Genetic Variants in P-Selectin and C-Reactive Protein Influence Susceptibility to Cognitive Decline After Cardiac Surgery

ObjectivesWe hypothesized that candidate gene polymorphisms in biologic pathways regulating inflammation, cell matrix adhesion/interaction, coagulation-thrombosis, lipid metabolism, and vascular reactivity are associated with postoperative cognitive deficit (POCD).BackgroundCognitive decline is a common complication of coronary artery bypass graft (CABG) surgery and is associated with a reduced quality of life.MethodsIn a prospective cohort study of 513 patients (86% European American) undergoing CABG surgery with cardiopulmonary bypass, a panel of 37 single-nucleotide polymorphisms (SNPs) was genotyped by mass spectrometry. Association between these SNPs and cognitive deficit at 6 weeks after surgery was tested using multiple logistic regression accounting for age, level of education, baseline cognition, and population structure. Permutation analysis was used to account for multiple testing.ResultsWe found that minor alleles of the CRP1059G/C SNP (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.16 to 0.78; p = 0.013) and the SELP1087G/A SNP (OR 0.51, 95% CI 0.30 to 0.85; p = 0.011) were associated with a reduction in cognitive deficit in European Americans (n = 443). The absolute risk reduction in the observed incidence of POCD was 20.6% for carriers of the CRP1059C allele and 15.2% for carriers of the SELP1087A allele. Perioperative serum C-reactive protein (CRP) and degree of platelet activation were also significantly lower in patients with a copy of the minor alleles, providing biologic support for the observed allelic association.ConclusionsThe results suggest a contribution of P-selectin and CRP genes in modulating susceptibility to cognitive decline after cardiac surgery, with potential implications for identifying populations at risk who might benefit from targeted perioperative antiinflammatory strategies

Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study

Background: Data regarding management of pediatric persons with hemophilia A (PwHA) with factor VIII (FVIII) inhibitors are limited. This prospective noninterventional study (NCT02476942) evaluated annualized bleeding rates (ABRs), safety, and health-related quality of life (HRQoL) in pediatric PwHA with FVIII inhibitors. Procedure: PwHA aged <12 years with current FVIII inhibitors and high-titer inhibitor history were enrolled. Participants remained on usual treatment; no interventions were applied. Outcomes included ABR, safety, and HRQoL. Results: Twenty-four PwHA aged 2-11 years (median 7.5) were enrolled and monitored for 8.7-44.1 weeks (median 23.4). In the episodic (n = 10) and prophylactic (n = 14) groups, respectively, 121 of 185 (65.4%) and 101 of 186 (54.3%) bleeds were treated using activated prothrombin complex concentrate (aPCC) and/or recombinant activated FVII (rFVIIa). ABRs (95% confidence interval) were 19.4 (13.2-28.4) and 18.5 (14.2-24.0) for treated bleeds, and 32.7 (20.5-52.2) and 33.1 (22.4-48.9) for all bleeds, respectively. Most prophylactic group participants (92.9%) were prescribed aPCC; 50% adhered to their prescribed treatment regimen. Adherence to prophylactic rFVIIa was not assessed. Serious adverse events included hemarthrosis (12.5%) and mouth hemorrhage (12.5%); the most common nonserious adverse event was viral upper respiratory tract infection (12.5%). HRQoL showed functional impairment at baseline; scores remained stable throughout, with little intergroup variation. Conclusions: ABRs remained high in pediatric PwHA with inhibitors receiving standard treatment. This study demonstrates the need for more effective treatments, with reduced treatment burden, to prevent bleeds, increase prophylaxis adherence, and improve patient outcomes.Was funded by F. Hoffmann-La Roche Ltd

Insensitivity of alkenone carbon isotopes to atmospheric CO₂ at low to moderate CO₂ levels

Atmospheric pCO₂ is a critical component of the global carbon system and is considered to be the major control of Earth's past, present, and future climate. Accurate and precise reconstructions of its concentration through geological time are therefore crucial to our understanding of the Earth system. Ice core records document pCO₂ for the past 800 kyr, but at no point during this interval were CO₂ levels higher than today. Interpretation of older pCO₂ has been hampered by discrepancies during some time intervals between two of the main ocean-based proxy methods used to reconstruct pCO₂: the carbon isotope fractionation that occurs during photosynthesis as recorded by haptophyte biomarkers (alkenones) and the boron isotope composition (δ^{11}B) of foraminifer shells. Here, we present alkenone and δ^{11}B-based pCO₂ reconstructions generated from the same samples from the Pliocene and across a Pleistocene glacial–interglacial cycle at Ocean Drilling Program (ODP) Site 999. We find a muted response to pCO₂ in the alkenone record compared to contemporaneous ice core and δ^{11}B records, suggesting caution in the interpretation of alkenone-based records at low pCO₂ levels. This is possibly caused by the physiology of CO₂ uptake in the haptophytes. Our new understanding resolves some of the inconsistencies between the proxies and highlights that caution may be required when interpreting alkenone-based reconstructions of pCO₂

