Biomedical subjects
Publications and source records attributed to M Behnke.
Potent and selective dipeptidyl boronic acid proteasome inhibitors are described. As compared to peptidyl aldehyde compounds, boronic acids in this series display dramatically enhanced potency. Compounds such as 15 are promising new therapeutics for treatment of cancer and inflammatory diseases.
OBJECTIVE: This study was undertaken to determine whether an increased incidence of structural brain abnormalities could be demonstrated in newborns exposed to cocaine. STUDY DESIGN: This study was part of a prospective, longitudinal study of 154 cocaine users matched to 154 control subjects on prenatal risk level, race, parity, and socioeconomic status. Subjects were enrolled prenatally from a rural public health department population or at delivery. Drug exposure was determined by means of repeated, detailed histories and urine screening for drug metabolites. Ultrasonographic examinations were performed within 4 days of birth by experienced technologists and were read by one experienced radiologist, each blinded to drug use history. RESULTS: Cranial ultrasonography results were available for 266 infants (134 cocaine-exposed; 132 control). Only 27 infants had ultrasonography results that were not considered normal, and there were no significant differences between groups (17 cocaine-exposed vs 10 control; p = 0.119). Identified abnormalities included choroid plexus cysts, subependymal cysts, mildly dilated ventricles, and a cyst of the third ventricle. CONCLUSIONS: The incidence of abnormal cranial ultrasonography results in our cocaine-exposed group was lower than that previously reported in the literature and not significantly different from the control group. In addition, the identified lesions were less severe than previously reported, despite a wide range of cocaine use in our sample, including heavy use.
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This study examined whether the widely disseminated negative image of the "cocaine baby" would lead adults to perceive a videotaped unexposed infant more negatively simply because they had been told the infant was prenatally cocaine-exposed. Two hundred and forty-nine students from three state universities used a seven-point Likert scale to rate either an African-American or a white female infant on 20 bipolar adjective-pairs. As predicted, participants who observed a labeled infant rated her more negatively than did those for whom the infant had not been labeled as cocaine-exposed. The potentially negative consequences of this documented bias toward cocaine-exposed infants should both alert and concern professionals and researchers. If adults view the behavior of a nonexposed infant more negatively merely because they believe that the infant has been exposed, then parents (biological and adoptive), professionals, and researchers may view and respond to the behavior of infants who are cocaine-exposed more negatively. Transactional models of development suggest a potential for self-fulfilling prophecy.
The effects of cocaine are well documented in the CNS; however, recent evidence suggests that cocaine may suppress the immune system. Maternal cocaine use essentially exposes the fetus to a continuous exposure of cocaine. The objective of this study was to investigate the immunomodulatory effects of cocaine and its metabolites on maternal and fetal immune systems. Subjects were recruited from an Investigational Review Board approved protocol, and biologic specimens were collected. For each subject peripheral blood mononuclear cells (PBMCs) were isolated by density gradient. Each PBMC sample was stimulated in separate wells with phytohemagglutinin and phrobol 12-myristate 13-acetate. Samples were radiolabeled and stimulation was measured. Cytokine measurements were made on the serum via ELISA assay techniques. In both the phorbol 12-myrisate 13-acetate and the phytohemagglutinin group, the PBMCs isolated from fetal cord blood in the cocaine-using group had significantly (p < 0.05) decreased responses compared with control subjects. IL 1 and IL 2 concentrations were suppressed in the cocaine-exposed fetal serum compared with controls (p < 0.005 and p < 0.05, respectively). We have shown that in utero cocaine exposure results in a nonspecific suppression of fetal T lymphocyte response. The clinical consequences of prenatal cocaine-induced immunosuppression need to be further explored.
