Human CAP cells represent a novel source for functional, miRNA-loaded exosome production.

Exosomes represent a promising delivery tool for nucleic acid-based pharmaceuticals. They are highly suitable for transporting therapeutic miRNAs to tumor cells, due to their natural membrane components. Further, exosomes are capable of effectively protecting nucleic acids against ribonucleases and enable the delivery of their content through cell membranes. However, no suitable production host for miRNA containing exosomes of non-tumorigenic origin has yet been identified. In this study we engineered an immortalised human amniocyte cell line (CAP® cells), whose exosomes were enriched and characterised. The cell line modifications not only enabled the production of GFP-labelled but also pro-apoptotic miRNA containing exosomes without negative influence on host cell growth. Furthermore, we demonstrated that pro-apoptotic miRNA containing CAP exosomes are taken up by ovarian cancer cells. Strikingly, delivery of functional exosomal miRNA led to downregulation of several reported target genes in the treated tumor cells. In summary, we revealed CAP cells of non-tumorigenic origin as a novel and efficient exosome production host with the potential to produce functional miRNA-loaded exosomes.

Adherence to a procalcitonin-guided antibiotic treatment protocol in patients with severe sepsis and septic shock.

BACKGROUND: In randomised controlled trials, procalcitonin (PCT)-guided antibiotic treatment has been proven to significantly reduce length of antibiotic therapy in intensive care unit (ICU) patients. However, concern was raised on low protocol adherence and high rates of overruling, and thus the value of PCT-guided treatment in real clinical life outside study conditions remains unclear. In this study, adherence to a PCT protocol to guide antibiotic treatment in patients with severe sepsis and septic shock was analysed. METHODS: From 2012 to 2014, surgical ICU patients with severe sepsis or septic shock were retrospectively screened for PCT measurement series appropriate to make treatment decisions on antibiotic therapy. We compared (1) patients with appropriate PCT measurement series to patients without appropriate series; (2) patients who reached the antibiotic stopping advice threshold (PCT < 0.5 ng/mL and/or decrease to 10% of peak level) to patients who did not reach a stopping advice threshold; and (3) patients who were treated adherently to the PCT protocol to non-adherently treated patients. The groups were compared in terms of antibiotic treatment duration, PCT kinetics, and other clinical outcomes. RESULTS: Of 81 patients with severe sepsis or septic shock, 14 were excluded due to treatment restriction or short course in the ICU. The final analysis was performed on 67 patients. Forty-two patients (62.7%) had appropriate PCT measurement series. In patients with appropriate PCT series, median initial PCT (p = 0.001) and peak PCT levels (p < 0.001) were significantly higher compared to those with non-appropriate series. In 26 patients with appropriate series, PCT levels reached an antibiotic stopping advice. In 8 of 26 patients with stopping advice, antibiotics were discontinued adherently to the PCT protocol (30.8%). Patients with adherently discontinued antibiotics had a shorter antibiotic treatment (7d [IQR 6-9] vs. 12d [IQR 9-16]; p = 0.002). No differences were seen in terms of other clinical outcomes. CONCLUSION: In patients with severe sepsis and septic shock, procalcitonin testing was irregular and adherence to a local PCT protocol was low in real clinical life. However, adherently treated patients had a shorter duration of antibiotic treatment without negative clinical outcomes. Procalcitonin peak values and kinetics had a clear impact on the regularity of PCT testing.

The Randomized Controlled STRAWINSKI Trial: Procalcitonin-Guided Antibiotic Therapy after Stroke.

