Elevated expression of Runx2 as a key parameter in the etiology of osteosarcoma

To understand the molecular etiology of osteosarcoma, we isolated and characterized a human osteosarcoma cell line (OS1). OS1 cells have high osteogenic potential in differentiation induction media. Molecular analysis reveals OS1 cells express the pocket protein pRB and the runt-related transcription factor Runx2. Strikingly, Runx2 is expressed at higher levels in OS1 cells than in human fetal osteoblasts. Both pRB and Runx2 have growth suppressive potential in osteoblasts and are key factors controlling competency for osteoblast differentiation. The high levels of Runx2 clearly suggest osteosarcomas may form from committed osteoblasts that have bypassed growth restrictions normally imposed by Runx2. Interestingly, OS1 cells do not exhibit p53 expression and thus lack a functional p53/p21 DNA damage response pathway as has been observed for other osteosarcoma cell types. Absence of this pathway predicts genomic instability and/or vulnerability to secondary mutations that may counteract the anti-proliferative activity of Runx2 that is normally observed in osteoblasts. We conclude OS1 cells provide a valuable cell culture model to examine molecular events that are responsible for the pathologic conversion of phenotypically normal osteoblast precursors into osteosarcoma cells.

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1-4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.

Electronic states and spin-forbidden cooling transitions of AlH and AlF

The feasibility of laser cooling AlH and AlF is investigated using ab initio quantum chemistry. All the electronic states corresponding to the ground and lowest two excited states of the Al atom are calculated using multi-reference configuration interaction (MRCI) and the large AV6Z basis set for AlH. The smaller AVQZ basis set is used to calculate the valence electronic states of AlF. Theoretical Franck-Condon factors are determined for the A(1)Pi -> X(1)Sigma(+) transitions in both radicals and found to agree with the highly diagonal factors found experimentally, suggesting computational chemistry is an effective method for screening suitable laser cooling candidates. AlH does not appear to have a transition quite as diagonal as that in SrF (which has been laser cooled) but the A(1)Pi -> X(1)Sigma(+) transition transition of AlF is a strong candidate for cooling with just a single laser, though the cooling frequency is deep in the UV. Furthermore, the a (3)Pi -> X(1)Sigma(+) transitions are also strongly diagonal and in AlF is a practical method for obtaining very low final temperatures around 3 mu K.

Prospects for ultracold carbon via charge exchange reactions and laser cooled carbides

Strategies to produce an ultracold sample of carbon atoms are explored and assessed with the help of quantum chemistry. After a brief discussion of the experimental difficulties using conventional methods, two strategies are investigated. The first attempts to exploit charge exchange reactions between ultracold metal atoms and sympathetically cooled C+ ions. Ab initio calculations including electron correlation have been conducted on the molecular ions [LiC]+ and [BeC]+ to determine whether alkali or alkaline earth metals are a suitable buffer gas for the formation of C atoms but strong spontaneous radiative charge exchange ensure they are not ideal. The second technique involves the stimulated production of ultracold C atoms from a gas of laser cooled carbides. Calculations on LiC suggest that the alkali carbides are not suitable but the CH radical is a possible laser cooling candidate thanks to very favourable Frank-Condon factors. A scheme based on a four pulse STIRAP excitation pathway to a Feshbach resonance is outlined for the production of atomic fragments with near zero centre of mass velocity.

Globalization, Police Reform and Development; Doing it the Western Way?

Under what conditions does successful police reform take place? Can democratic forms of policing exist within undemocratic state structures? What are the motives of donor and recipient nations, and can the norms of global civil society be cultivated in order to promote human rights, democratic governance, and fair and accountable policing? These questions are addressed in this volume, which presents a unique examination of Western-led police reform efforts by theoretically linking neoliberal globalization, police reform and development. The authors present seven country case studies based on this theoretical approach (Afghanistan, Brazil, Iraq, Northern Ireland, South Africa, Trinidad and Tobago, and Turkey) and assess the prospects for successful police reform in a global context.

Divine Events

I argue for a certain conception of events according to which they are essentially extended and temporal entities (contra Leftow), and then go on to argue that God is necessarily the subject of such events (even before creation--a claim which is particularly controversial). Together these claims entail that God is necessarily temporal.

Assessing the determinants of public confidence in the police: A case study of a post-conflict community in Northern Ireland

Drawing upon original survey research this article seeks to identify the generative processes that influence perceptions of the police in the context of an inner-city neighbourhood in Northern Ireland that has been affected by increases in crime and disorder in the aftermath of the peace process. Conceptually we draw upon recent research from England and Wales that outlines confidence in the police in terms of instrumental and expressive dimensions. We apply this framework and consider whether it provides a useful template for understanding the post-conflict dynamics of police-community relations in our study area. Contrary to much received wisdom our analysis suggests that instrumental concerns about crime and illegal activity are a more influential predictor of attitudes to the police than expressive concerns with disorder and anti-social behaviour. Consequently our discussion points to the variance in local and national survey data and questions the degree to which the latter can usefully inform our understanding of trends and developments in discrete micro-spaces. Our conclusion outlines the potential policy implications for state policing practice in deprived urban spaces.