OBJECTIVE: This prospective, longitudinal project was designed to determine the effects of prenatal cocaine use on the pregnancy outcomes of women from a historically understudied rural public health population. METHODOLOGY: We interviewed over 2500 women prenatally, identified 154 cocaine users, and matched 154 controls on race, parity, socioeconomic status, and location of prenatal care (that related to level of pregnancy risk). Drug testing was required at enrollment and at delivery; detailed demographic, psychosocial, and drug histories were taken at each available trimester and follow-up visit. After birth, neonatal nurse practitioners, blinded to maternal history of drug use, examined infants to assess gestational age and take growth measurements. Medical charts were reviewed and the Hobel Risk Scale was completed. RESULTS: Compared with controls, the cocaine users had significantly higher Hobel Prenatal and Total Risk Scores and more preterm infants (28 vs 14), but not a significantly greater number of fetal deaths (3 vs 1). After controlling for the effects of marijuana, alcohol, and tobacco use, the following results remained. There was no difference in gestational age, Ponderal Index, birth weight, or length between infants born to cocaine users and controls. There was a significant interaction effect such that infant head and chest circumference were smaller in cocaine users who also smoked tobacco. Significant correlation coefficients demonstrated the effects of the amount of drug usage on fetal growth during each trimester of pregnancy. The average cocaine use per day for trimesters one and three and for the entire pregnancy was negatively related to birth length. The mean amounts used in trimesters two and three were negatively related to head circumference. Amounts of tobacco and alcohol use in pregnancy were also inversely related to fetal growth measures. When the effects of marijuana, alcohol, and tobacco were partialed out, there continued to be a negative relationship between the amount of cocaine used in the third trimester and infant length and head circumference. CONCLUSIONS: The observed decrement in fetal growth, especially head circumference, among cocaine-exposed neonates raises concerns about later growth and development. Follow-up of these infants will reveal if these disadvantages continue. These early results also emphasize the importance of considering amount and time of drug exposure as well as the interactive effects of drug exposure and other risk variables.
OBJECTIVE: This prospective, longitudinal project was designed to determine the effects of prenatal cocaine use on the neurodevelopmental outcomes of infants from a historically understudied rural public health population. METHODOLOGY: We interviewed > 2500 women prenatally, identified 154 cocaine users, and matched 154 controls on race, parity, socioeconomic status, and location of prenatal care (that related to level of pregnancy risk). Drug testing was required at enrollment and at delivery; detailed demographic, psychosocial, and drug histories were taken at each available trimester and follow-up visit. After birth, certified evaluators, blinded to maternal history of drug use, administered the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) under controlled conditions. Evaluation time for preterm infants was adjusted for gestational age. RESULTS: After controlling for the effects of marijuana (users of other illicit drugs were excluded), alcohol, and tobacco use, the following results remained. There were significant drug group interactions on the BNBAS Qualifier Score of Alert Responsiveness that demonstrated lower scores among infants who were exposed to both cocaine and tobacco and among those exposed to both marijuana and tobacco. There were also significant correlations between the amount of cigarette, alcohol, marijuana, and cocaine exposure and several BNBAS scores. The reported amount of cocaine use in the third trimester was negatively related to scores of Orientation, Cost of Attention, and Alert Responsiveness (that was also related to amount of cocaine used over the entire pregnancy). When the effects of marijuana, alcohol, and tobacco were partialled out, the amount of cocaine use in the third trimester was negatively related to Regulation of State, a precursor of alertness, and the infant's ability to orient to the environment. CONCLUSIONS: The observed decrement in state regulation, attention, and responsiveness among cocaine-exposed neonates raises concerns about later developmental abilities as well as the effect these infants may have on caregivers (who themselves may be compromised in their parenting abilities by their drug use). Follow-up of these infants will reveal if these disadvantages continue. These early results also emphasize the importance of considering amount and time of drug exposure as well as the interactive effects of drug exposure and other risk variables.
