Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis.

A candidate gene for hereditary haemochromatosis, HLA-H, has recently been presented. Two missense mutations in the HLA-H gene sequence are predicted to account for nearly 90% of all cases of the disease. The aim of this study was to correlate the presence of these missense mutations with the expressivity of the disease, as assessed by standard biochemical evaluation of serum iron parameters. Detection of the known mutations in haemochromatosis, Cys282Tyr and His63Asp, was undertaken in a large pedigree showing variable expression of the disease in successive generations. In three sibs with overt disease (one male, two female, aged 50 to 53 years), homozygosity for the predominant G to A transition (Cys282Tyr) in HLA-H was detected. However, homozygosity for this mutation was also detected in an asymptomatic male sib, aged 50, harbouring an identical genotype. The finding of an asymptomatic homozygous Cys282Tyr subject, haplo-identical to affected sibs, indicates that clinical expression of symptomatic disease is variable, even in middle aged Cys282Tyr homozygotes. This has profound implications for the future use of genetic screening for haemochromatosis.     

The transparency of the mammalian cornea

1. A theoretical and experimental analysis of the relationship of the corneal stromal ultrastructure with light transmission has been made in an attempt to resolve recent contradictory explanations of corneal transparency.2. The spatial distribution of collagen fibrils in electronmicrographs of rabbit corneal stroma has been analysed in terms of a radial distribution function. The results indicate the presence of local order extending to at least 200 nm from individual fibrils.3. The observed spatial distribution of the collagen fibrils was used as a basis to compare the theoretically derived and the experimentally determined values of light transmission. It has been found that the transparency of the normal cornea may be explained by the quasi-random structure revealed by the electronmicroscope.4. Histograms of the collagen fibril diameter in normal rabbit corneal stroma revealed the range to be 12.5-32.5 nm and the mean value to be approximately 20 +/- 1.5 nm. Corneal swelling did not change the collagen fibril diameter significantly.5. It is concluded that the size and distribution of collagen fibrils revealed in electronmicrographs are consistent with the observed transparency of normal stromas.6. A marked heterogeneity in the spatial distribution of collagen fibrils was found in the swollen cornea. This is qualitatively consistent with the observed decrease in transparency.     

Osteonecrosis in HIV: a case-control study

BACKGROUND: Osteonecrosis (avascular necrosis) has been infrequently reported in HIV-infected patients. It is not known whether HIV itself is an independent risk factor for osteonecrosis. METHODS: We identified 25 patients with osteonecrosis from 1984 to 1999 from a large county teaching hospital and two large practices in Dallas County that specialize in HIV-disease related therapy. A retrospective chart review was performed to evaluate potential risk factors for osteonecrosis. Each case was matched with two controls for HIV positive status and date of osteonecrosis diagnosis. RESULTS: In the study, 22 of 25 (88%) case patients had at least one osteonecrosis risk factor compared with 24 of 50 (48%) controls, p =.003. The most common osteonecrosis risk factors were hyperlipidemia (32%), alcoholism (28%), pancreatitis (16%), corticosteroids (12%), and hypercoaguability (12%). Of the cases, 12% were idiopathic. Multiple joints were involved in 72% of cases. Four of the case patients compared with none of the controls received megesterol acetate before the diagnosis of osteonecrosis, p =.01. No significant differences were found between cases and controls with respect to liver function tests, testosterone levels, triglyceride levels, cholesterol levels, or CD4 cell counts. Saquinavir was independently associated with osteonecrosis, p <.05. However, no differences in overall use of protease inhibitors among cases and controls were noted: 79% versus 76%, respectively. CONCLUSIONS: The increased incidence of osteonecrosis in HIV/AIDS may be due to an increased frequency of risk factors previously associated with osteonecrosis such as hyperlipidemia, corticosteroid use, alcohol abuse, and hypercoaguability. Use of protease inhibitors was not independently associated with osteonecrosis.     

Sequence of a novel HLA-A*0301 intronic variant (A*03010103)

We report here the full-length sequence of a novel HLA-A*0301 allele, A*03010103, which differs from A*03010101 by a single nucleotide substitution (G>T) at position 492 within intron 2. The variant was originally identified by Reference Strand-mediated Conformational Analysis (RSCA) and was confirmed by cloning and sequencing. The difference in RSCA mobility between A*03010101 and A*03010103 demonstrates the sensitivity of RSCA to detect single nucleotide polymorphisms.     

Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides

Circulating angiotensin-1-converting enzyme (ACE) is a highly heritable trait, and a major component of the genetic variance maps to the region of the ACE gene. The strong effect of the locus, and the interest in ACE as a candidate gene for cardiovascular disorders, has led to extensive investigation of its relationship to the ACE phenotype, providing one of the most complete examples of quantitative trait locus (QTL) analysis in humans. Resequencing of ACE followed by haplotype analysis in families of British and French origin has shown that the genetic variants that are primarily associated with the ACE trait map to an 18 kb interval flanked by two intragenic, ancestral recombination breakpoints. This critical interval contains dozens of ACE-associated variants in Caucasians, but identification of which of these directly influence ACE concentration is ambiguous because of the almost complete linkage disequilibrium in European populations. In a complementary sequencing and genotyping study of individuals from West African families, we show that this population has much greater haplotype diversity across the gene. Through analysis of the contrasting relationships of the trait phenotype with haplotypes that carry different allelic combinations from those observed in Caucasians, we demonstrate that (at least) two major intragenic sites within the critical interval and (at least) one minor promoter site are associated with the ACE quantitative trait through additive effects. These results point to the importance of analysing diverse populations with different gene genealogies in gene-association studies.     

Autistic-spectrum disorders in Down syndrome: further delineation and distinction from other behavioral abnormalities.

The present study extends our previous work characterizing the behavioral features of autistic-spectrum disorder (ASD) in Down syndrome (DS) using the Aberrant Behavior Checklist (ABC) and Autism Behavior Checklist (AutBehav). We examined which specific behaviors distinguished the behavioral phenotype of DS + ASD from other aberrant behavior disorders in DS, by determining the relative contribution of ABC and AutBehav subscales and items to the diagnosis of ASD. A total of 127 subjects (aged 2-24 years; mean age: 8.4 years; approximately 70% male), comprising: a cohort of 64 children and adolescents with DS and co-morbid ASD (DS + ASD), 19 with DS and stereotypic movement disorder (DS + SMD), 18 with DS and disruptive behaviors (DS + DB), and 26 with DS and no co-morbid behavior disorders (DS + none) were examined using the aforementioned measures of aberrant behavior. We found that subjects with DS + ASD showed the most severe aberrant behavior, especially stereotypy compared to DS + none and lethargy/social withdrawal and relating problems compared to DS + SMD. Specifically, relatively simple stereotypic behavior differentiated DS + ASD from DS + DB, whereas odd/bizarre stereotypic and anxious behavior characterized DS + ASD relative to DS + SMD and DS + none. Additionally, in a subset of subjects with DS + ASD and anxiety, social withdrawal was particularly pronounced. Overall, our findings indicate that a diagnosis of DS + ASD represents a distinctive set of aberrant behaviors marked by characteristic odd/bizarre stereotypic behavior, anxiety, and social withdrawal.     

Computer-assisted work station timing analysis of instrument labor efficiency

Labor use ratings assigned to instruments by the Workload Recording Method (WRM) do not change with batch size or walk-away time use. The authors evaluated the effect of both on the labor use of the analyzers Paramax B6100 (Baxter Paramax, Irvine, CA) and Ektachem 700 (Eastman Kodak, Rochester, NY) by timing all worked and walk-away intervals on both instruments. Extrapolation of the data to a workload of slightly more than 1.1 million tests showed that reapportionment of tests to various batch sizes caused Paramax-Ektachem labor cost differences to fluctuate between $37,254 and $34,995. When the minimum usable walk-away interval length was varied from 1 to 20 minutes, Ektachem savings over Paramax increased from $8,700 to $61,400. The WRM predicted a constant $29,050 labor cost advantage for Ektachem over Paramax. If other instruments show similar labor use characteristics with respect to batch size and walk-away utility, laboratory managers who do not consider these factors may fail to select the most cost-effective instruments for their laboratories.     

Distribution of immunoreactive dynorphin in discrete brain nuclei; comparison with vasopressin

The distribution of the opioid peptide, dynorphin, has been studied in discrete, microdissected hypothalamic nuclei, and compared with the distribution of vasopressin. Both peptides were found in relatively high concentration in the supraoptic and paraventricular nuclei. However, dynorphin-like immunoreactivity (DYN-LI) was much more widely distributed in the hypothalamus than vasopressin-like immunoreactivity, with highest concentrations in the anterior hypothalamic and ventromedial nuclei. DYN-LI was also observed in some extra-hypothalamic structures; concentrations which were comparable to the highest levels in the hypothalamus were found in the tractus diagonalis and the nucleus interstitialis stria terminalis. Among the three brainstem nuclei examined, DYN-LI levels were highest in the sensory nucleus of the trigeminal nerve.