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Biomedical subjects

L P Park

Publications and source records attributed to L P Park.

At least 19 recordsLinked to original sources
PubMed2000

Race- and sex-specific ECG models for left ventricular mass in older populations. Factors influencing overestimation of left ventricular hypertrophy prevalence by ECG criteria in African-Americans.

The validity of the reported high prevalence of left ventricular hypertrophy (LVH) among African-American men and women has been questioned owing to conflicting echocardiographic evidence. We used echocardiographic left ventricular mass (LVM) from M-mode measurements to evaluate associations between LVM, body size, and electrocardiographic (ECG) variables in 3,627 white and African-American men and women 65 years of age and older who were participants of the Cardiovascular Health Study (CHS), a multicenter cohort study of risk factors for coronary heart disease and stroke. ECG amplitudes used in LVH criteria were substantially higher in African-Americans, with apparent LVH prevalence 2 to 3 times higher in African American men and women than in white men and women, although there was no significant racial difference in echocardiographic LVM. The higher apparent LVH prevalence by Sokolow-Lyon criteria in African-American men is in part owing to smaller lateral chest diameter. In women, reasons for racial differences in ECG LVH prevalence remain largely unexplained although a small part of the excess LVH in African-American women by the Sokolow-Lyon criteria appears to be owing to a larger lateral chest semidiameter in white women. ECG variables alone were too inaccurate for LVM prediction, and it was necessary to incorporate in all ECG models body weight that was properly adjusted for race and sex. This resulted in modest LVM prediction accuracy, with R-square values ranging from .22 to .36. Race- and sex-specific ECG models introduced for LVM estimation with an appropriate adjustment for body size differences are expected to facilitate evaluation of LVH status in contrasting racial population groups.

Age Factors↗
PubMed1998

The Novacode criteria for classification of ECG abnormalities and their clinically significant progression and regression.

Electrocardiographic (ECG) manifestations of clinical and subclinical cardiovascular disease are used as an important component in the evaluation of clinical trials, and there is an increasing demand for well-defined criteria for clinically significant evolution of ECG abnormalities. The Novacode ECG classification system provides a comprehensive hierarchical set of criteria for prevalent ECG abnormalities and for clinically significant serial ECG changes, both adverse and favorable, as a response to pharmacologic, surgical, and other interventions. These criteria are used to grade Q wave and ischemic abnormalities in order to achieve stable classification of both prevalent and incident myocardial infarctions by minimizing false classifications due to clinically insignificant ECG variations. This approach differs from the traditional Minnesota Code classification system, in which incident events are determined by changes in classification categories, with the application of additional elaborate validation rules to exclude frequent false classifications. Novacode hierarchy is so structured that for each abnormality, a general class is first determined with the simplest possible classification criteria and more specific abnormality subgroups are then classified with more elaborate criteria. This approach will satisfy differing needs of clinical trials for detail in classification. Explicit definition of ECG variables and condition statements for the classification criteria facilitate implementation of the Novacode with computer ECG programs.

Arrhythmias, Cardiac↗
PubMed1997

Effect of smoking on the clinical progression of HIV-1 infection.

Cigarette smoking as a risk factor in progression of HIV-1 disease was investigated in the Multicenter AIDS Cohort Study of homosexual men. Longitudinal data for T-cell subsets, HIV-related clinical symptoms, smoking behavior, and AIDS medication use were collected semiannually from 2,499 HIV-1-seropositive men for up to 9 years. Survival methods, including Kaplan-Meier analysis and multivariate Cox regression models, were used to assess the effect of cigarette smoking on development of Pneumocystis carinii pneumonia (PCP), AIDS, death, and self-reported oral thrush. After adjustment for CD4+ lymphocyte count and use of antiretroviral and anti-PCP medications, smoking was not significantly associated with progression to PCP, AIDS, or death in either the HIV-seroprevalent or-seroincident cohort members. Among men who had baseline CD4+ cell counts > 200/microliter, smoking was associated with a 40% increase in the hazard of oral thrush (p < or = 0.01). These data indicate that cigarette smoking does not have a major effect on the progression of HIV-1 infection to AIDS or death but may affect the incidence of oral thrush.

Candidiasis, Oral↗
PubMed1996

Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Multicenter AIDS Cohort Study Group.

