HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course

Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the HLA-DRB1*1501 allele and its associated haplotype (DRB1*1501-DQB1*0602 or DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data.     

Symposium: ethical considerations in HIV preventive vaccine research: examining the 18 UNAIDS guidance points. The 18 UNAIDS guidance points

Here are the 18 guidance points contained in the UNAIDS document on Ethical Considerations in HIV Preventive Vaccine Research, reproduced by kind permission of the Joint United Nations Programme on HIV/AIDS (UNAIDS).     

Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate,malate and malonate

Transport and metabolism of dicarboxylates may be important in the glial-neuronal metabolic interplay. Further, exogenous dicarboxylates have been suggested as cerebral energy substrates. After intrastriatal injection of [(14) C]fumarate or [(14) C]malate, glutamine attained a specific activity 4.1 and 2.6 times higher than that of glutamate, respectively, indicating predominantly glial uptake of these four-carbon dicarboxylates. In contrast, the three-carbon dicarboxylate [(14) C]malonate gave a specific activity in glutamate which was approximately five times higher than that of glutamine, indicating neuronal uptake of malonate. Therefore, neurones and glia take up different types of dicarboxylates, probably by different transport mechanisms. Labelling of alanine from [(14) C]fumarate and [(14) C]malate demonstrated extensive malate decarboxylation, presumably in glia. Intravenous injection of 75 micromol [U-(13) C]fumarate rapidly led to high concentrations of [U-(13) C]fumarate and [U-(13) C]malate in serum, but neither substrate labelled cerebral metabolites as determined by (13) C NMR spectroscopy. Only after conversion of [U-(13) C]fumarate into serum glucose was there (13) C-labelling of cerebral metabolites, and only at <10% of that obtained with 75 micromol [3-(13) C]lactate or [2-(13) C]acetate. These findings suggest a very low transport capacity for four-carbon dicarboxylates across the blood-brain barrier and rule out a role for exogenous fumarate as a cerebral energy substrate.     

Comparison and validation of novel pyrogen tests based on the human fever reaction

The Limulus amoebocyte lysate (LAL) test has replaced about 80% of the use of the rabbit pyrogen test. Ideally, human-based in vitro tests are needed, to replace the remaining use of the rabbit test and the use of the LAL test. The progress of an EU-funded project is described, in which a number of in vitro tests, based on the human fever reaction are passing through a prevalidation study on the way to evaluation in a formal validation study.     

Genetic analysis of functions involved in the late stages of biofilm development in Burkholderia cepacia H111

Burkholderia cepacia and Pseudomonas aeruginosa often co-exist as mixed biofilms in the lungs of patients suffering from cystic fibrosis (CF). Here, we report the isolation of 13 random mini-Tn5 insertion mutants of B. cepacia H111 that are defective in biofilm formation on a polystyrene surface. We show that the screening procedure used in this study is biased towards mutants defective in the late stages of biofilm development. A detailed quantitative analysis of the biofilm structures formed by wild-type and mutant strains revealed that the isolated mutants are impaired in their abilities to develop a typical three-dimensional biofilm structure. Molecular investigations showed that the genes required for biofilm maturation fall into several classes: (i). genes encoding for surface proteins; (ii). genes involved in the biogenesis and maintenance of an integral outer membrane; and (iii). genes encoding regulatory factors. It is shown that three of the regulatory mutants produce greatly reduced amounts of N-octanoylhomoserine lactone (C8-HSL). This compound serves as the major signal molecule of the cep quorum-sensing system. As this density-dependent regulatory system is involved in the regulation of biofilm maturation, we investigated the interplay between the three regulatory genes and the quorum-sensing cascade. The results of these investigations show that the identified genes encode for regulatory elements that are positioned upstream of the cep system, indicating that the quorum-sensing system of B. cepacia is a major checkpoint for biofilm formation.     

Likelihood of attending bowel screening after a negative genetic test result: the possible influence of health professionals

This study was undertaken to determine the extent to which the reported likelihood of attending future bowel screening following negative genetic testing results for familial adenomatous polyposis (FAP) varies between the type of health professional providing care and the country of testing. The study subjects were 103 unaffected adults at risk for FAP who received negative results following predictive DNA testing. Our study indicates that the reported likelihood of attending bowel screening was higher in those given results by nongenetics physicians, rather than by genetics professionals; the reported likelihood of attending bowel screening under these circumstances was also higher in the UK than in Australia. Both of these results were affected by the perceived chances of developing FAP, and, in the case of the country of testing, by the perceived accuracy of the genetic test result and the perceived seriousness of the disease. How and what health professionals communicate with patients about genetic testing may explain the differences between type of health professional and country of testing and attitudes toward bowel screening. If this is the case, training in communication may change patients' perceptions and, in turn, their behavioral intentions and actions following a negative test result.