Profile of fall injury in the New South Wales older adult population.

BACKGROUND: A previous report from the New South Wales (NSW) Trauma Registry identified falls and increasing age of severely injured patients as highly prevalent, but detailed injury and demographic profiles, outcomes and their predictors are poorly reported. This study describes the fall-injury profile in the older adult major trauma patient in NSW. METHODS: A retrospective registry based study between 2010 and 2014 on patients aged 55 years and over who sustained a moderate to critical injury from a fall, examining mortality and length of stay using regression analyses. RESULTS: There were 4263 major trauma falls between 2010 and 2014, most occurring at home (55.4%), on the same level (46.7%) and resulting in head injury (63.2%). Significant predictors for mortality following a fall were increased age, male gender, falls in residential care institutions, isolated head injuries and injury classified as critical (ISS 41-75). CONCLUSIONS: The outcomes of falls in the older adult are very poor and a focused prospective study is required to identify areas for intervention and prevention. The predictors of mortality following a fall identified in this study can be used with existing research to develop tools and design care pathways for implementation in the emergency context to improve patient care and outcomes.

Factors associated with cognitive function in older adults in Mexico.

BACKGROUND: As populations age, cognitive decline and dementia pose significant burdens for societies and health care systems, including low- and middle-income countries such as Mexico. Minor age-related declines in cognitive function appear to represent a stable but heterogeneous phase in the continuum between normal cognitive ageing and dementia. Loss of cognitive function has impacts at societal and individual levels and understanding the risk factors can help provide a framework for health policies and interventions to target at-risk groups. DESIGN: A cohort of older Mexican adults (50+) from the World Health Organization's Study on global AGEing and adult health (WHO SAGE) was used to examine cognitive function, including a total of 2315 respondents, with 325 respondents aged 80 years and older. Cognition was objectively evaluated using verbal recall, verbal fluency, forward digit span and backward digit span, with differences in an overall cognitive score assessed against sociodemographic variables, and associated factors using linear regression. RESULTS: The most significant predictors of poorer cognitive function were found to be older age (ß=-13.88), rural living (ß=-2.25), low income (ß=-8.28), self-reported severe or extreme memory difficulties (ß=-6.62), and difficulty with two or more activities of daily living (ß=-2.02). CONCLUSIONS: These findings can inform public health initiatives to address cognitive impairment in ageing populations in Mexico and other middle-income countries.

Globus pallidus internus deep brain stimulation as rescue therapy for refractory dyskinesias following effective subthalamic nucleus stimulation.

BACKGROUND: Deep brain stimulation (DBS) at the subthalamic nucleus (STN) or globus pallidus internus (GPi) can effectively treat the motor symptoms of Parkinson's disease, but dual implantation is rare. We report the first cases of additional GPi stimulation as rescue therapy for disabling dyskinesias following successful STN stimulation. METHODS: Two patients, initially treated with bilateral STN DBS, underwent subsequent bilateral GPi DBS after the development of refractory dyskinesias within 1 and 6 years of STN surgery. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) before and after surgeries for STN and GPi DBS. RESULTS: GPi DBS effectively suppressed dyskinesias in these patients and improved their quality of life, as demonstrated by their videos and UPDRS scores. CONCLUSIONS: Additional bilateral GPi DBS may be considered in the rare instance of patients who develop refractory dyskinesias early or late after bilateral STN DBS.

Regulating the adaptive immune response to blood-stage malaria: role of dendritic cells and CD4⁺Foxp3⁺ regulatory T cells.

Although a clearer understanding of the underlying mechanisms involved in protection and immunopathology during blood-stage malaria has emerged, the mechanisms involved in regulating the adaptive immune response especially those required to maintain a balance between beneficial and deleterious responses remain unclear. Recent evidence suggests the importance of CD11c⁺ dendritic cells (DC) and CD4⁺Foxp3⁺ regulatory T cells in regulating immune responses during infection and autoimmune disease, but information concerning the contribution of these cells to regulating immunity to malaria is limited. Here, we review recent findings from our laboratory and others in experimental models of malaria in mice and in Plasmodium-infected humans on the roles of DC and natural regulatory T cells in regulating adaptive immunity to blood-stage malaria.

Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling.

Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-κB and is associated with susceptibility to bacterial sepsis. A single-nucleotide polymorphism (T(125)C) in human Casp12 restricts its expression to Africa, Southeast Asia, and South America. Here, we investigated the role of caspase-12 in the control of parasite replication and pathogenesis in malaria and report that caspase-12 dampened parasite clearance in blood-stage malaria and modulated susceptibility to cerebral malaria. This response was independent of the caspase-1 inflammasome, as casp1(-/-) mice were indistinguishable from wild-type animals in response to malaria, but dependent on enhanced NF-κB activation. Mechanistically, caspase-12 competed with NEMO for association with IκB kinase-α/ß, effectively preventing the formation of the IκB kinase complex and inhibiting downstream transcriptional activation by NF-κB. Systemic inhibition of NF-κB or Ab neutralization of IFN-γ reversed the increased resistance of casp12(-/-) mice to blood-stage malaria infection.

Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria.

Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. In this study, two different approaches were used to examine the role of indoleamine 2,3-dioxygenase-1 (IDO-1) and its metabolites in the development of murine CM. Mice genetically deficient in IDO-1 were not protected against CM, but partial protection was observed in C57BL/6 mice treated with Ro 61-8048, an inhibitor of kynurenine-3-hydroxylase. This protection was associated with suppressed levels of picolinic acid (PA) within the brain, but not with changes in the levels of kynurenic acid (KA) or quinolinic acid (QA). These data suggest that although IDO-1 is not directly involved in the pathogenesis of CM in C57BL/6 mice, the production of the kynurenine pathway metabolite PA may contribute to the development of murine CM.

Predominance of interferon-related responses in the brain during murine malaria, as identified by microarray analysis.

Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. We examined global gene expression patterns during fatal murine CM (FMCM) and noncerebral malaria (NCM) by microarray analysis. There was differential expression of a number of genes, including some not yet characterized in the pathogenesis of FMCM. Some gene induction was observed during Plasmodium berghei infection regardless of the development of CM, and there was a predominance of genes linked to interferon responses, even in NCM. However, upon real-time PCR validation and quantitation, these genes were much more highly expressed in FMCM than in NCM. The observed changes included genes belonging to pathways such as interferon signaling, major histocompatibility complex processing and presentation, apoptosis, and immunomodulatory and antimicrobial processes. We further characterized differentially expressed genes by examining the cellular source of their expression as well as their temporal expression patterns during the course of malaria infection. These data identify a number of novel genes that represent interesting candidates for further investigation in FMCM.

Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency.

Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. Using murine models of malaria, we found much greater up-regulation of a number of chemokine mRNAs, including those for CXCR3 and its ligands, in the brain during fatal murine CM (FMCM) than in a model of non-CM. Expression of CXCL9 and CXCL10 RNA was localized predominantly to the cerebral microvessels and in adjacent glial cells, while expression of CCL5 was restricted mainly to infiltrating lymphocytes. The majority of mice deficient in CXCR3 were found to be protected from FMCM, and this protection was associated with a reduction in the number of CD8+ T cells in brain vessels as well as reduced expression of perforin and FasL mRNA. Adoptive transfer of CD8+ cells from C57BL/6 mice with FMCM abrogated this protection in CXCR3-/- mice. Moreover, there were decreased mRNA levels for the proinflammatory cytokines IFN-gamma and lymphotoxin-alpha in the brains of mice protected from FMCM. These data suggest a role for CXCR3 in the pathogenesis of FMCM through the recruitment and activation of pathogenic CD8+ T cells.

Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice.

Indoleamine 2,3-dioxygenase (INDO) and tryptophan 2,3-dioxygenase (TDO) each catalyze the first step in the kynurenine pathway of tryptophan metabolism. We describe the discovery of another enzyme with this activity, indoleamine 2,3-dioxygenase-like protein (INDOL1), which is closely related to INDO and is expressed in mice and humans. The corresponding genes have a similar genomic structure and are situated adjacent to each other on human and mouse chromosome 8. They are likely to have arisen by gene duplication before the origin of the tetrapods. The expression of INDOL1 is highest in the mouse kidney, followed by epididymis, and liver. Expression of mouse INDOL1 was further localized to the tubular cells in the kidney and the spermatozoa. INDOL1 was assigned its name because of its structural similarity to INDO. We demonstrate that INDOL1 catalyses the conversion of tryptophan to kynurenine therefore a more appropriate nomenclature for the enzymes might be INDO-1 and INDO-2, or the more commonly-used abbreviations, IDO-1 and IDO-2. Although the two proteins have similar enzymatic activities, their different expression patterns within tissues and during malaria infection, suggests a distinct role for each protein. This identification of INDOL1 may help to explain the regulation of the diversity of physiological and patho-physiological processes in which the kynurenine pathway is involved.

Interferon-gamma synergises with tumour necrosis factor and lymphotoxin-alpha to enhance the mRNA and protein expression of adhesion molecules in mouse brain endothelial cells.

