Biomedical subjects
Publications and source records attributed to J Kline.
Synthesis of an arylsulfone hydroxamate lead optimization library is presented. Biological activity of representative examples is given to demonstrate the value of this approach for lead optimization.
Prenatal cocaine use is more accurately measured by maternal hair assay than by urine toxicology screening or self-report. To investigate the consequences of improved measurement, the authors ascertained cocaine use during pregnancy by maternal hair test, urine test, and self-report in a sample of 691 patients recruited from one New York City hospital in 1990-1992. Associations with intrauterine growth retardation, head circumference, and length of gestation were investigated. A positive hair test at delivery was not more strongly associated with birth weight (-38.1 g; 95% CI: -164, 88.3) or head circumference (-1.73 mm; 95% CI: -5.91, 2.44) than a positive urine test at delivery (-182 g (95% CI: -295, -69.8) and -6.11 mm (95% CI: -9.99, -2.24), respectively). Cocaine concentration in hair (which was higher if urine tests were positive) had a dose-response relationship with birth weight: a 27-g decrease (95% CI: -51.9, -1.04) with each log-unit increase in concentration. Birth weights were similar among infants of never users and infants of users who stopped using cocaine before delivery. Heavier use of cocaine, but not lighter use, was associated with intrauterine growth retardation, and exposure in late pregnancy was necessary to the association. Although maternal hair tests were instrumental in clarifying these relations, their clinical use is probably not warranted.
We tested the hypothesis that the connection between advanced maternal age and autosomal trisomy reflects the diminution of the oocyte pool with age. Because menopause occurs when the number of oocytes falls below some threshold, our hypothesis is that menopause occurs at an earlier age among women with trisomic pregnancies than it does among women with chromosomally normal pregnancies. To determine their menstrual status, we interviewed women from our previous study of karyotyped spontaneous abortions who, in 1993, were age >/=44 years. Premenopausal women completed interviews every 4-5 mo, until menopause or until the study ended in 1997. The primary analyses compare 111 women whose index pregnancy was a trisomic spontaneous abortion with two groups: women whose index pregnancy was a chromosomally normal loss (n=157) and women whose index pregnancy was a chromosomally normal birth (n=226). We used a parametric logistic survival analysis to compare median ages at menopause. The estimated median age at menopause was 0.96 years earlier (95% confidence interval -0.18 to 2.10) among women with trisomic losses than it was among women with chromosomally normal losses and chromosomally normal births combined. Results were unaltered by adjustment for education, ethnicity, and cigarette smoking. Our results support the hypothesis that trisomy risk is increased with decreased numbers of oocytes. Decreased numbers may indicate accelerated oocyte atresia or fewer oocytes formed during fetal development.
We tested whether familial aggregation of Down syndrome and Alzheimer's disease (AD) is present for trisomies of other autosomes. We compared rates of Alzheimer-like dementia in the parents of women with trisomic pregnancy losses (n = 109) with those in parents of women with chromosomally normal losses (n = 151) and births (n = 216). Relative risks of Alzheimer-like dementia in parents of women with trisomic losses were 1.2 (95% CI 0.6, 2.2) and 0.9 (95% CI 0.5, 1.5) in comparison to parents of women with chromosomally normal losses and births, respectively. Associations were similar among women whose index pregnancy occurred before age 35 or later. Our data do not support an association between the occurrence of AD and trisomy of all autosomal chromosomes. They raise the possibility that familial aggregation with AD is specific to trisomy 21.
OBJECTIVE: To investigate associations between lead exposure and early motor development. STUDY DESIGN: We conducted standardized assessments of motor function (Bruininks-Oseretsky Test of Motor Proficiency and Beery Developmental Test of Visual-Motor Integration) at age 54 months in 283 children whose mothers were recruited in pregnancy from a smelter town and a non-lead-exposed town in Yugoslavia and who have been monitored twice yearly since birth. Blood lead concentration (BPb) was summarized in a measure reflecting the average of the child's semiannual serial log BPbs through 54 months. RESULTS: Multiple regression showed that taken together, anthropometric measures (birth weight, body mass index) and markers of a stimulating and organized home life (HOME scale, parental education and intelligence, availability of siblings) explained a significant 10% to 18% of the variance in motor functioning. Beyond these contributions, BPb was significantly associated with poorer fine motor and visual motor function but was unrelated to gross motor coordination. CONCLUSIONS: Modest associations between early lead exposure and fine motor and visual motor functioning appear even after statistical adjustment is done for other contributors to motor development. Associations with BPb are specific to these areas of motor skill; gross motor development was unaffected.
