Papers by Benjamin Bar-oz
Diabetes, 1987
Somatostatin has been widely used to suppress endogenous pancreatic hormone secretion in research... more Somatostatin has been widely used to suppress endogenous pancreatic hormone secretion in research studies. Many of these studies required the simultaneous infusion of a hormone together with somatostatin. A critical assumption for its use in metabolic investigation is that somatostatin has no effect on the action or clearance of a concomitantly infused hormone. To test whether clearance of an exogenously infused hormone is affected, we infused insulin with or without somatostatin in two sets of studies. Insulin (40 mU kg 1 • h 1) was infused for 100 min (n = 6). Plasma glucose levels fell to 55 ± 4.1 mg/dl with insulin alone and significantly lower, to 44 ± 1.9 mg/dl, when somatostatin (250 |ag h) was also infused (P < .01). Plasma immunoreactive insulin (IRI) rose to 57 ± 12.5 |xll/ml with insulin alone, which was significantly different from 88 ± 15 fxll/ml when insulin was infused together with somatostatin (P < .01). When a smaller dose of insulin (30 mU kg 1 h 1) was infused for 100 min (n = 4), similar results were observed. When somatostatin was infused together with insulin, plasma glucose fell to lower levels (41 ± 4.2 vs. 62 ± 9.5 mg/dl; P < .01) and plasma IRI rose higher (39 ± 8.5 vs. 27 ± 5.9 jxU/ml; P < .01) than when insulin was infused alone. C-peptide was equally suppressed by hypoglycemia regardless of whether somatostatin was administered, indicating suppression of endogenous insulin during these studies. We conclude that somatostatin infusion impairs the clearance of exogenous insulin. The resulting higher plasma IRI levels may contribute to the exaggerated hypoglycemia observed when somatostatin is infused with insulin. Impairment of clearance must be considered in the interpretation of metabolic studies where insulin and perhaps other
CNS Drugs, 2008
treatment of bipolar disorder and migraine. It is a known human teratogen. The objective of the s... more treatment of bipolar disorder and migraine. It is a known human teratogen. The objective of the study was to evaluate the teratogenic risk of valproate. Methods: All callers who contacted the Israeli Teratology Information Service (TIS) between 1994 and 2004 for information about gestational exposure to valproate were enrolled in the study. After the expected date of delivery, these women were followed up by telephone interview about their pregnancy outcome using a structured questionnaire. Data obtained from women who contacted the TIS about valproate exposure during pregnancy were then compared with data obtained from callers who were counselled for nonteratogenic exposures over the same timeframe. The main outcome measure was the rate of major congenital anomalies. Diav-Citrin et al. Conclusion: When valproate treatment cannot be avoided in the first trimester of pregnancy, the lowest effective dose should be prescribed, preferably as monotherapy, to minimize its teratogenic risk. graine. These illnesses are common in women of Registry, major congenital anomalies were reported childbearing age. In animal studies, valproate has in 26 of 268 (9.7%) children born to women treated been shown to be teratogenic in all of the six laborawith valproate monotherapy early in pregnancy. [15] tory species tested. [1] It has induced malformations This rate was significantly greater than the rate of multiple organs in mice, rats and gerbils; renal among infants whose mothers were treated with and skeletal defects in rabbits; neural tube defects other antiepileptics early in pregnancy. A similar (NTDs) in hamsters; and craniofacial and appendicmalformation rate of 16 of 149 (10.7%) children ular skeletal defects in primates. In a study comparwas recently described in the North American Aning the teratogenic potential of antiepileptic drugs in tiepileptic Drug Pregnancy Registry. [16] Other studmice, valproate had the greatest relative teratogenic ies have also found an increased risk of major malindex. [2] formations after gestational exposure to val-The first report suggesting teratogenicity of valproate. [14,17-24] In most of these studies, valproate proate in humans was published in 1980. [3] The first was associated with greater teratogenic potential cases of lumbosacral spina bifida with meningomythan other antiepileptic drugs. Some of these studelocele or meningocele in children whose mothers ies are retrospective