Identifying which septic patients have increased mortality risk using severity scores:a cohort study

Background: Early aggressive therapy can reduce the mortality associated with severe sepsis but this relies on prompt recognition, which is hindered by variation among published severity criteria. Our aim was to test the performance of different severity scores in predicting mortality among a cohort of hospital inpatients with sepsis. Methods: We anonymously linked routine outcome data to a cohort of prospectively identified adult hospital inpatients with sepsis, and used logistic regression to identify associations between mortality and demographic variables, clinical factors including blood culture results, and six sets of severity criteria. We calculated performance characteristics, including area under receiver operating characteristic curves (AUROC), of each set of severity criteria in predicting mortality. Results: Overall mortality was 19.4% (124/640) at 30 days after sepsis onset. In adjusted analysis, older age (odds ratio 5.79 (95% CI 2.87-11.70) for ≥80y versus <60y), having been admitted as an emergency (OR 3.91 (1.31-11.70) versus electively), and longer inpatient stay prior to sepsis onset (OR 2.90 (1.41-5.94) for >21d versus <4d), were associated with increased 30 day mortality. Being in a surgical or orthopaedic, versus medical, ward was associated with lower mortality (OR 0.47 (0.27-0.81) and 0.26 (0.11-0.63), respectively). Blood culture results (positive vs. negative) were not significantly association with mortality. All severity scores predicted mortality but performance varied. The CURB65 community-acquired pneumonia severity score had the best performance characteristics (sensitivity 81%, specificity 52%, positive predictive value 29%, negative predictive value 92%, for 30 day mortality), including having the largest AUROC curve (0.72, 95% CI 0.67-0.77). Conclusions: The CURB65 pneumonia severity score outperformed five other severity scores in predicting risk of death among a cohort of hospital inpatients with sepsis. The utility of the CURB65 score for risk-stratifying patients with sepsis in clinical practice will depend on replicating these findings in a validation cohort including patients with sepsis on admission to hospital

Activation of transforming growth factor-β(1 )and early atherosclerosis in systemic lupus erythematosus

The efficiency of activating latent transforming growth factor (TGF)-β(1 )in systemic lupus erythematosus (SLE) may control the balance between inflammation and fibrosis, modulating the disease phenotype. To test this hypothesis we studied the ability to activate TGF-β(1 )in SLE patients and control individuals within the context of inflammatory disease activity, cumulative organ damage and early atherosclerosis. An Activation Index (AI) for TGF-β(1 )was determined for 32 patients with SLE and 33 age-matched and sex-matched control individuals by quantifying the increase in active TGF-β(1 )under controlled standard conditions. Apoptosis in peripheral blood mononuclear cells was determined by fluorescence-activated cell sorting. Carotid artery intima-media thickness was measured using standard Doppler ultrasound. These measures were compared between patients and control individuals. In an analysis conducted in patients, we assessed the associations of these measures with SLE phenotype, including early atherosclerosis. Both intima-media thickness and TGF-β(1 )AI for SLE patients were within the normal range. There was a significant inverse association between TGF-β(1 )AI and levels of apoptosis in peripheral blood mononuclear cells after 24 hours in culture for both SLE patients and control individuals. Only in SLE patients was there a significant negative correlation between TGF-β(1 )AI and low-density lipoprotein cholesterol (r = -0.404; P = 0.022) and between TGF-β(1 )AI and carotid artery intima-media thickness (r = -0.587; P = 0.0004). A low AI was associated with irreversible damage (SLICC [Systemic Lupus International Collaborating Clinics] Damage Index ≥1) and was inversely correlated with disease duration. Intima-media thickness was significantly linked to total cholesterol (r = 0.371; P = 0.037). To conclude, in SLE low normal TGF-β(1 )activation was linked with increased lymphocyte apoptosis, irreversible organ damage, disease duration, calculated low-density lipoprotein levels and increased carotid IMT, and may contribute to the development of early atherosclerosis

Quinone reductase acts as a redox switch of the 20 S yeast proteasome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102111/1/embr2008218.pd

Treadmilling FtsZ polymers drive the directional movement of sPG-synthesis enzymes via a Brownian ratchet mechanism.

