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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 55 records · Page 3Linked to original sources
PubMed2001

Socio-economic disparities in preterm birth: causal pathways and mechanisms.

Preterm birth is the leading cause of infant mortality in industrialised societies. Its incidence is greatly increased among the socially disadvantaged, but the reasons for this excess are unclear and have been relatively unexplored. We hypothesise two distinct sets of causal pathways and mechanisms that may explain social disparities in preterm birth. The first set involves chronic and acute psychosocial stressors, psychological distress caused by those stressors, increased secretion of placental corticotropin releasing hormone (CRH), changes in sexual behaviours or enhanced susceptibility to bacterial vaginosis and chorioamnionitis, cigarette smoking or cocaine use, and decidual vasculopathy. The second hypothesised pathway is a gene-environment interaction based on a highly prevalent mutation in the gene for methylenetetrahydrofolate reductase (MTHFR), combined with low folate intake from the diet and from prenatal vitamin supplements, consequent hyperhomocysteinemia, and decidual vasculopathy. We propose to test these hypothesised pathways and mechanisms in a nested case-control study within a prospectively recruited and followed cohort of pregnant women with singleton pregnancies who deliver at one of four Montreal hospitals that serve an ethnically and socio-economically diverse population. Following recruitment during the late first or early second trimester, participating women are seen at 24-26 weeks, when a research nurse obtains a detailed medical and obstetric history; administers several scales to assess chronic and acute stressors and psychological function; obtains blood samples for CRH, red blood cell and plasma folate, homocysteine, and DNA for the MTHFR mutation; and performs a digital and speculum examination to measure cervical length and vaginal pH and to obtain swabs for bacterial vaginosis and fetal fibronectin. After delivery, each case (delivery at < 37 completed weeks following spontaneous onset of labour or prelabour rupture of membranes) and two controls are selected for placental pathological examination, hair analysis of cotinine, cocaine, and benzoylecgonine, and analysis of stored blood and vaginal specimens. Statistical analysis will be based on multiple logistic regression and structural equation modelling, with sequential construction of models of potential aetiological determinants and covariates to test the hypothesised causal pathways and mechanisms. The research we propose should improve understanding of the factors and processes that mediate social disparities in preterm birth. This improved understanding should help not only in developing strategies to reduce the disparities but also in suggesting preventive interventions applicable across the entire socio-economic spectrum.

Adult↗
PubMed2001

Hypothetical framework for a relationship between maternal thyroid function, nausea and vomiting of pregnancy, and congenital heart disease.

Our objective was to investigate whether a relationship exists among maternal thyroid function, nausea and vomiting of pregnancy, and congenital heart disease. A Medline search from 1966 to the present was conducted to look for reports on the existence of this relationship. The results were supplemented by abstract searches and personal communication with relevant authors. Our search found independent evidence that maternal hyperthyroidism is related to increased rates of nausea and vomiting of pregnancy, which in turn is significantly related to a decrease in the incidence of congenital heart disease. Early evidence indicates that the converse may be true: maternal hypothyroidism and thyroid replacement therapy are associated with an increase in congenital heart disease in children. The potential relationship between maternal thyroid function, nausea and vomiting of pregnancy, and thyroid replacement therapy needs further study. We propose a case-control study of children presenting for echocardiography to elicit specific information regarding the pregnancy.

Female↗
PubMed2001

Use of hair analysis for confirmation of self-reported cocaine use in users with negative urine tests.

INTRODUCTION: Identification of cocaine use based on a urine test may miss many cases because of the short elimination half-life of the drug. Our objective was to verify the sensitivity of the cocaine hair test in admitted users. PATIENTS AND METHODS: Admitted cocaine users (38), that were 18-70 years of age and reported to have refrained from using cocaine in the few days to months prior to the test, were compared to 10 controls who claimed never to have used cocaine. All had negative urine tests for cocaine and benzoylecgonine by thin-layer chromatography. Cocaine and benzoylecgonine were extracted from unwashed hair and tested by established immunoassays. RESULTS: The hair test was positive in 37/38 cases (97%) and in none of the controls. There was significantly more cocaine in black hair than in brown or blonde hair per mg of cocaine dose reported to have been consumed, highlighting a potential bias when interpreting test results in individuals with dark hair. There was a statistically significant correlation between reported dose used and hair concentrations of cocaine. DISCUSSION: The cocaine hair test appears to be highly sensitive and specific in identifying past cocaine use in the setting of a negative urine test.

