Meta-Analysis of NOS3 G894T Polymorphisms with Air Pollution on the Risk of Ischemic Heart Disease Worldwide.

The purpose of this updated meta-analysis was to investigate the effect of nitric oxide synthase-3 (NOS3) G894T polymorphisms, air pollution and their interaction on ischemic heart disease (IHD) risk across populations worldwide. Recursive partition trees, nonlinear association curve fit and geographic information system maps were incorporated to verify results of conventional pooled analyses for sources of heterogeneity. Results from 61 studies (16,219 cases, 12,222 controls) revealed a significant increased relative risk (RR) of IHD associated with NOS3 894 polymorphisms TT (RR = 1.44) and GT (RR = 1.37). Subgroup analysis revealed that the TT polymorphism genotype had significantly increased risk of IHD in Caucasian, East Asian, South Asian, and Middle Eastern populations (all p < 0.05). It is important to point out that many countries demonstrated an average risk of greater than two, which identifies the NOS3 894 TT polymorphism as a potential causal factor and biological marker of IHD, based on criteria for strong evidence used in international consensus panels. These 10 countries include Ukraine, the United Kingdom, Brazil, Chile, Japan, South Korea, India, Iran, Egypt and Morocco. For these countries with elevated risk (RR > 2) from the NOS3 894 TT polymorphism, meta-predictive analysis demonstrated an increasing trend in air pollution association with increased NOS3 894 polymorphisms. Further studies are needed to explore the complexity of the associations among NOS3 gene polymorphisms per population stratifications within countries, detailed air pollution data for added specificity for geographic location across time, and disease risk.

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium-Derived Endothelin-1.

BACKGROUND: Acute psychosocial stress provokes increases in circulating endothelin-1 (ET-1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress-induced ET-1 remain unanswered. We hypothesized that endothelium-derived ET-1 contributes to the acute pressor response to stress via activation of the endothelin A receptor. METHODS AND RESULTS: Adult male vascular endothelium-specific ET-1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium-specific ET-1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT-627, or the dual endothelin A/B receptor antagonist, A-182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET-1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET-1 in vascular endothelium-specific ET-1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1-adrenergic receptor-mediated vasoconstriction. CONCLUSIONS: These findings specify that acute stress-induced activation of endothelium-derived ET-1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.

APOA5 Gene Polymorphisms and Cardiovascular Diseases: Metaprediction in Global Populations.

BACKGROUND: Apolipoprotein A5 (APOA5) 1131 is one of the most investigated gene polymorphisms in association with cardiovascular diseases (CVD) for its roles in epigenetics pathways. OBJECTIVES: The major objective of this metaprediction study was to comprehensively examine the association of polymorphism risk subtypes of APOA5 1131 gene and potential contributing factors of CVD risks in global populations. METHODS: This study is a meta-analysis to determine APOA5 gene polymorphisms as risk factors for CVDs. Following the guidelines of meta-analyses, we applied big data analytics including the recursive partition tree, nonlinear association curve fit, and heat maps for data visualization-in addition to the conventional pooled analyses. RESULTS: A total of 17,692 CVD cases and 23,566 controls from 50 study groups were included. The frequency of APOA5 1131 CC and TC polymorphisms in Asian populations (22.2%-52.6%) were higher than that in other populations, including Caucasians and Eurasians (10.0%-25.0%). The homozygous CC and heterozygous TC genotypes (both p < .0001) were associated with increased risks for CVD and were higher in many Western nations, including Canada, Spain, the Czech Republic, Hungary, Turkey, Egypt, France, and Iran. The CC genotype was associated with greater risks (RR > 2.00, p < .0001) for dyslipidemia and myocardial infarction, whereas RR > 1.00 was associated with metabolic syndrome, coronary artery disease, and stroke. Air pollution was significantly associated with APOA5 1131 CC and TC polymorphisms. DISCUSSION: The findings of this study provided novel insight to further understand the associations among APOA5 1131 polymorphisms, air pollution, and the development of CVDs. Methylation studies are needed to examine epigenetic factors associated with APOA5 1131 polymorphisms and CVD and to suggest potential prevention strategies for CVD.