BACKGROUND: Pneumonia is among the most common acute complications after stroke and is associated with poor long-term outcome. Biomarkers may help identifying stroke patients at high risk for developing stroke-associated pneumonia (SAP) and to guide early treatment. AIMS: This trial investigated whether procalcitonin (PCT) ultrasensitive (PCTus)-guided antibiotic treatment of SAP can improve functional outcome after stroke. METHODS: In this international, multicenter, randomized, controlled clinical trial with blinded assessment of outcomes, patients with severe ischemic stroke in the middle cerebral artery territory were randomly assigned within 40 h after symptom onset to PCTus-based antibiotic therapy guidance in addition to stroke unit care or standard stroke unit care alone. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale (mRS) and dichotomized as acceptable (≤4) or unacceptable (≥5). Secondary endpoints included usage of antibiotics, infection rates, days of fever, and mortality. The trial was registered with http://ClinicalTrials.gov (Identifier NCT01264549). RESULTS: In the intention-to-treat-analysis based on 227 patients (112 in PCT and 115 in control group), 197 patients completed the 3-month follow-up. Adherence to PCT guidance was 65%. PCT-guided therapy did not improve functional outcome as measured by mRS (odds ratio 0.79; 95% confidence interval 0.45-1.35, p = 0.47). Pneumonia rate and mortality were similar in both groups. Days with fever tended to be lower (p = 0.055), whereas total number of days treated with antibiotics were higher (p = 0.004) in PCT compared to control group. A post hoc analysis including all PCT values in the intention-to-treat population demonstrated a significant increase on the first day of infection in patients with pneumonia and sepsis compared to patients with urinary tract infections or without infections (p < 0.0001). CONCLUSION: PCTus-guided antibiotic therapy did not improve functional outcome at 3 months after severe ischemic stroke. PCT is a promising biomarker for early detection of pneumonia and sepsis in acute stroke patients.

The Combination of Biomarkers for Prognostication of Long-Term Outcome in Patients Treated with Mild Hypothermia After Out-of-Hospital Cardiac Arrest-A Pilot Study.

To explore if the brain biomarker neuron-specific enolase (NSE) in combination with a biomarker for stress; CT-proAVP (copeptin), oxidation; peroxiredoxin 4 (Prx4), inflammation; procalcitonin (PCT), or with biomarkers from the heart; midregional proatrial natriuretic peptide (MR-proANP), or troponin T (TnT) can improve the prognostic accuracy of long-term outcome after out-of-hospital cardiac arrest (OHCA). Serum samples from cardiac arrest patients, treated at 33°C for 24 hours, were collected serially at 12, 24, and 48 hours after cardiac arrest. The concentration of the investigated biomarkers was measured using stored samples, and long-term outcome was evaluated by the cerebral performance category (CPC) at 6 months. Poor outcome was defined as CPC 3-5. Sixty-two patients with OHCA of presumed cardiac cause were included. NSE had best prognostic accuracy for poor outcome at 48 hours with a receiver operating characteristic area under curve (AUC) of 0.94 (95% confidence interval [CI] 0.87-1). The combination of NSE with TnT, both at 48 hours, increased the AUC to 0.98 (95% CI 0.95-1, likelihood ratio [LR] test p-value 0.07, net reclassification index [NRI] <0.001); NSE and MR-proANP, both at 12 hours, yielded an AUC of 0.91 (95% CI 0.80-1, LR test p-value 0.0014, NRI p-value 0.003); NSE at 48 hours with MR-proANP at 12 hours yielded an AUC of 0.97 (95% CI 0.92-1, LR test p-value 0.055, NRI p-value 0.04). This pilot study suggests that a combination of biomarkers with NSE could be beneficial for improving early prognostication of long-term outcome following OHCA.

Adrenomedullin for Risk Stratification of Emergency Patients With Nonspecific Complaints: An Interventional Multicenter Pilot Study.