and many are registry-based. took valproate in the first trimester of pregnancy Often, the time of outcome assessment was at birth. were reported in the early 1980s. [4-6] A French case-Data are lacking on elective terminations of pregcontrol study based on data collected by a birth nancy for fetal anomalies, and analysis of condefects surveillance system in Lyon found an unusufounding factors is not always available. In a metaally high proportion of infants with spina bifida analysis based on >1700 exposed infants reported in whose mothers took valproate in the first trimes-11 controlled cohort studies with first trimester exter. [7,8] The calculated odds ratio for the association posure to valproate, a 2.59-fold increase in the rate of spina bifida after exposure to valproate according of major malformations was found when compared to these investigators was 20.6. These findings were with all other antiepileptic drugs, and there was a confirmed by the International Clearinghouse for 3.77-fold increase when compared with the general Birth Defects Monitoring Systems. [9] In a prospecpopulation. [25] tive cohort study, [10] the prevalence of spina bifida In utero exposure to valproate also has a serious among all valproate-exposed children was >5%. In impact on the neurodevelopment of children. [26-28] this study, a valproate daily dose of 1000 mg was Polytherapy regimens with valproate and other defined as the threshold above which an increased antiepileptic drugs have been shown to carry a risk of spina bifida should be considered. Fetal higher teratogenic risk than monotherapy. [27,29-31] valproate syndrome was described in 1984 and refers to a consistent craniofacial phenotype, often Randomized clinical trials are unlikely to be conwith major malformations, growth deficiency or ducted among pregnant women for ethical and pracneurodevelopmental dysfunction. [11] Other congeni-tical considerations. The aim of the present study tal malformations associated with exposure to val-was to prospectively evaluate the rate of major con-gy,
Clinical Therapeutics, 2007
This review investigated whether first-trimester exposure to paroxetine is associated with an inc... more This review investigated whether first-trimester exposure to paroxetine is associated with an increased risk of congenital malformations. The authors concluded that first trimester exposure to paroxetine appears to be associated with a significant increase in the risk of cardiac malformation. However, the reliability of these conclusions is unclear as insufficient details of the included studies were provided. Searching MEDLINE, EMBASE, REPROTOX, Scopus and Biological Abstracts were searched from 1985 to 2006; the search terms were reported. Reference lists of retrieved studies, proceedings from meetings of professional societies, textbooks and Internet websites were also checked for additional articles. No language restrictions were applied. Study selection Study designs of evaluations included in the review Case-control and cohort studies (prospective and retrospective) were eligible for inclusion as long as both groups were drawn from the same population. Experimental studies and case reports were excluded. The included studies were of the following designs: nested case-control, prospective controlled, population-based cohort, retrospective cohort and prospective recording-registry. Specific interventions included in the review Studies that examined the effects of exposure to paroxetine were eligible for inclusion. The control groups consisted of women using antidepressants other than paroxetine, or other non-teratogenic medications. Participants included in the review Studies of women in the first trimester of pregnancy (0 to 14 weeks' gestation) were eligible for inclusion. Outcomes assessed in the review Studies that reported on the number of major congenital malformations and/or the number of cardiac congenital malformations were eligible for inclusion. Outcomes were only considered for live births. How were decisions on the relevance of primary studies made? Two reviewers independently selected studies for inclusion. Any discrepancies were resolved using a third reviewer. Assessment of study quality The quality of the included studies was assessed using a 27-item scale based on a published checklist, with a summary quality score based on the percentage of items fulfilled. The authors did not state how many reviewers performed the quality assessment.
