Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Human Molecular Genetics     

Concentric sclerosis (Baló): Morphometric and in situ hybridization study of lesions in six patients

Brain tissues from 6 patients with concentric sclerosis (Baló) were examined by in situ hybridization, immunocytochemistry, morphometry, and histological methods. The patients were 24 to 48 years old and had progressive cerebral symptoms and signs that lasted 15 to 100 days. Large demyelinative lesions, most frequent in the frontal white matter, contained alternating bands of demyelinated and partly myelinated white matter that were arranged in concentric or mosaic patterns. In the areas of demyelination, axons were relatively well preserved and there were perivascular inflammatory infiltrates. In 2 specimens, lesions contained regions with the characteristic appearance of actively demyelinating multiple sclerosis plaques. Oligodendroglial densities were highest in normal-appearing white matter, lower in partially myelinated areas, and lowest in demyelinated areas, which also contained many hypertrophic astrocytes closely associated with oligodendroglia. Messenger RNA levels for myelin-related proteins followed the same pattern; they were lowest in demyelinated areas, higher in partially myelinated areas, and highest in normal-appearing white matter beyond lesion margins. Our findings suggest that concentric sclerosis is a variant of multiple sclerosis, that oligodendroglial loss is important in the pathogenesis of demyelination, and that partially myelinated areas probably represent stages of ongoing myelin breakdown rather than remyelination of previously demyelinated areas.     

Proliferative and cytolytic responses of human gamma delta T cells display a distinct specificity pattern.

The function and physiological role of gamma delta T cells are still unknown. Concerning the specificity of these cells, a proliferative response towards microbial ligands has been noted, whereas in terms of effector functions in humans a cytolytic activity against a variety of tumour targets is most prominent. Here we show data demonstrating that the cytolytic activity of activated human gamma delta T cells does not reflect the specificity of these cells in primary in vitro stimulation; moreover, we provide evidence that the recognition of target cells by gamma delta T cells can have different qualities. gamma delta T cells proliferate vigorously in primary in vitro reaction upon stimulation with various B-cell tumour lines but not with the T-cell lines Jurkat or Molt-4. However, gamma delta T cells stimulated primarily with phytohaemagglutinin or with cells from B-cell lines gain unrestricted cytolytic activity against a broad set of tumour targets, including Jurkat and Molt-4; the same set of targets is capable of inducing release of serine esterases (SE) from gamma delta T-effector cells. Whereas the cytolytic activity in the 51Cr-assay against the B-cell lines and against Molt-4 depends on the presence of Ca2+ ions in the assay, the lysis of Jurkat cells is only slightly reduced upon removal of Ca2+ from the medium; the SE release, however, is Ca2+ dependent in all cases. Taken together, these data suggest several different ways of target cell recognition by gamma delta T cells leading to either proliferation or triggering of cytolytic activity, and argue against an involvement of the gamma delta T-cell receptor in the cytotoxic activity of gamma delta T cells.     

Rh phenotype prediction by DNA typing and its application to practice

The complexity of the RHD and RHCE genes, which is the greatest of all blood group systems, confounds analysis at the molecular level. RH DNA typing was introduced in 1993 and has been applied to prenatal testing. PCR-SSP analysis covering multiple polymorphisms was recently introduced for the screening and initial characterization of partial D. Our objective is to summarize the accrued knowledge relevant to the approaches to Rh phenotype prediction by DNA typing, their possible applications beyond research laboratories and their limitations. The procedures, results and problems encountered are highly detailed. It is recommended that DNA typing comprises an analysis of more than one polymorphism. We discuss future directions and propose a piecemeal approach to improve reliability and cost-efficiency of blood group genotyping that may eventually replace the prevalent serology-based techniques even for many routine tasks. Transfusion medicine is in the unique position of being able to utilize the most extensive phenotype databases available to check and develop genotyping strategies.     

Microalbuminuria in children and adolescents with and without Type-I diabetes mellitus (IDDM)

In 73 healthy (group I) and 32 children and juveniles with insulin dependent diabetes mellitus (IDDM, group II) urinary albumin excretion is determined by radioimmunoassay (RIA). In both groups albumin excretion is observed in every urine sample when measured by RIA (mean +/- SD: group I: 7-19 h: 5.17 +/- 5.28 mg, 19-7 h: 3.86 +/- 4.00 mg, 24 h: 9.03 +/- 8.60 mg; group II: 7-19 h: 6.68 +/- 6.86 mg, 19-7 h: 3.46 +/- 2.82 mg, 24 h: 10.13 +/- 9.25 mg). No significant difference is detected between the values of the two groups. However in diabetic patients a significant difference is observed between diurnal and nocturnal urinary albumin excretion. Microalbuminuria is defined as an albumin excretion above 30 mg/d and is present in 6.9% of the values in group I and in 3.1% in group II. The physiological limits of microalbuminuria in children and juveniles compared to adults and several methods of urine sampling are discussed.     

Sensitivity and specificity of screening for Down syndrome with alpha-fetoprotein, hCG, unconjugated estriol, and maternal age.

The sensitivity and specificity of maternal serum screening for Down syndrome with different biochemical markers were evaluated. Detection rates with different combinations of maternal serum alpha-fetoprotein (MSAFP), hCG, and unconjugated estriol (uE3) were established by retrieving and analyzing 54 serum specimens from women with confirmed Down syndrome pregnancies, compared with 657 specimens from women with normal outcomes. With a risk cutoff of 1:270 at the second trimester, the detection rate with MSAFP, hCG, and uE3 was two to three times higher than with MSAFP alone. With all three markers, the detection rate for Down syndrome increased from 50 to 77% as maternal age increased, and was 60% in a representative screened population. If uE3 was omitted, the detection rate decreased from 60 to 48%. One thousand women were screened prospectively, either with MSAFP or with all three markers prospectively, either with MSAFP or with all three markers and 4.1% with MSAFP. With the three markers, the positive predictive value for Down syndrome was 2.2% overall and as high as 5.9% in older women. Therefore, the addition of hCG and uE3 to the maternal serum screen increases the positive predictive value by 50-300%, depending on maternal age. These results confirm the efficacy of screening for Down syndrome using maternal age and three serum markers.