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Biomedical subjects

George Johnson

Publications and source records attributed to George Johnson.

8 recordsLinked to original sources
PubMed2005

Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.

BACKGROUND: Sudden death from cardiac causes remains a leading cause of death among patients with congestive heart failure (CHF). Treatment with amiodarone or an implantable cardioverter-defibrillator (ICD) has been proposed to improve the prognosis in such patients. METHODS: We randomly assigned 2521 patients with New York Heart Association (NYHA) class II or III CHF and a left ventricular ejection fraction (LVEF) of 35 percent or less to conventional therapy for CHF plus placebo (847 patients), conventional therapy plus amiodarone (845 patients), or conventional therapy plus a conservatively programmed, shock-only, single-lead ICD (829 patients). Placebo and amiodarone were administered in a double-blind fashion. The primary end point was death from any cause. RESULTS: The median LVEF in patients was 25 percent; 70 percent were in NYHA class II, and 30 percent were in class III CHF. The cause of CHF was ischemic in 52 percent and nonischemic in 48 percent. The median follow-up was 45.5 months. There were 244 deaths (29 percent) in the placebo group, 240 (28 percent) in the amiodarone group, and 182 (22 percent) in the ICD group. As compared with placebo, amiodarone was associated with a similar risk of death (hazard ratio, 1.06; 97.5 percent confidence interval, 0.86 to 1.30; P=0.53) and ICD therapy was associated with a decreased risk of death of 23 percent (0.77; 97.5 percent confidence interval, 0.62 to 0.96; P=0.007) and an absolute decrease in mortality of 7.2 percentage points after five years in the overall population. Results did not vary according to either ischemic or nonischemic causes of CHF, but they did vary according to the NYHA class. CONCLUSIONS: In patients with NYHA class II or III CHF and LVEF of 35 percent or less, amiodarone has no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduces overall mortality by 23 percent.

Aged↗
PubMed2005

The detection of genotoxic activity and the quantitative and qualitative assessment of the consequences of exposures.

A wide range of assays are now available which enable the effective detection of the mutagenic (the induction of gene and chromosomal changes) and more generally genotoxic (cellular interactions such as DNA lesion formation) activity of individual chemicals and mixtures. However, when genotoxic activity has been detected and human exposure occurs the critical questions relate to the qualitative and quantitative activity of the agent and the parameters such as routes of exposure, target organs and metabolism. Of major importance in hazard and risk estimation is the nature of the dose response relationship of each chemical and their potential interactions in mixtures. In this paper, we illustrate the methods available to produce quantitative and qualitative data in vitro using the micronucleus assay (as a measure of chromosomal structural and numerical mutations) and the HPRT assay (as a measure of induced gene and point mutations) and the current limitations (such as the large numbers of animals required) for obtaining such information in vivo. We recommend that in vivo studies should primarily focus upon confirmatory mechanistic analysis. For individual chemicals, profiles of the base changes induced can be obtained using the HPRT gene mutation assay and comparisons produced both in vitro and in vivo and thus allow identification of mechanistic differences between different modes of exposure.

Animals↗
PubMed2004

HIV vaccine candidates.

Amino acid sequences of the HIV-1 surface protein gp120 show extensive variations. Some of the peptide or DNA vaccines using the V3-loop of gp120 can trigger antibody production against some isolates of HIV, but these antibodies are not protective against other isolates. Thus, more conserved peptides from other HIV proteins have also been tried as vaccines. However, antibodies specific for these peptides cannot prevent the normal entry of HIV into the host cells, followed by integration of viral genomes into host chromosomes. Therefore, we decided to make a careful analysis of the aligned amino acid sequences of gp120 stored at Los Alamos National Laboratory. Unexpectedly, we found that there are several, not just one or two, segments of seven or more consecutive and nearly invariant amino acid residues present in the C1, C2 and C5 regions of this protein. Furthermore, four of these segments are physically close to each other in the known three-dimensional structure of the core portion of gp120. The remaining segments are not in that crystallized region; however, two of these are covalently linked with a disulfide bond. Therefore, we propose that these segments may be combined to form the basis of possible HIV vaccine candidates. In addition, it is necessary to incorporate the processed peptide from gp120 or other proteins and to understand the time-dependent effects of the highly variable loops of gp120 on triggering antibody production in human patients.