Clinical spectum of tuberculous optic neuropathy

Purpose Tuberculous optic neuropathy may follow infection with Mycobacterium tuberculosis or administration of the bacille Calmette–Guerin. However, this condition is not well described in the ophthalmic literature. Methods Ophthalmologists, identified through professional electronic networks or previous publications, collected standardized clinical data relating to 62 eyes of 49 patients who they had managed with tuberculous optic neuropathy. Results Tuberculous optic neuropathy was most commonly manifested as papillitis (51.6 %), neuroretinitis (14.5 %), and optic nerve tubercle (11.3 %). Uveitis was an additional ocular morbidity in 88.7 % of eyes. In 36.7 % of patients, extraocular tuberculosis was present. The majority of patients (69.4 %) had resided in and/or traveled to an endemic area. Although initial visual acuity was 20/50 or worse in 62.9 % of 62 eyes, 76.7 % of 60 eyes followed for a median of 12 months achieved visual acuities of 20/40 or better. Visual field defects were reported for 46.8 % of eyes, but these defects recovered in 63.2 % of 19 eyes with follow-up. Conclusion Visual recovery from tuberculous optic neuropathy is common, if the diagnosis is recognized and appropriate treatment is instituted. A tuberculous etiology should be considered when evaluating optic neuropathy in persons from endemic areas.Research to Prevent Blindness (unrestricted grant to Casey Eye Institute) provided partial support for this work

A novel survival model of cardioplegic arrest and cardiopulmonary bypass in rats: a methodology paper

<p>Abstract</p> <p>Background</p> <p>Given the growing population of cardiac surgery patients with impaired preoperative cardiac function and rapidly expanding surgical techniques, continued efforts to improve myocardial protection strategies are warranted. Prior research is mostly limited to either large animal models or <it>ex vivo </it>preparations. We developed a new <it>in vivo </it>survival model that combines administration of antegrade cardioplegia with endoaortic crossclamping during cardiopulmonary bypass (CPB) in the rat.</p> <p>Methods</p> <p>Sprague-Dawley rats were cannulated for CPB (n = 10). With ultrasound guidance, a 3.5 mm balloon angioplasty catheter was positioned via the right common carotid artery with its tip proximal to the aortic valve. To initiate cardioplegic arrest, the balloon was inflated and cardioplegia solution injected. After 30 min of cardioplegic arrest, the balloon was deflated, ventilation resumed, and rats were weaned from CPB and recovered. To rule out any evidence of cerebral ischemia due to right carotid artery ligation, animals were neurologically tested on postoperative day 14, and their brains histologically assessed.</p> <p>Results</p> <p>Thirty minutes of cardioplegic arrest was successfully established in all animals. Functional assessment revealed no neurologic deficits, and histology demonstrated no gross neuronal damage.</p> <p>Conclusion</p> <p>This novel small animal CPB model with cardioplegic arrest allows for both the study of myocardial ischemia-reperfusion injury as well as new cardioprotective strategies. Major advantages of this model include its overall feasibility and cost effectiveness. In future experiments long-term echocardiographic outcomes as well as enzymatic, genetic, and histologic characterization of myocardial injury can be assessed. In the field of myocardial protection, rodent models will be an important avenue of research.</p

Sex Determination in Honeybees: Two Separate Mechanisms Induce and Maintain the Female Pathway

Sex determination in honeybees is realized by the csd and the fem gene that establish and maintain, throughout development, sexual fates via the control of alternative splicing

Generation of dendritic cell-based vaccines for cancer therapy

Dendritic cells play a major role in the generation of immunity against tumour cells. They can be grown under various culture conditions, which influence the phenotypical and functional properties of dendritic cells and thereby the consecutive immune response mainly executed by T cells. Here we discuss various conditions, which are important during generation and administration of dendritic cells to elicit a tumouricidal T cell-based immune response

A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS.

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease

Intermediate water links to Deep Western Boundary Current variability in the subtropical NW Atlantic during marine isotope stages 5 and 4

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 22 (2007): PA3209, doi:10.1029/2006PA001409.Records from Ocean Drilling Program Sites 1057 and 1059 (2584 m and 2985 m water depth, respectively) have been used to reconstruct the behavior of the Deep Western Boundary Current (DWBC) on the Blake Outer Ridge (BOR) from 130 to 60 kyr B.P. (marine isotope stage (MIS) 5 and the 5/4 transition). Site 1057 lies within Labrador Sea Water (LSW) but close to the present-day boundary with Lower North Atlantic Deep Water (LNADW), while Site 1059 lies within LNADW. High-resolution sortable silt mean (inline equation) grain size and benthic δ 13C records were obtained, and changes in the DWBC intensity and spatial variability were inferred. Comparisons are made with similar proxy records generated for the Holocene from equivalent depth cores on the BOR. During MIS 5e, inline equation evidence at Site 1057 suggests slower relative flow speeds consistent with a weakening and a possible shoaling of the LSW-sourced shallower limb of the DWBC that occupies these depths today. In contrast, the paleocurrent record from the deeper site suggests that the fast flowing deep core of the DWBC was located close to its modern depth below 3500 m. During this interval the benthic δ 13C suggests little chemical stratification of the water column and the presence of a near-uniform LNADW-dominated water mass. After ∼111 kyr B.P. the inline equation record at Site 1057 increases to reach values similar to Site 1059 for the rest of MIS 5. The strengthening of flow speeds at the shallow site may correspond to the initiation of Glacial North Atlantic Intermediate Water formation also suggested by a divergence in the benthic δ 13C records with Site 1057 values increasing to ∼1.2‰. Coupled suborbital oscillations in DWBC flow variability and paleohydrography persisted throughout MIS 5. Comparison of these data with planktonic δ 18O records from the sites and alkenone-derived sea surface temperature (SST) estimates from the nearby Bermuda Rise suggest a hitherto unrecognized degree of linkage between oscillations in subtropical North Atlantic SST and DWBC flow.This work was funded by the United Kingdom Natural Environment Research Council and supported by the NERC Radiocarbon Laboratory