Biomedical subjects
Publications and source records attributed to J Chin.
An ion-selective electrode (ISE) based on receptor 1 is highly selective for binding NH(4)(+) over K(+) (lg K(NH(4)(+)/K(+))=-2.6); the three imine nitrogen atoms in 1 are ideally positioned for hydrogen bonding with the tetrahedral NH(4)(+) ion. This selectivity is considerably greater than that found for commercial ISEs based on nonactin (lg K(NH(4)(+)/K(+))=-1.0).
Ventricular fibrillation is the major cause of sudden cardiac death, the leading cause of death in the industrialized world; however, the mechanisms for its onset are not well understood. To further understand the dynamics of fibrillation at and near its onset, we compared spatial and temporal variability of mean interactivation intervals in a stable canine model for ventricular fibrillation. Temporal variability was very small, suggesting that the relevant physiological parameters remained constant during our experiments. Spatial variability was usually significantly larger and appeared incompatible with the dynamics of a single, meandering spiral wave. This confirmed recent results that a single spiral wave cannot generate ventricular fibrillation. Thus the onset of fibrillation is a multistage process, with spiral-wave breakdown providing a crucial step in the quasi-periodic route to fibrillation.
Investigation of furans, pyrroles and pyrazolones identified 3-pyridyl-2,5-diaryl-pyrroles as potent, orally bioavailable inhibitors of p38 kinase. 3-(4-pyridyl-2-(4-fluoro-phenyl)-5-(4-methylsulfinylphenyl)-pyrrol e (L-167307) reduces secondary paw swelling in the rat adjuvant arthritis model: ID50 = 7.4 mg/kg/b.i.d.
BACKGROUND/AIMS: The combination of non-selective beta-blockers and nitrates is an effective therapy for the prevention of rebleeding from oesophageal varices. However, a significant number of patients fail to respond and have further haemorrhage. It has been suggested that measurement of the hepatic venous pressure gradient response to long-term drug therapy may allow early selection of non-responders. We aimed to test this hypothesis in 63 patients with cirrhosis and variceal bleeding treated with propranolol+/-isosorbide mononitrate. METHODS: Hepatic venous pressure gradient was measured before and during treatment. Response was defined as a reduction of 20% or more in hepatic venous pressure gradient, or a fall in hepatic venous pressure gradient to 12 mmHg or less. RESULTS: Forty-four patients were evaluable: 28 responders and 16 non-responders. Hepatic venous pressure gradient fell significantly in the responder group (17.5+/-0.5 mmHg vs 12.2+/-0.5 mmHg; p<0.01) but not in the non-responders (18.0+/-1.0 vs 17.9+/-1.2 mmHg; p=n.s.). Overall, there was no difference in rebleeding rates between the two groups: responders 43%, non-responders 25%. However, rebleeding was uncommon in compliant patients with alcoholic cirrhosis, in whom the hepatic venous pressure gradient fell to less than 12 mmHg (9%). CONCLUSIONS: In this study a fall in hepatic venous pressure gradient of 20% was not a reliable predictor of clinical response. A threshold value of 12 mmHg was useful, but applied to relatively few patients.
