Inspiratory threshold loading reduces lipoperoxidation in obese and normal-weight subjects

Obesity is related to increased oxidative stress. Although low-intensity physical exercise reduces oxidative stress, obese subjects may show exercise intolerance. For these subjects, inspiratory threshold loading could be an alternative tool to reduce oxidative stress. We investigated the effects of inspiratory threshold loading on biomarkers of oxidative stress in obese and normal-weight subjects. Twenty obese (31.4 ± 6 years old, 10 men and 10 women, 37.5 ± 4.7 kg/m2) and 20 normal-weight (29.4 ± 8 years old, 10 men and 10 women, 23.2 ± 1.5 kg/m2) subjects matched for age and gender participated in the study. Maximal inspiratory pressure (MIP) was assessed by a pressure transducer. Blood sampling was performed before and after loading and control protocols to assess thiobarbituric acid reactive substances (TBARS), protein carbonylation, and reduced glutathione. Inspiratory threshold loading was performed at 60% MIP and maintained until task failure. The 30-min control protocol was performed at 0 cmH2O. Our results demonstrated that inspiratory threshold loading reduced TBARS across time in obese (6.21 ± 2.03 to 4.91 ± 2.14 nmol MDA/ml) and normal-weight subjects (5.60 ± 3.58 to 4.69 ± 2.80 nmol MDA/ml; p = 0.007), but no change was observed in protein carbonyls and glutathione in both groups. The control protocol showed no significant changes in TBARS and protein carbonyls. However, reduced glutathione was increased across time in both groups (obese: from 0.50 ± 0.37 to 0.56 ± 0.35 μmol GSH/ml; normal-weight: from 0.61 ± 0.11 to 0.81 ± 0.23 μmol GSH/ml; p = 0.002). These findings suggest that inspiratory threshold loading could be potentially used as an alternative tool to reduce oxidative stress in both normal-weight and obese individuals

Insight into trade‐off between wood decay and parasitism from the genome of a fungal forest pathogen

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91191/1/j.1469-8137.2012.04128.x.pd

Anthroposophic medical therapy in chronic disease: a four-year prospective cohort study

<p>Abstract</p> <p>Background</p> <p>The short consultation length in primary care is a source of concern, and the wish for more consultation time is a common reason for patients to seek complementary medicine. Physicians practicing anthroposophic medicine have prolonged consultations with their patients, taking an extended history, addressing constitutional, psychosocial, and biographic aspect of patients' illness, and selecting optimal therapy. In Germany, health benefit programs have included the reimbursement of this additional physician time. The purpose of this study was to describe clinical outcomes in patients with chronic diseases treated by anthroposophic physicians after an initial prolonged consultation.</p> <p>Methods</p> <p>In conjunction with a health benefit program in Germany, 233 outpatients aged 1–74 years, treated by 72 anthroposophic physicians after a consultation of at least 30 min participated in a prospective cohort study. Main outcomes were disease severity (Disease and Symptom Scores, physicians' and patients' assessment on numerical rating scales 0–10) and quality of life (adults: SF-36, children aged 8–16: KINDL, children 1–7: KITA). Disease Score was documented after 0, 6 and 12 months, other outcomes after 0, 3, 6, 12, 18, 24, and (Symptom Score and SF-36) 48 months.</p> <p>Results</p> <p>Most common indications were mental disorders (17.6% of patients; primarily depression and fatigue), respiratory diseases (15.5%), and musculoskeletal diseases (11.6%). Median disease duration at baseline was 3.0 years (interquartile range 0.5–9.8 years). The consultation leading to study enrolment lasted 30–60 min in 51.5% (120/233) of patients and > 60 min in 48.5%. During the following year, patients had a median of 3.0 (interquartile range 1.0–7.0) prolonged consultations with their anthroposophic physicians, 86.1% (167/194) of patients used anthroposophic medication.</p> <p>All outcomes except KITA Daily Life subscale and KINDL showed significant improvement between baseline and all subsequent follow-ups. Improvements from baseline to 12 months were: Disease Score from mean (standard deviation) 5.95 (1.74) to 2.31 (2.29) (p < 0.001), Symptom Score from 5.74 (1.81) to 3.04 (2.16) (p < 0.001), SF-36 Physical Component Summary from 44.01 (10.92) to 47.99 (10.43) (p < 0.001), SF-36 Mental Component Summary from 42.34 (11.98) to 46.84 (10.47) (p < 0.001), and KITA Psychosoma subscale from 62.23 (19.76) to 76.44 (13.62) (p = 0.001). All these improvements were maintained until the last follow-up. Improvements were similar in patients not using diagnosis-related adjunctive therapies within the first six study months.</p> <p>Conclusion</p> <p>Patients treated by anthroposophic physicians after an initial prolonged consultation had long-term reduction of chronic disease symptoms and improvement of quality of life. Although the pre-post design of the present study does not allow for conclusions about comparative effectiveness, study findings suggest that physician-provided anthroposophic therapy may play a beneficial role in the long-term care of patients with chronic diseases.</p

Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention. © 2014

Cardioembolic Stroke in Atrial Fibrillation-Rationale for Preventive Closure of the Left Atrial Appendage

Atrial fibrillation is the most common cardiac arrhythmias, and a major cause of morbidity and mortality due to cardioembolic stroke. The left atrial appendage is the major site of thrombus formation in non-valvular atrial fibrillation. Loss of atrial systole in atrial fibrillation and increased relative risk of associated stroke point strongly toward a role for stasis of blood in left atrial thrombosis, although thrombus formation is multifactorial, and much more than blood flow irregularities are implicated. Oral anticoagulation with vitamin-K-antagonists is currently the most effective prophylaxis for stroke in atrial fibrillation. Unfortunately, this treatment is often contraindicated, particularly in the elderly, in whom risk of stroke is high. Moreover, given the risk of major bleeding, there is reason to be skeptical of the net benefit when warfarin is used in those patients. This work reviews the pathophysiology of cardioembolic stroke and critically spotlights the current status of preventive anticoagulation therapy. Various techniques to exclude the left atrial appendage from circulation were discussed as a considerable alternative for stroke prophylaxis

Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons.

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1ß cytokine into the mature interleukin-1ß.Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals

De novo Assembly of a 40 Mb Eukaryotic Genome from Short Sequence Reads: Sordaria macrospora, a Model Organism for Fungal Morphogenesis

Filamentous fungi are of great importance in ecology, agriculture, medicine, and biotechnology. Thus, it is not surprising that genomes for more than 100 filamentous fungi have been sequenced, most of them by Sanger sequencing. While next-generation sequencing techniques have revolutionized genome resequencing, e.g. for strain comparisons, genetic mapping, or transcriptome and ChIP analyses, de novo assembly of eukaryotic genomes still presents significant hurdles, because of their large size and stretches of repetitive sequences. Filamentous fungi contain few repetitive regions in their 30–90 Mb genomes and thus are suitable candidates to test de novo genome assembly from short sequence reads. Here, we present a high-quality draft sequence of the Sordaria macrospora genome that was obtained by a combination of Illumina/Solexa and Roche/454 sequencing. Paired-end Solexa sequencing of genomic DNA to 85-fold coverage and an additional 10-fold coverage by single-end 454 sequencing resulted in ∼4 Gb of DNA sequence. Reads were assembled to a 40 Mb draft version (N50 of 117 kb) with the Velvet assembler. Comparative analysis with Neurospora genomes increased the N50 to 498 kb. The S. macrospora genome contains even fewer repeat regions than its closest sequenced relative, Neurospora crassa. Comparison with genomes of other fungi showed that S. macrospora, a model organism for morphogenesis and meiosis, harbors duplications of several genes involved in self/nonself-recognition. Furthermore, S. macrospora contains more polyketide biosynthesis genes than N. crassa. Phylogenetic analyses suggest that some of these genes may have been acquired by horizontal gene transfer from a distantly related ascomycete group. Our study shows that, for typical filamentous fungi, de novo assembly of genomes from short sequence reads alone is feasible, that a mixture of Solexa and 454 sequencing substantially improves the assembly, and that the resulting data can be used for comparative studies to address basic questions of fungal biology

Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10−8; permuted pvalue 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74±0.91]; P = 2.1×10−4) and TT genotypes (OR,0.62 [95% CI, 0.51±0.75]; P = 1.3×10−6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk

Financing loss and damage: reviewing options under the Warsaw International Mechanism

After decades of pressure from vulnerable developing countries, the Warsaw International Mechanism on Loss and Damage (the WIM) was established at the nineteenth Conference of the Parties (COP 19) in 2013 to address costly damages from climate change. However, little progress has been made towards establishing a mechanism to fund loss and damage. The WIM's Executive Committee issued its first two-year workplan the following year at COP 20 which offered, among other things, a range of approaches to financing loss and damage programmes, which we review here. We provide brief overviews of each mechanism proposed by the WIM ExCom, describe their current applications, their statuses under the United Nations Framework Convention on Climate Change (UNFCCC), some of their advantages and disadvantages, and their current or potential application to loss and damage. We find that several of these mechanisms may be useful in supporting loss and damage programmes, but identify some key gaps. First, most of the mechanisms identified by the WIM ExCom are insurance schemes subsidized with voluntary contributions, which may not be adequate or reliable over time. Second, none were devised to apply to slow-onset events, or to non-economic losses and damages. That is, if harms are inflicted on parts of a society or its ecosystems that have no price, or if they occur gradually, they would probably not be covered by these mechanisms. Finally, the lack of a dedicated and adequate flow of finance to address the real loss and damage being experienced by vulnerable nations will require the use of innovative financial tools beyond those mentioned in the WIM ExCom workplan