The predictors of outcome in immunocompetent patients with hematogenous candidasis

AbstractObjective: Clinical parameters that predict outcome in non-immunosuppressed candidemic patients are not fully understood.Methods: Eighty-one consecutive episodes of candidemia were retrospectively evaluated in 75 patients during 1998–2000.Results: Infection due to Candida albicans was common (n=30; 37%) followed by Candida glabrata (n=25; 31%), Candida parapsilosis (n=14; 17%), Candida tropicalis (n=6; 7%), Candida krusei (n=5; 6%), and Candida lusitaniae (n=1; 1%). Among 70 evaluable patients, 31 (44%) had fungemia-associated mortality; advanced age (P<0.004), underlying malignancy (P<0.025), coronary artery disease (P<0.01), and concurrent non-Candida species fungal infection (P<0.047) were significant prognosticators of compromised short-term survival by multivariate analysis. Mortality was higher in patients with Candida glabrata (60%) and C. tropicalis (75%) infection compared to 44% deaths in individuals with C. albicans infection (P>0.1). 11/25 (44%) of non-immunocompromised individuals died and 20/45 (44%) immunosuppressed patients succumbed to fungemia: persistent vs. non-persistent (<3 days) Candida bloodstream invasion, neutropenia, diabetes mellitus, renal insufficiency, prior antimicrobial therapy, cirrhosis of liver, abdomino-pelvis surgery, and critical-care-unit vs. non critical-care-unit admission did not significantly impact outcome in either group. All 11 infants, including nine with prematurity survived Candida species bloodstream infection (P<0.025).Conclusions: Short-term mortality in candidemic non-immunocompromised patients was comparable to fungemia-associated deaths in immunosuppressed patients. Ischemic heart disease has appeared as a new predictor of unfavorable outcome in patients with hematogenous candidiasis

An overview on the small heat shock proteins

In the last 25 years, a huge amount of literature has been accumulated describing the cell&#8217;s response to different kinds of environmental stress conditions, such as high temperatures, altered pH, exposure of the cell to toxins, starvation, oxygen, and water deprivation, among others. Heat shock proteins (HSPs) are one of the main expressed products of the cell in response to stresses. HSPs can be classified into six structurally conserved classes according to their molecular weight namely, HSP100, HSP90, HSP70, HSP60, small heat shock proteins (sHSPs) and ubiquitin (8.5 kDa). In eukaryotes, different heat shock genes are expressed uncoordinatedly, whereas in prokaryote, heat shock genes form a regulon and appear simultaneously. sHSPs are associated with nuclei, cytoskeleton and membranes. They bind partially to denatured proteins, preventing irreversible protein aggregation during stress. In animals, only one sHSP gene has been located in yeast cells, ten in mammalian, two in birds and four genes have been found in Drosophila. However, in plants more than 20 sHSPs have been reported and they can be divided into 6 classes, of which, 3 classes (CI, CII and CIII) are in the cytosole or in the nucleus and the other three (CIV, CV and CVI) in the plastids, endoplasmic reticulum and mitochondria. Mitochondrial and chloroplast sHSPs protect electron transport chain. During development in animals, sHSP genes are normally regulated at late neurula and early tailbud stage and in plants during pollen development, seed maturation, seed imbibition and germination. Transcriptional regulation of sHSPs depends on particular activation of heat shock factors (HSF) which recognize the highly conserved heat-shock elements (HSEs). After the heat stress has been released, the sHSPs are quite stable, suggesting that sHSPs may be important for recovery as well

Markers of Skeletal Muscle Mitochondrial Function and Lipid Accumulation Are Moderately Associated with the Homeostasis Model Assessment Index of Insulin Resistance in Obese Men

Lower skeletal muscle mitochondrial oxidative phosphorylation capacity (OXPHOS) and intramyocellular lipid (IMCL) accumulation have been implicated in the etiology of insulin resistance (IR) in obesity. The purpose of this study was to examine the impact of endurance exercise on biochemical and morphological measures of IMCL and mitochondrial content, and their relationship to IR in obese individuals. We examined mitochondrial content (subunit protein abundance and maximal activity of electron transport chain enzymes), IMCL/mitochondrial morphology in both subsarcolemmal (SS) and intermyofibrillar (IMF) regions by transmission electron microscopy, and intracellular lipid metabolites (diacylglycerol and ceramide) in vastus lateralis biopsies, as well as, the homeostasis model assessment index of IR (HOMA-IR) prior to and following twelve weeks of an endurance exercise regimen in healthy age- and physical activity-matched lean and obese men. Obese men did not show evidence of mitochondrial OXPHOS dysfunction, disproportionate IMCL content in sub-cellular regions, or diacylglycerol/ceramide accretion despite marked IR vs. lean controls. Endurance exercise increased OXPHOS and mitochondrial size and density, but not number of individual mitochondrial fragments, with moderate improvements in HOMA-IR. Exercise reduced SS IMCL content (size, number and density), increased IMF IMCL content, while increasing IMCL/mitochondrial juxtaposition in both regions. HOMA-IR was inversely associated with SS (r = −0.34; P = 0.051) and IMF mitochondrial density (r = −0.29; P = 0.096), IMF IMCL/mitochondrial juxtaposition (r = −0.30; P = 0.086), and COXII (r = −0.32; P = 0.095) and COXIV protein abundance (r = −0.35; P = 0.052); while positively associated with SS IMCL size (r = 0.28; P = 0.119) and SS IMCL density (r = 0.25; P = 0.152). Our findings suggest that once physical activity and cardiorespiratory fitness have been controlled for, skeletal muscle mitochondrial and IMCL profile in obesity may only partially contribute to the development of IR

