Biomedical subjects
L Farrell
Publications and source records attributed to L Farrell.
We won't forget you, bill
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No cure for the 'flu.
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Structural analysis of human immunodeficiency virus type 1 Gag protein interactions, using cysteine-specific reagents.
We have examined structural interactions of Gag proteins in human immunodeficiency virus type 1 (HIV-1) particles by utilizing cysteine mutagenesis and cysteine-specific modifying reagents. In immature protease-minus but otherwise wild-type (wt) particles, precursor Pr55Gag proteins did not form intermolecular cystines naturally but could be cross-linked at cysteines, and cross-linking appeared to occur across nucleocapsid (NC) domains. Capsid (CA) proteins in wt mature viruses possess cysteines near their carboxy termini at gag codons 330 and 350, but these residues are not involved in natural covalent intermolecular bonds, nor can they be intermolecularly cross-linked by using the membrane-permeable cross-linker bis-maleimido hexane. The cysteine at gag codon 350 (C-350) is highly reactive to thiol-specific modifying reagents, while the one at codon 330 (C-330) appears considerably less reactive, even in the presence of ionic detergent. These results suggest that the HIV-1 CA C terminus forms an unusually stable conformation. Mutagenesis of C-350 to a serine residue in the mutant C350S (C-350 changed to serine) virtually eliminated particle assembly, attesting to the importance of this region. We also examined a C330S mutant, as well as mutants in which cysteines were created midway through the capsid domain or in the C-terminal section of the major homology region. All such mutants appeared wt on the basis of biochemical assays but showed greatly reduced infectivities, indicative of a postassembly, postprocessing replicative block. Interestingly, capsid proteins of mature major homology region mutant particles could be cysteine cross-linked, implying either that these mutations permit cross-linking of the native C-terminal CA cysteines or that major homology regions on neighbor capsid proteins are in close proximity in mature virions.
Resuscitation with increasing doses of diaspirin crosslinked hemoglobin in swine.
This study examined the effects of administering 0.5, 4, 10, and 30 mL/kg of Diaspirin Crosslinked Hemoglobin (DCLHb) in a swine model of non-lethal hemorrhagic shock. Thirty unanesthetized animals were bled (30 mL/kg, 1 mL/kg/min) and either recovered without treatment (Untreated Control, UC) or infused with 10 g/dL DCLHb (0.5, 4.0, 10 or 30 mL/kg at 1 mL/kg/min) or Lactated Ringer (LR, 90 mL/kg at 3 mL/kg/min). DCLHb caused dose-related increases in MAP. Both the 10 and 30 mL/kg doses of DCLHb increased MAP more than UC or LR. Lower doses of DCLHb and LR had effects on MAP similar to UC. After hemorrhage, CO increased in all groups. The effect of DCLHb on CO was dose-related. Only LR and 30 mL/kg of DCLHb transiently (through 90 min) increased CO more than UC. CO in animals given lower doses of DCLHb was comparable to UC. DCLHb (10 and 30 mL/kg) improved base excess and lactate concentrations, two indices of global perfusion, more rapidly and to a greater extent than either UC or LR. In this swine model of hemorrhage, even small doses of DCLHb exerted measurable beneficial effects on blood pressure and perfusion.
Euthanasia debate. The choice to live or die should remain to the end.
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Role of the N-terminal 118 amino acids in the processing of the rat renal mitochondrial glutaminase precursor.