Clinical Genetics, 2008
To the Editor: The syndrome of osteopathia striata with cranial sclerosis (OSCS) is a rare autoso... more To the Editor: The syndrome of osteopathia striata with cranial sclerosis (OSCS) is a rare autosomal dominant disorder which affects mainly the skeletal system. Anomalies of the heart, central nervous system and the oral cavity have also been reported (Bass et al. 1980, Gorlin et al. 1990). We have recently encountered a case in which a duodenal malformation Wac found in addition to other features characteristic of o s c s . A 2020-g male newborn was delivered following 34 weeks of uneventful gestation. He was the second offspring of unrelated parents. The 28-year-old mother has macrocephaly, frontal bossing, prominent epicanthal folds, downslanting palpebral fissures and a broad nasal bridge. Maternal x-ray of the long bones demonstrated longitudinal striation characteristic of osteopathia striata. The skull x-ray showed severe sclerosis, bony obliteration of the sinuses and thickening of the base of the skull. Based on these features, she was diagnosed as having OSCS. Physical examination of the newborn disclosed a large triangular head with a circumference of 34 cm (90th percentile), low and wide nasal bridge and small dysplastic ears, features consistent with OSCS. Skull x-ray showed no sclerosis and long bone films showed no striations. Chromosomal study was normal. The baby had respiratory distress syndrome and later developed chronic lung changes requiring prolonged mechanical ventilation and supplementation of oxygen. Echocardiography demonstrated patent ductus arteriosus and ventricular septa1 defect. Attempts to feed the infant enterally were unsuccessful. Plain abdominal x-ray and ultrasonographic examination were considered normal. An upper gasReceived 26 April 1994, revised version received 15 September 1995, accepted for publication 10 October 1995
British Journal of Anaesthesia, 2009
Canadian Family Physician, 2003
QUESTION A 34-year-old patient of mine is taking a "statin" for hyperlipidemia. She is planning p... more QUESTION A 34-year-old patient of mine is taking a "statin" for hyperlipidemia. She is planning pregnancy and is worried about the safety of the drug. How should I advise her? ANSWER Limited evidence from animal and human studies indicates that statins should not be taken during pregnancy. If a patient is inadvertently exposed during pregnancy, however, termination does not appear to be medically indicated. RÉSUMÉ QUESTION Une de mes patientes prend des « statines » contre l'hyperlipidémie. Elle planifi e une grossesse et s'inquiète à propos de la sécurité de ce médicament. Comment puis-je la conseiller? RÉPONSE Des données scientifi ques limitées, tirées d'études chez les animaux et les humains, indiquent que les statines ne devraient pas être prises durant la grossesse. Si une patiente était exposée à ce médicament par inadvertance pendant qu'elle est enceinte, il n'est cependant pas indiqué sur le plan médical de mettre un terme à la grossesse. Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Drs Bar-Oz and Ito are members of the Motherisk Program.
Archives of Disease in Childhood - Fetal and Neonatal Edition, 2003
Background: Meconium and hair are two biological markers of in utero exposure to illicit drugs. O... more Background: Meconium and hair are two biological markers of in utero exposure to illicit drugs. Objective: To compare the sensitivity of the two tests for different drugs. Setting: Motherisk laboratory which tests in utero drug exposure in Toronto. Methods: Cocaine, benzoylecgonine, opiates, cannabis, benzodiazepines, methadone, and barbiturates were measured in pairs of hair and meconium samples from the same neonates. Results: Meconium was marginally more sensitive than neonatal hair for detection of cocaine and cannabis, possibly because it may detect second trimester exposure whereas hair grows only during the third trimester of pregnancy. There was a significant correlation between hair and meconium concentrations of cocaine, cannabis, and opiates. Conclusion: In cases of clinical suspicion and a negative neonatal urine test, both meconium and hair are effective biological markers of in utero illicit drug exposure. Meconium may be more sensitive, but neonatal hair is available for three months whereas meconium is available for only one or two days. In contrast, the use of meconium, being a discarded material, is more acceptable to some parents than hair testing, which entails cutting scalp hair from the newborn.
