Simultaneous turnover of normal and dysfunctional C1 inhibitor as a probe of in vivo activation of C1 and contact activatable proteases.

Simultaneous turnover of normal and dysfunctional C1-inhibitor (C1-INH) was carried out in 10 normal subjects and 13 patients with rheumatoid arthritis as a measure of the in vivo activation of C1 and the contact activatable enzymes. In the first series of experiments, dysfunctional protein We was used in simultaneous turnover studies in five normal subjects and nine patients. The fractional catabolic rate of the dysfunctional C1-INH, We, (FCR(d)) was unchanged in both groups but the fractional catabolic rate of the normal C1-INH (FCR(n)) was faster in the patients compared to the controls, in particular patients with vasculitis. The enzyme-dependent catabolism defined as FCR(n-d) X concentration of C1-INH X plasma volume, was raised in the patient group, and correlated with disease activity score (r = 0.83, P less than 0.05). Neither FCR(n) nor FCR(d) was dependent on C1-INH concentration. The latter was higher in the patients (206 mg/l compared with 155 mg/l) indicating a very high synthetic rate in the patients (280.81 micrograms/kg/h compared with 179.77 micrograms/kg). In the second series of turnovers in six patients and five normal subjects, another dysfunctional C1-INH, at, was used. The FCR of C1-INH was slower than C1-INH (We) (1.88%/h compared with 2.7%/h). Enzyme-dependent catabolism of C1-INH in these patients were raised and also correlated with disease activity score (r = 0.82, P less than 0.05).     

Brain tumor in the first year of life: a single institute study.

Brain tumors in infants present special diagnostic and therapeutic challenges. To figure out the clinical features, pathological classification of the tumors and the treatment outcome of infantile brain tumors, 458 children (age<16) with brain tumors were reviewed retrospectively. Among them 21 cases (4.6%) were diagnosed during the first 12 months of life. Two tumors were definitely of congenital origin. The majority of infants with brain tumors presented with increased intracranial pressure. Fourteen tumors were located at the supratentorial area. Sixteen cases had neuroepithelial tumors; astrocytoma (optic pathway), supratentorial primitive neuroectodermal tumor (PNET) and medulloblastoma were found in three cases each. There were two treatment-related mortalities. Compared with the outcomes in older children, the treatment outcome was poorer in medulloblastoma and the optic pathway glioma which showed a higher growth potential. Because of the limited application of postoperative adjuvant therapy, radical surgical removal played a more important role in this age group. The prognosis of patients in whom the tumors could not be totally removed, largely depended on the pathological malignancy of the tumors. Though the treatment outcome was not always dismal, immaturity of the brain, higher growth potential, perioperative risks, limitations in adjuvant therapy, and pessimistic attitude on the part of parents made management more challenging.     

Modulation of transglutaminase expression in rat skeletal muscle by induction of atrophy and endurance training.

The persistence of muscle fiber number regardless of size reduction in muscle atrophy has not yet been fully explained. For the mechanism inherent in skeletal muscle tissues for preventing cellular death, the protective function of muscle tissue through transglutaminases has been tested, since the enzyme is responsible for structural stabilization and participates in signal transduction. In the present experiment, hindlimb suspension for two weeks caused a marked muscle atrophy in Wistar female rats. Comparison of muscle weight and histological analysis showed that suspension-induced atrophy in the hindlimb was more prominent in the soleus muscle, comprised mainly of type I fiber than that in the plantaris muscle of type II fibers. The immunohistochemical analysis with antitransglutaminase C antibody (anti TGase C Ab) showed that some atrophic bundles of soleus muscle were positively reacted with the antibody. The anti-TGase C Ab-reactive substances were observed to disappear significantly after endurance exercise, indicating their characteristic atrophy-dependency. The enzymatic analysis of transglutaminase showed the increase in activity in the atrophic soleus muscle tissue, compared with that in the normal or exercise-trained muscle tissues. From these results, the expression of TGase in the atrophic muscle is suggested to be the possible marker for muscle atrophy and its expression is probably related with the protective mechanism of the muscle tissue to prevent further cellular damage in the atrophic process.     

Controlled elimination of intracellular H(2)O(2): regulation of peroxiredoxin, catalase, and glutathione peroxidase via post-translational modification

The predominant enzymes responsible for elimination of hydrogen peroxide (H(2)O(2)) in cells are peroxiredoxins (Prxs), catalase, and glutathione peroxidases (GPxs). Evidence suggests that catalytic activities of certain isoforms of these H(2)O(2)-eliminating enzymes are extensively regulated via posttranslational modification. Prx I and Prx II become inactivated when phosphorylated on Thr(90) by cyclin B-dependent kinase Cdc2. In addition, the active-site cysteine of Prx I-IV undergoes a reversible sulfinylation (oxidation to cysteine sulfinic acid) in cells. Desulfinylation (reduction to cysteine) is achieved by a novel enzyme named sulfiredoxin. c-Abl and Arg nonreceptor protein tyrosine kinases associate with catalase in cells treated with H(2)O(2) by mechanisms involving the SH3 domains of the kinases and the Pro(293)PheAsnPro motif of catalase and activate catalase by phosphorylating it on Tyr(231) and Tyr(386). Similarily, GPx1 is activated by c-Abl- and Arg-mediated phosphorylation. The tyrosine phosphorylation is critical for ubiquitination-dependent degradation of catalase.     