Characterization of Chronic Obstructive Pulmonary Disease Patients with a Long Length of Stay: A Retrospective Observational Cohort Study.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) exacerbation is one of the most common reasons for hospital admission. Patients with COPD with a long length of stay (LoS) occupy a disproportionately high fraction of hospital bed-days. The objective of this study was to identify associations of long LoS in patients admitted with COPD exacerbation. MATERIAL AND METHODS: From December 2012 until June 2013, 499 patients were admitted to Queens Hospital, Romford, UK, with COPD exacerbation. Mean LoS was 7 days, with a median of 5 days, and a 90th percentile of 14 days. In this retrospective observational cohort study, 64 patients with a short LoS were compared with 62 patients with a long LoS. RESULTS: Relative to the short LoS, patients with long LoS had significantly lower arterial blood pH, higher arterial PaCO2 and HCO3, higher white cell count, higher globulin and more frequent chest X-ray changes, lower albumin levels, and lower Barthel and Braden scores. They were less likely to have seen the hospital COPD specialist nurse, more likely to require escalation of social care on discharge, and more likely to die during admission. Nearly 66% of the long LoS patients remained in hospital beyond the time of being medically fit for discharge. Commonly cited reasons for delayed discharge were the wait for therapy and social services assessments and the wait for commencement of community social care. CONCLUSION: Meticulous targeting of features peculiar to long LoS patients has the potential to reduce future hospital bed-days for patients with COPD in our and other hospitals.

Medical handovers across shifts within a five-day-working model: results from an electronic handover system in an acute NHS trust.

Electronic handover tools have been advocated as a potential strategy to improve the quality of handover, especially during on-call periods at night and weekends. We aimed to quantify, categorise and explore the temporal relationship of handover tasks stored on an electronic handover system (eHandover) in an acute UK hospital trust in which the day-time primary team worked only weekdays, with only the day-time and night-time on-call teams being available at weekends. Second, we evaluated whether tasks that remained in the eHandover system throughout several shifts were likely to be completed. We defined the shift gap as the number of clinical shifts that passed between the creation of the handover task and its completion. 11,071 electronic handover parcels created on eHandover between March 2010 and January 2011 were analysed. More handovers were requested for completion on weekends (70 parcels a day) than on routine weekdays (22 parcels a day; p<0.001). The receiving teams reported that 89.4% (9,900) of the handover parcels were completed. Greater amounts of handover work was requested over weekends, when tasks were often transferred across many clinical shifts. Despite this, task-completion rates on eHandover remained consistently high. The use of a well-designed electronic handover system as part of a systematic intervention, in combination with organised verbal handover meetings, can help to reduce the risk of communication failure across shifts.

Considerations and proposals for the management of patients after prolonged intensive care unit admission.

The majority of patients admitted to the intensive care unit (ICU) have a short stay of only a few days. However a small but significant number require prolonged intensive care. This is typically due to persisting, and sometimes complex, medical/surgical problems. Discharge of such ICU patients requires a comprehensive, multidisciplinary, verbal and written handover to the receiving ward team. As with any acutely ill adult in hospital, post-ICU patients should be carefully monitored with 'track and trigger' systems such as the Early Warning Score. Those with unexpected physiological deterioration should be promptly reviewed by senior clinicians and/or medical emergency/critical care outreach teams and considered for ICU re-admission where appropriate. Patients who have received prolonged organ support in the ICU are often affected by a number of specific medical problems such as ventilatory insufficiency, cardiac dysfunction, kidney injury, nutritional deficiency, ICU acquired weakness, and brain injury. They also frequently experience physical disability and psychosocial problems including delirium, anxiety, depression, post-traumatic stress disorder, cognitive dysfunction, and disturbed sleep. Structured rehabilitation programmes for post-ICU patients, tailored to individual needs, should be commenced on the ICU and continued through to and beyond hospital discharge. Care bundles, which are widely used on the ICU, are groups of interventions employed to optimise treatments or minimise complication rates. They may be additionally useful in the post-ICU ward setting by prompting clinicians to focus on, and address, commonly occurring medical and psychosocial problems in these patients.

Successful treatment of HIV-associated multicentric Castleman's disease and multiple organ failure with rituximab and supportive care: a case report.

INTRODUCTION: Multicentric Castleman's Disease (MCD), a lymphoproliferative disorder associated with Human Herpes Virus-8 (HHV-8) infection, is increasing in incidence amongst HIV patients. This condition is associated with lymphadenopathy, polyclonal gammopathy, hepato-splenomegaly and systemic symptoms. A number of small studies have demonstrated the efficacy of the anti-CD20 monoclonal antibody, rituximab, in treating this condition. CASE PRESENTATION: We report the case of a 46 year old Zambian woman who presented with pyrexia, diarrhoea and vomiting, confusion, lymphadenopathy, and renal failure. She rapidly developed multiple organ failure following the initiation of treatment of MCD with rituximab. Following admission to intensive care (ICU), she received prompt multi-organ support. After 21 days on the ICU she returned to the haematology medical ward, and was discharged in remission from her disease after 149 days in hospital. CONCLUSION: Rituximab, the efficacy of which has thus far been examined predominantly in patients outside the ICU, in conjunction with extensive organ support was effective treatment for MCD with associated multiple organ failure. There is, to our knowledge, only one other published report of its successful use in an ICU setting, where it was combined with cyclophosphamide, adriamycin and prednisolone. Reports such as ours support the notion that critically unwell patients with HIV and haematological disease can benefit from intensive care.

