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Purpose. We examined the effect of cancer caregiver stress and negative attribution style (NAS) on depressive symptoms and salivary cortisol. Method. The sample came from a hospital bone marrow unit and caregiver support organizations and included 60 informal cancer caregivers (51.7% partners) of cancer patients (provided care for a median of 27.5 hours per week for 12 months) and 46 non-caregiver participants. In this cross-sectional study, participants completed questionnaires assessing NAS and depressive symptoms and provided saliva samples to measure cortisol. Results. Linear regressions demonstrated that cancer caregiver stress (p=0.001) and the cancer caregiver stress by NAS interaction (p=0.017), but not NAS alone (p=0.152), predicted depressive symptoms. Caregivers independent of their NAS and non-caregivers high in NAS reported high depression while non-caregivers low in NAS reported low depression. Neither cancer caregiver stress (p=0.920) nor NAS alone (p=0.114), but their interaction, predicted cortisol (p=0.036). Higher NAS was associated with a higher cortisol in both groups while non-caregivers had higher cortisol than caregivers. Conclusions. If the findings can be replicated, the implementation of interventions to support informal caregivers in managing their chronic stress and modify their NAS appears warranted.

Objective:To describe a pilot project infection prevention and control (IPC) assessment conducted in skilled nursing facilities (SNFs) in New York State (NYS) during a pivotal 2-week period when the region became the nation’s epicenter for coronavirus disease 2019 (COVID-19).Design:A telephone and video assessment of IPC measures in SNFs at high risk or experiencing COVID-19 activity.Participants:SNFs in 14 New York counties, including New York City.Intervention:A 3-component remote IPC assessment: (1) screening tool; (2) telephone IPC checklist; and (3) COVID-19 video IPC assessment (ie, “COVIDeo”).Results:In total, 92 SNFs completed the IPC screening tool and checklist: 52 (57%) were conducted as part COVID-19 investigations, and 40 (43%) were proactive prevention-based assessments. Among the 40 proactive assessments, 14 (35%) identified suspected or confirmed COVID-19 cases. COVIDeo was performed in 26 (28%) of 92 assessments and provided observations that other tools would have missed: personal protective equipment (PPE) that was not easily accessible, redundant, or improperly donned, doffed, or stored and specific challenges implementing IPC in specialty populations. The IPC assessments took ∼1 hour each and reached an estimated 4 times as many SNFs as on-site visits in a similar time frame.Conclusions:Remote IPC assessments by telephone and video were timely and feasible methods of assessing the extent to which IPC interventions had been implemented in a vulnerable setting and to disseminate real-time recommendations. Remote assessments are now being implemented across New York State and in various healthcare facility types. Similar methods have been adapted nationally by the Centers for Disease Control and Prevention.

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma–related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Patients with dyskeratosis congenita (DC) and related telomeropathies resulting from premature telomere dysfunction suffer from multi-organ failure. In the liver, DC patients present with nodular hyperplasia, steatosis, inflammation, and cirrhosis. We model DC liver pathologies using isogenic human induced pluripotent stem (iPS) cells harboring a causal DC mutation in DKC1, or a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-corrected control allele. Differentiation of these iPS cells into hepatocytes or hepatic stellate cells followed by generation of genotype-admixed hepatostellate organoids revealed a dominant phenotype in the parenchyma, with DC hepatocytes eliciting a pathogenic hyperplastic response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes could be rescued via suppression of AKT activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation. Thus, isogenic iPS-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies.

Approximately 20% of patients infected with SARS-CoV-2 (COVID-19) develop potentially life-threatening pathologies involving hyperinflammation, cytokine storm, septic shock complications, coagulation dysfunction, and multiple organ failure. Blood levels of the prototypic acute phase reactant, C-reactive protein (CRP), which is hepatically synthesized and released in response to interleukin-6 stimulation, is markedly elevated in patients with COVID-19. Markedly high CRP levels correlate with poor prognosis for survival. Insights into CRP structure–function relationships have uncovered both pro- and anti-inflammatory isoforms that may be used to monitor the extent of tissue damage associated with COVID-19 pathologies and prognoses. Herein, rationale is given for interpretation of CRP blood levels as a simple, rapid, and cost-effective way to assess disease severity and help guide therapeutic options in COVID-19 patients.

Objectives To examine the effect of informal cancer caregiving and repetitive negative thinking (RNT) on depressive symptoms and salivary cortisol levels. Sample & setting The sample was recruited from a hospital bone marrow unit and caregiver support organizations. It included 60 informal cancer caregivers (52% partners) of individuals with cancer who provided care for a median of 27.5 hours per week for 12 months, and 46 noncaregiver participants. Methods & variables In this cross-sectional study, participants completed questionnaires assessing RNT and depressive symptoms and provided saliva samples to measure cortisol levels. Results Cancer caregiving and RNT, but not the interaction, were associated with more depressive symptoms. RNT, but not cancer caregiving, was associated with salivary cortisol. A disordinal interaction effect suggests that cancer caregiving was associated with lower cortisol levels, and RNT in noncaregivers was associated with higher cortisol levels. Implications for nursing Given that RNT is related to depressive symptoms and cortisol, connecting cancer caregivers who experience RNT to resources and the development and evaluation of brief nurse-led interventions to reduce RNT in informal cancer caregivers seems warranted.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified ‘Age, RNAemia’ and ‘Age, PTX3’ as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro., Here the authors use RT-qPCR and mass spectrometry to analyze longitudinal blood samples from intensive care unit (ICU) COVID-19 patients and controls. They find that viral RNA and pentraxin-3 predict 28-day ICU mortality and that galectin-3-binding protein is an interaction partner of SARS-CoV-2 spike glycoprotein with antiviral properties.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is higher in HIV-infected patients compared to the general population. While metabolic risk factors such as obesity, insulin resistance and the metabolic syndrome have been identified as key risk factors in all individuals, there is limited information regarding the mechanisms that contribute to the higher prevalence among individuals living with HIV, particularly among women and ethnic minorities. The aim of this study was to determine the association, over two time points, of a panel of biomarkers with liver steatosis in a cohort of HIV-seropositive women and age-matched negative controls and to investigate whether the association differed by HIV status. To this effect, plasma samples obtained from 105 HIV-positive and –negative participants enrolled in the Women’s Interagency HIV study (WIHS) Washington DC site were assayed for biomarkers associated with inflammation, adipose tissue function, fibrinolysis, gut permeability and hepatocyte apoptosis/necrosis. Their association with liver steatosis, measured using Controlled-Attenuation Parameter (CAP) scores determined by transient elastography, were then analyzed. HIV positivity was associated with lower median IL-17A and higher IL-22 and sCD14 values. There were no statistically significant associations between HIV status, biomarkers or covariates with CAP measurement over two time points. However, IL-1β levels were associated with higher CAP scores at the second visit. Across all statistical models, an increase in BMI was associated with an increase in CAP measurements. No statistically significant associations were found between viral load history, CD4 + T-cell count, biomarkers and covariates, including ART use, on CAP measurements. These results confirm that BMI is a key risk factor for liver steatosis independent of HIV status. The potential contributions to NAFLD of differences in IL-1β, Th17-family cytokines and gut permeability between HIV-positive vs. negative individuals require further study.