Rat renal mitochondrial glutaminase (GA) is synthesized as a 74-kDa cytosolic precursor that is translocated into mitochondria and processed via a 72-kDa intermediate to yield a 3:1 ratio of mature 66- and 68-kDa subunits, respectively. The 66-kDa subunit is derived by removal of a 72-amino-acid presequence. The structural determinants necessary for translocation and proteolytic processing were further delineated by characterizing the processing of different chimeric constructs formed by fusing various segments of the N-terminal sequence of the GA precursor to chloramphenicol acetyl transferase (CAT). GA1-118 CAT is translocated and processed in isolated rat liver mitochondria or cleaved by purified mitochondrial processing peptidase (MPP) to yield an intermediate peptide and two mature subunits that are analogous to the products of processing of the GA precursor. The two reactions also occur with kinetics which are similar to those observed for processing of the GA precursor. Thus, all of the information required for the translocation and synthesis of the mature subunits of GA reside in the N-terminal 118 amino acids of the GA precursor. In contrast, GA1-72 CAT, a construct that contains the GA presequence fused to CAT, is apparently translocated and processed less efficiently. It yields only two peptides that are analogous to the intermediate and 68 kDa forms of GA. In addition, GA1-31 CAT associates with mitochondria but is not proteolytically processed and GA1-31,73-118 CAT is slowly translocated and processed to a single peptide that is analogous to the 66 kDa form of GA. The latter results suggest that the MPP cleavage reactions which yield the GA intermediate and the 66-kDa subunit depend primarily on information that is present C-terminal to the respective sites of cleavage.
Resuscitation with Diaspirin Crosslinked Hemoglobin in a pig model of hemorrhagic shock.
The efficacy of Diaspirin Crosslinked Hemoglobin (DCLHb) as a resuscitative fluid in hemorrhagic shock was compared to another colloid solution (human serum albumin, HSA) and a crystalloid solution (Lactated Ringer's, LR). Hemorrhage (35 mL/kg) was followed by isovolemic exchange then volume replacement. This modeled the clinical situation where resuscitative fluids are administered prior to stopping the hemorrhage, the hemorrhage is stopped, then blood volume is restored. Four combinations of resuscitative fluids were evaluated during isovolemic exchange: volume replacement: DCLHb:LR, HSA:LR, HSA:HSA and LR:LR. All doses were 10 mL/kg:35 mL/kg except LR:LR which was 10 mL/kg:125 mL/kg. Volume replacement was followed by a stabilization period and reinfusion of shed blood (35 mL/kg). MAP increased most rapidly using DCLHb (from 48 to 102 mmHg after 10 min of isovolemic exchange) and was maintained for at least 2 hours. Arterial oxygen content and acid-base status were significantly improved after resuscitation with DCLHb:LR vs. other resuscitative therapies. In conclusion, DCLHb:LR was an effective resuscitative therapy in treatment of hemorrhagic shock.
The influence of atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies. The V-HeFT VA Cooperative Studies Group.
BACKGROUND: Atrial fibrillation occurs commonly in heart failure; however, its importance in terms of prognosis is controversial. METHODS AND RESULTS: We assessed the relation of atrial fibrillation on first Holter monitor to morbidity and mortality in mild to moderate heart failure in 632 patients in the Veterans Affairs Vasodilator-Heart Failure Trial (V-HeFT) I and 795 patients in V-HeFT II: Ninety-nine patients in atrial fibrillation and 533 patients in sinus rhythm were followed for a mean of 2.5 years (range, 6 months to 5.7 years) in V-HeFT I; 107 patients in atrial fibrillation and 688 patients in sinus rhythm in V-HeFT II were followed for a mean of 2.5 years (range, 6 months to 5.0 years). V-HeFT I compared treatment with prazosin, hydralazine-isosorbide dinitrate, and placebo, whereas V-HeFT II compared hydralazine-isosorbide dinitrate with enalapril. Follow-up evaluations included serial Holter monitors, serial metabolic exercise testing, hospitalization data, and clinical examinations. In V-HeFT I, cumulative mortality at 2 years was 0.34 for patients with atrial fibrillation and 0.30 for patients in sinus rhythm (p = 0.25). Overall cumulative mortality was 0.54 for atrial fibrillation patients and 0.64 for sinus rhythm patients (p = 0.86). In V-HeFT II, cumulative mortality at 2 years was 0.20 for patients with atrial fibrillation and 0.21 for patients with sinus rhythm (p = 0.68), and overall cumulative mortality was 0.46 for atrial fibrillation patients and 0.52 for those in sinus rhythm (p < 0.46). Sudden death was not increased with atrial fibrillation in V-HeFT I patients (p = 0.64) or in V-HeFT II (p = 0.68). By multivariate analysis, the relative mortality risk for atrial fibrillation was 0.95 in V-HeFT I and 0.76 in V-HeFT II: Metabolic exercise testing, showed no significant difference in mean change in peak oxygen consumption between patients with atrial fibrillation and those with sinus rhythm in V-HeFT I and a slight decrease late in V-HeFT II: Hospitalization rate for heart failure was not increased in either study. The embolic event rate was not increased for atrial fibrillation patients: 3% versus 4.9% of patients in sinus rhythm (p = 0.41) in V-HeFT I and 4.0% versus 6.0% in V-HeFT II patients (p = 0.44). A secondary analysis compared mortality of patients in atrial fibrillation with that of patients in sinus rhythm on all Holters: Mortality was not increased overall (p = 0.72 in V-HeFT I and p = 0.35 in V-HeFT II). CONCLUSIONS: Atrial fibrillation does not increase major morbidity or mortality in mild to moderate heart failure.
