Diagnostic/prognostic significance of photo-evoked eyelid microvibration in neonates with intracranial hemorrhage

Photo-evoked eyelid microvibration (PEMV) was recorded in neonates with intracranial hemorrhage in order to determine whether it serves as a useful indicator of clinical course and also prognosis. Although the latency of PEMV was prolonged or absent in the acute stage of ICH, it returned to a normal range in these subjects with the improvement of symptoms. Three infants whose PEMV were still prolonged in the convalescent stage developed mental retardation or cerebral palsy. PEMV may be a useful predictor of the prognosis of neonatal ICH and its prolongation may signal later neurological sequelae.     

The morphological and biochemical changes in skeletal muscle fibers by dietary protein restriction.

The effects of dietary protein restriction on skeletal muscle fibers were studied according to morphological and biochemical approaches. Protein and DNA content of quadriceps muscles from young adult rats were decreased by the low protein and protein-free diet. Morphological examination demonstrated that there was a significant decrease in the size of muscle fibers without change in their numbers due to protein restriction. The protein/DNA ratio, accepted as an index of cell size in biochemical approaches, was compared with cell size on photomicrographs. Actual fiber size appeared much smaller than that indicated by the protein/DNA ratio.     

Effect of phosphatidylcholine, phosphatidylethanolamine and lysophosphatidylcholine on the protein C/protein S anticoagulation system.

Phosphatidylserine is known to significantly accelerate the blood coagulation reaction. In a previous communication submitted for publication, we demonstrated that phosphatidylcholine, phosphatidylethanolamine and lysophosphatidylcholine showed effects on the blood coagulation reaction using the factor Xa-prothrombin reaction system, and discuss a new function of membrane phospholipids. The present study examined the role of phospholipids in the blood coagulation regulatory reaction (anticoagulation system), by studying the effects of phospholipids on the protein C/protein S reaction. We have established quantitative methods for measuring activated protein C activity and protein S activity, and used them to measure their activity after the addition of liposomes with different phospholipid compositions. We found that phosphatidylcholine inhibited activated protein C and protein S activities in a dose-dependent manner, as in the factor Xa-prothrombin reaction system. On the other hand, phosphatidylethanolamine and lysophosphatidylcholine showed no effect on activated protein C activity. Phosphatidylethanolamine inhibited and lysophosphatidylcholine accelerated coagulation activity in the factor Xa-prothrombin system, but such effects were not observed in the protein C/protein S reaction system. The coagulation and anticoagulation reactions are exquisitely balanced by thrombin, with a role both as a procoagulant and anticoagulant. Therefore, it is understandable that phosphatidylethanolamine and lysophosphatidylcholine show different effects in the factor Xa-prothrombin and protein C/protein S reaction systems. It appears that coagulation and anticoagulation reactions are co-ordinated and controlled by changes in phospholipid composition of the cellular membrane where the coagulation reaction takes place.     

Histopathological observations on orbital fatty tissue in dysthyroid ophthalmopathy

Seventeen specimens of orbital fatty tissue taken from cases of dysthyroid ophthalmopathy at the time of operation were observed by light and electron microscopy, and also by immunohistochemical staining. The pathological changes observed were infiltration of the chronic inflammatory cells, deposit of fibrin, sclerosis of vascular wall, occlusion of the vascular lumen, and accumulation of hydrophilic mucopolysaccharide. Immunoglobulin G was detected in fat cells and lymphocytes, and some of the infiltrating lymphocytes were determined to be T cells, by immunohistochemistry. These findings suggested that the pathology of the dysthyroid ophthalmopathy was closely related to the chronic inflammation induced by the immune reaction. The exophthalmos was considered to occur due to edema secondary to chronic inflammation and accumulation of the mucopolysaccharides.     

The determination of thymidylate synthetase inhibition for testing fluoropyrimidines--pharmacokinetics and metabolism of carmofur (HCFU) in patients with gynecologic malignancies--Tokai HCFU Study Group for Gynecologic Malignancies

The pharmacokinetics and metabolism of carmofur (HCFU) were studied. Sixty-six patients were administered 100 mg of HCFU orally, and the plasma levels of the HCFU fraction (HCFUf) and 5-fluorouracil (5-FUra) were determined at 0, 1, 2, 4 and 6 hours. The average half-life of HCFUf and 5-FUra were 1.05 and 1.31 hours, and the average areas under the curves (AUC) of the plasma concentration were 6.51 hr X mcg/ml and 0.46 hr X mcg/ml, respectively. Surgical specimens of the tumors were obtained about three hours after the administration and assayed for HCFUf. 5-FUra fluorodeoxyuridine-monophosphate (FdUMP), deoxyuridine-monophosphate (dUMP), total thymidylate synthetase (TS total), and non-FdUMP-bound free enzyme (TS free). The TS inhibition rate (IR) was calculated by the follow method: IR = (TS total-TS free)/TS total X 100 levels of the TS total varied from not-detected (less than 0.10 pmol/g) to 20.5 pmol/g. The average FdUMP: dUMP ratio was 3.44 X 10(3), However, more than 80% inhibitions of TS were observed in nine cases (21.4%). The correlation indicates between TS IR and tissue FdUMP level or FdUMP: dUMP ratio were 0.57 and 0.62 in ovarian malignancies respectively. No significant correlations were observed between TS inhibition and levels of tissue 5-FUra or AUC of 5-FUra.     