BACKGROUND: Among patients who begin receiving zidovudine during intermediate-stage human immunodeficiency virus (HIV) infection, it is unclear whether changing to combination therapy (adding didanosine or zalcitabine) or sequential monotherapy (changing to didanosine or zalcitabine) significantly improves survival. OBJECTIVE: To determine, among patients who began receiving zidovudine during intermediate-stage HIV infection, the differential effects of changing to combination therapy (zidovudine with didanosine or zalcitabine) or sequential monotherapy (with didanosine or zalcitabine) or continuing zidovudine monotherapy. PATIENTS: 1077 HIV-seropositive men in the Multicenter AIDS (acquired immunodeficiency syndrome) Cohort Study who began receiving zidovudine before an AIDS-defining illness developed. SETTING: University-affiliated clinics in Baltimore, Chicago, Los Angeles, and Pittsburgh. DESIGN: Longitudinal cohort study, Treatment groups and important prognostic variables were modeled as time-dependent covariates in Cox proportional hazards models. MEASUREMENTS: Progression to AIDS and death. RESULTS: Compared with patients receiving continued zidovudine monotherapy, patients receiving combination therapy had a 45% improvement in survival (relative risk, 0.55 [95% Cl, 0.41 to 0.74; P < 0.001]) and patients who changed to sequential monotherapy had a 32% improvement in survival (relative risk, 0.68 [Cl, 0.52 to 0.89; P = 0.005]). In the landmark analyses, the median prolongation of survival associated with changing therapy was, at best, 3 to 6 months. Survival curves converged at 3.5 years for the 50 cells/mm3 disease-stage landmark, at 4.4 years for the 100 cells/mm3 landmark and at 4.9 years for the 150 cells/mm3 landmark. Mortality within these periods was 100%, regardless of treatment group or landmark. CONCLUSIONS: For patients who began receiving zidovudine during intermediate-stage disease, changing to either combination therapy or sequential monotherapy was associated with a statistically significant survival benefit compared with continuation of zidovudine monotherapy. The absolute increase in survival was modest, however, and long-term survival remained poor. Simultaneous time-dependent adjustment for changes in therapy and in important prognostic variables is necessary to derive relatively unbiased estimates of treatment effects in observational studies of HIV infection.

Antiviral Agents↗
PubMed1996

Improved ECG models for left ventricular mass adjusted for body size, with specific algorithms for normal conduction, bundle branch blocks, and old myocardial infarction.

Considerable efforts have been invested recently to improve electrocardiographic (ECG) classification accuracy for left ventricular hypertrophy (LVH). This study examines how LVH classification accuracy is influenced by (1) the selection of an echocardiographic standard for LVH, (2) LVH severity level in the test groups, and (3) the adjustment of LVH criteria for obesity and age. Using data obtained from large, community-based populations, this study explores prospects for improving ECG models for LVH classification and examines some of the general characteristics of newer ECG models for estimating left ventricular mass (LVM) on a continuous scale. The results indicate that the apparent ECG classification accuracy for LVH is substantially influenced by echocardiographic standards and criteria for LVH, LVH severity level, and selection criteria for test populations, and these differences explain some of the often substantial differences in test results from clinical versus community-based evaluation studies. The low reproducibility of echocardiographic LVM as the standard is a limiting factor in attempts to improve ECG criteria for LVH and LVM prediction models. Adjustment of ECG amplitudes to anthropometric factors that simultaneously influence LVM may result in confounding effects and may lead to the development of inappropriate models. The performance of ECG models for LVM prediction improved substantially by the inclusion of body weight as a covariate with ECG variables. The addition of standing height and various covariates reflecting obesity did not improve LVM prediction accuracy. Compared to the older LVM prediction models of the Novacode ECG program, the correlation between echocardiographic and ECG estimates of LVM increased sufficiently (from 0.33 to 0.54 in women and from 0.46 to 0.62 in men) to suggest that these improved ECG models are suitable for monitoring LVH progression/ regression in study groups participating in hypertension intervention trials.

Adult↗
PubMed1995

Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. The Multicenter AIDS Cohort Study.

We and others have postulated that a constant number of T lymphocytes is normally maintained without regard to CD4+ or CD8+ phenotype ('blind' T-cell homeostasis). Here we confirm essentially constant T-cell levels (despite marked decline in CD4+ T cells and increase in CD8+ T cells) in homosexual men with incident human immunodeficiency virus, type 1 (HIV-1), infection who remained free of acquired immunodeficiency syndrome (AIDS) for up to eight years after seroconversion. In contrast, seroconverters who developed AIDS exhibited rapidly declining T cells (both CD4+ and CD8+) for approximately two years before AIDS, independent of the time between seroconversion and AIDS, suggesting that homeostasis failure is an important landmark in HIV disease progression. Given the high rate of T-cell turnover in HIV-1 infection, blind T-cell homeostasis may contribute to HIV pathogenesis through a CD8+ T lymphocytosis that interferes with regeneration of lost CD4+ T cells.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Prognostic value of combined response markers among human immunodeficiency virus-infected persons: possible aid in the decision to change zidovudine monotherapy.

