Finite Coxeter Groups and Generalized Elnitsky Tilings

In [5], Elnitsky constructed three elegant bijections between classes of reduced words for Type $\mathrm{A}$, $\mathrm{B}$ and $\mathrm{D}$ families of Coxeter groups and certain tilings of polygons. This paper offers a particular generalization of this concept to all finite Coxeter Groups in terms of embeddings into the Symmetric Group. [5] Elnitsky, Serge. Rhombic tilings of polygons and classes of reduced words in Coxeter groups. PhD dissertation, University of Michigan, 1993

Ultrasonic plaque character and outcome after lower limb angioplasty

AbstractPurpose: The value of ultrasonic plaque characteristics in identifying patients at “high-risk” of restenosis after percutaneous transluminal angioplasty (PTA) was studied. Methods: Thirty-one arterial stenoses (6 common iliac, 2 external iliac, 1 profunda femoris, 21 superficial femoral, and 1 popliteal) in 17 patients who underwent angioplasty were studied by means of duplex scanning. With a computer-based program, B-mode images were digitized and normalized using 2 reference points, blood and adventitia. A grey level of 0 to 5 was allocated for the lumen (blood) and 180 to 190 for the adventitia on a linear gray scale of 0 to 255 (0 = absolutely black; 255 = absolutely white), and the overall plaque gray-scale median (GSM) of the pixels of the plaque was used as a measure of plaque echodensity. After PTA, follow-up of stenoses was done on day 1, weekly for 8 weeks, at 3 months, 6 months, and 1 year. The total plaque thickness (sum of anterior and posterior components), minimal luminal diameter (MLD), and peak systolic velocity ratio (PSVR) were measured for all stenoses. An increase of more than 2 in the PSVR was the duplex criterion used to signify restenosis. Results: The GSM of the stenoses before angioplasty ranged from 6 to 71 (mean, 31.3 ± 17.9); 17 stenoses had a GSM less than 25 (mean, 18.7 ± 5.3), and 14 had a GSM more than 25 (mean, 46.4 ± 15.8). When the GSM was less than 25, the absolute reduction in plaque thickness on day 1 post-PTA was 3.3 ± 1.8 mm, in contrast to 1.8 ± 1.6 mm when GSM was more than 25 (P < .03). The restenosis rate (PSVR more than 2) was 41% at 6 months and remained unchanged at 1 year. When the GSM was less than 25, restenosis occurred in 11% of lesions, in comparison with 78% when the GSM was more than 25 (P < .001). Conclusion: Plaque echodensity can be used to evaluate stenoses before PTA, to predict initial success and identify a subgroup that has a high prevalence of restenosis. The identification of a group at “high-risk” of restenosis can improve the selection of patients for the procedure and also be used in prospective studies on the prevention of restenosis. (J Vasc Surg 1999;29:110-21.

Sebomic identification of sex- and ethnicity-specific variations in residual skin surface components (RSSC) for bio-monitoring or forensic applications

Background: “Residual skin surface components” (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of “normal” RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity. Methods: Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography–atmospheric pressure chemical ionisation–mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis. Results: The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride. Conclusions: The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.Peer reviewedFinal Published versio

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

The impact of transcranial direct current stimulation on inhibitory control in young adults

In recent years, many important discoveries have been made to challenge current policy, guidelines, and practice regarding how best to prevent stroke associated with atherosclerotic stenosis of the origin of the internal carotid artery. TheUnited States Center forMedicare andMedicaid Services (CMS), for instance, is calling for expert advice as to whether its current policies should be modified. Using a thorough review of literature, 41 leading academic stroke-prevention clinicians from the United States and other countries, have united to advise CMS not to extend current reimbursement indications for carotid angioplasty/stenting (CAS) to patients with asymptomatic carotid stenosis or to patients with symptomatic carotid stenosis considered to be at low or standard risk from carotid endarterectomy (CEA). It was concluded that such expansion of reimbursement indications would have disastrous health and economic consequences for the United States and any other country that may follow such inappropriate action. This was an international effort because the experts to best advise CMS are relatively few and scattered around the world. In addition, US health policy, practice, and research have tended to have strong influences on other countries. © 2012 The Authors. Published by Wiley Periodicals, Inc

FDA Critical Path Initiatives: Opportunities for Generic Drug Development

FDA’s critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document “Critical Path Opportunities for Generic Drugs” that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs

Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.</p> <p>Methods</p> <p>To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.</p> <p>Results</p> <p>Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.</p> <p>Conclusion</p> <p>The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.</p