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.     

Ultrathin films of charged polysaccharides assembled alternately with linear polyions

As a means of preparation of biocompatible molecular surfaces, an alternate assembly of charged polysaccharides and oppositely-charged synthetic polymers was conducted. Cationic chitosan was assembled alternately with anionic poly(sodium styrenesulfonate) (PSS) at pH 4. Regular film growth and its dependence on ionic strength were detected by the quartz crystal microbalance (QCM) method. Averaged film thicknesses for the chitosanCPSS layer were 15, 31, 46, and 69 A° , respectively, when 0, 0.25, 0.5, and 1 M of NaCl was contained in aqueous chitosan. Adsorption of chitosan did not reach saturation in 20 min at 0 M NaCl, while the adsorption became saturated within 6 min with 0.25 M NaCl. Anionic sodium chondroitin sulfate was also assembled in alternation with cationic poly(dimethyldiallylammonium chloride) (PDDA) at pH 6.5. The adsorption of chondroitin sulfate was less sensitive to ionic strength. Surface morphology of chitosan–PSS films was investigated by non-contact atomic force microscopy (AFM) observation. Maximum height difference and Ra value for a 1000 × 1000 nm area were 11 and 0.69 nm, respectively, indicating the formation of a molecularly flat surface by alternate layer-by-layer adsorption.     

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.     

New Diagnostic Finding to Assess Para-Hisian Pacing Observed in a Patient with a Permanent Form of Junctional Reciprocating Tachycardia

Morphologic Change During Para-Hisian Pacing. Para-Hisian pacing, a useful method to differentiate conduction over an accessory pathway from conduction over the AV node, is assessed essentially by comparing the timing of local atrial electrograms between Hisbundle captured heats and His-bundle noncaptured heats. We describe the case of a patient with a permanent form of junctional reciprocating tachycardia, in whom an atrial double potential was recorded only during the tachycardia at the right posterior septum. During para-Hisian pacing, a morphologic change in the atrial electrogram at the posterior septum was also identified, as well as a change in the retrograde atrial sequence. Since the morphologic change of atrial electrograms during para-Hisian pacing cannot be demonstrated in a patient without an accessory pathway, this new finding could he considered a new additional diagnostic criterion suggesting the presence of an accessory pathway.     

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.     

Inhibitory Effects of Daunorubicin on Endothelium-dependent Vasorelaxing Response to Acetylcholine of Rat Aorta

Abstract— The effect of daunorubicin on the endothelium-dependent vasorelaxing response to acetylcholine was investigated using rat isolated aorta and compared with the effect of aclarubicin. Treatment of aortic strips with daunorubicin (20 μM) significantly attenuated the relaxing response to acetylcholine in the absence of tetraethylammonium, but not in its presence. Pretreatment with daunorubicin at a higher concentration (50 μM) or with aclarubicin (20 μM) strongly attenuated the relaxing response to acetylcholine; this attenuation was unaffected by the presence of tetraethylammonium. The increase in aortic cGMP in response to acetylcholine was also significantly suppressed by pretreatment with 50 μM daunorubicin or 20 μM aclarubicin, but not by treatment with 20 μM daunorubicin. The inhibitory effect of 20 μM aclarubicin on the acetylcholine-induced responses was stronger than that of 50 μM daunorubicin. Even in strips pretreated with both 50 μM daunorubicin and 20 μM aclarubicin, relaxation induced by 0·1 μM sodium nitroprusside was retained. These results suggest that daunorubicin at 20 μM inhibits the endothelium-dependent vasorelaxing response to acetylcholine via a mechanism other than the nitric oxide-mediated pathway, whilst at 50 μM, it inhibits the nitric oxide-mediated vasorelaxation.     

Effects of nifedipine on hepatic venous pressure gradient and portal vein blood flow in patients with cirrhosis

Abstract We investigated the effects of nifedipine on splanchnic haemodynamics in 13 patients with cirrhosis and portal hypertension, and in 10 control subjects using hepatic venous catheterization and pulsed Doppler ultrasound. There were no significant changes in systemic or splanchnic haemodynamics in control patients. In contrast, systemic vascodilatation, evidenced by significant decreases in mean arterial pressure and systemic vascular resistance, was observed in patients 20 min after sublingual application of 10 mg nifedipine. Moreover, hepatic venous pressure gradient and portal vein blood flow significantly increased after nifedipine administration. There was a significant correlation between the percentage increases in portal vein blood flow and in hepatic venous pressure gradient. However, no correlation was found between the percentage change in cardiac output and that in portal vein blood flow. Thus the increase in portal vein blood flow appears to be related to splanchnic arterial vasodilatation by nifedipine. Consequently, nifedipine has deleterious effects on portal haemodynamics in patients with cirrhosis. As nifedipine may potentially increase the risk of variceal haemorrhage in patients with less advanced varices, this drug should be used with caution in patients with chronic liver disease.     

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.