Showing papers by "Gideon Koren published in 2021"

Transgenic rabbit models for cardiac disease research.

Abstract: To study the pathophysiology of human cardiac diseases and to develop novel treatment strategies, complex interactions of cardiac cells on cellular, tissue and on level of the whole heart need to be considered. As in vitro cell-based models do not depict the complexity of the human heart, animal models are used to obtain insights that can be translated to human diseases. Mice are the most commonly used animals in cardiac research. However, differences in electrophysiological and mechanical cardiac function and a different composition of electrical and contractile proteins limit the transferability of the knowledge gained. Moreover, the small heart size and fast heart rate are major disadvantages. In contrast to rodents, electrophysiological, mechanical and structural cardiac characteristics of rabbits resemble the human heart more closely, making them particularly suitable as an animal model for cardiac disease research. In this review, various methodological approaches for the generation of transgenic rabbits for cardiac disease research, such as pronuclear microinjection, the sleeping beauty transposon system and novel genome-editing methods (ZFN and CRISPR/Cas9)will be discussed. In the second section, we will introduce the different currently available transgenic rabbit models for monogenic cardiac diseases (such as long QT syndrome, short-QT syndrome and hypertrophic cardiomyopathy) in detail, especially in regard to their utility to increase the understanding of pathophysiological disease mechanisms and novel treatment options.

Measuring the severity of nausea and vomiting of pregnancy; a 20-year perspective on the use of the pregnancy-unique quantification of emesis (PUQE)

Abstract: Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expectant women Measuring the severity of the condition over time is important for management decisions, as well as for research into different therapeutic modalities Twenty years ago we described and validated the Pregnancy Unique Quantification of Emesis scale (PUQE), as a clinical and research tool PUQE has become widely used for both ends, and has been incorporated in numerous practice guidelines worldwide In this review we describe the inception of the tool, its rational, and its wide range of use worldwide

Use of Cannabis in Fetal Alcohol Spectrum Disorder.

Abstract: Background: Fetal alcohol spectrum disorder (FASD) has been recently estimated to afflict up to 5% of American children. Most of these children exhibit different degrees of symptomatology of disruptive behaviors. Yet, there has been very little research on the efficacy and safety of pharmacological modalities, limited mostly to stimulants for attention deficit hyperactive disorder or second generation atypical antipsychotics for aggression. Recently, the use of cannabinoids has been described for symptoms related to autistic spectrum disorder with apparent favorable effects, as well as for other disruptive behaviors. The objective of our study was to follow up in a retrospective case series the effect of cannabis in children and young adults diagnosed with FASD. Methods: In two children and three FASD young adults with severe disruptive behavior, changes in behavior after cannabis use were measured by the parent version of the Nisonger Child Behavior Rating Form. Results: In all five cases, there was a highly statistical decrease in the disruptive behavior score from 18±1.0 before cannabis use to 6±2.1 after introduction of cannabis (p=0.0002). Discussion: In children and young adults with FASD, cannabis, mostly cannabidiol (CBD), has been associated with a marked and statistically significant improvement in serious disruptive behavior. These cases suggest that the efficacy and safety of CBD should be tested in well-controlled studies.

The Use of Methylphenidate for Cognitive Enhancement in Young Healthy Adults: The Clinical and Ethical Debates.

Abstract: Objective Methylphenidate (MP), a drug of choice for attention-deficit/hyperactivity disorder (ADHD), is a federally restricted substance CII in the United States because of abuse and dependence, and similar restrictions are practiced in Canada and around the world. This designation is given to drugs with medical value that present a high potential for abuse. In view of these severe restrictions, it is concerning to find out that a large group of healthy young adults, at least as large as the ADHD group of patients, take MP for cognitive enhancement, in an attempt to improve their academic achievements during studies and examinations. These young adults buy MP illegally and consume it without any medical supervision. The objective of the present debate piece is to present the ethical and clinical issues that need to be addressed in an attempt to solve this dilemma. Methods The issues presented here are systematically reviewed and discussed along the following lines: MP effectiveness in enhancing cognitive achievements in healthy people; "As these are normal healthy people, what is the duty of physicians to 'treat' them?"; potential benefits of cognitive enhancement to healthy people; the risks of MP; "How do these young people get their MP?"; and "What can be done?" Results Methylphenidate is widely used for cognitive enhancement without medical supervision. The effectiveness of MP for cognitive enhancement is well documented along a dose-response curve. Congruent with the results of the randomized trials, repeated studies based on interviews suggest that numerous young people report that cognitive enhancement helps them in improving their academic achievements, and hence also improve their feeling of well-being. Presently, most regulatory and medical organizations limit the use of MP to ADHD and narcolepsy. Yet, the American Academy of Neurology ruled that there is a moral, ethical, and legal basis to prescribe the drug for cognitive enhancement. The drug has known dose-dependent adverse effects that can have serious ramifications and may often lead to poor adherence. The relative risk of MP causing sudden death/arrhythmia is 1.46 (95% confidence interval, 1.03-2.07), and there are estimated 20 million college and university students in the United States in 2020. The rate of sudden death/arrhythmias in this age group ranges between 1 and 10 per 100,000. This translates to an excess of 146 deaths caused by MP every year in the United States considering postsecondary students only. Discussion We propose that an ethical-clinical debate should be followed by an action plan to ensure that the present reality of millions of young people taking unsupervised MP is not accepted as a force majeure that cannot be changed.