REIPI-SEIMC COVID-19 group and COVID@HULP group., [Background] The clinical presentation of COVID-19 in patients admitted to hospital is heterogeneous. We aimed to determine whether clinical phenotypes of patients with COVID-19 can be derived from clinical data, to assess the reproducibility of these phenotypes and correlation with prognosis, and to derive and validate a simplified probabilistic model for phenotype assignment. Phenotype identification was not primarily intended as a predictive tool for mortality., [Methods] In this study, we used data from two cohorts: the COVID-19@Spain cohort, a retrospective cohort including 4035 consecutive adult patients admitted to 127 hospitals in Spain with COVID-19 between Feb 2 and March 17, 2020, and the COVID-19@HULP cohort, including 2226 consecutive adult patients admitted to a teaching hospital in Madrid between Feb 25 and April 19, 2020. The COVID-19@Spain cohort was divided into a derivation cohort, comprising 2667 randomly selected patients, and an internal validation cohort, comprising the remaining 1368 patients. The COVID-19@HULP cohort was used as an external validation cohort. A probabilistic model for phenotype assignment was derived in the derivation cohort using multinomial logistic regression and validated in the internal validation cohort. The model was also applied to the external validation cohort. 30-day mortality and other prognostic variables were assessed in the derived phenotypes and in the phenotypes assigned by the probabilistic model., [Findings] Three distinct phenotypes were derived in the derivation cohort (n=2667)—phenotype A (516 [19%] patients), phenotype B (1955 [73%]) and phenotype C (196 [7%])—and reproduced in the internal validation cohort (n=1368)—phenotype A (233 [17%] patients), phenotype B (1019 [74%]), and phenotype C (116 [8%]). Patients with phenotype A were younger, were less frequently male, had mild viral symptoms, and had normal inflammatory parameters. Patients with phenotype B included more patients with obesity, lymphocytopenia, and moderately elevated inflammatory parameters. Patients with phenotype C included older patients with more comorbidities and even higher inflammatory parameters than phenotype B. We developed a simplified probabilistic model (validated in the internal validation cohort) for phenotype assignment, including 16 variables. In the derivation cohort, 30-day mortality rates were 2·5% (95% CI 1·4–4·3) for patients with phenotype A, 30·5% (28·5–32·6) for patients with phenotype B, and 60·7% (53·7–67·2) for patients with phenotype C (log-rank test p, [Interpretation] Patients admitted to hospital with COVID-19 can be classified into three phenotypes that correlate with mortality. We developed and validated a simplified tool for the probabilistic assignment of patients into phenotypes. These results might help to better classify patients for clinical management, but the pathophysiological mechanisms of the phenotypes must be investigated., [Funding] Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA., Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Fundación SEIMC/GeSIDA.

SummaryDyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human iPSC-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC related pathologies.

The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres. We discuss how these findings are different from previous observations connecting WNT and telomere biology, and discuss potential links between WNT and clinical manifestations of the DC spectrum of diseases. Finally, we argue for exploring the use of WNT agonists, specifically lithium, as a possible therapeutic approach for patients with DC.

Background Understanding the burden of community-acquired pneumonia (CAP) is critical to allocate resources for prevention, management, and research. The objectives of this study were to define incidence, epidemiology, and mortality of adult patients hospitalized with CAP in the city of Louisville, and to estimate burden of CAP in the US adult population. Methods This was a prospective population-based cohort study of adult residents in Louisville, Kentucky, from 1 June 2014 to 31 May 2016. Consecutive hospitalized patients with CAP were enrolled at all adult hospitals in Louisville. The annual population-based CAP incidence was calculated. Geospatial epidemiology was used to define ecological associations among CAP and income level, race, and age. Mortality was evaluated during hospitalization and at 30 days, 6 months, and 1 year after hospitalization. Results During the 2-year study, from a Louisville population of 587499 adults, 186384 hospitalizations occurred. A total of 7449 unique patients hospitalized with CAP were documented. The annual age-adjusted incidence was 649 patients hospitalized with CAP per 100000 adults (95% confidence interval, 628.2-669.8), corresponding to 1591825 annual adult CAP hospitalizations in the United States. Clusters of CAP cases were found in areas with low-income and black/African American populations. Mortality during hospitalization was 6.5%, corresponding to 102821 annual deaths in the United States. Mortality at 30 days, 6 months, and 1 year was 13.0%, 23.4%, and 30.6%, respectively. Conclusions The estimated US burden of CAP is substantial, with >1.5 million unique adults being hospitalized annually, 100000 deaths occurring during hospitalization, and approximately 1 of 3 patients hospitalized with CAP dying within 1 year.

We present a case of a woman with a history of Congenital Adrenal Hyperplasia (CAH) diagnosed at the age of 12, who was referred to our unit for surgical treatment. Despite the initial diagnosis was an indirect inguinal hernia, it was a misdiagnosis. Once in our service, this was corrected into clitoromegaly secondary to CAH. Physical examination and imaging test discarded other abnormalities, such as secondary effects androgenization. Regarding surgical treatment, the techniques used were Spencer and Allen combined with Kumar, which are the most used for clitoroplasty but also less used in Peru. Keywords: Congenital Adrenal Hyperplasia (CAH), Clitoromegaly, Surgical techniques

Background HIV-positive patients on anti-retroviral therapy (ART) are at higher risk of developing many non-AIDS related chronic diseases, including chronic obstructive pulmonary disease (COPD), compared to HIV-negative individuals. While the mechanisms are not clear, a persistent pro-inflammatory state appears to be a key contributing factor. The aims of this study were to investigate whether HIV-positive patients without COPD present evidence of potentially predisposing abnormal pulmonary cytokine/chemokine environment and to explore the relationship between pulmonary and systemic cytokine levels. Methods This study included 39 HIV-seropositive and 34 HIV-seronegative subjects without COPD. All were subjected to outpatient bronchoscopy with bronchoalveolar lavage fluid (BALF) aspiration and blood sample collection. The levels of 21 cytokines and chemokines were measured in plasma and BALF using a bead-based multi-analyte assay. Results In plasma, HIV-infected patients showed significantly increased circulating levels of pro-inflammatory (TNFα) and Th1-associated cytokines (IL-12p70) as well as several chemokines (CXCL11 and CX3CL1). However, no statistically significant differences were found in the numbers of cells, the concentrations of protein and urea as well as cytokine levels in the BALFs of HIV-positive patients when compared to controls. Correlation analysis indicated a potential modulatory effect of the BMI in HIV-seropositive individuals. Conclusions While our results are consistent with the existence of a systemic pro-inflammatory state in HIV-infected patients, they did not detect significant differences in cytokine levels and other inflammatory markers in the lungs of HIV-positive individuals when compared to HIV-negative controls.