Archives of Disease in Childhood, 2013
Pediatric Drugs, 2000
Progress in the diagnosis and management of seizure disorders and the availability of effective a... more Progress in the diagnosis and management of seizure disorders and the availability of effective anticonvulsive medications has enabled increasing numbers of epileptic women of child-bearing age to raise families. Breast feeding, which these women may wish to choose, provides health, nutritional, immunological, developmental, social, economic and environmental benefits. The traditional anticonvulsants, such as phenytoin, carbamazepine and valproic acid (valproate sodium), are generally considered safe for use during breast feeding; however, observation for adverse effects is recommended. The use of phenobarbital while breast feeding is controversial because of its slow elimination by the nursing infant.
Isr Med Assoc J, 2008
It has been estimated that 770,000 patients are injured or die yearly from medication errors and ... more It has been estimated that 770,000 patients are injured or die yearly from medication errors and adverse drug events in the United States. Studies have estimated that 2 to 7 of every 100 admissions are affected by adverse drug events. It has further been estimated that approximately half ...
The Lancet, 1999
The rate of congenital malformations after first-trimester exposure to itraconazole was four time... more The rate of congenital malformations after first-trimester exposure to itraconazole was four times higher when ascertained retrospectively than prospectively (13.0 vs 3.2%, p=0.006). Reporting bias in retrospective studies should be acknowledged in interpretation of such data.
The Journal of Physiological Sciences, 2008
Preterm infants are highly susceptible to ischemic damage. This damage is most obvious in the bra... more Preterm infants are highly susceptible to ischemic damage. This damage is most obvious in the brain, retina, and gastrointestinal tract. Studies focusing on the rheological properties of premature red blood cells (pRBCs) have consistently shown minimal or no RBC aggregation. Previously, measurements of pRBC aggregation kinetics indicated that specific plasma properties are responsible for the decreased RBC aggregation observed in the neonates, but that their specific RBC properties do not affect it. However, the strength of interaction in the pRBC aggregates as a function of medium composition has not been tested. In our previous research, we described clinically relevant parameters, that is, the aggregate resistance to dis-aggregation by flow. With the help of a cell flow property analyzer (CFA), we can monitor RBC aggregation by direct visualization of its dynamics during flow. We used the CFA to examine pRBC (from 9 premature babies) in the natural plasma and in PBS buffer supplemented with dextran (500 kDa) to distinguish between RBC intrinsic-cellular and plasma factors. pRBCs suspended in the native plasma showed minimal or no aggregation in comparison to normal adult RBC. When we transferred pRBCs from the same sample to the dextran solution, enhanced resistance to disaggregation by flow was apparent.
Drug Safety, 2003
logical treatment. Because of the many health advantages of human milk to infants, breast feeding... more logical treatment. Because of the many health advantages of human milk to infants, breast feeding should be interrupted only when the needed drug might be harmful to the nursing child and exposure via the breast milk will be sufficient to pose a risk. Since the majority of drugs have not been shown to cause adverse
Pediatric …, 2009
In cardiology, B-type natriuretic peptide and the amino terminal segment of its prohormone (NT-pr... more In cardiology, B-type natriuretic peptide and the amino terminal segment of its prohormone (NT-proB-NP) are important biomarkers. The importance of these peptides as markers for heart disease in pediatric cardiology is reviewed. The peptide levels are dependent on age, assay, and possibly gender. The normal value range and upper limits for infants and children are needed. To determine reference values, data were combined from four studies that measured NT-proBNP levels in normal infants and children using the same electrochemiluminescence assay. The age intervals for the upper limits of normal were chosen for intervals in which no age-dependent change was observed. Statistical analysis was performed on log-transformed data. A total of 690 subjects (47% males) ages birth to 18 years were included in the review. The levels of NT-proBNP were highest in the first days of life, then showed a marked decline in the first week or weeks. The peptide levels continued to decline gradually with age (r = 0.43; p \ 0.001). Male and female levels differed only for children ages 10 to 14 years. However, the upper limit of normal did not differ between the boys and girls in any age group. The findings lead to the conclusion that B-type natriuretic peptide (BNP) and NT-proBNP are important markers for heart disease in pediatric cardiology. The levels of NT-proBNP are highest in the first days of life and decrease drastically thereafter. A mild gradual decline occurs with age throughout childhood. Girls have somewhat higher levels of NT-proBNP during puberty.
