Allelic association with SNPs: metrics, populations, and the linkage disequilibrium map

Comparison of different metrics, using three large samples of haplotypes from different populations, demonstrates that rho is the most efficient measure of association between pairs of single nucleotide polymorphisms (SNPs). Pairwise data can be modeled, using composite likelihood, to describe the decline in linkage disequilibrium with distance (the Malecot model). The evidence from more isolated populations (Finland, Sardinia) suggests that linkage disequilibrium extends to 427-893 kb but, even in samples representative of large heterogeneous populations, such as CEPH, the extent is 385 kb or greater. This suggests that isolated populations are not essential for linkage disequilibrium mapping of common diseases with SNPs. The in parameter of the Malecot model (recombination and time), evaluated at each SNP, indicates regions of the genome with extensive and less extensive disequilibrium (low and high values of in respectively). When plotted against the physical map, the regions with extensive and less extensive linkage disequilibrium may correspond to recombination cold and hot spots. This is discussed in relation to the Xq25 cytogenetic band and the HFE gene region.     

Glycoproteins present in human follicular fluid that inhibit the zona- binding capacity of spermatozoa

Previous studies have suggested that human follicular fluid contains factors that reduce the zona-binding capacity of spermatozoa. The present study provides further evidence of the existence of such factors. Using the hemizona binding assay (HZA), we have shown that the inhibitory effect of human follicular fluid on the zona-binding capacity of spermatozoa is concentration-dependent, an inhibitory effect being detected when the concentration of human follicular fluid was > or = 10%. A 1% concentration of human follicular fluid did not possess this inhibitory activity. Heating human follicular fluid at 56 degrees C for 30 min did not affect its inhibitory properties; treatment with proteinase-K abolished such inhibition. Human follicular fluid was fractionated sequentially by concanavalin-A affinity chromatography, Mono Q ion-exchange chromatography and Superose-12 gel filtration. The zona binding inhibitory activity resided in the fraction which bound to the lectin and Mono Q column and contained molecules with native molecular weights of 32 and 192 kDa. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis suggested that the 192 kDa glycoprotein was a tetramer, while the 32 kDa glycoprotein remained as a single molecular species under denaturing conditions. We conclude that two glycoproteins were responsible for the zona binding inhibitory activity of human follicular fluid. The physiological role of these factors remains unclear.      

Reproductive tract abnormalities in rats treated neonatally with DES

Neonatal female Sprague-Dawley rats were given daily injections of 3 μg diethylstilbestro (DES) for 5 days beginning within 24 hours of birth. Some of these rats were ovariectomized between the 15th and 18th postnatal days, and on the 60th postnatal day were given daily injections of 3 μg estradiol for 1, 3, or 5 weeks. Intact rats were sacrificed at 60, 95, or 130 days. The morphology of the upper vagina, cervix, and lower uterus was examined by light and scanning electron microscopy. Two abnormalities resulting from neonatal DES exposure were found. The first was squamous metaplasia observed in the uteri of rats given DES and later exposed to exogenous or endogenous estrogen. Metaplasia was seen in both the luminal and glandular epithelium. The longer the rats were exposed to exogenous or endogenous estrogen, the more extensive was the metaplasia. The second was a gross morphologic abnormality seen in all rats given DES regardless of any later treatment. That part of the cervix that protrudes into the cranial limit of the vagina was absent and, thus, a vaginal fornix was nonexistent. Previous investigations have emphasized abnormalities of the lower reproductive tract. The present study indicates that the upper reproductive tract also must be considered in investigations of the effects of hormones administered to neonates.     

Some studies on the mechanism of action of antibodies to nerve growth factor.

The effects of antibodies to the nerve growth factor from mouse salivary gland were examined in vitro and in vivo. Treatment of explants of receptive ganglia with antibody and complement did not produce cell damage as judged by the ability of the tissue to respond to nerve growth factor. New-born mice experimentally depleted of or genetically deficient in key complement components were susceptible to the action of the antiserum.These results show that the effect of the antibody is independent of complement and are consistent with the view that it acts by neutralization of endogenous nerve growth factor.     

Meeting report

Inflammation Research -     

A potent excitatory input to the nucleus locus coeruleus from the ventrolateral medulla

Our recent anatomic experiments reveal major innervation of the nucleus locus coeruleus (LC) from the nucleus paragigantocellularis (PGi), located in the rostral ventrolateral medulla. In the present studies, low intensity, single pulse electrical stimulation of the PGi synaptically activated most LC neurons examined (69%), while a smaller percentage of LC cells (20%) exhibited pure inhibitory responses. Pharmacologic experiments suggest that the excitatory response may be mediated by an amino acid transmitter.     

Effect of cyclic AMP on histamine release induced by compound 48/80.

Bu2 cAMP(N6, O2'-dibutyryl adenosine-3',5'-cyclic monophosphate) inhibited the response of rat peritoneal mast cells to compound 48/80 in the presence of calcium ions. In the absence of calcium, the nucleotide partially prevented the desensitization induced by chelating agents. The response of cells, allowed to accumulate Bu2 cAMP in the presence of calcium (to avoid depletion of intracellular stores of the ion) and then challenged in the absence of extracellular calcium, was also inhibited. These results are discussed in terms of the postulated effects of Bu2 cAMP on the calcium-gatubg mechanism operative in histamine secretion.     

A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice

Huntington's disease (HD) is a dominant disorder characterized by premature and progressive neurodegeneration. In order to generate an accurate model of the disease, we introduced an HD-like mutation (an extended stretch of 72-80 CAG repeats) into the endogenous mouse Hdh gene. Analysis of the mutation in vivo reveals significant levels of germline instability, with expansions, contractions and sex-of-origin effects in evidence. Mice expressing full-length mutant protein display abnormal social behaviour in the absence of acute neurodegeneration. Given that psychiatric changes, including irritability and aggression, are common findings in HD patients, our data are consistent with the hypothesis that some clinical features of HD may be caused by pathological processes that precede gross neuronal cell death. This implies that effective treatment of HD may require an understanding and amelioration of these dysfunctional processes, rather than simply preventing the premature death of neurons in the brain. These mice should facilitate the investigation of the molecular mechanisms that underpin the pathway from genotype to phenotype in HD.     

The Effects of Permeation Enhancers on the Surface Morphology of the Rat Nasal Mucosa: A Scanning Electron Microscopy Study

A rat model has been developed to compare relative morphological changes in the nasal mucosa after exposure to potential membrane permeation enhancers. Scanning electron microscopy was used to characterize gross structural and specific cellular changes following exposure. Micrographs of the rat nasal mucosa were scored in four categories: (1) mucosal surface integrity, (2) ciliary morphology, (3) mucus/extracellular debris, and (4) presence of red blood cells. The order of increasing morphological damage resulting from a 5-min exposure to each surfactant was 0.5% Solulan C-24 0.5% Solulan C-24/0.5% sodium tauro-24,25-dihydrofusidate (STDHF) < 0.5% STDHF < 1.0% STDHF 1.0% Laureth-9 < 1.0% sodium taurodeoxycholate 1.0% sodium deoxycholate. The changes observed in the mucosal morphology after exposure to the various surfactants are in general agreement with data in the literature. This model is able to compare rapidly the relative morphological effects on the mucosal membrane of different nasal formulations.