BACKGROUND: Sepsis-associated brain dysfunction (SABD) is associated with high morbidity and mortality. The pathophysiology of SABD is multifactorial. One hypothesis is that impaired cerebral autoregulation (CAR) may result in brain hypoperfusion and neuronal damage leading to SABD. METHODS: We studied 100 adult patients with sepsis (July 2012-March 2017) (age = 62 [52-71] years; Acute Physiology and Chronic Health Evaluation II score on admission = 21 [15-26]). Exclusion criteria were acute or chronic intracranial disease, arrhythmias, extracorporeal membrane oxygenation, and known intra- or extracranial supra-aortic vessel disease. The site of infection was predominantly abdominal (46%) or pulmonary (28%). Transcranial Doppler was performed, insonating the left middle cerebral artery with a 2-MHz probe. Middle cerebral artery blood flow velocity (FV) and arterial blood pressure (ABP) signals were recorded simultaneously; Pearson's correlation coefficient (mean flow index [Mxa]) between ABP and FV was calculated using MATLAB. Impaired CAR was defined as Mxa > 0.3. RESULTS: Mxa was 0.29 [0.05-0.62]. CAR was impaired in 50 patients (50%). In a multiple linear regression analysis, low mean arterial pressure, history of chronic kidney disease and fungal infection were associated with high Mxa. SABD was diagnosed in 57 patients (57%). In a multivariable analysis, altered cerebral autoregulation, mechanical ventilation and history of vascular disease were independent predictors of SABD. CONCLUSIONS: Cerebral autoregulation was altered in half of the patients with sepsis and was associated with the development of SABD. These findings support the concept that cerebral hypoxia could contribute to the development of SABD., SCOPUS: ar.j, info:eu-repo/semantics/published

To the Editor: We thank Mr Chatburn for his positive comments on our review.[1][1] Chatburn highlights our previous finding[2][2],[3][3] that asynchronies, in particular, ineffective efforts during expiration, were slightly more frequent in pressure support ventilation (PSV) compared with volume

Thromboangiitis obliterans (TAO), also known as Buerger’s Disease, is an occlusive vasculitis linked with high morbidity and amputation risk. To date, TAO is deemed incurable due to the lack of a definitive treatment. The immune system and inflammation are proposed to play a central role in TAO pathogenesis. Due to their immunomodulatory effects, mesenchymal stromal cells (MSCs) are the subject of intense research for the treatment of a wide range of immune-mediated diseases. Thus far, local intramuscular injections of autologous or allogeneic MSCs have shown promising results in TAO. However, sequential intravenous allogeneic MSC administration has not yet been explored, which we hypothesized could exert a systemic anti-inflammatory effect in the vasculature and modulate the immune response. Here, we report the first case of a TAO patient at amputation risk treated with four sequential intravenous infusions of bone marrow-derived allogeneic MSCs from a healthy donor. Following administration, there was significant regression of foot skin ulcers and improvements in rest pain, Walking Impairment Questionnaire scores, and quality of life. Sixteen months after the infusion, the patient had not required any further amputations. This report highlights the potential of sequential allogeneic MSC infusions as an effective treatment for TAO, warranting further studies to compare this approach with the more conventionally used intramuscular MSC administration and other cell-based therapies.

The objective of this study was to measure plasma cytokine levels and blood neutrophil functions as well as clinical outcomes in hospitalized patients with community-acquired pneumonia (CAP) treated with or without macrolide use—a known modulator of inflammatory response. Subjects with CAP had peripheral blood analyzed for some neutrophil functions (degranulation of secretory vesicles and specific granules, respiratory burst response and phagocytosis) and ten cytokine levels measured in serum and sputum supernatants. Neutrophil function in healthy volunteers was also measured for reference. Values were measured on the day of enrollment, days 2–4 and 5–7, depending on a patient’s length of stay. Early and late clinical outcomes were also evaluated. All values were compared between those treated with or without a macrolide. A total of 40 subjects were in this study; 14 received macrolide treatment, and 26 did not. Neutrophil function in the macrolide group was not significantly different compared to the non-macrolide group. None of the median cytokine levels or IQRs were statistically significant between the groups. However, a trend toward decreased IL-6, IL-8, and IFN-γ levels, and favorable clinical outcomes were present in the macrolide group. This pilot study showed no statistical difference between cytokine levels or neutrophil activity for CAP patients prescribed a macrolide containing regimen. Considering the trend of lower cytokine levels in the macrolide group when comparing the 5- to 7-day time period with the non-macrolide group, a full study with an appropriate sample size may be warranted.

The beneficial effect of macrolides for the treatment of community-acquired pneumonia (CAP) in combination with beta-lactams may be due to their anti-inflammatory activity. In patients with pneumococcal meningitis, the use of steroids improves outcomes only if they are administered before beta-lactams. The objective of this study was to compare outcomes in hospitalized patients with CAP when macrolides were administered before, simultaneously with, or after beta-lactams.Secondary data analysis of the Community-Acquired Pneumonia Organization (CAPO) International Cohort Study database. Study groups were defined based on the sequence of administration of macrolides and beta-lactams. The study outcomes were time to clinical stability (TCS), length of stay (LOS) and in-hospital mortality. Accelerated failure time models were used to evaluate the adjusted impact of sequential antibiotic administration and time-to-event outcomes, while a logistic regression model was used to evaluate their adjusted impact on mortality.A total of 99 patients were included in the macrolide before group and 305 in the macrolide after group. Administration of a macrolide before a beta-lactam compared to after a beta-lactam reduced TCS (3 vs. 4 days, p = .011), LOS (6 vs. 7 days, p = .002) and mortality (3 vs. 7.2%, p = .228).The administration of macrolides before beta-lactams was associated with a statistically significant decrease in TCS and LOS and a non-statistically significant decrease in mortality. The beneficial effect of macrolides in hospitalized patient with CAP may occur only if administered before beta-lactams.

Introduction Patients with severe community-acquired pneumonia (CAP) are believed to have an exaggerated inflammatory response to bacterial infection. Therapies aiming to modulate the inflammatory response have been largely unsuccessful, perhaps reflecting that CAP is a heterogeneous disorder that cannot be modulated by a single anti-inflammatory approach. We hypothesize that the host inflammatory response to pneumonia may be characterized by distinct cytokine patterns, which can be harnessed for personalized therapies. Methods Here, we use hierarchical cluster analysis of cytokines to examine if patterns of inflammatory response in 13 hospitalized patients with CAP can be defined. This was a secondary data analysis of the Community-Acquired Pneumonia Inflammatory Study Group (CAPISG) database. The following cytokines were measured in plasma and sputum on the day of admission: interleukin (IL)-1β, IL-1 receptor antagonist (IL-1ra), IL-6, CXCL8 (IL-8), IL-10, IL-12p40, IL-17, interferon (IFN)γ, tumor necrosis factor (TNF)α, and CXCL10 (IP-10). Hierarchical agglomerative clustering algorithms were used to evaluate clusters of patients within plasma and sputum cytokine determinations. Results A total of thirteen patients were included in this pilot study. Cluster analysis identified distinct inflammatory response patterns of cytokines in the plasma, sputum, and the ratio of plasma to sputum. Conclusions Inflammatory response patterns in plasma and sputum can be identified in hospitalized patients with CAP. Characterization of the local and systemic inflammatory response may help to better discriminate patients for enrollment into clinical trials of immunomodulatory therapies.