Imaging adiabatic control of charge transfer in molecules

Charge transfer is a subfemtosecond process in molecules that creates chemical and electronic structure changes. At the quantum level the process can be coherently controlled by ultrashort light pulses. We show how the charge transfer process can be manipulated using a combination of dynamic and static fields and predict how this can be observed experimentally by imaging with photoionization.

Metal organic frameworks as NO delivery materials for biological applications

Metal organic frameworks (MOFs) are highly porous materials that can store significant amounts of gas, including nitric oxide. The chemical composition and toxicology of many (but not all) of these materials makes them potentially suitable for medical applications. In this paper, we will describe how triggered release methods can be used to deliver biologically relevant amounts of NO and then show how Ni, Co and Cu-containing MOFs are biologically active materials with potential applications in several different areas (anti-thrombosis, dermatology and wound healing, anti-bacterial, vasodilation etc.). We will also discuss the pros and cons of MOFs, including their chemical and biological stability and the toxicology of MOFs in general. (C) 2009 Elsevier Inc. All rights reserved.

Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria:an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort

Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus. Long-term outcomes after the development of microalbuminuria are variable.

Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration:the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005)

Clinical treatment goals of type 1 diabetes mellitus (T1DM) have changed since the Diabetes Control and Complications Trial (DCCT) demonstrated reduced long-term complications with intensive diabetes therapy. There have been few longitudinal studies to describe the clinical course of T1DM in the age of intensive therapy. Our objective was to describe the current-day clinical course of T1DM.

S-(2-Succinyl)cysteine:a novel chemical modification of tissue proteins by a Krebs cycle intermediate

S-(2-Succinyl)cysteine (2SC) has been identified as a chemical modification in plasma proteins, in the non-mercaptalbumin fraction of human plasma albumin, in human skin collagen, and in rat skeletal muscle proteins and urine. 2SC increases in human skin collagen with age and is increased in muscle protein of diabetic vs. control rats. The concentration of 2SC in skin collagen and muscle protein correlated strongly with that of the advanced glycation/lipoxidation end-product (AGE/ALE), N(epsilon)-(carboxymethyl)lysine (CML). 2SC is formed by a Michael addition reaction of cysteine sulfhydryl groups with fumarate at physiological pH. Fumarate, but not succinate, inactivates the sulfhydryl enzyme, glyceraldehyde-3-phosphate dehydrogenase in vitro, in concert with formation of 2SC. 2SC is the first example of spontaneous chemical modification of protein by a metabolic intermediate in the Krebs cycle. These observations identify fumarate as an endogenous electrophile and suggest a role for fumarate in regulation of metabolism.

Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial

Type 1 diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) that is not fully explained by conventional risk factors. The Diabetes Control and Complications Trial (DCCT) showed that intensive diabetes therapy reduced levels of LDL cholesterol and triglycerides but increased the risk of major weight gain, which might adversely affect CVD risk. The present study examined the effect of intensive therapy on levels of several markers of inflammation that have been linked to risk of CVD.

In vivo glycated low-density lipoprotein is not more susceptible to oxidation than nonglycated low-density lipoprotein in type 1 diabetes

It has been suggested that low-density lipoprotein (LDL) modified by glycation may be more susceptible to oxidation and thus, enhance its atherogenicity. Using affinity chromatography, LDL glycated in vivo (G-LDL) and relatively nonglycated. (N-LDL) subfractions can be isolated from the same individual. The extent of and susceptibility to oxidation of N-LDL compared with G-LDL was determined in 15 type 1 diabetic patients. Total LDL was isolated and separated by boronate affinity chromatography into relatively glycated (G-) and nonglycated (N-) subfractions. The extent of glycation, glycoxidation, and lipoxidation, lipid soluble antioxidant content, susceptibility to in vitro oxidation, and nuclear magnetic resonance (NMR)-determined particle size and subclass distribution were determined for each subfraction. Glycation, (fructose-lysine) was higher in G-LDL versus N-LDL, (0.28 +/- 0.08 v 0.13 +/- 0.04 mmol/mol lysine, P <.0001). However, levels of glycoxidation/lipoxidation products and of antioxidants were similar or lower in G-LDL compared with N-LDL and were inversely correlated with fructose-lysine (FL) concentrations in G-LDL, but positively correlated in N-LDL. In vitro LDL (CuCl2) oxidation demonstrated a longer lag time for oxidation of G-LDL than N-LDL (50 +/- 0.16 v 37 +/- 0.15 min, P <.01), but there was no difference in the rate or extent of lipid oxidation, nor in any aspect of protein oxidation. Mean LDL particle size and subclass distribution did not differ between G-LDL and N-LDL. Thus, G-LDL from well-controlled type 1 diabetic patients is not more modified by oxidation, more susceptible to oxidation, or smaller than relatively N-LDL, suggesting alternative factors may contribute to the atherogenicity of LDL from type 1 diabetic patients.

A Case Report on Parvovirus B19 Associated Myositis

Introduction: Whilst there are reports of viral myopathies affecting children and the immunocompromised, infective myositis is a relatively rare inflammatory myopathy in adults. The clinical spectrum can range from benign myalgias to more serious complications in certain risk groups. Case Presentation: We present two cases of myositis as a result of parvovirus B19 infection.
Conclusion: Viral myositis and parvovirus B19 associated myositis should be considered in adults presenting with significant myalgia.