Vitamin K has multiple important physiological roles, including blood coagulation and beneficial effects on myelin integrity in the brain. Some intestinal microbes possess the genes to produce ...vitamin K in the form of menaquinone (MK). MK appears in higher concentration in tissues, such as the brain, particularly MK4, than the dietary form of phylloquinone (PK). Lower PK concentrations have been reported in patients with Alzheimer disease while higher serum PK concentrations have been positively associated with verbal episodic memory. Despite knowledge of the importance of vitamin K for various health parameters, few studies have measured MK concentration and biosynthesis by gut commensals.
The aim of the current study was to investigate the relation between genes involved in gut-microbiota derived MK, concentrations of MK isoforms, and cognitive function.
Shotgun metagenomic sequencing of the gut microbiome of 74 elderly individuals with different cognitive ability levels was performed. From this, gene counts for microbial MK biosynthesis were determined. Associations between clusters of individuals, grouped based on a similar presence and prevalence of MK biosynthesis genes, and cognitive ability were investigated. Fecal MK concentrations were quantified by HPLC to investigate correlations with subject clusters.
Separation of subject groups defined by banded quantification of the genetic potential of their microbiome to biosynthesize MK was associated with significant differences in cognitive ability assessed using the Mini-Mental State Examination (MMSE). Three MK isoforms were found to be positively associated with MMSE, along with the identification of key components of the MK pathway that drive this association. Although the causality and direction of these associations remain unknown, these findings justify further studies.
This study provides evidence that although total concentrations of MK did not covary with cognition, certain MK isoforms synthesized by the gut microbiome, particularly the longer chains, are positively associated with cognition.
Chronic heart failure remains a major cause of mortality and morbidity. The role of antithrombotic therapy in patients with chronic heart failure has long been debated. The objective of this study ...was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm.
This prospective, randomized clinical trial of open-label warfarin (target international normalized ratio of 2.5 to 3.0) and double-blind treatment with either aspirin (162 mg once daily) or clopidogrel (75 mg once daily) had a 30-month enrollment period and a minimum of 12 months of treatment. We enrolled 1587 men and women >/=18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of </=35%. The primary outcome was the time to first occurrence of death, nonfatal myocardial infarction, or nonfatal stroke. For the primary composite end point, the hazard ratios were as follows: for warfarin versus aspirin, 0.98 (95% CI, 0.86 to 1.12; P=0.77); for clopidogrel versus aspirin, 1.08 (95% CI, 0.83 to 1.40; P=0.57); and for warfarin versus clopidogrel, 0.89 (95% CI, 0.68 to 1.16; P=0.39). Warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel. Hospitalization for worsening heart failure occurred in 116 (22.2%), 97 (18.5%), and 89 (16.5%) patients treated with aspirin, clopidogrel, and warfarin, respectively (P=0.02 for warfarin versus aspirin).
The primary outcome measure and the mortality data do not support the primary hypotheses that warfarin is superior to aspirin and that clopidogrel is superior to aspirin.
Introduction: This study used reliable and validated instruments to compare pain severity in multiple sclerosis (MS) to that in other chronic painful conditions, and to examine relationships between ...chronic pain in MS and health-related quality of life (HRQOL). Methods: Ninety-nine MS patients completed a self-administered survey comprised of the Medical Outcomes 36-Item Short-Form Health Survey, the Short-Form McGill Pain Questionnaire, and the Hospital Anxiety and Depression Scale. Results: Pain severity was not different between MS patients with pain and rheumatoid arthritis (P=0.77) or osteoarthritis (P=0.98) patients. Chronic pain in MS was less often neurogenic than non-neurogenic, although severity of neurogenic pain was greater than that of non-neurogenic pain (P=0.048). Chronic pain in MS was found to have no significant relationship to age, disease duration or disease course. Instead, we found that pain was correlated with aspects of HRQOL, particularly mental health (r=0.44, P<0.0001) versus physical functioning (r=0.19, P>0.05). Chronic pain was significantly related to anxiety and depression for females but not for males with MS. Conclusions: Chronic pain in MS is as severe as pain in arthritic conditions and is associated with reduced HRQOL. Thus, pain can be a significant symptom for MS patients and the need for treatment may be underestimated.
A recent comparative genomic hybridization study in our laboratory revealed considerable plasticity within the bacteriocin locus of gastrointestinal strains of Lactobacillus salivarius. Most notably, ...these analyses led to the identification of two novel unmodified bacteriocins, salivaricin L and salivaricin T, produced by the neonatal isolate L. salivarius DPC6488 with immunity, regulatory and export systems analogous to those of abp118, a two-component bacteriocin produced by the well characterized reference strain L. salivarius UCC118. In this addendum we discuss the intraspecific diversity of our seven bacteriocin-producing L. salivarius isolates on a genome-wide level, and more specifically, with respect to their salivaricin loci.
There are a number of oral agents emerging as potential disease-modifying agents in multiple sclerosis (MS). Among these investigational agents, teriflunomide has shown promise in large, multicenter, ...phase III clinical trials with respect to safety and efficacy in relapsing MS patients, and is the latest disease-modifying agent approved for use in MS patients in the United States. This review will summarize teriflunomide's historical development, clinical pharmacology, studies in animals, clinical trials, and safety data, and will end with a discussion of the role of teriflunomide in MS in the context of existing treatment options.
The multiple sclerosis functional composite (MSFC) is a three-part quantitative objective measure of neurologic function, measuring leg (Timed 25-foot Walk 25FTW), arm (Nine-hole Peg Test 9HPT) and ...cognitive (Three-second Paced Auditory Serial Addition Test PASAT3) function. The MSFC was developed to be a more sensitive measure of disability than the expanded disability status scale (EDSS) and has excellent reliability. Validity is supported by moderately strong correlations with EDSS, brain atrophy and quality of life. Advantages of the MSFC include its continuous scale and inclusion of several disease dimensions. Limitations include practice effects, the lack of a visual function component, variations in reference populations and limited understanding of clinically relevant MSFC z-score changes. MSFC z-score change has been used as a secondary end-point in MS trials, but EDSS progression remains the primary disability outcome. A new approach to MSFC data involves defining MSFC progression as worsening in an MSFC component by 15–20% over three months. With further study, this could be used as a primary disability outcome in future clinical trials.
Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small ...polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.
The Total Carbon Column Observing Network Wunch, Debra; Toon, Geoffrey C.; Blavier, Jean-François L. ...
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
05/2011, Letnik:
369, Številka:
1943
Journal Article
Recenzirano
Odprti dostop
A global network of ground-based Fourier transform spectrometers has been founded to remotely measure column abundances of CO 2 , CO, CH 4 , N 2 O and other molecules that absorb in the ...near-infrared. These measurements are directly comparable with the near-infrared total column measurements from space-based instruments. With stringent requirements on the instrumentation, acquisition procedures, data processing and calibration, the Total Carbon Column Observing Network (TCCON) achieves an accuracy and precision in total column measurements that is unprecedented for remote-sensing observations (better than 0.25% for CO 2 ). This has enabled carbon-cycle science investigations using the TCCON dataset, and allows the TCCON to provide a link between satellite measurements and the extensive ground-based in situ network.
Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel ...diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host's immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm's excretory-secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.
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