Lactobacillus acidophilus NCFM affects colonic mucosal opioid receptor expression in patients with functional abdominal pain - a randomised clinical study.

BACKGROUND: In a recent double-blinded clinical trial, the probiotic combination of Lactobacillus acidophilus NCFM (L-NCFM) and B-LBi07 reduced bloating symptoms in patients with functional bowel disorders; an effect more evident in those who reported abdominal pain. In mice, L-NCFM but not B-LBi07 induced colonic mu-opioid receptor (MOR) and cannabinoid receptor 2 (CB2) expression, and reduced visceral sensitivity. AIMS: To determine if L-NCFM was the active component in the clinical trial and to investigate the mechanism of action in humans with mild to moderate abdominal pain. METHODS: Caucasian women (n = 20) 18-70 years with mild to moderate abdominal pain were enrolled in a double-blind, two-armed, single-centre study. Patients were given either L-NCFM alone or in combination with B-LBi07 for 21 days at a total dose of 2 × 10(10) CFU b.d. Colonic biopsies were collected during unsedated, unprepped flexible sigmoidoscopy before and at the end of probiotic consumption. mRNA and immunostaining were then performed on these biopsies. Patients kept symptom diaries for the 7 days prior to starting probiotic therapy and for the last 7 days of therapy. RESULTS: L-NCFM alone, but not with B-LBi07, induced colonic MOR mRNA and protein expression, as well as downstream signalling, as measured by enterocyte STAT3-phosphorylation. In contrast, CB2 expression was decreased. Both treatment groups trended towards improvement in symptoms, but the study was insufficiently powered to draw meaningful conclusions. CONCLUSIONS: Lactobacillus acidophilus NCFM modulates mu-opioid receptor expression and activity, while the combination of L-NCFM and B-LBi07 does not. This study provides a possible mechanism for action by which probiotics modulates pain sensation in humans (Clinical Trial Number: NCT01064661).

Think small: zebrafish as a model system of human pathology.

Although human pathologies have mostly been modeled using higher mammal systems such as mice, the lower vertebrate zebrafish has gained tremendous attention as a model system. The advantages of zebrafish over classical vertebrate models are multifactorial and include high genetic and organ system homology to humans, high fecundity, external fertilization, ease of genetic manipulation, and transparency through early adulthood that enables powerful imaging modalities. This paper focuses on four areas of human pathology that were developed and/or advanced significantly in zebrafish in the last decade. These areas are (1) wound healing/restitution, (2) gastrointestinal diseases, (3) microbe-host interactions, and (4) genetic diseases and drug screens. Important biological processes and pathologies explored include wound-healing responses, pancreatic cancer, inflammatory bowel diseases, nonalcoholic fatty liver disease, and mycobacterium infection. The utility of zebrafish in screening for novel genes important in various pathologies such as polycystic kidney disease is also discussed.

Dietary and clastogenic factors in children who immigrated to Israel from regions contaminated by the Chernobyl accident.

The authors evaluated the possible association between dietary history and plasma clastogenic factors in children who immigrated to Israel between 1989 and 1993 from regions contaminated by the Chernobyl accident. The authors compared questionnaire data about demographic variables, dietary histories before and after immigration occurred, and health status with clastogenic factor scores for 162 immigrants. Logistic regression analysis revealed a negative association between clastogenic factor scores and frequency of consumption of fresh vegetables and fruit among children < or = 7 yr of age during the postimmigration period. Intake of eggs and fish by boys who were < or = 7 yr of age prior to immigration was associated positively with clastogenic factor scores. Consumption of fresh vegetables and fruits afforded protection to the immune systems of children who were < or = 7 yr of age.

A case-control study of Parkinson's disease in urban population of southern Israel.

