An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions.

Atrial fibrillation (AF) is a progressive arrhythmia with underlying mechanisms that are not fully elucidated, partially due to lack of reliable and affordable animal models. Here, we introduce a system for long-term assessment of AF susceptibility (substrate) in ambulatory rats implanted with miniature electrodes on the atrium. Rats were subjected to excessive aldosterone (Aldo) or solvent only (Sham). An additional group was exposed to myocardial infarction (MI). AF substrate was tested two- and four-weeks post implantation and was also compared with implanted rats early post-implantation (Base). Aldo and MI increased the AF substrate and atrial fibrosis. In the MI group only, AF duration was correlated with the level of atrial fibrosis and was inversely correlated with systolic function. Unexpectedly, Shams also developed progressive AF substrate relative to Base individuals. Further studies indicated that serum inflammatory markers (IL-6, TNF-alpha) were not elevated in the shams. In addition, we excluded anxiety\depression due to social-isolation as an AF promoting factor. Finally, enhanced biocompatibility of the atrial electrode did not inhibit the gradual development of AF substrate over a testing period of up to 8 weeks. Overall, we successfully validated the first system for long-term AF substrate testing in ambulatory rats.

ß-Alanine supplementation reduces anxiety and increases neurotrophin expression in both young and older rats.

The effect of 30 days of ß-alanine supplementation (100 mg/kg) on behavioral response and expression of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and markers of inflammation was examined in both young (4 months) and older (14 months) rats. We hypothesized that animals fed ß-alanine would experience reduced inflammation and an enhanced neurotrophin and behavioral response. Animals were assigned to either a control group, in which young or older rats were fed regular chow and water, or a ß-alanine group, in which rats were fed regular chow and provided ß-alanine in their water. Behavior measures were conducted following the 30-day supplementation period, which included spatial learning, memory, and an anxiety index. Hippocampal expressions of BDNF, NPY, glial fibrillary acidic protein, nuclear factor-κB p50 and p65 subunits, tumor necrosis factor-α, and cyclooxygenase-2 were also analyzed. Learning ability was reduced (P = .001) and anxiety index was higher (P = .001) in older compared to young rats. Similarly, BDNF and NPY expressions were reduced and all inflammatory markers were elevated (P < .05) in the older animals. ß-Alanine increased BDNF expressions in the cornu ammonis area 1 (P = .003) and 3 (P < .001) subregions of the hippocampus. BDNF expression for younger rats in the ß-alanine group was also significantly greater than younger rats in the control group in cornu ammonis area 3. Learning for young animals fed ß-alanine was significantly better than all other groups. Significant reductions in anxiety were noted in both older and younger rats fed ß-alanine compared to age-matched controls. Results indicated that ß-alanine ingestion in both young and older rats was effective in attenuating anxiety and augmenting BDNF expression in the hippocampus.

Distinctive hippocampal zinc distribution patterns following stress exposure in an animal model of PTSD.

Emerging evidence suggests that zinc (Zn) deficiency is associated with depression and anxiety in both human and animal studies. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of Zn distribution. The work has focused on one case study, the association between an animal model of posttraumatic stress disorder (PTSD) and the Zn distribution in the rat hippocampus. Behaviors were assessed with the elevated plus-maze and acoustic startle response tests 7 days later. Preset cut-off criteria classified exposed animals according to their individual behavioral responses. To further characterize the distribution of Zn that occurs in the hippocampus 8 days after the exposure, laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging was used. It has been found that Zn distribution in the dentate gyrus (DG) sub-region in the hippocampus is clearly more widely spread for rats that belong to the extreme behavioral response (EBR) group as compared to the control group. Comparison of the Zn concentration changes in the cornu ammonis 1 (CA1) and the DG sub-regions of the hippocampus shows that the concentration changes are statistically significantly higher in the EBR rats compared to the rats in the control and minimal behavioral response (MBR) groups. In order to understand the mechanism of stress-induced hippocampal Zn dyshomeostasis, relative quantitative analyses of metallothionein (MT), B-cell lymphoma 2 (Bcl-2) and caspase 3 immunoreactivity were performed. Significant differences in the number of caspase-ir and Bcl-2 cells were found in the hippocampal DG sub-region between the EBR group and the control and MBR groups. The results of this study demonstrate a statistically significant association between the degree of behavioral disruption resulting from stress exposure and the patterns of Zn distribution and concentration changes in the various hippocampal regions. Taken together, these findings indicate that Zn distribution patterns play an active role in the neurobiological response to predator scent stress.

Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD.

The hypothalamic-pituitary-adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic-pituitary-gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

Early post-stressor intervention with minocycline, a second-generation tetracycline, attenuates post-traumatic stress response in an animal model of PTSD.

We assessed the effects of minocycline, a tetracycline with anti-inflammatory, anti-apoptotic and neuroprotective capacities, in an animal model of post-traumatic stress disorder (PTSD). Rats were exposed to psychogenic stress and treated 1h later with minocycline or saline. Behavioral measures included the elevated plus-maze (EPM) and acoustic startle response (ASR) 7 days post stress-exposure. One day after behavioral testing, animals were exposed to a trauma cue and freezing response was assessed. Local levels of cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the hippocampus, frontal cortex (FC) and hypothalamus were then examined. Minocycline attenuated anxious-like behaviors in stress-exposed rats. In addition, decreased levels of cytokines were measured in exposed rats treated with minocycline compared to their counterparts treated with saline. This study suggests a potential use of minocycline in preventing physiological and behavioral alternations resulting from acute exposure to psychological stress. As this is the first study to report beneficial outcomes for minocycline treatment in an animal model of PTSD, further investigations of the use of minocycline in stress-related conditions with emphasis on PTSD is needed.

Gender differences in animal models of posttraumatic stress disorder.

Epidemiological studies report higher prevalence rates of stress-related disorders such as acute stress disorder and post-traumatic stress disorder (PTSD) in women than in men following exposure to trauma. It is still not clear whether this greater prevalence in woman reflects a greater vulnerability to stress-related psychopathology. A number of individual and trauma-related characteristics have been hypothesized to contribute to these gender differences in physiological and psychological responses to trauma, differences in appraisal, interpretation or experience of threat, coping style or social support. In this context, the use of an animal model for PTSD to analyze some of these gender-related differences may be of particular utility. Animal models of PTSD offer the opportunity to distinguish between biological and socio-cultural factors, which so often enter the discussion about gender differences in PTSD prevalence. In this review, we present and discuss sex-differences in behavioral, neurochemical, neurobiological and pharmacological findings that we have collected from several different animal studies related to both basal conditions and stress responses. These models have used different paradigms and have elicited a range of behavioral and physiological manifestations associated with gender. The overall data presented demonstrate that male animals are significantly more vulnerable to acute and chronic stress, whereas females are far more resilient. The stark contradiction between these findings and contemporary epidemiological data regarding human subjects is worthy of further study. The examination of these gender-related differences can deepen our understanding of the risk or the pathophysiology of stress-related disorders.

Accuracy of the diagnosis of fibromyalgia by family physicians: is the pendulum shifting?

OBJECTIVE: We evaluated the accuracy of diagnosis of fibromyalgia (FM) by family physicians. METHODS: We performed a retrospective cohort analysis of 646 consecutive patients newly referred to the outpatient rheumatology clinic of Soroka University Medical Center from January 1, 2005, until December 31, 2007. The kappa statistic was used to measure agreement between family-physician and rheumatologist diagnoses for FM in the total patient cohort as well as in groups stratified by ethnicity. Sensitivity and specificity of family-physician diagnosis of FM were calculated using rheumatologist diagnosis as the gold standard. There were no exclusion criteria. RESULTS: During the time period of the study, 646 new patients were seen in the rheumatology clinic. Of 196 patients referred with an initial diagnosis of FM, the consultant rheumatologist confirmed this diagnosis in 71% of cases. The overall kappa for FM diagnosis between family physicians and rheumatologists was 0.70 (p<0.001), indicating a good level of agreement. Agreement was substantially lower among Bedouin patients (kappa=0.35, p=0.003). All other patients in our study were Jewish Israelis. Using rheumatologist diagnosis as the gold standard, overall sensitivity and specificity of FM diagnosis by family physicians were 87.4% and 88.3%, respectively. CONCLUSION: Family physicians in our region are able to accurately diagnose FM. Future studies might focus on evaluating the factors and biases accounting for differences in level of diagnostic accuracy for FM among various ethnic groups.

IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer's disease.

The generation of new neurons and glia from a precursor stem cell appears to take place in the adult brain. However, new neurons generated in the dentate gyrus decline sharply with age and to an even greater extent in neurodegenerative diseases. Here we raise the question whether peripheral immune mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin-6 and tumor necrosis factor-alpha, the adaptive immunity cytokine IFN-gamma enhances neurogenesis in the dentate gyrus of adult mice and improves the spatial learning and memory performance of the animals. In older mice, the effect of IFN-gamma is more pronounced in both wild-type mice and mice with Alzheimer's-like disease and is associated with neuroprotection. In addition, IFN-gamma reverses the increase in oligodendrogenesis observed in a mouse model of Alzheimer's disease. We demonstrate that limited amounts of IFN-gamma in the brain shape the neuropoietic milieu to enhance neurogenesis, possibly representing the normal function of the immune system in controlling brain inflammation and repair.

Symptoms of posttraumatic stress disorder after ritual female genital surgery among bedouin in Israel: myth or reality?

OBJECTIVE: Ritual female genital surgery (RFGS), or female circumcision, is common among certain ethnic groups in Asia and Africa and describes a range of practices involving complete or partial removal of the female external genitalia for nonmedical reasons. Several studies in African populations, in which more severe forms of RFGS are performed, reported an increased prevalence of posttraumatic stress disorder and other psychiatric syndromes among circumcised women than among uncircumcised controls. Among the Bedouin population in southern Israel, RFGS has become a symbolic operation without major mutilation. However, in a study performed in 1999, Bedouin women after RFGS reported difficulties in mother-daughter relationships and trust. This pilot study assessed the mental health of Bedouin women from southern Israel after RFGS compared to age-matched controls without RFGS. METHOD: The psychological impact of RFGS was assessed in 19 circumcised Bedouin women compared to 18 age-matched controls. The Post Traumatic Stress Disorder Scale, Symptom Checklist, Impact of Event Scale, and a demographics and background questionnaire were used to assess traumatization and psychiatric illnesses. The study was conducted from March to July 2007. RESULTS: No statistically significant differences were found between the 2 groups. CONCLUSIONS: The prevailing procedure of RFGS among the Bedouin population of southern Israel had no apparent effect on mental health.

Coping styles in fibromyalgia: effect of co-morbid posttraumatic stress disorder.

To analyze coping styles of fibromyalgia (FM) patients with specific emphasis on differences in coping styles between fibromyalgia patients with and without post traumatic stress disorder (PTSD). Seventy-seven consecutive patients (40 women and 37 men) who fulfilled ACR criteria for FM, and 48 healthy controls, completed questionnaires measuring prevalence and severity of PTSD symptoms, including the structured clinical interview for DSM-III-R-non-patient edition (SCID-NP) and the clinician administered PTSD scale (CAPS). Subjects were divided into two groups based on the presence or absence of PTSD symptoms. Subsequently, coping styles were measured using the Albert Einstein College of Medicine (AECOM) Coping Style Questionnaire. Student t tests were used to compare the means of quantitative variables, and proportions were compared by Chi square tests. Analysis of variance (ANOVA) was used to compare the scores of the FM patients with and without PTSD, as well as to estimate the effect of gender on psychiatric variables. FM patients exhibit significantly higher levels of suppression (P<0.00001), help-seeking (P<0.007), replacement (P<0.003), substitution (P<0.002), and reversal (P<0.004) compared with healthy controls. FM patients with PTSD and without PTSD differed significantly only on the suppression subscale (P<0.02). FM patients that have PTSD presented higher suppression scores compared to FM patients without PTSD. No significant difference was noted on scales of minimization, help-seeking, replacement, blame, substitution, mapping, and reversal. Our results have delineated coping patterns of FM patients, identifying suppression, help-seeking, replacement, substitution and replacement as strategies more common among these patients. We further identified suppression as the only coping style significantly more common among FM patients with co-morbid PTSD then among FM patients without such a diagnosis. Our results may serve to further characterize cognitive and behavioral aspects of FM patients and subsequently guide therapeutic interventions.

