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Biomedical subjects

C Tierney

Publications and source records attributed to C Tierney.

18 recordsLinked to original sources
PubMed2003

Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) burden, CMV end-organ disease, and survival in subjects with advanced HIV infection (AIDS Clinical Trials Group Protocol 360).

We undertook a prospective study to analyze cytomegalovirus (CMV) end-organ disease (EOD) in subjects with advanced human immunodeficiency virus (HIV) infection. Of 403 individuals without prior CMV EOD who were followed up for a median of 151 weeks, 56 died and 21 developed CMV EOD. Twenty of the subjects with CMV EOD had CD4 cell counts of < or =50 cells/mm3 and HIV RNA level of >10,000 copies/mL of plasma at baseline; in these 20 subjects, an increase of CMV DNA level to greater than the quantification limits was associated with CMV EOD. A CD4 cell count of < or =100 cells/mm3 and an HIV RNA level of >10,000 copies/mL of plasma at baseline, a CMV DNA level of >200 copies/mL of blood during follow-up, or development of CMV EOD were all associated with decreased survival. HIV-infected subjects with CD4 cell counts of < or =50 cells/mm3 and HIV RNA levels of >10,000 copies/mL of plasma should have blood fractions screened for CMV DNA; if CMV DNA is detected, CMV prophylaxis might be considered.

AIDS-Related Opportunistic Infections↗
PubMed2001

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.

Adult↗
PubMed2000

Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

OBJECTIVES: At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. DESIGN: Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. METHODS: Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. RESULTS: In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. CONCLUSION: A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.

Anti-HIV Agents↗
PubMed2000

In vivo antagonism with zidovudine plus stavudine combination therapy.

Human immunodeficiency virus (HIV)-infected subjects receiving zidovudine were randomized either to add stavudine (d4T) or didanosine (ddI) to their current regimen or to switch to ddI or d4T monotherapy. After 16 weeks of therapy, the mean reduction in HIV RNA from baseline was 0.14 log(10) copies/mL in patients receiving d4T or zidovudine plus d4T. In subjects receiving ddI or ddI plus zidovudine, reductions were 0.39 and 0.56 log(10), respectively. CD4 cell counts remained stable or showed modest increases in all arms except the zidovudine plus d4T arm. Patients receiving zidovudine plus d4T showed progressive declines in CD4 cell counts with a median of 22 cells/mm(3) below baseline by 16 weeks. Examination of intracellular levels of d4T-triphosphate in 6 subjects was consistent with previous in vitro studies demonstrating pharmacologic antagonism between zidovudine and d4T. Analysis of these data suggests that zidovudine and d4T should not be prescribed in combination and that ddI provides greater antiviral activity than d4T in zidovudine-treated patients.

Adult↗
PubMed1998

A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS. AIDS Clinical Trial Group 193A Study Team.

OBJECTIVE: The primary objective was to compare the effects of dual or triple combinations of HIV-1 reverse transcriptase inhibitors with respect to survival. The time to new HIV disease progression or death, toxicities, the change in CD4 cells, and plasma HIV-1 RNA concentrations in a subset of study subjects were evaluated. DESIGN: This was a multicenter randomized, double-blind, placebo-controlled study. SETTING: The study was conducted among 42 adult AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation centers. PATIENTS: 1313 HIV-infected patients with CD4 counts < or = 50 cells/mm3 participated in this study, which was conducted from June 1993 to June 1996. INTERVENTION: Patients were randomized to one of four daily regimens containing 600 mg of zidovudine: zidovudine alternating monthly with 400 mg didanosine; zidovudine plus 2.25 mg of zalcitabine; zidovudine plus 400 mg of didanosine; or zidovudine plus 400 mg of didanosine plus 400 mg of nevirapine (triple therapy). MAIN OUTCOME MEASURES: The main outcome was survival (i.e., time to death). RESULTS: A significant difference in survival time was found between the four treatment groups, favoring those assigned to triple therapy (p = .02). A significant difference was also found in the delay of disease progression or death among the four treatment arms favoring the group assigned to triple therapy (p = .002). Baseline CD4 cell counts and plasma HIV-1 RNA concentrations as well as changes of CD4 counts at week 8 predicted survival for subjects in the virology substudy. CONCLUSIONS: In the pre-protease inhibitor era, a combination of triple reverse transcriptase inhibitors prolonged life and delayed disease progression in AIDS patients with advanced immune suppression.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Likelihood-based inference for the genetic relative risk based on affected-sibling-pair marker data.