BACKGROUND: In recent years, an increased prevalence of Parkinson's disease (PD) in southern Israel was observed. The aim of this study was to determine which exposures are associated with PD in the urban population of this region. METHODS: Ninety-three PD patients living in towns were compared to 93 age and sex matched controls. A previously validated questionnaire, including demographic data, education, data on exposures, previous diseases, family history and habits, was administered. RESULTS: In multivariate logistic regression analysis, it was found that history of work in construction sites was the strongest predictor of PD risk, followed by exposure to pesticides. In contrast, there was a negative association with smoking and history of mechanical factory employment. When the same statistical analysis was limited to association of PD with smoking, pesticides and construction work, the latter was found to be the strongest risk factor. CONCLUSION: The risk factors for PD in this population are work on a construction site and exposure to pesticides.

The residential radon-lung cancer association in U.S. counties: a commentary.

There is little doubt that underground miners exposed to radon and its progeny have increased rates of lung cancer. Residential radon exposures should carry a possibly smaller risk of increased cancer. When it became possible to collect radon data in a large number of U.S. homes and the data were aggregated by counties, the apparent association with lung cancer was a negative one, even when many other variables were taken into account. Residential radon levels are higher in suburban residences leading to a negative association with population density. Population density is strongly positively associated with lung cancer. It follows that aggregate residential radon and lung cancer rates should be negatively associated for reasons having nothing to do with the possibility of radon being carcinogenic to the lung. A second problem presented by the data is the one of sampling bias since the county lung cancer data are from the whole county population, but only a few residences are tested. Examples of other inherent associations in environmental epidemiology are cited. One strategy is to study areas of the same population density but with radon exposure gradients. This is approximated by choice of rural high radon states. Counties in such states have weak and inconsistent associations between radon and lung cancer, some of which are positive. I conclude that counties are generally inappropriate units for study of radon and lung cancer associations.

Juvenile hypothyroidism among two populations exposed to radioiodine.

We found an epidemic of juvenile hypothyroidism among a population of self-defined "downwinders" living near the Hanford nuclear facility located in southeast Washington State. The episode followed massive releases of 131I. Self-reported data on 60 cases of juvenile hypothyroidism (<20 years of age) among a group of 801 Hanford downwinders are presented, as well as data concerning the thyroid status of approximately 160,000 children exposed to radioiodine before 10 years of age as a result of the 26 April 1986 Chernobyl explosion in the former Soviet Union. These children were residents of five regions near Chernobyl. They were examined by standardized screening protocols over a period of 5 years from 1991 to 1996. They are a well-defined group of 10 samples. Fifty-six cases of hypothyroidism were found among boys and 92 among girls. Body burdens of 137Cs have been correlated with hypothyroidism prevalence rates. On the other hand, the group of juvenile (<20 years of age) Hanford downwinders is not a representative sample. Most of the 77 cases of juvenile hypothyroidism in the Hanford group were diagnosed from 1945 to 1970. However, the ratio of reported cases to the county population under 20 years of age is roughly correlated with officially estimated mean levels of cumulative thyroid 131I uptake in these counties, providing evidence that juvenile hypothyroidism was associated with radioiodine exposures. Because even subtle hypothyroidism may be of clinical significance in childhood and can be treated, it may be useful to screen for the condition in populations exposed to radioiodine fallout. Although radiation exposure is associated with hypothyroidism, its excess among fallout-exposed children has not been previously quantified.

On the mechanism of the positive feedback action of estradiol on luteinizing hormone secretion in the rhesus monkey.

In women and rhesus monkeys, both the negative and positive feedback actions of estradiol (E2) on gonadotropin secretion (inhibition followed by a surge) can be exerted directly at the level of the pituitary gland. We have tested the hypothesis that the positive feedback action of E2 represents but an "escape" from its negative feedback inhibition of gonadotropin secretion consequent to a desensitization of the gonadotropes occasioned by sustained exposure to elevated concentrations of the steroid. We have attempted to replicate such a desensitization by blocking the negative feedback action of E2 by the administration of a potent estrogen receptor antagonist devoid of any agonistic properties (ZM 182,780) to rhesus monkeys in the midfollicular phase of the menstrual cycle (n = 14). The estrogen antagonist, administered at a dose that in separate experiments completely blocked both the negative and the positive feedback effect of exogenous E2 on pituitary LH secretion, failed to produce a surge-like increase in serum LH concentrations. The present results do not support the hypothesis that the LH surge is the consequence of the removal of the negative feedback action of E2. Evidence is presented that ZM 182,780, in contrast to its inhibition of E2-induced LH surges, cannot block the inhibition of hypothalamic GnRH pulse generator activity by E2.