Comorbidity of fibromyalgia and psychiatric disorders.

There are mounting data supporting comorbidity of fibromyalgia syndrome (FMS) and psychiatric conditions. These include depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). The nature of the relationship between depression and FMS is not fully understood, and it was hypothesized that chronic pain causes depression, or vice versa, and that chronic pain syndromes are variants of depression. A link between PTSD symptoms and FMS has been reported, and both conditions share similar symptomatology and pathogenetic mechanisms. Assessment of comorbid psychiatric disorders in FMS patients has clinical implications because treatment in these patients should focus both on physical and emotional dimensions of dysfunction.

Post-traumatic stress disorder and other co-morbidities in a sample population of patients with irritable bowel syndrome.

BACKGROUND: High rates of psychiatric co-morbidity have been reported in patients with irritable bowel syndrome (IBS) and high rates of post-traumatic stress disorder (PTSD) have been reported in fibromyalgia, a disorder also associated with IBS. The primary aim of this study was to assess the frequency of PTSD in IBS patients. METHODS: Sixty-four patients who fulfilled the Rome II diagnostic criteria for IBS were asked to complete questionnaires measuring the prevalence and severity of symptoms of PTSD and psychological distress. RESULTS: Although 86% of IBS patients reported a traumatic life experience, only 7.8% met the diagnostic criteria for PTSD. High rates of somatization, obsessive-compulsive behavior, interpersonal sensitivity, and anxiety symptoms were seen among the IBS patients. CONCLUSIONS: The results show a lower than expected prevalence of PTSD among IBS patients, which is similar to that of the general population. Thus, we did not find that PTSD is over-represented in a sample population of IBS patients.

Mechanisms of Disease: genetics of fibromyalgia.

Fibromyalgia is characterized by widespread pain and tenderness, and has a significant familial component. The etiology of fibromyalgia remains unclear, but genetic factors seem to have a significant role, and are influenced by environmental factors. Research over the past two decades has demonstrated that genetic polymorphisms in the serotoninergic, dopaminergic and catecholaminergic systems of pain transmission and processing are involved in the etiology of fibromyalgia, but additional candidates continue to emerge. Fibromyalgia is thought to belong to the group of affective spectrum disorders, which include related psychiatric and medical disorders. As the concept of affective spectrum disorders continues to evolve, progress in the understanding of the genetic basis of related functional disorders, such as irritable bowel syndrome and post-traumatic-stress disorder, is aiding our understanding of the genetic basis of fibromyalgia.

Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1.

Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP/PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated beta-amyloid, and characterized as CD11b(+)/CD11c(-)/MHC class II(-)/TNF-alpha(+) cells, impeded neurogenesis from adult neural stem/progenitor cells, whereas CD11b(+)/CD11c(+)/MHC class II(+)/TNF-alpha(-) microglia, a phenotype induced by IL-4, counteracted the adverse beta-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.

T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions.

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.

Prevalence of post-traumatic stress disorder in fibromyalgia patients: overlapping syndromes or post-traumatic fibromyalgia syndrome?

OBJECTIVES: The primary aim of this study was to assess the frequency of post-traumatic stress disorder (PTSD) in patients with the fibromyalgia syndrome (FMS). The influence of gender on measures of PTSD in fibromyalgia (FM) patients also was examined. METHODS: Seventy-seven consecutive patients (40 women and 37 men) who fulfilled the criteria for FM were asked to complete questionnaires measuring the prevalence and severity of symptoms of PTSD, anxiety, and depression. The subjects were divided in 2 groups based on the presence or absence of PTSD symptoms. RESULTS: In this study, 57% of the FM sample had clinically significant levels of PTSD symptoms. The FM patients with PTSD reported significantly greater levels of avoidance, hyperarousal, reexperiencing, anxiety, and depression than did the patients without clinically significant levels of PTSD symptoms. The prevalence of PTSD among the FM patients in this study was significantly higher than in the general population. Women with FM and PTSD reported a greater number of past traumatic events than did their male counterparts. CONCLUSIONS: The results represent the first comprehensive study applying structured clinical assessment of trauma exposure and PTSD to a group of FM patients. This study shows a significant overlap between FM and PTSD, according to the currently accepted diagnostic criteria for each.