Epigenetic mechanisms integrate genetic and environmental causes of disease, but comprehensive genome-wide analyses of epigenetic modifications have not yet demonstrated robust association with ...common diseases. Using Illumina HumanMethylation450 arrays on 354 anti-citrullinated protein antibody-associated rheumatoid arthritis cases and 337 controls, we identified two clusters within the major histocompatibility complex (MHC) region whose differential methylation potentially mediates genetic risk for rheumatoid arthritis. To reduce confounding factors that have hampered previous epigenome-wide studies, we corrected for cellular heterogeneity by estimating and adjusting for cell-type proportions in our blood-derived DNA samples and used mediation analysis to filter out associations likely to be a consequence of disease. Four CpGs also showed an association between genotype and variance of methylation. The associations for both clusters replicated at least one CpG (P < 0.01), with the rest showing suggestive association, in monocyte cell fractions in an independent cohort of 12 cases and 12 controls. Thus, DNA methylation is a potential mediator of genetic risk.
We randomly allocated 50 total knee replacements to scrub teams wearing body-exhaust suits (BES) or Rotecno occlusive clothing. The effectiveness of the clothing was assessed using air andwound ...bacterial counts. Bacteria were recovered from 62% of wounds (64% BES, 60% Rotecno). The mean air count was 0.5 CFU/ m3 with BES and 1.0 CFU/m3 with Rotecno (p = 0.014). The mean wound counts were 14 bacteria/wound with BES and eight bacteria/wound with Rotecno (p = 0.171). There was no correlation between the air and wound counts (r = -0.011, Spearman's). The higher air counts suggest that Rotecno occlusive clothing is less effective than BES, but wounds were equally contaminated with both types of clothing suggesting that at very low levels of air contamination the contribution of bacteria to the wound from the air is irrelevant. Even doubling the air counts from 0.5 to 1.0 CFU/m3 had no detectable effect on the wound. This allows a reassessment to be made of other sources of contamination the effect of which would previously have been overwhelmed by contamination from air.
This white paper provides updated International Transporter Consortium (ITC) recommendations on transporters that are important in drug development following the 3rd ITC workshop. New additions ...include prospective evaluation of organic cation transporter 1 (OCT1) and retrospective evaluation of organic anion transporting polypeptide (OATP)2B1 because of their important roles in drug absorption, disposition, and effects. For the first time, the ITC underscores the importance of transporters involved in drug‐induced vitamin deficiency (THTR2) and those involved in the disposition of biomarkers of organ function (OAT2 and bile acid transporters).
Prevention of blood loss is a chief consideration in plastic and reconstructive surgery. The antifibrinolytic drugs tranexamic acid and ε-aminocaproic acid have emerged as promising agents to reduce ...both perioperative blood loss and transfusion requirements. However, published reports in the plastic surgery literature are lacking. The authors sought to summarize the current knowledge of the use of antifibrinolytics in plastic surgery by reviewing the existing literature for clinical outcomes and recommendations.
A systematic review of the PubMed, Cochrane, and Google Scholar databases was conducted for publications examining the use of antifibrinolytics in plastic surgery. Studies were abstracted for procedure type, antifibrinolytic dose, time and mode of administration, blood loss, transfusion requirements, and complications.
Thirty-three studies were deemed eligible for inclusion, comprising a total of 1823 patients undergoing plastic surgical procedures with tranexamic acid (n = 1328) and/or ε-aminocaproic acid (n = 495).
Tranexamic acid and ε-aminocaproic acid are widely used to reduce blood loss and transfusion requirements in craniofacial and orthognathic surgery, without an increased risk of adverse events. Intravenous administration is most commonly used, although topical formulations show similar efficacy with a reduced systemic distribution. Tranexamic acid has also emerged as a promising agent in aesthetic surgery and burn care, due to its favorable safety profile and role in reducing blood loss, achieving an improved surgical field, and reducing edema and ecchymosis. Further investigation of these agents in the fields of burn care, aesthetic surgery, and microsurgery is warranted to standardize protocols for clinical use.
Traumatic drill overshoot during dorsal fixation of coronal hamate and fifth metacarpal base fractures risks iatrogenic ulnar nerve injury. This study describes the anatomic relationships between ...exiting volar drill tips and ulnar nerve branches.
Dorsal drilling of hamate bones and fifth metacarpal bases was performed on cadavers. Dorsal hamate bodies were subdivided into 4 quadrants: (1) distal-ulnar, (2) distal-radial, (3) proximal-ulnar, and (4) proximal-radial. Screws measuring 5 mm more than the dorsal-to-volar bone depths were placed in each quadrant to represent drill exit trajectories with consistent overshoot. A single screw was similarly placed 5 mm distal to the midline articular surface of the dorsal fifth metacarpal base. Distances between estimated drill tips and ulnar nerve branches were measured.
Ten cadaver hands were examined. The fifth metacarpal base screw tips directly abutted the ulnar motor branch in 6 hands, and were within 1 mm in 4 hands (mean, 0.4 ± 0.5 mm). Distances from the tips to the ulnar motor and sensory branches were largest in the distal-radial quadrant (11.8 ± 0.8 mm and 9.2 ± 1.9 mm, respectively) and smallest in the proximal-ulnar quadrant (7.3 ± 1.5 mm and 4.3 ± 1.1 mm, respectively). Distances to the ulnar motor and sensory branches were similar between the proximal-ulnar and distal-ulnar quadrants, and between the proximal-radial and distal-radial quadrants.
Dorsal drilling of coronal hamate fractures appears to be safe, as volar drill tips are well away from ulnar nerve motor and sensory branches. Distances to ulnar nerve branches are largest, and theoretically safest, with dorsal drilling in the distal-radial hamate. Dorsal drilling of fifth metacarpal base fractures appears to carry a high risk for potential ulnar motor nerve injury.
These findings may help minimize potential risks for iatrogenic ulnar nerve injury with dorsal drilling of hamate and fifth metacarpal base fractures.
Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism ...for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.
Ecology Letters (2011) 14: 407-418 ABSTRACT: A general understanding of biological invasions will provide insights into fundamental ecological and evolutionary problems and contribute to more ...efficient and effective prediction, prevention and control of invasions. We review recent papers that have proposed conceptual frameworks for invasion biology. These papers offer important advances and signal a maturation of the field, but a broad synthesis is still lacking. Conceptual frameworks for invasion do not require invocation of unique concepts, but rather should reflect the unifying principles of ecology and evolutionary biology. A conceptual framework should incorporate multicausality, include interactions between causal factors and account for lags between various stages. We emphasize the centrality of demography in invasions, and distinguish between explaining three of the most important characteristics by which we recognize invasions: rapid local population increase, monocultures or community dominance, and range expansion. As a contribution towards developing a conceptual synthesis of invasions based on these criteria, we outline a framework that explicitly incorporates consideration of the fundamental ecological and evolutionary processes involved. The development of a more inclusive and mechanistic conceptual framework for invasion should facilitate quantitative and testable evaluation of causal factors, and can potentially lead to a better understanding of the biology of invasions.
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