Using genetic marker data from affected sibling pairs, we study likelihood-based linkage analysis under quasi-recessive, quasi-dominant, and general single-locus models. We use an epidemiologic parameterization under a model where the marker locus is closely linked to the putative disease susceptibility gene. This model and parameterization allow inferences about the relative risk associated with the susceptible genotype. We base inferences on approximate likelihoods that focus on the affected siblings in the sibship and, using these likelihoods, we derive closed-form maximum likelihood estimators for model parameters and closed-form likelihood ratio statistics for tests that the relative risk associated with the susceptible genotype is one. Under the general single-locus model, our likelihood ratio test is the same as the iteratively computed triangle test proposed by Holmans (1993, American Journal of Human Genetics 52, 362-374) for the case where marker identity-by-descent is known; our derivation gives a closed form for the test statistic. We present quartiles of the distribution of parameter estimates and critical values for the exact null distribution of our likelihood ratio test statistics; we also give large-sample approximations to their null distributions. We show that the powers of our likelihood ratio tests exceed the powers of more commonly used nonparametric affected-sibling-pair tests when the data meet the inheritance model assumptions used to derive the test; we also show that our tests' powers are robust to violation of model assumptions. We conclude that our model-based inferences provide a practical alternative to more common affected-sibling-pair tests when investigators have some knowledge about the mode of inheritance of a disease and that our methods may sometimes be useful for comparing the genetic relative risk with environmental relative risks.

Disease Susceptibility↗
PubMed1997

An examination of methods for sample size recalculation during an experiment.

In designing experiments, investigators frequently can specify an important effect that they wish to detect with high power, without the ability to provide an equally certain assessment of the variance of the response. If the experiment is designed based on a guess of the variance, an under-powered study may result. To remedy this problem, there have been several procedures proposed that obtain estimates of the variance from the data as they accrue and then recalculate the sample size accordingly. One class of procedures is fully sequential in that it assesses after each response whether the current sample size yields the desired power based on the current estimate of the variance. This approach is efficient, but it is not practical or advisable in many situations. Another class of procedures involves only two or three stages of sampling and recalculates the sample size based on the observed variance at designated times, perhaps coinciding with interim efficacy analyses. The two-stage approach can result in substantial oversampling, but it is feasible in many situations, whereas the three-stage approach corrects the problem of oversampling, but is less feasible. We propose a procedure that aims to combine the advantages of both the fully sequential and the two-stage approaches. This quasi-sequential procedure involves only two stages of sampling and it applies to the stopping rule from the fully sequential procedure to data beyond the initial sample which we obtain via multiple imputation. We show through simulations that when the initial sample size is substantially less than the correct sample size, the mean squared error of the final sample size calculated from the quasi-sequential procedure can be considerably less than that from the two-stage procedure. We compare the distributions of these recalculated sample sizes and discuss our findings for alternative procedures, as well.

Anti-HIV Agents↗
PubMed1997

A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate.

Two bilaterally symmetric eyes arise from the anterior neural plate in vertebrate embryos. An interesting question is whether both eyes share a common developmental origin or they originate separately. We report here that the expression pattern of a new gene ET reveals that there is a single retina field which resolves into two separate primordia, a suggestion supported by the expression pattern of the Xenopus Pax-6 gene. Lineage tracing experiments demonstrate that retina field resolution is not due to migration of cells in the median region to the lateral parts of the field. Removal of the prechordal mesoderm led to formation of a single retina both in chick embryos and in Xenopus explants. Transplantation experiments in chick embryos indicate that the prechordal plate is able to suppress Pax-6 expression. Our results provide direct evidence for the existence of a single retina field, indicate that the retina field is resolved by suppression of retina formation in the median region of the field, and demonstrate that the prechordal plate plays a primary signaling role in retina field resolution.

Amino Acid Sequence↗
PubMed1994

Feasibility of half-sibling designs for detecting a genetic component to a disease.

In genetic epidemiology, adoption and twin study designs are the most commonly used designs to identify genetic and common environmental components underlying familial aggregation. Other fixed family set designs such as a half-sibling design can also be applied to test the same hypothesis. The feasibility of half-sibling designs for detecting a genetic (single-locus or multifactorial) source of familial aggregation of a disease is studied and is compared to both adoption and twin study designs. Results are presented for two types of design when the sampling units are relative pairs reared apart (I) or reared together (II). Although they generally require more observations to achieve the same power, designs involving half-siblings may be more feasible in situations where there is greater availability of these relatives.

Adoption↗
PubMed1992

Isoflurane and hypothermic cardiopulmonary bypass: vasodilation without metabolic effects.

