E3 ubiquitin ligase rififylin has yin and yang effects on rabbit cardiac transient outward potassium currents (Ito) and corresponding channel proteins.

Genome-wide association studies have reported a correlation between a SNP of the RING finger E3 ubiquitin protein ligase rififylin (RFFL) and QT interval variability in humans (Newton-Cheh et al., 2009). Previously, we have shown that RFFL downregulates expression and function of the human-like ether-a-go-go-related gene potassium channel and corresponding rapidly activating delayed rectifier potassium current (IKr) in adult rabbit ventricular cardiomyocytes. Here, we report that RFFL also affects the transient outward current (Ito), but in a peculiar way. RFFL overexpression in adult rabbit ventricular cardiomyocytes significantly decreases the contribution of its fast component (Ito,f) from 35% to 21% and increases the contribution of its slow component (Ito,s) from 65% to 79%. Since Ito,f in rabbits is mainly conducted by Kv4.3, we investigated the effect of RFFL on Kv4.3 expressed in HEK293A cells. We found that RFFL overexpression reduced Kv4.3 expression and corresponding Ito,f in a RING domain-dependent manner in the presence or absence of its accessory subunit Kv channel-interacting protein 2. On the other hand, RFFL overexpression in Kv1.4-expressing HEK cells leads to an increase in both Kv1.4 expression level and Ito,s, similarly in a RING domain-dependent manner. Our physiologically detailed rabbit ventricular myocyte computational model shows that these yin and yang effects of RFFL overexpression on Ito,f, and Ito,s affect phase 1 of the action potential waveform and slightly decrease its duration in addition to suppressing IKr. Thus, RFFL modifies cardiac repolarization reserve via ubiquitination of multiple proteins that differently affect various potassium channels and cardiac action potential duration.

Minimizing treatment-induced emergence of antibiotic resistance in bacterial infections.

Treatment of bacterial infections currently focuses on choosing an antibiotic that matches a pathogen's susceptibility, with less attention paid to the risk that even susceptibility-matched treatments can fail as a result of resistance emerging in response to treatment. Combining whole-genome sequencing of 1113 pre- and posttreatment bacterial isolates with machine-learning analysis of 140,349 urinary tract infections and 7365 wound infections, we found that treatment-induced emergence of resistance could be predicted and minimized at the individual-patient level. Emergence of resistance was common and driven not by de novo resistance evolution but by rapid reinfection with a different strain resistant to the prescribed antibiotic. As most infections are seeded from a patient's own microbiota, these resistance-gaining recurrences can be predicted using the patient's past infection history and minimized by machine learning-personalized antibiotic recommendations, offering a means to reduce the emergence and spread of resistant pathogens.

Evaluation of fetal and neonatal outcomes after ingestion of Cnidium root (Cnidium officinale Makino) during pregnancy.

Cnidium officinale Makino is a perennial plant, a member of the Umbelliferae family. Cnidium root has traditionally been used as a medicinal herb. It has analgesic, antiinflammatory, antipyretic, antibacterial, antispasmodic, vasodilatory, hypertensive, and sedative effects. However, there are no studies of reproductive toxicity in humans. Therefore, this study aimed to prospectively evaluate the fetal and neonatal outcomes in the children of women who inadvertently used Cnidium root during pregnancy. In a prospective cohort study design, 111 singleton pregnant women taking Cnidium root for various reasons, and 219 age-matched singleton pregnant women unexposed to any herbal agent (unexposed group), were followed up until delivery. In the exposed group, Cnidium root was indicated as controlling cough and cold in 54.1% of patients, at the maximal dose of 12,000 mg/day between 1 day to 12.4 weeks of gestation. Fetal outcomes, including birth weight and 1- and 5-min Apgar score, were similar for the two groups. There were four babies born with major malformations in the exposed group vs. 14 in the unexposed group (OR = 0.5; 95% CI 0.2-1.6; p = 0.190). The gestational age, length, and head circumference were relatively shorter among babies born in the exposed group. Even after adjusting for gender, there was a tenfold increase in the frequency of shorter newborns (<2SD) in the exposed group (OR = 10.1; 95% CI 1.2-87.6; p = 0.019). Our study suggests that Cnidium root is not a major human teratogen. Whether lesser gestational ages at birth and shorter birth lengths are clinically relevant after exposure to Cnidium remains to be elucidated in further studies.