The FtsZ protein is a central component of the bacterial cell division machinery. It polymerizes at mid-cell and recruits more than 30 proteins to assemble into a macromolecular complex to direct cell wall constriction. FtsZ polymers exhibit treadmilling dynamics, driving the processive movement of enzymes that synthesize septal peptidoglycan (sPG). Here, we combine theoretical modelling with single-molecule imaging of live bacterial cells to show that FtsZ's treadmilling drives the directional movement of sPG enzymes via a Brownian ratchet mechanism. The processivity of the directional movement depends on the binding potential between FtsZ and the sPG enzyme, and on a balance between the enzyme's diffusion and FtsZ's treadmilling speed. We propose that this interplay may provide a mechanism to control the spatiotemporal distribution of active sPG enzymes, explaining the distinct roles of FtsZ treadmilling in modulating cell wall constriction rate observed in different bacteria

Hand-held echocardiography: added value in clinical cardiological assessment

BACKGROUND: The ultrasonic industry has recently produced echocardiographic Hand Held Devices (miniaturized, compact and battery-equipped echocardiographic systems). Their potential usefulness has been successfully assessed in a wide range of clinical conditions. The aim of the study was to verify if the routine use of a basic model of echocardiographic Hand Held Device (HHD) could be an important diagnostic tool during outpatient cardiologic consulting or in non-cardiologic hospital sections. METHODS: 87 consecutive patients were included in this study; they underwent routine physical examination, resting ECG and echocardiographic evaluation using a basic model of HHD performed by trained echocardiographists; the cardiologist, whenever possible, formulated a diagnosis. The percentage of subjects in whom the findings were judged reasonably adequate for final diagnostic and therapeutic conclusions was used to quantify the "conclusiveness" of HHD evaluation. Successively, all patients underwent a second echocardiographic evaluation, by an examiner with similar echocardiographic experience, performed using a Standard Echo Device (SED). The agreement between the first and the second echocardiographic exam was also assessed. RESULTS: Mean examination time was 6.7 ± 1.5 min. using HHD vs. 13.6 ± 2.4 min. using SED. The echocardiographic examination performed using HHD was considered satisfactory in 74/87 patients (85.1% conclusiveness). Among the 74 patients for whom the examination was conclusive, the diagnosis was concordant with that obtained with the SED examination in 62 cases (83.8% agreement). CONCLUSION: HHD may generally allow a reliable cardiologic basic evaluation of outpatient or subjects admitted to non-cardiologic sections, more specifically in particular subgroups of patients, with a gain in terms of time, shortening patient waiting lists and reducing healthy costs

Mediastinal abscess after endobronchial ultrasound with transbronchial needle aspiration: a case report

Endobronchial ultrasound (EBUS) with transbronchial needle aspiration is now becoming widely accepted as a preferred staging technique. It has been perceived as a non-invasive and well tolerated procedure with minimal complications. We report the development and treatment of a severe complication that developed 2 weeks after the initial procedure in the form of a complex mediastinal abscess. EBUS although useful in its non-invasive application for diagnosing mediastinal or hilar disease, must be regarded with caution since the potential exists to develop severe complications

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

Treatment outcomes of new tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study.

BACKGROUND: In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda. METHODS AND FINDINGS: Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 - 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 - 4.01, P = 0.045). CONCLUSION: Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART

Leading causes of certification for blindness and partial sight in England & Wales

Prevention of visual impairment is an international priority agreed at the World Health Assembly of 2002--yet many countries lack contemporary data about incidence and causes from which priorities for prevention, treatment and management can be identified

Saccade Generation by the Frontal Eye Fields in Rhesus Monkeys Is Separable from Visual Detection and Bottom-Up Attention Shift

The frontal eye fields (FEF), originally identified as an oculomotor cortex, have also been implicated in perceptual functions, such as constructing a visual saliency map and shifting visual attention. Further dissecting the area’s role in the transformation from visual input to oculomotor command has been difficult because of spatial confounding between stimuli and responses and consequently between intermediate cognitive processes, such as attention shift and saccade preparation. Here we developed two tasks in which the visual stimulus and the saccade response were dissociated in space (the extended memory-guided saccade task), and bottom-up attention shift and saccade target selection were independent (the four-alternative delayed saccade task). Reversible inactivation of the FEF in rhesus monkeys disrupted, as expected, contralateral memory-guided saccades, but visual detection was demonstrated to be intact at the same field. Moreover, saccade behavior was impaired when a bottom-up shift of attention was not a prerequisite for saccade target selection, indicating that the inactivation effect was independent of the previously reported dysfunctions in bottom-up attention control. These findings underscore the motor aspect of the area’s functions, especially in situations where saccades are generated by internal cognitive processes, including visual short-term memory and long-term associative memory