The subtotally nephrectomized rat has often been used to investigate the etiology and treatment of secondary hyperparathyroidism (secondaryHPT), but it has been used less frequently to study the effects of secondaryHPT on bone. The recent development of a reliable and specific rat parathyroid hormone (PTH) immunoradiometric assay has provided an opportunity for a thorough investigation of the relationship between circulating, biologically active PTH, and the skeletal abnormalities that occur in chronic renal insufficiency (CRI). Rats were 5/6 nephrectomized (Nx) or sham operated and fed diets with varying levels of Ca and P for 12-14 weeks to induce differing magnitudes of secondaryHPT. Parathyroid gland volume increased by 80%-90% in 5/6 Nx rats in the mild and moderate secondaryHPT groups (2.3- and 7.7-fold higher PTH levels, respectively) and by 3.3-fold in the severe secondaryHPT group (12-fold increase in PTH). The increases in gland volume were caused primarily by cell hyperplasia. Mild secondaryHPT resulted in a 12% decrease in bone mineral density (BMD) across the entire femur, increased osteoclast numbers (N.Oc), unchanged osteoblast numbers (N.Ob), and decreased cancellous bone volume (Cn.BV) in the tibial metaphysis but, apart from increased marrow area, no major changes in cortical bone at the tibio-fibular junction. Moderate secondaryHPT was associated with no changes in femoral BMD, or in tibial Cn.BV, but N.Ob and bone formation rate (BFR) were markedly elevated. Increased periosteal, intracortical, and endocortical BFR and turnover were evident, and contributed to increased cortical porosity (Ct.Po). The changes were exaggerated in the severe secondaryHPT group; BMD was lower in the proximal, but higher in the distal femur, and Cn.BV, N.Ob, N.Oc, and BFR were increased by six-, seven-, three-, and 30-fold, respectively. Endocortical BFR was elevated 31-fold and the extensive Ct.Po (10%) decreased bone strength. However, Ct.Po was not apparent until PTH levels exceeded 500 pg/mL. Thus, in rats with CRI of similar magnitude, progressive secondaryHPT is associated with dramatically different effects on bone. Mild secondaryHPT caused loss of cancellous and endocortical bone, and moderate secondaryHPT tended to maintain both types of osseous tissue, whereas PTH levels >500 pg/mL resulted in substantial cortical bone loss, but cancellous bone gain.
There is now compelling evidence that intradermal vaccination with an efficacious adjuvanted antigen triggers a series of coordinated responses characterized initially by the rapid mobilization and recruitment of granulocytes to the lung. Activation of effector cells of the innate immune system is intended to provide surveillance and temporary protective cover at vulnerable mucosal sites while both T and B cell precursors, as well as haematopoietic progenitor cells, are undergoing dramatic reductions in numbers during the first 2-4 days post-vaccination. Some of these events recapitulate those seen after infection with a pathogen. Initial decreases in cell numbers in the thymus and bone marrow (BM) are followed by rapid increases in cellular proliferation in these organs, probably in response to peripheral signals. Vaccine-induced cell death (by apoptosis) in the thymus may provide one of many stimuli needed to up-regulate BM production of progenitor cells, and cells of the B, myeloid and monocytic lineages so that depleted peripheral compartments are replenished. Reconstitution of the latter cell population is critical in ensuring sufficient numbers of APC are generated to deal with extraneous antigen resulting from either vaccination or proliferation of a pathogen. Ultimately, these APC, as effector cells of the innate immune system, must provide pattern recognition of dangerous pathogens and serve to activate appropriate T cell responses. Vaccination not only educates both the innate and adaptive arms of the immune response but also more interestingly, appears to regulate subsequent innate immune responses following exposure to a lethal challenge dose of bacteria. Under these conditions, the rate of loss of BM precursors is greatly attenuated in mice previously vaccinated with adjuvanted antigen compared to unvaccinated controls or mice that had received only antigen. Mice intradermally vaccinated with adjuvanted antigen also displayed increased rates of granulocyte and monocyte recruitment in the lung and spleen. These events occurred very rapidly within 12-36 h of challenge and may be crucial in providing complete protection in vaccinated mice against a challenge dose that was otherwise lethal for unvaccinated controls. Therefore, an important characteristic of an efficacious intradermal vaccine may be the ability to deplete T and B precursors in the thymus and BM lymphoid compartments followed by increased rates of haematopoiesis to re-supply peripheral requirements for granulocytes/monocytes, and T and B cells. Adaptive immunity elicited by intradermal vaccination is, therefore, dependent upon prior activation of the innate immune system.
