700,000 years of tropical Andean glaciation.

Our understanding of the climatic teleconnections that drove ice-age cycles has been limited by a paucity of well-dated tropical records of glaciation that span several glacial-interglacial intervals. Glacial deposits offer discrete snapshots of glacier extent but cannot provide the continuous records required for detailed interhemispheric comparisons. By contrast, lakes located within glaciated catchments can provide continuous archives of upstream glacial activity, but few such records extend beyond the last glacial cycle. Here a piston core from Lake Junín in the uppermost Amazon basin provides the first, to our knowledge, continuous, independently dated archive of tropical glaciation spanning 700,000 years. We find that tropical glaciers tracked changes in global ice volume and followed a clear approximately 100,000-year periodicity. An enhancement in the extent of tropical Andean glaciers relative to global ice volume occurred between 200,000 and 400,000 years ago, during sustained intervals of regionally elevated hydrologic balance that modified the regular approximately 23,000-year pacing of monsoon-driven precipitation. Millennial-scale variations in the extent of tropical Andean glaciers during the last glacial cycle were driven by variations in regional monsoon strength that were linked to temperature perturbations in Greenland ice cores1; these interhemispheric connections may have existed during previous glacial cycles.

The free plasma amyloid Aß1-42/Aß1-40 ratio predicts conversion to dementia for subjects with mild cognitive impairment with performance equivalent to that of the total plasma Aß1-42/Aß1-40 ratio. The BALTAZAR study.

BACKGROUND AND PURPOSE: Blood-based biomarkers are a non-invasive solution to predict the risk of conversion of mild cognitive impairment (MCI) to dementia. The utility of free plasma amyloid peptides (not bound to plasma proteins and/or cells) as an early indicator of conversion to dementia is still debated, as the results of studies have been contradictory. In this context, we investigated whether plasma levels of the free amyloid peptides Aß1-42 and Aß1-40 and the free plasma Aß1-42/Aß1-40 ratio are associated with the conversion of MCI to dementia, in particular AD, over three years of follow-up in a subgroup of the BALTAZAR cohort. We also compared their predictive value to that of total plasma Aß1-42 and Aß1-40 levels and the total plasma Aß1-42/Aß1-40 ratio. METHODS: The plasma Aß1-42 and Aß1-40 peptide assay was performed using the INNO-BIA kit (Fujirebio Europe). Free amyloid levels (defined by the amyloid fraction directly accessible to antibodies of the assay) were obtained with the undiluted plasma, whereas total amyloid levels were obtained after the dilution of plasma (1/3) with a denaturing buffer. Free and total Aß1-42 and Aß1-40 levels were measured at inclusion for a subgroup of participants (N = 106) with mild cognitive impairment (MCI) from the BALTAZAR study (a large-scale longitudinal multicenter cohort with a three-year follow-up). Associations between conversion and the free/total plasma Aß1-42 and Aß1-40 levels and Aß1-42/Aß1-40 ratio were analyzed using logistic and Cox Proportional Hazards models. Demographic, clinical, cognitive (MMSE, ADL and IADL), APOE, and MRI characteristics (relative hippocampal volume) were compared using non-parametric (Mann-Whitney) or parametric (Student) tests for quantitative variables and Chi-square or Fisher exact tests for qualitative variables. RESULTS: The risk of conversion to dementia was lower for patients in the highest quartile of free plasma Aß1-42/Aß1-40 (≥ 25.8%) than those in the three lower quartiles: hazard ratio = 0.36 (95% confidence interval [0.15-0.87]), after adjustment for age, sex, education, and APOE ε4 (p-value = 0.022). This was comparable to the risk of conversion in the highest quartile of total plasma Aß1-42/Aß1-40: hazard ratio = 0.37 (95% confidence interval [0.16-0.89], p-value = 0.027). However, while patients in the highest quartile of total plasma Aß1-42/Aß1-40 showed higher MMSE scores and a higher hippocampal volume than patients in the three lowest quartiles of total plasma Aß1-42/Aß1-40, as well as normal CSF biomarker levels, the patients in the highest quartile of free plasma Aß1-42/Aß1-40 did not show any significant differences in MMSE scores, hippocampal volume, or CSF biomarker levels relative to the three lowest quartiles of free plasma Aß1-42/Aß1-40. CONCLUSION: The free plasma Aß1-42/Aß1-40 ratio is associated with a risk of conversion from MCI to dementia within three years, with performance comparable to that of the total plasma Aß1-42/Aß1-40 ratio. Threshold levels of the free and total plasma Aß1-42/Aß1-40 ratio could be determined, with a 60% lower risk of conversion for patients above the threshold than those below.