Patients with nonspecific complaints (NSC) presenting to the emergency department (ED) are at risk of life-threatening conditions. New stress biomarkers such as the midregional portion of adrenomedullin (MR-proADM) promise to support decision-making. This study tested the following hypotheses: biomarker-assisted disposition of patients with NSC will not increase mortality. Second, discharge from the ED will increase if clinical risk assessment is combined with low MR-proADM levels. Third, inappropriate disposition to a lower level of care will decrease, if clinical assessment is combined with high MR-proADM levels, and fourth that this algorithm is feasible in the ED setting. Prospective, multicenter, randomized, controlled interventional feasibility study with a 30-day follow-up, including patients with NSC. Patients were randomly assigned to either the standard group (decision-making solely based on clinical assessment) or the Novum group (biomarker-assisted). Regarding disposition, patients were assigned to 1 of 3 risk classes: high-risk (admission to hospital), intermediate risk (community geriatric hospital), and low-risk patients (discharge). In the Novum group, in addition to clinical risk assessment, the information of the MR-proADM level was used. Unless there were overruling criteria, patients were transferred or discharged according to the risk assessment. Primary endpoint was 30-day mortality. Secondary endpoints were comparisons of patient disposition and related mortality rates, ED, and hospital length of stay and readmission. The final study cohort consisted of 398 patients (210 in the Standard group and 188 in the Novum group). Overruling, that is, disposition not according to the result of the proposed algorithm occurred in 51 cases. Baseline characteristics between Standard and Novum groups were similar. The mortality rate in the Novum group was 4.3%, as compared to the Standard group mortality of 6.2%, which was not significantly different (intention-to treat analysis). This was confirmed by the perprotocol analysis as well as by sensitivity analysis. For the secondary endpoints, no significant differences were detected. Biomarker-assisted disposition is safe in patients with NSC. Discharge rates did not increase. Feasibility could only partly be shown due to an unexpectedly high overruling rate. Inappropriate disposition to lower levels of care did not change. ClinicalTrials. gov Identifier: NCT00920491.

MR-proADM Predicts Exercise Capacity and Survival Superior to Other Biomarkers in PH.

PURPOSE: Besides the established biomarker NT-proBNP, the new cardiovascular biomarkers MR-proANP, MR-proADM, Copeptin, and CT-proET-1 are promising to evaluate hemodynamics, exercise parameters, and prognosis in patients with pulmonary hypertension (PH). METHODS: 125 consecutive patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were prospectively enrolled at five German PH centers. Blood samples were taken during right heart catheterization. The primary study endpoint was the correlation between biomarkers and hemodynamic and exercise parameters. As secondary endpoint, prediction of 1-year mortality was evaluated. RESULTS: MR-proADM showed the strongest correlations with 6MWD and VO2peak, whereas NT-proBNP showed the strongest correlations with PVR, PAPm, and CI. In multivariate analysis, only MR-proADM was independently associated with exercise variables, whereas only NT-proBNP independently predicted hemodynamic parameters. All biomarkers were associated with 1-year survival, with MR-proADM showing the highest C index of 0.78. In multivariate analysis, MR-proADM predicted survival independent of age, 6-MWD, CI, RAP, and NT-proBNP. The cut-off of 1.08 nmol/l provided a sensitivity of 83 % and specificity of 66 %. CONCLUSIONS: Different biomarkers reflect distinctive disease aspects in PH. NT-proBNP best predicts hemodynamic impairment while MR-proADM strongly correlates with exercise capacity. Additionally, MR-proADM represents a promising new marker to evaluate prognosis in patients with PAH and CTEPH. Multi-marker strategies should further be evaluated.

Copeptin Levels in Patients With Acute Ischemic Stroke and Stroke Mimics.