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Cholesterol released from ingested low density lipoproteins in lysosomes moves both to the plasma membrane and to the endoplasmic reticulum (ER) where it is re-esterified. Whether cholesterol can move directly from lysosomes to ER or first must traverse the plasma membrane has not been established. To examine this question, the endocytic pathway of rat hepatoma cells was loaded at 18 degrees C with low density lipoproteins (LDL) labeled with [3H]cholesteryl linoleate, and the label then was chased at 37 degrees C. The hydrolysis of the accumulated ester proceeded linearly for several hours. Almost all of the released [3H]cholesterol moved to the plasma membrane rapidly and without a discernable lag. In contrast, the re-esterification in the ER of the released [3H]cholesterol showed a characteristic lag of 0.5-1 h. These data are inconsistent with direct cholesterol transfer from lysosomes to ER; rather, they suggest movement through the plasma membrane. Furthermore, we found that progesterone, imipramine and 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one (U18666A) strongly inhibited the re-esterification of lysosomal cholesterol in the ER. However, contrary to previous reports, they did not block transfer of [3H]cholesterol from lysosomes to the cell surface. Therefore, the site of action of these agents was not at the lysosomes. We suggest instead that their known ability to block cholesterol movement from the plasma membrane to the ER accounts for the inhibition of lysosomal cholesterol esterification. These findings are consistent with the hypothesis that cholesterol released from lysosomes passes through the plasma membrane on its way to the ER rather than proceeding there directly. As a result, ingested cholesterol is subject to the same homeostatic regulation as the bulk of cell cholesterol, which is located in the plasma membrane.
Many elegant dinuclear transition metal and lanthanide complexes that efficiently hydrolyze phosphate esters including RNA and DNA have been reported recently. In most cases, the dinuclear complexes are much more reactive than the corresponding mononuclear metal complexes. Furthermore, structural and kinetic data indicate that substantial rate acceleration for phosphate diester cleavage is obtained by bridging the dinuclear metal centers with the two phosphoryl oxygens. Interestingly, such bridging structures have recently been implicated in several metalloenzyme catalyzed phosphate hydrolyses.
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The approach of somatic cell and molecular genetics for the study of intracellular regulation of cholesterol metabolism has blossomed in recent years. This review lists all the Chinese hamster ovary cell mutants involved in cholesterol metabolism. In addition, it summarizes the characteristics of mutants involved in three different processes: (1) sequential cleavage of the membrane-bound sterol regulatory element-binding proteins; (2) cholesterol esterification; and (3) intracellular cholesterol transport from the lysosome/endosome.
OBJECTIVE: To investigate the protective efficacy of a pool of denatured membrane protein antigens of Mycoplasma hyopneumoniae (J strain) in the molecular size range 70 to 85 kDa (F3 antigen) in combination with adjuvants for pigs challenged with M hyopneumoniae. DESIGN: A vaccine efficacy experiment with assessment of serum and respiratory tract antibody responses. PROCEDURE: F3 antigens were emulsified with five different adjuvants. To groups of three pigs per vaccine, four vaccines were given by intramuscular injection, and two vaccines, including one of those given intramuscularly, were given by intraperitoneal injection. RESULTS: Compared to six unvaccinated pigs, animals vaccinated with F3 antigen displayed significantly reduced pneumonia (54% reduction in mean lung score) following experimental challenge. Analysis of post-vaccination, pre-challenge IgG and IgA ELISA antibody absorbances in serum and respiratory tract washings revealed no correlation with lung score. Six weeks after challenge, pigs previously vaccinated intramuscularly mostly demonstrated greater IgG and IgA responses in respiratory tract washings, and greater IgG serum antibody responses, than those vaccinated by intraperitoneal injection. CONCLUSION: Pigs vaccinated with M hyponeumoniae antigens in the molecular size range of 70 to 85 kDa showed a significant reduction in lung lesions compared with unvaccinated control animals after experimental challenge. IgG and IgA antibody concentrations in serum and respiratory tract washings after vaccination do not provide a useful prognostic indicator of protection from enzootic pneumonia.
Mycoplasma hyopneumoniae is the etiological agent of porcine enzootic pneumonia, a commercially expensive respiratory disease of swine. Salmonella typhimurium SL3261 was used as a live carrier of plasmid pKF1, which encodes a 15-kDa recombinant M. hyopneumoniae protein. This expressed recombinant protein consists of the carboxy-terminal 11 kDa of a 42-kDa M. hyopneumoniae NrdF ribonucleotide reductase R2 subunit protein. Rabbit anti-15-kDa serum was able to inhibit the growth of viable M. hyopneumoniae J in vitro. When used as a live oral vaccine, S. typhimurium SL3261(pKF1) induced a significant secretory immunoglobulin A immune response in the lungs of mice orally immunized against the M. hyopneumoniae antigen. Utilization of live oral vaccines expressing potentially protective M. hyopneumoniae proteins, such as the NrdF antigen, which can stimulate a lung mucosal response against surface-accessible proteins may provide a cost-effective alternative to the present control strategies used for porcine enzootic pneumonia.
