Quantification of mechanical vibration during diffusion tensor imaging at 3 T

Subjects sense clear mechanical vibrations during diffusion tensor imaging (DTI). These vibrations, likely resulting from diffusion-sensitizing gradients, have been assumed to be of the same strength and phase in all parts of the magnetic resonance imaging (MRI) scanner so that they could be ignored. However, our measurements, carried out from several parts of the MRI scanner and its surroundings using an optical laser-based interferometer, demonstrate an uneven distribution of mechanical vibrations within the scanner. The measurements were performed during DT scanning at 3 T, with various diffusion-weighting parameters, by positioning a phantom in the head coil and/or a human subject on the patient bed. The vibration-related movement was caused by the diffusion-sensitizing gradients and was maximally 0.5 mm with typical settings used in brain imaging. The compensation for eddy currents, done with gradients in our DTI sequence, increased the vibration level by a factor of 1.5 or more with diffusion-weighting parameter b = 1000 s/mm(2) and by a factor of 3 or more with b = 3000 s/mm(2). Mechanical vibrations stayed at an acceptable level with b < or = 1000 s/mm(2), resulting in additional signal losses of 5-17%. Vibration levels might be reduced by adjusting imaging parameters, by modifying the gradient waveforms in the DTI sequence, and by redesigning the mechanics of patient bed to effectively dampen the movements.     

IgAs against acetaldehyde-modified red cell protein as a marker of ethanol consumption in male alcoholic subjects, moderate drinkers, and abstainers

BACKGROUND: Alcohol abuse has been shown to result in the production of antibodies against acetaldehyde-modified epitopes in proteins. However, as yet, only limited information has been available on the clinical usefulness of such responses as markers of hazardous drinking. METHODS: We developed an ELISA to measure specific IgAs against acetaldehyde-protein adducts. This method was evaluated in cross-sectional and follow-up studies on male heavy drinkers with a current ethanol consumption of 40 to 540 g/d (n=40), moderate drinkers consuming 1 to 40 g/d (n=25), and abstainers (n=16). The clinical assessments included detailed interviews on the amounts and patterns of ethanol consumption and various biochemical markers of alcohol abuse and liver function. RESULTS: The mean antiadduct IgAs (198+/-28 U/L) in the alcohol abusers were significantly higher than those in the moderate drinkers (58+/-11 U/L, p<0.001) or abstainers (28+/-8 U/L, p<0.001). The values of moderate drinkers were also higher than those in abstainers (p<0.05). The amount of ethanol consumed during the period of 1 month preceding blood sampling correlated strongly with antiadduct IgAs (r=0.67, p<0.001). The sensitivity (73%) and specificity (94%) of this marker were found to exceed those of the conventional laboratory markers of alcohol abuse in comparisons contrasting heavy drinkers with abstainers although not in comparisons contrasting heavy drinkers with moderate drinkers. During abstinence, antiadduct IgAs disappeared with a mean rate of 3% per day. In additional analyses of possible marker combinations, antiadduct IgAs, together with CDT, were found to provide the highest sensitivity and specificity. CONCLUSIONS: Measurements of antiadduct IgAs may provide a new clinically useful marker of alcohol abuse, providing a close relationship between marker levels and the actual amounts of recent ethanol ingestion.     

Thrombospondins,Potential Drug Targets for Cardiovascular Diseases

The thrombospondin (TSP) family consists of five multimeric, multidomain calcium‐binding glycoproteins that act as regulators of cell–cell and cell–matrix associations as well as interact with other extracellular matrix molecules affecting their function. Increasing interest on cardiac TSP‐1, TSP‐2 and TSP‐4 has emerged, and they have been studied in cardiac hypertrophy, myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis. The aim of this MiniReview is to summarize the current knowledge on each TSP in various cardiovascular pathologies. We specifically emphasize the role of TSPs in cardiac remodelling and evaluate TSPs as potential cardiovascular drug targets. Thrombospondin‐1 (TSP‐1) is the most studied TSP, being antiangiogenic and able to activate transforming growth factor‐β. The functions of TSP‐2 and TSP‐4 are linked in maintaining the composition of the matrix of the hypertrophied heart, whereas there is very little knowledge on cardiac TSP‐3 and TSP‐5. TSP‐1, TSP‐2 and TSP‐4 have been shown to affect cardiac remodelling in vivo, for example, by modulating matrix metalloproteinase and transforming growth factor‐β activity, collagen synthesis, myofibroblast differentiation, cell death and stretch‐mediated augmentation of cardiac contractility. The detrimental role for TSPs in cardiovascular pathophysiology has been clearly demonstrated in knockout mouse models, and augmentation of TSP signalling in the heart during stress and haemodynamic overload might be beneficial. In conclusion, the role of TSP‐1, TSP‐2 and TSP‐4 in cardiac hypertrophy, remodelling after myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis encourages further investigation to validate them as potential drug targets.     