AIDS Vaccines↗
PubMed2003

Nelfinavir pharmacokinetics in stable human immunodeficiency virus-positive children: Pediatric AIDS Clinical Trials Group Protocol 377.

OBJECTIVE: Pharmacokinetic data obtained from children who have human immunodeficiency virus (HIV) infection are essential for the safe and effective use of antiretroviral agents in pediatric populations. The objective of this study was to assess the impact of body weight on the pharmacokinetic disposition of nelfinavir (NFV) in the absence and presence of nevirapine (NVP) and compare the pharmacokinetic profiles of twice-daily (BID) and three-times-daily (TID) NFV regimens. METHODS: This was an intensive pharmacokinetic substudy nested in a phase II, multicenter, randomized, open-label trial. Forty-five HIV-infected children receiving NFV 30 mg/kg TID and 6 HIV-infected children receiving NFV 55 mg/kg BID were enrolled in this study and assigned to 1 of 4 stavudine-containing regimens, 3 containing NFV and 2 containing NVP. Area under the plasma concentration-time curves from 0 to 8 hours (AUC(0-8 hours)) and from 0 to 12 hours (AUC(0-12 hours)) for the TID and BID regimens, respectively, were determined. For comparative purposes, the AUC(0-24 hours) was also calculated for each regimen. RESULTS: NFV exposure in the absence of NVP was decreased in children who were <25 kg compared with those who were >25 kg (a 2.6-fold difference in median AUC(0-8 hours)). NFV pharmacokinetics in the presence of NVP did not differ between the <25 kg and >25 kg groups. The AUC(0-24 hours) for children who were <30 kg and on NFV BID was comparable to the AUC(0-24 hours) for children who were >25 kg and on NFV TID but was 2.7-fold greater than AUC(0-24 hours) for children who were <25 kg and on NFV TID. CONCLUSIONS: NFV in the absence of NVP resulted in less than half the drug exposure in children who were <25 kg compared with children who were >25 kg. NFV dosed at 55 mg/kg BID in children who are <30 kg provides comparable exposure to that measured in children who are >25 kg and receiving NFV 30 mg/kg TID.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Mother-to-child transmission in the United States of subtypes D and A/G human immunodeficiency virus type 1.

In the United States and Western Europe, most human immunodeficiency virus type 1 (HIV-1) infections are caused by subtype B. We analyzed the nucleotide sequence of HIV-1 RNA in plasma samples from 141 children enrolled into PACTG 377, a comparative study of several antiretroviral therapy regimens. Phylogenetic analysis revealed that two children, both born in the United States, were infected with non-B subtypes that are most commonly found in Africa: one with subtype D and the other with circulating recombinant form CRF02, an A/G recombinant lineage. Viral load assays performed to monitor treatment response underestimated the levels of HIV-1 RNA in the child with the A/G recombinant. These cases demonstrate mother-to-child transmission of non-B subtypes of HIV-1 in the United States. Non-B subtypes should be considered in the management of HIV-1-infected pregnant women and children to optimize strategies to prevent and treat pediatric HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1.

The relative potency and tolerability of multidrug regimens used to treat infants and children infected with human immunodeficiency virus type 1 (HIV-1) are largely unknown. In Pediatric AIDS Clinical Trials Group (PACTG) Protocol 377, 181 infants and children were assigned to receive stavudine (d4T) plus nevirapine (NVP) and ritonavir (RTV); d4T plus lamivudine (3TC) and nelfinavir (NFV); d4T plus NVP and NFV; or d4T plus 3TC, NVP, and NFV. Eleven additional children received d4T and NVP plus NFV given twice daily. All subjects had not previously received protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and all had been immunologically stable while receiving reverse-transcriptase inhibitor therapy. After 48 weeks of therapy, 17 (41%) of 41 subjects receiving d4T-NVP-RTV, 13 (30%) of 44 receiving d4T-NVP-NFV, 21 (42%) of 50 receiving d4T-3TC and NFV (3 times daily), and 22 (52%) of 42 receiving d4T-3TC-NVP-NFV were still receiving their assigned therapy and had HIV-1 RNA suppression to </= 400 copies/mL. These regimens were similar in their drug activity, but the 4-drug regimen offered slightly more durable suppression of viremia.

Anti-HIV Agents↗