Analysis of photon beam exit dose using photon point kernels

The Monte Carlo method is used to analyse the dose fall-off at the exit surface of a megavoltage photon beam. The convolution/superposition method of dose calculation using Monte-Carlo-generated homogeneous photon kernels is shown to be in error for exit dose calculation. Instead, photon kernels that incorporate modelling of the exit surface were generated, also using Monte Carlo, to analyse the problem, and the calculated dose fall-off using these kernels agrees well with measured data. In addition, the physics underlying the characteristics of the dose fall-off is analysed based on complete Monte Carlo modelling. Practical improvements to the convolution/superposition method are suggested.     

Effect of biphenyl dimethyl dicarboxylate on the humoral immunosuppression by ethanol

The present study was undertaken to investigate the effect of biphenyl dimethyl dicarboxylate (PMC) on the humoral immunosuppression by ethanol (EtOH) in ICR mice. PMC at a dose of 6 mg/kg was orally administered to mice daily for 28 consecutive days, and the control mice were given vehicle. Mice treated with EtOH were given freely with 20% EtOH instead of water. The results of this study are summarized as follows; a gain of body weight and the relative weights of spleen and liver were significantly increased by combination of PMC and EtOH, as compared with those in mice treated with EtOH alone. Splenic plaque forming cells (PFC) and hemagglutination (HA) titers to sheep red blood cells (SRBC), and the secondary IgG antibody response to bovine serum albumin (BSA) were decreased by the treatment of EtOH alone, then restored to normal level by PMC treatment. The elevations of serum glutamic-pyruvic transaminase (S-GPT) and total protein levels caused by EtOH were reduced to normal level by the combination of PMC and EtOH. In addition, lower serum albumin and A/G ratio were also increased to normal level. These findings indicate that PMC has a protective effect against EtOH-induced humoral immunosuppression.     

Hypertrophic obstructive cardiomyopathy with infundibular stenosis treated by alcohol ablation therapy

This report describes an uncommon case of hypertrophic obstructive cardiomyopathy (HOCM) accompanying infundibular stenosis of the right ventricle treated by alcohol ablation therapy, in a 28-yr-old male patient presenting with dyspnea on exertion. HOCM with infundibular stenosis was detected by echocardiogram and cardiac catheterization and patient has dynamic obstructions of both ventricular outflow tracts. We performed alcohol ablation therapy to improve clinical symptoms and to relieve dynamic obstructions of both ventricular outflow tracts. This is the first case in which HOCM with infundibular stenosis of the right ventricle was treated by alcohol ablation therapy.     

HLA and Thyrotoxicosis (Graves' Disease) in Chinese

HLA locus A and B typing was performed on 86 Chinese thyrotoxicosis (Graves' Disease) patients and 238 normal Chinese subjects. The frequency of HLA-Bw46 (Sin 2) was found to be significantly higher among the patients than controls (X²= 26.15, corrected P <.003, relative risk = 3.74). The risk associated with Bw46 was reflected in the Bw46 heterozygotes. The relative risks of the joint occurrence of Bw46/B40 and Bw46/B13 were 8.74 and 5.88 respectively.     

A quantitative approach to the design of antitumor drug dosage schedule via cell cycle kinetics and systems theory

A discrete-time kinetic model for chemotherapy was developed to deal with the effects of antitumor drugs on the cell cycle and proliferation kinetics of experimental tumor cell populations in which cell kinetic responses of chemotherapy are represented in terms of perturbation of cell kinetic parameters—cell age, cell size and DNA content distributions. The time-course behavior of these cell kinetic parameters was predicted by solving the discrete-time state equations which characterize the dynamics of tumor-drug interactions. The amount of antitumor drug administered was expressed to be the control function of the state equations and the transition matrix representing two modes of drug action, namely, cell kill and progression delay or accumulation of cells due to drug, was derived. The performance of the model, assessed by examining the effects of cell cycle stage-specific agents such as cytosine arabinoside on spontaneous AKR leukemia, compared favorably with experimental data. Utilizing an optimization scheme in engineering systems studies, an analytical method is described for optimizing the regimen of drug administration so as to maximize the effectiveness of drug dosage schedules and minimize the use of toxic amounts of the drug. The superiority of the schedule designed by an optimization scheme was evident at the termination of therapy, although the schedule designed by experimental trials reduced the number of surviving tumor cells more effectively than the one designed by an optimization scheme during the earlier therapy period. In the model, the proposed schedule will function more effectively for the entire therapy period when additional parameters of drug characteristics, such as the toxicity to the host and drug resistance, are encompassed.     

Hematological indices and the prevalence of anemia in an elderly Chinese population

Hematological indices were determined in a group of 427 elderly Chinese subjects over 60 years old; reference ranges were established after excluding subjects with hemoglobinopathies or diseases giving rise to anemia and those with values less or greater than 3 SD from the mean. The values were similar to those for elderly Caucasians. All the red cell indices were significantly higher in men than women, possibly reflecting the influence of androgens on bone marrow function. Previously reported age-related decline in hemoglobin, red cell count and hematocrit from studies of all age groups was not seen in men or women above age 60 years, but a fall in platelet count with age, which had not been previously reported, was observed. There were no age-related changes in any other indices. Reference ranges were lower for Hb, MCV, and MCH in men and women, compared to those derived from a study of Chinese of all age groups. The prevalence of anemia due to disease and hemoglobinpathies in this population was 6.4% in men and 6.3% in women.