The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis

Abstract: Objective Isotretinoin is among the most notorious human teratogens, documented originally as causing up to 30% of malformations. This systematic review and meta-analysis aimed to evaluate the rates of major malformation (MM) among isotretinoin-exposed pregnant women over the years through a systematic review and meta-analysis. Methods Eligible studies were searched and identified using various databases. Single-arm meta-analysis and meta-analysis of odd ratios among controlled studies were performed using Review Manager version 5.3. Results Ten eligible studies that combined 2,783 isotretinoin-exposed women were included in our study. The rate of MM weighted for the sample size was 15%. Three studies that included an unexposed comparison group were eligible for the meta-analysis. The pooled odds ratio of MM for isotretinoin-exposed women was 3.76. After 2006, the pooled odds ratio of MM for isotretinoin exposure was significantly lower at 1.04. Conclusion The current rate of MM in isotretinoin-exposed women was substantially lower after 2006.

Three-Week-Old Rabbit Ventricular Cardiomyocytes as a Novel System to Study Cardiac Excitation and EC Coupling

Abstract: Cardiac arrhythmias significantly contribute to cardiovascular morbidity and mortality. The rabbit heart serves as an accepted model system for studying cardiac cell excitation and arrhythmogenicity. Accordingly, primary cultures of adult rabbit ventricular cardiomyocytes serve as a preferable model to study molecular mechanisms of human cardiac excitation. However, the use of adult rabbit cardiomyocytes is often regarded as excessively costly. Therefore, we developed and characterized a novel low-cost rabbit cardiomyocyte model, namely, 3-week-old ventricular cardiomyocytes (3wRbCMs). Ventricular myocytes were isolated from whole ventricles of 3-week-old New Zealand white rabbits of both sexes by standard enzymatic techniques. Using wheat germ agglutinin, we found a clear T-tubule structure in acutely isolated 3wRbCMs. Cells were adenovirally infected (multiplicity of infection of 10) to express GFP and cultured for 48 h. The cells showed action potential duration (APD90 = 253±24 ms) and calcium transients similar to adult rabbit cardiomyocytes. Freshly isolated and 48 h cultured cells expressed critical ion channel proteins: calcium voltage-gated channel subunit alpha1 C (Cavα1c), sodium voltage-gated channel alpha subunit 5 (Nav1.5), potassium voltage-gated channel subfamily D member 3 (Kv4.3) and subfamily A member 4 (Kv1.4), as well as subfamily H member 2 (RERG. Kv11.1), KvLQT1 (K7.1) protein and inward-rectifier potassium channel (Kir2.1). The cells displayed an appropriate electrophysiological phenotype including fast sodium current (INa), transient outward potassium current (Ito), L-type calcium channel peak current (ICa,L), rapid and slow components of the delayed rectifier potassium current (IKr and IKs), and inward rectifier (IK1). Although expression of the channel proteins and some currents decreased during the 48 h of culturing, we conclude that 3wRbCMs are a new, low-cost alternative to the adult-rabbit-cardiomyocytes system, which allows the investigation of molecular mechanisms of cardiac excitation on morphological, biochemical, genetic, physiological, and biophysical levels.

The Effects of Drugs used for the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) on Pregnancy Outcome and Breast-feeding: A Critical Review.

Abstract: Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral condition found in 5-10% of school-age children and in 2-5% of adults. Stimulants affecting the dopaminergic, noradrenergic and/or serotonergic systems are commonly used for treatment in children and adults, including women of childbearing age. The data on the effects of stimulants (methylphenidate and amphetamines) in pregnancy are generally reassuring, but methylphenidate might slightly increase the rate of cardiac malformations and of spontaneous abortions, while amphetamines might slightly increase the risk for premature birth, low birth weight and other pregnancy complications. Bupropion, a dopamine and norepinephrine reuptake inhibitor, when used as an antidepressant, appears to be safe in pregnancy. The data on the use of atomoxetine, guanfacine and clonidine in pregnancy are scarce. Importantly, there are practically no data on the long-term neurodevelopmental effects of most of these drugs. The published data on the development of children born to methamphetamineabusing women may be misleading since these women generally use other drugs, including alcohol, and the home environment where the child is raised may not be optimal. The treating physician should judge the need for treatment during pregnancy in relation to the severity of the clinical symptoms. If needed, methylphenidate is preferred over amphetamines because breast feeding is possible. If one uses non-stimulant medications, bupropion seems to be the preferred drug.