To clarify useful clinical parameters for determining the need for changes in antiretroviral regimens, 586 persons who were seropositive for the human immunodeficiency virus (HIV) and who had intermediate-stage HIV disease underwent follow-up semiannually for a median of 3.1 years after zidovudine monotherapy was instituted. The strongest predictors of time to the development of AIDS and of survival were an increased CD4 lymphocyte count (> 50/microL), a decreased neopterin level (> 2.4 nmol/L), and no increase in the number of symptoms after 7-12 months of zidovudine therapy. Men who had the best quartile CD4 lymphocyte and neopterin responses and who also had no increase in the number of symptoms were 23 times less likely to die (reflecting a 96% increase in survival) than were men who had the worst responses in these variable categories. After 7-12 months of zidovudine therapy, 5-year survival rates were 63% for men with good responses in all three variable categories, 47%-49% for those with good CD4 lymphocyte responses and good responses in one other variable category, 31% for those with only a good CD4 lymphocyte response, and 0 for those with poor responses in all three variable categories.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Factors associated with changes in the use of antiretroviral therapy by a cohort of homosexual men infected with human immunodeficiency virus type 1.

Changes in the use of antiretroviral drugs and factors associated with changes from monotherapy with zidovudine (ZDV) to other regimens were quantified in the Multicenter AIDS Cohort Study. Participants who had been receiving monotherapy with ZDV were categorized as (1) discontinuing ZDV monotherapy; (2) switching to disanosine (ddI), zalcitabine (ddC), or stavudine (d4T) monotherapy; (3) switching to combination therapy (ZDV with ddI, ddC, or d4T); or (4) continuing ZDV monotherapy. From 1990 to 1994, the percentage of participants using ZDV monotherapy decreased from 27% to 17% (among participants without AIDS) and from 60% to 17% (among those with AIDS). At the same time, the proportion of participants using combination therapy increased from zero to 8% (no AIDS) and from 8% to 26% (AIDS). Polychotomous logistic regression methods were used to identify the factors predicting changes from ZDV monotherapy. Among participants without AIDS, indicators of drug failure (such as a lower CD4 lymphocyte count or symptoms of human immunodeficiency virus type 1 infection) were predictive of the initiation of combination therapy, while among patients with AIDS they were predictive of a switch to an alternative monotherapy. A decrease in hemoglobin levels, a marker of ZDV toxicity, was predictive for all patients of a switch to other monotherapy. These data show that clinicians and patients are opting for more aggressive antiretroviral regiments and that changes in CD4 lymphocyte count and in the status of symptoms remain the primary guides for changes in therapy.

Antiviral Agents↗
PubMed1994

The effect of the interaction of acyclovir with zidovudine on progression to AIDS and survival. Analysis of data in the Multicenter AIDS Cohort Study.