A case-referent study of extrapyramidal signs (preparkinsonism) in rural communities of Israel.

BACKGROUND: In previous studies we reported an increased prevalence of Parkinson's disease in several kibbutzim of Southern Israel (cluster kibbutzim). Subsequent studies revealed a significant prevalence of subjects presenting extrapyramidal signs (preparkinsonism) in the same kibbutzim. On follow-up worsening of these signs was observed in some of the older subjects, some of them actually being diagnosed as suffering from 1-Dopa responsive Parkinson's disease. The current study was designed to evaluate possible etiologic factors for the development of preparkinsonism. METHODS: 317 subjects over the age of 40, living in five kibbutzim were examined and interviewed. 95 subjects presenting extrapyramidal signs were compared with 95 control subjects. They were matched for age, sex and length of residence in the kibbutz. Odds ratios were computed to identify exposure variables for logistic regression analyses. Detectors for carbamates and organic phosphates were applied at different sites of these kibbutzim. RESULTS: The severity and frequency of the extrapyramidal signs were higher in the older age groups, more in the "cluster", than in other kibbutzim. A very strong association was found between field crop work exposure, particularly cotton, and preparkinsonism (p = 0.0007) and a slightly weaker association for landscape work. The detectors picked up abundant pesticide traces (carbamates and organic phosphates) in the residential areas fairly distant from sites of aerial spray. CONCLUSIONS: We assume a chronic passive exposure of the residents in these kibbutzim to pesticides, in addition to any occupational exposures.

On the mechanism of lactational anovulation in the rhesus monkey.

The relative roles of infant suckling and of maternal prolactin (PRL) secretion in lactational anovulation were studied in ovary-intact and ovariectomized rhesus monkeys nursing young that had been removed from their natural mothers. Hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator activity was monitored electrophysiologically in freely behaving animals by radiotelemetry. Serum luteinizing hormone, PRL, estradiol, and progesterone were also measured. Suckling inhibited GnRH pulse generator activity and ovarian cyclicity in all ovary-intact females but had no such effect on the pulse generator in long-term ovariectomized animals. When PRL secretion was suppressed by daily bromocriptine administration, GnRH pulse generator activity remained significantly inhibited and ovulation was prevented in four monkeys (6 trials), whereas in two females (6 trials) a rapid increase in pulse generator frequency and the resumption of ovarian cyclicity were observed although suckling activity was maintained. One monkey displayed both response types. Although these results indicate that suckling per se is able to restrain GnRH pulse generator activity in the absence of PRL, they also suggest that the relative importance of these determinants is variable depending on factors that remain to be determined. The present study also confirms the permissive role of the ovary in the lactational suppression of GnRH pulse generator activity.

On the role of gonadotropin-releasing hormone (GnRH) in the operation of the GnRH pulse generator in the rhesus monkey.

