Showing papers by "Gideon Koren published in 2011"

The Human Placental Perfusion Model: A Systematic Review and Development of a Model to Predict In Vivo Transfer of Therapeutic Drugs

Abstract: Dual perfusion of a single placental lobule is the only experimental model to study human placental transfer of substances in organized placental tissue. To date, there has not been any attempt at a systematic evaluation of this model. The aim of this study was to systematically evaluate the perfusion model in predicting placental drug transfer and to develop a pharmacokinetic model to account for nonplacental pharmacokinetic parameters in the perfusion results. In general, the fetal-to-maternal drug concentration ratios matched well between placental perfusion experiments and in vivo samples taken at the time of delivery of the infant. After modeling for differences in maternal and fetal/neonatal protein binding and blood pH, the perfusion results were able to accurately predict in vivo transfer at steady state (R² = 0.85, P < 0.0001). Placental perfusion experiments can be used to predict placental drug transfer when adjusting for extra parameters and can be useful for assessing drug therapy risks and benefits in pregnancy.

Recurrence and Outcomes of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children

Abstract: OBJECTIVES: To report clinical course, etiology, management, and long-term outcomes of children suffering from Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). METHODS: We conducted a study of all pediatric patients with SJS or TEN admitted between 2000 and 2007 to the Hospital for Sick Children and Children9s Hospital Boston, and particular attention was paid to clinical manifestations, etiology, mortality, and long-term outcomes. RESULTS: We identified 55 cases of SJS (n = 47), TEN (n = 5), or SJS/TEN overlap syndrome (n = 3). Drugs were identified as the most likely etiologic agent in 29 children (53%); antiepileptic drugs were the most common agents (n = 16), followed by sulfonamide antibiotics (n = 7) and chemotherapy drugs (n = 2). Acute Mycoplasma pneumoniae infection was confirmed in 12 children (22%), and herpes simplex virus was confirmed in 5 children (9%). Treatment regimens differed significantly between participating sites and included systemic antimicrobial agents (67%), systemic corticosteroids (40%), and antiviral drugs (31%). Intravenous immunoglobulin was administered to 21 children (38%), of whom 8 received concomitant systemic corticosteroids. Ten children (18%) had recurrence of SJS up to 7 years after the index episode, and 3 experienced multiple recurrences. Twenty-six children (47%) suffered long-term sequelae that mostly involved the skin and eyes. CONCLUSIONS: Mortality rate in children was lower than that reported in adults, but half of affected children suffered long-term complications. The recurrence rate of SJS was high (1 in 5), which suggests vulnerability and potential genetic predisposition. In the absence of standardized management guidelines for these conditions, treatment regimens differed significantly between participating institutions.

Hair cortisol and the risk for acute myocardial infarction in adult men.

Abstract: Acute stress is increasingly recognized as a precipitant of acute myocardial infarction (AMI). However, the role of chronic stress in developing AMI is less clear. We have developed a method to measure cortisol in hair, which allows longitudinal assessment of cortisol levels prior to an acute event. We aimed to evaluate the hypothesis that chronic stress, as assessed by hair cortisol content, is associated with the development of AMI. A prospective case-control study included 56 patients admitted to hospital with AMI and 56 control patients, admitted to internal medicine wards for other indications. An enzyme immunoassay technique was used to measure cortisol in the most proximal 3 cm of hair, considered to represent the most recent 3 months of exposure. Median hair cortisol contents (range) were 295.3 (105.4-809.3)ng/g in AMI patients and 224.9 (76.58-949.9)ng/g in controls (p = 0.006, Mann-Whitney U-test). After controlling for other risk factors for AMI using multiple logistic regression, log-transformed hair cortisol content remained the strongest predictor (OR 17.4, 95% CI 2.15-140.5; p = 0.007). We demonstrated elevated hair cortisol concentrations in patients with AMI. This suggests that chronic stress, as assessed by increased hair cortisol in the 3 months prior to the event, may be a contributing factor for AMI.

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients.

Abstract: Background Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. Method We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. Results Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements ( r s = –0.447, p = 0.004) and the concentration/dose ratio (r s = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio ( R 2 = 0.351, p = 0.001 and R 2 = 0.521, p CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. Conclusion Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.