Overview of the blood biomarkers in Alzheimer's disease: Promises and challenges.

The increasing number of people with advanced Alzheimer's disease (AD) represents a significant psychological and financial cost to the world population. Accurate detection of the earliest phase of preclinical AD is of major importance for the success of preventive and therapeutic strategies (Cullen et al., 2021). Advances in analytical techniques have been essential for the development of sensitive, specific and reliable diagnostic tests for AD biomarkers in biological fluids (cerebrospinal fluid and blood). Blood biomarkers hold promising potential for early and minimally invasive detection of AD, but also for differential diagnosis of dementia and for monitoring the course of the disease. The aim of this review is to provide an overview of current blood biomarkers of AD, from tau proteins and amyloid peptides to biomarkers of neuronal degeneration and inflammation, reactive and metabolic factors. We thus discuss the informative value of currently candidate blood biomarkers and their potential to be integrated into clinical practice for the management of AD in the near future.

Keratin 6a mutations lead to impaired mitochondrial quality control.

BACKGROUND: Epidermal differentiation is a multilevel process in which keratinocytes need to lose their organelles, including their mitochondria, by autophagy. Disturbed autophagy leads to thickening of the epidermis as seen in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17. OBJECTIVES: To ask if mitophagy, the selective degradation of mitochondria by autophagy, is disturbed in PC and, if so, at which stage. METHODS: Immortalized keratinocytes derived from patients with PC were used in fluorescence-based and biochemical assays to dissect the different steps of mitophagy. RESULTS: PC keratinocytes accumulated old mitochondria and displayed disturbed clearance of mitochondria after mitochondrial uncoupling. However, early mitophagy steps and autophagosome formation were not affected. We observed that autolysosomes accumulate in PC and are not sufficiently recycled. CONCLUSIONS: We propose an influence of keratins on autolysosomal degradation and recycling. What's already known about this topic? Terminal epidermal differentiation is a multistep process that includes the elimination of cellular components by autophagy. Autophagy-impaired keratinocytes have been shown to result in thickening of epidermal layers. Hyperkeratosis also occurs in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17. What does this study add? Keratins contribute to mitochondrial quality control as well as maintenance of mitochondria-endoplasmic reticulum contact sites. Keratins influence autolysosomal maturation or reformation. What is the translational message? Overaged mitochondria and autolysosomes accumulate in PC. Mutations in keratin 6a lead to severely impaired mitophagy, which might contribute to PC pathogenesis.

Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The prognostic value of serum neurofilament light chain (sNfL), a biomarker of neurodegeneration, compared to other prognostic factors of amyotrophic lateral sclerosis (ALS) at the time of diagnosis, remains unclear. METHODS: Sera from ALS patients were prospectively collected at the first diagnostic visit in our centre. sNfL levels were determined by single molecule array in 207 ALS patients and in 21 healthy controls. The prognostic value of sNfL was compared with that of other known clinical prognostic factors using a Cox regression model and multivariate analysis. RESULTS: Serum neurofilament light chain levels were higher in ALS patients than in controls (P < 0.0001). Seven parameters were predictive of death in ALS: older age, bulbar onset, higher ALS Functional Rating Scale revised (ALSFRS-R) score, greater weight loss, lower maximal inspiratory pressure, forced vital capacity and higher sNfL levels. A Cox regression model showed that sNfL (P < 0.0001), weight loss (P = 0.040) and site at onset (P = 0.048) were independent predictive factors of death. In a sub-cohort restricted to 139 patients with complete spirometry data, sNfL level (P < 0.005) and forced vital capacity (P = 0.022) were independent factors predictive of death. In a subgroup of 142 patients in whom ALSFRS-R score was available at several time points, sNfL levels positively correlated with ALSFRS-R rate of decline (r = 0.571, P < 10-12 ). CONCLUSIONS: Higher sNfL concentration is a strong and independent prognostic factor of death in ALS as early as the time of diagnosis.