Adolescent↗
PubMed2001

Heavily smoking women who cannot quit in pregnancy: evidence of pharmacokinetic predisposition.

SUMMARY: Smoking in pregnancy is associated with a well-characterized increase in perinatal risks. Despite their wish to discontinue smoking, some pregnant women cannot stop. To characterize nicotine and cotinine levels in women who could not quit smoking after the first trimester, the authors recruited 19 white women (age 17-41 years) between 14-23 weeks of gestation who could not quit smoking. They started smoking at ages 11-22 years (mean 14.5) and smoked for 17 +/- 6 years. They had their first cigarettes 5-60 minutes after waking up (mean 12). Nicotine levels were compared with those expected in white patients in the general population, and the cotinine levels per cigarette smoked were compared with the population-based values. Sixteen of the 19 women had nicotine levels substantially lower than those expected. The mean level of serum cotinine produced by one cigarette per day was 19.1 +/- 15.8 ng/mL (range 6.1-67). The expected levels in white patients in the general population are 13 +/- 7.7 ng/mL. The data suggest that pregnant women who cannot quit heavy smoking in the second trimester form a selective group with pharmacokinetic predisposition to a high rate of nicotine metabolism.

Adolescent↗
PubMed2001

The role of acetaldehyde in pregnancy outcome after prenatal alcohol exposure.

It is not known why some heavy-drinking women give birth to children with alcohol-related birth defects (ARBD) whereas others do not. The objective of this study was to determine whether the frequency of elevated maternal blood acetaldehyde levels among alcoholics is in the range of ARBD among alcoholic women. MEDLINE was searched from 1980 to 2000 using the key words acetaldehyde, pharmacokinetics, and alcoholism for controlled trials reporting blood or breath acetaldehyde levels in alcoholics and nonalcoholics. Separately, using the key words fetal alcohol syndrome, epidemiology, prevalence, incidence, and frequency, articles were identified reporting ARBD incidences among the offspring of heavy drinkers. Of 23 articles reporting acetaldehyde levels in alcoholics, four met the inclusion criteria. Forty-three studies reported on the rate of ARBD in heavy drinkers, and 14 were accepted. Thirty-four percent of heavy drinkers had a child with ARBD, and 43% of chronic alcoholics had high acetaldehyde levels. The similar frequencies of high acetaldehyde levels among alcoholics and the rates of ARBD among alcoholic women provide epidemiologic support to the hypothesis that acetaldehyde may play a major role in the cause of ARBD.

Acetaldehyde↗
PubMed2001

Glutathione stability in whole blood: effects of various deproteinizing acids.

High-performance liquid chromatography separation of reduced and oxidized glutathione (GSH and GSSG) in biologic samples using electrochemical detection offers the convenience of both simultaneous quantitation and simple sample preparation. Rapid acidification is required to prevent GSH autooxidation, GSH and GSSG degradation, and precipitate proteins that interfere with analysis. Currently, little consistency exists in the literature regarding acid selection or the feasibility of sample storage before analysis. The purpose of this work was to examine the effects of perchloric (PCA), trichloroacetic (TCA), metaphosphoric (MPA), and 5-sulfosalicylic (SSA) acids on the short-term stability of GSH and GSSG measurements in whole blood. Samples were collected from adult volunteers and treated with multiple concentrations of each acid. The samples were analyzed immediately and aliquots were stored at -80 degrees C for up to 28 days. The suitability of each acid was assessed by percentage change of GSH and GSSG from baseline, efficiency of protein removal, and alteration of chromatogram characteristics. In general, increasing the acid concentration improved sample stability. Nevertheless, SSA did not achieve acceptable sample stability at any concentration tested. MPA was found to leave substantial amounts of protein in the samples, and TCA may interfere with the peaks of interest. Based on these results, a final concentration of 15% PCA is suggested for analysis of glutathione in whole blood. Although immediate sample preparation is preferred, 15% PCA can maintain sample integrity for 4 weeks after storage at -80 degrees C.

