iNOS Ablation Does Not Improve Specific Force of the Extensor Digitorum Longus Muscle in Dystrophin-Deficient mdx4cv Mice

Nitrosative stress compromises force generation in Duchenne muscular dystrophy (DMD). Both inducible nitric oxide synthase (iNOS) and delocalized neuronal NOS (nNOS) have been implicated. We recently demonstrated that genetic elimination of nNOS significantly enhanced specific muscle forces of the extensor digitorum longus (EDL) muscle of dystrophin-null mdx4cv mice (Li D et al J. Path. 223:88–98, 2011). To determine the contribution of iNOS, we generated iNOS deficient mdx4cv mice. Genetic elimination of iNOS did not alter muscle histopathology. Further, the EDL muscle of iNOS/dystrophin DKO mice yielded specific twitch and tetanic forces similar to those of mdx4cv mice. Additional studies suggest iNOS ablation did not augment nNOS expression neither did it result in appreciable change of nitrosative stress markers in muscle. Our results suggest that iNOS may play a minor role in mediating nitrosative stress-associated force reduction in DMD

Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era

Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country’s late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g−1), than black males (ME = 3.80 µg·g−1) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead

Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome

Children with congenital heart disease (CHD) who survive surgery often present impaired neurodevelopment and qualitative brain anomalies. However, the impact of CHD on total or regional brain volumes only received little attention. We address this question in a sample of patients with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition frequently associated with CHD. Sixty-one children, adolescents, and young adults with confirmed 22q11.2 deletion were included, as well as 80 healthy participants matched for age and gender. Subsequent subdivision of the patients group according to CHD yielded a subgroup of 27 patients with normal cardiac status and a subgroup of 26 patients who underwent cardiac surgery during their first years of life (eight patients with unclear status were excluded). Regional cortical volumes were extracted using an automated method and the association between regional cortical volumes, and CHD was examined within a three-condition fixed factor. Robust protection against type I error used Bonferroni correction. Smaller total cerebral volumes were observed in patients with CHD compared to both patients without CHD and controls. The pattern of bilateral regional reductions associated with CHD encompassed the superior parietal region, the precuneus, the fusiform gyrus, and the anterior cingulate cortex. Within patients, a significant reduction in the left parahippocampal, the right middle temporal, and the left superior frontal gyri was associated with CHD. The present results of global and regional volumetric reductions suggest a role for disturbed hemodynamic in the pathophysiology of brain alterations in patients with neurodevelopmental disease and cardiac malformations

Effect of β-alanine supplementation on 20 km cycling time trial performance

The effects of β-alanine supplementation on high-intensity cycling performance and capacity have been evaluated, although the effects on longer duration cycling performance are unclear. Nineteen UK category 1 male cyclists completed four 20 km cycling time trials, two before and two after supplementation with either 6.4 g•d -1 β-alanine (n = 10; BA) or a matched placebo (n = 9; P). Performance time for the 20 km time trial and 1 km split times were recorded. There was no significant effect of β-alanine supplementation on 20 km time trial performance (BA-pre 1943 ± 129 s; BA-post 1950 ± 147 s; P-pre 1989 ± 106 s; P-post 1986 ± 115 s) or on the performance of each 1 km split. The effect of β-alanine on 20 km time trial performance was deemed unclear as determined by magnitude based inferences. Supplementation with 6.4 g•d -1 of β-alanine for 4 weeks did not affect 20 km cycling time trial performance in well trained male cyclists

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Search for New Particles Decaying to top-antitop in proton-antiproton collisions at squareroot(s)=1.8 TeV

We use 106 \ipb of data collected with the Collider Detector at Fermilab to search for narrow-width, vector particles decaying to a top and an anti-top quark. Model independent upper limits on the cross section for narrow, vector resonances decaying to \ttbar are presented. At the 95% confidence level, we exclude the existence of a leptophobic \zpr boson in a model of topcolor-assisted technicolor with mass M_{\zpr} $<$ 480 \gev for natural width $\Gamma$ = 0.012 M_{\zpr}, and M_{\zpr} $<$ 780 \gev for $\Gamma$ = 0.04 M_{\zpr}.Comment: The CDF Collaboration, submitted to PRL 25-Feb-200

A Measurement of the Differential Dijet Mass Cross Section in p-pbar Collisions at sqrt{s}=1.8 TeV

We present a measurement of the cross section for production of two or more jets as a function of dijet mass, based on an integrated luminosity of 86 pb^-1 collected with the Collider Detector at Fermilab. Our dijet mass spectrum is described within errors by next-to-leading order QCD predictions using CTEQ4HJ parton distributions, and is in good agreement with a similar measurement from the D0 experiment.Comment: 18 pages including 2 figures and 3 tables. Submitted to Phys. Rev. D Rapid Communication

Personalized Drug Dosage – Closing the Loop

A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, computer-guided dosage using ‘dashboards’, and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her ‘virtual twin’ through the application of physiologically-based pharmacokinetic modeling is also discussed