Predictors of the first cardiovascular event in patients with systemic lupus erythematosus - a prospective cohort study

Systemic Lupus Erythematosus (SLE) is an autoimmune, inflammatory disease that mainly affects women. The prognosis of SLE has improved dramatically, but mortality rates are still higher than in the general population. With the improved general prognosis, cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality among SLE patients. Previous studies have demonstrated that the development of atherosclerosis is accelerated in SLE, and have identified a set of traditional and nontraditional risk factors that characterize SLE patients with CVD. Nevertheless, many unsolved issues with respect to SLE related CVD remain. The general aim of this thesis was to investigate risk factors for manifest CVD and for cardiovascular mortality (CVM) in SLE, with special focus on traditional risk factors, lupus phenotype, inflammatory and endothelial biomarkers, autoantibodies and genetic predisposition. In the first paper, we prospectively studied traditional and non-traditional risk factors for the development of the first cardiovascular event (CVE) in 182 SLE patients with a follow-up time of 8 years. 24(13%) patients had a first event. We demonstrated that of the traditional risk factors, only age and smoking predicted the first CVE. Additionally, antiphospholipid antibodies (aPL), endothelial biomarkers, represented by soluble vascular cell adhesion molecule 1(sVCAM-1), and absence of thrombocytopenia were independent predictors of CVE. Thus, activation of the endothelium and the coagulation system are important features in SLE-related CVD and the importance to advocate smoking cessation among SLE patients is underscored In the second paper, we prospectively investigated causes of mortality and risk factors for overall mortality and CVM in a cohort of 208 SLE patients, with a follow-up time of 12 years. We also evaluated Systematic coronary risk evaluation (SCORE, tool for evaluating the 10 year risk for cardiovascular death in the age span 40-65 years, based on traditional risk factors) in this population. Cystatin C, a sensitive measure of renal function, in addition to traditional and non-traditional risk factors, were evaluated as risk factors. 42 patients died, 48 % of which were due to CVM. Age, previous arterial events and high cystatin C levels were the strongest predictors for overall mortality and for CVM. After adjusting for these three variables, smoking, sVCAM-1 and high sensitiviy C-reactive protein (hsCRP) predicted CVM. SCORE estimated 4 but we observed 9 cases of CVM, a non-significant difference. We conclude that except for smoking, traditional risk factors are less important than cystatin C, endothelial and inflammatory biomarkers as predictors of CVM in SLE patients. In the third paper, we investigated whether a risk allele for SLE in the signal transducer and activator of transcription factor 4 gene (STAT4) was associated with vascular events or presence of antiphospholipid antibodies (aPL). A total of 578 unrelated SLE patients (424 from mid-Sweden and 154 from southern-Sweden) were included in a cross-sectional design. Occurrence of previous cardiovascular events and aPL were tabulated. Matched controls (N=651) were genotyped as a comparison. The results demonstrate that the STAT4 risk allele was associated with ischemic cerebrovascular disease (ICVD), with a dose-dependent relationship between ICVD and number of risk alleles. The risk allele was furthermore associated with the presence of two or more aPLs, also in a dose-dependent manner. The association remained after adjustment for known traditional risk factors. We conclude that patients with the STAT4 risk allele have an increased risk of ICVD. Our results imply that genetic predisposition is an important risk factor for ICVD in SLE patients, and that aPL may be one underlying mechanism. In the fourth paper, we evaluated the potential association between smoking and aPL. 367 SLE patients were investigated in a cross-sectional study. Occurrence of aPL (anticardiolipin (aCL) IgG and IgM, anti-β2 glycoprotein-1 IgG (aβ2GP1 IgG), lupus anticoagulant (LAC)) and smoking habits (never, ever, former, current) were tabulated. Never smoking was used as reference in all calculations. In multivariable models, adjusted for age, sex and age at disease onset, aCL and aβ2GP1 of the IgG isotype and LAC were associated with ever smoking, this association seemed to be driven mainly by the former smoking group. Our results demonstrate that smoking is associated with pro-thrombotic aPL in SLE patients, though we can not from this study draw firm conclusions about the temporal relationship between exposure to smoking and occurrence of aPL. Further studies are warranted to investigate the mechanisms behind these observations. In prospective studies we have demonstrated that in particular smoking, systemic inflammation, endothelial activation and aPL are major risk factors for SLE related CVD and CVM. Furthermore, genetic predisposition, in our studies represented by a STAT4 SLE risk allele, contributes to the high risk of ICVD and to the occurrence of aPL, a possible underlying pathogenic mechanism. Finally we demonstrate that smoking, known to have unfavorable effects on the immune system and to significantly increase cardiovascular risk in SLE patients, is also associated with pro-thrombotic aPL in patients with SLE. Thus in SLE smoking stands out as the most important of the traditional risk factors with potential influence also on lupus related risk factors such as aPL

