Bile acids drive the newborn's gut microbiota maturation.

Following birth, the neonatal intestine is exposed to maternal and environmental bacteria that successively form a dense and highly dynamic intestinal microbiota. Whereas the effect of exogenous factors has been extensively investigated, endogenous, host-mediated mechanisms have remained largely unexplored. Concomitantly with microbial colonization, the liver undergoes functional transition from a hematopoietic organ to a central organ of metabolic regulation and immune surveillance. The aim of the present study was to analyze the influence of the developing hepatic function and liver metabolism on the early intestinal microbiota. Here, we report on the characterization of the colonization dynamics and liver metabolism in the murine gastrointestinal tract (n = 6-10 per age group) using metabolomic and microbial profiling in combination with multivariate analysis. We observed major age-dependent microbial and metabolic changes and identified bile acids as potent drivers of the early intestinal microbiota maturation. Consistently, oral administration of tauro-cholic acid or ß-tauro-murocholic acid to newborn mice (n = 7-14 per group) accelerated postnatal microbiota maturation.

The Sheep Grimace Scale as an indicator of post-operative distress and pain in laboratory sheep.

The EU Directive 2010/63/EU changed the requirements regarding the use of laboratory animals and raised important issues related to assessing the severity of all procedures undertaken on laboratory animals. However, quantifiable parameters to assess severity are rare, and improved assessment strategies need to be developed. Hence, a Sheep Grimace Scale (SGS) was herein established by observing and interpreting sheep facial expressions as a consequence of pain and distress following unilateral tibia osteotomy. The animals were clinically investigated and scored five days before surgery and at 1, 3, 7, 10, 14 and 17 days afterwards. Additionally, cortisol levels in the saliva of the sheep were determined at the respective time points. For the SGS, video recording was performed, and pictures of the sheep were randomized and scored by blinded observers. Osteotomy in sheep resulted in an increased clinical severity score from days 1 to 17 post-surgery and elevated salivary cortisol levels one day post-surgery. An analysis of facial expressions revealed a significantly increased SGS on the day of surgery until day 3 post-surgery; this elevated level was sustained until day 17. Clinical severity and SGS scores correlated positively with a Pearson´s correlation coefficient of 0.47. Further investigations regarding the applicability of the SGS revealed a high inter-observer reliability with an intraclass correlation coefficient of 0.92 and an accuracy of 68.2%. In conclusion, the SGS represents a valuable approach for severity assessment that may help support and refine a widely used welfare assessment for sheep during experimental procedures, thereby meeting legislation requirements and minimizing the occurrence of unrecognized distress in animal experimentation.

Successful sanitation of an EDIM-infected mouse colony by breeding cessation.

Despite decreasing prevalence, rotavirus infections still rank among the most important viral infections in colonies of laboratory mice. Although the disease is characterized by low mortality and a relatively short and mild clinical period, the infection has the potential to alter the outcome of experiments substantially. For animal facilities, it is therefore essential to eradicate the virus. Here we report a successful sanitation of a rotavirus-infected mouse colony in an animal facility. Despite a high ratio of transgenic and partially immunodeficient strains, a permanent eradication of the virus was achieved by euthanasia of highly susceptible mice, a prolonged breeding cessation in areas containing immunocompromised mice and a strict hygienic management. The management of a rotavirus infection reported here is a feasible and inexpensive opportunity for sanitation that benefits from maintaining most of the animal population, even in today's mouse colonies comprising mainly transgenic mice with unknown or compromised immune status.

Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic debilitating disease resulting from a complex interaction of multiple genetic factors with the environment. To identify modifier genes of IBD, we used an F2 intercross of IBD-resistant C57BL/6J-Il10(-/-) mice and IBD-susceptible C3H/HeJBir-Il10(-/-) (C3Bir-Il10(-/-)) mice. We found a prominent involvement of lymphatic vessels in IBD and applied a scoring system to quantify lymphatic vascular changes. Quantitative trait locus (QTL) analyses revealed a large-effect QTL on chromosome 3, mapping to an interval of 43.6 Mbp. This candidate interval was narrowed by fine mapping to 22 Mbp, and candidate genes were analyzed by a systems genetics approach that included quantitative gene expression profiling, search for functional polymorphisms, and haplotype block analysis. We identified vascular adhesion molecule 1 (Vcam1) as a candidate modifier gene in the interleukin 10-deficient mouse model of IBD. Importantly, VCAM1 protein levels were increased in susceptible C3H/HeJ mice, compared with C57BL/6J mice; systemic blockade of VCAM1 in C3Bir-Il10(-/-) mice reduced their inflammatory lymphatic vessel changes. These results indicate that genetically determined expression differences of VCAM1 are associated with susceptibility to colon inflammation, which is accompanied by extensive lymphatic vessel changes. VCAM1 is, therefore, a promising therapeutic target for IBD.