During cardiopulmonary bypass, isoflurane may have beneficial effects on systemic oxygen uptake and vascular resistance. For this reason, the effects of isoflurane during low-flow (1.6 L/min/m2), hypothermic (27 degrees to 29 degrees C) cardiopulmonary bypass on systemic hemodynamics and oxygen uptake were studied in 20 patients in a cross-over experiment. Mean arterial and central venous pressures were measured during two consecutive periods of 10 minutes' duration. Blood samples were aspirated at the end of each period from the arterial and venous lines and analyzed for oxygen content. The concentration of isoflurane in the arterial samples was also determined. Systemic oxygen uptake and vascular resistance were calculated. Isoflurane had no significant effect on systemic oxygen uptake. Significant inverse relationships between blood isoflurane concentration and both mean arterial pressure and systemic vascular resistance were found. It is concluded that isoflurane is a vasodilator under the abnormal conditions of hypothermic cardiopulmonary bypass, but has no effect on systemic oxygen uptake.

Alkalies↗
PubMed1992

Closure of a genetic linkage map of human chromosome 7q with centromere and telomere polymorphisms.

We have constructed a 2.4-cM resolution genetic linkage map for chromosome 7q that is bounded by centromere and telomere polymorphisms and contains 66 loci (88 polymorphic systems), 38 of which are uniquely placed with odds for order of at least 1000:1. Ten genes are included in the map and 11 markers have heterozygosities of at least 70%. This map is the first to incorporate several highly informative markers derived from a telomere YAC clone HTY146 (locus D7S427), including HTY146c3 (HET 92%). The telomere locus markers span at least 200 kb of the 7q terminus and no crossovers within the physical confines of the locus were observed in approximately 240 jointly informative meioses. The sex-equal map length is 158 cM and the largest genetic interval between uniquely localized markers in this map is 11 cM. The female and male map lengths are 181 and 133 cM, respectively. The map is based on the CEPH reference pedigrees and includes over 4000 new genotypes, our previously reported data plus 29 allele systems from the published CEPH version 5 database, and was constructed using the program package CRI-MAP. This genetic linkage map can be considered a baseline map for 7q, and will be useful for defining the extent of chromosome deletions previously reported for breast and prostate cancers, for developing additional genetic maps such as index marker and 1-cM maps, and ultimately for developing a fully integrated genetic and physical map for this chromosome.

Centromere↗
PubMed1990

Biobehavioral variables and mortality or cardiac arrest in the Cardiac Arrhythmia Pilot Study (CAPS).

The frequency of ventricular premature complexes and the degree of impairment of left ventricular ejection fraction are major predictors of cardiac mortality and sudden death in the year after acute myocardial infarction. Recent studies have implicated psychosocial factors, including depression, the interaction of social isolation and life stress, and type A-B behavior pattern, as predictors of cardiac events, controlling for known parameters of disease severity. However, results tend not to be consistent and are sometimes contradictory. The present investigation was designed to test the predictive association between biobehavioral factors and clinical cardiac events. This evaluation occurred in the context of a prospective clinical trial, the Cardiac Arrhythmia Pilot Study (CAPS). Five-hundred two patients were recruited with greater than or equal to 10 ventricular premature complexes/hour or greater than or equal to 5 episodes of nonsustained ventricular tachycardia, recorded 6 to 60 days after a myocardial infarction. Baseline behavioral studies, conducted in approximately 66% of patients, included psychosocial questionnaires of anxiety, depression, social desirability and support, and type A-B behavior pattern. In addition, blood pressure and pulse rate reactivity to a portable videogame was assessed. The primary outcome was scored on the basis of mortality or cardiac arrest. Results indicated that the type B behavior pattern, higher levels of depression and lower pulse rate reactivity to challenge were significant risk factors for death or cardiac arrest, after adjusting statistically for a set of known clinical predictors of disease severity. The implication of these results for future research relating behavioral factors to cardiac endpoints is discussed.

Affect↗
PubMed1988

Cardiovascular and central nervous system effects of rilmenidine (S 3341) in rats.

Rilmenidine (S 3341) is a new alpha 2 agonist, with antihypertensive properties. Pharmacologic data concerning its hemodynamic and central nervous system effects in the rat are described in this report. In the anesthetized or conscious spontaneously hypertensive rat, rilmenidine was found effective and potent as an antihypertensive agent, lowering blood pressure in a dose-dependent manner after intravenous and oral administration. These effects are related to a reduction in sympathetic tone as seen by the decrease in plasma catecholamines induced by rilmenidine in the spontaneously hypertensive rat. Studies in the normotensive pithed rat (electrical stimulation and adrenalectomization) confirmed the presynaptic alpha 2-stimulating properties of rilmenidine and suggested that a component of the antihypertensive activity of rilmenidine could be exerted through these peripheral receptors. A study of the central effects of rilmenidine was performed using classic neuropharmacologic tests. No effect was observed on the pentobarbitone-induced sleeping time in the rat. Rilmenidine caused only a minimal and non-dose-dependent inhibition of the righting reflex in the chick. In the rat, rilmenidine did not decrease the motor activity at concentrations up to 50 times higher than the antihypertensive dose. These results confirmed the contrast between rilmenidine and clonidine and suggest that a dissociation between sedative and antihypertensive effects could occur with rilmenidine.