Mass poisoning with NPS: 2C-E and Bromo-DragonFly.

BACKGROUND: Reports of intoxications with new psychoactive substances (NPS) mostly involve young people, as they are the main consumers of these types of drugs. This report centers on a case that was unusual due to it being a mass-poisoning event involving middle-aged individuals who had consumed a combination of the two different new psychoactive drugs 2,5-dimethoxy-4-ethylphenethylamine (2C-E) and 1-(8-bromofuro[2,3-f][1]benzofuran-4-yl)-2-propanamine (Bromo-DragonFly, BDF). CASE HISTORY: The mass poisoning of 29 individuals (24-56 years old) resulted in their admission to six different hospitals with severe symptoms of intoxication. All symptoms manifested after consumption of an unknown drug formulation around lunchtime during an esoteric weekend seminar. INVESTIGATION: Urine (n = 11) and blood samples (n = 29), collected from the 29 individuals for police investigation, were analyzed with immunochemical techniques, GC/MS and LC-MS/MS. 2C-E was confirmed in seven urine samples, but not in blood. BDF was confirmed in all urine samples, and in 17 blood samples. The blood samples exhibited BDF concentrations between ca. 0.6 and ca. 2.0 µg/L, while urine concentrations of BDF ranged from ca. 1.6 to 35 µg/L. The concentration of 2C-E in urine was found to be between ca. 1.5 and 183 µg/L. All patients made a complete recovery, although some had required mechanical ventilation. CONCLUSION: The investigation and the presentation of this case illustrates not only mass intoxication with 2C-E and BDF, with corresponding blood and urine concentrations, but also the necessity of collecting urine samples in cases where NPS-consumption is suspected, in order to improve the chances of analytical detection.

Correction to: Mass poisoning with NPS: 2C-E and Bromo-DragonFly.

The original version of this article contains an error. The Author S. Lehmann incorrectly listed as S. Lehman. The correct spelling is presented above. The original article has been corrected.

Achieving short high-quality gate-all-around structures for horizontal nanowire field-effect transistors.

We introduce a fabrication method for gate-all-around nanowire field-effect transistors. Single nanowires were aligned perpendicular to underlying bottom gates using a resist-trench alignment technique. Top gates were then defined aligned to the bottom gates to form gate-all-around structures. This approach overcomes significant limitations in minimal obtainable gate length and gate-length control in previous horizontal wrap-gated nanowire transistors that arise because the gate is defined by wet-etching. In the method presented here gate-length control is limited by the resolution of the electron-beam-lithography process. We demonstrate the versatility of our approach by fabricating a device with an independent bottom gate, top gate, and gate-all-around structure as well as a device with three independent gate-all-around structures with 300, 200, and 150 nm gate length. Our method enables us to achieve subthreshold swings as low as 38 mV dec-1 at 77 K for a 150 nm gate length.

Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage.

BACKGROUND: In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES: This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS: Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS: Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P < 0.001). Histamine, capsaicin and cowhage-induced pruritus, the duration of which was shorter for cowhage than for histamine (13.5 ± 1.4 vs. 8.8 ± 1.2 min, P = 0.005). Different mediators induced sensations of different intensities. Capsaicin produced less itch and physical urge to scratch than histamine (P = 0.001) and cowhage (P < 0.001). However, both capsaicin and cowhage induced more burning than histamine (P = 0.002 and P = 0.04, respectively). Provocation with cowhage caused more intense sensations of pricking than histamine (P = 0.033). CONCLUSION: This study shows that provocation with histamine, capsaicin and cowhage results in itch responses that are different in their duration, the profile of accompanying sensations, and the flare that comes with the itch.

Using Ultrathin Parylene Films as an Organic Gate Insulator in Nanowire Field-Effect Transistors.