Vox Sanguinis, 1995
In order to examine the effect of intravenous immunoglobulin (IVIG) on the rate of hemolysis in i... more In order to examine the effect of intravenous immunoglobulin (IVIG) on the rate of hemolysis in immune hemolytic hyperbilirubinemia, we measured the carboxyhemoglobin levels of 5 newborn infants who were subjected to IVIG treatment. The pretreatment rate of hemolysis, in the 5 patients with isoimmune hemolytic jaundice (3 patients with Rh hemolytic disease of the newborn and 2 patients with ABO hemolytic disease of the newborn), as reflected by caboxyhemoglobin levels was higher than the rate of hemolysis in normal newborn infants. In 4 out of the 5 patients treated with IVIG, there was a rapid decline (> 30%) of carboxyhemoglobin levels, a pattern which was different from that observed in normal newborn infants with no hemolytic jaundice and in 3 untreated patients with ABO hemolytic disease of the newborn. None of the treated patients required an exchange transfusion. Our preliminary results support the theory that the attenuation of jaundice observed following IVIG treatment i...
European Journal of Obstetrics & Gynecology and Reproductive Biology, 1999
Objective: To compare the neonatal outcome (survival, intraventricular hemorrhage and bronchopulm... more Objective: To compare the neonatal outcome (survival, intraventricular hemorrhage and bronchopulmonary dysplasia) of inborn and outborn very-low-birth-weight infants accounting for sociodemographic, obstetric and perinatal variables. Study design: Ninety-one premature infants with birth weights of 750-1250 g delivered between 1990 and 1994 in a hospital providing neonatal intensive care were compared with 76 premature babies delivered in a referring hospital. In the statistical analysis, variables with a statistically significant association with the outcome variables and dissimilar distributions in the two hospitals were identified and entered together with the hospital of birth as explanatory variables in a logistic regression. Results: No statistically significant differences between the outcome variables of the two populations examined were observed, whether before or after accounting for the covariates. The odds ratios (outborns relative to inborns) were 1.18 for mortality, 1.25 for bronchopulmonary dysplasia and 1.53 for severe intraventricular hemorrhage. In the multivariate analyses, respiratory distress syndrome was significantly associated with mortality; both low birth weight and the presence of respiratory distress syndrome were associated with the development of bronchopulmonary dysplasia; the evolvement of severe intraventricular hemorrhage was associated with respiratory distress syndrome, initial low Apgar score, advanced multiparity and delivery at the 28-29th week compared to the 23rd-27th week. Antenatal steroid administration had a protective effect. Conclusion: Our results concur with the notion that a tertiary center is the optimal location for delivery of the high risk neonate. Improvement in medical and nursing care prenatally and at delivery and transportation, including frequent administration of antenatal steroids and earlier administration of surfactant prior to transportation, may minimize the disadvantage of delivery in a referring hospital.
Toxicology letters, 2009
Hepcidin is an important and recently discovered regulator of iron homeostasis. Acute iron intoxi... more Hepcidin is an important and recently discovered regulator of iron homeostasis. Acute iron intoxication is one of the leading causes of overdose mortality in children. It is difficult to estimate the degree of iron intoxication since iron serum levels do not correlate with the actual clinical severity. In the current study we aimed to investigate whether serum hepcidin levels are elevated in acute iron intoxication. Rats were divided into two iron dose groups and one control group. Each group was further subdivided into four time groups following the administration of iron. Levels of hepcidin, iron and liver enzymes were measured, and animals were followed for signs of toxicity. Serum hepcidin levels were significantly higher in the group treated with toxic doses of iron (p=0.005). No significant difference in serum iron levels was found between the groups. In acute iron intoxication serum hepcidin levels increase significantly and remain elevated for at least 6h. We postulate that beyond the first hour after iron administration, serum hepcidin levels provide a better estimate of the amount of iron intake than do serum iron levels.
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Papers by Benjamin Bar-oz