How growth factors help chronic wounds heal.
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Becaplermin↗
Biomedical subjects
M Barry
Publications and source records attributed to M Barry.
Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis.
Two open-label studies assessed the pharmacokinetics of single orally administered doses of 40 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CL(CR)) normalized by body surface area (ml/min/1.73 m(2)): mild (CL(CR), 60 to 80), moderate (30 to 50), and severe (</=20) renal impairment. Five healthy subjects (CL(CR) >/= 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC(0-infinity)) increased nonlinearly with declining renal function: 1,864, 2,215, 3,609, and 5,928 ng. h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively (P = 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing >/=60 kg: CL(CR) of >50 ml/min/1.73 m(2), 40 mg every 12 h; CL(CR) of 21 to 50 ml/min/1. 73 m(2), 20 mg every 12 h; and CL(CR) of 10 to 20 ml/min/1.73 m(2), 20 mg every 24 h. For subjects weighing <60 kg, the proposed doses were 30, 15, and 15 mg, respectively, with the same dosing intervals specified above. In a second study (study II), 12 subjects with end-stage renal disease requiring hemodialysis three times a week were enrolled in a randomized, open-label crossover study (dialysis 2 h after dosing and lasting 4 h or dosing without dialysis). There were no statistically significant differences for AUC(0-infinity), AUC(2-6), time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.
Administration, Oral↗
Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid.
Cytotoxic T lymphocytes (CTL) can trigger an apoptotic signal through the Fas receptor or by the exocytosis of granzyme B and perforin. Caspase activation is an important component of both pathways. Granzyme B, a serine proteinase contained in granules, has been shown to proteolytically process and activate members of the caspase family in vitro. In order to gain an understanding of the contributions of caspases 8 and 3 during granule-induced apoptosis in intact cells, we have used target cells that either stably express the rabbitpox virus-encoded caspase inhibitor SPI-2 or are devoid of caspase 3. The overexpression of SPI-2 in target cells significantly inhibited DNA fragmentation, phosphatidylserine externalization, and mitochondrial disruption during Fas-mediated cell death. In contrast, SPI-2 expression in target cells provided no protection against granzyme-mediated apoptosis, mitochondrial collapse, or cytolysis, leading us to conclude that SPI-2-inhibited caspases are not an essential requirement for the granzyme pathway. Caspase 3-deficient MCF-7 cells were found to be resistant to CTL-mediated DNA fragmentation but not to CTL-mediated cytolysis and loss of the mitochondrial inner membrane potential. Furthermore, we demonstrate that granzyme B directly cleaves the proapoptotic molecule Bid, bypassing the need for caspase 8 activation of Bid. These results provide evidence for a two-pronged strategy for mediating target cell destruction and provide evidence of a direct link between granzyme B activity, Bid cleavage, and caspase 3 activation in whole cells.
Apoptosis↗
Measuring leg muscle and fat mass in humans: comparison of CT and dual-energy X-ray absorptiometry.
Dual-energy X-ray absorptiometry (DEXA) is reported to be inferior to computed tomography (CT) to measure changes in appendicular soft tissue composition. We compared CT- and DEXA-measured thigh muscle and fat mass to evaluate the random and systematic discrepancies between these two methods. Thigh skeletal muscle area (single-slice CT) was suboptimally (r(2) = 0.74, P < 0.0001) related to DEXA-measured thigh fat-free mass (FFM). In contrast, thigh muscle and adipose tissue volumes (multislice CT) were highly related to DEXA-measured thigh FFM and fat (both r(2) = 0.96, P < 0.0001). DEXA-measured leg fat was significantly less than multislice-CT-measured leg adipose tissue volume, whereas multislice-CT-measured leg muscle mass was less (P < 0.0001) than DEXA-measured leg FFM. The systematic discrepancies between the two approaches were consistent with the 10-15% nonfat components of adipose tissue. In conclusion, CT and DEXA measures of appendicular soft tissue are highly related. Systematic differences between DEXA and CT likely relate to the underlying principles of the techniques.
Absorptiometry, Photon↗
Taurine prevents interleukin-2-induced acute lung injury in rats.