This study examined the relation between maternal prepregnant body mass index (BMI) and development of schizophrenia and schizophrenia spectrum disorders in adult offspring from the Prenatal Determinants of Schizophrenia Study. The study drew on a previously studied cohort of births occurring between 1959 and 1967 to women enrolled in a prepaid health plan. Computerized treatment registries were used to identify possible cases of schizophrenia and spectrum disorders in adult offspring belonging to the health plan from 1981 to 1997. Diagnostic interviews and medical record reviews resulted in diagnosis of 63 cases of schizophrenia and spectrum disorders; these cases and 6,570 unrelated and unaffected cohort members whose mothers also had prepregnancy measures of BMI comprised the sample for analyses. High (> or = 30.0), compared with average (20.0-26.9), maternal prepregnant BMI (kg/m2) was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk [RR] = 2.9; 95% confidence interval [CI] 1.3-6.6), independently of maternal age, parity, race, education, or cigarette smoking during pregnancy. Low (< or = 19.9) maternal BMI was not associated with schizophrenia and spectrum disorders (RR = 1.2; 95% CI 0.64-2.2). Future studies of this cohort will examine factors that may help explain the relationship of high maternal prepregnant BMI with schizophrenia, including nutritional and metabolic factors, toxic exposures, and obstetrical complications.
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BACKGROUND: Cigarette smoking and cocaine use may be risk factors for spontaneous abortion, but data supporting such a link are limited. METHODS: We studied the associations between cocaine and tobacco use and spontaneous abortion among pregnant adolescents and women (age range, 14 to 40 years) who sought care at an inner-city emergency department. A total of 400 adolescents and women had spontaneous abortions either at study entry or during follow-up (which lasted until 22 weeks' gestation), and 570 adolescents and women remained pregnant past 22 weeks' gestation. Cocaine use was measured at base line by self-reports and analysis of urine and hair samples. Cigarette smoking was measured by self-reports and urine analysis. RESULTS: The adolescents and women in both groups were predominantly black and of lower socioeconomic status. Among those who had spontaneous abortions, 28.9 percent used cocaine on the basis of hair analysis and 34.6 percent smoked on the basis of a urine cotinine assay, as compared with 20.5 percent and 21.8 percent, respectively, of the adolescents and women who did not have spontaneous abortions. The presence of cocaine in hair samples was independently associated with an increase in the occurrence of spontaneous abortion (odds ratio, 1.4; 95 percent confidence interval, 1.0 to 2.1) after adjustment for demographic and drug-use variables. However, the use of cocaine as measured by self-reports and by urine analysis was not. The presence of cotinine in urine was also independently associated with an increased risk of spontaneous abortion (odds ratio, 1.8; 95 percent confidence interval, 1.3 to 2.6). Twenty-four percent of the risk of spontaneous abortion could be related to cocaine or tobacco use. CONCLUSIONS: Cocaine and tobacco use were common in our study population and were associated with a significant risk of spontaneous abortion.
OBJECTIVES: This report examines the reliability and validity of Darryl, a cartoon-based measure of the cardinal symptoms of posttraumatic stress disorder (PTSD). METHODS: We measured exposure to community violence through the reports of children and their parents and then administered Darryl to a sample of 110 children aged 7 to 9 residing in urban neighborhoods with high crime rates. RESULTS: Darryl's reliability is excellent overall and is acceptable for the reexperiencing, avoidance, and arousal subscales, considered separately. Child reports of exposure to community violence were significantly associated with child reports of PTSD symptoms. CONCLUSIONS: Darryl possesses acceptable psychometric properties in a sample of children with frequent exposure to community violence.
We examined whether exercise during pregnancy is associated with chromosomally normal spontaneous abortion. We hypothesized that associations would be confined to chromosomally normal losses since only these can be influenced appreciably by experiences during pregnancy. The study population comprises women with chromosomally normal (N = 173) and aberrant (N = 173) losses. Women who exercised during pregnancy had a lower risk of a chromosomally normal spontaneous abortion (OR 0.6; 95% CI 0.3-0.9). Other types of physical activity had little effect.