Adrenalectomy↗
PubMed1988

Effects of two alpha 2 agonists, rilmenidine and clonidine, on the morphine withdrawal syndrome and their potential addictive properties in rats.

The interaction between adrenergic systems and opiate receptors or neuronal systems linked to these receptors has been previously demonstrated. For this reason, clonidine can be used to reduce withdrawal syndrome to opiates. Rilmenidine (S 3341) is a new agonist of alpha 2 adrenoceptors. The purpose of these experiments was to compare the effects of rilmenidine and clonidine on morphine withdrawal syndrome and their potential addictive properties in the rat. Rats were made morphine-dependent by repeated intraperitoneal (i.p.) administration of increasing doses of morphine. Withdrawal was precipitated by injecting naloxone subcutaneously. Withdrawal scores were evaluated for 10 minutes. Clonidine (0.05, 0.1 and 0.2 mg/kg, i.p.) and rilmenidine (5 and 10 mg/kg, i.p.) significantly reduced overall withdrawal scores. Addictive potential was evaluated in the rat by a place preference test after the following treatments (mg/kg, i.p.): rilmenidine 0.1 to 5, clonidine 0.01 to 0.5, heroin 0.12, and d-amphetamine 1.5. Rilmenidine did not modify the time spent in the conditioned side at doses of 0.1 to 1 and 5 mg/kg, but increased it at 2.5 mg/kg (+25%). In contrast, a reinforcing effect was induced by clonidine (+21%, +43%, +34% at 0.1, 0.25, 0.5 mg/kg), heroin (+39%) and amphetamine (+52%). In conclusion, rilmenidine as well as clonidine reduced the morphine withdrawal syndrome. However, rilmenidine was 100 times less active than clonidine. Clonidine, heroin and d-amphetamine have clear reinforcing properties. Rilmenidine did not exhibit dose-dependent reinforcing properties and the isolated effect noted after 2.5 mg/kg is difficult to interpret because it is minor and is not observed with a higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1985

Preferential antagonism by diltiazem of alpha 2-adrenoceptor mediated vasoconstrictor responses in perfused tail arteries of spontaneous hypertensive rats.

Vasoconstrictor responses mediated by the alpha 2-adrenoceptor agonist TL99, were particularly sensitive to blockade by the calcium antagonist drug diltiazem in isolated perfused tail arteries of spontaneously hypertensive rats (SHR). In contrast, the vasoconstrictor responses induced by the alpha 1-adrenoceptor agonist methoxamine were significantly more resistant to antagonism by diltiazem. At higher concentrations (greater than 300 nmol/l) diltiazem became an effective antagonist of all alpha-adrenoceptor mediated responses. In normotensive Wistar Kyoto (WKY) or Sprague-Dawley (SD) rats diltiazem was significantly less potent against vasoconstrictor responses to TL99 than in SHR. The blockade of alpha 1-adrenoceptor mediated vasoconstriction by diltiazem was not significantly different when normotensive rats and SHR were compared. The vasoconstrictor responses evoked by 5HT in the perfused tail arteries were particularly resistant to blockade by diltiazem in SHR arteries. The responses to endogenously released noradrenaline, evoked by electrical field stimulation, were significantly antagonised by diltiazem (30 nmol/1-3 mumol/l) in SHR-tail arteries, while they were not modified in WKY-tail arteries. At the concentrations of diltiazem which blocked end organ responses to field stimulation, there was no modification of total tritium overflow from SHR-tail arteries after labelling the tissue with 3H-noradrenaline, indicating that diltiazem does not inhibit transmitter release at these concentrations. The tail artery preparation of SHR contains a population of postsynaptic alpha 2-adrenoceptors which mediate contraction in this blood vessel and the calcium entry blocker diltiazem is a potent antagonist of vasoconstrictor responses mediated by vascular alpha 2-adrenoceptors in hypertensive rats. These findings may be relevant to the antihypertensive action of diltiazem.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Power of affected sibling method tests for linkage.

When the mode of inheritance of a disease susceptibility (DS) gene is unknown, the affected sibling method can be applied to study whether a DS gene and a marker gene are linked. This method considers how k affected siblings (k > or = 2) share marker alleles identically by descent from their parents. Several nonparametric and likelihood ratio test statistics have been proposed for the use with affected sibling marker gene data. We compare the power of these proposed tests for linkage under different genetic models via simulation. We find that, in general, the likelihood ratio tests are slightly more powerful, but the gain in power may not warrant the additional computation burden imposed.

Alleles↗