Intelligence and neuroticism in relation to depression and psychological distress: Evidence from two large population cohorts.

BACKGROUND: Neuroticism is a risk factor for selected mental and physical illnesses and is inversely associated with intelligence. Intelligence appears to interact with neuroticism and mitigate its detrimental effects on physical health and mortality. However, the inter-relationships of neuroticism and intelligence for major depressive disorder (MDD) and psychological distress has not been well examined. METHODS: Associations and interactions between neuroticism and general intelligence (g) on MDD, self-reported depression, and psychological distress were examined in two population-based cohorts: Generation Scotland: Scottish Family Health Study (GS:SFHS, n=19,200) and UK Biobank (n=90,529). The Eysenck Personality Scale Short Form-Revised measured neuroticism and g was extracted from multiple cognitive ability tests in each cohort. Family structure was adjusted for in GS:SFHS. RESULTS: Neuroticism was strongly associated with increased risk for depression and higher psychological distress in both samples. Although intelligence conferred no consistent independent effects on depression, it did increase the risk for depression across samples once neuroticism was adjusted for. Results suggest that higher intelligence may ameliorate the association between neuroticism and self-reported depression although no significant interaction was found for clinical MDD. Intelligence was inversely associated with psychological distress across cohorts. A small interaction was found across samples such that lower psychological distress associates with higher intelligence and lower neuroticism, although effect sizes were small. CONCLUSIONS: From two large cohort studies, our findings suggest intelligence acts a protective factor in mitigating the effects of neuroticism on psychological distress. Intelligence does not confer protection against diagnosis of depression in those high in neuroticism.

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.

Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects. EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1ß deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1ß signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1ß deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.

Altered neuropathic pain behaviour in a rat model of depression is associated with changes in inflammatory gene expression in the amygdala.

The association between chronic pain and depression is widely recognized, the comorbidity of which leads to a heavier disease burden, increased disability and poor treatment response. This study examined nociceptive responding to mechanical and thermal stimuli prior to and following L5-L6 spinal nerve ligation (SNL), a model of neuropathic pain, in the olfactory bulbectomized (OB) rat model of depression. Associated changes in the expression of genes encoding for markers of glial activation and cytokines were subsequently examined in the amygdala, a key brain region for the modulation of emotion and pain. The OB rats exhibited mechanical and cold allodynia, but not heat hyperalgesia, when compared with sham-operated counterparts. Spinal nerve ligation induced characteristic mechanical and cold allodynia in the ipsilateral hindpaw of both sham and OB rats. The OB rats exhibited a reduced latency and number of responses to an innocuous cold stimulus following SNL, an effect positively correlated with interleukin (IL)-6 and IL-10 mRNA expression in the amygdala, respectively. Spinal nerve ligation reduced IL-6 and increased IL-10 expression in the amygdala of sham rats. The expression of CD11b (cluster of differentiation molecule 11b) and GFAP (glial fibrillary acidic protein), indicative of microglial and astrocyte activation, and IL-1ß in the amygdala was enhanced in OB animals when compared with sham counterparts, an effect not observed following SNL. This study shows that neuropathic pain-related responding to an innocuous cold stimulus is altered in an animal model of depression, effects accompanied by changes in the expression of neuroinflammatory genes in the amygdala.

Alterations in the endocannabinoid system in the rat valproic acid model of autism.

The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders.

The monoacylglycerol lipase inhibitor JZL184 attenuates LPS-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action.

BACKGROUND AND PURPOSE: JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved. EXPERIMENTAL APPROACH: JZL184 and/or the CB1 receptor antagonist, AM251 or the CB2 receptor antagonist, AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen. KEY RESULTS: JZL184 attenuated LPS-induced increases in IL-1ß, IL-6, TNF-α and IL-10 but not the expression of the inhibitor of NFkB (IκBα) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1ß expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF-α and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1ß in the presence, but not absence, of JZL184. CONCLUSION AND IMPLICATIONS: Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders.

Pharmacological inhibition of endocannabinoid degradation modulates the expression of inflammatory mediators in the hypothalamus following an immunological stressor.

