Inherited haemoglobin variants in a South African population.

We present the findings of a survey to determine the prevalence of inherited haemoglobin disorders in the Coloured (mixed ethnic origin) population of South Africa. A variety of haemoglobins was found. Of the structural variants, Hb E and Hb S were the most common, the former probably originating from South-East Asia and the latter from East Africa and possibly Madagascar. The alpha+ (-alpha) thalassaemia haplotype is particularly common with an observed frequency of 0.023. Beta thalassaemia was rather less common, while hereditary persistence of fetal haemoglobin was found for the first time in this population group, occurring in two subjects.     

Computer-Assisted Detection of Pulmonary Nodules: Preliminary Observations Using a Prototype System with Multidetector-Row CT Data Sets

The continued revolution in multidetector-row CT (MDCT) scanning increases the quality of lung imaging but at the cost of a greater burden of data for review and interpretation. This article discusses our preliminary experience with prototype software for lung nodule detection and characterization using MDCT data sets. We discuss the potential role of computer-assisted detection (CAD) as applied to the automatic detection of lung nodules. We also review the process of CAD, outline its potential results, and explore how it may fit into existing radiology practice. Finally, we discuss MDCT data-acquisition parameters and how they may affect the performance of CAD.     

Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees

Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21- hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.      

Predicting development of sustained unresponsiveness to milk oral immunotherapy using epitope-specific antibody binding profiles

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Gradient moment nulling for steady-state free precession MR imaging of cerebrospinal fluid

Steady-state free precession (SSFP) pulse sequences can produce magnetic resonance (MR) images rapidly, in which cerebrospinal fluid (CSF) is several times more intense than the other tissues. However, motion in the presence of magnetic field gradients reduces the intensity of CSF drastically, unless the time integral of the gradient waveform between each radio-frequency (rf) pulse vanishes. The consequences of motion on SSFP are explored here in detail theoretically and experimentally. The principle of gradient moment nulling is applied with the objective of giving CSF in SSFP images uniformly high intensity everywhere, in spite of motion. Theoretical analysis of the phase of the transverse magnetization from a group of isochromats, with a trajectory described by a Taylor series, reveals how motion along each direction disrupts SSFP and also causes ghost artifacts. Images of CSF in the cervical spine are found to have less extensive flow voids and weaker ghosts from pulsation if the first moment calculated from the rf pulse to the center of the gradient echo vanishes for both the frequency encoding and slice selection gradient waveforms. However, first-order moment nulling of the phase encoding gradient waveform is unnecessary for SSFP imaging of CSF.     

Presentation of antigen to suppressor cells by a dimethylbenz (a) anthracene-resistant, Ia-positive, Thy-1-negative, I-J-restricted epidermal cell

The epidermal layer of the skin contains class II major histocompatibility (MHC)-positive antigen-presenting cells (APC), the most well characterized population being Langerhans' cells (LC). The chemical carcinogen 7,12 dimethylbenz (a) anthracene (DMBA) depletes about two-thirds of these cells from murine epidermis, and contact sensitizers applied to DMBA-treated skin induce specific immunological tolerance. This tolerance results from epidermal cells migrating to local lymph nodes within 3-6 hr after contact with antigen where they present the antigen to suppressor cells. Here we demonstrate that this epidermal cell which activates suppressor cells is a class II MHC-positive. Thy-1-negative, I-J-restricted APC. Hence at least two types of class II MHC-positive epidermal cells migrate to local lymph nodes and present antigen to lymphocytes; LC, which are sensitive to the effects of DMBA and activate helper lymphocytes, and another, which is resistant to DMBA and activates suppressor cells in an I-J-restricted manner. During the early stages of carcinogenesis any antigen present in the epidermis would be presented only by the cells which activate suppressor lymphocytes, resulting in tolerance induction. This may enable neoplastic cells to avoid the initiation of anti-tumour immunity.     

Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene

The difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of genetic association studies, and calls for the definition of protocols for the follow-up of associated variants. One recent example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1, associated with protein expression and activity, and with several clinical conditions. Available data suggest that 3435C>T may not directly cause altered transport activity, but may be associated with one or more causal variants in the poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here we describe a strategy for the follow-up of reported associations, including a Bayesian formalization of the associated interval concept previously described by Goldstein. We focus on the region of high LD around 3435C>T to compile an exhaustive list of variants by (1) using a relatively coarse set of marker typings to assess the pattern of LD, and (2) resequencing derived and ancestral chromosomes at 3435C>T through the associated interval. We identified three intronic sites that are strongly associated with the 3435C>T polymorphism. One of them is associated with multidrug resistance in patients with epilepsy (chi2 = 3.78, P = 0.052), and sits within a stretch of significant evolutionary conservation. We argue that these variants represent additional candidates for influencing multidrug resistance due to P-glycoprotein activity, with the IVS 26+80 T>C being the best candidate among the three intronic sites. Finally, we describe a set of six haplotype tagging single-nucleotide polymorphisms that represent common ABCB1 variation surrounding 3435C>T in Europeans.