Use of Cannabis in Fetal Alcohol Spectrum Disorder.

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.

Medicinal Use of Cannabis in Children and Pregnant Women.

The increasing medicinal use of cannabis during recent years has largely overlooked children and pregnant women due to litigious and ethical concerns. However, over the last few years medicine has observed increasing numbers of children treated with cannabis for autism spectrum disorder (ASD) and fetal alcohol spectrum disorder (FASD), and pregnant women treated for hyperemesis gravidarum (HG). This review provides an account of major findings discovered through this research. Specifically, cannabis may offer therapeutic advantages to behavioral symptoms of autism spectrum disorder and fetal alcohol spectrum disorder, and to the severe nausea and vomiting in hyperemesis gravidarum. The use of medical cannabis in children and pregnant women should be further discussed and researched in this patient population.

Pre-conceptional folic acid supplementation: A possible cause for the increasing rates of ankyloglossia.

BACKGROUND: There is an increasing awareness to ankyloglossia (tongue-tie) in infants, with marked increase in its report in the medical literature. Some reports indicate increase in prevalence. Whether the increase ankyloglossia rate is a real phenomenon or merely reflects increased awareness and reports has to be determined. One explanation for the increasing ankyloglossia rates is the growing trend of breast feeding initiation, often impaired by ankyloglossia, which brings it to medical attention. We propose an alternative hypothetical explanation based on increasing utilization of periconceptional folic acid supplementation for the prevention of neural tube defects (NTDs). Inadequate folic acid supply during organogenesis impairs cell division, and the mid-line structures are at the highest risk. We postulated that higher folic acid supply during organogenesis might enhance tissue synthesis with tighter closure of mid-line structures including the lingual frenulum, resulting in ankyloglossia. METHODS: To assess this hypothesis, we undertook an observational case control study comparing folic acid utilization before pregnancy in mothers of infants with and without ankyloglossia. Infants with ankyloglossia (n = 85) were compared to a control group without ankyloglossia (n = 140). RESULTS: There was a slight, insignificant elevated frequency of reported utilization of folic acid ("any intake") among mothers of infants with ankyloglossia compared with controls (74.1% and 66.4%, respectively). This difference was slightly higher, yet insignificant when folic acid intake "in most days" was considered (65.9% and 53.6%, respectively, OR = 1.67, 95%CI = 0.93-3.05, P = 0.07). In contrast, the reported intake of pre-conceptional folic acid "on a regular basis" was significantly higher among mothers of infants with ankyloglossia compared with controls (54.1% and 25.7%, respectively, OR = 3.41, 95%CI = 1.85-6.27, p < 0.0001). INTERPRETATION: The reported association between higher frequency of regular pre-conceptional folic acid intake and ankyloglossia, supports the hypothesis for this association. More studies are required to test this hypothesis.

The prevalence of iron deficiency anemia among African asylum seeking children residing in Tel Aviv.

BACKGROUND: It has been the impression of pediatricians at the Terem Clinic for African asylum seekers in Tel Aviv that they encounter large numbers of anemic children. The objectives of this study were 1) to quantify the prevalence of anemia among African African asylum seeking children treated in the Terem Clinic for refugees in Tel Aviv; 2) to compare it to the rates among Jewish Israeli children; 3) and to correlate it with their nutritional iron intake. Overall, this effort aims at informing changes in policies and practices that will ensure healthy development of African asylum seeking children in Israel. METHODS: The prevalence of anemia was calculated for all toddlers and children under the age of twelve years visiting the refugee clinic and compared to the recently reported rates of anemia among urban Jewish Israeli children of similar ages; Nutritional iron intake was calculated in a subgroup by a food frequency questionnaire translated to Amharic and Tigrinya. RESULTS: Mean age of the children (SD) was 2.96 yr. (SD 2.77) and mean hemoglobin 10.88 g/dl (1.47). Out of 386 eligible children, 131(34%) were anemic, fourfold more prevalent than reported among 263 Jewish toddlers and young children of the same age group [(11%), OR 4.15(95% ci 2.67-6.43)]. In a subgroup (n = 26) investigated for amount of daily iron intake, 46.2% did not receive the recommended daily allowance for their age. Nine of them had received iron supplements. CONCLUSIONS: Low hemoglobin levels are four-fold more prevalent among the African asylum seeking children. The dietary data suggest iron deficiency as a major cause, although other etiologies need to be ruled out. Because of the adverse long term impact of early anemia on child development, new policies need to be developed to ensure that refugee children develop in a healthy manner. These should include routine mandatory supplements of iron for all refugee children, in parallel to developing an educational program for parents how to achieve iron-sufficient diets for their children. Further research is needed to guide public health action for these children.