Adult↗
PubMed2001

Characterization of mice with a combined suppression of I(to) and I(K,slow).

Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward K(+) current (I(K,slow)), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current (I(to)) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic. To test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Kv1/Kv4DN) expressing both transgenes in an identical genetic background. Whole cell voltage-clamp recordings from left ventricular apex cells confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of I(to) and the 4-aminopyridine-sensitive component of I(K,slow) are eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring (n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R intervals in Kv1/Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous arrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast I(to) in addition to I(K,slow) in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias.

4-Aminopyridine↗
PubMed2001

SAP97 interacts with Kv1.5 in heterologous expression systems.

PDZ domain-containing proteins such as SAP97 and ZO-1 have been implicated in the targeting and clustering of ion channels. We have explored the interactions of these polypeptides with a cardiac voltage-gated potassium channel. Immunocytochemistry in cardiac myocytes revealed colocalization of SAP97 and Kv1.5, both at the intercalated disks and the lateral membranes. Transient transfection experiments in COS-7 cells revealed that SAP97 and Kv1.5 polypeptides formed perinuclear clustered complexes that could be coimmunoprecipitated. Mutation of the three COOH-terminal amino acid residues of Kv1.5 (T-D-L to A-A-A) abolished these interactions. Whereas in most COS-7 cells the SAP97-Kv1.5 complexes were retained in the ER, functional analyses in Xenopus oocytes showed that Kv1.5-encoded outward potassium currents were augmented by coexpression with SAP97. By contrast, cotransfected ZO-1 and Kv1.5 polypeptides in COS-7 cells could not be coprecipitated nor did the coinjection of ZO-1 augment the Kv1.5-encoded currents in oocytes. Collectively, our results suggest that SAP97 may play an important role in the modulation of Kv1.5 channel function in cardiac myocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Alcohol and breast feeding: calculation of time to zero level in milk.

OBJECTIVE: To create a nomogram that will guide lactating women who drink socially on how to avoid neonatal exposure to ethanol through breast milk. DESIGN: Pharmacokinetic modeling of ethanol elimination from milk based on reference values. Calculation of the time to zero alcohol in breast milk for a range of doses and body weights. RESULTS: The elimination of alcohol and time-to-zero levels in breast milk are described in a nomogram as a function of the amount of alcohol consumed and the body weight of the woman. CONCLUSIONS: Careful planning of a breast feeding schedule, by storing milk before drinking and/or waiting for complete alcohol elimination from the breast milk, can ensure women that their babies are not exposed to any alcohol.

Body Weight↗
PubMed2001

Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study.

OBJECTIVE: Because there are no studies available on the safety of venlafaxine during pregnancy, the authors' goal in this study was to determine whether venlafaxine increases the risk for major malformations. METHOD: Data on 150 women exposed to venlafaxine during pregnancy in seven pregnancy counseling centers were compared with data from studies of pregnant women who 1) received selective serotonin reuptake inhibitor antidepressants (SSRIs) (N=150) and 2) who received nonteratogenic drugs (N=150). RESULTS: Among the 150 women who were exposed to venlafaxine during pregnancy, 125 had live births, 18 had spontaneous abortions, and seven had therapeutic abortions; two of the babies had major malformations. There were no significant differences between these women and the two comparison groups on any of the measures analyzed. CONCLUSIONS: These results suggest that the use of venlafaxine during pregnancy does not increase the rates of major malformations above the baseline rate of 1%-3%.

