Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases

Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize GM2 ganglioside by beta-hexosaminidase A (Hex A) due to mutations of the alpha subunit (Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B (beta beta homodimer) is also defective in Sandhoff disease. We previously developed mouse models of both diseases and showed that Hexa-/- (Tay-Sachs) mice remain asymptomatic to at least 1 year of age while Hexb-/- (Sandhoff) mice succumb to a profound neurodegenerative disease by 4-6 months of age. Here we find that neuron death in Hexb-/- mice is associated with apoptosis occurring throughout the CNS, while Hexa-/- mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated GM2 ganglioside or a derivative in triggering of the apoptotic cascade.      

Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP- sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.      

Overcoming perceived barriers to employment among people with arthritis

Work disability is a major problem for people with arthritis. The INTO WORK Personal Development (IWPD) programme aims to prevent work disability by addressing the internal and external barriers faced by people with arthritis seeking to fulfil their employment potential. The effectiveness of the programme was examined in a pretest-post-test study with an intervention group (n = 37) and a comparison control group (n = 42). Data were collected through self-administered questionnaires and focus groups. Significant decreases on anxiety (p = .0002), depression (p = .009) and negative mood (p = .029), and significant improvements on positive mood (p = .011), self-esteem (p = .002) and satisfaction with life (p = .010) were found for the intervention group only. The IWPD programme appears to promote self-determination, psychological well-being and strategies for overcoming perceived barriers to employment among people with arthritis.     

Standardization of lipoprotein reporting

We wanted to ascertain whether the current format of lipid laboratory reports seemed adequate to promote identification and treatment of patients with dyslipidemia. In a random survey of lipid laboratory reports from 25 laboratories, we found great inconsistencies among reporting formats and contents. Fewer than half the laboratories correctly reported the ranges for cholesterol, only 4 correctly reported ranges for high-density lipoprotein cholesterol, only 2 correctly reported ranges for triglycerides, and none presented low-density lipoprotein cholesterol ranges in terms of risk factors for coronary heart disease. Reports typically were disjointed and difficult to read. The current practice of reporting results for lipid panels is confusing and does not follow the National Cholesterol Education Program (NCEP) guidelines. We recommend that reporting of results be standardized, and a "model" standardized report is presented herein, based on consensus from a team of experts. The standardized report uses current recommendations for ranges, follows the flowcharts of the NCEP guidelines, and takes the patient's clinical condition (the number of risk factors and the presence of coronary heart disease) into consideration. Standardizing lipid reports should decrease confusion and perhaps increase application of the guidelines and patient compliance with treatment.     

Clonal population structure of encapsulated Haemophilus influenzae.

Chromosomal genotypes of 2,209 isolates of the six polysaccharide capsule types of Haemophilus influenzae recovered from human hosts worldwide were characterized by an analysis of electrophoretically demonstrable allelic profiles at 17 metabolic enzyme loci. For 222 representative isolates, restriction fragment length polymorphism patterns produced by digestion of cap region DNA were also determined. With few exceptions, isolates belonging to individual phylogenetic lines or groups of allied lineages identified by multilocus enzyme electrophoresis had characteristic cap region restriction fragment length polymorphism patterns and characteristic combinations of cap region patterns and outer membrane protein types. The occurrence of strong associations of characters and the recovery of isolates with identical genetic properties in widely separated geographic regions and over a 40-year period indicated that the population structure of encapsulated H. influenzae is clonal. Recombination of chromosomal genes, including those mediating capsule synthesis, apparently is not a major factor in the short-term evolution of these pathogenic organisms and, therefore, may be of minor clinical significance.