Epidemiology of severe Streptococcus pyogenes disease in Europe

The past 2 decades have brought worrying increases in severe Streptococcus pyogenes diseases globally. To investigate and compare the epidemiological patterns of these diseases within Europe, data were collected through a European Union FP-5-funded program (Strep-EURO). Prospective population-based surveillance of severe S. pyogenes infection diagnosed during 2003 and 2004 was undertaken in 11 countries across Europe (Cyprus, the Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Romania, Sweden, and the United Kingdom) using a standardized case definition. A total of 5,522 cases were identified across the 11 countries during this period. Rates of reported infection varied, reaching 3/100,000 population in the northern European countries. Seasonal patterns of infection showed remarkable congruence between countries. The risk of infection was highest among the elderly, and rates were higher in males than in females in most countries. Skin lesions/wounds were the most common predisposing factor, reported in 25% of cases; 21% had no predisposing factors reported. Skin and soft tissue were the most common foci of infection, with 32% of patients having cellulitis and 8% necrotizing fasciitis. The overall 7-day case fatality rate was 19%; it was 44% among patients who developed streptococcal toxic shock syndrome. The findings from Strep-EURO confirm a high incidence of severe S. pyogenes disease in Europe. Furthermore, these results have identified targets for public health intervention, as well as raising awareness of severe S. pyogenes disease across Europe.     

Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions

Breast cancer is the most common cancer in women in developed countries and has a well-established genetic component. Germline mutations in a network of genes encoding BRCA1, BRCA2, and their interacting partners confer hereditary susceptibility to breast cancer. Abraxas directly interacts with the BRCA1 BRCT (BRCA1 carboxyl-terminal) repeats and contributes to BRCA1-dependent DNA damage responses, making Abraxas a candidate for yet unexplained disease susceptibility. Here, we have screened 125 Northern Finnish breast cancer families for coding region and splice-site Abraxas mutations and genotyped three tagging single-nucleotide polymorphisms within the gene from 991 unselected breast cancer cases and 868 female controls for common cancer-associated variants. A novel heterozygous alteration, c.1082G>A (Arg361Gln), that results in abrogated nuclear localization and DNA response activities was identified in three breast cancer families and in one additional familial case from an unselected breast cancer cohort, but not in healthy controls (P = 0.002). On the basis of its exclusive occurrence in familial cancers, disease cosegregation, evolutionary conservation, and disruption of critical BRCA1 functions, the recurrent Abraxas c.1082G>A mutation connects to cancer predisposition. These findings contribute to the concept of a BRCA-centered tumor suppressor network and provide the identity of Abraxas as a new breast cancer susceptibility gene.     

Mapping of the binding sites for the OX1 orexin receptor antagonist, SB-334867, using orexin/hypocretin receptor chimaeras

The binding sites for agonists and antagonist of orexin receptors are not know, hampering progressive drug design approaches. In the current study, we utilized chimaeric orexin receptor approach to map the receptor areas contributing to the selectivity of the classical antagonist, SB-334867, for OX₁ receptors. Altogether ten chimaeras between OX₁ and OX₂ orexin receptors were utilized. The receptors were transiently expressed in HEK-293 cells. The ability (K_B) of SB-334867 to inhibit orexin-A-induced inositol phosphate release (phospholipase C activity) was measured. The results, in synthesis, suggest that there are several possible interactions contributing to the high affinity binding, all of which are not required simultaneously. This is indicated by the fact that most of the chimaeras display affinity (at least somewhat) higher than OX₂. As previously shown for the agonist distinction, the second quarter of the receptor, from the C-terminal part of the transmembrane helix 2 to the transmembrane helix 4 seems to be most central also for SB-334867 binding, but also the third quarter, from the transmembrane helix 4 to the transmembrane helix 6 is able to contribute (and compensate for loss of other sites). A previous study has suggested that amino acids conserved between OX₁ and OX₂ receptors would somehow confer selectivity for subtype-selective antagonists. In contrast to previous findings, our results indicate that the amino acids distinct between the receptor subtypes are in key position.