Motherisk Rounds: The Fetal Safety of Benzodiazepines: An Updated Meta-analysis

Abstract: Benzodiazepines are commonly used by women of reproductive age, and hence many pregnant women are exposed to them. An updated meta-analysis of their fetal safety synthesized nine studies with over one million pregnancies, yielding an odds ratio of 1.07 (95% CI 0.91 to 1.25). While benzodiazepines do not appear to increase teratogenic risk in general, case-controls suggest a twofold increased risk of oral cleft.

Quality assessment of observational studies in psychiatry: an example from perinatal psychiatric research.

Abstract: In perinatal psychiatry, randomized controlled trials are often not feasible on ethical grounds. Many studies are observational in nature, while others employ large databases not designed primarily for research purposes. Quality assessment of the resulting research is complicated by a lack of standardized tools specifically for this purpose. The aim of this paper is to describe the Systematic Assessment of Quality in Observational Research (SAQOR), a quality assessment tool our team devised for a series of systematic reviews and meta-analyses of evidence-based literature regarding risks and benefits of antidepressant medication during pregnancy.

Proximity-induced superconductivity in topological Bi 2 Te 2 Se and Bi 2 Se 3 films: Robust zero-energy bound state possibly due to Majorana fermions

Abstract: Point contact conductance measurements on topological Bi${}_{2}$Te${}_{2}$Se and Bi${}_{2}$Se${}_{3}$ films reveal a signature of superconductivity below 2--3 K. In particular, critical current dips and a robust zero-bias conductance peak are observed. The latter suggests the presence of zero-energy bound states that could be assigned to Majorana fermions in an unconventional topological superconductor. We attribute these observations to proximity-induced local superconductivity in the films by small amounts of superconducting Bi inclusions or segregation to the surface, and provide supportive evidence for these effects.

Safety of Insulin Glargine Use in Pregnancy: A Systematic Review and Meta-Analysis

Abstract: BackgroundThe prevalence of diabetes in women of childbearing age is increasing. As such, the number of pregnancies complicated by diabetes will inevitably increase. New insulin analogues such as the long-acting analogue Insulin glargine may represent beneficial treatment options in pregnancy by ensuring that patients achieve excellent glycemic control without risk of maternal hypoglycemia.ObjectiveTo determine the fetal safety of insulin glargine use in the treatment of diabetes in pregnancy compared with NPH insulin therapy.MethodsA systematic review and meta-analysis was performed of all original human studies that reported neonatal outcomes among women with pregestational or gestational diabetes who were managed with either insulin glargine or NPH insulin during pregnancy. A systematic literature search was conducted using MEDLINE, EMBASE, CINAHL, the Cochrane Central Register for Controlled Trials database, and Web of Science from 1980 to June 1, 2010. Outcomes included large size for gestational age...

Ocular Toxicity in Children Exposed in Utero to Antimalarial Drugs: Review of the Literature

Abstract: Objective. The antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been used for decades to treat rheumatic diseases. CQ is still beneficial for the management of malaria during pregnancy. A growing body of research suggests that antimalarials are safe during pregnancy. There have been concerns about adverse longterm effects, mainly retinal toxicity, in offspring of women exposed to antimalarials during pregnancy. Our objective was to review the published evidence on safety of antimalarials during pregnancy, focusing on ocular toxicity in the offspring. Methods. Ovid Medline, Embase, and Cochrane Library databases were searched for the period from their inception to May 2010 inclusive with no restrictions on language or year of publication. Randomized controlled trials (RCT) and observational studies examining the safety of CQ or HCQ during pregnancy and reporting on visual function or ocular toxicity in the offspring of exposed women at any point of the followup were eligible for inclusion. The quality of evidence was assessed according to established criteria (the GRADE approach). Results. Twelve studies with a total of 588 offspring born to mothers treated with CQ or HCQ during pregnancy met the inclusion criteria. Five studies with a total of 251 exposed children reported no clinical visual abnormalities in any case. In an RCT on malaria prophylaxis, visual acuity in 251 infants exposed to CQ in utero did not differ from the placebo group. Detailed ophthalmological examination was performed in 4 studies and normal results were reported in all children (n = 59). Electro-physiological testing using electroretinogram was performed in 3 small cohorts and results were normal in all but 6 infants aged 3–7 months. All 6 children had normal fundoscopy before 4 years of age. Heterogeneity in comparison groups and in outcome measures precluded formal metaanalysis. Conclusion. Current evidence suggests no fetal ocular toxicity of antimalarial medications during pregnancy. The clinical significance of early electroretinogram anomalies reported in a small subset of infants remains to be established. Larger followup studies are warranted to confirm low risk of ocular toxicity in children following antenatal exposure to antimalarial medications.