BACKGROUND: The therapeutic efficacy of interleukin-2 (IL-2) has been limited by a dose-dependent vascular leak syndrome. This may be related to neutrophil-mediated endothelial injury. Taurine has been shown to decrease this injury in vitro. This study investigates the role of taurine in preventing IL-2-induced lung injury, and the role of neutrophil-endothelial interactions in mediating this injury. METHODS: Study 1: Sprague-Dawley rats (n = 12/groups) were randomised to controls, IL-2-treated (1 x 10(6) units), and IL-2-treated with taurine (4% solution, orally for 48 h prior to IL-2 therapy). Lung injury was measured by extravascular lung water (wet/dry weight) and bronchoalveolar lavage protein concentration. Neutrophil infiltration was evaluated by measuring myeloperoxidase activity and bronchoalveolar lavage neutrophil concentration. Study 2: Rats (n = 10/group) were randomised into the same groups as study 1. Neutrophil-endothelial interactions in mesenteric vessels were assessed by intravital microscopy at half-hourly intervals. RESULTS: Taurine reduced IL-2-induced acute lung injury as reflected by a decrease in wet-to-dry lung weight ratio from 7.2 +/- 0.5 in the IL-2 group to 4.7 +/- 0.3 in the taurine group (p < 0.05), and a decrease in bronchoalveolar neutrophil concentration from 823 +/- 19.5 in the IL-2 group to 538 +/- 18 in the taurine group (p < 0.05). Intravital microscopy demonstrated that IL-2 increased leucocyte adhesion and migration in mesenteric vessels, and that this was significantly reduced by taurine. CONCLUSION: These data suggest that taurine prevents IL-2-induced tissue injury in part by decreasing neutrophil-endothelial interactions.
Acute Disease↗
[Subacute sclerosing panencephalitis. Study of 32 cases observed in Conakry, Guinea].
Thirty two cases of subacute sclerosing panencephalitis were reported. Diagnosis was based on epidemiological, clinical and electroencephalographic data; myoclonies and alterations of intellectual functions were the most frequent symptoms.
Cerebrospinal Fluid Proteins↗
Management guidelines for hypotensive pelvic fracture patients.
Pelvic fractures are common in blunt trauma patients and are often associated with other system injuries. Most studies describe the type of pelvic fractures and classify them by the forces creating the injury. Mortality from these fractures is due most often to other system injuries or to hemorrhage. Mortality ranges from 5 to 20 per cent depending on complexity and number of systems injured. We studied 692 cases of pelvic fractures and analyzed the seriously ill patients. They were identified by blood pressure (BP) less than 90 systolic on presentation to the trauma room and having a complex pelvic fracture. The management of these patients was by a protocol used by a group of eight trauma surgeons. This group of 75 hypotensive pelvic fracture patients were analyzed to identify significant factors in their management that predicted mortality. Patients with base excess (BE) values < or =-5 were significantly more likely to die (P<0.05). Patients with BP < or =90 on leaving the trauma room had a significantly higher mortality (P<0.01). Injury Severity Score predicted mortality and can be useful as a tool for quality assurance and process improvement. The early operative intervention to fix associated fractures within 24 hours was not detrimental to patient outcome. Overall mortality in this very sick population was 14.7 per cent. Emergent angiography was used successfully on 14 patients. Seven patients died of continued bleeding. The most important management guidelines for these seriously injured, complex patients are: 1) resuscitate with BE used as a monitor; 2) keep patient blood volume as close to normal as possible; 3) use BP, BE, and ISS to evaluate management of these patients.
Adolescent↗
Drug reimbursement in Ireland.
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Cost Savings↗
Granzyme B-induced loss of mitochondrial inner membrane potential (Delta Psi m) and cytochrome c release are caspase independent.
CTLs kill targets by inducing them to die through apoptosis. A number of morphological and biochemical events are now recognized as characteristic features of the apoptotic program. Among these, the disruption of the inner mitochondrial transmembrane potential (Delta Psi m) and the release of cytochrome c into the cytoplasm appear to be early events in many systems, leading to the activation of caspase-3 and, subsequently, nuclear apoptosis. We show here that, in Jurkat targets treated in vitro with purified granzyme B and perforin or granzyme B and adenovirus, Delta Psi m collapse, reactive oxygen species production, and cytochrome c release from mitochondria were observed. Loss of Delta Psi m was also detected in an in vivo system where green fluorescent protein-expressing targets were attacked by a cytotoxic T cell line that kills predominantly through the granzyme pathway. DNA fragmentation, phosphatidylserine externalization, and reactive oxygen species production were inhibited in the presence of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (zDEVD-fmk) in our in vitro system. Importantly, in either the in vitro or in vivo systems, these inhibitors at concentrations up to 100 microM did not prevent Delta Psi m collapse. In addition, cytochrome c release was observed in the in vitro system in the absence or presence of zVAD-fmk. Thus the granzyme B-dependent killing pathway in Jurkat targets involves mitochondrial alterations that occur independently of caspases.
Adenoviruses, Human↗
Role of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and viral pathogenesis.