BACKGROUND AND PURPOSE: Copeptin levels are increased in patients diagnosed with stroke and other vascular diseases. Copeptin elevation is associated with adverse outcome, predicts re-events in patients with transient ischemic attack and is used in ruling-out acute myocardial infarction. We evaluated whether copeptin can also be used as a diagnostic marker in the prehospital stroke setting. METHODS: We prospectively examined patients with suspected stroke on the Stroke Emergency Mobile-an ambulance that is equipped with computed tomography and point-of-care laboratory. A blood sample was taken from patients immediately after arrival. We analyzed copeptin levels in patients with final hospital-based diagnosis of stroke or stroke mimics as well as in vascular or nonvascular patients. In addition, we examined the associations of symptom onset with copeptin levels and the prognostic value of copeptin in patients with stroke. RESULTS: Blood samples of 561 patients were analyzed. No significant differences were seen neither between cerebrovascular (n=383) and other neurological (stroke mimic; n=90) patients (P=0.15) nor between vascular (n=391) and nonvascular patients (n=170; P=0.57). We could not detect a relationship between copeptin levels and time from onset to blood draw. Three-month survival status was available in 159 patients with ischemic stroke. Copeptin levels in nonsurviving patients (n=8: median [interquartile range], 27.4 [20.2-54.7] pmol/L) were significantly higher than in surviving patients (n=151: median [interquartile range], 11.7 [5.2-30.9] pmol/L; P=0.024). CONCLUSIONS: In the prehospital setting, copeptin is neither appropriate to discriminate between stroke and stroke mimic patients nor between vascular and nonvascular patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382862. The Pre-Hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients study (PHANTOM-S) was registered (NCT01382862). This sub-study was observational and not registered separately, therefore.

Addition of copeptin improves diagnostic performance of point-of-care testing (POCT) for cardiac troponin T in early rule-out of myocardial infarction - A pilot study.

BACKGROUND: Point of care testing (POCT) assays for cardiac troponin (cTn) are hampered by lower analytical sensitivity and thus suboptimal rule-out of myocardial infarction (MI). We investigated, whether additional measurement of copeptin using an ultrasensitive assay improves diagnostic performance of POCT for cTn T compared to a high sensitivity troponin T (hsTnT) assay. METHODS: 131 patients with suspected acute coronary syndrome were prospectively enrolled in our center 08/2010 to 11/2011. In blood samples obtained at presentation, ultrasensitive copeptin (Kryptor, BRAHMS) and two commercially available POCT assays, AQT90 Flex Radiometer (Radiometer) and Cobas h232 POC-System (Cobas), were tested. HsTnT (Cobas E411, Roche) at baseline and after 3 and 6h in the central laboratory served as reference. RESULTS: Copeptin improved rule-out of non-STEMI combined with all tested troponin assays. Addition of copeptin increased sensitivity of Cobas from 67.9% (95% CI: 0.506; 0.852) to 89.3% (95% CI: 0.778; 1.007) and Radiometer from 71.4% (95% CI: 0.547; 0.882) to 85.7% (95% CI: 0.728; 0.987), achieving the sensitivity of hsTnT alone at admission of 85.7% (95% CI: 0.728; 0.987). The area under the curve (AUC) of Radiometer (0.822) was numerically but insignificantly (p=0.17) higher than AUC of Cobas (0.725). Addition of copeptin increased AUC of Radiometer to 0.826 (p=0.96) and AUC of Cobas to 0.814 (p=0.20). CONCLUSIONS: Additional use of ultrasensitive copeptin improves diagnostic performance of conventional sensitive POCT assays overcoming lower sensitivities at the cost of a drop of clinical specificity. When hsTn is temporarily unavailable, copeptin and POCT for cTn may allow initial evaluation at a comparable performance as hsTnT at admission.

Long-term residential exposure to urban air pollution, and repeated measures of systemic blood markers of inflammation and coagulation.