The endocannabinoid system is an important regulator of the nervous, neuroendocrine, and immune systems, thus representing a novel therapeutic target for stress-related neuroinflammatory and psychiatric disorders. However, there is a paucity of data relating to the effects of endocannabinoids on neuroinflammatory mediators following an immune stress/challenge in vivo. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolyase (FAAH), the enzyme that preferentially metabolizes anandamide, on lipopolysaccharide (LPS)-induced increases in the expression of immune mediators in the hypothalamus. Systemic administration of URB597 increased the levels of anandamide and the related N-acylethanolamines, N-palmitoylethanolamide, and N-oleoylethanolamide, but not 2-arachidonoyl glycerol, in the hypothalamus and spleen. URB597 attenuated the LPS-induced increase in interleukin (IL)-1ß expression while concurrently augmenting the LPS-induced increase in suppressor of cytokine signalling (SOCS)-3 expression. In addition, URB597 tended to enhance and reduce the LPS-induced increase in IL-6 and IL-10 mRNA expression, respectively. LPS-induced increases in peripheral cytokine levels or plasma corticosterone were not altered by URB597. The present study provides evidence for a role for FAAH in the regulation of LPS-induced expression of inflammatory mediators in the hypothalamus. Improved understanding of endocannabinoid-mediated regulation of neuroimmune function has fundamental physiological and potential therapeutic significance in the context of stress-related disorders.

Neurokinin-1 receptor deletion modulates behavioural and neurochemical alterations in an animal model of depression.

The substance P/NK1 receptor system plays an important role in the regulation of stress and emotional responding and as such had been implicated in the pathophysiology of anxiety and depression. The present study investigated whether alterations in the substance P/NK1 receptor system in brain areas which regulate emotional responding accompany the depressive behavioural phenotype observed in the olfactory bulbectomised (OB) mouse. The effect of NK1 receptor deletion on behavioural responding and monoamine levels in discrete brain regions of the OB model, were also examined. Substance P levels in the frontal cortex and NK1 receptor expression in the amygdala and hippocampus were enhanced following olfactory bulbectomy. Although NK1 receptor knockout (NK1-/-) mice did not exhibit altered behavioural responding in the open field test, noradrenaline levels were enhanced in the frontal cortex, amygdala and hippocampus, as were serotonin levels in the frontal cortex. Locomotor activity and exploratory behaviour were enhanced in wild type OB mice, indicative of a depressive-like phenotype, an effect attenuated in NK1-/- mice. Bulbectomy induced a decrease in noradrenaline and 5-HIAA in the frontal cortex and an increase in serotonin in the amygdala, effects attenuated in OB NK1-/- mice. The present studies indicate that alterations in substance P/NK1 receptor system underlie, at least in part, the behavioural and monoaminergic changes in this animal model of depression.

Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions.

Altered pain responding in depression is a widely recognized but poorly understood phenomenon. The present study investigated nociceptive responding to acute (thermal and mechanical) and persistent (inflammatory) noxious stimuli in two animal models of depression, the olfactory bulbectomized (OB) and the Wistar-Kyoto (WKY) rat. In addition, this study examined if altered nociceptive behaviour was associated with changes in monoamine levels in discrete brain regions. OB rats exhibited mechanical allodynia (von Frey test) but not thermal hyperalgesia (hot plate and tail-flick tests) when compared to sham-operated counterparts. Formalin-induced nociceptive behaviour was both heightened and prolonged in OB versus sham-operated controls. An inverse correlation was observed between 5-hydroxyindoleacetic acid (5-HIAA) concentration in the hippocampus and amygdaloid cortex and nociceptive behaviour in the formalin test. In comparison, WKY rats exhibited thermal hyperalgesia in the hot plate test, while behaviour in the tail-flick and von Frey tests did not differ between WKY and Sprague-Dawley rats. Furthermore, WKY rats exhibited enhanced formalin-evoked nociceptive responding up to 40 min post administration, an effect inversely correlated with serotonin and 5-HIAA levels in the hypothalamus. In conclusion, these findings demonstrate that altered pain responding observed in clinically depressed patients can be modelled pre-clinically, providing a means of investigating the neurochemical basis of, and possible treatments for, this phenomenon.

Gastrointestinal basidiobolomycosis. Morphologic findings in a cluster of six cases.

We describe the histopathologic features of 6 cases of gastrointestinal basidiobolomycosis examined at 4 Phoenix, AZ, area hospitals during the last 4 years. Resected stomach and intestinal specimens were characterized by marked mural thickening with fibrosis, prominent tissue eosinophil infiltration and palisading granulomatous inflammation around pale fungal hyphae. In 2 cases, there was colonic perforation. Basidiobolus ranarum hyphae (associated with spore-like spherules in 4 cases) were identified within tissue sections; the irregularly branched, thin-walled, occasionally septated hyphae were typically surrounded by a thick eosinophilic cuff (Splendore-Hoeppli phenomenon). Although the histologic features of B ranarum are well described in the skin and subcutaneous tissue, gastrointestinal involvement has presented considerable diagnostic difficulty. Before the occurrence of this cluster of cases, intra-abdominal B ranarum infection has been reported only rarely.

