Koagulationsfaktor XIII – inte bara ett kongenitalt blödningsproblem

Factor XIII (FXIII) cross-links fibrin monomers to strengthen clots. The congenital severe autosomal type of FXIII deficiency wit

Aerosol formation and emissions from realistic compartment fires

Firefighters are occupationally exposed to a large number of toxic compounds (IARC 2010). The occupational exposure of firefighters has been classified as potentially carcinogenic (class 2B, IARC; (Straif K. et al. 2007)). Poorly quantified emission factors and low understanding of when various aerosol emissions are likely to form during a fire event (initiation, combustion, extinguishing) inhibit efforts to reduce exposure by interventions to the firefighting strategy. The study was designed to evaluate firefighters’ exposure to air pollutants and to allow identification of how aerosol emissions respond to burning conditions and interventions of the firefighting. The study was conducted at the MSB firefighter training facility in Revinge outside Lund, Sweden. Eight small (5x3x2 m) sheds were built to imitate small compartment environments: apartment, bedroom, workshop, etc. These sheds were ignited under realistic fire scenarios (e.g., accident, arson) and later used for training new fire investigators (forensic police). Firefighter students and teachers monitored and extinguished the fires in similar procedures to real fire events. A supervisor monitored the combustion conditions, allowing or restricting fresh-air flow into the fire by opening or closing of the main door.Fire emissions were extracted from the fire through a 10 m (Ø 6 mm) stainless steel pipe, diluted ~1:50 with HEPA and active charcoal filtered air. The diluted emissions were monitored with a battery of aerosol monitoring instruments. Instrumentation included an aerosol mass spectrometer (Aerodyne SP-AMS, Billerica USA), an aethalometer (AE33, Magee Sci. USA), a differential mobility spectrometer (DMS500, Cambustion, UK), CO2 monitor (LI-COR, USA), and a NO/NO2 monitor (2BTech, USA). Complementary background measurements were positioned downwind or sidewind of the fires. With this equipment we collected data with the aim to resolve relationships between combustion conditions and pollution formation during different phases of a fire response. The results showed that total particle mass (PM1) emissions correlated with CO2 emissions and thus fire intensity. The emissions were speciated according to equivalent black carbon (eBC), organic aerosol (OA) and polycyclic aromatic hydrocarbon (PAH) derived from AMS data. When speciated, different particle emissions were found to depend on activities of the firefighting and the supervisor responsible for allowing or restricting fresh air into the combustion environment. Most evidently, we found that restricting the access to O2 by closing the door resulted in a sharp increase of OA and even more pronounced, PAH. PAH increased by several orders of magnitude, suggesting that PAH exposure-risks may increase drastically when fires become under-ventilated. Extinguishing the fire with water quickly decreased all particle emissions. The results described are illustrated in Figure 1.Further analysis involves additional off-line analyses, derivation of emission factors, time-resolved speciated emission analysis and evaluation of relationships between emissions, burning conditions and firefighting strategies

Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD - A longitudinal study

Background Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. Patients and methods This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII: C) and soluble thrombomodulin (s-TM) at 6-8 time points over three months. Results Overall, PC, AT and FVIII: C increased in parallel after engraftment. Significant correlations between PC and FVIII: C (r = 0.64-0.82, p Conclusion The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.Peer reviewe

Factor IX antibodies and tolerance in hemophilia B in the Nordic countries - The impact of F9 variants and complications

Introduction: The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited.The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant.Materials and methods: Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence -immunoassay (xFLI) and an ELISA method were conducted.Results: Seventy-nine PwHB were enrolled. Null variants were seen in 33 (42 %) PwHB and 12 (15 %) had a current or former inhibitor. Eleven (92 %) of the inhibitor patients had experienced allergic manifestations and three (25 %) nephrotic syndrome. Of 10 PwHB with at least one ITI attempt, eight (80 %) were considered tolerant at enrolment. Immunosuppression was included in seven of eight successful or partially successful at-tempts. Five PwHB had at least one ITI failure before a successful or partially successful ITI. No NNA could be identified.Conclusion: A high proportion of severe F9 gene defects among persons with severe HB in the Nordic countries may explain the observed relatively high prevalence of inhibitors. ITI success was independent of the F9 variant and attained despite allergic manifestations and previous ITI failures. Inclusion of immunosuppression tenta-tively enhances the chances of ITI success. No NNA were observed.Peer reviewe

Mice Chronically Fed High-Fat Diet Have Increased Mortality and Disturbed Immune Response in Sepsis

BACKGROUND: Sepsis is a potentially deadly disease that often is caused by gram-positive bacteria, in particular Staphylococcus aureus (S. aureus). As there are few effective therapies for sepsis, increased basic knowledge about factors predisposing is needed. METHODOLOGY/PRINCIPAL FINDINGS: The purpose of this study was to study the effect of Western diet on mortality induced by intravenous S. aureus inoculation and the immune functions before and after bacterial inoculation. Here we show that C57Bl/6 mice on high-fat diet (HFD) for 8 weeks, like genetically obese Ob/Ob mice on low-fat diet (LFD), have increased mortality during S. aureus-induced sepsis compared with LFD-fed C57Bl/6 controls. Bacterial load in the kidneys 5-7 days after inoculation was increased 10-fold in HFD-fed compared with LFD-fed mice. At that time, HFD-fed mice had increased serum levels and fat mRNA expression of the immune suppressing cytokines interleukin-1 receptor antagonist (IL-1Ra) and IL-10 compared with LFD-fed mice. In addition, HFD-fed mice had increased serum levels of the pro-inflammatory IL-1beta. Also, HFD-fed mice with and without infection had increased levels of macrophages in fat. The proportion and function of phagocytosing granulocytes, and the production of reactive oxygen species (ROS) by peritoneal lavage cells were decreased in HFD-fed compared with LFD-fed mice. CONCLUSIONS: Our findings imply that chronic HFD disturb several innate immune functions in mice, and impairs the ability to clear S. aureus and survive sepsis