The pulsatile secretion of luteinizing hormone (LH), occasioned by the pulsatile release of gonadotropin-releasing hormone (GnRH), is closely associated with concurrent increases in multiunit electrical activity in the mediobasal hypothalamus (MUA volleys), the electrophysiological correlates of GnRH pulse generator activity. These volleys represent a highly synchronized increase in firing frequency of individual neurons. The origin of these rhythmic oscillations in unit activity and the mechanisms responsible for their synchronization are unknown. The purpose of the present study was to examine the role, if any, of GnRH in the functioning of the GnRH pulse generator in rhesus monkeys. Ovariectomized animals bearing recording electrodes chronically implanted in the mediobasal hypothalamus and fitted with intracerebroventricular (ICV) cannulae in the lateral ventricle and with indwelling cardiac catheters were studied. LH was measured in venous blood withdrawn from the cardiac catheters every 10 min while hypothalamic electrical activity was monitored continuously. In Experiment 1, following a 3- to 4-hour control period, GnRH was infused ICV at a rate of 300 ng/kg body weight (BW)/h over 4-5 h. In Experiment 2, antide, a long-acting GnRH antagonist, was injected ICV in a dose of 105 microg/kg BW after a control period of 3-4 h. Additional control experiments were performed in each animal using vehicle alone. Neither GnRH nor antide affected the frequency of MUA volleys and attendant LH pulses despite significant alterations in LH secretion. These results suggest that, in the rhesus monkey, GnRH may not be involved in the operation of the GnRH pulse generator.

Dynamics of parkinsonism-Parkinson's disease in residents of adjacent kibbutzim in Israel's Negev.

From serial studies of clinical findings and Webster's scores, we determined the incidence of Parkinson's disease and the pattern of progression of the components of parkinsonism in residents older than 40 in rural settlements with unusually high rates of Parkinson's disease in southern Israel (Negev). In 1988, the authors reported on three adjacent kibbutzim at which were identified 13 cases of Parkinson's disease in a population of 413 persons older than 50 years. In the region as a whole, there were 143 additional cases among a population of 64,185 who were 40 years of age or older. The age-standardized prevalence ratio for the kibbutz population was 5.43. By 1993, 2 of the persons with Parkinson's disease had died, and 8 new cases had been diagnosed. The age-standardized prevalence ratio in 1993 was 8.09. The crude incidence ratio for persons older than 40 was 3.4 per 1000 per year. Webster's score is used as an estimator of the severity of pre-parkinsonism. In the normal population of elderly persons from other areas in the Negev, only 20 of 110 had a score greater than 0 (11, 8, and 1 scored 1, 2, and 3, respectively). When the Webster's score was first applied systematically-in 1989 to asymptomatic persons from the kibbutzim who were older than 40-46 of 104 had scores of 2 or more, and some subjects also had impaired vibration sense. The tests were repeated by different observers on a casual sample in 1991 and 1993. Of the persons older than 60 in 1989 (n = 14), the scores increased from an average of 2.3 in 1989 to 3.9 in 1991 and to 5.7 in 1993. In a younger sample (n = 7), the mean scores were 2.3 in 1989, 3.6 in 1991, and 2.9 in 1993. These results are evidence of an age-specific peak in incidence and prevalence in the 70- to 79-year-old age group and may represent a cohort exposure phenomenon. The results may also reflect the critical role of age in the transformation of pre-parkinsonism to Parkinson's disease. Finally, in this population with high initial rates of Parkinson's disease, there was evidence of pre-parkinsonism in about half of those older than 40, and active progression of pre-parkinsonism in those older than 60. Therefore, this group is an ideal population to test for effects of preventive interventions.

Chemical exposures and Parkinson's disease in residents of three Negev kibbutzim.

We consider whether chemical pollutants in drinking water (including aromatic hydrocarbons, alkanes, halogenated aliphatic hydrocarbons, and phthalic acid) or used occupationally in agriculture that have shown no parkinsonism-inducing effect may be responsible for excess cases of Parkinson's disease (PD) in three adjacent kibbutzim in southern Israel (Negev). Literature data on PD pathogenesis have been compared with common pathogenetic pathways to xenobiotics effects; the following neurotoxic mechanisms, besides individual sensitivity, have been suggested: (1) impairment of the protective role of the substantia nigra against toxicants by binding of chemicals to melanin; (2) oxidative stress induction, including glutathione reduction, impaired calcium metabolism, and alteration of cytochrome P-450 activity; (3) blockade of iron chelators because of structural similarities to them or their precursors; (4) mediation of the production of endogenous dopaminergic neurotoxins, such as trichloroharmanes or isoquinolines; (5) blockade of dopamine receptors because of their resemblance to chemicals with affinity to these receptors; (6) stimulation of prostaglandin-H synthase and monooxygenase activity; and (7) stimulation of autoimmune processes and creation of autoimmunity to structures of the dopaminergic system caused by chemical similarity.

Blood pressure among immigrants to Israel from areas affected by the Chernobyl disaster.

OBJECTIVES: To validate and analyze apparent association of hypertension with exposures to radiation at Chernobyl among immigrants to Israel from the contaminated areas. METHODS: Data were collected in 1991 and 1994 from two samples of persons who immigrated to Israel from the contaminated zone around the Chernobyl nuclear power plant. The first sample were self-referred for evaluation in a clinic by whole-body cesium measurement, physical examination, and questionnaire (N = 756, 328 from less exposed and 438 from more exposed areas). The second wave data were collected in 1994 during home interviews for evaluation of psychosocial factors associated with their experience (N = 708, 121 from more exposed and 253 from less exposed areas). In the second study a referent group was included (n = 334) who were matched by age, sex, and year of immigration who immigrated from other areas outside of the contaminated zone. Estimates of exposure were based on the IAEA map of ground-level cesium isotope (137Cs) contamination. RESULTS: In the 1991 sample, 21% from high exposure areas and 16% from less exposed areas had elevated systolic blood pressure (> 140 mmHg). Elevated diastolic blood pressure (> 90 mmHg) had a similar difference between more and less exposed groups (21% and 16%). Age- and sex-specific analyses showed that statistically different levels were found in the older age groups. In the 1994 sample, we confirmed a relationship between exposure and elevated blood pressure. 33% of those from the more exposed areas and 34% of those from less exposed areas had elevated systolic blood pressure, compared with 23% of the comparison group, with a similar trend found in diastolic blood pressure. The relationship between exposure and blood pressure was accentuated in the group of respondents who had high scores on PTSD symptoms. Of the psychological variables analyzed, systolic blood pressure was most strongly related to cancer-related anxiety and somatization. A discriminant function analysis showed that three variables: age, reporting a significant loss from the Chernobyl accident, and fear of cancer correctly differentiated 72% of those with normal and high blood pressure. CONCLUSIONS: There is a relationship between exposure to Chernobyl and high blood pressure, partly due to the psychological reactions to the accident.

Dibromochloropropane: epidemiological findings and current questions.

Dibromochloropropane, DBCP, has had a seminal role in our current understanding of how to prevent chemical risks to health. Early toxicological studies showed its special impact on the testes, and detection of its mutagenic potency was soon followed by demonstration of its carcinogenicity to animals. Its commercial use as a useful nematocide ignored, at first, these warnings from the laboratory. When production workers, first in California and then in Israel, found they were sterile as a result of their exposure, this was convincing evidence that prevention had failed. The evidence, azospermia, oligospermia, and gonadotrophin response to testicular damage, were found first in production workers. In agricultural applicators in California who used the material, decreased sperm count and increased gonadotrophin levels were found. While production in California, Texas, and Israel was halted, studies continued and so, it seems, did use. Our first Israeli study was of workers on banana crops, and we found convincing evidence of increased spontaneous abortion in their family histories. Follow-up studies among production workers in Israel showed that some recovered testicular function, but among their offspring, otherwise in good health, there was a predominance of females. Those who did not recover from azospermia were those with high levels of follicle stimulating hormone. However data for production workers did not show increased spontaneous abortion. Nor have any studies so far shown increased birth defects or increased infant mortality. Unfavorable reproductive outcomes can be due to other agents, as shown by sprayers in Dutch orchards having hypofecundity (increased interpregnancy period) and sex ratio changes; but the agents responsible have not yet been identified. These experiences have lead to the general acceptance of some implications: (1) Paternal exposures can lead to a variety of unfavorable effects on reproductive outcome, including infertility, spontaneous abortion, and altered sex ratio. (2) Patterns of effects of potent agents in production workers and in applicators or users of chemicals may differ. (3) Although human carcinogenesis has not yet been confirmed, unfavorable reproductive outcomes are a reasonable early indicator of such risk. (4) Shifts in sex ratios of populations may be a subtle sign of more serious risks. (5) Continued use of an agent such as this under circumstances in which these UROs cannot be prevented is unconscionable.