The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing State-based telephone survey of adults, administered through State health departments. The survey estimates health status and the prevalence of various risk factors among respondents, who include both fee-for-service and managed care Medicare beneficiaries. In this article the authors present an overview of the BRFSS and report 1995 regional results among respondents who were 65 years of age or over and who had health insurance. The advantages and disadvantages of using the BRFSS as a tool to monitor beneficiary health status and risk factors are also discussed.
Most medically important bacterial and viral pathogens gain entry into the body either via the skin or a mucosal surface. Vaccination provides a viable and cost-effective strategy for the prevention of such diseases and it has always been a principal aim with vaccinologists, to be able to promote simultaneously, protective immune responses both systemically and at mucosal surfaces. The paradigm that mucosal immunity is best stimulated by exposure to antigen via a mucosal route simply because inductive sites such as Peyer's patches and bronchial associated lymphoid tissues are located in the mucosal epithelium, has promoted a plethora of immunizing strategies aimed at delivering both antigen and adjuvant to mucosal surfaces. We have developed a novel adjuvant system capable of intradermal delivery of antigens complexed in an ISCOSOME delivery vehicle. This adjuvant, referred to as a skin and mucosal adjuvant or SAMA4, was efficacious in eliciting both systemic and mucosal IgG and IgA antibodies in sheep, pigs and mice. SAMA4 does not induce granulomatous lesions at the site of vaccine delivery and can be used to deliver adjuvanted antigens by other routes including intranasal, oral and intravaginal. Using ovalbumin as a test antigen, intradermally delivered ovalbumin-SAMA4 complexes was found to be very effective in promoting a cytotoxic T cell response. Attempts to dissect the mode of action of SAMA4 by flow cytometric analysis of lymphocyte populations from the spleen, lung, liver and thymus revealed an effect of route of vaccine delivery upon the composition of specific lymphocyte subsets in these various organ compartments. From this, it can be inferred that SAMA4 induced a route-dependent re-mobilization and alteration in lymphocyte trafficking patterns. Other mucosal adjuvants such as cholera toxin B and microspheres, when injected intradermally, tended to promote primarily, an IgG and not an IgA response against hte carrier antigen.
A Mycoplasma hyopneumoniae clone bank was screened with hyperimmune pig serum. One clone exhibited sequence homology to the prokaryotic R2 subunit of ribonucleotide reductase and was expressed as an 11-kDa protein fused to beta-galactosidase. The vaccine potential of the fusion protein was assessed in pig trials. Following experimental challenge with a virulent isolate of M. hyopneumoniae, gross lung pathology (mean Goodwin lung score) of vaccinated animals, irrespective of adjuvant treatment, was significantly reduced compared with that of control unvaccinated pigs (P < 0.05).
PURPOSE: A prospective, multicenter, randomized study was done to test the hypothesis that neoadjuvant androgen withdrawal decreases the incidence of positive margins following radical prostatectomy for localized prostate cancer. MATERIALS AND METHODS: Observations were made of 213 patients randomized to undergo radical prostatectomy alone (101) or to receive a 12-week course of 300 mg. cyproterone acetate daily followed by surgery (112). Groups were similar at baseline in terms of clinical stage, serum prostate specific antigen and Gleason score. Of 192 patients available for efficacy analysis 9 had stage T1b, 8 stage T1c, 63 stage T2a, 36 stage T2b and 76 stage T2c disease. RESULTS: One or more positive surgical margins were found in 59 of 91 patients (64.8%) in the surgery only group compared to 28 of 101 (27.7%) in the cyproterone acetate group (p = 0.001). Patients who received preoperative therapy had a statistically significantly lower rate of apical margin involvement than those who did not (17.8 versus 47.8%, respectively, p < 0.0001). There was no statistically significant difference in surgical (p = 0.8645) or postoperative (p = 0.173) complications between the 2 groups. CONCLUSIONS: Neoadjuvant androgen withdrawal with a 12-week course of 300 mg. cyproterone acetate daily results in a lower rate of positive margins without adversely affecting postoperative recovery. The impact on patient survival will be determined by long-term followup.