Relation of Statin Use and Mortality in Community-Dwelling Frail Older Patients With Coronary Artery Disease

Clinical decision-making for statin treatment in older patients with coronary artery disease (CAD) is under debate, particularly in community-dwelling frail patients at high risk of death. In this retrospective observational study on 2,597 community-dwelling patients aged >= 65 years with a previous hospitalization for CAD, we estimated mortality risk assessed with the Multidimensional Prognostic Index (MPI), based on the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA), used to determine accessibility to homecare services/nursing home admission in 2005 to 2013 in the Padua Health District, Veneto, Italy. Participants were categorized as having mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) baseline mortality risk, and propensity score-adjusted hazard ratios (HRs) of 3-year mortality rate were calculated according to statin treatment in these subgroups. Greater MPI-SVaMA scores were associated with lower rates of statin treatment and higher 3-year mortality rate (MPI-SVaMA-1 = 23.4%; MPI-SVaMA-2 = 39.1%; MPI-SVaMA-3 = 76.2%). After adjusting for propensity score quintiles, statin treatment was associated with lower 3-year mortality risk irrespective of MPI-SVaMA group (HRs [95% confidence intervals] 0.45 [0.37 to 0.55], 0.44 [0.36 to 0.53], and 0.28 [0.21 to 0.39] in MPI-SVaMA-1,-2, and-3 groups, respectively [interaction test p = 0.202]). Subgroup analyses showed that statin treatment was also beneficial irrespective of age (HRs [95% confidence intervals] 0.38 [0.27 to 0.53], 0.45 [0.38 to 0.54], and 0.44 [0.37 to 0.54] in 65 to 74, 75 to 84, and Z85 year age groups, respectively [interaction test p = 0.597]). In conclusion, in community-dwelling frail older patients with CAD, statin treatment was significantly associated with reduced 3-year mortality rate irrespective of age and multidimensional impairment, although the frailest patients were less likely to be treated with statins. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer

Introduction We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up. Methods The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS). Results In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours. Conclusions HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status

Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen

ABSTRACT: INTRODUCTION: We previously reported an association between tumor-specific 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) expression and a good prognosis in breast cancer. Here, the predictive value of HMG-CoAR expression in relation to tamoxifen response was examined. METHODS: HMG-CoAR protein and RNA expression was analyzed in a cell line model of tamoxifen resistance using western blotting and PCR. HMG-CoAR mRNA expression was examined in 155 tamoxifen-treated breast tumors obtained from a previously published gene expression study (Cohort I). HMG-CoAR protein expression was examined in 422 stage II premenopausal breast cancer patients, who had previously participated in a randomized control trial comparing 2 years of tamoxifen with no systemic adjuvant treatment (Cohort II). Kaplan-Meier analysis and Cox proportional hazards modeling were used to estimate the risk of recurrence-free survival (RFS) and the effect of HMG-CoAR expression on tamoxifen response. RESULTS: HMG-CoAR protein and RNA expression were decreased in tamoxifen-resistant MCF7-LCC9 cells compared with their tamoxifen-sensitive parental cell line. HMG-CoAR mRNA expression was decreased in tumors that recurred following tamoxifen treatment (P < 0.001) and was an independent predictor of RFS in Cohort I (hazard ratio = 0.63, P = 0.009). In Cohort II, adjuvant tamoxifen increased RFS in HMG-CoAR-positive tumors (P = 0.008). Multivariate Cox regression analysis demonstrated that HMG-CoAR was an independent predictor of improved RFS in Cohort II (hazard ratio = 0.67, P = 0.010), and subset analysis revealed that this was maintained in estrogen receptor (ER)-positive patients (hazard ratio = 0.65, P = 0.029). Multivariate interaction analysis demonstrated a difference in tamoxifen efficacy relative to HMG-CoAR expression (P = 0.05). Analysis of tamoxifen response revealed that patients with ER-positive/HMG-CoAR tumors had a significant response to tamoxifen (P = 0.010) as well as patients with ER-positive or HMG-CoAR-positive tumors (P = 0.035). Stratification according to ER and HMG-CoAR status demonstrated that ER-positive/HMG-CoAR-positive tumors had an improved RFS compared with ER-positive/HMG-CoAR-negative tumors in the treatment arm (P = 0.033); this effect was lost in the control arm (P = 0.138), however, suggesting that HMG-CoAR predicts tamoxifen response. CONCLUSIONS: HMG-CoAR expression is a predictor of response to tamoxifen in both ER-positive and ER-negative disease. Premenopausal patients with tumors that express ER or HMG-CoAR respond to adjuvant tamoxifen