Somatic mutations at the glycophorin A (GPA) locus measured in red cells of Chernobyl liquidators who immigrated to Israel.

Glycophorin A (GPA) assays for human erythrocytes with gene expression loss and duplication phenotypes (NO, NN) were carried out on 15 Chernobyl clean-up workers (liquidators) who immigrated to Israel within the preceding 5 years, 19 local Israeli controls, and 14 Russian (nonliquidator) immigrants. GPA phenotype variants in red blood cells of the 15 liquidators showed values ranging from 1 to 101 events/10(6) cells, with a mean +/- SD of 25.6 +/- 7.0. In comparison, the 19 Israeli controls had values ranging from 0 to 13 GPA events per 10(6) cells, with a mean +/- SD of 3.9 +/- 0.8. The difference was highly significant (p < 0.001). Another group of 14 volunteer control subjects (nonliquidators) who had emigrated from the former Soviet Union to Israel during the past 5 years showed values ranging from 0.0 to 35.0 events per 10(6) cells, with a mean +/- SD of 6.1 +/- 2.7. The difference between this group and the liquidator group was significant at p < 0.01. The results are compatible with past exposure to radiation in the group identified as liquidators.

Thyroid-stimulating hormone levels in children from Chernobyl.

This study assesses parameters of thyroid function in persons who resided in Ukraine, Belarus, and southern Russia and exposed at 0 to 16 years of age to radioiodine contamination from the Chernobyl accident. Six to eight years after the accident a group of 300 young people who had immigrated to Israel were interviewed, underwent physical and ultrasound thyroid examination, and had their serum tested for thyroid-stimulating hormones (TSH), thyroid hormones, thyroglobulin, and antithyroid antibodies. Comparative groups came from areas with high (>1 Ci/km2) or low (< 1 Ci/km2) 137Cs ground contamination. Girls from high contamination areas, when compared to girls from areas with low ground contamination, showed significant upward shifts in levels of serum TSH (p = 0.023) although remaining within normal limits. Boys showed no significant differences. There was no evidence for differences in thyroid size or nodularity between the two groups of girls. A working hypothesis is proposed by which the shift in TSH levels in girls from high radiocontamination areas was associated with subclinical radiation damage from environmental radioiodine at the time of the accident.

Lessons learned from the study of immigrants to Israel from areas of Russia, Belarus, and Ukraine contaminated by the Chernobyl accident.

During the past 6 years, immigration to Israel of 700,000 persons from the former Soviet Union (FSU) included about 140,000 from radiocontaminated regions of Belarus, Ukraine, and Russia near Chernobyl. In Beer Sheva, a major center for immigrant absorption in Israel, a primary objective was to evaluate their health status and to refer them for care. 137Cs levels in 1228 men, women, and children were measured with a portable whole-body counter. Whole-body counts showed clear correlation with the degree of 137Cs ground contamination in previous regions of residence. The population could thus be sub-divided according to degree of exposure, based on previous regions of residence. The thyroid status of 300 local immigrant children was evaluated because of the increased risk of childhood thyroid cancer in the regions from which they came. This group was subdivided into comparative groups of children who came from less and more contaminated areas according to the International Atomic Energy Agency soil 137Cs contamination maps. Enlarged thyroids were found in about 40% of both groups. One 12-year-old girl from Gomel had a malignant papillary carcinoma. Thyroid-stimulating hormone levels, though within normal limits, were significantly greater (p < 0.02) for girls from high exposure regions. Liquidators showed significant increases in serum clastogenic factor and in the number of circulating glycophorin A-mutated red cells. In studies of over 700 people from both radiocontaminated and unaffected regions of the FSU, evidence for posttraumatic stress disorder was found more frequently in persons coming from the more contaminated areas.