OBJECTIVE: Our goals were to document hospital costs associated with prenatal cocaine exposure in an understudied population-women using rural county public health units who had minimal access to drug rehabilitation and whose cocaine of choice was crack with little other illicit drug use- and to explore why increased costs occur in an effort to identify cost-reduction strategies. METHODS: We identified a sample of cocaine-exposed infants who were computer-matched to a control group with no history or evidence of cocaine exposure. Matching was performed one-to-one on the variables of maternal race, age, parity, time of entry into prenatal care, and alcohol and nicotine use. There were 327 live births, for whom 311 were correctly classified as to their prenatal cocaine use and had billing and medical records available for review (156 exposed, 155 nonexposed). RESULTS: Hospital charges were positively correlated with length of stay. Cocaine-exposed infants had an across-the-board increase in utilization of hospital resources as well as higher hospital charges and longer lengths of stay. Cocaine-exposed infants were significantly younger in gestational age and lower in birth weight. Significantly more cocaine-exposed infants were admitted to the neonatal intensive care unit, had more social and family problems delaying discharge, and received more septic work-ups. In addition, of those infants urine-screened for cocaine at delivery, 92% were screened secondary to a maternal history of prenatal use. CONCLUSIONS: Cost-reduction strategies should be aimed at measures that reduce length of stay by addressing problems identified prenatally as an outpatient before delivery and by influencing objective decision-making regarding the need for medical interventions with the infant after birth.
Since its development in the 1950s, the Apgar index has come into widespread use as a tool to evaluate neonatal condition, with predictive implications for mortality and morbidity. However, Apgar scores were validated in predominantly term infants and have questionable prognostic value for low birthweight infants. The purpose of this study was to develop a survival index applicable to premature infants. Thirty-six perinatal variables were evaluated initially, based on data from 441 neonates weighing 500 to 1800 g. A multifactorial index of nine variables was derived, each independently related to mortality. Sensitivity of the index was 95%, specificity was 68%, positive predictive value was 90%, and negative predictive value was 81%. This index provides the most accurate tool yet reported in the literature for predicting concurrent survival of premature infants. The tool is recommended for use as an index of neonatal condition for low birthweight infants. Its additional use, as a predictor of the likelihood of survival would require time and place specific validation.
Addictive, affordable and accessible crack cocaine has become epidemic in Florida's small towns and rural areas as well as large cities. Because of increases in the estimates of newborns prenatally exposed to cocaine, public concern has been aroused about the effects, and wide media coverage has not always been scientifically supported. Studies dispel some myths, support concern, and leave unanswered questions about long-term neurodevelopmental outcomes. Separating the effects on development of crack cocaine, other risk factors, and the caregiver environment is difficult. Strategies to identify pregnant drug users and facilitate cooperation in treatment and research protocols are suggested; related legal and ethical issues are raised. Drug use prevention and treatment needs of pregnant and postpartum women and children are outlined. To maintain hope for exposed infants and their families is a challenge. A loving, nurturing and teaching environment is essential in fulfilling a child's potential, and solutions that help provide that environment should be the goal of health-care providers, educators, politicians, and citizens.
A series of benzoxazolamine and benzothiazolamine analogs that inhibit leukotriene (LT) biosynthesis are described. The initial lead, (S)-N-(benzothiazol-2- yl)phenylalanine ethyl ester (5a), was discovered in a screening program for inhibition of Ca-ionophore-A23187-induced LTB4 release in human polymorphonuclear leukocytes (IC50 0.23 microM). Through structural modification, it was determined that hydrophobic substituents in the 5-position and replacement of the phenyl ring of phenylalanine with a cyclohexyl group greatly enhance potency. Several ester bioisosteres that retain potency and enantiomeric selectivity are described. Lead optimization culminated in (S)-N-[2-cyclohexyl-1-(2-pyridinyl)ethyl]-5-methyl-2-benzoxazolamine+ ++ (43b), IC50 0.001 microM. The compounds described are not inhibitors of 5-lipoxygenase but, rather, act at the level of arachidonic acid release.
