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.

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.

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.

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.

Death without warning? A clinical postmortem study of suicide in 43 Israeli adolescent males.

Forty-three consecutive Israeli male suicides, 18 to 21 years of age, that occurred during compulsory military service were studied using preinduction assessment data, service records, and extensive postmortem interviews with family and peers. At preinduction, subjects, as a group, appeared above average in intelligence, physical fitness, and measures predictive of successful adaptation to military service. Active duty performance was generally satisfactory. Ascertained post mortem, 53.5% met formal criteria for major depressive disorder; most cases, however, appeared recent and reactive. Narcissistic and/or schizoid traits were common. Substance abuse was absent and antisocial personality disorder was rare (4.7%). Furthermore, in eight patients (18.6%) no Axis I diagnosis could be made; half of these also lacked any significant Axis II pathology. These findings, at partial variance with US studies, suggest a complex relationship between suicide and mental disorder. The striking failure of intensive screening and preventive measures to prevent these suicides highlights unresolved questions of etiology and intervention.

Posttraumatic stress disorder in Israeli combat veterans. Effect of phenelzine treatment.

Twenty-five Israeli combat veterans fulfilling DSM-III criteria for posttraumatic stress disorder (PTSD) participated in an open, prospective trial of phenelzine sulfate administration (median daily dose, 60 mg; range, 30 to 90 mg); three patients withdrew early due to side effects. Treatment was continued for at least four weeks in 22 cases and thereafter for as long as it was felt to be of benefit. Therapeutic efficacy was rated using a new PTSD scale, the Hamilton Depression Scale, and the Hamilton Anxiety Scale administered at four weekly intervals. Six patients completed four to eight weeks of phenelzine treatment; seven patients, nine to 13 weeks; and nine patients, 14 to 18 weeks. Comparison of mean prediscontinuation scores with pretreatment ratings showed, at best, only small (23% to 38%) differences (on the PTSD and Hamilton Anxiety scales) in the group treated for nine to 13 weeks. Two patients with a concurrent diagnosis of panic disorder and two with a concurrent diagnosis of dysthymic disorder were the most improved symptomatically but fell short of clinically significant remission. Although statistically significant improvement was observed on seven of the 12 items of the PTSD scale, sleep disturbance was the only symptom showing a clinically impressive change. These results only partially support previous positive reports of phenelzine treatment of PTSD.

An epidemiologic study of Gilles de la Tourette's syndrome in Israel.

OBJECTIVES: The goal of this study was to estimate the lifetime prevalence of Gilles de la Tourette's syndrome (GTS) in adolescents aged 16 to 17 years. DESIGN: Population-based epidemiologic study. SUBJECTS: Eighteen thousand three hundred sixty-four males and 9673 females aged 16 to 17 years screened for induction into the Israel Defense Force. RESULTS: Of the 28,037 individuals screened, 12 met diagnostic criteria for GTS. The point prevalence in this population was 4.3 +/- 1.2 (mean +/- SE) per 10,000. The 95% confidence interval for this estimate is 1.9 to 6.7 per 10,000. The point prevalence was 4.9 +/- 1.6 per 10,000 for males (95% confidence interval, 1.8 per 10,000) and 3.1 +/- 1.8 per 10,000 for females (95% confidence interval, 0 to 6.6 per 10,000). The rate of obsessive-compulsive disorder (OCD) was significantly elevated among the subjects with GTS (41.7%) compared with the population point prevalence of OCD (3.4) in those without GTS. In contrast, the rate of attention deficit hyperactivity disorder was only 8.3% compared with the population point prevalence of 3.9% in those individuals without GTS. CONCLUSIONS: The prevalence estimates from this population-based study are in agreement with previous results based on surveys of younger children. The sex ratio observed in this study is not as large as reported in previous studies and remains to be explored in other studies of adolescents and adults.

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.

Elevated awakening thresholds in sleep stage 3-4 in war-related post-traumatic stress disorder.

Awakening thresholds from sleep stage 3/4 were investigated in 19 DSM-III-defined, war-related post-traumatic stress disorder (PTSD) patients compared with 6 normal controls. Patients had significantly higher awakening thresholds and significantly longer latencies to an arousal response than controls. These results are interpreted to suggest modifications in the depth of sleep as one of the long-term sequelae of traumatic events.

Event-related potentials in post-traumatic stress disorder of combat origin.

Visual event-related potentials (ERPs) of primary interest in this study of post-traumatic stress disorder (PTSD) were N1, N2, P2, and P3. Forty Israeli combat veterans consisting of 20 PTSD sufferers and 20 normal controls were evaluated. ERPs were recorded in response to three sets of computer-generated visual stimuli, presented in the form of a modified oddball paradigm. These stimuli included: domestic animal pictures (targets), emotionally neutral pictures of furnishings (nontargets), and combat-related pictures (nontarget probes). Subjects were required to discriminate between target and nontarget stimuli by pressing a button in response to target stimuli only. Subjects were instructed to ignore all nontarget stimuli. As expected, target stimuli evoked accentuated P3 amplitudes in both controls and PTSD patients. The nontarget combat-related pictures elicited enhanced P3 and N1 amplitudes in the PTSD patients only. N2 amplitudes were accentuated in PTSD patients for both targets and combat-related pictures. P3 latencies and reaction times to target stimuli were prolonged in PTSD patients. The same tendency was observed for N1 latencies. These results may indicate that an altered state of early and late cognitive selective attention processing exists in PTSD patients in addition to a vulnerability to traumatic reminiscences.

