Increased North Atlantic dust deposition linked to Holocene Icelandic glacier fluctuations

Mineral dust concentrations are coupled to climate over glacial-interglacial cycles with increased dust deposition occurring during major cold phases over the last ~100 ka. Holocene records suggest considerable spatial and temporal variability in the magnitude, frequency and timing of dust peaks that reflects regional or local drivers of dust emissions and transport. Here, we present stratigraphical, geochemical and isotopic evidence for dust deposition from two high-resolution peat sequences 200 km apart in northern Scotland spanning the last c. 8200 years. εNd isotope data suggest the dominant minerogenic dust source switches between a low latitude (likely Saharan) and a high latitude, Icelandic source. Marked peaks in increased minerogenic dust deposition at: c. 5.4–5.1, 4.0–3.9, 2.8–2.6, 1.0 and 0.3 ka BP occur against a backdrop of low dust deposition during the mid-Holocene (c. 5.0–4.0 ka BP) and increased background levels of dust during the neoglacial period (<4.0 ka BP). These dust peaks coincide with periods of glacial advance in Iceland and heightened storminess in the North Atlantic. Isotope data for additional dust peaks at c. 1.0 and 0.7 ka BP and the last ~50 years suggest these reflect increased dust from the Sahara associated with aridity and land-use change in North Africa during the Late-Holocene, and modern anthropogenic sources. This work highlights the complexity of Holocene records of dust deposition in the North Atlantic and emphasises the role of dynamic sub-Polar glaciers and their meltwater systems as a significant dust source.Output Status: Forthcoming/Available Onlin

MFN2 mutations cause compensatory mitochondrial DNA proliferation.

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot–Marie–Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy ‘plus’ phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A&gt;T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with ‘mitochondrial DNA breakage’ syndrome. Contrary to previous studies in patients with Charcot–Marie–Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability. <br/

MFN2 mutations cause compensatory mitochondrial DNA proliferation.

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot–Marie–Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy ‘plus’ phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A&gt;T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with ‘mitochondrial DNA breakage’ syndrome. Contrary to previous studies in patients with Charcot–Marie–Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability. <br/

Characterising the neurobiological mechanisms of action of exercise and cognitive behavioural interventions for rheumatoid arthritis fatigue: an MRI brain study

Objective: Chronic fatigue is a major clinical unmet need among patients with rheumatoid arthritis (RA). Current therapies are limited to nonpharmacological interventions, such as personalized exercise programs (PEPs) and cognitive–behavioral approaches (CBAs); however, most patients still continue to report severe fatigue. To inform more effective therapies, we conducted a magnetic resonance imaging (MRI) brain study of PEPs and CBAs, nested within a randomized controlled trial (RCT), to identify their neurobiological mechanisms of fatigue reduction in RA. Methods: A subgroup of patients with RA (n = 90), participating in an RCT of PEPs and CBAs for fatigue, undertook a multimodal MRI brain scan following randomization to either usual care (UC) alone or in addition to PEPs and CBAs and again after the intervention (six months). Brain regional volumetric, functional, and structural connectivity indices were curated and then computed employing a causal analysis framework. The primary outcome was fatigue improvement (Chalder fatigue scale). Results: Several structural and functional connections were identified as mediators of fatigue improvement in both PEPs and CBAs compared to UC. PEPs had a more pronounced effect on functional connectivity than CBAs; however, structural connectivity between the left isthmus cingulate cortex (L-ICC) and left paracentral lobule (L-PCL) was shared, and the size of mediation effect ranked highly for both PEPs and CBAs (ßAverage = −0.46, SD 0.61; ßAverage = −0.32, SD 0.47, respectively). Conclusion: The structural connection between the L-ICC and L-PCL appears to be a dominant mechanism for how both PEPs and CBAs reduce fatigue among patients with RA. This supports its potential as a substrate of fatigue neurobiology and a putative candidate for future targeting

A qualitative study of primary care clinicians' views of treating childhood obesity

Background: The prevalence of childhood obesity is rising and the UK Government have stated a commitment to addressing obesity in general. One method has been to include indicators relating to obesity within the GP pay-for-performance Quality and Outcomes Framework (QOF) contract. This study aimed to explore general practitioners' and practice nurses' views in relation to their role in treating childhood obesity. Methods: We interviewed eighteen practitioners (twelve GPs and six nurses) who worked in general practices contracting with Rotherham Primary Care Trust. Interviews were face to face and semi structured. The transcribed data were analysed using framework analysis. Results: GPs and practice nurses felt that their role was to raise the issue of a child's weight, but that ultimately obesity was a social and family problem. Time constraint, lack of training and lack of resources were identified as important barriers to addressing childhood obesity. There was concern that the clinician-patient relationship could be adversely affected by discussing what was often seen as a sensitive topic. GPs and practice nurses felt ill-equipped to tackle childhood obesity given the lack of evidence for effective interventions, and were sceptical that providing diet and exercise advice would have any impact upon a child's weight. Conclusion: GPs and practice nurses felt that their role in obesity management was centred upon raising the issue of a child's weight, and providing basic diet and exercise advice. Clinicians may find it difficult to make a significant impact on childhood obesity while the evidence base for effective management remains poor. Until the lack of effective interventions is addressed, implementing additional targets (for example through the QOF) may not be effective