BACKGROUND: In several studies, exposure to fine particulate matter (PM) has been associated with inflammation, with inconsistent results. We used repeated measurements to examine the association of long-term fine and ultrafine particle exposure with several blood markers of inflammation and coagulation. METHODS: We used baseline (2000-2003) and follow-up (2006-2008) data from the Heinz Nixdorf Recall Study, a German population-based prospective cohort of 4814 participants. A chemistry transport model was applied to model daily surface concentrations of PM air pollutants (PM10, PM2.5) and particle number on a grid of 1 km(2). Applying mixed regression models, we analysed associations of long-term (mean of 365 days prior to blood draw) particle exposure at each participant's residence with the level of high-sensitivity C reactive protein (hs-CRP), fibrinogen, platelet and white cell count (WCC), adjusting for short-term PM exposure (moving averages of 1-7 days), personal characteristics, season, ambient temperature (1-5 days), ozone and time trend. RESULTS: We analysed 6488 observations: 3275 participants with baseline data and 3213 with follow-up data. An increase of 2.4 µg/m(3) in long-term PM2.5 was associated with an adjusted increase of 5.4% (95% CI 0.6% to 10.5%) in hs-CRP and of 2.3% (95% CI 1.4% to 3.3%) in the platelet count. Fibrinogen and WCC were not associated with long-term particle exposure. CONCLUSIONS: In this population-based cohort, we found associations of long-term exposure to PM with markers of inflammation (hs-CRP) and coagulation (platelets). This finding supports the hypothesis that inflammatory processes might contribute to chronic effects of air pollution on cardiovascular disease.

Exertional hypoxemia in stable COPD is common and predicted by circulating proadrenomedullin.

BACKGROUND: The prevalence of exertional hypoxemia in unselected patients with COPD is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) upregulation through the hypoxia-inducible factor-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD. METHODS: A total of 1,233 6-min walk tests and circulating proadrenomedullin (proADM) levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed up for 2 years were concomitantly analyzed. RESULTS: The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multistate model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related quality of life, higher severe exacerbation, and death annual rates. In the logistic linear and conditional Cox regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (P < .001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation rate did not influence results. Relative to using FEV1% predicted alone, adding proADM resulted in a significant improvement of the predictive properties (P = .018). Based on the suggested nonlinear nomogram, patients with moderate COPD (FEV1% predicted = 50%) but high proADM levels (> 2 nmol/L) presented increased risk (> 30%) for exertional desaturation. CONCLUSIONS: Exertional desaturation is common and associated with poorer clinical outcomes in COPD. ADM improves prediction of exertional desaturation as compared with the use of FEV1% predicted alone. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN99586989; URL: www.controlled-trials.com.

Adrenomedullin refines mortality prediction by the BODE index in COPD: the "BODE-A" index.

The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro-adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p<0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi-squared 13.0, p<0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable.

Stress markers predict mortality in patients with nonspecific complaints presenting to the emergency department and may be a useful risk stratification tool to support disposition planning.

OBJECTIVES: To the authors' knowledge, no prospectively validated, biomarker-based risk stratification tools exist for elderly patients presenting to the emergency department (ED) with nonspecific complaints (NSCs), such as generalized weakness, despite the fact that an acute serious disease often underlies nonspecific disease presentation. The primary purpose for this study was to validate the retrospectively derived model for outcome prediction using copeptin and peroxiredoxin 4 (Prx4), in a different group of patients, in a prospective fashion, in a multicenter setting. The secondary goals were to evaluate the potential contribution of the midregional portion of the precursor of adrenomedullin (MR-proADM) for outcome prediction and to investigate whether disposition decisions show promise for potential improvement by using biomarker levels in addition to a clinical assessment. METHODS: The Basel Nonspecific Complaints (BANC) study is a delayed-type cross-sectional diagnostic study, carried out in three EDs in Switzerland, with a prospective 30-day follow-up. Patients presenting to the ED with NSCs, as defined previously, were included if their vital signs were within predefined limits. Measurement of biomarkers was performed in serum samples with sandwich immunoluminometric assays. To examine the disposition process, the final disposition was compared with a combination of the first clinical disposition decision and the risk assessment, which included the biomarker MR-proADM in a retrospective simulation. Patients were divided into three groups according to MR-proADM concentration, defining three risk classes with three disposition possibilities (admission to tertiary care, transfer to geriatric hospital, discharge). RESULTS: Thirty-three 30-day nonsurvivors were observed from among 504 study patients with NSCs. Biomarker levels were significantly greater in nonsurvivors than survivors (p < 0.0001 for all three biomarkers). Univariate Cox models reveal a C-index of 0.732 for MR-proADM, 0.719 for Prx4, and 0.723 for copeptin. The incremental added value for chi-square obtained via multivariate modeling showed that models inclusive of MR-proADM, copeptin, or Prx4 are superior to and independent of models limited to sex and age. The incrementally added chi-square for MR-proADM, beyond the chi-square of a base model consisting of age and sex, was 29.79 (p < 0.00001). In a multimarker approach, only Prx4 provided additional information to MR-proADM alone (C-index = 0.77). Applying an algorithm combining physicians' first clinical assessment plus biomarker information to derive a modified risk assessment, reassignment would lead to a potential decrease of 48 admissions to acute care, seven additional transfers to geriatric care, and 41 additional discharges (negative likelihood ratio [-LR] = 0.13). Analysis of 30-day mortality reveals that our algorithm is not inferior in terms of safety. CONCLUSIONS: In this study the authors confirm that these new stress biomarkers permit reliable prognostication of adverse outcomes in a heterogeneous group of patients with NSCs. A simulation showed that this prognostic information could be useful to enhance the appropriateness of disposition decisions of ED patients with NSC. The use of biomarkers for risk stratification in this patient group should be evaluated with prospective intervention studies.