High dose folic acid during pregnancy and the risk of autism; The birth order bias: A nested case-control study.

OBJECTIVE: To examine whether there is an association between the cumulative dose of folic acid (FA) purchased by mothers, and risk of autistic spectrum disorders (ASD) in their progeny. METHODS: We identified 2009 singletons who received an ASD diagnosis from a cohort of 480,526 children born in a large health organization in Israel from 2000 through 2013. ASD patients were individually matched to ASD-free children (n = 19,886). Median cumulative daily doses of supplemented FA during the 12-month period prior to the end of pregnancy (from dispensing records) were compared using conditional logistic regression models. RESULTS: Children with ASD were more likely to be first-born, and birth-order was significantly associated with FA use. In multivariable analysis, there were no statistically significant differences in the cumulative dose of FA between the groups. CONCLUSION: Birth order effects need to be accounted for in analyses aiming to decipher the associations between gestational FA use and developmental outcomes.

Does high-dose gestational folic acid increase the risk for autism? The birth order hypothesis.

There has been a dramatic increase in the incidence of autism spectrum disorder (ASD) in recent decades but the causes have not been elucidated. To date, numerous studies have shown that the FDA-recommended doses of folic acid (400 mcg/d) render a protective effect against ASD. Yet, a recent prospective study has claimed that while self-reported folic acid supplementation was associated with decreased risk of ASD, very high levels of maternal plasma folate levels (<60.3 nmol/L) were associated with 2.5 time increased risk of ASD. This study has led to high levels of public anxiety because many women use high dose folic acid to prevent neural tube defects. We hypothesize that because ASD children have been documented to be much more likely to be first or second born, and women consume significantly more folic acid during their first and second pregnancies, the claim that high dose folic acid causes ASD is based on a previously unrecognized birth order bias. This article presents evidence for the wrong claim that high dose folic acid causes ASD. The question whether high exposure level of folic acid is associated with increased risk of ASD is not merely a theoretical issue, because many women at increased risk for NTD in their offspring need substantially higher daily doses of folic acid (1 mg, or 5 mg), than the FDA-recommended 400 mcg daily.

Effects of Hyperbaric Oxygen Therapy on Brain Perfusion, Cognition and Behavior in Fetal Alcohol Spectrum Disorder-A Case Study.

A 15-year-old girl diagnosed with FASD underwent 100 courses of hyperbasic oxygen therapy (HBOT). Prior to HBOT, single motion emission compute tomographic begin imaging (SPECT) revealed areas of hypo-perfusion bilaterally in the orbitofrontal region, temporal lobes and right dorsolateral-frontal, as well the medial aspect of the left cerebellum. Following two sets of HBOT treatments (60 plus 40), over 6 months, there was improvement in perfusion to the left cerebellum as well as the right frontal lobe. This was paralleled by improvement in immediate cognitive tests and an increase in functional brain volume. A follow-up 18 months after HBOT showed sustained improvement in attention with no need for methylphenidate, as well as in math skills and writing.

Comparison of sublingual vs. intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency.

There are several methods to treat vitamin B12 deficiency (VB12d): intramuscular (IM), oral, sublingual (SL), and intranasal vitamin B12 (VB12) preparations. Large studies comparing the efficacy of SL vs. IM supplements are lacking. The aim of the present study was to compare the efficacy of SL versus the standard IM administration of VB12 in restoring B12 levels. This was a retrospective analysis of data from the computerized pharmacy records of Maccabi Health Service (MHS). Data were recorded for all patients older than 18 years of age who were prescribed VB12 during January 2014-December 2017. The main outcome was the change in levels of serum vitamin B12 (sVB12) after treatment. Overall, there were 4281 patients treated with VB12 supplements. Of them, 830 (19.3%) patients were treated with VB12 IM injections and 3451 (80.7%) with SL tablets. The mean ± SD difference between sVB12 levels before and after administration of VB12 supplements was significantly higher in the SL group vs. IM injection group (252 ± 223 vs. 218 ± 184 ng/L, p < 0.001). SL VB12 significantly increased the odds ratio (OR) for an increase of sVB12 levels, compared to the IM group, OR 1.85, CI 95% 1.5-2.3, p < 0.001. This is the largest study that documents therapy with SL preparations of VB12 sufficient and even superior to the IM route. The SL overcomes the challenges of IM injections and should be the first line option for patients with VB12d.