Hair cortisol concentrations predict change in girls’ depressive symptoms

Abstract: Hypothalamic-Pituitary-Adrenal (HPA) axis activity is related to negative mental health outcomes, including depression. Most developmental research uses salivary cortisol to index HPA activity; how...

Docosahexaenoic acid normalizes QT interval in long QT type 2 transgenic rabbit models in a genotype-specific fashion.

Abstract: AIM Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Since current therapies often fail to prevent arrhythmic events in certain LQTS subtypes, new therapeutic strategies are needed. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing IKs current. METHODS AND RESULTS We investigated the effects of DHA in wild type (WT) and transgenic long QT Type 1 (LQT1; loss of IKs), LQT2 (loss of IKr), LQT5 (reduction of IKs), and LQT2-5 (loss of IKr and reduction of IKs) rabbits. In vivo ECGs were recorded at baseline and after 10 µM/kg DHA to assess changes in heart-rate corrected QT (QTc) and short-term variability of QT (STVQT). Ex vivo monophasic action potentials were recorded in Langendorff-perfused rabbit hearts, and action potential duration (APD75) and triangulation were assessed. Docosahexaenoic acid significantly shortened QTc in vivo only in WT and LQT2 rabbits, in which both α- and β-subunits of IKs-conducting channels are functionally intact. In LQT2, this led to a normalization of QTc and of its short-term variability. Docosahexaenoic acid had no effect on QTc in LQT1, LQT5, and LQT2-5. Similarly, ex vivo, DHA shortened APD75 in WT and normalized it in LQT2, and additionally decreased AP triangulation in LQT2. CONCLUSIONS Docosahexaenoic acid exerts a genotype-specific beneficial shortening/normalizing effect on QTc and APD75 and reduces pro-arrhythmia markers STVQT and AP triangulation through activation of IKs in LQT2 rabbits but has no effects if either α- or β-subunits to IKs are functionally impaired. Docosahexaenoic acid could represent a new genotype-specific therapy in LQT2.

Institutionalized Children and the Risk of Fetal Alcohol Spectrum Disorder (FASD); A Primer for Clinicians, Adoption Staff and Parents.

Abstract: Objectives:Our objective was to estimate the likelihood of abnormal development among institutionalized children, addressing either the risk in general, or the risk for fetal alcohol spectrum disor...

Obesity, neural tube defects and folic acid—A complex relationship

Abstract: Obesity is associated with twofold increased risk of neural tube defects (NTD). Research has repeatedly shown that about 70% of NTD are folic-acid dependent. Yet, there is controversy whether folic acid status is the main determinant of the increased risk of obesityinduced NTD. The rational for this review is to update and discuss the evidence on the link between obesity, folic acid and NTD, in an attempt to shed light on the question whether optimal folic acid dose schedule canmitigate this risk. During pregnancymaternal folate requirements increase by 5--10-fold, as folate is diverted towards the placenta and fetus, as well as supporting di ferent maternal organs. Correspondingly, low maternal folate status has been associatedwith birth defects in fetal anatomical regions particularly sensitive to reduced folate intake including oral cle t, cardiovascular defects and NTD. A recent study has documented decreased placental folate transporter expression and activity in the first and second trimesters among obese mothers. This may explain the higher incidence on NTD in infants of obese women, as less folate may find its way to the developing fetus during the sensitive periods for creating NTD. Recent pharmacokinetic results indicate that steady state levels of folate are almost perfectly defined by the dose per lean body weight (LBW). Themean dose per kg LBW that would be expected to result in steady state serum folate level of > 15.9 nmol/L was identified as 0.0073 mg/kg LBW. A large study found no di ferences in dietary supplementations of folic acid, yet obese women exhibited lower median serum folate as well as lower mean serum B12 levels, but no di ferences in mean RBC folate levels. There was a negative correlation between increasing BMI and both serum folate and plasmaB12. Future researchwill beneeded to incorporatemore fully, in addition to evidence of NTD, obesity and folic acid intake, also direct measurements of serum and RBC folate, as well as other confounders, inorder to createamodel thatwill shed lighton these complex interactions.