Association between thymoma and persistent hypothermia: a case report.

INTRODUCTION: Thymomas are rare, slow-growing tumours that present in a variety of ways such as incidental findings on chest radiographs following symptoms of cough and dyspnoea. Thymomas may also present with symptoms due to intrathoracic spread such as superior vena cava obstruction, or with symptoms of an associated paraneoplastic disorder. Such paraneoplastic disorders are typified by the generation of autoantibodies directed against a variety of self antigens including myasthenia gravis, neuromyotonia, and hypogammaglobulinaemia. Significant hypothermia in association with thymoma has been described previously in one published case report. The basis for hypothermia in that case was not clear, but was postulated to relate to abnormal central thermal regulation and was resolved completely following treatment with intravenous gammablobulin, thus suggesting an autoimmune aetiology. CASE PRESENTATION: We present the case of an 88-year-old man with Type A thymoma and persistent hypothermia. An extensive investigation of the hypothermia revealed no aetiology other than the thymoma itself. Symptoms of hypothermia were treated effectively with passive and active external rewarming. The patient's dyspnoea was much improved by intercostal drainage of a left-sided pleural effusion and talc pleurodesis. He was not offered definitive treatment for the thymoma in view of its relatively favourable prognosis, and because his symptoms were well controlled at the time of discharge. CONCLUSION: We suggest that the possibility of thymoma be investigated once the more common causes of hypothermia have been excluded in an appropriate clinical context. To the best of our knowledge, this is only the second published case report describing such an association.

Pulmonary epithelium is a prominent source of proteinase-activated receptor-1-inducible CCL2 in pulmonary fibrosis.

RATIONALE: Studies in patients and experimental animals provide compelling evidence of the involvement of the major thrombin receptor, proteinase-activated receptor-1 (PAR(1)), and the potent chemokine, chemokine (CC motif) ligand-2 (CCL2)/monocyte chemotactic protein-1, in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PAR(1) knockout mice are protected from bleomycin-induced lung inflammation and fibrosis and this protection is associated with marked attenuation in CCL2 induction. OBJECTIVES: The aim of this study was to determine which cell types represent the major source of PAR(1)-inducible CCL2 in the fibrotic lung. METHODS: Using immunohistochemistry and dual immunofluorescence, we examined PAR(1) and CCL2 expression in the bleomycin model and human IPF lung. PAR(1) and CCL2 gene expression was also assessed in laser-captured alveolar septae from patients with IPF. The ability of PAR(1) to induce CCL2 production by lung epithelial cells was also examined in vitro. MEASUREMENTS AND MAIN RESULTS: We report for the first time that PAR(1) and CCL2 are coexpressed and co-up-regulated on the activated epithelium in fibrotic areas in IPF. Similar observations were found in bleomycin-induced lung injury. Furthermore, we show that thrombin is a potent inducer of CCL2 gene expression and protein release by cultured lung epithelial cells via a PAR(1)-dependent mechanism. CONCLUSIONS: These data support the notion that PAR(1) activation on lung epithelial cells may represent an important mechanism leading to increased local CCL2 release in pulmonary fibrosis. Targeting PAR(1) on the pulmonary epithelium may offer a unique opportunity for therapeutic intervention in pulmonary fibrosis and other inflammatory and fibroproliferative conditions associated with excessive local generation of thrombin and CCL2 release.

Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis.

Activation of the coagulation cascade is commonly observed in the lungs of patients with both acute and chronic inflammatory and fibrotic lung disorders, as well as in animal models of these disorders. The aim of this study was to examine the contribution of the major thrombin receptor, proteinase-activated receptor-1 (PAR-1), during the acute inflammatory and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Inflammatory cell recruitment and increases in bronchoalveolar lavage fluid (BALF) protein were attenuated by 56 +/- 10% (P < 0.05) and 53 +/- 12% (P < 0.05), respectively, in PAR-1-deficient (PAR-1-/-) mice compared with wild-type (WT) mice. PAR-1-/- mice were also protected from bleomycin-induced pulmonary fibrosis with total lung collagen accumulation reduced by 59 +/- 5% (P < 0.05). The protection afforded by PAR-1 deficiency was accompanied by significant reductions in pulmonary levels of the potent PAR-1-inducible proinflammatory and profibrotic mediators, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta-1 (TGF-beta1), and connective tissue growth factor/fibroblast-inducible secreted protein-12 (CTGF/FISP12). In addition, PAR-1 was highly expressed in inflammatory and fibroproliferative lesions in lung sections obtained from patients with fibrotic lung disease. These data show for the first time that PAR-1 signaling plays a key role in experimentally induced lung injury, and they further identify PAR-1 as one of the critical receptors involved in orchestrating the interplay between coagulation, inflammation, and remodeling in response to tissue injury.