Rationale for a Swedish cohort consortium

We herein outline the rationale for a Swedish cohort consortium, aiming to facilitate greater use of Swedish cohorts for world-class research. Coordination of all Swedish prospective population-based cohorts in a common infrastructure would enable more precise research findings and facilitate research on rare exposures and outcomes, leading to better utilization of study participants' data, better return of funders' investments, and higher benefit to patients and populations. We motivate the proposed infrastructure partly by lessons learned from a pilot study encompassing data from 21 cohorts. We envisage a standing Swedish cohort consortium that would drive development of epidemiological research methods and strengthen the Swedish as well as international epidemiological competence, community, and competitiveness.Peer reviewe

Secondary insults following traumatic brain injury enhance complement activation in the human brain and release of the tissue damage marker S100B

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.OBJECT: Complement activation has been suggested to play a role in the development of secondary injuries following traumatic brain injury (TBI). The present study was initiated in order to analyze complement activation in relation to the primary brain injury and to secondary insults, frequently occurring following TBI. METHODS: Twenty patients suffering from severe TBI (Glasgow coma score ≤ 8) were included in the study. The "membrane attack complex," C5b9, which is the cytolytic end product of the complement system was analyzed in cerebrospinal fluid (CSF). The degree of brain tissue damage was assessed using the release of S100B and neuron-specific enolase (NSE) to the CSF and blood. The blood-brain barrier was assessed using the CSF/serum quotient of albumin (Q (A)). RESULTS: Following impact, initial peaks (0-48 h) of C5b9, S100B, and NSE with a concomitant loss of integrity of the blood-brain barrier were observed. Secondary insults at the intensive care unit were monitored. Severe secondary insults were paralleled by a more pronounced complement activation (C5b9 in CSF) as well as increased levels of S100B (measured in CSF), but not with NSE. CONCLUSION: This human study indicates that complement activation in the brain is triggered not only by the impact of trauma per se but also by the amount of secondary insults that frequently occur at the scene of accident as well as during treatment in the neurointensive care unit. Complement activation and in particular the end product C5b9 may in turn contribute to additional secondary brain injuries by its membrane destructive properties

Temperature and Resource Availability May Interactively Affect Over-Wintering Success of Juvenile Fish in a Changing Climate

The predicted global warming may affect freshwater systems at several organizational levels, from organism to ecosystem. Specifically, in temperate regions, the projected increase of winter temperatures may have important effects on the over-winter biology of a range of organisms and especially for fish and other ectothermic animals. However, temperature effects on organisms may be directed strongly by resource availability. Here, we investigated whether over-winter loss of biomass and lipid content of juvenile roach (Rutilus rutilus) was affected by the physiologically relatively small (2-5°C) changes of winter temperatures predicted by the Intergovernmental Panel on Climate Change (IPCC), under both natural and experimental conditions. This was investigated in combination with the effects of food availability. Finally, we explored the potential for a correlation between lake temperature and resource levels for planktivorous fish, i.e., zooplankton biomass, during five consecutive winters in a south Swedish lake. We show that small increases in temperature (+2°C) affected fish biomass loss in both presence and absence of food, but negatively and positively respectively. Temperature alone explained only a minor part of the variation when food availability was not taken into account. In contrast to other studies, lipid analyses of experimental fish suggest that critical somatic condition rather than critical lipid content determined starvation induced mortality. Our results illustrate the importance of considering not only changes in temperature when predicting organism response to climate change but also food-web interactions, such as resource availability and predation. However, as exemplified by our finding that zooplankton over-winter biomass in the lake was not related to over-winter temperature, this may not be a straightforward task

C-reactive protein in clinical practice with special regard to infectious diseases

