Urinary concentrations of environmental contaminants and phytoestrogens in adults in Israel.

BACKGROUND: The Ministry of Health Biomonitoring Study estimated exposure of individuals in the Israeli population to bisphenol A (BPA), organophosphate (OP) pesticides, phthalates, cotinine, polycyclic aromatic hydrocarbons (PAHs), and the phytoestrogenic compounds genistein and daidzein. METHODS: In 2011, 250 individuals (ages 20-74) were recruited from five different regions in Israel. Urine samples were collected and questionnaire data were obtained, including detailed dietary data (food frequency questionnaire and 24hour recall). Urinary samples were analyzed for BPA, OP metabolites (dialkyl phosphates), phthalate metabolites, cotinine, PAH metabolites, genistein, and daidzein. RESULTS AND DISCUSSION: BPA urinary concentrations were above the limit of quantification (LOQ) in 89% of the samples whereas urinary concentrations of phthalate metabolites were above the LOQ in 92-100% of the samples. PAH metabolites were above the LOQ in 63-99% of the samples whereas OP metabolites were above the LOQ in 44-100% of the samples. All non-smoking participants had detectable levels of cotinine in their urine; 63% had levels above the LOQ, and the rate of quantification was high compared to the general non-smoking population in Canada. Median creatinine adjusted concentrations of several OP metabolites (dimethyl phosphate, dimethyl thiophosphate) were high in our study population compared to the general US and Canadian populations. Median creatinine adjusted urinary BPA concentrations in the study population were comparable to those in Belgium and Korea; higher than those reported for the general US, German, and Canadian populations; and very low compared to health-based threshold values. Phthalate concentrations were higher in our study population compared to the general US population but values were very low compared to health-based threshold values. Median creatinine adjusted PAH concentrations were generally comparable to those reported for the general US population; median creatinine adjusted daidzein concentrations were high in our population compared to the general US population whereas genistein concentrations were comparable. CONCLUSIONS: We interpreted observed urinary contaminant levels observed in our study by comparing values with health-based threshold values and/or values from international human biomonitoring studies. Using this data interpretation scheme, we identified two contaminants as being of potential public health concern and high priority for public health policy intervention: environmental tobacco smoke (ETS) and OP pesticides. We used the data collected in this study to support public health policy interventions. We plan to conduct a follow-up biomonitoring study in 2015 to measure ETS and OP exposure in the general population in Israel, to evaluate the effectiveness of relevant policy interventions.

Apparent life-threatening events in infants and homeopathy: an alternative explanation.

BACKGROUND: A recent report showed increased frequency of apparent life-threatening events (ALTEs) in infants treated with the homeopathic medication GaliCol-Baby (GCB). The premise was that the ALTEs resulted from toxic effects of the drug's components. We examine an alternative explanation. METHOD: The toxicological literature was searched for known reactions to the various GCB components, noting doses and reported symptoms. Dosage quantities and severity of reaction to the GCB were ranked independently by two groups of physicians, and a dose-response curve was generated. Reported toxic doses and symptoms were compared with those of the GCB series. The homeopathic literature was searched as well to determine the propensity of the GCB components to cause ALTE symptoms, when given in homeopathic doses to healthy volunteers (proving). RESULTS: Doses ingested in the GCB series were 10-13 orders of magnitude smaller than those reported to cause toxic reactions in humans. There was poor correlation between symptoms with GCB and toxic profiles of the components. A nonsignificant, inverse relationship between dose and severity of reaction was observed. Conversely, four GCB components (in homeopathic doses) had a high propensity to produce at least one of five symptoms which define ALTE, two of which had intermediate to high propensity to produce three symptoms. CONCLUSIONS: It is unlikely that the ALTE following ingestion of GCB was a toxic reaction to any of the drug's component. Homeopathic theory may explain this linkage, though further research is needed to understand the pathogenic effects of highly diluted homeopathic compounds.

Dietary folate and the incidence and prevention of neural tube defects: a proposed triple intervention approach in Israel.

The efficacy of folic acid in the prevention of neural tube defects depends on whether it is administered to women during the period surrounding conception. Optimizing the compliance of women at this critical time is a public health challenge. We assess the need for formulation of public health policy in Israel aimed at enhancing folate intake by women, examine policy implementation strategies, and review policy options regarding the approaches to enhance folic acid intake.