Impact of hair-care products on FAEE hair concentrations in substance abuse monitoring

Abstract: Previous studies have indicated that the use of high-ethanol-content (>65%) hair-care products may elevate fatty acid ethyl ester (FAEE) concentrations in hair. In this case series, nine individuals were identified by FAEE analysis to be chronic alcohol abusers in the context of child-welfare substance abuse monitoring. Based on patient claims of moderate or no alcohol consumption, the presence of ethanol in the patients’ hair-care regimens was investigated. Samples were additionally tested for the presence of ethyl glucuronide (EtG). From a total of nine patients, 12 hair samples were submitted for analysis. Patient histories were obtained as well as Material Safety Data Sheets (MSDS) listing hair-care product ethanol content. Hair samples were pre-washed to remove external contamination and analyzed for FAEE and EtG by GC-MS. According to the Society of Hair Testing consensus guidelines, FAEE levels exceeding 0.50 ng/mg and/or EtG levels exceeding 30 pg/mg indicate chronic excessive alcohol consumption. Upon initial analysis, the nine samples exhibited positive FAEE findings ranging from 0.496 to 4.984 ng/mg. MSDS review revealed the presence of ethanol from 10% to 95% by volume in at least one hair-care product used by each individual. Results of the EtG analysis ranged from 1.9 to 23.5 pg/mg. These findings indicate that regular use of products with ethanol content as low as 10% can impact FAEE results. EtG analysis should be used to confirm FAEE findings and appears to be unaffected by hair-care products, likely due to alternative mechanisms of incorporation.

Teratogenicity of angiotensin converting enzyme inhibitors or receptor blockers

Abstract: Studies of 1st trimester exposure to ACE inhibitors and angiotensin receptor blockers examining teratogenicity have shown conflicting results. We systematically reviewed the literature and performed a meta-analysis evaluating the risk of major malformations. For the meta-analysis, we included studies comparing 1st trimester exposure to no exposure, or to exposure to other antihypertensives. Additionally, we conducted a qualitative analysis of studies that did not meet the inclusion criteria for the meta-analysis. A significant risk ratio was found when the exposed group was compared with healthy controls but not when compared with other antihypertensives. The qualitative analysis did not demonstrate a specific pattern of major malformations. Our results suggest that 1st trimester exposure to ACE inhibitors and angiotensin receptor blockers is not associated with an elevated risk of major malformations compared with other antihypertensives. A 1st trimester exposure to antihypertensives in general may be associated with an elevated risk of major malformations.

Hair cortisol content in patients with adrenal insufficiency on hydrocortisone replacement therapy.

Abstract: Summary Objective Patients with adrenal insufficiency (AI) require life-long replacement therapy with exogenous glucocorticoids. Several studies have shown impaired subjective health status in these patients as well as increased morbidity and mortality risk, which may be caused by glucocorticoid over-replacement. As a measure of long-term cortisol exposure, the usefulness of hair cortisol analysis in patients receiving glucocorticoid replacement therapy was investigated. Patients and design Hair samples, demographics, medical history and perceived stress scale questionnaires were collected from 93 patients across North America diagnosed with primary or secondary AI. Sixty-two household partners served as a control group. Cortisol was measured in the proximal 2 cm of hair, representing the most recent 2 months of exposure. A modified enzyme immunoassay was used for the measurement of cortisol. Results The male patients had significantly higher hair cortisol levels than the male controls (P < 0·05), while there was no significant difference among females. Hair cortisol content correlated significantly with glucocorticoid dose (r = 0·3, P < 0·01). Patients with AI had significantly higher subjective stress scores than control subjects. Conclusions Hair cortisol content correlates with hydrocortisone (HC) dose in patients with AI. Our results suggest that some AI patients may be over-treated and hence may be at risk for the adverse effects of cortisol. Measurement of HC in hair may become a useful monitoring tool for long-term cortisol exposure in patients treated with glucocorticoids.

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

Abstract: Purpose In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients.