Genetic dissection of granulomatous enterocolitis and arthritis in the intramural peptidoglycan-polysaccharide-treated rat model of IBD.

BACKGROUND: Inflammatory arthropathies are common extraintestinal manifestations of inflammatory bowel diseases (IBD). As genetic susceptibility plays an important role in the etiology of IBD, we questioned how granulomatous enterocolitis and arthritis are genetically controlled in an experimental animal model displaying both conditions. METHODS: Chronic intestinal and systemic inflammation was induced by intramural injection of peptidoglycan-polysaccharide (PG-PS) polymers in the ileocecal region of female F2 progeny derived from susceptible LEW and resistant F344 rats. Animals were followed for 24 days after injection and phenotyped by evaluating gross gut lesions, liver weight and granulomas, hematocrit, white blood cell count, and change in rear ankle joint diameters. Coinheritance of the phenotypic parameters with polymorphic DNA markers was analyzed by genome-wide quantitative trait locus (QTL) analysis. RESULTS: Linkage analysis revealed significant QTLs for enterocolitis and/or related phenotypes (liver granulomas, white blood cell count) on chromosomes 8 and 17. The QTL on chromosome 8 also showed suggestive linkage to arthritis. Significant QTLs for arthritis were detected on chromosomes 10, 13, 15, and 17. Analyses of the modes of inheritance showed arthritogenic contributions by both parental genomes. In addition, several other loci with suggestive evidence for linkage to 1 or several phenotypes were found. CONCLUSIONS: Susceptibility to PG-PS-induced chronic intestinal and systemic inflammation in rats is under complex multigenic control in which the genetic loci regulating arthritis are largely different from those controlling enterocolitis. Possible candidate genes within these QTL (including Tnfrsf11a/RANK, Gpc5, Il2ra, and Nfrkb) are also implicated in the respective human diseases.

Anti-inflammatory role of sympathetic nerves in chronic intestinal inflammation.

BACKGROUND: Substance P (SP) is a pro-inflammatory neuropeptide in colitis, whereas sympathetic neurotransmitters are anti-inflammatory at high concentrations. AIM AND METHODS: In all layers of the colon, nerve fibre densities of SP(+) and sympathetic nerve fibres were investigated (22 Crohn's disease, six diverticulitis, and 22 controls). In addition, the nerve fibre repellent factor semaphorin 3C (SEMA3C) was studied. The functional role of the sympathetic nervous system was tested in dextran sodium sulfate (DSS) and Il10(-/-) colitis. RESULTS: In all layers, Crohn's disease patients demonstrated a loss of sympathetic nerve fibres. Sprouting of SP(+) nerve fibres was particularly observed in the mucosa and muscular layer in Crohn's disease. SEMA3C was detected in epithelial cells, and there was a marked increase of SEMA3C-positive crypts in the mucosa of Crohn's disease patients compared to controls. In Crohn's disease, the number of SEMA3C-positive crypts was negatively related to the density of mucosal sympathetic nerve fibres. Sympathectomy reduced acute DSS colitis but increased chronic DSS colitis. Sympathectomy also increased chronic colitis in Il10(-/-) mice. CONCLUSIONS: This study demonstrated a loss of sympathetic and an increase of SP(+) nerve fibres in Crohn's disease. SEMA3C, a sympathetic nerve repellent factor, is highly expressed in the epithelium of Crohn's disease patients. In chronic experimental colitis, the sympathetic nervous system confers an anti-inflammatory influence. Thus, the loss of sympathetic nerve fibres in the chronic phase of the disease is most probably a pro-inflammatory signal, which might be related to repulsion of these fibres by SEMA3C and other repellents.