Reason Proportional assist ventilation plus (PAV+) applies pressure depending on the patient's inspiratory effort, automatically adjusting flow and volume assist to changes in respiratory mechanics. We aimed to assess the clinical factors associated with the success of PAV+ as first-line support in the acute phase of critical illness. Methods A prospective cohort study was carried out. Mechanically ventilated patients >24 h were switched from assist-control ventilation to PAV+ as soon as they regained spontaneous breathing activity. PAV+ was set to deliver the highest assistance. We compared patients in whom PAV+ succeeded vs those in whom it failed. Results PAV+ succeeded in 12 (63%) patients, but failed in 7 (37%) due to tachypnea (n = 4), hypercapnia (n = 2), and metabolic acidosis (n = 1), but without statistical significance. Both groups had similar clinical parameters. On the day of inclusion, total work of breathing per breath was lower in the successful PAV+ group (WOBTOT: 0.95 [0.8–1.35] vs 1.6 [1.4–1.8] J/l; P Conclusion PAV+ proved feasible as first-line ventilatory support in 63% of the patients, mostly in individuals without extreme derangements in WOBTOT. Tachypnea and hypercapnia were the clinical factors associated with failure, though statistical significance was not reached.

Purpose Development of cancer is recognized as one of the main causes of death after lung transplantation. We aimed to propose an equation for cancer risk after lung transplantation. Methods Retrospective study of all cases of cancer diagnosed in a Spanish Transplant Unit between 1999 and 2017. A control group consisted of lung transplant patients that did not develop cancer during the follow-up, matched by date of lung transplantation. The excess risk of cancer was calculated as odds ratio, being the best equation selected that which uses the allsets method with subsequent inclusion of the parameters in a logistic regression. Survival curves were analyzed with Kaplan-Meier. The statistical analysis was done with Stata 14.2 Results Out of 630 lung transplantations, 48 cancers were diagnosed: 11 skin (22.92%), 8 lymphoma (16.67%), 8 lung (16.67%), 7 gastrointestinal (14.58%) and 7 others (14.58%). There were no significant differences regarding: indication for lung transplantation (p 0.86), age (p 0.50), gender (p 0.09), follow-up time (p 0.84), acute rejection (p 0.58), chronic rejection (p 0.69) or immunosupprive regimen (p 0.22). In the univariate analysis, cancer development was associated with cytomegalovirus infection/disease (p 0.005) and bilateral lung transplant (p 0.01). In the multivariate analysis adjusted for gender according to allsets method CMV infection/disease had an OR of 3.83 (95% IC 1.31-11.13), bilateral comparing to single lung transplant had an OR of 0.38 (95% IC 0.15-0.97) and men comparing to women had an OR of 1.67 (95% IC 0.78-4.80). A final risk equation for cancer after lung transplantation was developed, as follows: p(cancer)= -0,38 + (1,34 x CMV) + (-0,96 x lung transplant type)+(0,52 x gender). Conclusion CMV infection/disease and the type of lung transplant procedure were strong predictors for the development of cancer. There is a need to identify specific tests that permit early diagnosis of the most frequent cancers in these high-risk patients.

Objective To determine the life-sustaining treatment limitation (LSTL) predisposition upon patient admission to the Intensive Care Unit (ICU), the criteria upon which such predisposition is based, and whether these decisions are related to structural factors of the surveyed hospitals. Design A descriptive multicenter study was made in 2010, involving the conduction of a survey in 90 hospitals, with a view to documenting the usual practise referred to LSTL upon admission in these centers. Setting Spanish ICUs. Intervention Opinion survey. Main variables of interest Type of hospital, number of hospital beds, ICU and semicritical patient beds, usual bed availability in the ICU, use of restrictive admission criteria, use of LSTL criteria upon admission, and type of criterion used to decide LSTL. Results A total of 43 (48%) hospitals participated in the study, with LSTL being a common practise in these centers (93%). LSTL was fundamentally decided on the basis of the presence of prior severe chronic disease (95%), observation of previously declared patient will (95%), prior functional limitation (85%), and qualitative futility of care (82%). Frequent ICU bed availability (77% of the hospitals) and the use of restrictive criteria (79% of the hospitals) were also associated to patient admission with LSTL. Conclusions Admission to ICU with LSTL is a generalized practise in Spanish Hospitals. LSTL is decided not only based on physiological futility from an objective medical point of view, but also in observance of ethical and moral implications based on the qualitative futility of medical care.

To determine the effects of deflating the tracheal cuff during disconnections from mechanical ventilation (MV) in tracheostomized patients. This was a single-center, randomized trial conducted in a general ICU of a tertiary hospital with regional referral for trauma patients. Patients at high risk of aspiration based on the drink test were excluded. Critically ill tracheostomized patients were randomized to have the tracheal cuff deflated or not during spontaneous breathing trials. Weaning was protocolized on progressive T-tube trials, and patients were considered weaned after 24 consecutive hours disconnected from MV. The primary end point was time to definitive withdrawal of MV; secondary end points were ventilator-associated respiratory infection (pneumonia and/or tracheobronchitis) and swallowing function. Statistical analyses included Cox proportional risk models. We randomized 195 patients and 181 patients completed the study (94 patients with deflated cuff and 87 with inflated cuff). Variables independently related to weaning time in the multivariate analysis were tracheostomy-to-first MV disconnection time (HR 0.5, 95 % CI 0.3–0.8; p

Although low doses of oxygen (FiO20.50) are considered nontoxic, recent studies have shown that even lower doses increase pulmonary inflammatory mediators. We aimed to evaluate the acute effects of reducing FiO2 on pulmonary inflammation in mechanically ventilated patients without respiratory failure.This study was a prospective, single-center crossover study in a medical/surgical intensive care unit at a university hospital. Hemodynamically stable patients under mechanical ventilation for24 h without severe respiratory failure (PaO2/FiO2250). A basal FiO2 of 0.40 was reduced to 0.21 provided SpO2 remained higher than 90 %. Patients who could not tolerate the reduction in FiO2 to 0.21 were excluded.We screened 40 patients, but only 28 (70 %) tolerated FiO2 0.21. We measured common clinical variables and inflammatory mediators in plasma and in exhaled breath condensate (EBC) at the end of three 4-h periods: (1) basal (FiO2 0.40), (2) after FiO2 reduction to 0.21, and (3) after returning FiO2 0.40. We used one-way ANOVA for repeated measurements with FiO2 as the grouping variable. Median values of inflammatory mediators in EBC showed nonsignificant changes among the three periods: NO2 + NO3 17.1, 14.1 and 11.0 μmol/L (p = 0.2), and 8-isoprostane 4.4, 8.2 and 5.3 pg/ml (p = 0.6) for the three periods, respectively. Plasma levels also showed nonsignificant changes during the period of the study: NO2 + NO3 12.6, 16.3 and 15.0 μmol/L (p = 0.9), TNFα 13.5, 18.0 and 14.5 pg/ml (p = 0.8), IL-4 12.9, 18.7 and 23.9 pg/ml (p = 0.1), IL-6 50.9, 35.1 and 28.3 pg/ml (p = 0.6), and IL-10 15.2, 22.2 and 22.2 pg/ml (p = 0.7) for the three periods, respectively.FiO2 0.40 in mechanically ventilated patients without severe respiratory failure did not increase systemic or pulmonary inflammation.