OBJECTIVE: To examine the effect of acyclovir use on disease progression and survival in human immunodeficiency virus (HIV)-seropositive persons treated with zidovudine. SETTING: Four university-based or -affiliated clinics. DESIGN: Prospective cohort study of homosexual and bisexual men with semi-annual follow-up. Intent-to-treat Cox models were fit to determine the relation between the use of acyclovir (modeled as a time-dependent covariate) and disease progression, controlling for baseline and time-dependent clinical and laboratory prognostic variables. The acquired immunodeficiency syndrome (AIDS)-free duration and survival time were calculated from the first use of zidovudine. Analysis included study visits 7 to 17 (from 1987 to 1992). PATIENTS: 786 HIV-seropositive participants in the Multicenter AIDS Cohort Study who began zidovudine therapy before a clinical diagnosis of AIDS; of these, 515 subsequently received acyclovir. Participants were asked at each visit whether they had "used any medication for health reasons not related to AIDS or if they had taken any medication to help fight AIDS or the HIV virus"; 488 patients indicated acyclovir use under either or both questions, and 242 patients indicated only the latter use. RESULTS: The use of acyclovir for any indication was not associated with an effect on progression to AIDS but was associated with a 26% decrease in the risk for death (relative hazard, 0.74; P = 0.07). The use of acyclovir for HIV infection was also not associated with an effect on progression to AIDS but was associated with a 36% decrease in the risk for death (relative hazard, 0.64; P = 0.01). To further investigate these findings, we examined dose, constancy, and timing of acyclovir use. The median daily dose of acyclovir used for HIV infection was between 600 and 800 mg. No apparent dose effect on survival was found. Longer uninterrupted use of acyclovir for any indication was associated with an 18% decrease in the risk for death for three or more consecutive visits (relative hazard, 0.82; P = 0.23), a 28% decrease for four or more consecutive visits (relative hazard, 0.72; P = 0.09), and a 7% decrease per visit based on the cumulative number of visits while the patient received acyclovir (relative hazard, 0.93 per visit increase; P = 0.03). Use of acyclovir for any indication and use of acyclovir for HIV infection were each associated with a 44% decreased probability of death if the drug was used after AIDS developed (P = 0.007 and P = 0.005, respectively) but not before. To further investigate the prolongation of survival, two landmark analyses were done. The first analysis began at a landmark of 1 year after initiation of zidovudine therapy and compared three groups of patients: those who used acyclovir at or before this landmark, those who had never started acyclovir or started the drug after the landmark, and those who had never used acyclovir. The 90% survival times were 1325, 1059, and 982 days, respectively. The second analysis began at a landmark of developing either a CD4 count less than 50 cells/microL or clinical AIDS. The 90% survival times for the three groups were 398, 261, and 176 days, respectively. CONCLUSIONS: Our analysis suggests that consistent use of acyclovir at a dose sufficient to suppress herpetic recurrences (that is, 600 to 800 mg/d) has a clinically significant effect on prolonging survival in a well-characterized cohort with extensive previous exposure to herpesvirus infections. Further clinical investigation of low-dose acyclovir with concomitant antiretroviral therapy is warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Clustering of high density lipoprotein cholesterol levels in premenopausal and postmenopausal female twins.

Previous family and twin studies indicate that genetic variation makes an important contribution to individual variation in high density lipoprotein cholesterol (HDL) levels, even after adjustment for covariates (such as obesity and alcohol consumption) that also cluster in families. However, most studies assume that genetic mechanisms affecting variation in HDL level are the same in all subgroups of the population (e.g., men versus women, by age). Using data from the Kaiser-Permanente Women Twins Study, we found different patterns of clustering for monozygotic (MZ) and dizygotic (DZ) twins depending on menopausal status. Premenopausal MZ twins were more similar than postmenopausal MZ twins (r(i) = 0.79 and r(i) = 0.61, respectively, after adjustment for age, alcohol consumption, smoking status, degree of obesity, and leisure-time exercise); premenopausal and postmenopausal DZ twins were alike to the same extent (r(i) = 0.31 and r(i) = 0.32, respectively, adjusted as above). These data suggest that either postmenopausal MZ twins have a greater degree of shared environment than postmenopausal DZ twins (e.g., postmenopausal female hormone use) or that genetic mechanisms that affect individual variation in HDL level differ in pre- and postmenopausal women. Data were not available on postmenopausal female hormone use. If genetic mechanisms that influence variation in HDL levels differ between pre- and postmenopausal women, genetic epidemiologic methods that assume that genetic and environmental sources of variation are the same for all groups of individuals may lead to false conclusions.

Adult↗
PubMed1993

CD4+ lymphocyte response to zidovudine as a predictor of AIDS-free time and survival time.

It is unknown whether the early rise in CD4+ lymphocyte count seen in zidovudine-treated patients is associated with increased AIDS-free time and survival time. To determine the association of this and other changes in immunologic and hematologic markers with prognosis for time to AIDS and survival, we followed 747 AIDS-free patients from initiation of zidovudine therapy in the Multicenter AIDS Cohort Study (MACS). Participants were seen semiannually and had data collected on medication use, immunologic and hematologic variables, and clinical outcomes. AIDS was diagnosed in 216 participants and 165 died during the median follow-up period of 2.0 years. Duration of zidovudine use was categorized into 1-6 months (after 6 months of follow-up) and 7-12 months (12 months of follow-up). During the 6-month follow-up period in which zidovudine was first used, CD4+ lymphocyte levels rose by 17 cells/microliters compared with a mean decrease of 30 cells/microliters/6 months in untreated individuals (after adjusting for baseline CD4+ lymphocyte count). Baseline levels of CD4+ lymphocytes, platelets, and hemoglobin were significant predictors of AIDS and death. After 1-6 months with patients taking zidovudine and controlling for baseline (pretreatment) variables, change in markers after 6 months of follow-up and use of Pneumocystis carinii pneumonia prophylaxis and other antivirals, change in CD4+ lymphocyte count significantly predicted progression to AIDS [relative hazard (RH) = 0.71 for each 100 cell/microliters increase, p = 0.0001] and survival (RH = 0.78 per 100 cell/microliters increase; p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1993