One hundred eighty-four premature infants, < 1800 g at birth and < 36 wk gestation, were entered into a study investigating the role of additional folate and vitamin B-12 supplementation of the anemia of prematurity. All patients initially received vitamin E and iron in accordance with accepted standards. Patients were randomly assigned to four groups to receive orally 0.1 mg folate/d for 4 mo, 100 micrograms vitamin B-12 intramuscularly monthly for 4 mo, both supplements, or neither. All other activities including parenteral nutrition were carried out according to established practices, irrespective of study group. By 10-12 wk, infants treated with vitamin B-12 alone or combined with folate had higher hemoglobin values than the untreated (P < 0.0005) or solely folate-treated (P < 0.01) groups. These findings held true irrespective of wide variations in treatment and feeding practices. The only uncontrolled hematologic nutritional factor, selenium, showed a similar pattern of decline for 10-12 wk in all study patients, whether or not they received additional vitamin supplements.
Cocaine and its metabolites were measured in urine, meconium, and amniotic fluid specimens collected from 30 maternal-infant pairs with histories of prenatal cocaine use. Cocaine, benzoylecgonine, and ecgonine methyl ester were measured by isotope dilution gas chromatography-mass spectrometry. Mothers were interviewed at delivery regarding their cocaine use during pregnancy. There was qualitative agreement between the results of drug determinations in maternal urine, amniotic fluid, infant urine, and meconium. Although all of the mothers in this study admitted to using cocaine during their pregnancy, cocaine or its metabolites were detected only in the 20 cases in which cocaine was used within 3 weeks before delivery. We conclude that when sufficiently sensitive analytic methods are used, maternal urine, infant urine, and meconium analyses yield equivalent results for detection of prenatal cocaine exposure. Importantly, neither meconium nor urinary drug measurements detected cocaine exposure when the last reported use was prior to 3 weeks before delivery.
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Although substance use has been a worldwide problem at all levels of society since ancient times, recent attention has been focused on the use of legal and illegal substances by the pregnant woman. Almost all drugs taken by the pregnant woman are known to cross the placenta and have some effect on the fetus. This article reviews the effects of the drugs most frequently used by pregnant women in the United States--nicotine, alcohol, marijuana, opiates, and cocaine--on the fetus and neonate; when possible, information regarding long-term medical problems is included.
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Forty-two pre-term infants were studied to determine the effect of nonnutritive sucking pre-feeding on behavioral state. Infants were randomly assigned to pacifier or rest groups. Pacifiers or rest were given for 5 minutes following routine caregiving and before each of the first 16 bottle feedings. A 12-category scale was used to measure state immediately before the 5-minutes and after. Frequencies of states that precede optimal feedings changed for infants given pacifiers versus rest: alert inactivity (+6 vs. -2), quiet awake (+19 vs. -6), and active awake (-24 vs. +12); infants given pacifiers had more sleep and fewer restless states. Group differences were non-significant before nonnutritive sucking (p = 0.16) but significant after (p = 0.00001). When self-regulatory feeding policies based on early hunger cues are not allowed, nonnutritive sucking for 5 minutes pre-feeding is simple, brief, and appropriate for busy intensive care units. These findings confirm those from earlier less conclusive research and indicate that nonnutritive sucking modulates behavioral state.
Isolated rabbit ventricular cardiac myocytes adapt readily to primary culture. As the myocytes spread and flatten over the culture substratum, the myofibrillar apparatus retains a "rod-like" orientation. Development of contractile activity is crucial in the maintenance of the integrity of the myofibrillar apparatus during prolonged culture. Myocytes that fail to beat display morphological indications of atrophy; conversely, myocytes that commence beating show no such morphological signs of myofibrillar disorganization. The subcellular organization of other elements of the contractile apparatus, including the transverse tubular system and the sarcoplasmic reticulum, retain their structural relationship with the myofibrils in beating myocytes but not in quiescent cells. Cultured adult myocytes represent an important model to investigate the influence of mechanical factors on the organization and maintenance of the adult cardiac phenotype.