Background The role and relationship between pro- and anti-inflammatory cytokines represents one of the least studied aspects of the pathogenesis of community-acquired pneumonia (CAP). The aim of the present study was to evaluate pro- and anti-inflammatory cytokines at both local (lung) and systemic (blood) levels and their relationship with the severity of the disease on admission and time for a patient to reach clinical stability during hospitalisation. Methods This was an observational, prospective, cohort study of hospitalised patients with a diagnosis of CAP at the IRCCS Policlinico Hospital, Milan, Italy, between April 2010 and January 2012. Ten pro-inflammatory cytokines (interleukin [IL]-1, IL-1α, IL-1β, IL-2, IL-6, IL-8, tumor necrosis factor [TNF]α and interferon [IFN]γ) and anti-inflammatory cytokines (IL-4 and IL-10) were measured in both serum and exhaled breath condensate within 24 h after hospital admission. Results A total of 74 patients (median age: 76 years; gender: 61 % male) were enrolled. The anti- to pro-inflammatory cytokine ratio was reduced in patients with severe disease on admission and prolonged time to reach clinical stability. This was due to lower levels of anti-inflammatory cytokines in the exhaled breath condensate and higher levels of pro-inflammatory cytokines in serum. Conclusions Dis-regulation between pro- and anti-inflammatory pathways might be a part of the pathogenic mechanisms that lead to severe infection and worse early clinical outcomes in CAP patients. Electronic supplementary material The online version of this article (doi:10.1186/s41479-016-0009-7) contains supplementary material, which is available to authorized users.

Subjective sleep quality refers to perceived ease of falling asleep, staying asleep, and obtaining adequate sleep that leaves one feeling rested. Such perceptions do not necessarily correspond to objective measures of sleep quality provided by polysomnography. Nevertheless, they are the key to diagnosing some sleep disturbances, such as insomnia (1). Insomnia can be treated, and subjective sleep quality improved, by interventions that help people identify and change beliefs and behaviors that interfere with sleep (2). Livingston et al. (3) examined whether responses to such cognitive–behavioral interventions are associated with changes in the expression of genes involved in the regulation of inflammation. Participants were 68 active duty United States military personnel (97% males) seeking sleep evaluations. All had been deployed within the previous 18 months and had current diagnoses of insomnia or insomnia comorbid with obstructive sleep apnea. Probable syndromal depression or posttraumatic stress disorder (PTSD) was present in 47 and 28% of participants, respectively. Participants were assessed before, and immediately after, completing treatment for insomnia (cognitive–behavioral therapy for insomnia) or for comorbid insomnia and obstructive sleep apnea (either sleep education or cognitive–behavioral therapy for insomnia combined with positive airway pressure). Assessments included subjective sleep quality, depression and posttraumatic stress symptoms, and peripheral blood gene expression profiles. After 3 months of treatment, two clusters of participants were identified, those with any improvement in subjective sleep quality (68% of the sample) and those without any improvement (32% of the sample). The former group, compared to the latter, showed decreases in symptoms of depression from pre- to posttreatment. Microarray data identified 217 genes, whose expression was differentially altered in those participants with improved sleep. Consistent with reduced inflammation, downregulated genes included those for key proinflammatory cytokines [interleukin (IL)-1β, IL-6, and TNF-α] and chemokines (CCL3, 4, and 5). Among the upregulated genes were also inflammation/immune response-associated genes, including several toll-like receptors (TLR1, 4, 7, and 8) and cytokine/chemokine receptors (i.e., IFNγR1 and the IL-8R) as well as stress-related genes. Analysis of the gene expression data using ingenuity pathway analysis (IPA) (4) identified six gene networks, including ubiquitin. Insomnia is an important clinical problem in its own right. In addition, it is increasingly recognized as a contributory factor in multiple mental and physical health problems (5–7), including those that arise post-trauma (5). Connections between insomnia and health problems may partially reflect the importance of sleep in regulating adaptive and innate immunity (8). Indeed, disturbances in sleep that include insomnia and poor subjective sleep quality are associated with elevations in systemic inflammation (9). Critically, Livingston and colleagues identified potentially salutary changes in gene expression among trauma-exposed persons who responded favorably to cognitive–behavioral sleep interventions. Their results provoke questions about whether interventions for sleep disturbances might feed-forward to promote better health and protect against the emergence of health problems after trauma exposure. While reduction in the expression of key proinflammatory cytokine/chemokine genes is consistent with reduced inflammation as a potential mechanism, the relevance of changes in the expression of other genes, such as those for immune receptors and stress-related molecules, remains to be further investigated. Several directions for future research are suggested by this preliminary investigation. Regarding the sample, it will be important to test whether results generalize to sleep disturbances that arise in the context of exposure to other traumatic stressors; sleep disturbances in military personnel are determined by myriad factors that may not apply in other contexts (e.g., time zone changes and potential circadian disruption, long and varying work shifts, and health behaviors used to manage these challenges) (10). Similarly, testing whether these results extend to trauma-exposed women is a high priority, given sex and gender differences in multiple aspects of sleep (11). Regarding the intervention, controlled trials will be necessary to determine whether improved subjective sleep quality is due to the intervention per se, as opposed to the passage of time or non-specific factors. A recent randomized controlled trial for later-life insomnia provides evidence for the specific value of cognitive–behavioral interventions, including for salutary changes in gene expression (12). Also, the persistence of the effects over time should be addressed. Regarding the results, because the cognitive–behavioral sleep interventions were associated with improved gene expression profiles in a subset of insomnia patients – those with improved sleep quality after treatment – the next logical step is to identify factors that differentiate treatment responders from non-responders. Also, microarray data of the key genes need to be further validated and more mechanistic studies performed. Finally, the interplay of sleep quality improvements, depression reductions, and gene expression requires attention – what is the order of the causal chain and are reciprocal influences present? Among trauma-exposed persons, sleep disturbances do not always respond to interventions for PTSD. Even when participants no longer meet diagnostic criteria for syndromal PTSD, clinically significant sleep disturbances may persist (13, 14). Similarly, in observational studies, trauma history helps explain clinically significant sleep disturbances, independent of current mental health symptoms (15). Thus, among trauma-exposed persons, sleep problems may not always be by-products of other mental health problems. The results of Livingston et al. (3) raise the intriguing question of whether specifically addressing such sleep problems, in addition to other post-trauma stress reactions, might yield broader health benefits for trauma-exposed persons.

The Wnt/GSK3β signaling pathway was implicated in mood disorders. Beta-catenin is a protein targeted by this signaling axis. We aimed to examine whether there is an abnormality in this signaling axis in major depression.Postmortem brains from 20 depressed and 20 non-depressed subjects were used. In both groups, suicide and non-suicide were included in equal number. Protein levels of β-catenin, tGSK3β and ser(9)-pGSK3β were determined in prefrontal cortex.ANOVA yielded significant variations between groups in β-catenin (F(3,36)=19.5; p0.001) and pGSK3β protein (F(3,36)=14.3; p0.001) and in tGSK3β-to-pGSK3β ratio (F(3,36)=10.9; p0.001). Fisher tests showed decrease in both groups of MDD and MDD with suicide (MDD+S) for β-catenin (p0.001) and pGSK3β levels (p0.001) respectively. The tGSK3β-to-pGSK3β ratio was increased in MDD and MDD+S subjects (p0.001). A negative correlation was observed between β-catenin levels and the activation state of the GSK3β (r2=0.358; p0.005).The sample was small and only a fraction of s(9)-pGSK3β, albeit significant, was used and; the mood state at the time of death was unknown.The study observed a dysregulation of Wnt/GSK3β signaling associated with a lifetime of major depression. The study may have relevance in further development of drugs based on GSK3β inhibition.