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Lead (Pb) poisoning has numerous effects on the erythropoietic system, but the precise mechanism whereby high dose exposure causes anemia is not entirely clear. We previously reported that Pb exposure is associated with depressed serum erythropoietin (EPO) in pregnant women residing in a Pb mining town and in a nonexposed town in Kosovo, Yugoslavia. In a prospective study, we tested the hypothesis that blood Pb concentration (BPb) may be associated with depressed EPO in children. BPb, hemoglobin (Hgb), and serum EPO were measured at ages 4.5, 6.5, and 9.5 years in 211, 178, and 234 children, respectively. At 4.5 years of age, mean BPbs were 38.9 and 9.0 microg/dl in the exposed and nonexposed towns, respectively; BPbs gradually declined to 28.2 and 6.5 microg/dl, respectively, by age 9.5 years. No differences were found in Hgb at any age. At age 4. 5 years, a positive association between BPb and EPO (beta = 0.21; p = 0.0001), controlled for Hgb, was found. The magnitude of this association declined to 0.11 at age 6.5 years (p = 0.0103) and 0.03 at age 9.5 years (p = 0.39). These results were confirmed using repeated measures analyses. We concluded that in Pb-exposed children, the maintenance of normal Hgb requires hyperproduction of EPO. With advancing age (and continuing exposure), this compensatory mechanism appears to be failing, suggesting a gradual loss of renal endocrine function due to Pb exposure.
We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inhibitors of human leukocyte elastase (HLE). The enzyme inhibition is regulated by the size of the oligomer, as well as, the number of charges. Lipophilicity is an important element in determining potency and specificity against other basic enzymes. Compounds whose scaffolds contain three phenoxyacetic acid groups and three alkyl ethers are competitive and specific inhibitors of HLE with Ki = 20 nM. The mechanism of action of this class of compounds is believed to involve multidendate interactions with the surface of HLE near the active site which prevents substrate access to the catalytic site.
OBJECTIVE: To test a priori hypotheses that miscarrying women are at increased risk for a first or recurrent episode of major depressive disorder in the 6 months following loss and that this increased risk is greater for childless women, women with prior reproductive loss, and women aged 35 years or older; and to evaluate whether risk varies by time of gestation or by attitude toward the pregnancy. DESIGN: Cohort study. SETTING: The miscarriage cohort consisted of women attending a medical center for a spontaneous abortion (n=229); the comparison group was a population-based cohort of women drawn from the community (n=230). PARTICIPANTS: Miscarriage was defined as the involuntary termination of a nonviable intrauterine pregnancy before 28 completed weeks of gestation. Half of all participants were between 25 and 34 years of age; 40% were white and 35% Hispanic; 55% had more than a high school education. Participants constituted 60% of miscarrying women and 72% of community women who completed the first phase of this cohort study. MAIN OUTCOME MEASURE: Major depressive disorder was measured using the Diagnostic Interview Schedule. RESULTS: Risk for an episode of major depressive disorder among miscarrying women in the 6 months following loss was compared with the 6-month risk among community women who had not been pregnant in the preceding year. Among miscarrying women, 10.9% experienced an episode of major depressive disorder, compared with 4.3% of community women. The overall relative risk (RR) for an episode of major depressive disorder for miscarrying women was 2.5 (95% confidence interval [CI], 1.2-5.1) and was substantially higher for childless women (RR, 5.0; 95% CI, 1.7-14.4) than for women with children (RR, 1.3; 95% CI, 0.5-3.5) (P<.06). Among miscarrying women, 72% of cases of major depressive disorder began within the first month after loss; only 20% of community cases started during the comparable period. Among miscarrying women with a history of major depressive disorder, 54% experienced a recurrence. However, RR did not vary significantly by history of prior reproductive loss or by maternal age, nor did risk vary by time of gestation or attitude toward the pregnancy. CONCLUSIONS: Physicians should monitor miscarrying women in the first weeks after reproductive loss, particularly women who are childless or who have a history of major depressive disorder. Where appropriate, supportive counseling or psychopharmacologic treatment should be considered.
We used the AAMR's Adaptive Behavior Scale to ascertain current menstrual status in a population-based sample of 157 women with Down's syndrome (DS) and 187 women with other intellectual disability, all 40 years of age or older. The age-adjusted likelihood of menopause was twice as high in women with DS syndrome as in women with other intellectual disability (OR = 2.3; 95% CI = 1.1-4.9). Treated thyroid conditions did not influence menstrual status and did not modify the relationship between DS and menstrual status. These findings support the hypothesis that women with DS experience menopause at an earlier age and that this may be associated with accelerated aging.