The mental health impact of terrorism in Israel: a repeat cross-sectional study of Arabs and Jews.

OBJECTIVE: Since September 2000 Israeli society has been subjected to numerous deadly terror attacks. Few studies have studied the comparative mental health vulnerability of minorities and majorities to continuous terror attacks. METHOD: Two telephone surveys (N = 512 and 501) on two distinct representative samples of the Israeli population after 19 months and after 44 months of terror. The Arab minority and Jewish majority were compared on measures of exposure to terrorism, posttraumatic stress symptomatology, feeling depressed, coping, sense of safety, future orientation, and previous traumatic experiences. RESULTS: After 19 months of terrorist attacks Arab Israelis and Jewish Israelis reacted roughly similarly to the situation, however after 44 months of terror, posttraumatic symptom disorder in the Arab population increased three-fold, posttraumatic symptomatology doubled and resiliency almost disappeared. CONCLUSION: We suggest that certain conditions inherent to political conflict situations may potentially put minorities at risk and may only be observable as terrorism-related stressors become chronic.

Rederivation of Helicobacter hepaticus-infected Mongolian gerbils by Caesarean section and cross-fostering to rats and mice.

The Mongolian gerbil serves as an animal model for a wide range of diseases. As these animals are extensively used for the study of Helicobacter pylori-induced gastritis, naturally occurring infections with rodent Helicobacter species in gerbils are a possible source of interference in studies of H. pylori-associated disease. The gerbil stock at the Central Animal Facility in Hannover was persistently infected with H. hepaticus. The aim of this study was to derive Helicobacter species-free Mongolian gerbils. Therefore, germfree gerbil pups were obtained by Caesarean section and the pups were transferred to female rats and mice with recently delivered litters. In total, four Ztm:NMRI mice, four Ztm:SPRD rats and one DA/Ztm rat that originated from a specified pathogen-free area were selected to serve as foster mothers. With this approach, it was possible to obtain Helicobacter-free gerbils. Rearing by mice was more successful than by rats, as six of nine gerbils were reared by mice, but only one of 29 gerbils was reared by rats.

Multiple in vivo passages enhance the ability of a clinical Helicobacter pylori isolate to colonize the stomach of Mongolian gerbils and to induce gastritis.

The Mongolian gerbil is an excellent animal model for Helicobacter pylori-induced gastritis in humans. In this study, initially low colonization rates of the H. pylori strains ATCC 43504, SS1, or HP87 inoculated into gerbils caused difficulties in establishing this model. In order to increase the colonization ability and pathogenicity, the clinical HP87 isolate was selected for adaptation to the gerbil stomach by multiple in vivo passages through gerbils. Development of gastritis was examined histologically at 4-52 weeks after infection. The proportion of gerbils which tested positive for H. pylori by culture at four weeks after inoculation gradually increased from 11.1% of gerbils inoculated with HP87 without prior in vivo passage (P0) to 100% of gerbils inoculated with HP87 with seven in vivo passages (P7). In addition, adaptation of HP87 resulted in more severe histopathological changes. Gerbils infected with adapted HP87 (P7) exhibited severe infiltration by monomorphonuclear and polymorphonuclear leukocytes in the mucosa, submucosa, and subserosa of the gastric antrum, as well as epithelial changes consisting of hyperplasia, erosion, and ulceration. Histopathological changes increased in severity from four to 52 weeks after infection. Adaptation of HP87 during its passages through gerbils could be due to genetic changes in bacterial colonization factors. Identification of these changes might be useful to understand the underlying mechanism of gastric adaptation and pathogenesis of H. pylori.

Environment as a critical factor for the pathogenesis and outcome of gastrointestinal disease: experimental and human inflammatory bowel disease and helicobacter-induced gastritis.

Environmental factors play an important role in the manifestation, course, and prognosis of diseases of the gastrointestinal tract such as inflammatory bowel disease (IBD) and Helicobacter pylori-induced gastritis. These two disease complexes were chosen for a discussion of the contribution of environmental factors to the disease outcome in humans and animal models. Dissecting complex diseases like IBD and Helicobacter-induced gastritis has shown that the outcome of disease depends on the allelic constellation of a host and the microbial and physical environments. Host alleles predisposing to a disease in one genomic and/or environmental milieu may not be deleterious in other constellations; on the other hand, microbes can have different effects in different hosts and under different environmental conditions. The impact of the complex interaction between host genetics and environmental factors, particularly microflora, also underlines the importance of a defined genetic background and defined environments in animal studies and is indicative of the difficulties in analyzing complex diseases in humans.

