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William Lewis

Publications and source records attributed to William Lewis.

25 records · Page 2Linked to original sources
PubMed2003

Cocaine increases mortality and cardiac mass in a murine transgenic model of acquired immune deficiency syndrome.

Cardiac dysfunction in AIDS is an important problem. Cocaine is an epidemic associated with sudden death, cardiac dysfunction, and congestive heart failure. Cocaine use and HIV infection frequently coexist in the same patient, yet the combined impact of both is poorly understood. The present study uses cocaine treatment of an established murine AIDS transgenic model (NL4-3Delta gag/pol; TG) to define the combined effects of AIDS and cocaine on cardiac pathophysiology. To determine the effects of cocaine and HIV-1 proteins on mortality, wild-type and NL4-3Delta gag/pol mice received saline or cocaine via continuous infusion by Alzet osmotic pumps for 28 days (chronic). Acute cocaine administration (10 days; 40 mg/kg/day) was used to study the nonlethal effects of cocaine in TGs. Echocardiograms and single time point electrocardiograms were performed at the termination of each experiment. Hearts were removed and examined histopathologically. Chronic cocaine treatment (80 mg/kg/day; 28 days) markedly decreased median survival in both wild-type and TG; however, TG survival was significantly more decreased. In acute studies, TG echocardiographic changes included increased left ventricular mass and increased left ventricular fractional shortening compared with all cohorts. Electrocardiographic changes were absent among the groups. Histopathologically, perivascular fibrosis and interstitial fibrosis were evident in cocaine-treated TG. Data suggest that additive cardiac insults (from AIDS and cocaine) result in combined deleterious effects.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Evaluation and development of potentially better practices for the prevention of brain hemorrhage and ischemic brain injury in very low birth weight infants.

OBJECTIVE: Neonatal care providers from 5 institutions formed a multidisciplinary focus group with the purpose of identifying potentially better practices, the implementation of which would lead to a reduction in the incidence of intracranial hemorrhage and periventricular leukomalacia in very low birth weight infants. METHODS: Practices were analyzed, 4 benchmark neonatal intensive care units were identified and evaluated, and the literature was assessed using an evidence-based approach. The work was also reviewed by a nationally respected expert. RESULTS: Ten potentially better clinical practices were identified. In addition, variability in cranial ultrasound practice, related to both procedural process and interpretation, was identified as a confounding problem in evaluating quality. Using the same process, potentially better cranial ultrasound practices were also identified. CONCLUSIONS: Implementation of these practices will improve clinical outcomes as well as the reliability of sonogram interpretation, the basis for evaluating the quality of the team's work.

Benchmarking↗
PubMed2002

Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide.

Nucleoside reverse transcriptase inhibitors (NRTIs) have been used successfully to reduce acquired immunodeficiency syndrome mortality. However, the use of these compounds is associated with numerous tissue toxicities, including cardiomyopathy. These studies address the effects of NRTIs on vascular function. Functional assays of contraction and relaxation were performed on isolated mouse aorta segments obtained from FVB/n mice exposed to zidovudine (AZT), stavudine, or water for 35 days. AZT and stavudine treatment impaired sensitivity to endothelium-dependent relaxation by acetylcholine. Dihydroethidium staining revealed that AZT treatment was associated with an increase in superoxide levels. Pretreatment of AZT-treated vessels with tiron (1 mM), a free radical scavenger, restored endothelium-dependent relaxation in mice. In cellular preparations, electron spin resonance measurements revealed elevated superoxide in cultured endothelial cells exposed to AZT; elevation was dependent on the length of exposure. These results indicate that NRTIs impair endothelium-dependent relaxation by increasing superoxide levels and suggest that NRTI therapy contributes to cardiovascular complications in acquired immunodeficiency syndrome.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2002

Targeted myocardial transgenic expression of HIV Tat causes cardiomyopathy and mitochondrial damage.

Cardiac effects of human immunodeficiency virus (HIV) transactivator (Tat) are unclear, but Tat decreases liver glutathione (an important mitochondrial antioxidant) when ubiquitously expressed in transgenic mice (TG). With an alpha-myosin heavy chain promoter, Tat was selectively targeted to murine cardiac myocytes. One high-expression hemizygous ((+/-)Tat(high); 12 copies) and two low-expression ((+/-)Tat(lowA,B); 2-5 copies) TG lines were created. Cardiomyopathy was documented with increased left ventricle (LV) mass, ventricular expression of atrial natriuretic factor (ANF) mRNA, mitochondrial ultrastructural defects, and myocardial depletion of glutathione. In (+/-)Tat(high) TGs, normalized LV mass (determined echocardiographically) increased 46% (90 days), 134% (240 days), and 96% (365 days) compared with wild-type littermates (WT). LV fractional shortening was decreased to 28% (90 days), 27% (240 days), and 19% (365 days). (+/-)Tat(low) LV mass was unchanged ( or=210 days); however, profound mitochondrial destruction occurred in homozygous (+/+)Tat(high) hearts (10 days) and the pups died (14 days). Tat caused cardiac dysfunction in this TG and may impact on cardiomyopathy in acquired immunodeficiency syndrome.

Animals↗
PubMedDate not supplied

A brief overview of mechanisms of mitochondrial toxicity from NRTIs.

Nucleoside reverse transcriptase inhibitors (NRTIs) in combinations with other antiretrovirals (highly active antiretroviral therapy, HAART) are the cornerstones of AIDS therapy, turning HIV infection into a manageable clinical entity. Despite the initial positive impact of NRTIs, therapeutic experience revealed serious side effects that appeared to originate in the mitochondria and which ultimately manifested as dysfunction of that organelle. It may be reasonable to consider that as the AIDS epidemic continues and as survival with HIV infection is prolonged by treatment with HAART, long-term side effects of NRTIs may become increasingly common. This consideration may be underscored in children who are born to HIV-infected mothers who received NRTI therapy in utero during gestation. The long-term effect of that NRTI exposure in utero is not clear yet. This review examines some proposed mechanisms of NRTI mitochondrial toxicity, including genetic predisposition, defects in mitochondria DNA replication, the encompassing "DNA pol-gamma hypothesis," the relationship between mitochondrial nucleotide and NRTI pools, mitochondrial DNA mutation and dysfunction, and oxidative stresses related to HIV infection and NRTIs. Mechanisms of mitochondrial toxicity are reviewed with respect to key cell biological, pathological, and pharmacological events.

Animals↗
PubMedDate not supplied

Mitochondrial DNA replication, nucleoside reverse-transcriptase inhibitors, and AIDS cardiomyopathy.

Nucleoside reverse-transcriptase inhibitors (NRTIs) in combination with other antiretrovirals (HAART) are the cornerstones of current AIDS therapy, but extensive use brought mitochondrial side effects to light. Clinical experience, pharmacological, cell, and molecular biological evidence links altered mitochondrial (mt-) DNA replication to the toxicity of NRTIs in many tissues, and conversely, mtDNA replication defects and mtDNA depletion in target tissues are observed. Organ-specific pathological changes or diverse systemic effects result from and are frequently attributed to HAART in which NRTIs are included. The shared features of mtDNA depletion and energy depletion became key observations and related the clinical and in vivo experimental findings to inhibition of mtDNA replication by NRTI triphosphates in vitro. Subsequent to those findings, other observations suggested that mitochondrial energy deprivation is concomitant with or the result of mitochondrial oxidative stress in AIDS (from HIV, for example) or from NRTI therapy itself.

Acquired Immunodeficiency Syndrome↗