Changes in T and non-T lymphocyte subsets following seroconversion to HIV-1: stable CD3+ and declining CD3- populations suggest regulatory responses linked to loss of CD4 lymphocytes. The Multicenter AIDS Cohort Study.

We investigated changes in lymphocyte subsets (total, CD4+ and CD8+ T cells, as well as non-T cells) associated with human immunodeficiency virus type I (HIV-1) seroconversion in 321 homosexual or bisexual men in the Multicenter AIDS Cohort Study (MACS). These subjects had serial lymphocyte characterizations for up to 4 years before and 5 years after seroconversion. CD4+ lymphocyte levels declined rapidly in the first 18 months following seroconversion and less rapidly thereafter, while CD8 lymphocytes increased with similar kinetics. In contrast, total T (CD3+) lymphocytes declined only slightly in the first 18 months following seroconversion, and then remained stable. These results support the hypothesis of physiologic regulation of the total number of circulating T cells, such that lost CD4+ lymphocytes are replaced by newly generated CD4+ and CD8+ lymphocytes; over time, continued loss of CD4+ lymphocytes due to HIV-1 infection would result in net replacement of lost CD4+ lymphocytes with CD8+ lymphocytes. Non-T (CD3-) lymphocytes also declined after seroconversion, and this decline paralleled that of CD4+ lymphocytes. Thus, changes in both T and non-T lymphocytes after HIV-1 seroconversion may reflect the operation of homeostatic or regulatory mechanisms. Whether these mechanisms contribute to the development of immune deficiency requires further study.

CD3 Complex↗
PubMed1992

The effects on survival of early treatment of human immunodeficiency virus infection.

BACKGROUND: Zidovudine has been shown to prolong survival in patients with the acquired immunodeficiency syndrome (AIDS) and, in persons with human immunodeficiency virus (HIV) infection but not AIDS, to delay the progression to AIDS. However, it is still uncertain whether treatment before the development of AIDS prolongs survival. METHODS: We analyzed data from a cohort of 2162 high-risk men who were already seropositive for HIV type 1 (HIV-1) and 406 men who seroconverted from October 1986 through April 1991. There were 306 deaths. The probabilities of death were compared among men at similar stages of disease who began zidovudine therapy before the diagnosis of AIDS and among those who did not. Relative risks of death were calculated for each of five initial disease states on the basis of CD4+ cell counts and clinical symptoms and signs appearing over follow-up periods of 6, 12, 18, and 24 months. Adjustments were also made for the use of prophylaxis against Pneumocystis carinii pneumonia (PCP). RESULTS: After we controlled for CD4+ cell count and symptoms, the use of zidovudine with or without PCP prophylaxis before the development of AIDS significantly reduced mortality in all follow-up periods. The relative risks of death were 0.43 (95 percent confidence interval, 0.23 to 0.78) at 6 months, 0.54 (95 percent confidence interval, 0.38 to 0.78) at 12 months, 0.59 (95 percent confidence interval, 0.44 to 0.79) at 18 months, and 0.67 (95 percent confidence interval, 0.52 to 0.86) at 24 months. After we adjusted for the effects of PCP prophylaxis, zidovudine alone significantly reduced mortality at 6, 12, and 18 months (relative risks, 0.45, 0.59, and 0.70, respectively), but not at 24 months (relative risk, 0.81). Among zidovudine users, those who also used PCP prophylaxis before the development of AIDS had significantly lower mortality at 18 and 24 months than those who did not (relative risks, 0.62 and 0.60, respectively). CONCLUSIONS: The results of this study support the hypothesis that in HIV-1 infection, early treatment with zidovudine and PCP prophylaxis improves survival in addition to slowing the progression to AIDS.

CD4-Positive T-Lymphocytes↗
PubMed1992

Influence of HIV-1 infection and cigarette smoking on leukocyte profiles in homosexual men. The Multicenter AIDS Cohort Study.