The purpose of this study was to investigate the significance of the C-terminal RDEL motif of the myxoma virus M-T4 protein in terms of apoptosis regulation and role in viral virulence. To accomplish this, a recombinant myxoma virus was created in which the C-terminal RDEL motif of M-T4 was deleted and a selectable marker (Ecogpt) was inserted immediately downstream. We hypothesized that removal of the RDEL motif from M-T4 would alter the subcellular localization of the protein and provide insight into its antiapoptotic role. Surprisingly, removal of the RDEL motif from M-T4 did not affect localization of the protein within the endoplasmic reticulum (ER), but it did reduce the stability of the mutant protein. Pulse-chase immunoprecipitation and endoglycosidase H analysis coupled with confocal fluorescent light microscopy demonstrated that the M-T4 RDEL(-) mutant protein is retained in the ER like wildtype M-T4 and suggests that the C-terminal RDEL motif is not the sole determinant for M-T4 localization to the ER. Infection of cultured rabbit lymphocytes with the M-T4 RDEL(-) mutant virus results in an intermediate apoptosis phenotype compared with the wildtype and M-T4 knockout mutant viruses. A novel myxomatosis phenotype was observed in European rabbits when infected with the recombinant M-T4 RDEL(-) mutant virus. Rabbits infected with the M-T4 RDEL(-) virus on day 9 postinfection exhibited an exacerbated edematous and inflammatory response at secondary sites of infections, particularly the ears. Our results indicate that the C-terminal RDEL motif may not be solely responsible for retention of M-T4 to the ER and that M-T4 may have a dual function in protecting infected lymphocytes from apoptosis and in modulating the inflammatory response to virus infection.
Amino Acid Motifs↗
Decision aids for patients facing health treatment or screening decisions: systematic review.
OBJECTIVE: To conduct a systematic review of randomised trials of patient decision aids in improving decision making and outcomes. DESIGN: We included randomised trials of interventions providing structured, detailed, and specific information on treatment or screening options and outcomes to aid decision making. Two reviewers independently screened and extracted data on several evaluation criteria. Results were pooled by using weighted mean differences and relative risks. RESULTS: 17 studies met the inclusion criteria. Compared with the controls, decision aids produced higher knowledge scores (weighted mean difference=19/100, 95% confidence interval 14 to 25); lower decisional conflict scores (weighted mean difference=-0.3/5, -0.4 to -0.1); more active patient participation in decision making (relative risk = 2.27, 95% confidence interval 1. 3 to 4); and no differences in anxiety, satisfaction with decisions (weighted mean difference=0.6/100, -3 to 4), or satisfaction with the decision making process (2/100,-3 to 7). Decision aids had a variable effect on decisions. When complex decision aids were compared with simpler versions, they were better at reducing decisional conflict, improved knowledge marginally, but did not affect satisfaction. CONCLUSIONS: Decision aids improve knowledge, reduce decisional conflict, and stimulate patients to be more active in decision making without increasing their anxiety. Decision aids have little effect on satisfaction and a variable effect on decisions. The effects on outcomes of decisions (persistence with choice, quality of life) remain uncertain.
Choice Behavior↗
Endosomal/lysosomal retention and degradation of major histocompatibility complex class I molecules is induced by myxoma virus.
The highly immunosuppressive leporipoxvirus myxoma, previously was shown to promote the loss of cell surface class I major histocompatibility complex (MHC I) molecules. Here, we show that myxoma virus induces the loss of both cell surface and intracellular post-Golgi, beta(2)-microglobulin-associated MHC I. Myxoma-induced loss of these MHC I molecules is abrogated by vacuolar ATPase inhibitors, NH(4)Cl, and leupeptin. Furthermore, immunofluorescence microscopic studies reveal that in myxoma-infected cells, beta(2)-microglobulin-associated MHC I accumulates in Lamp-1(+) vesicular structures, suggesting that myxoma virus targets MHC I for degradation in late endosomes and/or lysosomes. These events are regulated by early gene product or products because they occur unabated in cells infected with myxoma virus in the presence of cytosine arabinoside, an inhibitor of DNA synthesis. Studies with baby green monkey kidney cells transfected with wild-type and tail-less forms of a mouse MHC I molecule, H-2L(d), indicate that the MHC I cytoplasmic tail is required for myxoma-induced localization in Lamp-1(+) organelles. Myxoma-induced endocytosis and degradation of MHC I may provide the virus with a means of dispensing with cell surface MHC I molecules that were loaded with peptides derived from viral proteins synthesized early in infection.
Animals↗
Hydroxyurea-induced neurotoxicity in HIV disease.
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Adult↗
Primaquine prophylaxis against malaria.
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Antimalarials↗
Vitamin C reduces ischaemia-reperfusion-induced acute lung injury.