Monitoring of particulate matter concentrations at high altitude ecosystems of Pakistan and China

Particulate matter exhibits different behavior with altitude. A comparative analysis was carried out to monitor PM1, PM2.5, PM4, PM10 and PMTotal at elevations above 3000 m in both China and Pakistan. Real time monitoring of PM was carried out at both sites using a DustTrak DRX (model 8533, TSI Inc.) for 24 hours each. In Pakistan, the average value of PMTotal was 415 ± 16 μg/m3 while in China the value was considerably lower i.e. 110 ± 57 μg/m3. The 24-hour mean values recorded were well above the WHO recommended limit of 25 μg/m3. These results indicate that, even at sites some distance from anthropogenic sources, PM concentrations still pose a health risk

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

Can a Point-of-Care Troponin I Assay be as Good as a Central Laboratory Assay? A MIDAS Investigation.

BACKGROUND: We aimed to compare the diagnostic accuracy of the Alere Triage Cardio3 Tropinin I (TnI) assay (Alere, Inc., USA) and the PathFast cTnI-II (Mitsubishi Chemical Medience Corporation, Japan) against the central laboratory assay Singulex Erenna TnI assay (Singulex, USA). METHODS: Using the Markers in the Diagnosis of Acute Coronary Syndromes (MIDAS) study population, we evaluated the ability of three different assays to identify patients with acute myocardial infarction (AMI). The MIDAS dataset, described elsewhere, is a prospective multicenter dataset of emergency department (ED) patients with suspected acute coronary syndrome (ACS) and a planned objective myocardial perfusion evaluation. Myocardial infarction (MI) was diagnosed by central adjudication. RESULTS: The C-statistic with 95% confidence intervals (CI) for diagnosing MI by using a common population (n=241) was 0.95 (0.91-0.99), 0.95 (0.91-0.99), and 0.93 (0.89-0.97) for the Triage, Singulex, and PathFast assays, respectively. Of samples with detectable troponin, the absolute values had high Pearson (R(P)) and Spearman (R(S)) correlations and were R(P)=0.94 and R(S)=0.94 for Triage vs Singulex, R(P)=0.93 and R(S)=0.85 for Triage vs PathFast, and R(P)=0.89 and R(S)=0.73 for PathFast vs Singulex. CONCLUSIONS: In a single comparative population of ED patients with suspected ACS, the Triage Cardio3 TnI, PathFast, and Singulex TnI assays provided similar diagnostic performance for MI

Trait and state authenticity across cultures

We examined the role of culture in both trait and state authenticity, asking whether the search for and experience of the 'true self' is a uniquely Western phenomenon or is relevant cross-culturally. We tested participants from the US, China, India, and Singapore. US participants reported higher average levels of trait authenticity than those from Eastern cultures (i.e., China, India, Singapore), but this effect was partially explained by cultural differences in self-construal and thinking style. Importantly, the experience of state authenticity, and especially state inauthenticity, was more similar than different across cultures. In all, people from different cultures do experience authenticity, even if they do not endorse the (Western) value of “independence.” The findings contribute to a more nuanced understanding of state authenticity

The epidemiology and outcomes of invasive \u3ci\u3eCandida\u3c/i\u3e infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET)

Background: Invasive candidiasis (IC) is a common cause of mortality in solid organ transplant recipients (OTRs), but knowledge of epidemiology in this population is limited. Method: The present analysis describes data from 15 US centers that prospectively identified IC from nearly 17 000 OTRs. Analyses were undertaken to determine predictors of infection and mortality. Results: A total of 639 cases of IC were identified. The most common species was Candida albicans (46.3%), followed by Candida glabrata (24.4%) and Candida parapsilosis (8.1%). In 68 cases \u3e1 species was identified. The most common infection site was bloodstream (44%), followed by intra-abdominal (14%). The most frequently affected allograft groups were liver (41.1%) and kidney (35.3%). All-cause mortality at 90 days was 26.5% for all species and was highest for Candida tropicalis (44%) and C. parapsilosis (35.2%). Non-white race and female gender were more commonly associated with non-albicans species. A high rate of breakthrough IC was seen in patients receiving antifungal prophylaxis (39%). Factors associated with mortality include organ dysfunction, lung transplant, and treatment with a polyene antifungal. The only modifiable factor identified was choice of antifungal drug class based upon infecting Candida species. Conclusion: These data highlight the common and distinct features of IC in OTRs

Smooth Muscle Myosin Inhibition: A Novel Therapeutic Approach for Pulmonary Hypertension

Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension