Little loss of information due to unknown phase for fine-scale linkage-disequilibrium mapping with single-nucleotide-polymorphism genotype data.

We present the results of a simulation study that indicate that true haplotypes at multiple, tightly linked loci often provide little extra information for linkage-disequilibrium fine mapping, compared with the information provided by corresponding genotypes, provided that an appropriate statistical analysis method is used. In contrast, a two-stage approach to analyzing genotype data, in which haplotypes are inferred and then analyzed as if they were true haplotypes, can lead to a substantial loss of information. The study uses our COLDMAP software for fine mapping, which implements a Markov chain-Monte Carlo algorithm that is based on the shattered coalescent model of genetic heterogeneity at a disease locus.

The re-invention of residential treatment: an agenda for research and practice.

I am not particularly optimistic about achieving even a few of these mod-est changes absent a more focused and thoughtful discussion on substitute care asa whole. My strong sense is that we must bring the worlds of policy, research, and practice in residential and foster care into much closer proximity so that we can assess what the challenges and strengths are in each domain and chart a course of action for renewal. To do this, we need fresh conceptual thinking on milieu treatment and empirical research.

Variance components linkage analysis for adjusted systolic blood pressure in the Framingham Heart Study.

We performed variance components linkage analysis in nuclear families from the Framingham Heart Study on nine phenotypes derived from systolic blood pressure (SBP). The phenotypes were the maximum and mean SBP, and SBP at age 40, each analyzed either uncorrected, or corrected using two subsets of epidemiological/clinical factors. Evidence for linkage to chromosome 8p was detected with all phenotypes except the uncorrected maximum SBP, suggesting this region harbors a gene contributing to variation in SBP.

Are reported preterm birth rates reliable? An analysis of interhospital differences in the calculation of the weeks of gestation at delivery and preterm birth rate.

We investigated the possibility of preterm birth misclassification as a determinant of variation in its reported rates. Using a database of 497,105 deliveries from 17 hospitals, the best estimate of gestational age made at delivery and entered into the database at that time was recalculated from the menstrual dates and mid-trimester ultrasound scan. The recalculated completed weeks of gestation at delivery was compared with that made at birth.

Trypanosome apoptotic factor mediates apoptosis in human brain vascular endothelial cells.

Human African trypanosomiasis (HAT, sleeping sickness) is a devastating disease caused by infection with Trypanosoma brucei ssp. These hemoflagellates invade the central nervous system (CNS) and induce meningo-encephalitis, neuronal demyelination, blood-brain-barrier (BBB) dysfunction, peri-vascular infiltration, astrocytosis and apoptosis. The molecular basis of these manifestations is unclear.

Characterization of psu dic(6;5)(p21.3;q13) with reverse chromosome painting in a patient with secondary myelodysplastic syndrome following treatment for multiple myeloma.

We report a case of a psu dic(6;5)(p21.3;q13) in a patient with secondary myelodysplastic syndrome (sMDS) following treatment for multiple myeloma. The abnormal chromosome was isolated by flow karyotyping and initially identified by reverse chromosome painting.

SNP subset selection for genetic association studies.

Association studies for disease susceptibility genes rely on the high density of SNPs within candidate genes. However, the linkage disequilibrium between SNPs imply that not all SNPs identified in the candidate region need be genotyped. Here we develop several approaches to SNP subset selection, which can substantially reduce the number of SNPs to be genotyped in an association study.

The irony of manganese superoxide dismutase.

The manganese and iron SODs (superoxide dismutases) form a superfamily of closely related antioxidant defence metalloenzymes. MnSOD requires Mn (not Fe) for activity. However, when MnSOD is expressed in Escherichia coli grown in medium supplemented with ferrous salts, Fe substitutes for Mn in the active site, reflecting relatively indiscriminate uptake of either Mn or Fe and a surprisingly low selectivity for the identity of the bound metal ion.

Low-threshold L-type calcium channels in rat dopamine neurons.

Ca(2+) channel subtypes expressed by dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) were studied using whole cell patch-clamp recordings and blockers selective for different channel types (L, N, and P/Q). Nimodipine (Nim, 2 microM), omega-conotoxin GVIA (Ctx, 1 microM), or omega-agatoxin IVA (Atx, 50 nM) blocked 27, 36, and 37% of peak whole cell Ca(2+) channel current, respectively, indicating the presence of L-, N-, and P-type channels. Nim blocked approximately twice as much Ca(2+) channel current near activation threshold compared with Ctx or Atx, suggesting that small depolarizations preferentially opened L-type versus N- or P-type Ca(2+) channels.

Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus.

Relative deficiency of pentraxin proteins is implicated in the pathogenesis of systemic lupus erythematosus. The C-reactive protein (CRP) response is defective in patients with acute flares of disease, and mice with targeted deletions of the serum amyloid P component gene (Sap) develop a lupus-like illness. In humans, the genes for CRP (CRP) and SAP (APCS) map to 1q23.

Multipoint linkage-disequilibrium mapping narrows location interval and identifies mutation heterogeneity.

Single-nucleotide polymorphism (SNP) genotypes were recently examined in an 890-kb region flanking the human gene CYP2D6. Single-marker and haplotype-based analyses identified, with genomewide significance (P < 10-7), a 403-kb interval displaying strong linkage disequilibrium (LD) with predicted poor-metabolizer phenotype. However, the width of this interval makes the location of causal variants difficult: for example, the interval contains seven known or predicted genes in addition to CYP2D6.

A Bayesian approach to disease gene location using allelic association.

A Bayesian approach to analysing data from family-based association studies is developed. This permits direct assessment of the range of possible values of model parameters, such as the recombination frequency and allelic associations, in the light of the data. In addition, sophisticated comparisons of different models may be handled easily, even when such models are not nested.

The PEP respiratory monitor: a validation study.

The search for a reliable and accurate respiratory rate monitor for use in non-intubated patients has proved to be a long and fruitless one. A new device fulfilling the criteria for such a monitor has recently been described. The pyroelectric polymer (PEP) device is safe, non-invasive, and cheap.

Likelihood-based estimation of microsatellite mutation rates.

Microsatellites are widely used in genetic analyses, many of which require reliable estimates of microsatellite mutation rates, yet the factors determining mutation rates are uncertain. The most straightforward and conclusive method by which to study mutation is direct observation of allele transmissions in parent-child pairs, and studies of this type suggest a positive, possibly exponential, relationship between mutation rate and allele size, together with a bias toward length increase. Except for microsatellites on the Y chromosome, however, previous analyses have not made full use of available data and may have introduced bias: mutations have been identified only where child genotypes could not be generated by transmission from parents' genotypes, so that the probability that a mutation is detected depends on the distribution of allele lengths and varies with allele length.

Different mutations in the NF1 gene are associated with Neurofibromatosis-Noonan syndrome (NFNS).

The association of the Noonan phenotype with neurofibromatosis type 1 (NF1) was first noted by Allanson et al. [Am J Med Genet 1985;21:457-462.] and 30 further cases have subsequently been reported.

Cu(I)-dependent biogenesis of the galactose oxidase redox cofactor.

Galactose oxidase is a copper metalloenzyme containing a novel protein-derived redox cofactor in its active site, formed by cross-linking two residues, Cys228 and Tyr272. Previous studies have shown that formation of the tyrosyl-cysteine (Tyr-Cys) cofactor is a self-processing step requiring only copper and dioxygen. We have investigated the biogenesis of cofactor-containing galactose oxidase from pregalactose oxidase lacking the Tyr-Cys cross-link but having a fully processed N-terminal sequence, using both Cu(I) and Cu(II).

Estimation and testing of parent-of-origin effects for quantitative traits.

Recent progress in developing family-based association methods has extended their use to the analysis of quantitative traits in the offspring and to the estimation, for dichotomous traits, of the relative contribution of genetic and environmental mechanisms for parent-of-origin effects. However, many traits of interest are not naturally measured on a binary scale yet are suspected or known to be influenced by imprinted genes, and there is consequent interest in seeking evidence for parent-of-origin effects at these loci. Here we show how simple linear models can be used to estimate these parent-of-origin effects for a broad class of phenotypes; in particular, normally distributed quantitative traits are easily dealt with.

The structure of interrupted human AC microsatellites.

Microsatellite lengths change over evolutionary time through a process of replication slippage. A recently proposed model of this process holds that the expansionary tendencies of slippage mutation are balanced by point mutations breaking longer microsatellites into smaller units and that this process gives rise to the observed frequency distributions of uninterrupted microsatellite lengths. We refer to this as the slippage/point-mutation theory.

Outer sphere mutagenesis of Lactobacillus plantarum manganese catalase disrupts the cluster core. Mechanistic implications.

X-ray crystallography of the nonheme manganese catalase from Lactobacillus plantarum (LPC) [Barynin, V.V., Whittaker, M.