OBJECTIVES: to evaluate vitamin C supplementation in the prevention of ischaemia-reperfusion (I-R) induced acute lung injury. DESIGN: Sprague-Dawley rats (n =6/group) were randomised into Control, I-R and I-R pretreated with vitamin C (3.3 g over 5 days). Ischaemia-reperfusion injury was induced by 30 minutes infrarenal aortic cross-clamping and 120 minutes reperfusion. METHODS: pulmonary microvascular injury was measured by broncho-alveolar lavage protein concentration, pulmonary neutrophil infiltration by tissue myeloperoxidase activity and bronchoalveolar lavage neutrophil counts. In a second experiment (n =5/group) neutrophil respiratory burst activity was measured in Control and vitamin C groups. RESULTS: ischaemia-reperfusion resulted in a significant increase in both microvascular leakage and pulmonary neutrophil infiltration as measured by bronchoalveolar lavage protein concentration and pulmonary myeloperoxidase activity respectively. Pretreatment with vitamin C significantly attenuated both microvascular leakage and neutrophil infiltration. Neutrophil respiratory burst activity was significantly reduced in the vitamin C group (13.02 m.c.f.+/-0.3) compared with Control (19.04 m.c.f.+/-1. 9),p <0.02. CONCLUSION: these data suggest that oral vitamin C therapy protects against ischaemia-reperfusion-induced acute lung injury, possibly by attenuating neutrophil respiratory burst activity.
Animals↗
Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection.
There are 3 groups of drugs available for the treatment of patients with HIV disease. These are the nucleoside reverse transcriptase inhibitors ('nucleoside analogues') [zidovudine, didanosine, zalcitabine, lamivudine and abacavir]; the non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz); and the protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and amprenavir). The preferred initial regimen should reduce and maintain plasma HIV RNA below the level of detection. Presently, the regimen of choice consists of 2 nucleoside analogues plus a protease inhibitor with high in vivo efficacy. An alternative combination consists of 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor. Drug interactions are one of the major problems associated with these multidrug regimens. Changes in plasma concentrations of the nucleoside analogues are unlikely to be of clinical relevance as drug effect is mainly dependent on the rate and extent of intracellular phosphorylation. Combinations of zidovudine plus stavudine, and probably zalcitabine plus lamivudine, should be avoided as competition for phosphorylating enzymes may occur. The antiviral efficacy of some nucleoside analogues, e.g. stavudine, may be compromised by prior treatment with other nucleosides (e.g. zidovudine). However, these data need to be clarified in further studies. It is unlikely that administration of other antiretrovirals will influence the activity of nucleoside analogues. Protease inhibitors are metabolised by hepatic cytochrome P450 (CYP) 3A4. Combination protease inhibitor therapy can result in drug interactions mediated by enzyme inhibition. Ritonavir is the most potent inhibitor, saquinavir the least. The protease inhibitors also interact with the non-nucleoside reverse transcriptase inhibitors. Nevirapine and efavirenz induce drug metabolising enzymes and may reduce plasma concentrations of protease inhibitors. A study in healthy volunteers showed that nelfinavir concentrations are increased by combination with efavirenz. Delavirdine inhibits drug metabolising enzymes and increases the plasma concentration of coadministered protease inhibitors. The nucleoside analogues would not be expected to interact with the protease inhibitors. Apart from the ability of didanosine to reduce the area under the concentration-time curve of delavirdine, there are no reports of clinically significant interactions of other antiretrovirals with the non-nucleoside reverse transcriptase inhibitors. Triple therapy is the current standard of care for patients with HIV disease. However, studies of quadruple therapy are already under way. Drug interactions are likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV.
Antiviral Agents↗
The International Health Program: the fifteen-year experience with Yale University's Internal Medicine Residency Program.
The purpose of this study was to assess the impact of international health electives on physicians-in-training. A retrospective study was conducted using an anonymous, self-administered mailed survey to internal medicine residents who trained at Yale from 1982 to 1996 based on their experience with our International Health Program (IHP). The response rate was 61%, with 96 completed surveys in the participant group and 96 completed surveys in the nonparticipant group. Participants were more likely than nonparticipants to care for patients on public assistance (77 versus 49; P < 0.001) and immigrant patients (41 versus 23; P = 0.006). Among residents who changed their career plans, participants (22) were more likely than nonparticipants (14) to switch from subspecialty medicine to general medicine (P = 0.02). Participants were significantly more likely to have a positive view of health care delivery in developing countries. Compared with nonparticipants (64), IHP participants (74) believed that the physical examination is under-used by physicians from the United States as a diagnostic skill (P = 0.03). International health experiences appeared to have an important impact on the decisions and attitudes of residents.
Adult↗