We report the development of nanowire field-effect transistors featuring an ultrathin parylene film as a polymer gate insulator. The room temperature, gas-phase deposition of parylene is an attractive alternative to oxide insulators prepared at high temperatures using atomic layer deposition. We discuss our custom-built parylene deposition system, which is designed for reliable and controlled deposition of <100 nm thick parylene films on III-V nanowires standing vertically on a growth substrate or horizontally on a device substrate. The former case gives conformally coated nanowires, which we used to produce functional Ω-gate and gate-all-around structures. These give subthreshold swings as low as 140 mV/dec and on/off ratios exceeding 103 at room temperature. For the gate-all-around structure, we developed a novel fabrication strategy that overcomes some of the limitations with previous lateral wrap-gate nanowire transistors. Finally, we show that parylene can be deposited over chemically treated nanowire surfaces, a feature generally not possible with oxides produced by atomic layer deposition due to the surface "self-cleaning" effect. Our results highlight the potential for parylene as an alternative ultrathin insulator in nanoscale electronic devices more broadly, with potential applications extending into nanobioelectronics due to parylene's well-established biocompatible properties.

Expression profile of pattern recognition receptors in skeletal muscle of SOD1(G93A) amyotrophic lateral sclerosis (ALS) mice and sporadic ALS patients.

AIMS: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons and progressive muscle wasting. Inflammatory processes, mediated by non-neuronal cells, such as glial cells, are known to contribute to disease progression. Inflammasomes consist of pattern recognition receptors (PRRs), apoptosis-associated speck-like protein (ASC) and caspase 1 and are essential for interleukin (IL) processing and a rapid immune response after tissue damage. Recently, we described inflammasome activation in the spinal cord of ALS patients and in SOD1(G93A) ALS mice. Since pathological changes in the skeletal muscle are early events in ALS, we hypothesized that PRRs might be abnormally expressed in muscle fibre degeneration. METHODS: Western blot analysis, real-time PCR and immunohistochemistry were performed with muscle tissue from presymptomatic and early-symptomatic male SOD1(G93A) mice and with muscle biopsies of control and sporadic ALS (sALS) patients. Analysed PRRs include nucleotide-binding oligomerization domain-like (NOD-like) receptor protein 1 (NLRP1), NLR protein 3 (NLRP3), NLR family CARD domain-containing 4 (NLRC4) and absent in melanoma 2. Additionally, expression levels of ASC, caspase 1, interleukin 1 beta (IL1ß) and interleukin 18 (IL18) were evaluated. RESULTS: Expression of PRRs and ASC was detected in murine and human tissue. The PRR NLRC4, caspase 1 and IL1ß were significantly elevated in denervated muscle of SOD1(G93A) mice and sALS patients. Furthermore, levels of caspase 1 and IL1ß were already increased in presymptomatic animals. CONCLUSION: Our findings suggest that increased inflammasome activation may be involved in skeletal muscle pathology in ALS. Furthermore, elevated levels of NLRC4, caspase 1 and IL1ß reflect early changes in the skeletal muscle and may contribute to the denervation process.

Simple screening tools predict death and cardiovascular events in patients with rheumatic disease.

OBJECTIVES: Patients with rheumatic disease (RD) have an increased mortality risk compared with the general population, mainly due to cardiovascular disease (CVD). We aimed to identify patients at high risk of CVD and mortality by comparing three screening tools suitable for clinical practice. METHOD: In this prospective, single-centre study, consecutive patients with rheumatoid arthritis (RA), systemic autoimmune disease (SAI), or spondyloarthritides (SpA) including psoriatic arthritis underwent a comprehensive cardiovascular risk assessment. Patients were predefined as being at high risk for cardiovascular events or death if any of the following were present: European Systematic COronary Risk Evaluation (SCORE) ≥ 3%, N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 200 pg/mL, or any pathological electrocardiogram pattern. RESULTS: The patient population (n = 764) comprised 352 patients with RA, 260 with SAI, and 152 with SpA. After a median follow-up of 5.2 years, 6.0% of RD patients had died (7.0%, 7.2%, and 1.4% of patients in the RA, SAI, and SpA subgroups), and 5.0% had experienced a cardiovascular event (5.0%, 6.4%, and 2.8%, respectively). For all RD patients and the RA and SAI subgroups, NT-proBNP ≥ 200 pg/mL and SCORE ≥ 3% identified patients with a 3.5-5-fold increased risk of all-cause death and cardiovascular events. Electrocardiogram pathology was associated with increased mortality risk, but not with cardiovascular events. CONCLUSION: NT-proBNP ≥ 200 pg/mL or SCORE ≥ 3% identifies RA and SAI patients with increased risk of cardiovascular events and death. Both tools are suitable as easy screening tools in daily practice to identify patients at risk for further diagnostics and closer long-term follow-up.