Thalamocortical synaptic connections: efficacy, modulation, inhibition and plasticity.

The thalamic input to the neocortex is communicated by glutamatergic synapses. The properties and organization of these synapses determine the primary level of cortical processing. Similar to intracortical synapses, both AMPA and NMDA receptors in young and mature animals mediate thalamocortical transmission. Kainate receptors participate in thalamocortical transmission during early development. The shape of thalamocortical synaptic potentials is similar to the shape of intracortical potentials. On the other hand, thalamocortical synapses have on average a higher release probability than intracortical synapses, and a much higher number of release sites per axon. As a result, the transmission of each thalamocortical axon is significantly more reliable and efficient than most intracortical axons. Thalamic axons specifically innervate a subset of inhibitory cells, to create a strong and secure feed-forward inhibitory pathway. Thalamocortical connections display many forms of synaptic plasticity in the first postnatal week, but not afterwards. The implications of the functional organization of thalamocortical synapses for neocortical processing are discussed.

Five decades of trends in anemia in Israeli infants: implications for food fortification policy.

OBJECTIVE: To describe the secular trends in the prevalence rates of iron-deficiency anemia (IDA) in infants in Israel, identify population group differences and assess the effectiveness of the 1985 Public Health directives on iron supplementation and avoidance of cow's milk in the first year of life. DESIGN: A systematic analysis of published and unpublished cross-sectional studies. METHODS: IDA rates in 1-y-old infants between 1946 and 1997 were assessed from published papers and reports. Rates for Arab infants were available from 1984. Data on routine hemoglobin tests on 1-y-old infants for Arabs and Jews separately were obtained from four health districts for the period 1987 to 1997. Analyses were done for the periods prior to and following the Public Health directives. RESULTS: The prevalence of IDA in Jewish infants declined from 68% in 1946 to 50% in 1985 at an average annual rate of -1.43%. Following the iron supplementation directives, the average annual rate of decline increased to -4.0% and reached a prevalence of about 11% in 1996. IDA rates in Arab infants declined by an annual average of -3.7%, and were consistently almost twice as high as for Jewish infants. CONCLUSIONS: Despite the contribution of the iron supplementation program to the reduction in TDA, the persistently high rates indicate inadequate iron content in the diet. This emphasizes the important role of a national food fortification program, using staple foods commonly consumed.

Evidence for proportional synaptic scaling in neocortex of intact animals.

Neocortical neurons in culture can modify their global synaptic strength according to their recent activity level. This process has been termed synaptic scaling. We explored possible effects of synaptic scaling in intact animals by comparing EPSPs of two identified synaptic tracts on single cortical neurons in acute slices. We show that the amplitude and rise-time of unitary thalamocortical and intracortical EPSPs vary among different neurons, but are highly correlated on single cells. Likewise, the AMPA-to-NMDA receptor ratio in EPSPs evoked from the two tracts is correlated in single neurons, although intracortical pathways within layer 5 exhibit a significantly larger NMDA component. These findings demonstrate that, under physiological conditions, cortical neurons actively regulate their own response magnitude, regardless of the input source.

Efficacy of thalamocortical and intracortical synaptic connections: quanta, innervation, and reliability.

Thalamocortical (TC) synapses carry information into the neocortex, but they are far outnumbered by excitatory intracortical (IC) synapses. We measured the synaptic properties that determine the efficacy of TC and IC axons converging onto spiny neurons of layer 4 in the mouse somatosensory cortex. Quantal events from TC and IC synapses were indistinguishable. However, TC axons had, on average, about 3 times more release sites than IC axons, and the mean release probability at TC synapses was about 1.5 times higher than that at IC synapses. Differences of innervation ratio and release probability make the average TC connection several times more effective than the average IC connection, and may allow small numbers of TC axons to dominate the activity of cortical layer 4 cells during sensory inflow.

Differential regulation of neocortical synapses by neuromodulators and activity.

Synapses are continually regulated by chemical modulators and by their own activity. We tested the specificity of regulation in two excitatory pathways of the neocortex: thalamocortical (TC) synapses, which mediate specific inputs, and intracortical (IC) synapses, which mediate the recombination of cortical information. Frequency-sensitive depression was much stronger in TC synapses than in IC synapses. The two synapse types were differentially sensitive to presynaptic neuromodulators: only IC synapses were suppressed by activation of GABA(B) receptors, only TC synapses were enhanced by nicotinic acetylcholine receptors, and muscarinic acetylcholine receptors suppressed both synapse types. Modulators also differentially altered the frequency sensitivity of the synapses. Our results suggest a mechanism by which the relative strength and dynamics of input and associational pathways of neocortex are regulated during changes in behavioral state.