The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplementation during pregnancy: A nested case-control study.

BACKGROUND AND RATIONALE: Several studies have suggested that the incidence of infantile hypertrophic pyloric stenosis (IHPS) has decreased in recent decades. This decrement is controversial and not fully explained. Concurrently, there has been a major increase in folic acid consumption by pregnant women to prevent neural tube defects. We aimed to describe IHPS incidence in Israel in recent years and to assess its potential association with folic acid consumption. METHODS: Using the electronic medical database of a 2.1 million member health organization in Israel, we identified all cases (n = 1899) of IHPS occurring between 1999 and 2015. Cases were individually matched with up to 5 controls (n = 7350) by birth date, sex, and region. Odds ratios and 95% confidence intervals by tertiles of cumulative dose of supplemented folic acid between three months prior to pregnancy and up to birth of index child were calculated using conditional logistic regression. RESULTS: During the study period IHPS incidence declined from 4.3 in 1999 to 2.1 per 1000 live births in 2015(p < 0.0001). No significant (p = 0.81) association was observed between folic acid intake during pregnancy and risk of IHPS incidence. Preterm birth and infant's use of macrolides during first 3 postnatal months were significantly (p < 0.01) associated with increased risk of IHPS. CONCLUSIONS: Similar to other countries, IHPS incidence in Israel has decreased in recent years. The decrement cannot be explained by increased use of folic acid. TYPE OF STUDY: Case Control Study. LEVEL OF EVIDENCE: Level III. SUMMARY: Using linkage to a large electronic patient database, this study investigated the association between the decrease in infantile hypertrophic pyloric stenosis and maternal exposure to folic acid during pregnancy.

Parity and the use of folic acid supplementation during pregnancy.

OBJECTIVE: Folic acid (FA) supplementation has long been recommended before and during pregnancy to reduce the risk of neural tube defects. Factors influencing adherence to FA supplementation have been extensively evaluated, but little is known on the effect of parity. This study comes to examine the association between parity and maternal use of FA prior to and during pregnancy. METHODS: In this retrospective population-based study, we identified mothers (N=228 555) of all children (N=578 204) born between the years 2000 and 2016 among members of a large health provider in Israel. Data on FA supplementation purchases were obtained from centralised medical databases. RESULTS: The median (IQR) total dose of FA purchased 12 months prior to child birth among previously nulliparous women (120 mg, 48-240) was significantly (p<0.001) higher than the dose purchased by women with one (90 mg (39-202)) and two prior births (84 mg (36-182)). The dose was even lower in women for three or more prior births (75 mg (36-165)). Despite the overall increasing secular trend in FA purchases during the study period, the negative relationship with parity remained. CONCLUSIONS: Adherence to FA supplementation is negatively associated with parity. Women with increasing parity may be at higher risk for pregnancy complications associated with low FA levels. The results of this study may inform the design of interventions to specifically increase adherence to FA supplementations among multiparous women.

Is post exposure prevention of teratogenic damage possible: Studies on diabetes, valproic acid, alcohol and anti folates in pregnancy: Animal studies with reflection to human.

We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol-induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention.

Vaginal antimycotics and the risk for spontaneous abortions.