[What is the role of compulsory ECT therapy today?].

Electro-convulsive therapy (ECT) has been effective for years, but it arouses opposition among patients and especially in the general public. ECT treatment is limited and compared to other medical treatment it is considered exceptional by the law, regulations and treatment personnel. A question arises as to the position of therapists regarding compulsory ECT treatment. A questionnaire was sent on this subject to all the units utilizing ECT in Israel. Opinions ranged from complete negation of compulsory ECT, to regarding such treatment as possible in cases when the patient is compulsorily hospitalized and/or when the patient's guardian supports this treatment. The authors' opinion is that the Law of Patients' Rights regarding special treatment when the patient is in extreme danger must be followed. The law requires that three physicians agree to the treatment, and compulsory treatment is no longer applicable when the danger passes. ECT treatment is important and imperative in certain conditions, especially conditions endangering patients' lives. In these conditions the law provides the authority to physicians to make decisions regarding treatment.

[A treatment unit within a medical center for adult survivors of childhood sexual abuse: an interdisciplinary approach].

Childhood sexual abuse is A highly prevalent phenomenon that has disastrous lifelong effects on emotional and physical development, interfering with almost every aspect of a persons existence. Research and clinical observations of psychological trauma have led to a clinical recognition of the complexity of survivors clinical presentation and needs, helping therapists to develop special treatment models for them. In this article we present a treatment model for survivors of childhood sexual abuse that was designed and implemented over the past three years in a specialized unit of psychiatric services at the Tel-Aviv Medical Center. Three case studies are used to illustrate the treatment process and the guiding theoretical model. The existence of such a treatment unit within a general medical center makes it possible to provide a diverse population of survivors with integrated psychological and physical care geared to their various needs. The former focuses on mental stabilization, strengthening of the ego, and improved adjustment to the trauma and its effects. Interdisciplinary guidance by the therapist ensures appropriate medical attention to the wide range of problems typical of survivors, such as gynecological and gastroenterological problems, eating disorders, and sexual differences.

A naturalistic study on ending blind dosing in a methadone maintenance clinic in Israel.

Since many methadone maintenance treatment (MMT) clinics in the United States do not share with patients, information concerning their methadone dosage, we aimed to investigate the impact of patients being informed of their methadone dosage and the influence of ending blind dosing on treatment outcome. Seventy-four patients who were unaware of their methadone dosage took part in this study. We compared changes in opiate abuse, levels of methadone dosage and patients' perceptions of dosage adequacy before and after they were informed of their dosage. Data on opiate abuse were based upon bi-weekly randomly taken and observed urine tests provided the data on opiate abuse. Records on methadone dosage were kept and a short questionnaire on dosage-related attitudes, devised for this study, was administered. Most patients expressed the desire to know their dosage, but there were no significant changes in opiate abuse, methadone dosage or the patients' perceptions of dosage adequacy after they knew what it was. We conclude that informing patients of their methadone dosage and thereby ending blind dosing does not seem to have any negative effect on treatment outcomes. We believe that this policy is in accord with the patients' rights and expressed will to know their dosage and this justifies putting an end to blind dosing policies.

Post traumatic stress disorder with psychotic features.

AIM: To study the combined course and interaction of post-traumatic stress disorder (PTSD) and psychosis through detailed case studies. METHODS: We described 6 case studies of Israeli veterans with PTSD and psychosis, who were referred to our Center for the evaluation of their psychiatric status. RESULTS: All the patients developed PTSD shortly after the exposure to a combat/military trauma. Psychosis appeared after months or even years, sometimes after a trauma-related trigger. Psychotic symptoms, such as delusions or auditory hallucinations, were usually paranoid or depressive and related in content to the traumatic experience. CONCLUSION: The combined course of PTSD and psychotic disorder may reflect two distinct disorders, but in some cases it seems justified to make a diagnosis of PTSD with psychotic features. In addition, it seems that in certain conditions, traumatic exposure and/or PTSD may serve as a trigger for psychosis.

