Corneal SurgeryEssential Techniques /

XII, 146 p. 153 illus., 149 illus. in color.onlin

Neural correlates of deductive reasoning: An ERP study with the Wason Selection Task

The Wason Selection Task (WST) is a well-known test of reasoning in which one turns over cards to test a rule about the two faces. Modifications were made to the WST to enable more direct and analytical investigation of reasoning processes. The modifications included extensive training to reduce variations in task interpretation, isolation of working memory in the decision phase, a separate rule for each card and variations in the form of the rule (number-letter as well as letter-number), separate scoring for each card, and inclusion of control cards that could be recognized by features without relational processing. The cognitive complexity of each card was also analyzed to enable investigation of this factor. Behavioral and event-related potential data were recorded. Negative cards differed from positive cards and control cards were differentiated from cards involved in inferences. The N2 component differentiated the negative conditions (not-P, not-Q cards) from the positive conditions (P, Q cards). The P3 component was largest for control and P cards (the simpler conditions). The late slow wave tended to show more sustained processing of not-P, not-Q and Q cards and was little influenced by the simpler control and P cards. Effects were interpreted in terms of cognitive complexity. In particular, the negative conditions had a larger N2 response than the positive conditions, reflecting greater cognitive complexity of the former and their sustained processing

Analysis of microbial keratitis incidence, isolates and in-vitro antimicrobial susceptibility in the East of England: a 6-year study.

BACKGROUND/OBJECTIVES: To report the incidence, microbiological profile and in-vitro antimicrobial susceptibilities of microbial keratitis (MK) in the East of England (EoE) over a 6-year period. SUBJECTS/METHODS: A retrospective study of patients diagnosed with MK who underwent corneal scraping at participating trusts, within the EoE, between 01/01/2015-01/07/2020. Analysis was performed on MK isolate profiles, in-vitro anti-microbial sensitivities and trends over time. RESULTS: The mean incidence of IK, in the EoE, was estimated at 6.96 per 100 000 population/year. 1071 corneal scrapes were analysed, 460 were culture positive (42.95%) of which 87.2% were bacteria (50.3% gram-positive and 49.7% gram-negative), 2.4% polymicrobial, 9.3% fungi and 1.1% acanthamoeba. The most common organisms were pseudomonas spp (29.57%). There was a non-statistically significant trend (NST) in increasing incidence of pseudomonas spp, staph aureus and serratia (p = 0.719, p = 0.615, and p = 0.099 respectively) and a declining NST in Fungi (p = 0.058). Susceptibilities in-vitro to, penicillin classes, fluoroquinolone and aminoglycosides were 76.7% and 89.4%, 79.2% and 97.2% and 95.4 and 96.1% to gram-positive and gram-negative bacteria respectively. Gram-negative organisms were increasingly resistant to cephalosporins with a 19.2% reduction in sensitivity over time. (p = 0.011). Ceftriaxone showed the greatest decrease in sensitivity of 41.67% (p = 0.006). CONCLUSION: In the EoE, MK is relatively prevalent though likely underestimated. Profiles are similar to other UK regions with the exception of a higher fungal and lower acanthamoeba incidence. Common first and second-line antimicrobial selection provides, on the whole, good coverage. Nevertheless, anti-microbial resistance, to cephalosporins, was observed so selection should be carefully considered when treating MK empirically

Vascular bed-specific regulation of the von Willebrand factor promoter in the heart and skeletal muscle

A region of the human von Willebrand factor (VWF) gene between -2812 and the end of the first intron (termed vWF2) was previously shown to direct expression in the endothelium of capillaries and a subset of larger blood vessels in the heart and skeletal muscle. Here, our goal was to delineate the DNA sequences responsible for this effect. A series of constructs containing deletions or mutations of vWF2 coupled to LacZ were targeted to the Hprt locus of mice, and the resulting animals were analyzed for reporter gene expression. The findings demonstrate that DNA sequences between -843 and -620 are necessary for expression in capillary but not large vessel endothelium in heart and skeletal muscle. Further, expression of VWF in capillaries and larger vessels of both tissues required the presence of a native or heterologous intron. In vitro assays implicated a role for ERG-binding ETS motif at -56 in mediating basal expression of VWF. In Hprt-targeted mice, mutation of the ETS consensus motif resulted in loss of LacZ expression in the endothelium of the heart and skeletal muscle. Together, these data indicate that distinct DNA modules regulate vascular bed-specific expression of VWF. (Blood. 2011;117(1):342-351

PGC-1&agr; Induces SPP1 to Activate Macrophages and Orchestrate Functional Angiogenesis in Skeletal Muscle

RationaleMechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle.ObjectiveTo test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle.Methods and resultsHere, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease.ConclusionsPGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise

A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity

Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms. However, there is no evidence for a similar mechanism operating in metazoans. Here we show that the endothelial-restricted gene, von Willebrand factor (VWF), is expressed in a mosaic pattern in the capillaries of many vascular beds and in the aorta. In capillaries, the mosaicism is dynamically regulated, with VWF switching between ON and OFF states during the lifetime of the animal. Clonal analysis of cultured endothelial cells reveals that dynamic mosaic heterogeneity is controlled by a low-barrier, noise-sensitive bistable switch that involves random transitions in the DNA methylation status of the VWF promoter. Finally, the hearts of VWF-null mice demonstrate an abnormal endothelial phenotype as well as cardiac dysfunction. Together, these findings suggest a novel stochastic phenotype switching strategy for adaptive homoeostasis in the adult vasculature