Leukemia and Lymphoma in Pregnancy

Abstract: Treatment of pregnant women with chemotherapy may pose a risk to the fetus, raising therapeutic, ethical, moral, and social dilemmas. Publications on this issue are limited to retrospective series and case reports, thus further complicating decision making. Diagnosis and staging are usually performed as in nonpregnant women, but procedures that expose the fetus to radiation are excluded. Chemotherapy is not recommended in the first trimester to avoid fetal malformations. Thus, the option is either treatment delay or pregnancy termination. Later in pregnancy, treatment is often initiated without delay, with no apparent evidence of teratogenicity.

CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study.

Abstract: Background:Codeine, a common opiate prescribed for pain postcesarean section (c-section), is biotransformed by the highly polymorphic Cytochrome P450 enzyme 2D6 (CYP2D6). Ultrarapid metabolizers (UMs), individuals with multiple active copies of CYP2D6, can biotranform up to 50% more codeine into mor

Congenital varicella syndrome: the evidence for secondary prevention with varicella-zoster immune globulin

Abstract: A 33-year-old woman who was engaged to be married presented for her initial visit with an obstetrician. Her varicella-zoster IgG antibody titer, as measured by latex agglutination, was < 0.91, which signified nonimmunity. The patient did not know if she had previously had varicella. She had not been

Perception of teratogenic risk and the rated likelihood of pregnancy termination: association with maternal depression.

Abstract: Objective:Women are often exposed to various medications and medical conditions during pregnancy. Unrealistically high maternal teratogenic risk perception, related to these exposures, may lead to abrupt discontinuation of therapy and (or) termination of a wanted pregnancy. The association between maternal depression and the teratogenic risk perception has not been studied, nor were the actions resulting from this perception. Our objectives were to explore the association between maternal depression, teratogenic risk perception, and the rated likelihood to terminate pregnancy. Additionally, we evaluated possible benefits of counselling.Methods:We administered the Edinburgh Postnatal Depression Scale (EPDS) to all women who attended the Motherisk Clinic between October 2007 and April 2010. A visual analogue scale was used to determine maternal risk perception in relation to the specific exposure, and the rated likelihood to terminate the pregnancy, before and after counselling.Results:We analyzed data from...

Pediatric cancer rates after universal folic acid flour fortification in Ontario.

Abstract: Following the introduction of mandatory Canadian folic acid flour fortification in mid-1997, the incidence of selected childhood cancers that declined in Ontario prior to and subsequent to this public policy initiative was examined. A population-based cohort study of all incident cases of childhood malignancy in Ontario between the years 1985 and 2006 was conducted. Participants were identified from a database provided by the Pediatric Oncology Group of Ontario and included children 0 to 4 years of age and 5 to 9 years of age who were diagnosed with cancer. Among children aged 0 to 4 years, the incidence rate of Wilms' tumor declined from 1.94 to 1.43 per 100,000 (incidence rate ratio 0.74, 95% confidence interval, 0.57-0.95). No significant change was seen in the prefortification vs postfortification time periods for acute lymphoblastic leukemia, brain cancers, or embryonal cancers among the 0- to 4-year or 5- to 9-year age groups. There was an approximately 30% reduction in risk of Wilms' tumor following introduction of the initiative. This corroborates a recent case-control study from Germany. These data may also provide some reassurance that universal flour fortification does not heighten the risk of pediatric cancer.

Cyclosporine and lactation: when the mother is willing to breastfeed.

Abstract: We describe a woman treated with cyclosporine after renal transplantation who commenced breastfeeding of her newborn infant. The child had no apparent clinical adverse effects to cyclosporine. To confirm the safety of breastfeeding and guide the patient and her clinician, cyclosporine concentrations in maternal blood, breast milk, and infant blood were measured. Maternal cyclosporine concentration (1-hour postdose) was 49 μg/L, and the breast milk cyclosporine concentration (2-hour postdose) was 46 μg/L. Infant cyclosporine blood concentration shortly after breastfeeding was undetectable (<10 μg/L). Analysis revealed that the estimated infant exposure to cyclosporine via breast milk was minimal and provided reassurance to continue breastfeeding in this case.