Audiological evaluation of nonalcoholic, drug-free posttraumatic stress disorder patients.

Auditory functions of 32 Israeli soldiers with posttraumatic stress disorder (PTSD) were evaluated and compared with those of 32 matched controls without PTSD. The evaluation included peripheral auditory functions, tolerance to noise, and central auditory informational functions. Tolerance of intense auditory stimuli by PTSD patients was similar to that of controls. Significant differences were found between left and right ear central auditory functions in a subgroup of 13 PTSD subjects, but neither in other PTSD patients nor in controls. These findings are discussed in the light of previous research concerning abnormal responses to auditory stimulus in PTSD, hemispheric disconnection, alexithymia, and psychosomatic disorders.

Platelet adenylate cyclase and phospholipase C activity in posttraumatic stress disorder.

Adenylate cyclase and phospholipase C activity were examined in platelet membranes obtained from 19 male subjects with combat-related posttraumatic stress disorder (PTSD) and 35 age- and gender-matched healthy controls. Basal and forskolin-stimulated adenylate cyclase activity were significantly lower in the PTSD group whereas aluminum chloride plus sodium fluoride (AlCl3/NaF)- and prostaglandin E1 (PGE1)-stimulated responses were normal. There was no difference in phospholipase C activity between the two groups. The lower basal and forskolin-stimulated adenylate cyclase responses replicate a previous report and suggest that PTSD may be associated with an abnormality of the catalytic subunit of the receptor-adenylate cyclase complex.

Elevated levels of serum interleukin-1 beta in combat-related posttraumatic stress disorder.

Levels of serum interleukin-1 beta (IL-1 beta) and soluble interleukin-2 receptor (sIL-2R) were assessed in 19 male patients with combat-related posttraumatic stress disorder (PTSD) in comparison to 19 age- and sex-matched healthy volunteers. Serum IL-1 beta levels (but not sIL-2R) were significantly higher (p < .001) in the PTSD patients than in the controls. IL-1 beta levels did not correlate with cortisol levels, severity of PTSD, anxiety, depressive symptoms, or alexithymia score; however, they did correlate significantly (r = .54, p < .005) with the duration of PTSD symptoms. It is possible that desensitization of the hypothalamic-pituitary-adrenal axis in chronic PTSD patients counteracts the stimulatory effect of IL-1 beta on cortisol secretion.

Reactivation of combat-related posttraumatic stress disorder.

The authors conducted an exploratory study of the nature and course of reactivation of combat-related posttraumatic stress disorder. Experienced psychiatrists, they each independently assessed 35 men with recurrent combat-related posttraumatic stress disorder. Two major types of reactivated posttraumatic stress disorder, each representing a different degree of pathology, were delineated: uncomplicated reactivation and heightened vulnerability. The second category was further subdivided into specific sensitivity, moderate generalized sensitivity, and severe generalized sensitivity. The authors conclude that reactivation of war-related trauma is a complex phenomenon that may take different forms.

Increased serotonin 5-HT2 receptor binding on blood platelets of suicidal men.

In search of a physiological marker of depression and suicidal behavior, serotonin receptors of the 5-HT2 type were studied on platelet membranes from 19 control and 22 suicidal subjects. All were young, drug- and medication free men (18-21-years-old). 5-HT2 receptor binding was assayed using tritiated ketanserin at two concentrations. Receptor binding in the suicidal subjects was significantly higher than controls at both concentrations, the mean difference being around 50%. A similar difference between patients with major depressive disorder and matched controls has been observed previously. These findings support the use of 5-HT2 receptors on platelets as a research and diagnostic tool in depression and suicide.

Post-traumatic stress disorder: issues of co-morbidity.

There is considerable controversy over whether or not post-traumatic stress disorder (PTSD) should be considered as a separate diagnostic entity. The present study utilized the Symptom Checklist-90 (SCL-90) in order to examine the degree of overlap between PTSD and the related diagnoses of anxiety, depression and obsession-compulsion in a group of Israeli Lebanon War PTSD casualties. We found that the SCL-90 was able both to identify and discriminate between the clinical groups. Multiple discriminant analysis showed that although there is overlap between PTSD and obsessive-compulsive disorder, PTSD is, in fact, discriminated from all the other patient groups.

Assessing the validity of the Plutchik Suicide Risk Scale.

One of the newer scales of suicide risk devised by Plutchik and colleagues was tested to see if it could discriminate between levels of suicide ideation and suicide attempts. A sample of 80 subjects were placed into various categories of suicide risk on the basis of a psychiatric examination. Results showed that the full scale did not adequately discriminate among groups. An explantation of the results has been proposed and a design to test this suggestion described.

Seven-year follow-up of child survivors of a bus-train collision.

OBJECTIVE: To assess the long-term effects of a traumatic bus-train collision and to examine the effect of levels of exposure and immediate reactions on long-term adjustment. METHOD: Seven years after the accident, 389 subjects, all doing compulsory army service, filled out self-report questionnaires assessing symptoms of posttraumatic stress disorder (PTSD), psychiatric symptomatology, and military functioning. In addition, subjects were questioned about their immediate reactions to the traumatic event. RESULTS: The most highly exposed subjects reported the highest levels of somatization, depression, phobic anxiety, and psychoticism and more PTSD symptoms. Acute stress symptoms and manifestations of fear immediately after the accident were strongly related to long-term maladjustment CONCLUSIONS: The results suggest that the investigation and assessment of long-term adjustment after traumatic events should take into account both contextual factors, such as the level of exposure to the event, and personal factors, such as the victims' immediate reactions.