Although little is known about the etiology of progressive supranuclear palsy (PSP), genetic and epigenetic factors, oxidative injury and inflammation are thought to contribute to its development and/or progression. Evidence for activated glia involvement in PSP has raised the possibility that neuroinflammation may contribute to its pathogenesis. To investigate the correlation between neuroinflammation and PSP, a comparative study was conducted on the patterns of cytokine expression in different regions of the brains of PSP, Alzheimer's disease (AD) patients and normal controls. Our results show different patterns of cytokine expression in each disease, with the expression of IL-1β transcripts being significantly higher in the substantia nigra of PSP than in AD and controls, while AD brains had significantly higher IL-1β expression in the parietal cortex compared to PSP and controls. In addition, expression of TGFβ was significantly higher in the cortical areas (particularly frontal and parietal lobes) of AD compared to PSP and controls. These results show a disease-specific topographical relationship among the expression of certain cytokines (IL-1β and TGFβ), microglial activation and neurodegenerative changes, suggesting that these cytokines may contribute to the pathologic process. If so, the use of cytokine-inhibitors and/or other anti-inflammatory agents may be able to slow disease progression in PSP.

Tuberculosis (TB) is the worldwide leading cause of death among HIV-infected individuals, accounting for more than half of AIDS-related deaths. A high risk of tuberculosis (TB) has been shown in early stages of the HIV disease, even in the presence of normal CD4+ cell counts. Moreover, the factors that determine protective immunity vs. susceptibility to M. tuberculosis cannot be fully explained by simple changes in IFNγ levels or a shift from Th1 to Th2 cytokines. This work investigated the relationship between cytokine expression profiles in peripheral blood mononuclear cells (PBMC) and susceptibility to M. tuberculosis in ten HIV+ women who went on to develop TB. RNA transcripts for IL-4, IL-4δ2, IL-10, IL-12(p35), IL-13, IL-17A, IFNγ and TNFα were measured by real-time quantitative PCR in unstimulated or TB peptide antigen-stimulated PBMCs from ten HIV+ women with positive tuberculin skin tests (TST) and compared with HIV-seropositive and seronegative women without previous TB and negative TST. Stimulated PBMC cultures showed significantly lower expression of IL-12p35 (p=0.004) and IL-10 (p=0.026) in the HIV+TB+ group six to twelve months before onset of TB compared to HIV+TB− women. Unstimulated PBMC from HIV+TB+ women also had lower expression of Th2 cytokines [IL-4 (p=0.056) and IL-13 (p=0.050)] compared to HIV+TB− women. These results suggest that lower IL-12 production by PBMC in response to TB antigens and lower levels of both Th1 and Th2 cytokines by PBMC correlate with future development of TB in HIV-infected women and may be responsible for their increased susceptibility.

Objective. To describe hemodynamic changes in normal pregnancy and postpartum by means of thoracic electrical bioimpedance (TEB). Methods. Eighteen healthy pregnant women were included in the study. Eight different hemodynamic variables were measured by thoracic electrical bioimpedance, from 12th week of gestation until 6th month of postpartum period. Data along pregnancy and postpartum were analyzed with SAS statistical software to compare the different values, so normality curves are reported. Results. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and peripheral vascular resistances (PVRs) seem to significantly decrease until 24th week of gestation, and then they seem to increase until delivery, recovering normal values gradually during postpartum period. End-diastolic volume (EDV), systolic volume (SV), cardiac output (CO), and ejection fraction (EF) seem to decrease until 48 h after delivery; statistical significance was found. Conclusions. Thoracic electrical bioimpedance may be the most appropriate and accurate technique to measure normal hemodynamic changes during pregnancy and postpartum.

The relationship between psychosocial factors and an increased risk for disease has been related to a heightened pro-inflammatory status reflected in increased circulating levels of pro-inflammatory cytokines and/or C-reactive protein (CRP). Routinely, epidemiological studies rely on measurements of inflammatory markers in serum or plasma, but the use of biological fluids such as saliva or oral mucosal transudate (OMT) may offer potential advantages. This study investigated correlations among plasma CRP and levels of IL-6 and soluble IL-6 receptor (sIL-6R) in plasma, saliva and OMT in a population of middle aged women with histories of past intimate partner violence (IPV). A total of 67 women without existing chronic diseases participated in the study, which included two visits each in which psychological tests were administered, and blood, saliva and OMT samples were collected. Although significantly higher plasma CRP levels were found in past IPV sufferers compared to controls, there were no significant differences in IL-6 or sIL-6R levels in plasma, saliva or OMT between the two groups. There were only relatively modest correlations between IL-6 levels in plasma and those in saliva or OMT and between plasma IL-6 and CRP levels. A significant correlation between IL-6 and sIL-6R levels in both saliva and OMT, but not in plasma, was also detected. No significant correlations were found between levels of IL-6 in saliva or OMT and periodontal health measures. Results indicate that IL-6 and sIL-6R levels in saliva or OMT do not closely reflect those in plasma, and therefore are not a good surrogate for systemic levels.

Background Intensive care unit (ICU) patients often need blood transfusion, but no reliable predictors of transfusion requirements are available at ICU admission. The authors hypothesized that ICU patients with functional iron deficiency may be at higher risk for developing anemia, requiring blood transfusion. Their objective was to determine whether low reticulocyte hemoglobin content (CHr) was associated with transfusion requirements in ICU patients. Methods This is a prospective cohort study in a general ICU. The authors studied 62 patients, after excluding those transfused on or before ICU admission. The authors recorded age, diagnosis, severity score, presence of sepsis, ICU complications, ICU treatments, and transfusion-free interval. Threshold for low CHr was 29 pg. The authors also recorded ICU and hospital outcome. The statistical analysis included Cox proportional hazard function for transfusion. Results Twenty-three patients (37%) presented with low CHr on ICU admission and tended to be sicker and more likely to have sepsis than those with normal CHr. They were also more prone to complications, particularly acute renal failure (39 vs. 13% P = 0.02) and ICU-acquired infection (30 vs. 10% P = 0.04). The overall transfusion rate was 22.6%, being higher in low-CHr patients than in normal-CHr patients (39.1 vs. 12.8%, P = 0.02). After adjusting for severity of illness, age, trauma, and hemoglobin level, low CHr remained significantly associated with transfusion, with a hazard ratio of 3.6 (95% CI, 1.2-10.7; P = 0.02). Median ICU stay was also longer in patients with low CHr (8 vs. 5 days, P = 0.01). Differences in mortality did not reach statistical significance. Conclusion Low CHr is common at ICU admission and is associated with higher transfusion requirements.