Impact of copeptin on diagnosis, risk stratification, and intermediate-term prognosis of acute coronary syndromes.

BACKGROUND: The aim of the current study was to evaluate the diagnostic and intermediate-term prognostic impact of C-terminal portion of provasopressin (copeptin) in combination with troponin I. METHODS: In this prospective single-center study we recruited a total of 230 unselected patients with suspected recent acute coronary syndrome (ACS) presenting consecutively at our chest pain unit. Troponin I and copeptin levels were determined at presentation and after 3-6 h. Follow-up was performed after 180 days. RESULTS: Acute myocardial infarction (AMI) was the final diagnosis in 107 patients (STEMI: 24, NSTEMI: 83). The median copeptin level was significantly higher in patients having AMI than in those without (20.83 vs. 12.2 pmol/L, p < 0.0001). A troponin I level <0.04 ng/mL in combination with copeptin <14 pmol/L at admission ruled out AMI with an negative predictive value (NPV) of 97.3 %. p = 0.0045 for the added value of copeptin to troponin I. Kaplan-Meier analysis showed that copeptin levels above the diagnostic cut-off were associated with an elevated intermediate-term (180 days) mortality (p = 0.019), while no patient with copeptin values below the cut-off died. Univariate Cox regression analysis identified copeptin as strong predictor of intermediate-term mortality (HR 4.28, 95 % CI 1.58-11.6, p = 0.004). The predictive performance for prediction of 180-day mortality was significantly better if copeptin was included (C-index of 0.80) compared with that of troponin alone (C-index 0.78, p = 0.01 for the added value of copeptin to troponin I). CONCLUSIONS: Additional assessment of copeptin allows a rapid and reliable exclusion of AMI and improves diagnostic accuracy in myocardial ischemia. This study showed for the first time that copeptin provides valuable predictive information for risk stratification and intermediate-term outcome in ACS patients.

Therapy with compression stockings in Germany - results from the Bonn Vein Studies.

BACKGROUND: Despite the frequent use of medical compression stockings (MCS), reliable data are lacking on the frequency of MCS use and experience of patients with the treatment. PATIENTS AND METHODS: The Bonn Vein Study included 3,072 participants from the general population aged 18 to 79 years (1,350 men/1,722 women). Between 2007 and 2008 (Bonn Vein Study 2) 1,978 participants from the Bonn Vein Study 1 were reinvestigated. This paper combines the results of both investigations. RESULTS: 14.6% (7.5% men, 20.3% women) reported having previously undergone treatment with compression stockings. A mean of 71.3% reported an improvement in their venous disease as a result of MCS treatment. During the 6.6 years of follow-up (Bonn Vein Study 2), significantly more prescriptions of MCS were given to patients in higher CEAP clinical stages. 12.2% of the population in C2 was treated with MCS as were 19.1% in C3 and 27.0% in C4-C6. Among participants with chronic venous insufficiency (CVI) (skin changes up to venous ulcers), about 60% were not treated by MCS or bandages in the past years. CONCLUSIONS: These results show that MCS is the most common treatment of venous disorders in the German population. At the same time, these figures also demonstrate severely lacking treatment with MCS in CVI.