Evaluation by patients with heart failure of the effects of enalapril compared with hydralazine plus isosorbide dinitrate on quality of life. V-HeFT II. The V-HeFT VA Cooperative Studies Group.
BACKGROUND: Two new questionnaires concerning the quality of life of patients with heart failure were used in a randomized, controlled trial to determine if the patients' perceptions of the effects of enalapril on their daily activities and sense of well-being were different from those of a group treated with hydralazine and isosorbide dinitrate. METHODS AND RESULTS: The questionnaires were completed at baseline and at 3 months, 6 months, and subsequently every 6 months during follow-up, which averaged 2.5 years (range, 0.5-5.7 years). Data from the questionnaires were reliable as indicated by correlation coefficients between repeated baseline scores of 0.88 and 0.87. Both treatment groups showed a progressive deterioration in quality of life as measured by both questionnaires. The questionnaire scores of the two treatment groups were not significantly different at any follow-up visit. Furthermore, there were no differences between treatments among subgroups defined by baseline questionnaire scores, peak oxygen consumption, ejection fraction, previous vasodilator use, and plasma norepinephrine concentration. CONCLUSIONS: Although several factors may limit the generalization of these results, the lack of a difference with regard to patients' quality of life is an important consideration for the evaluation of the relative therapeutic efficacy of these vasodilators.
Incidence of thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative Studies Group.
BACKGROUND: The incidence of thromboembolism and the benefit of anticoagulation in congestive heart failure are controversial. METHODS AND RESULTS: The data base provided by the Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT I and II) was examined retrospectively to address these issues. In V-HeFT I, 642 men with heart failure were followed an average of 2.28 years, providing 1,464 patient-years of follow-up. In V-HeFT II, 804 men were followed an average of 2.56 years, with 2,061 patient-years of follow-up. Mean left ventricular ejection fraction was 30% in V-HeFT I and 29% in V-HeFT II: Functional capacity was at the interface of classes II and III with a peak exercise oxygen consumption of 14.7 mL.kg-1 x min-1 in V-HeFT I and 13.7 mL.kg-1 x min-1 in V-HeFT II: Warfarin and antiplatelet agents were administered at the discretion of individual investigators. The incidence of all thromboembolic events during 1,068 patient-years without warfarin in V-HeFT I was 2.7/100 patient-years and during 1,188 patient-years in V-HeFT II was 2.1/100 patient-years and was not reduced in patients treated with warfarin. Patients experiencing events had a lower peak exercise oxygen consumption (p < 0.03 in V-HeFT I and p < 0.001 in V-HeFT II) and a lower mean ejection fraction (p = 0.10 in V-HeFT I and p = 0.07 in V-HeFT II). Atrial fibrillation was not associated with an increased risk of thromboembolic events. CONCLUSIONS: The incidence of thromboembolism and stroke in class II or III congestive heart failure is not high and may not be significantly reduced with warfarin treatment. Routine use of anticoagulants in patients with heart failure may not be justified.