Abnormalities, Drug-Induced↗
PubMed2001

The safety of higher than standard dose of doxylamine-pyridoxine (Diclectin) for nausea and vomiting of pregnancy.

A delayed-release combination of doxylamine-pyridoxine (D-P) (Diclectin) is the only approved antiemetic medication for use in pregnancy in Canada. The standard recommended dose is up to 4 tablets a day, regardless of body weight or severity of symptoms. The objective of this study was to determine the incidence of adverse maternal and fetal effects and pregnancy outcome in 225 women taking Diclectin at the recommended (n = 123) or higher than recommended (n = 102) doses. In this observational, prospective study, one-third (33.6%) of women reported having adverse effects (sleepiness, tiredness, and/or drowsiness) temporally related to the medication. There was no association between the dose per kg and rates of reported maternal adverse effects with doses ranging from 0.1 mg/kg to 2.0 mg/kg (1-12 tablets). Nausea and vomiting of pregnancy (NVP) was reported as severe by the majority (75.8%) of women. Mean birth weight (BW) was 3,400 g and gestational age (GA) 39 weeks. Multivariate analysis revealed that only prepregnancy weight and GA predicted lower BW, not the dose of D-P or the severity of NVP. There were two pregnancies with major malformation, a finding that is consistent with the rates of birth defects in the general population. It was concluded that the higher than standard dose of Diclectin, when calculated per kg of body weight, does not affect either the incidence of maternal adverse effects or pregnancy outcome. If needed, Diclectin can be given at doses higher than 4 tablets/day to normalize for body weight or optimize efficacy.

Antiemetics↗
PubMed2001

The safety of dextromethorphan in pregnancy : results of a controlled study.

BACKGROUND: Dextromethorphan (DM), the d-isomer of the codeine analog levorphanol, is an active ingredient present in a variety of cough and cold remedies. Recently, data generated from a study in chick embryos were extrapolated to suggest that pregnant women should not use this drug because of the risk of birth defects. We conducted a controlled study of pregnant women who used DM, to examine the possible teratogenic risk in humans. MATERIALS AND METHODS: We followed up women who used DM and had been counseled by the Motherisk Program during their pregnancy. A control group of women was matched for age, smoking, alcohol use, and disease state (upper respiratory tract infection, not treated with DM). RESULTS: We were able to ascertain pregnancy outcome in 184 women. There were 172 live births, 10 spontaneous abortions, 1 therapeutic abortion, and 1 stillbirth. One hundred twenty-eight of the women used the drug during the first trimester of pregnancy. There were three major malformations (2.3%) among the babies of women who used DM in the first trimester, seven minor malformations, and the mean (+/- SD) birth weight was 3,381 +/- 670 g. In the control group, there were 174 live births, 8 spontaneous abortions, and 2 therapeutic abortions. There were five major malformations, one of which was a chromosomal abnormality (2.8%), eight minor malformations, and the mean birth weight was 3,446 +/- 571 g. CONCLUSION: This study fails to show that DM use during pregnancy increases the rates of major malformations above the expected baseline rate of 1% to 3%.

Adult↗
PubMed2001

Repeated doses of porcine secretin in the treatment of autism: a randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVES: Anecdotal reports on the efficacy of secretin in autism raised great hopes for the treatment of children with this disorder. Initial single-dose, randomized, controlled trials failed to demonstrate any therapeutic effects of secretin. The present study is the first to test the outcome of repeated doses and to examine whether there is a subgroup of children who are more likely to achieve positive effects. METHOD: Sixty-four children with autism (ages 2-7 years; 55 boys and 9 girls) with a range of intelligence quotient and verbal ability were randomly assigned, in a double-blind manner, to secretin or placebo groups. Children received 2 doses of placebo or porcine secretin, 6 weeks apart. Assessments were performed at baseline and 3 weeks after each injection using several outcome measures. RESULTS: There were no group differences on formal measures of language, cognition, or autistic symptomatology. Subgroupings based on cognitive level, the presence or absence of diarrhea, or a history of regression failed to show any significant therapeutic effects of secretin. CONCLUSION: No evidence is provided for the efficacy of repeated doses of porcine secretin in the treatment of children with autism. The possible relationship between relief of biological symptoms and enhanced skill performance is discussed.