Malignant rhabdoid tumors (MRTs) are aggressive childhood neoplasms, occurring mainly in the kidney and brain. We describe 2 unusual cases of extrarenal and noncranial location (liver and soft tissue with dissemination) mimicking hepatoblastoma, neuroblastoma or Ewing sarcoma. Both cases revealed a polyphenotypic profile, combined with cytokeratin, vimentin, and CD99 expression. INI1/BAF-47 showed negative protein nuclear expression in both cases, suggesting a diagnosis of MRT. An extensive immunohistochemical panel was performed to exclude pediatric tumors reminiscent of MRT. The genetic studies failed to detected MYCN amplification, 11q23 deletion, and EWS break-apart positivity. No alterations of 22q integrity were demonstrated with the probes used for the study (N25 Di George/22q11.2, 22qter, and EWS/22q12). We discuss the differential diagnosis in pediatric polyphenotypic tumors (Wilms tumor, neuroblastoma, desmoplastic small round cell tumor, and Ewing sarcoma). Analysis of INI1/BAF-47 expression can offer important clues in the diagnosis of pediatric tumors with rhabdoid phenotype. The integration of clinical, morphologic, immunohistochemical, and genetic data is required to approach a correct diagnosis of pediatric tumor in unusual location with atypical or undifferentiated morphology.

13 páginas, 6 figuras.-- et al., The ATP-dependent protein chaperone heat-shock protein 70 (Hsp70) displays broad anti-aggregation functions and has a critical function in preventing protein misfolding pathologies. According to in vitro and in vivo models of Parkinson's disease (PD), loss of Hsp70 activity is associated with neurodegeneration and the formation of amyloid deposits of α-synuclein (αSyn), which constitute the intraneuronal inclusions in PD patients known as Lewy bodies. Here, we show that Hsp70 depletion can be a direct result of the presence of aggregation-prone polypeptides. We show a nucleotide-dependent interaction between Hsp70 and αSyn, which leads to the aggregation of Hsp70, in the presence of ADP along with αSyn. Such a co-aggregation phenomenon can be prevented in vitro by the co-chaperone Hip (ST13), and the hypothesis that it might do so also in vivo is supported by studies of a Caenorhabditis elegans model of αSyn aggregation. Our findings indicate that a decreased expression of Hip could facilitate depletion of Hsp70 by amyloidogenic polypeptides, impairing chaperone proteostasis and stimulating neurodegeneration., CR and AA held FEBS Long-Term Fellowships. CWB is an EMBO Long-Term Postdoctoral Fellow, ATvdG was the recipient of a Topmaster fellowship of the graduate school GUIDE for Drug Exploration of the University of Groningen. STDH is a recipient of a Human Frontier Science Program Long-termFellowship (LT0798/ 2005) and is supported in part by the National Science Council of the Republic of China, Taiwan(NSC97-2917-1-564-102). JC is recipient of a Human Frontier Young Investigators Award (RGY67/ 2007) and also thanks the BBSRC (9015651/1). CMD and JC acknowledge funding from The Wellcome Trust and The Leverhulme Trust. DP is grateful to The Spanish Ministry of Health (PI05/2056; PI06/1641), The Spanish Ministry of Science and Innovation (SAF2007-29418E) and the PAIDI Program from the Regional Government (BIO323) for funding. EAAN acknowledges ZonMW Research Institute of Diseases in the Elderly and De Nederlandse Hersenstichting for funding.

Alzheimer's disease (AD) is a complex disease, with no definitive biomarkers available that allow clinical diagnosis; this represents a major problem for the advance of efficient drug discovery programs. A successful approach towards the understanding and treatment of AD should take into consideration this complex nature. In this sense, metabolic networks are subject to severe stoichiometric restrictions. Metabolomics amplifies changes both in the proteome and the genome, and represents a more accurate approximation to the phenotype of an organism in health and disease. In this article, we will examine the current rationale for metabolomics in AD, its basic methodology and the available data in animal models and human studies. The discussed topics will highlight the importance of being able to use the metabolomic information in order to understand disease mechanisms from a systems biology perspective as a non-invasive approach to diagnose and grade AD. This could allow the assessment of new therapies during clinical trials, the identification of patients at risk to develop adverse effects during treatment and the final implementation of new tools towards a more personalized medicine., This work was supported by grants from the SpanishMinistry of Health (PI052056; PI061641 to D.P) and the Spanish Ministryof Science (SAF2007–29418-E to D.P). DP's laboratory is part of thenational cooperative research network in multiple sclerosis RETIC-REEM,Spanish Ministry of Health. IB's and DGD's laboratory is part of the nationalcooperative research network in cardiovascular diseases RETIC-RECAVA,Spanish Ministry of Health.

Summary Syncytial giant cell hepatitis (SGCH) among adult human immunodeficiency virus (HIV)–infected patients has been rarely described. Most cases have been reported in subjects coinfected with the hepatitis C virus (HCV), but its prevalence and outcome remain unknown. We performed a retrospective analysis of all cases of SGCH among 332 liver biopsies from HIV-infected patients seen at a tertiary center in Madrid, Spain, between 1984 and March 2004. Two hundred fifty specimens were obtained from HCV-coinfected patients. There were 2 cases of SGCH, leading to an observed overall prevalence of 0.6% (0.8% when considering only HCV-coinfected patients). In addition to histological changes secondary to chronic hepatitis C, the liver cords were replaced by syncytial giant cells with up to 30 nuclei. There was no histological evidence of measles (among paramyxoviruses) or herpes viruses group infections. In patient 1, there was a progressive clinical worsening after a 3-month course of prednisone, leading to liver failure and death. His postmortem liver biopsy showed more abundant giant hepatocytes accompanied with the development of a histologic pattern of severe fibrosing cholestatic hepatitis. The second patient received a prolonged course of pegylated interferon- α -2b and ribavirin with clearance of syncytial giant hepatocytes despite HCV-RNA persistence. SGCH is a rare histological finding among HIV-infected patients with chronic hepatitis C. Specific treatment with pegylated interferon and ribavirin can lead to histological resolution and biochemical improvement, even in the absence of HCV-RNA clearance.

Aims To describe atrial fibrillation (AF) management in member countries of the European Society of Cardiology (ESC) and to verify cardiology practices against guidelines. Methods and results Among 182 hospitals in 35 countries, 5333 ambulant and hospitalized AF patients were enrolled, in 2003 and 2004. AF was primary or secondary diagnosis, and was confirmed on ECG in the preceding 12 months. Clinical type of AF was reported to be first detected in 978, paroxysmal in 1517, persistent in 1167, and permanent in 1547 patients. Concomitant diseases were present in 90% of all patients, causing risk factors for stroke to be also highly prevalent (86%). As many as 69% of patients were symptomatic at the time of the survey; among asymptomatic patients, 54% were previously experienced symptoms. Oral anticoagulation was prescribed in 67 and 49% of eligible and ineligible patients, respectively. A rhythm control strategy was applied in 67% of currently symptomatic patients and in 44% of patients who never experienced symptoms. Conclusion This survey provides a unique snapshot of current AF management in ESC member countries. Discordance between guidelines and practice was found regarding several issues on stroke prevention and antiarrhythmic therapy.

The incidence of alloimmune neonatal neutropenia combined with neonatal alloimmune thrombocytopenia is very low. We report a case of a neonate who suffered severe neutropenia and thombocytopenia with widespread petechial spots. The presence of alloantibodies in mother's and patient's sera was analyzed by lymphocytotoxicity test, agglutination test, granulocyte indirect immunofluorescence test, platelet immunofluorescence test (PIFT) and solid phase enzyme-linked immunosorbent assay. Human neutrophil antigens (HNA) and human platelet antigen (HPA) genotypes were tested by polymerase chain reaction analyses. The mother's and patient's sera reacted with neutrophils and lymphocytes of the father. PIFT revealed the presence of IgG anti-platelet antibodies in the patient's serum but the test was negative in the maternal serum. Analyses of HNA-1 and HPA genotypes of the family revealed maternal-neonatal HNA-1a and HPA-3b mismatch. The study of the mother's and patient's sera showed the presence of anti HNA1a, HPA-3b and HLA antibodies specific for HLA-A3 and HLA-B38 antigens. These results suggest that the transplacental passage of maternal HNA-1a, HPA-3b and HLA alloantibodies caused neutropenia and thrombocytopenia in this patient.