Reliability of an adherence monitoring sensor embedded in an oral appliance used for treatment of obstructive sleep apnoea.

The aim of this study was to test whether digitally registered use of a mandibular advancement device (MAD) by a built-in thermal sensor was reliable compared to a self-reported diary of MAD use. Eighty consecutive patients referred to a specialist outpatient sleep medicine clinic (HUS) were recruited. Patients of both genders, aged from 25 to 70 years with a diagnosis of mild, moderate or severe, were included. All participants signed a written informed consent when they received the MAD. For the purpose of this reliability study, we found it sufficient to include the first 30 nights of MAD use in the reliability analysis. At the 30th night follow-up visit, the self-reported diary with duration of MAD use was returned and data on the duration of MAD use with the built-in sensor were retrieved. From a total of 2400 nights, complete data from both methods were retrieved for 2108 nights (84.6%). Missing data were largely a result of missing self-reported diaries, whereas technical failure occurred in 6 nights (0.002%). The relative reliability was very high with ICC3,1 0.847, and the absolute reliability for digitally registered MAD usage was calculated to -0.17 (95% CI: 1.47 to -1.81) hours in decimal conversion. Objectively collected data from built-in thermal sensors in MADs are as reliable as those of the self-report assessments. This opens new possibilities for more accurate measurements of MAD adherence.

Landscape scale heterogeneity in the East Turkana ecosystem during the Okote Member (1.56-1.38 Ma).

Placing the biological adaptations of Pleistocene hominins within a well-resolved ecological framework has been a longstanding goal of paleoanthropology. This effort, however, has been challenging due to the discontinuous nature of paleoecological data spanning many important periods in hominin evolution. Sediments from the Upper Burgi (1.98-1.87 Ma), KBS (1.87-1.56 Ma) and Okote (1.56-1.38 Ma) members of the Koobi Fora Formation at East Turkana in northern Kenya document an important time interval in the evolutionary history of the hominin genera Homo and Paranthropus. Although much attention has been paid to Upper Burgi and KBS member deposits, far less is known regarding the East Turkana paleoecosystem during Okote Member times. This study pairs spatially-resolved faunal abundance data with stable isotope geochemistry from mammalian enamel to investigate landscape-scale ecosystem variability during Okote Member times. We find that during this period 1) taxa within the East Turkana large mammal community were distributed heterogeneously across space, 2) the abundance of C3 and C4 vegetation varied between East Turkana subregions, and 3) the Karari subregion, an area with abundant evidence of hominin stone tool manufacture, had significantly more C3 vegetation than regions closer to the central axis of the Turkana Basin (i.e., Ileret and Koobi Fora). These findings indicate that the East Turkana paleoecosystem during the Okote Member was highly variable across space and provided a complex adaptive landscape for Pleistocene hominins.

Skin provocation tests may help to diagnose atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common skin disorder. Its diagnosis relies on clinical judgment. Mild and untypical manifestations may cause diagnostic difficulties. Biomarkers for the differential diagnostic workup of AD are needed. OBJECTIVE: To test whether the results of skin provocation with cowhage, an established model of histamine-independent pruritus, and histamine are different in AD patients and healthy subjects and whether these tests may be used as diagnostic markers of AD. METHODS: Twenty-two AD patients and 18 healthy controls were subjected to topical cowhage provocation and skin prick testing with histamine and assessed for differences in the quality, intensity, and persistence of itch, for wheal diameter, volume, and flare size and intensity. RESULTS: Patients with AD, compared with healthy controls, exhibited significantly smaller histamine-induced flares (P < 0.01) and markedly longer itch persistence after provocation with cowhage (P < 0.01). Both parameters showed good diagnostic properties for AD (area under the receiver operating characteristic (ROC) curve 0.78 and 0.80, respectively). The persistence of cowhage-induced itch for at least 30 min and a histamine-induced flare of less than 2 cm in diameter were reliable thresholds for the diagnosis of AD. If combinations of the results of both tests were used, their sensitivity and specificity of diagnosing AD were up to 91% and 94%, respectively. CONCLUSION: The clinical benefit of cowhage and histamine skin provocation tests should be investigated in further studies. Long persistence of cowhage-induced itch and diminished histamine-induced flare in nonlesional skin may support diagnosis of AD.

