Combat experience and the acquired capability for suicide

Rising suicide rates are an increasing concern among military personnel. The interpersonal‐psychological theory of suicide proposes that three necessary factors are needed to die by suicide: feelings that one does not belong with other people, feelings that one is a burden on others or society, and an acquired capability to overcome the fear and pain associated with suicide. The current study tests the theory's proposal that acquired capability may be particularly influenced by military experience, because combat exposure may cause habituation to fear of painful experiences such as suicide. Utilizing clinical and nonclinical samples of military personnel deployed to Iraq, results of the current study indicate that a greater range of combat experiences predicts acquired capability above and beyond depression and post‐traumatic stress disorder symptoms, previous suicidality, and other common risk factors for suicide. Combat experiences did not, however, predict perceived burdensomeness or thwarted belongingness. The authors discuss how combat experiences might serve as a mechanism for elevating suicide risk and implications for clinical interventions and suicide prevention efforts. © 2010 Wiley Periodicals, Inc. J Clin Psychol: 66:1–13, 2010.     

Genome‐wide transcriptome analyses reveal p53 inactivation mediated loss of miR‐34a expression in malignant peripheral nerve sheath tumours

Malignant peripheral nerve sheath tumours (MPNSTs) are aggressive soft tissue tumours that occur either sporadically or in patients with neurofibromatosis type 1. The malignant transformation of the benign neurofibroma to MPNST is incompletely understood at the molecular level. We have determined the gene expression signature for benign and malignant PNSTs and found that the major trend in malignant transformation from neurofibroma to MPNST consists of the loss of expression of a large number of genes, rather than widespread increase in gene expression. Relatively few genes are expressed at higher levels in MPNSTs and these include genes involved in cell proliferation and genes implicated in tumour metastasis. In addition, a gene expression signature indicating p53 inactivation is seen in the majority of MPNSTs. Subsequent microRNA profiling of benign and malignant PNSTs indicated a relative down‐regulation of miR‐34a in most MPNSTs compared to neurofibromas. In vitro studies using the cell lines MPNST‐14 (NF1 mutant) and MPNST‐724 (from a non‐NF1 individual) show that exogenous expression of p53 or miR‐34a promotes apoptotic cell death. In addition, exogenous expression of p53 in MPNST cells induces miR‐34a and other miRNAs. Our data show that p53 inactivation and subsequent loss of expression of miR‐34a may significantly contribute to the MPNST development. Collectively, our findings suggest that deregulation of miRNAs has a potential role in the malignant transformation process in peripheral nerve sheath tumours. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Croton cajucara crude extract and isolated terpenes: activity on Trypanosoma cruzi

Croton cajucara is a plant found in the Amazon region and is known for its medicinal properties. The effects of the methanolic extract of the stem bark of C. cajucara (MCC) and of the isolated terpenes, trans-dehydrocrotonin (t-DCTN) and acetyl aleuritolic acid (AAA), were investigated using four isolates of Trypanosoma cruzi. In assays with trypomastigotes, the extract was more active than the isolated compounds, presenting IC₅₀ in the range of 10 to 50 μg/mL. The trypanocidal effect of MCC, AAA and benznidazole was significantly higher in the GLT291 and C45 strains, which were recently isolated from wild animals. MCC and AAA caused a dose-dependent inhibition of epimastigote proliferation. In assays using intracellular amastigotes, AAA and MCC reduced the percent of infection and the endocytic index after 96 h of treatment, at concentrations that were non-toxic to the host cells. MCC inhibited the trypanothione reductase pathway in both epimastigotes and trypomastigotes of all the subpopulations. The absence of AAA activity on the trypanothione reductase pathway in epimastigotes of Dm28c suggests heterogeneity of the biochemical profile between this clone and the three strains. Epimastigotes and trypomastigotes (GLT291) were treated for 24 h with MCC or AAA, and both induced alterations of the plasma membrane, while AAA-treated epimastigotes also displayed mitochondrial damage.     

Population variation of West Nile virus confers a host-specific fitness benefit in mosquitoes

West Nile virus is similar to most other RNA viruses in that it exists in nature as a genetically diverse population. However, the role of this genetic diversity within natural transmission cycles and its importance to virus perpetuation remain poorly understood. Therefore, we determined whether highly genetically diverse populations are more fit compared to less genetically diverse WNV populations. Specifically, we generated three WNV populations that varied in their genetic diversity and evaluated their fitness relative to genetically marked control WNV in vivo in Culex quinquefasciatus mosquitoes and chickens. Our results demonstrate that high genetic diversity leads to fitness gains in vector mosquitoes, but not chickens.     

Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fischer 344 rat

This study probed possible age-related changes in mitochondrial bioenergetics in naïve Fischer 344 rats. Synaptic and extrasynaptic mitochondria were isolated from the cortex of one hemisphere of young (3-5 months), middle (12-14 months), or aged (22-24 months) rats. Respiration parameters were obtained using a Clarke-type electrode. Aged rats displayed no significant alterations in respiration, indicating mitochondria must be more resilient to the aging process than previously thought. Synaptic mitochondria displayed lower respiration capacities than the extrasynaptic fraction. Aged F344 rats appear capable of normal electron transport chain function without declines in ability to produce ATP. Markers of cortical oxidative damage (3-nitrotyrosine [3-NT], 4-hydroxynonenal [4-HNE], and protein carbonyls [PC]) were collected from the post-mitochondrial supernatant (PMS) from the contralateral hemisphere, and from mitochondrial samples following respiration analysis. Age-related increases in PC and 3-NT levels were found in synaptic mitochondria, whereas significant extrasynaptic elevations were only found in middle aged rats. These findings support an age-related increase in oxidative damage in the cortex, while proposing the two fractions of mitochondria are differentially affected by the aging process. Levels of oxidative damage that accumulates in the cortex with age does not appear to significantly impair cortical mitochondrial respiration of F344 rats.     

Distribution of NMDA receptor subunit NR1 in arctic ground squirrel central nervous system

Hibernation is a natural model of neuroprotection and adult synaptic plasticity. NMDA receptors (NMDAR), which play key roles in excitotoxicity and synaptic plasticity, have not been characterized in a hibernating species. Tolerance to excitotoxicity and cognitive enhancement in Arctic ground squirrels (AGS, Spermophilus parryii) suggests that NMDAR expression may decrease in hibernation and increase upon arousal. NMDAR consist of at least one NMDAR1 (NR1) subunit, which is required for receptor function. Localization of NR1 reflects localization of the majority, if not all, NMDAR complexes. The purpose of this study, therefore, was to characterize the distribution of NR1 subunits in AGS central nervous system using immunohistochemistry. In addition, we compare NR1 expression in hippocampus of hibernating AGS (hAGS) and inter-bout euthermic AGS (ibeAGS) and assess changes in cell somata size using NR1 stained sections in three hippocampal sub-regions (CA1, CA3, and dentate gyrus). For the first time, we report that immunoreactivity of anti-NR1 is widely distributed throughout the central nervous system in AGS and is similar to other species. No differences exist in the expression and distribution of NR1 in hAGS and ibeAGS. However, we report a significant decrease in size of hippocampal CA1 and dentate gyrus NR1-expressing neuronal somata during hibernation torpor.     

Plasticity of neuromuscular junction architectures in rat slow and fast muscle fibers following temporary denervation and reinnervation processes

We evaluated the effects of brief, temporary denervation caused by ischiadic nerve-freezing on the processes of degeneration and regeneration of ultrastructural features in neuromuscular junction (NMJ) architecture in different types of rat skeletal muscle fibers. Nerve terminal (NT) area was decreased significantly 12 h after nerve freezing in both fast-twitch (FT) and slow-twitch (ST) fibers. One day after nerve freezing, some terminal axons were absent; decrease in NT area was remarkable in ST fibers, and there was retraction of Schwann cells and perineural epithelial cells. Fiber type-specific differences were observed in pattern of decrease in NT area between 24 h and 7 days after nerve freezing (there was significantly more decrease in FT fibers). The primary synaptic cleft became shallow, and the secondary junctional folds shorter and wider, but the basement lamina filling the subneural apparatus was unaltered. The number of secondary junctional folds decreased gradually between 6 h and 14 days after nerve freezing in both types of fiber. In control muscle fibers, synaptic vesicle density (SVD) per terminal area was significantly higher in FT fibers. The SVD densities decreased following nerve freezing-induced destruction of NMJs, and were minimal 3 days in FT fibers or 7 days ST fibers after nerve freezing. At 3 weeks, regeneration of both FT and ST fibers was well advanced, and all parameters had recovered to control values in FT fibers 28 days after nerve freezing. Severe degradation of the ultrastructural features in NMJs occurred due to temporary denervation during muscle fiber degeneration processes, and these structural changes were all reversible and fiber type-specific.     

Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment

We determined whether oxidative stress is an early event in the pathogenesis of sporadic Alzheimer disease (AD), and correlated oxidative stress with neuropsychological functions and neurofibrillary pathology in AD and mild cognitive impairment (MCI). Oxidative stress was measured as the percentage of astrocytes expressing heme oxygenase-1 (HO-1) in post mortem temporal cortex and hippocampus after dual HO-1/glial fibrillary acidic protein (GFAP) immunohistochemistry. Glial HO-1 expression in the MCI temporal cortex and hippocampus was significantly greater than in the non-demented group and did not differ from AD values. Astroglial HO-1 expression in the temporal cortex was associated with decreased scores for global cognition, episodic memory, semantic memory and working memory. Hippocampal astroglial HO-1 expression was associated with lower scores for global cognition, semantic memory and perceptual speed. Glial HO-1 immunoreactivity in the temporal cortex, but not hippocampus, correlated with the burden of neurofibrillary pathology. Cortical and hippocampal oxidative stress is a very early event in the pathogenesis of sporadic AD and correlates with the development of specific cognitive deficits in this condition.     

Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia

The posterior cingulate cortex (PCC) has recently been implicated in the pathophysiology of schizophrenia, through both animal and human studies. We have recently shown abnormal glutamate, GABA, and muscarinic receptor binding in the PCC in schizophrenia. In addition, there is evidence for an abnormal endogenous cannabinoid system in schizophrenia. The endogenous cannabinoid system, including CB1 receptors, is proposed to play a role in modulating neurotransmission via affecting the release of a variety of neurotransmitters, (e.g. GABA). In the present study, we used quantitative autoradiography to investigate the binding of [³H]CP-55940 to CB1 receptors in the PCC in schizophrenia subjects compared to controls. A significant 25% increase in CB1 binding was found in the superficial layers (layer I, II) of the PCC of schizophrenia subjects compared to controls, none of whom had recently used cannabis. There was no statistical difference in CB1 binding in the deeper layers (layers III–VI) between the two groups. There were no significant correlations between CB1 binding density and age, PMI, pH, brain weight, freezer storage time, or final recorded antipsychotic drug dose. These results show an increase in CB1 receptor density in the PCC in schizophrenia, and therefore provide support for a role of the endogenous cannabinoid system in schizophrenia.     

Human airway and peripheral blood eosinophils enhance Th1 and Th2 cytokine secretion

BACKGROUND: The effector function of eosinophils involves their release of toxic granule proteins, reactive oxygen species, cytokines, and lipid mediators. Murine studies have demonstrated that eosinophils can also enhance T cell function. Whether human eosinophils, in particular, airway eosinophils, have similar immunoregulatory activity has not been fully investigated. The aim of this study was to determine whether human blood and airway eosinophils can contribute to Th1 and Th2 cytokine generation from CD4+ T cells stimulated with superantigen. METHODS: Eosinophils were obtained from blood or bronchoalveolar lavage fluid 48 h after segmental allergen bronchoprovocation. Purified eosinophils were co-cultured with autologous CD4+ blood T cells in the presence of staphylococcal enterotoxin B (SEB). Cytokine levels in the supernatant fluid were determined by enzyme-linked immunosorbent assay (ELISA). Eosinophil expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules was assessed by flow cytometry before culture, 24 h after granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, and 24 h after co-culture with CD4+ T cells and SEB. RESULTS: Interleukin (IL)-5, IL-13, and interferon (IFN)-gamma generation increased when CD4+ T cells were co-cultured with either blood or airway eosinophils in the presence of SEB. The ability of eosinophils to enhance cytokine generation was independent of their source (blood vs airway), activation by GM-CSF, or detectable expression of human leukocyte antigen (HLA)-DR, CD80, or CD86. CONCLUSION: Our data demonstrate that SEB-induced generation of Th1 and Th2 cytokines is increased in the presence of human blood and airway eosinophils. Thus, eosinophils can have an immunoregulatory function in pathogen-associated allergic diseases such as atopic dermatitis, chronic sinusitis, and asthma exacerbations.