Properties of convergent thalamocortical and intracortical synaptic potentials in single neurons of neocortex.

We explored differences in the properties of convergent afferent inputs to single neurons in the barrel area of the neocortex. Thalamocortical slices were prepared from mature mice. Recordings were made from neurons in layer V, and either thalamocortical afferents or horizontal intracortical axons were stimulated. Monosynaptic EPSPs from both sources had latencies shorter than 1.8 msec and low shape variance. Disynaptic thalamocortical IPSPs had latencies longer than 1.8 msec. All neuronal types, as defined by intrinsic firing patterns, received both thalamocortical and intracortical monosynaptic input. The shape parameters (rate of rise and half-width) of monosynaptic EPSPs from the two inputs did not differ significantly. The rate of rise of EPSPs varied considerably across cells, but the rates of rise of thalamocortical and intracortical EPSPs onto single cells were strongly correlated. The relative thresholds for activation of synaptic excitation and inhibition were strikingly different between the two tracts: thalamocortical stimulation induced GABAA-dependent IPSPs at stimulus intensities equal to or less than those required for evoking EPSPs in 35% (24 of 68) of the cells. In contrast, the threshold response to intracortical stimulation was always an EPSP, and only stronger stimuli could generate di- or polysynaptic IPSPs. We suggest that postsynaptic factors may tend to equalize the waveforms of EPSPs from thalamocortical and intracortical synapses onto single neurons. A major difference between the two convergent tracts is that the thalamocortical pathway much more effectively activates feedforward inhibitory circuits than does the horizontal intracortical pathway.

Cortical synchronized activity evoked by thalamocortical stimulation in vitro.

Epileptiform activity was studied in the thalamocortical (THC) slice preparation. Inhibition was gradually attenuated with increasing doses of bicuculline methiodide (BMI). We compared the ability of thalamic and intracortical (INC) stimulation to evoke epileptiform activity. Synchronized population activity was identified by its all-or-none appearance at a threshold stimulus intensity, by a variable latency and by horizontal propagation to large distances. For most slices (20 out of 24) we could establish a threshold dose of BMI (0.4-0.7 microM) under which THC-evoked population events had epileptiform properties, while INC-evoked ones did not. Increasing the BMI dose by 0.2 microM resulted in the appearance of epileptiform field potentials when stimulating intracortically. It is concluded that the tendency of the neocortex to generate synchronized population activity is higher when it is activated through the THC pathway.

Treatment of neonatal hyperbilirubinemia with repetitive oral activated charcoal as an adjunct to phototherapy.

The efficacy of multiple dose oral activated charcoal (OAC) therapy for neonatal hyperbilirubinemia was prospectively studied in 30 jaundiced newborns receiving phototherapy, randomly assigned to a study group (n = 14) or control group (n = 16). The study group received OAC before meals with a total amount of 8.5 +/- 0.85 gms (M +/- SEM). Serum bilirubin levels upon initiation of phototherapy were (M +/- SEM) 265 +/- 8 and 253 +/- 4 mumol/L respectively. After 24 hours there was no significant decrease in serum bilirubin levels in the control group (M +/- SEM = 240 +/- 8 mumol/L) but bilirubin levels of the study group decreased (M +/- SEM = 235 +/- 7 mumol/L, p < 0.02). At 48 hours serum bilirubin levels were significantly lower than baseline values in both groups. However, the decline in bilirubin levels in the study group (M +/- SEM = 56 +/- 10 mumol/L) was greater than that of the controls (M +/- SEM = 21 +/- 10 mumol/L p < 0.02). Oral activated charcoal seems to be an effective adjunct to phototherapy in the treatment of neonatal hyperbilirubinemia.

Residential deleading: effects on the blood lead levels of lead-poisoned children.