A new simple affinity purification methodfor human CRP using Arginine-Sepharose4B was developed with a recovery of >90 %and containing 100 mg/l. However, 32 % of thepatients with bacterial infections had WBC100 mg/l) and viral meningitis ohen hadsigns of extensive tissue involvement.The median duration of illness prior to ad-mission for 97 patients (mean age 69.6years) with community-acquired pneumonia(CAP) was four days (range: <1-25 days). Onadmission 64 % of the patients were hy-poalbuminemic (<37g/1). The serum level ofalbumin at admission did not correlate withthe nutritional measurements, however. a sig-nificant negative correlation was found forserum albumin with the acute phase proteins:CRP, haptoglobin, a-l-antitrypsin and oro-somucoid. These results strongly indicate thatinflammatory reaction is the main causes ofthe low serum albumin level in patients withCAP. The serum level of CRP was high-est atadmission (geometric mean: 154 mg/l) andbegan to decrease from day 3 indicating avery earlier response to the recovery of thepatients. The median normalisation rate ofCRP was 3.3 days. Albumin, transferrin. a-1anti-trypsin, haptoglobin, and orosomucoidwere not useful for evaluation of response totherapy during the hospitalisation phase inpatients with CAP.CRP was evaluated together with other plasmaproteins as prognostic markers in patientswith malignant melanoma (N=643). Theserum levels of the different serum proteinshad independent prognostic value in relationto the clinical stage in multivariate analyses.For each clinical stage the serum valuesbelow respectively above the different cut-offlevels for albumin and transthyretin on onehand and the acute phase proteins CRP,haptoglobin, and orosomucoid on the otherhand significantly influenced the survivalrate and the relative hazard with respect todeath .Key words: CRP, general practice, septi-caemia, endocarditis, influenza, bacterialmeningitis, viral meningitis, community-acquired pneumonia, malignant melanoma,albumin, transferrin, a-1 anti-trypsin, hapto-globin, orosomucoid, transthyretin, iron

Vedskalbaggar och andra insekter i tallskogar i Västmanlands län.

Faunan av främst vedlevande skalbaggar i tjugo områden med äldre tallskog i Västmanlands län undersöktes sommaren 2008. Tio områden studerades mer intensivt med trädfönsterfällor placerade på tallved. Sållning av bark och ved samt observationer av arter direkt eller deras gnagspår användes som en kompletterande metod på dessa tio lokaler, samt som enda metod på de övriga tio lokalerna som undersöktes mer översiktligt. Totalt erhölls ca 11000 individer av drygt 400 arter skalbaggar, samt en rad intressanta barkskinnbaggar, parasitsteklar, ormhalssländor och klokrypare. Av dessa var 27 arter med på aktuell rödlista för år 2005 (hänsynskrävande (NT) 21 arter, sårbara (VU) fem arter och starkt hotade (EN) en art). Ett stort antal s.k. signalarter knutna till främst äldre tallskog med naturskogskaraktär påträffades. Samtliga områden innehöll intressanta arter knutna till tallved. De mest intressanta fynden gjordes i arealmässigt stora områden som Lapplands naturreservat (Skinnskattebergs kommun) och Acksjön (Sala kommun) samt mindre lokaler inom landskap med hög andel äldre tallskog. Det senare gäller särskilt Slogmossen tillsammans med brandfältet på Stora Flyten (Surahammar), och Fermansbo urskog med närliggande Höskovsmossen och Jan-Ols skogen (Surahammar/Sala kommun). Det sedan tidigare undersökta naturreservatet Stora Hoberget (Norberg) inventerades nu översiktligt med ytterligare fynd av tallvedinsekter som följd. På ett brandfält i närheten påträffades slät tallkapuschongbagge Stephanopachys linearis, en art som ingår i åtgärdsprogrammet för brandinsekter i boreal skog. På sydliga lokaler vid Mälaren hittades likaledes en rik vedfauna på tall inom reservaten Ängsö och Strömsholm (Västerås kommun). På Ängsö finns en rad intressanta arter knutna till grov levande tall samt nyligen död tall. Länets sannolikt största population av reliktbock finns på Ängsö i hagmarker med grov tall. Här påträffades även en intressant fauna av vedlevande parasitsteklar, bl.a. en art (Xorides depressus) som är specialiserad på reliktbock. Strömsholm präglas av att ädellövskogens rika vedfauna (främst hålträdsarter) spiller över på tall. Sammantaget uppvisade flera lokaler (bl.a. Lapplands NR) en artrik fauna knuten till lövträd, särskilt gammal vårtbjörk, som är ett naturligt inslag i gamla tallskogar med brandhistorik. Två rödlistade arter som ingår i förslaget till åtgärdsprogram för skalbaggar på nyligen död tall påträffades - linjerad plattstumpbagge Platysoma linearis och tallgångbagge Cerylon impressum. Båda arter påträffades i Lapplands naturreservat. Övriga förekomster för tallgångbagge var Fermansbo urskog, samt för linjerad plattstumpbagge fyra andra lokaler (Ängsö, Stora Flyten, Kråksten och Passboberget). Av arter i förslag till åtgärdsprogram för skalbaggar på äldre tallved påträffades skrovlig flatbagge Calitys scabra på fem lokaler (Fermansbo, Stingsberget, Höskovsmossen, Kråksten och Acksjön). Raggbock Tragosoma depsarium är tidigare rapporterad från länet, men kunde ej påträffas trots fällor och direkt sök efter gnagspår på lämplig tallved på flera lokaler. En del lokaler var dock olämpliga för denna art, så för att fastställa dess status i länet skulle det behövas en riktad studie. Om raggbocken eventuellt finns kvar i länet är dess populationer sannolikt små och i behov av direkta stödåtgärder. Faunan på nydöd tall var mest artrik inom sammanhängande landskap med stor andel äldre tallskog (ofta tack vare stora naturreservat). Brandpåverkan är positivt då det ofta skapar ett successivt döende av tall, vilket är särskilt gynnsamt för flera sällsynta arter. Avgörande tycks dock vara att tillräckligt stora delar av landskapet hålls fria från skogsbruk, som annars ensidigt gynnar vissa mycket allmänna vedinsekter vilket leder till en trivialisering av faunan. Naturvårdsbränningar bör i första hand förläggas till större skyddade områden, eller i anslutning till stora värdekärnor av äldre tall inom den brukade skogen. I Västmanlands län har åtgärder inom Färna ekopark stor betydelse för att bevara tallvedsfaunan tack vare ekoparkens storlek och läge intill flera fina tallområden (Lappland, Stora Flyten och Slogmossen, samt andra lokaler på längre avstånd). Arter på äldre tallved har i flera fall ytterst små populationer (t.ex. tallpraktbagge och skrovlig flatbagge) vilket medför stor risk för utdöende. Dessa arter kräver solexponering och missgynnas av en fortgående naturlig succession mot en allt tätare skog genom uppväxt av yngre träd av olika slag (tall, gran och ibland lövträd). De är framförallt beroende av olika former av ved uppkommen ur långsamt växande träd, vilket gör att det krävs planering och lång tid att öka tätheten av lämplig ved. Det är därför viktigt att i dagsläget bevara sådan ved, och se till att den ej beskuggas. Många av lokalerna är i behov av restaurering för att återskapa eller öka andelen solöppen gles tallskog med exponerad ved. Naturvårdsbränning är en viktig metod, men ibland kan selektiv utglesning (fällning eller ringbarkning) vara ett lämpligare alternativ. Ett annat mål bör vara att gynna lövträden, särskilt vårtbjörk som utgör ett naturligt inslag i tallskogen. Detta kan uppnås bl.a. genom särskilt anpassad naturvårdsbränning.Regionala inventeringsrapporter import från MDP 2015-05</p