Procalcitonin after cardiac arrest - an indicator of severity of illness, ischemia-reperfusion injury and outcome.

AIM: To investigate serial serum concentrations of procalcitonin (PCT) and C-reactive protein (CRP) in patients treated with mild hypothermia after cardiac arrest, and to study their association to severe infections, post cardiac arrest syndrome (PCAS) and long-term outcome. METHODS: Serum samples from cardiac arrest patients treated with mild hypothermia were collected serially at admission, 2, 6, 12, 24, 36, 48 and 72 h after cardiac arrest. PCT and CRP concentrations were determined and tested for association with three definitions of infection, two surrogate markers of PCAS (circulation-SOFA and time to return of spontaneous circulation (ROSC)) and cerebral performance category (CPC) at six months. RESULTS: Eighty-four patients were included. PCT displayed an earlier release pattern than CRP with a significant increase within 2h, increasing further at 6h and onwards in patients with poor outcome. CRP increased later and continued to rise during the study period. PCT was strongly associated with circulation-SOFA and time to ROSC, and predicted a poor neurologic outcome with high accuracy (area under the receiver operating characteristic curve of 0.88, 0.86 and 0.87 at 12, 24 and 48 h respectively). No association of PCT or CRP to infection was observed. CONCLUSION: Our results suggest that PCT is released early after resuscitation following cardiac arrest, is associated with markers of PCAS but not with infection, and is an accurate predictor of poor outcome. Validation of these findings in larger studies is warranted.

Long-term urban particulate air pollution, traffic noise, and arterial blood pressure.

BACKGROUND: Recent studies have shown an association of short-term exposure to fine particulate matter (PM) with transient increases in blood pressure (BP), but it is unclear whether long-term exposure has an effect on arterial BP and hypertension. OBJECTIVES: We investigated the cross-sectional association of residential long-term PM exposure with arterial BP and hypertension, taking short-term variations of PM and long-term road traffic noise exposure into account. METHODS: We used baseline data (2000-2003) on 4,291 participants, 45-75 years of age, from the Heinz Nixdorf Recall Study, a population-based prospective cohort in Germany. Urban background exposure to PM with aerodynamic diameter ≤ 2.5 µm (PM(2.5)) and ≤ 10 µm (PM(10)) was assessed with a dispersion and chemistry transport model. We used generalized additive models, adjusting for short-term PM, meteorology, traffic proximity, and individual risk factors. RESULTS: An interquartile increase in PM2.5 (2.4 µg/m(3)) was associated with estimated increases in mean systolic and diastolic BP of 1.4 mmHg [95% confidence interval (CI): 0.5, 2.3] and 0.9 mmHg (95% CI: 0.4, 1.4), respectively. The observed relationship was independent of long-term exposure to road traffic noise and robust to the inclusion of many potential confounders. Residential proximity to high traffic and traffic noise exposure showed a tendency toward higher BP and an elevated prevalence of hypertension. CONCLUSIONS: We found an association of long-term exposure to PM with increased arterial BP in a population-based sample. This finding supports our hypothesis that long-term PM exposure may promote atherosclerosis, with air-pollution-induced increases in BP being one possible biological pathway.

Influence of short-term exposure to ultrafine and fine particles on systemic inflammation.