Safety of azathioprine use during pregnancy

Abstract: Question Quite a few of my female patients with rheumatic diseases and inflammatory bowel disease are using azathioprine. They are afraid to take a “cancer drug” during pregnancy. What is known about the risks? Answer An increasing body of evidence from prospective cohort studies suggests that azathioprine is safe for the fetus during pregnancy.

The effect of distant reiki on pain in women after elective Caesarean section: a double-blinded randomised controlled trial

Abstract: Introduction Approximately 25% of all babies in North America are delivered via Caesarean section (C-section). Though a common surgical procedure, C-section recovery can be painful. Opioids, specifically codeine, are commonly used to ease pain; however, its active metabolite, morphine, passes into breast milk, and may produce unwanted side effects in neonates; therefore, alternatives to opioids are being sought. Reiki is an ancient Japanese form of healing where practitioners transfer healing energy through light touch and positive healing intention. Although 1.2 million Americans use reiki to reduce pain or depression, there is a lack of strong evidence supporting its effectiveness. A recent systematic review showed existing studies to be of poor methodological quality, with the common limitation of lack of blinding. To overcome this issue, the authors used distant reiki to assess its effectiveness in reducing pain following an elective C-section. Methods In this randomised, double-blinded study, women who underwent an elective C-section were allocated to either usual care (control, n=40) or three distant reiki sessions in addition to usual care (n=40). Pain was assessed using a visual analogue scale (VAS). The primary endpoint was the Area Under the VAS-Time Curve (AUC) for days 1–3. Secondary measures included: the proportion of women who required opioid medications and dose consumed, rate of healing and vital signs. Results AUC for pain was not significantly different in the distant reiki and control groups (mean±SD; 212.1±104.7 vs 223.1±117.8; p=0.96). There were no significant differences in opioid consumption or rate of healing; however, the distant reiki group had a significantly lower heart rate (74.3±8.1 bpm vs 79.8±7.9 bpm, p=0.003) and blood pressure (106.4±9.7 mm Hg vs 111.9±11.0 mm Hg, p=0.02) post surgery. Conclusion Distant reiki had no significant effect on pain following an elective C-section. Clinical Trial Registration Number ISRCTN79265996.

A comparison of folic acid pharmacokinetics in obese and nonobese women of childbearing age.

Abstract: Background:Although maternal folate deficiency during the periconceptional period represents a major risk factor for neural tube defects, obesity has been recognized as an additional risk factor. Studies have identified an increased risk for neural tube defect-affected births among obese mothers eve

Pharmacological activation of Kv11.1 in transgenic long QT-1 rabbits.

Abstract: :Transgenic rabbits expressing pore mutants of KV7.1 display a long QT syndrome 1 (LQT1) phenotype. Recently, NS1643 has been described to increase IKr. We hypothesized that NS1643 would shorten the action potential duration (APD90) in LQT1 rabbits. Transgenic LQT1 rabbits were compared with

A differential approach for examining the behavioural phenotype of fetal alcohol spectrum disorders.

Abstract: Background In 2006, Nash and colleagues published results suggesting that individual items from the Child Behavior Checklist (CBCL) could be used as a screening tool that was highly sensitive in differentiating children with FASD from controls and children with Attention Deficit Hyperactivity Disorder (ADHD). Since many of the items referred to features of Oppositional Defiant/Conduct Disorder (ODD/CD), it was not clear whether the items reflected comorbidity with ODD/CD, or were unique to children with FASD. Objectives The present study sought to replicate the results of our 2006 paper using a new and larger sample, which also includes a group of children diagnosed with ODD/CD. Methods Retrospective psychological chart review was conducted on 56 children with FASD, 50 with ADHD, 60 with ODD/CD, and 50 normal control (NC) children. Receiver operating characteristic curve (ROC) analysis of CBCL items discriminating FASD from NC was used to compare FASD to the ADHD and ODD/CD groups. Results ROC analyses showed scores of a) 3 or higher on 10 items differentiated FASD from NC with a sensitivity of 98%, specificity of 42% and b) 2 or higher on 5 items reflecting oppositional behaviors differentiated FASD from ADHD with a sensitivity of 89% and specificity of 42%. Conclusion Our findings partially replicate the results of our 2006 study and additionally elucidate the behavioural differences between children with FASD and those with ODD/CD. The proposed screening tool is currently the only tool available that is empirically derived and able to differentiate children with FASD from children with clinically similar profiles.