Changes to the cerebral microvasculature are evident during cerebral malaria (CM). Activation of the endothelium is likely to be due to the actions of cytokines, circulating levels of which are elevated during CM. Endothelial cells are known to up-regulate the expression of cellular adhesion molecules, which can lead to cellular sequestration and obstruction of vessels. However, it is unknown whether cytokines synergise in the up-regulation of the adhesion molecules involved in CM. In this study, the mRNA and/or protein expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin and E-Selectin were examined in a mouse brain endothelial cell line. Endothelial cells were stimulated with interferon-gamma (IFN-gamma), tumour necrosis factor (TNF) and lymphotoxin-alpha (LT-alpha), alone or in combination. The expression of ICAM-1, VCAM-1, P-selectin and E-Selectin mRNA in mouse brain endothelial cells by TNF and/or LT-alpha was found to be significantly enhanced in the presence of IFN-gamma. The same synergistic effect was found when analyzing ICAM-1 protein expression in cytokine stimulated mouse brain endothelial cells. The findings show that cytokines can synergise to influence gene expression and protein expression in a mouse brain endothelial cell line.

Immunopathogenesis of cerebral malaria.

Malaria is one of the most important global health problems, potentially affecting more than one third of the world's population. Cerebral malaria (CM) is a deadly complication of Plasmodium falciparum infection, yet its pathogenesis remains incompletely understood. In this review, we discuss some of the principal pathogenic events that have been described in murine models of the disease and relate them to the human condition. One of the earliest events in CM pathogenesis appears to be a mild increase in the permeability to protein of the blood-brain barrier. Recent studies have shown a role for CD8+T cells in mediating damage to the microvascular endothelium and this damage can result in the leakage of cytokines, malaria antigens and other potentially harmful molecules across the blood-brain barrier into the cerebral parenchyma. We suggest that this, in turn, leads to the activation of microglia and the activation and apoptosis of astrocytes. The role of hypoxia in the pathogenesis of cerebral malaria is also discussed, with particular reference to the local reduction of oxygen consumption in the brain as a consequence of vascular obstruction, to cytokine-driven changes in glucose metabolism, and to cytopathic hypoxia. Interferon-gamma, a cytokine known to be produced in malaria infection, induces increased expression, by microvascular endothelial cells, of the haem enzyme indoleamine 2,3-dioxygenase, the first enzyme in the kynurenine pathway of tryptophan metabolism. Enhanced indoleamine 2,3-dioxygenase expression leads to increased production of a range of biologically active metabolites that may be part of a tissue protective response. Damage to astrocytes may result in reduced production of the neuroprotectant molecule kynurenic acid, leading to a decrease in its ratio relative to the neuroexcitotoxic molecule quinolinic acid, which might contribute to some of the neurological symptoms of cerebral malaria. Lastly, we discuss the role of other haem enzymes, cyclooxygenase-2, inducible nitric oxide synthase and haem oxygenase-1, as potentially being components of mechanisms that protect host tissue against the effects of cytokine- and leukocyte-mediated stress induced by malaria infection.

Increased expression of indoleamine 2,3-dioxygenase in murine malaria infection is predominantly localised to the vascular endothelium.

Products of the kynurenine pathway of tryptophan metabolism have been implicated in the pathogenesis of murine and human cerebral malaria. Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme in this pathway and we have developed an immunohistochemical method for its detection in tissues from normal and malaria-infected mice. Mice were infected with Plasmodium berghei ANKA, a murine model of cerebral malaria, or P. berghei K173, a non-cerebral malaria model. Vascular endothelial cells were the primary sites of indoleamine 2,3-dioxygenase expression in both types of malaria infection and this response was systemic, with positive staining of vascular endothelium in all tissues examined. No indoleamine 2,3-dioxygenase expression was detected in uninfected or interferon-gamma-/- mice. Corroborative data were obtained using quantitative reverse transcription PCR for indoleamine 2,3-dioxygenase mRNA. These results suggest that interferon-gamma-dependent indoleamine 2,3-dioxygenase expression is part of a normal systemic host response to the parasite, perhaps performing some tissue protective functions that may become deranged under some circumstances and contribute to the pathogenesis of cerebral malaria. On the other hand, constitutive indoleamine 2,3-dioxygenase expression in the epididymis and the placenta was detected in both C57Bl/6 wild-type and interferon-gamma-/- mice, suggesting a distinct regulatory mechanism for its induction in these normal physiological situations. Although increased indoleamine 2,3-dioxygenase production during murine malaria infection may not by itself cause cerebral pathology, metabolites of the kynurenine pathway may combine with other features of cerebral malaria, such as breakdown of the blood-brain barrier, to influence CNS function and contribute to the symptoms and pathology observed.