Daily to monthly variations in fine particulate matter have been linked to systemic inflammatory responses. It has been hypothesized that smaller particles resulting from combustion processes confer higher toxicity. We aim to analyze the association between short-term exposure to ultrafine and fine particles and systemic inflammation. We use baseline data (2000-2003) of the Heinz Nixdorf Recall Study, a population-based cohort study of 4,814 participants in the Ruhr Area in Germany. A chemistry transport model was applied to model daily surface concentrations of particulate air pollutants on a grid of 1 km(2). Exposure included particle number (PN) and particulate matter mass concentration with an aerodynamic diameter < or = 2.5 microm (PM(2.5)) and < or = 10 microm (PM(10)). Generalized additive models were used to explore the relation of air pollutants using single day lags and averaging times of up to 28 days with high-sensitivity C-reactive protein (hs-CRP). We adjusted for meteorology, season, time trend, and personal characteristics. Median hs-CRP level in the 3,999 included participants was 1.5 mg/l. Median daily concentration of PN was 8,414 x 10(4)/ml (IQR 4,580 x 10(4)/ml), of PM(2.5) 14.5 microg/m(3) (IQR 11.5 microg/m(3)) and of PM(10) 18.5 microg/m(3) (IQR 13.9 microg/m(3)). A positive association between PN and hs-CRP could be observed only for single day lags and for averaged PN concentrations with higher estimates for longer averaging times. The highest hs-CRP-increase of 7.1% (95%-CI: 1.9, 12.6%) was found for the 21-day average. These results support the hypothesis that short-term exposure to traffic-related particles might lead to detrimental cardiovascular health effects via an inflammatory mechanism.

Quantification of the heat wave effect on cause-specific mortality in Essen, Germany.

The impact of high temperatures on mortality is well known, but not all deaths that occur during heat waves can be explained by this effect. We evaluated whether an additional mechanism caused by periods of sustained heat without nightly cooling influenced mortality during the European heat wave in 2003 and whether this mechanism is different for varying causes of death. We obtained daily counts of total and cause-specific mortality for Essen, Germany, for the years 2000-2006. We used time-series regression methods to separate a possible additional effect of sustained heat from the temperature effect and included air pollution, influenza epidemics, long-term and seasonal trends, days of week and bank holidays as covariates. The maximum daily relative risk of all-cause mortality during the heat wave was 1.28 (95% CI 1.06-1.53). The maximum relative risks of cardiovascular and neoplastic mortality were 1.25 (95% CI 0.95-1.65) and 1.35 (95% CI 1.00-1.82), respectively. The effect on respiratory mortality was delayed; the maximum relative risk was 1.66 (95% CI 1.19-2.23) 6 days after the heat wave. We found that periods with sustained heat especially affected respiratory mortality, whereas for cardiovascular and neoplastic mortality no distinct influence could be shown.

Increased cause-specific mortality associated with 2003 heat wave in Essen, Germany.

During the 2003 heat wave an increase in mortality was observed in several European countries. Evidence suggests that the heat wave effect on mortality varies based upon underlying disease. In this study we examined the effects of the 2003 heat wave on all-cause and cause-specific mortality (neoplasms, cardiovascular and respiratory diseases) in a large west German city. Daily weather data for Essen was obtained from the German meteorological service. Death certificates for all deaths in Essen from 2002 to 2003 were coded according to the World Health Organization (WHO) guidelines. Mean numbers of daily deaths during and after the heat wave were compared with the average mortality in summer months (reference period). Poisson generalized additive models, adjusted for weekday and season, were fitted for overall and cause-specific mortality for the entire study period. During the 2003 heat wave (August 6-12), daily mortality increased by 15% (neoplasms), 30% (cardiovascular), and 61% (respiratory), with a decrease in the week after the heat wave of 17% for neoplasms and a sustained rise for respiratory mortality (77%). Regression analysis showed an association between heat and overall mortality in 2003 and greatest associations for respiratory mortality. Even the comparatively short heat wave in Essen in the year 2003 was associated with a rise in overall and cause-specific mortality. Different mechanisms appear to influence cause-specific mortality, with strongest associations for respiratory mortality. Harvesting might play a role in mortality due to neoplasms.