Analysis of Variance↗
PubMed2001

Management of paracetamol overdose: current controversies.

Paracetamol (acetaminophen) is one of the most frequently used analgesics, and is the most commonly used substance in self-poisoning in the US and UK. Paracetamol toxicity is manifested primarily in the liver. Treatment with N-acetyl-cysteine (NAC), if started within 10 hours from ingestion, can prevent hepatic damage in most cases. Pharmacokinetic data relating plasma paracetamol concentration to time after ingestion have been used to generate a 'probable hepatoxicity line' to predict which cases of paracetamol overdose will result in hepatotoxicity and should be treated with NAC. However, later studies use a 25% lower line as their 'possible hepatotoxicity line'. Although adopting the original line may save considerable resources, further studies are needed to determine whether such an approach is safe. On the basis of the metabolism of paracetamol, several risk factors for paracetamol toxicity have been proposed. These risk factors include long term alcohol (ethanol) ingestion, fasting and treatment with drugs that induce the cytochrome P450 2E1 enzyme system. Although some studies have suggested that these risk factors may be associated with worse prognosis, the data are inconclusive. However, until further evidence is available, we suggest that the lower line should be used when risk factors are present. In Canada and the UK, the intravenous regimen for NAC is used almost exclusively; in the US, an oral regimen is used. Both regimens have been shown to be effective. There is no large scale study with direct comparison between these 2 therapeutic protocols and controversy still exists as to which regimen is superior. During the last few years there has been an increase in the number of reports of liver failure associated with prolonged paracetamol administration for therapeutic reasons. The true incidence of this phenomenon is not known. We suggest testing liver enzyme levels if a child has received more than 75 mg/kg/day of paracetamol for more than 24 hours during febrile illness, and to treat with NAC when transaminase levels are elevated. Paracetamol overdose during pregnancy should be treated with either oral or intravenous NAC according to the regular protocols in order to prevent maternal, and potentially fetal, toxicity. Unless severe maternal toxicity develops, paracetamol overdose does not appear to increase the risk for adverse pregnancy outcome.

Acetaminophen↗
PubMed2001

Effects of antibacterials on the unborn child: what is known and how should this influence prescribing.

Antibacterials are among the most commonly prescribed drugs worldwide. In general, infections occur in pregnant women at much the same rate as in the general population. However, as a result of physiological changes brought about by pregnancy, some infections, such as those of the urinary tract, may have an increased incidence. It is important to remember that almost every drug crosses the placenta, ensuring that the unborn fetus is also exposed. When prescribing an antibacterial agent to a pregnant woman, it is important that the mother is treated appropriately while at the same time protecting the unborn child. Certain factors need to be addressed, such as the possible teratogenic risk, changes in pharmacokinetics and the potential toxicity of the drug. In this paper we have reviewed various classes of antibacterials which are commonly used during pregnancy, including penicillins, beta-lactam inhibitors, cephalosporins, macrolides, aminoglycosides, tetracyclines, lincosamides, fluoroquinolones, sulfonamides, nitrofurans, and anti-tubercular agents. Some of these drugs have been on the market for many years, whereas others are relatively new and increasingly popular, despite the fact that the older drugs remain very effective. After reviewing the evidence-based information from epidemiological studies, it appears that most antibacterial agents can be used relatively safely during pregnancy. Women who are pregnant should not be denied appropriate antibacterial therapy because of a lack of information. It is possible to treat the mother, while protecting the unborn child, by prescribing an agent that the causative bacteria is sensitive to, rather than a perceived 'safer' option that may not effectively treat the infection and which may also add to the growing problem of bacterial resistance.

Animals↗