OBJECTIVES: This paper compares the sensitivity of two tests of cocaine use, interview and urine test, with that of a radioimmunoassay of hair. METHODS: Interviews and hair samples were provided by 397 obstetric patients in one New York City hospital; urine samples were obtained in 377. Of these patients, 241 were receiving prenatal care (were registered) and 156 delivered without prenatal care (were unregistered). The 241 registered patients were derived from 400, comprising all reporting use of cocaine ever ("ever-users"), all reporting use by the father but not themselves ("lifestylers"), and a sample of women who were neither ever-users nor lifestylers. The 156 unregistered patients were derived from 352 women interviewed at delivery, unselected for reported use. RESULTS: Thirty-two percent reported ever using cocaine, 45% of these within 6 months before interview. Urine tests were positive in 20%, hair tests in 59%. The estimated sensitivity of the hair test (92%) was 3.1 times higher than that of the urine test (95% confidence interval [CI] = 2.5, 3.8) and 4 times higher than that of reported use in the past 6 months (95% CI = 3.2, 5.0). CONCLUSIONS: Self-report and urine tests alone miss most of cocaine users during pregnancy. Hair tests greatly improve detection and thus can enhance evaluations of the effects of prenatal cocaine use on fetal and child development.
Spontaneous abortion is the most common adverse reproductive outcome. Despite evidence that negative life events increase risk for a number of medical disorders, their role in pregnancy disruption has not been investigated. The present study tested an a priori hypothesis that recent negative life events increase the odds of spontaneous abortion of a chromosomally normal conceptus. Between 1984 and 1986, 192 women aged 18-42 years who visited a medical center after spontaneous abortion were interviewed about positive and negative events that had occurred in the 4-5 months preceding the loss. Subsequently, women with chromosomally normal (n = 111) and chromosomally abnormal (n = 81) losses were identified on the basis of tissue culture after interview. The women with chromosomally abnormal loss provided an estimate of the expected frequency of life events against which to compare the event frequencies of women with chromosomally normal loss. Analyses were adjusted for duration of the recall period, payment status, maternal age, education, and ethnicity. Seventy percent of the women with chromosomally normal losses reported having had one or more negative life events in the months preceding loss, compared with 52% of the women with chromosomally abnormal losses (adjusted odds ratio = 2.6, 95% confidence interval (CI) 1.3-5.2). For private patients (n = 69), the adjusted odds ratio was 4.2 (95% CI 1.3-13.4); for public patients (n = 123), it was 1.9 (95% CI 0.8-4.8). The associations held for postconception events alone and were absent for positive events. Results were unaltered by adjustment for smoking, caffeine intake, and alcohol consumption. With recall bias precluded by the study design, the strength, timing, and specificity of these associations suggest that recent negative life events play a role in chromosomally normal spontaneous abortion. Efforts to replicate these results and to elucidate underlying biologic mechanisms are required.
The mechanism of beta-blocker induced cardiotoxicity is poorly understood. One possible explanation is that beta-blockers induce ion dyshomeostasis, resulting in cardiac hyperpolarization. The intent of this study was to determine if modifying extracellular ions would reverse cardiotoxicity from two beta-blockers: propranolol (PROP) and atenolol (ATEN). Two treatments were studied: low extracellular K+ and high extracellular Na+. Isolated rat hearts were perfused on a Langendorff apparatus with Krebs-Henseleit- Bicarbonate buffer (KHB) solution. Toxicity (Tox) was induced by perfusing hearts for 30 min with KHB + PROP [5 microgram/ml] or KHB + ATEN [2.5 mg/ml]. Subsequently, hearts were perfused with KHB containing either PROP or ATEN, but modified by lowering K+ [2.3 mM] or raising Na+ [160 mM] for a 30-min treatment (Tx) period. Hearts were paced near the end of treatment. Cardiodynamics were monitored via a balloon-tipped catheter in the left ventricle. The first derivative of LV pressure (dP/dt) with respect to time served as our index of myocardial performance. Tx groups were as follows: (1) KHB only, (2) PROP only, (3) PROP + K, (4) PROP + Na, (5) ATEN only, (6) ATEN 4 K, and (7) ATEN + Na. PROP induced negative chronotropic effects and rendered the hearts refractory to pacing. ATEN demonstrated similar chronotropic toxicity plus decreased myocardial contractility. Tx with low extracellular K+ and high extracellular Na+ increased HR and restored the ability to pace, thereby reversing toxicity. These data suggest that beta-blocker toxicity is mediated via hyperpolarization.