<0.01). At 180 W the oxygen pulse increased only in the placebo group (+8%; p<0.05). The estimated stroke volume at 120 and 180 W, as determined by impedance cardiography, did not change significantly with training although there was a tendency towards an increase in the placebo group only. The resting left ventricular wall thickness and diameter, as determined by echocardiography, did not change significantly with training in either group.—In conclusion, the present study indicates that a moderate degree of β-adrenergic blockade does not prevent or impair the training-induced increase in the maximal oxygen uptake. During submaximal work, however, the circulatory adaptation may be less apparent if training has been performed during partial blockade of the sympathoadrenal system.     

Quantitative structure–activity relationship (QSAR) study of elastase substrates and inhibitors

One hundred Suc-X-Y-Ala-pNA peptides (SUC: succinyl, pNA: p-nitroanilide, X, Y: Gly, Ala, Val, Leu, Ile, Phe, Pro, x-aminobutyric acid, norvaline, norleucine) were synthesized and their reaction constants with porcine pancreatic elastase (K_m, K_cat and K_cat/K_m) were determined. These reaction constants were quantitatively analyzed using the Free–Wilson/Fujita–Ban method. The contribution of amino acid side chains to the reaction constants K_m, K_cat and K_cat/K_m), expressed logarithmically, was found to be additive. On the other hand, 19 elastase inhibitors of the general formula CF₃CO-X-Y-Ala-pNA (X,Y: ten amino acids) were synthesized, and their inhibition constants were compared with the Michaelis constant for the corresponding substrates and analyzed using free-energy-related substituent constants. In the analysis of amino acid side chains in the Y position, the K_i value of the inhibitor was generally correlated to the K_m value of the substrate, which corresponded to the inhibitor, thus confirming the validity of the equation This study may serve as a prototypical approach to unraveling structure–activity relationships of peptide substrates and inhibitors of medicinal or agricultural importance.     

The Preclinical Safety Evaluation of Human Monoclonal Antibody against Cytomegalovirus

The human monoclonal antibody against cytomegalovinis (Mab C23)was examined pharmacokinetically and toxicologically as partof the preclinical studies prior to approval for human use.Rats given repeated intravenous administrations of Mab C23 producedno antibodies against Mab C23 and maintained a blood Mab C23level in a dose-dependent manner. However, pregnant rabbitsproduced antibodies against Mab C23. The half-life of Mab C23in plasma was 15.9 days in rats, which was similar to that ofnormal human serum -globulin (NHSG). Neither behavioral effectsnor circulatory disturbance was found in mice, rats, and dogseven after a single intravenous injection of 100 or 200 mg/kg,which corresponds to 50 or 100 times the intended clinical dosage.The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasionswith 1- or 2-week intervals elicited a transient decrease inleukocyte counts in rats given 10 or 20 mg/kg, but no adverseeffects in cynomolgus monkeys. Mab C23 did not cause any reproductiveor developmental toxicity when administered to rats and rabbitsat dose levels of 20 mg/kg or less. However, pregnant animalsshowed lower plasma levels of Mab C23 than non-pregnant animals.The chromosomal aberration test disclosed no clastogenicityin human lymphocytes. An immunostaining for Mab C23 revealedno localizations in several tissues of cynomolgus monkeys givenintravenous doses of Mab C23. The preclinical safety evaluationin animals other than rabbits, which produced no antibodiesagainst Mab C23, showed that the behavior of Mab C23 is pharmacokineticallysimilar to that of NHSG and is as safe as NHSG, which has longbeen used as a biological agent. However, because there wasa difference in blood levels of Mab C23 between pregnant andnonpregnant animals, its clinical administration to pregnantpatients should differ from that to non-pregnant patients.     

Comparison of 11C-Methionine, 11C-Choline,and 18F-Fluorodeoxyglucose-Positron Emission Tomography for Distinguishing Glioma Recurrence from Radiation Necrosis

The aim of this study is to assess the different metabolic activities characteristic of glioma recurrence and radiation necrosis (RN) and to explore the diagnostic accuracy for differentiation of the two conditions using ¹¹C-methionine (MET), ¹¹C-choline (CHO), and ¹⁸F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). Fifty patients with lesions suggestive of recurrent glioma by magnetic resonance imaging (MRI) underwent MET, CHO, and FDG-PET. All patients who had previously been treated with radiotherapy for malignant glioma were subjected to open surgery and pathological diagnosis (17 recurrent grade 3- gliomas (Gr.3s) comprising 7 anaplastic astrocytomas (AAs) and 10 anaplastic oligodendrogliomas (AOs), 17 recurrent glioblastomas (Gr.4s), and 16 RNs). We measured the PET/Gd volume ratio, the PET/Gd overlap ratio, and the lesion/normal brain uptake ratio (L/N ratio) and determined the optimal index of each PET scan. The PET/Gd volume ratio and the PET/Gd overlap ratio for RN were significantly lower than those of glioma recurrence only with MET-PET (P < 0.05). The L/N ratio of RN was significantly lower than that of Gr.4 with all PET imaging (P < 0.001) and was significantly lower than that of Gr.3, especially for AO, only with MET-PET images (P < 0.005). Receiver operating characteristic (ROC) analysis showed that the area under the curve of MET, CHO, and FDG was 92.5, 81.4, and 77.4, respectively. MET L/N ratio of greater than 2.51 provided the best sensitivity and specificity for establishing glioma recurrence (91.2% and 87.5%, respectively). These results demonstrated that MET-PET was superior to both CHO and FDG-PET for diagnostic accuracy in distinguishing glioma recurrence from RN.     

Enhanced production of leukotriene B4 by peripheral blood mononuclear cells in patients with fulminant hepatitis

Abstract The production rate of leukotriene B₄ (LTB4) was measured using peripheral blood mononuclear cells (PBMC) in patients with fulminant hepatitis (FH) or other liver diseases. LTB4 in the culture media of PBMC under stimulation with Ca-ionophore was fractionated by HPLC and measured by radioimmunoassay. The production rate of LTB4 was elevated in 16 of 17 FH patients (3.3 ± 0.2 ng/10⁶ cells for 5 min), while the production was below detectable level in patients with acute or chronic hepatitis and in healthy controls. In FH patients, the highest production rate of LTB4 was observed in the initial period of the disease. Enhanced LTB4 production may indicate the primed state of PBMC — the primed mononuclear cells are regarded as participating in the development of massive liver necrosis and of other organ failures in FH.     

Varicella infection complicated with meningitis after immunization

A healthy 45 month old boy who had received varicella vaccine 21 months previously developed aseptic meningitis along with an episode of varicella. The presence of viral DNA in cerebrospinal fluid (CSF) detected by polymerase chain reaction (PCR) with Southern blot hybridization confirmed the relationship between the symptoms and the CSF pleocytosis. This is the first reported case of this complication of varicella meningitis occurring in a child with documented immunization and seroconversion.     

Beneficial Effects of Cervical Spinal Cord Stimulation (cSCS) on Patients with Impaired Consciousness: A Preliminary Report

Electrical stimulation of the spinal cord can be used for treatment of intractabie pain and spasticity. Based on our experimental findings cervical spinal cord stimulation (cSCS) was performed on eight patients with severe brain dysfunction due to traffic accidents, pronounced vasospasm caused by subarachnoid hemorrhage or surgery of huge cerebral tumors (chordoma). After a 1 to 2 month period of stimulation, two patients became conscious and began to speak. It remains unclear whether cSCS induced the restoration of consciousness and improved neurological deficits. Although the successful results might be due to chance, cSCS might have stimulated brain function. This preliminary report shows such excellent results that further studies are warranted.