Acute elevations of venous blood lead levels (PbB) are periodically reported in children with chronic lead poisoning, during deleading of their houses. To evaluate this phenomenon 114 preschool children who entered the Massachusetts Childhood Lead Poisoning Prevention Program case management system during 1984 and 1985 were retrospectively studied. PbB increased from a mean (+/- SE) of 1.76 +/- 0.03 mumol/L (36.4 +/- 0.6 micrograms/dL) prior to deleading to 2.03 +/- 0.07 mumol/L (42.1 +/- 1.5 micrograms/dL) during deleading (P less than .001). Among 41 subjects for whom deleading was done by dry scraping and sanding, the mean mid-deleading PbB was higher than the pre-deleading PbB by 0.44 +/- 0.12 mumol/L (9.1 +/- 2.4 micrograms/dL). However, when deleading was done by covering or replacement of painted surfaces in the residences of 12 subjects, mid-deleading PbB decreased 0.11 +/- 0.12 mumol/L (2.25 +/- 2.4 micrograms/dL) (P less than .005). In a subset of 59 subjects who had no chelation therapy and were available for follow-up 250 +/- 14 days after completion of deleading, PbB had decreased from 1.72 +/- 0.04 mumol/L (35.7 +/- 0.9 micrograms/dL) to 1.24 +/- 0.04 mumol/L (25.5 +/- 0.9 micrograms/dL) (P less than .001). The long-term effect of deleading is a significant reduction in PbB. However, deleading resulted in a significant, albeit transient, increase in PbB.

Serum lidocaine concentrations in children during bronchoscopy with topical anesthesia.

To evaluate the safety of topical lidocaine anesthesia in children undergoing bronchoscopy, we determined SLC in 15 children aged 3 months to 9.5 years during flexible fiberoptic bronchoscopy. A total lidocaine dose of 3.2 to 8.5 (mean +/- SEM = 5.7 +/- 0.5) mg/kg was administered to nose, larynx and bronchial tree over 9 to 45 (mean +/- SEM = 20 +/- 2.7) minutes. No complication occurred during the procedure. Peak SLC were 1-3.5 (mean +/- SEM = 2.5 +/- 0.2) micrograms/ml. The Vd beta was 1.79 +/- 0.19 L/kg, the t1/2 beta was 109 +/- 12 minutes, and the total body clearance 12.2 +/- 1.1 ml/min/kg. Peak SLC correlated well with the dose expressed as mg/kg (r = 0.59, p less than 0.025), and even better when related to body surface area (r = 0.63, p less than 0.01). Lidocaine doses up to 8.5 mg/kg proved safe and resulted in therapeutic SLC in our patients. Lidocaine dose up to 7 mg/kg appears to be safe provided that it does not exceed an upper limit of 175 mg/m2 and is gradually administered over a minimum of 15 minutes. Doses of 7-8.5 mg/kg appear to be safe when administered over longer periods.

Ipecac-induced emesis and reduction of plasma concentrations of drugs following accidental overdose in children.

Syrup of ipecac is widely used following accidental drug overdosage in children. Proof of its efficacy, however, in reducing the risk of poisoning is limited. We prospectively studied the effect of early v late induction of emesis by ipecac in 50 children younger than 5 years of age with accidental acetaminophen poisoning. The mean estimated ingested dose was 165 mg/kg, and all patients vomited within 15 to 255 (mean 78) minutes postingestion. Although the predicted four-hour plasma acetaminophen concentration was 97 +/- 4 micrograms/mL (mean +/- SEM, calculated on the basis of the estimated ingested dose), the measured four-hour plasma acetaminophen concentration was 34 +/- 5 micrograms/mL (P less than .01). To assess the efficacy of early v late ipecac-induced emesis, we used the ratio of measured to predicted four-hour acetaminophen plasma concentration. The ratio of the measured to predicted four-hour level increased as the delay in time to vomiting increased (r = .60, P less than .001). Ipecac syrup was administered more promptly when available in the home than when obtained from a pharmacy or a medical facility (26 +/- 8 v 83 +/- 13 minutes postingestion, respectively; P less than .001) and vomiting occurred earlier (49 +/- 9 v 103 +/- 12 minutes postingestion; P less than .01). Although the mean estimated doses ingested were greater in patients who received ipecac syrup at home, their four-hour plasma acetaminophen concentrations were lower. These data suggest that prompt administration of ipecac syrup results in a greater reduction in plasma acetaminophen concentrations in potentially toxic overdosages in children.(ABSTRACT TRUNCATED AT 250 WORDS)

Hazards of 'deleading' homes of children with lead poisoning.