Experimental study of spinal cord compression by epidural tumors using electron probe X-ray microanalysis and confocal laser scanning microscopy

Changes in the nerve fibers of the spinal cord were studied in rat experimental epidural tumor models. Light microscopy showed demyelinization in all with rats paraparesis and paraplegia. Cross-sectional views of nerve fibers stained with 3,3dipentyloxacarbo-cyanine iodide, obtained by confocal laser scanning microscopy, showed distorted, shrunken fibers with a low fluorescence intensity. Changes in the electrolyte contents of nerve fibers were studied by electron probe X-ray microanalysis. The K concentration in axons and the myelin sheath was increased in the paraparesis group, but was decreased in the paraplegia group. These findings suggest that, in the paraparesis group, compression of the spinal cord damaged cell membrane channels, which subsequently caused an increase in intracellular K, a decline in the action potential, and low-intensity fluorescence of nerve fibers. On the other hand, in the paraplegia group, destruction of cell membranes caused a decrease in intracellular K until it approached the extracellular level. This reduced both the action potential and the fluorescence intensity. As Ca and Mg concentrations in both axons and the myelin sheath increased in relation to the severity of neurologic damage, it appears that these electrolytes may also play an important role in damage to nerve fibers.     

Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

AUGMENTED ENDOGENOUS NITRIC OXIDE PRODUCTION IN PARTIAL PORTAL VEIN-LIGATED RATS

1. Endothelium-derived nitric oxide (NO) is a potent vasodilator. Because the body oxidizes it to nitrate ions, NO₃-, measurement of the serum concentration and the urinary excretion of NO₃- may be an index for endogenous NO. We investigated the role of NO on hyperdynamic circulation in cirrhotic and partial portal vein-ligated rats by measuring NO₃. 2. Liver cirrhosis was induced by administration of thioacetamide. Systemic and splanchnic haemodynamics and splenic-systemic shunting were determined by tracer microspheres. The concentration of NO₃- was measured by using high-performance liquid chromatography with an anion-column. 3. We found that systemic and splanchnic hyperdynamic circulation existed to almost the same extent in cirrhotic and in portal vein-ligated rats as compared to the controls and sham-operated rats, respectively. Splenic-systemic shunting was markedly greater in portal vein-ligated rats than in cirrhotic rats. 4. Serum NO₃- levels and urinary excretion of NO₃- in cirrhotic rats tended to increase as compared to the controls. On the other hand, the levels in portal vein-ligated rats were significantly increased as compared to those of the sham-operated rats, and were significantly and negatively correlated to the splanchnic arterial resistance and total vascular resistance. The amount of urinary excretion of NO₃- significantly correlated to splenic-systemic shunting (r = 0.61, P<0.05) only in portal vein-ligated rats. 5. We suggest that these high levels of NO₃- in portal vein-ligated rats relate to the extensive formation of porto-collateral vasculature or acute changes in systemic and splanchnic haemodynamics due to portal vein-ligation.     

Hemodynamic and volume changes by recombinant human erythropoietin (rHuEPO) in the treatment of anemic hemodialysis patients

Hemodynamic and volume changes induced by recombinant human erythropoietin (rHuEPO) treatment were investigated in 12 chronic hemodialysis patients with refractory anemia. After rHuEPO administration for 49 to 151 days, hematocrit (Ht) significantly improved from 19.4 +/- 2.3 to 30.1 +/- 1.1% (Mean +/- SD). Mean blood pressure (MBP) increased slightly but significantly from 78.8 +/- 13.2 to 88.9 +/- 16.9 mmHg. Hemodynamically, total peripheral resistance index (TPRI) increased significantly from 1,444 +/- 367 to 2,146 +/- 470 dynes.sec.cm-5.m2, while cardiac index (CI) decreased significantly from 4.49 +/- 0.85 to 3.37 +/- 0.60 l/min/m2. Both pulse rate (PR) and stroke volume index (SVI) also decreased significantly, but blood volume (BV) remained unchanged. Plasma renin activity and plasma norepinephrine decreased significantly. There were positive correlations between the change of MBP and that of CI, and between the change in CI and that of BV, respectively (p less than 0.05 or less). In conclusion the improvement of anemia using rHuEPO is hemodynamically associated with an increase in TPRI and a decrease in CI as well. Blood pressure elevation seems to be caused by an inappropriately minor reduction of CI. The contribution of humoral factors is not suggested.