Risk and protective factors associated with multiproblem behaviours of Ethiopian young adults in Israel

Abstract: Immigrants and second-generation immigrants from Ethiopia in Israel are assumed to be more vulnerable to problematic risk behaviours than host culture population. The aim of this study was to assess risk and protective factors associated with multiproblem behaviours such as committing driving violations, alcohol use, drugs use and violence among Ethiopian young adult immigrants and second-generation immigrants in Israel. This is a cross-sectional study, based on a self-reported anonymous structured questionnaire distributed to 383 Ethiopian emerging adults (mean age 25.3; SD = 3.27, 59.3% female). Multiple Problem Behavior Index (MPBI) was created from their responses to 21 risk behaviour variables including driving violations, alcohol use, Marijuana use and violence. Logistic regression to predict multiproblem behaviours was used. We found that unplanned leisure activity hours during weekends (adjusted odds ratio - AOR = 2.594, p < .01, 95% CI 1.332-5.052), excitement seeking (AOR = 2.122, p<.01, 95% CI 1.257-3.582), depression symptoms (AOR = 2.521, p < .01, 95% CI 1.491-4.261) and gender (AOR = 0.277, p < .001, 95% CI 0.164-0.469) were associated with MPBI. In contrast, racism, perceived discrimination, Israeli and Ethiopian identities were not significantly associated with MPBI after adjusting for gender and family status. These results suggest that in a minority of Ethiopian emerging adult immigrants similar to host culture populations, risk factors such as unplanned leisure activities, excitement seeking and depression symptoms are stronger and significant factors associated with multiproblem behaviours rather than racism, perceived discrimination or Israeli and Ethiopian identities. Resources should be allocated to produce appropriate intervention programs with planned content for leisure time, especially on weekends.

Factors associated with medical complications after body art among Israeli adults: a retrospective study.

Abstract: INTRODUCTION Body-art, including tattoos and piercings, is steadily increasing world-wide but with relatively limited reporting of adverse outcomes. The objective of the present study was to identify correlates that would facilitate a preventative strategy to minimize adverse effects of body-art. METHODS We examined patterns of body-art, health risk and perceptions among 921 participants (54% female, mean age of 35; SD = 10.8) through in-person questionnaire. RESULTS A significantly lower frequency of those with body-art acknowledged that not all venues (parlors, clinics, etc.) are safe in terms of health and hygiene (84.7%t vs. 96.6%, p < .001) as compared to those without body-art. Similarly, knowledge of the need for a Ministry of Health certification was reported with lower frequency (77.2% vs. 94.5%, p < .001) among those with body-art. Those who experienced medical complications reported higher frequencies of smoking cigarettes and hookah as well as using ecstasy (MDMA). The risk of medical complication after body-art was 4 times higher in those who used ecstasy (OR = 3.97; CI 1.0-14.4; p < 0.05). In addition, it was more than 3 times higher for street or home tattooing as compared to studio or a licensed medical center (OR = 3.59; CI 1.32-9.76; p < .01), as well as almost 3 times higher among those who did not receive information before performing body-art (OR = 2.70; CI 1.05-6.92; p < .05) and who had somebody other than themselves decide on the body-art design (OR = 2.68; CI 1.00-7.19; p < .05). CONCLUSIONS A targeted informational-preventative program should be developed, informed by the risks highlighted in this study. In addition, it would be necessary to draft policies related to regulation and enforcement in order to more effectively manage body-art service provision. The Ministry of Health should supervise and guide tattooists and practitioners regarding the health risks of body-art and offer training and raise awareness among potential clients.

Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model.

Abstract: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. The (S)-(−)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(−)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min−1) and Interaction (0.0019 vs 0.0021 min−1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(−)] were approximately 1. Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.

Association between oral contraceptives and serious infections: A population-based cohort study.

Abstract: Aims Oral contraceptives (OC)s are commonly used worldwide. In a recent study, we showed that the use of OCs is associated with an increased risk for neutropenia. We aimed to investigate the clinical implications of this finding by examining the infection rates of 4 serious infections before, during and after OCs. Methods A retrospective cohort study using the electronic medical records of a large health organization. We selected 2 retrospective cohorts of women aged 16-40 between years 2005 and 2019. The first cohort examined infection rates during 2 years before OC use and 2 consecutive years of adherent OC use. The second cohort included women who consumed OCs adherently for 2 years and then discontinued their use for 2 consecutive years. Women's infection rates were compared by χ2 test, results were stratified by OC type and age. Results Overall, 21 595 and 20 728 women were included in Cohorts 1 and 2 respectively. We found a statistically significant higher relative risk for infection while using OCs; the overall risk ratios (95% confidence intervals) for infection in Cohorts 1 and 2 were 1.35 (1.32-1.38) and 1.27 (1.24-1.31), respectively. The overall infection risk remained statistically significant when stratified by age. Conclusions This study demonstrates a high statistically and clinically significant risk for all infections followed during OC consumption, which is likely to have major clinical and economic implications. These findings may have implications to millions of women worldwide and should lead to more research on the safety of the pill.