Plasma biomarkers of inflammation, endothelial function and haemostasis in cerebral small vessel disease

Background: The cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH. Methods: We prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline. Results: We recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model. Conclusion: Plasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population

Updated protocol and guest participant results from the ACCeRT clinical study

Introduction Cancer cachexia is a condition often seen at diagnosis, throughout chemotherapeutic treatments and in end stage Non-Small Cell Lung Cancer patients. These patients often experience a shorter life-expectancy and deterioration in performance status and reduced quality of life. New multi˗targeted regimens are required to be tested in this population to address these issues. Materials and methods The ACCeRT study is an open label, prospective, randomised controlled feasibility study investigating the use of eicosapentaenoic acid and COX-2 inhibitor (celecoxib) versus eicosapentaenoic acid, COX-2 inhibitor (celecoxib), progressive resistance training followed by ingestion of essential amino acids high in leucine in Non-Small Cell Lung Cancer cachectic patients. The study protocol was published in November 2011. Due to study participants and study team preferences a number of changes were made. Firstly, a change from a bolus drink containing 20 g of essential amino acids to an encapsulated form in divided doses over three days. Secondly, a change in leg strength analysis from utilising a leg/back dynamometry to a customised chair with a load cell testing extension isometric force. Thirdly, study drug dose reductions were now permitted. Fourthly, addition of two study sites which allowed participants to attend progressive resistance training sessions in their local area. Finally, a change in inclusion criteria to include participants that had received any first-line anti-cancer treatment. A guest participant was invited onto the study in April 2012, followed by the first study participant in June 2012. Results The guest participant showed trends in efficacy in a number of outcomes; stable fat free mass in the context of decreasing total body weight, with stable FAACT˗PWB, MFSI-SF physical, and WHOQOL-BREF QOL scores at week 20, all during documented disease progression now termed refractory cachexia. There were no treatment or exercise-related adverse events. Conclusion Publishing feasibility study protocols allows transparency in study interventions and assessments. The above ACCeRT regimen stabilised fat free mass and a number of physical/performance indicators and QOL in the guest participant

A multi-targeted treatment approch to cancer cachexia: Auckland's Cancer Cachexia evaluating Resistance Training (ACCeRT) trial

Abstract Background Cancer cachexia is a condition often seen at diagnosis, throughout anti-cancer treatments and in end-stage nonsmall- cell lung cancer patients. Methods and results Participants with late-stage non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 12 months) were randomly assigned 1:2 to 2.09 g of eicosapentaenoic acid (EPA) and 300 mg of cyclo-oxygenase-2 inhibitor celecoxib orally once daily vs. same dosing of EPA, celecoxib, plus two sessions per week of progressive resistance training and 20 g of oral essential amino acids high in leucine in a split dose over 3 days, after each session. Primary endpoint was the acceptability of the earlier multi-targeted approach. Main secondary endpoints included change in body weight and fat-free mass, by bioelectric impedance analysis and total quadriceps muscle volume by magnetic resonance imaging over 20 weeks. Sixty-nine patients were screened resulting in 20 patients being enrolled. Acceptability scored high, with 4.5/5 (Arm A) and 5/5 (Arm B) for EPA and 5/5 for celecoxib within both arms and 4.8/5 for progressive resistance training sessions and 4.5/5 for essential amino acids within Arm B, all at Week 20. Results showed a net gain in bioelectric impedance analysis fat-free mass of +1.3 kg, n = 2 (Arm A), compared with +0.7 kg, n = 7 (Arm B) at Week 12, and —1.5 kg, n = 2 (Arm A), compared with —1.7 kg, n = 4 (Arm B) at Week 20. Trends in efficacy in terms of improvement and/or stability in cachexia markers were seen within magnetic resonance imaging muscle volume, albumin, and C-reactive protein levels within both arms. There were no exercise-related adverse events, with one possible related adverse event of asymptomatic atrial fibrillation in one participant within Arm A. Conclusions Non-small-cell lung cancer cachectic patients are willing to be enrolled onto a multi-targeted treatment regimen and may benefit from cachexia symptom management even during the late/refractory stage