A prospective, controlled analysis of endoscopic cytotechniques for diagnosis of malignant biliary strictures.

We prospectively collected brushings and bile for cytology in 30 consecutive patients with bile duct strictures (17 malignant, 13 benign) who were assessed by endoscopic retrograde cholangiography. When appropriate, the cellular debris on stents that were removed from individuals who were managed with these devices was evaluated for malignant cells as well. Our aim was to assess the value of these endoscopic cytotechniques for making a diagnosis of obstructing cancer of the biliary tract. A cumulative total of 78 specimens were obtained. Overall, sensitivity was highest for stent (36%) and brush (33%) cytology, compared with results obtained from bile (6%). If the results for all methods are combined, 47% of patients with cancer (eight of 17) could be diagnosed by one or more cytological technique. There were no false-positive results (specificity, 100%). Our results show that brush and stent cytology are nearly equivalent for detecting cancer, but because a diagnosis is delayed until the endoprosthesis is removed (mean 3.4 months), the brush technique is preferred. Results for bile cytology are marginal. Specificity for these cytotechniques is high; therefore, a positive result by any method is sufficient evidence for cancer, and other invasive diagnostic procedures are unnecessary.

Endoscopic retrograde wire-guided brush cytology for diagnosis of patients with malignant obstruction of the bile duct.

A brush was adapted for use over a guide wire to facilitate reliable acquisition of cytological specimens from tight and potentially malignant strictures encountered during ERCP. Cells collected in this manner were assessed for abnormalities indicative of cancer. We have called this technique endoscopic retrograde wire-guided brush cytology (ERWBC). Thirty-nine strictures (24 malignant, 15 benign) in 34 patients were brushed. There were no complications, and all specimens were adequate for evaluation. Sixty percent of patients with cancer were diagnosed by ERWBC. Sensitivity was highest for cholangiocarcinoma (100%), intermediate for pancreatic cancer (60%), and lowest for patients with biliary obstruction due to metastatic disease (22%). There were no false-positive results (specificity, 100%). The positive and negative predictive values were 100% and 58%, respectively, and accuracy for the test was 72%. Collection of cytological specimens using a brush with a wire guide is effective especially for diagnosis of cholangiocarcinoma. A positive result is sufficient evidence for malignancy, and other invasive diagnostic tests are unnecessary. We recommend ERWBC for brushing all strictures of unknown cause during ERCP in an effort to make a diagnosis of cancer.

Acute myelofibrosis: response to recombinant human interferon alpha-2a.

Acute myelofibrosis is a rare myeloproliferative syndrome characterized by bone marrow proliferation of atypical megakaryocytes, poor response to conventional leukemic therapy, and a fulminant clinical course. Because alpha interferon exhibits potent antiproliferative effects against megakaryocyte progenitors and human fibroblast cell lines, we treated two patients with acute myelofibrosis or the related syndrome of acute myelodysplasia with myelofibrosis with recombinant human interferon alpha-2a. Patient 1 received a 12-week course of interferon alpha (1-6 x 10(6) IU/d) after failure of two cytarabine-based chemotherapy regimens. Interferon administration resulted in prompt improvement in symptoms, stabilization of leukocyte count, and a reduction in circulating blast forms. Primary treatment with interferon (1-3 x 10(6) IU/d x 4 weeks) in patient 2 produced complete hematologic recovery with restoration of marrow cellularity and reduced marrow fibrosis. Our findings suggest that interferon alpha may have significant activity in the treatment of patients with acute myelofibrosis.

Acute gastrointestinal bleeding as the presenting manifestation of prostate cancer.

Gastrointestinal bleeding was the presenting manifestation in four patients without readily apparent prostate cancer. Three of these patients had laboratory evidence of acute disseminated intravascular coagulation (DIC) and one patient had a friable rectal mass. The diagnosis of prostate cancer was made in three patients by employing an immunoperoxidase technique for prostatic acid phosphatase in metastatic foci. Dramatic resolution of DIC occurred in two patients following hormone therapy. Radiation therapy was effective in controlling bleeding in another patient. Two patients are alive with no further bleeding episodes at 8 and 18 months follow-up, respectively. In patients who present with a bleeding diathesis and adenocarcinoma of unknown primary, it is important to consider prostate cancer because of its frequent and prolonged responsiveness to hormonal therapy.