This study analyzed the effect of phasic tracheal gas insufflation at mid- to end-expiration in patients with severe head trauma and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).A prospective interventional study in a 16-bed intensive care unit.Seven patients with severe head trauma (Glasgow Coma Scale9) and ALI/ARDS.Patients were ventilated in assist/control mode with a ventilatory strategy providing adequate oxygenation (PaO(2)70 mmHg) and normocapnia (PaCO(2) between 35-40 mmHg). Mid to end expiratory tracheal gas insufflation at 8 l/min flow rate was delivered for 90 min while normocapnia was maintained by simultaneous reductions in tidal volume. We measured (hemodynamics, oxygenation, lung mechanics, and cerebral parameters) in basal situation and during and after tracheal insufflation.Tracheal gas insufflation allowed a significant decrease in tidal volume from 9.1 to 7.2 ml/kg, with associated reduction in driving pressure (plateau pressure minus positive end-expiratory pressure, PEEP) from 18.1 to 13.2 cm H(2)O. Total PEEP increased from 9.3 to 12.7 cm H(2)O due to the generation of lung hyperinflation. Oxygenation improved slightly during tracheal gas insufflation, and this improvement remained after stopping tracheal insufflation. No changes in hemodynamic or cerebral parameters were observed during the study.In patients with severe head trauma and ALI receiving mechanical ventilation, expiratory tracheal gas insufflation allowed the targeted arterial PCO(2) level to be maintained together with a substantial reduction in tidal volume.

Acute respiratory distress syndrome/acute lung injury is characterised by profound hypoxaemia due to a permeability pulmonary oedema. In this setting, recruitment manoeuvres (RMs) can be a useful tool as adjuncts to lung protective ventilatory strategies to prevent cyclic alveolar stress and avoid alveolar collapse. Many experimental and physiological studies have discussed the use of RMs but only a few heterogeneous clinical experiences have demonstrated the beneficial and deleterious effects that can occur using these manoeuvres. Besides, a lot of questions remain to be answered to find the best way to perform optimal RMs. Further experimental and clinical trials are needed to understand the potential beneficial effects of recruitment manoeuvres when using a protective mechanical ventilation strategy. This paper is a general review of experimental works that support application of recruitment manoeuvres emphasising the clinical studies that have been published to date in acute respiratory distress syndrome patients.

Further examination of clinical outcomes and inflammatory response of bacteremic pneumococcal community-acquired pneumonia (CAP) is of great interest to enhance the care of patients with pneumococcal CAP. This is a secondary analysis of the Community Acquired Pneumonia Organization (CAPO) to compare the time to clinical stability (TCS), length of hospital stay (LOS), and in-hospital mortality of hospitalized pneumococcal CAP patients with and without bacteremia. To measure the effect of bacteremia in pneumococcal CAP patients on outcomes, we modeled all-cause in-hospital mortality using a Poisson regression model, and TCS and LOS using Cox proportional hazards models. Adjusted multivariate regression models were also used to predict the probability of occurrence of each of the study outcomes. To investigate the inflammatory response, we measured the plasma levels of pro- and anti-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1rα, IL-6, IL-8, IL-10], inflammatory biomarkers [C-reactive protein (CRP), pro-calcitonin (PCT), and B-type natriuretic peptide (BNP)], and peripheral blood neutrophil responses in 10 patients, 4 bacteremic and 6 non-bacteremic pneumococcal CAP, upon admission and every other day during the first 6 days of hospitalization. Functional data were presented as median and standard error of the median (SEM); due to small number of samples no statistical comparisons were performed between groups. From 833 pneumococcal CAP patients, 394 patients (47 %) were bacteremic. Bacteremic pneumococcal CAP were less likely to reach TCS with an adjusted hazard ratio (AHR) of 0.82 (95 % CI 0.69–0.97; p = 0.02) and had higher in-hospital mortality with an AHR of 1.63 (95 % CI 1.06–2.50, p = 0.026). Bacteremic pneumococcal CAP patients had a longer LOS than non-bacteremic pneumococcal CAP (p

The role of host response-related factors in the fast progression of liver disease in individuals co-infected with HIV and HCV viruses remains poorly understood. This study compared patterns of cytokines, caspase-1 activation, endotoxin exposure in plasma as well as interferon signaling in peripheral blood mononuclear cells from HIV/HCV co-infected (HIV(+)/HCV(+)), HCV mono-infected (HIV(-)/HCV(+)), HIV mono-infected (HIV(+)/HCV(-)) female patients and HIV- and HCV-uninfected women (HIV(-)/HCV(-)) who had enrolled in the Women's Interagency HIV Study (WIHS). HIV(+)/HCV(+) women had higher plasma levels of pro-inflammatory cytokines as well as caspase-1 compared with other groups. Both HIV(+)/HCV(+) and HIV(+)/HCV(-) women had significantly higher sCD14 levels compared with other groups. Peripheral blood mononuclear cells from HCV mono-infected patients had reduced levels of phosphorylation of STAT1 compared with other groups as well as lower basal levels of expression of the IFN-stimulated genes, OAS1, ISG15, and USP18 (UBP43). Basal expression of USP18, a functional antagonist of ISG15, as well as USP18/ISG15 ratios were increased in the HIV(+)/HCV(+) group compared with HIV(-)/HCV(+) and HIV(+)/HCV(-) groups. A more pronounced systemic inflammatory profile as well as increased expression ratios of USP18 to ISG15 may contribute to the more rapid progression of liver disease in HIV(+)/HCV(+) individuals.

Measles virus circulates endemically in African and Asian large urban populations, causing outbreaks worldwide in populations with up-to-95% immune protection. We studied the natural genetic variability of genotype B3.1 in a population with 95% vaccine coverage throughout an imported six month measles outbreak. From first pass viral isolates of 47 patients we performed direct sequencing of genomic cDNA. Whilst no variation from index case sequence occurred in the Nucleocapsid gene hyper-variable carboxy end, in the Hemagglutinin gene, main target for neutralizing antibodies, we observed gradual nucleotide divergence from index case along the outbreak (0% to 0.380%, average 0.138%) with the emergence of transient and persistent non-synonymous and synonymous mutations. Little or no variation was observed between the index and last outbreak cases in Phosphoprotein, Nucleocapsid, Matrix and Fusion genes. Most of the H non-synonymous mutations were mapped on the protein surface near antigenic and receptors binding sites. We estimated a MV-Hemagglutinin nucleotide substitution rate of 7.28 × 10-6 substitutions/site/day by a Bayesian phylogenetic analysis. The dN/dS analysis did not suggest significant immune or other selective pressures on the H gene during the outbreak. These results emphasize the usefulness of MV-H sequence analysis in measles epidemiological surveillance and elimination programs, and in detection of potentially emergence of measles virus neutralization-resistant mutants.