Oral appliance treatment in moderate and severe obstructive sleep apnoea patients non-adherent to CPAP.

The aim of this retrospective study was to evaluate the effect of individually adjusted custom-made mandibular advancement device/oral appliance (OA) in treatment of patients with moderate and severe obstructive sleep apnoea (OSA), who were non-adherent to continuous positive airway pressure (CPAP) therapy. During 2007-2013, 116 patients with moderate (n = 82) and severe (n = 34) OSA non-adherent to CPAP treatment were referred for dental management with an individually adjusted OA at a specialist sleep clinic. Ten of the participants (8·6%) were lost to follow-up, leaving the data set to consist of 106 patients (71 men/35 women, mean age 57 year, range 28-90). Nocturnal respiratory polygraphic recordings were performed at baseline and follow-up. Average time between baseline polygraphy and follow-up was 12 months. A successful OA treatment outcome was based on polygraphy at the follow-up and divided into three groups: 1 = AHI <5; 2 = 5 ≤ AHI <10 and >50% reduction in baseline AHI; and 3. >50% reduction in baseline AHI. If there was a ≤ 50% reduction in baseline AHI at the follow-up, the treatment was considered as a failure. The overall treatment success rate was 75%. There was no significant difference in success rates between patients in the moderate and severe categories (69% and 77%, respectively). Low oxygen saturation (SpO2 nadir) had a high predictive value for OA treatment failure. OA treatment of patients non-adherent to CPAP is efficient and especially promising for the severe OSA group who are at greatest risks for developing serious comorbidities, if left untreated.

Developmental determinants in non-communicable chronic diseases and ageing.

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.

Rosuvastatin treatment in stable chronic obstructive pulmonary disease (RODEO): a randomized controlled trial.

OBJECTIVES: The objective of this study was to examine whether statin therapy is associated with enhanced endothelium-dependent vascular function, improved pulmonary function and reduced systemic inflammation in patients with chronic obstructive pulmonary disease (COPD). DESIGN AND SETTING: This randomized, placebo-controlled, double-blind, parallel trial including patients with COPD was performed at two University hospitals in Norway. SUBJECTS, INTERVENTION AND MEASUREMENTS: Patients with stable COPD (n = 99) were assigned randomly to receive rosuvastatin 10 mg (n = 49) or matching placebo (n = 50) once daily for 12 weeks. The primary outcome measure was change in endothelium-dependent vascular function measured using peripheral arterial tonometry and expressed as the reactive hyperaemia index. Secondary end-points were change in pulmonary function, as assessed by forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC), and change in the circulating levels of the inflammatory markers interleukin-6 (IL6) and high-sensitivity C-reactive protein (hsCRP). RESULTS: In the overall study population, no significant between-group difference in change in endothelium-dependent vascular or pulmonary function was observed. Rosuvastatin therapy was associated with a reduction in hsCRP (-20% vs. 11%, P = 0.017) and an attenuation of the rise in IL6 concentration (8% vs. 30%, P = 0.028) compared with placebo. In a prespecified subgroup analysis of patients with a supra-median circulating hsCRP concentration (>1.7 mg L(-1) ), rosuvastatin was associated with improved endothelium-dependent vascular function (13% vs. 2%, P = 0.026). CONCLUSIONS: In stable COPD patients without the standard indications for statin therapy, rosuvastatin treatment is associated with a significant attenuation of systemic inflammation and improvement in endothelial-dependent vascular function in patients with evidence of systemic inflammation.