"Deleading" the homes of children with lead poisoning is a necessary step to terminate the child's exposure to lead. Lead poisoning as a result of lead exposure during the process of deleading has occurred in deleading workers but has not been well documented among children whose homes are deleaded. We treated four children with classes I through III lead poisoning (range of blood lead [Pb-B] level, 1.6 to 2.75 mumol/L [33 to 57 micrograms/dL]) who had significant elevation of their Pb-B levels (range, peak 4.34 to 6.27 mumol/L [90 to 130 micrograms/dL]) following deleading of their homes. The methods used for deleading included scraping, sanding, and burning of the paint. Symptoms included irritability (n = 3) and vomiting (n = 1). The elevation of the Pb-B levels was detected early, allowing prompt chelation therapy. Because exacerbation of lead poisoning may occur in children following deleading of their homes, safer approaches of deleading should be determined.

Patterns of calling time and ipecac availability among poison center callers.

Over a one-month period all telephone calls from the public (n = 3828) to a regional poison center were analyzed. The proportion of early calls (within ten minutes of exposure) decreased with age. Late calls (greater than 30 minutes) were significantly associated with higher hospital referral rates when compared with earlier calls in children younger than 5 years (4.6% vs 1.8%) and adults (33% vs 15%). Ipecac was available in 59% of the homes of callers with children younger than 5 years. Hospital referrals were significantly less common among children who had ipecac at home (1%) compared with children who did not (3%). While the availability of ipecac was similar among callers and a matched sample of households who previously called the poison center (58%), ipecac was much less frequently available (24%) among households whose members had not previously called the center. These data infer that educating the public to call the poison center promptly may result in reduction of hospital referrals. Poison education efforts should be targeted to populations with low ipecac availability and low utilization of the poison center.

Characteristics of vomiting associated with acute sustained release theophylline poisoning: implications for management with oral activated charcoal.

Vomiting in acute theophylline toxicity has assumed increased clinical importance since the introduction of multiple dose activated charcoal therapy. We performed a prospective study of 26 patients with acute overdose of sustained release theophylline to characterize vomiting, and its possible interference with the acceptance of activated charcoal. Twenty five of 26 patients vomited. The duration of vomiting correlated with both peak serum theophylline concentrations (p less than 0.001) and the duration of theophylline toxicity (p less than 0.001). Vomiting extended over 63% of the drug's absorptive phase (the time interval between ingestion and the peak level) and 49% of the elimination phase (the time interval between the peak level and decrease of theophylline level to less than 20 mcg/ml). Patients with peak serum theophylline concentrations less than 70 mcg/ml were able to accept larger amounts of activated charcoal than patients with serum theophylline concentrations greater than 70 mcg/ml (113 +/- 15 gms vs. 57 +/- 24 gms, p less than 0.05). Vomiting in acute sustained release theophylline toxicity is protracted, and limits the use of activated charcoal especially in patients with severe acute theophylline poisoning.

Tea drinking and microcytic anemia in infants.

To evaluate the effect of tea drinking on the occurrence of microcytic anemia in infants, we studied 122 healthy infants who underwent routine blood counts at the age of 6-12 months. An overall high frequency of anemia (Hb less than 11 gm/dl-48.4%), microcytosis (MCV less than 70 Mm3-21.3%) and microcytic anemia (19%) was found in the whole group. The percentage of tea drinking infants with microcytic anemia (32.6%) was significantly higher than that of the non-tea drinkers (3.5%). The daily amount of tea drinking was 50-750 ml (median 250 ml). The tea drinkers had significantly lower mean levels of hemoglobin than that of the non-tea drinkers (10.5 +/- 1.2 gm/dl vs 11.2 +/- 0.8 gm/dl, respectively) and significantly lower mean levels of mean corpuscular volume than that of the non-tea drinkers (71.5 +/- 7.1 micron 3 vs 76.1 +/- 4.6 micron 3). There were no significant differences between the two groups in their sex distribution and in the duration of breast feeding. The two groups differed with regard to their ages and social class but a multivariate analysis had excluded the possible confounding effect of these differences on the hematological results. Based on our finding we do not recommend giving tea to infants whose main source of iron is from milk, grains, vegetables or medicinal sources.