[Military psychiatry in Israel: a 50-year perspective].

The history of military psychiatry in Israel may be divided into 2 main periods. The first extended from the War of Independence in 1948, through the Sinai, Six Day and Yom Kippur Wars. Its outstanding feature was avoidance of the issue of combat stress reaction (CSR). The Yom Kippur War made the recognition of CSR inescapable, assisted in breaking up denial, and served as a stimulus for development of the next phase of the system. This second phase was characterized by impressive progress in all areas of military psychiatry. The rich experience accumulated during the wars, together with the assimilation of a research culture which began blooming, especially in the wake of the Lebanon War, aided the development and crystallization of concepts related to combat and non-combat military psychiatry alike. The build-up of the mental health organization overlapped field deployment of the Medical Corps.

A comparison between demographic and clinical characteristics of younger and older elderly new referrals to an out-patient psychogeriatric service.

We compared the demographic and clinical characteristics of 37 subjects under and 41 subjects over 75 years of age who were consecutive new referrals to an out-patient psychogeriatric service in order to examine if an age-related dichotomy emerges in this population. Even though the groups were similar in most demographic (gender, education, years in Israel, family status) and some clinical aspects (number of physical diagnoses, medications taken) they differed significantly in some other clinical variables. "Functional" disorders, independence in performing household activities and Activities of Daily Living (ADL) and more recommendations for ambulatory follow-up were more prominent in the younger group. This profile has much in common with elderly patients newly referred to the general mental health services. The older group had more "organic" disorders, significant need for assistance in household activities and ADL, and more recommendations for follow-up in day-care centers, a profile more characteristic of patients who are treated in memory/dementia clinics. Thus, from a services organizational point of view, it is possible to subdivide out-patient elderly individuals with cognitive and emotional disturbances into separate groups, each with its own characteristics and needs.

Clock drawing test: correlation with linear measurements of CT studies in demented patients.

OBJECTIVES: To investigate a presumed correlation between clock drawing ratings and linear measurements of computerized tomography (CT) studies in demented patients. DESIGN: Blinded evaluations of clock drawing tests and CT studies of elderly dementia patients were conducted by a geriatric psychiatrist and a neuroradiologist. SUBJECTS: Fifty-one community-dwelling elderly subjects meeting the criteria for DSM-IV diagnosis of dementia (Alzheimer's type dementia: N=31; vascular dementia: N=15; "mixed" type dementia: N=5). MATERIALS: Mini-Mental State Examination (MMSE), Cambridge Cognitive Examination (CAMCOG), Clinical Dementia Rating (CDR). CAMCOG derived scored clock drawings were evaluated using adaptations of Shulman et al.'s and Freedman et al.'s methods. CT studies were evaluated using six different linear measurements of brain atrophy described in the literature. RESULTS: Of the CT linear measurements, only the Cerebro-Ventricular Index-2 (CVI-2; bicaudate index) significantly correlated with clock drawing ratings (CAMCOG's clock r=-0.407, p=0.003; Shulman's method r=0.357, p=0.01, Freedman's method r=-0.413, p=0.003) in the dementia group. There was no significant correlation between CVI-2 with demographic (age), cognitive (MMSE, CAMCOG) and clinical (duration of illness, CDR) ratings. Alzheimer's patients generally maintained a significant correlation between CVI-2 and clock drawings, but vascular dementia patients did not; CVI-2 also correlated significantly with the Praxis subtest of the CAMCOG in dementia and Alzheimer's patients but not in the vascular dementia group. Similarly, multiple stepwise regression analysis showed that only CVI-2 but not the other radiological measures studied, was selected as the significant variable to correlated with clock drawing test ratings in the dementia group and Alzheimer's patients. Partial correlation analysis controlling for demographic and clinical variables shows that controlled variables had no significant effect on the relationship between clock drawing ratings and CVI-2. CONCLUSION: A single and easy to perform measure of caudate atrophy correlates specifically and consistently with impairments revealed in the clock drawing test and with a Praxis subtest, suggesting possible caudate involvement with clock drawings in dementia in general and of the Alzheimer's type in particular.