BACKGROUND: Spontaneous abortions are the most common complication of pregnancy. Clotrimazole and miconazole are widely used vaginal-antimycotic agents used for the treatment of vulvovaginal candidiasis. A previous study has suggested an increased risk of miscarriage associated with these azoles, which may lead health professionals to refrain from their use even if clinically indicated. OBJECTIVE: The aim of the current study was to assess the risk for spontaneous abortions following first trimester exposure to vaginal antimycotics. STUDY DESIGN: A historical cohort study was conducted including all clinically apparent pregnancies that began from January 2003 through December 2009 and admitted for birth or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Beer-Sheva, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. Time-varying Cox regression models were constructed adjusting for mother's age, diabetes mellitus, hypothyroidism, obesity, hypercoagulable or inflammatory conditions, recurrent miscarriages, intrauterine contraceptive device, ethnicity, tobacco use, and the year of admission. RESULTS: A total of 65,457 pregnancies were included in the study: 58,949 (90.1%) ended with birth and 6508 (9.9%) with a spontaneous abortion. Overall, 3246 (5%) pregnancies were exposed to vaginal antimycotic medications until the 20th gestational week: 2712 (4.2%) were exposed to clotrimazole and 633 (1%) to miconazole. Exposure to vaginal antimycotics was not associated with spontaneous abortions as a group (crude hazard ratio, 1.11; 95% confidence interval, 0.96-1.29; adjusted hazard ratio, 1.11; 95% confidence interval, 0.96-1.29) and specifically for clotrimazole (adjusted hazard ratio, 1.05; 95% confidence interval, 0.89-1.25) and miconazole (adjusted hazard ratio, 1.34; 95% confidence interval, 0.99-1.80). Furthermore, no association was found between categories of dosage of vaginal antimycotics and spontaneous abortions. CONCLUSION: Exposure to vaginal antimycotics was not associated with spontaneous abortions.

Folate status of women in Toronto: Implications of folate fortification and supplementation.

OBJECTIVES: To assess the percentage of women of childbearing age with suboptimal levels of folate for protecting against neural tube defects (<906 nM), and assess folate status among the elderly. METHODS: A total of 1,035 anonymous blood samples from a centralized clinical laboratory, with a catchment area across the Greater Toronto Area, were assessed for red blood cell (RBC) folate concentrations using a chemiluminescent immunoassay. Folate analysis was requested by physicians as part of clinical care. Available data included age, sex, and RBC folate concentration. Descriptive statistics were used to characterize the percent of women who had suboptimal blood folate concentrations, and a multiple regression was used to analyze determinants of folate status. RESULTS: Our data from 2013 show that 7% of women of childbearing age (15-45 years) had RBC folate concentrations below 906 nM, a substantially lower percentage than in our 2006 study (40%). Results from the multiple regression showed that age is a significant positive predictor of higher RBC folate status (p < 0.001). CONCLUSION: Compared to our earlier data, we report a significant decrease in the suboptimal folate status among women of childbearing age. We also show that age is a predictor of higher RBC folate levels. Our data are limited due to a lack of information regarding patient or physician characteristics, and to the nature of our sample, yet our results are consistent with the continued increase in folate status observed among several population-level studies in the US and Canada post-fortification. Further research is needed to determine the reasons for and future implications of this continued increase in the elderly.

Folic acid supplementation for pregnant women and those planning pregnancy: 2015 update.

During the last decade critical new information has been published pertaining to folic acid supplementation in the prevention of neural tube defects (NTDs) and other folic acid-sensitive congenital malformations. These new data have important implications for women, their families, and health care professionals. We performed a review looking for the optimal dosage of folic acid that should be given to women of reproductive age who are planning or not avoiding conception to propose updated guidelines and thus help health care providers and patients. In addition to fortification of dietary staples with folic acid, women of reproductive age should supplement before conception with 0.4-1.0 mg of folic acid daily as part of their multivitamins. In the United States all enriched rice is also fortified with folic acid at 0.7 mg per pound of raw rice. However, this is not the case in many countries, and it has been estimated that only 1% of industrially milled rice is fortified with folic acid. In countries where rice is the main staple (eg, China), this does not allow effective folate fortification. Whereas the incidence of NTDs is around 1/1000 in the United States, it is 3- to 5-fold higher in Northern China and 3-fold higher in India. A recent population-based US study estimated that the reduction in NTD rates by folic acid is more modest than previously predicted. The potential of NTD prevention by folic acid is underutilized due to low adherence with folic acid supplementation, and calls for revising the policy of supplementation have been raised. We identified groups of women of reproductive age who may benefit from higher daily doses of folic acid, and this should be considered in current practice. These include women who have had previous pregnancies with NTDs, those who did not plan their pregnancy and hence did not supplement, and women with low intake or impaired adherence to daily folic acid supplementation. In addition, women with known genetic variations in the folate metabolic cycle, those exposed to medications with antifolate effects, smokers, diabetics, and the obese may benefit from higher doses of folic acid daily during the first trimester.