Atrophy of the posterior subiculum is associated with memory impairment, Tau- and Aβ pathology in non-demented individuals

Alzheimer's disease (AD) is associated with atrophy of the cornu ammonis (CA) 1 and the subiculum subfield of the hippocampus (HC), and with deficits in episodic memory and spatial orientation. These deficits are mainly associated with the functionality of the posterior HC. We therefore hypothesized that key AD pathologies, i.e., β-amyloid and tau pathology would be particularly associated with the volume of the posterior subiculum in non-demented individuals. In our study we included 302 cognitively normal elderly participants (CN), 183 patients with subjective cognitive decline (SCD) and 171 patients with amnestic mild cognitive impairment (MCI), all of whom underwent 3T magnetic resonance images (MRI). The subicular subfield was segmented using Freesurfer 5.3 and divided into 10 volumetric segments moving from the most posterior (segment 1) to the most anterior part along the axis of the hippocampal head and body (segment 10). Cerebrospinal fluid (CSF) Aβ42 and phosphorylated tau (P-tau) were quantified using ELISA and were used as biomarkers for β-amyloid and tau pathology, respectively. In the total sample, tau-pathology and Aβ-pathology and (measured by elevated P-tau and low Aβ42 levels in CSF) and mild memory dysfunction were mostly associated with the volume changes of the posterior subiculum. Both SCD and MCI patients with elevated P-tau or low Aβ42 levels displayed predominantly posterior subicular atrophy in comparisons to control subjects with normal CSF biomarker levels. Finally, there was no main effect of Aβ42 or P-tau when comparing SCD with abnormal P-tau or Aβ42 with SCD with normal levels of these CSF-biomarkers. However, in the left subiculum there was a significant interaction revealing atrophy in the left posterior but not the anterior subiculum in participants with low Aβ42 levels. The same pattern was observed on the contralateral side in participants with elevated P-tau levels. In conclusion, AD pathologies and mild memory dysfunction are mainly associated with atrophy of the posterior parts of the subicular subfields of the HC in non-demented individuals. In light of these findings we suggest that segmentation of the HC subfields may benefit from considering the volume of the different anterior-posterior subsections of each subfield