The interaction between the effects of HIV-1 infection and cigarette smoking on leukocyte profiles was studied in 307 HIV-1 seroconverters in the Multicenter AIDS Cohort Study (MACS). Longitudinal data for white blood cell (WBC) counts, WBC differentials, T cell subsets, and smoking behavior were collected semiannually for up to 7 years. Prior to seroconversion, total WBC count increased in direct proportion to daily cigarette consumption, but this effect disappeared within 3 years of seroconversion. Analyses of WBC subsets (lymphocytes, monocytes, and granulocytes) and lymphocyte subsets (CD4+, CD8+ and non-T[CD3-]) showed that smoking had only minor effects on the proportions of these cells. In contrast, HIV-1 seroconversion was associated with a dramatic decrease in CD4+ lymphocyte percentage, a large increase in CD8+ lymphocyte percentage, a small increase in total lymphocyte percentage, and small decreases in the non-T lymphocyte and granulocyte percentages. These findings indicate that the effect of smoking on CD4 cell counts is (a) nonspecific, (b) maximal in seronegative individuals; and (c) lost by 3 years after seroconversion. Although the mechanism of the loss of smoking-induced leukocytosis after seroconversion remains to be determined, our results suggest that the effects of smoking are not likely to be important in the clinical use of leukocyte measurements, including measurements of CD4 lymphocytes, in individuals who have been HIV-1 seropositive for more than 3 years.

CD4-CD8 Ratio↗
PubMed1991

Effect of zidovudine and Pneumocystis carinii pneumonia prophylaxis on progression of HIV-1 infection to AIDS. The Multicenter AIDS Cohort Study.

Although used widely, the effectiveness of zidovudine therapy and primary prophylaxis for Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals, has not been assessed in a large cohort. We have done an observational study between October, 1986, and October, 1990, of a cohort of 2145 HIV-1-seropositive men and 371 who seroconverted during the study. A Markov chain transitional analysis was used to examine the effect of zidovudine and PCP prophylaxis on the probability of progression of HIV-1 infection to AIDS (after 6, 12, 18, and 24 months) after follow-up visits categorised into one of six disease states. The six starting states were based on CD4+ lymphocyte counts and the presence of HIV-related symptoms. Use of pre-AIDS zidovudine and PCP prophylaxis was associated with significant reductions in rates of progression to AIDS at 6, 12, 18, and 24 months for participants starting with less than 350 CD4+ lymphocytes/microliter. For those starting with 350 or more CD4+ lymphocytes/microliter, non-significant protective trends were seen during 12, 18, and 24 month intervals. In multivariate log-linear models virtually all the treatment effect was due to zidovudine. However, after adjusting for the effects of zidovudine, PCP prophylaxis reduced significantly the probability of progression to a first episode of PCP during 6, 12, 18, and 24 month intervals. This study suggests that early primary PCP prophylaxis is effective in preventing first episodes of PCP, and that the efficacy of zidovudine demonstrated in clinical trials can be translated to the population level.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Structure of the precursor to an enzyme mediating COOH-terminal amidation in peptide biosynthesis.

Many bioactive peptides terminate with an amino acid alpha-amide at their COOH terminus. The enzyme responsible for this essential posttranslational modification is known as peptidyl-glycine alpha-amidating monooxygenase or PAM. We identified cDNAs encoding the enzyme by using antibodies to screen a bovine intermediate pituitary lambda gt11 expression library. Antibodies to a beta-galactosidase/PAM fusion protein removed PAM activity from bovine pituitary homogenates. The 108,207 dalton protein predicted by the complete cDNA is approximately twice the size of purified PAM. An NH2-terminal signal sequence and short propeptide precede the NH2 terminus of purified PAM. The sequences of several PAM cyanogen bromide peptides were localized in the NH2-terminal half of the predicted protein. The cDNA encodes an additional 430 amino acid intragranular domain followed by a putative membrane spanning domain and a hydrophilic cytoplasmic domain. The forms of PAM purified from bovine neurointermediate pituitary may be generated by endoproteolytic cleavage at a subset of the 10 pairs of basic amino acids in the precursor. High levels of PAM mRNA were found in bovine pituitary and cerebral cortex. In corticotropic tumor cells, levels of PAM mRNA and pro-ACTH/endorphin mRNA were regulated in parallel by glucocorticoids and CRF.

Amides↗