Association of ulcerative colitis with the inflammatory bowel disease susceptibility locus IBD2 in non-Jewish Caucasians and evidence of genetic heterogeneity among racial and ethnic populations with Crohn disease

Genomewide scanning has been used to identify chromosomal regions encoding susceptibility loci to inflammatory bowel disease (IBD). The greatest evidence for linkage to IBD has been reported for a region of chromosome 12q14 surrounding the microsatellite marker D12S83, with a logarithm of odds score of 5.47 and a positive transmission disequilibrium test, and which was subsequently named IBD2. We wished to confirm this locus by genotyping the highly polymorphic microsatellites D12S1022, D12S1056, and D12S83, spanning a continuous region on chromosome 12 of 342 kb, in a cohort of nonrelated individuals with ulcerative colitis (89 patients), Crohn disease (121 patients), and population-based control subjects (100 patients). In non-Jewish Caucasians, one D12S1022 allele, one D12S1056 genotype, and three D12S83 alleles were found to have statistically significant differences in distribution between the two disease groups and the control population. These data support a significant association of IBD with the IBD2 locus in close vicinity to the three markers studied. The replication of genetic risk loci in a case control association study may indicate susceptibility genes in this region and may facilitate identification of candidate genes for IBD. Subgroup analysis revealed a notable difference in genotype distribution among Jewish Caucasian and African American patients affected with Crohn disease when compared with similarly affected non-Jewish Caucasians. Using Fisher exact test, statistically significant distribution differences were observed for D12S1022 and D12S83. These data indicate that there may be significant genetic heterogeneity between different ethnic and racial IBD populations or may simply reflect differences in marker allele frequencies among populations.     

Ageing is associated with a decrease in the number of sarcolemmal ATP-sensitive K+ channels in a gender-dependent manner

The opening of sarcolemmal K(ATP) channels is considered to be an important endogenous cardioprotective mechanism. On the other hand, age-dependent changes in the myocardial susceptibility to ischemia and hypoxia have been observed in different species, including humans. Here, we have hypothesized that aging might be associated with the changes in sarcolemmal K(ATP) channels. Therefore, the main objective of the present study was to establish whether aging changes expression of cardiac sarcolemmal ATP-sensitive K+ (K(ATP)) channels. RT-PCR using primers specific for K(ATP) channel subunits, Kir6.2, Kir6.1 and SUR2A subunits was performed using total RNA from guinea-pig ventricular tissue. Whole cell electrophysiology was done on isolated guinea-pig ventricular cardiomyocytes. Western blotting using anti-Kir6.2 and anti-SUR2A antibodies was performed on cardiac membrane fraction. Tissue and cells were harvested from young and old, male and female guinea-pigs. RT-PCR analysis did not reveal significant age-related changes in levels of Kir6.1 or Kir6.2 mRNAs. However, levels of SUR2A were significantly lower in old than in young females. Such age-differences were not observed with cardiac tissue from male animals. In both old and young males, pinacidil (100 microM) induced outward currents. The difference between current density of pinacidil-sensitive component in females, but not males, was statistically significant. Western blotting analysis revealed higher levels of Kir6.2 and SUR2A proteins in cardiac membrane fraction from young than old females. The present study demonstrates that in females, but not males, aging is associated with decrease in number of cardiac K(ATP) channels which is due to decrease in levels of the SUR2A subunit.     

Utilization of acidophil bodies in the diagnosis of recurrent hepatitis C infection after orthotopic liver transplantation.

BACKGROUND: The distinction between acute rejection and early recurrent hepatitis C infection (RHCV) in the setting of orthotopic liver transplantation is often difficult. In liver biopsies acidophil bodies and lobular hepatitis are used to suggest a diagnosis of RHCV over rejection, however, the reliability of this practice has not been established. Because portal tract changes in RHCV and rejection often overlap, we sought to determine whether the degree of hepatocyte acidophil body formation seen on liver biopsies could be used to distinguish between these two conditions. METHODS: Quantification of acidophil bodies was performed on liver biopsies in orthotopic liver transplant patients with RHCV (n = 10), non-hepatitis C orthotopic liver transplant patients with uncomplicated rejection episodes (n = 10) and non-transplant patients with chronic hepatitis C infection (n = 10). Hematoxylin and Eosin stained slides from all three groups were randomized and tissue segments 1.0 cm in length and of variable width (0.04-0.13 cm) were examined at 200x magnification in a blinded fashion by two pathologists in order to quantify the number of acidophil bodies/cm(2). Lobular chronic inflammation was also graded on a 0-3+ scale. RESULTS: Liver biopsies taken at the onset of RHCV exhibited 606 +/- 101 acidophil bodies/cm(2) (mean +/- standard error of mean, range 200-1390). These counts were significantly greater (P =.0061, paired 2-tailed t-test) than the 241 +/- 53 acidophil bodies/cm(2) (range 80-514) for acute rejection, and the 194 +/- 21 acidophil bodies/cm(2) (range 100-333) for non-liver transplant chronic hepatitis C infection (P =.0013). No difference in lobular inflammation between index RHCV and rejection biopsies was detected. CONCLUSIONS: Although there is overlap, on average there are twice as many acidophil bodies in the initial stage of RHCV when compared with acute rejection (average of 55 per linear cm in RHCV versus 21 per linear cm for rejection). Lobular inflammation was not a reliable indicator of the initial onset of RHCV.     

Megalencephaly in the epileptic chicken: a morphometric study of the adult brain

The epileptic chicken is a genetic model of generalized epilepsy in which epilepsy is combined with megalencephaly. We have performed a morphometric study of the brains of adult epileptic hens, using heterozygous carrier hens as controls. There is no obvious disorder of cell form or of architectural arrangement in the megalencephalic brains. We have found that the enlargement of the epileptic brain is not uniform: it is most marked in the telencephalon, and is present to a lesser degree in the cerebellum, but neither the optic tectum nor the diencephalic nucleus rotundus shows a significant increase in size. The enlarged regions are characterized by a decrease in the packing density of neurons. There is an increase in the total neuron population in some of the enlarged areas (archistriatum), despite the lower density per unit volume, but in other enlarged areas (hippocampus) there is no difference in total neuron numbers. The glial cells, by contrast, show no significant alteration in packing density. These findings suggest that the megalencephaly of the epileptic chicken is due to an increase in neuron size, with a contribution from increased numbers of neurons and glial cells. The epileptic chicken may provide a valuable model for further dynamic studies of aberrant neuronal development, and of structural-functional relationships in epilepsy.     

A controlled trial of leuprolide with and without flutamide in prostatic carcinoma

To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.     

Gender differences at birth and differences in fetal growth

The discrepancy between the number of boys and girls born hasbeen interpreted as a natural selection response to differentialsurvival prospects. There also exists a discrepancy in birthweight, length, head circumference at birth of boys and girls;on the other hand, placental weights were not so strongly biasedby the sex of the fetus. Metabolic differences between the sexesare clearly recognized in adults. It is therefore argued thatthe anthropometric differences at birth, examples of which arepresented in this paper, can only be achieved if the productsof conception are also expressing a sexual bias in metabolismand physiology. It would then be this bias which would determinethe efficiency of the implantation and growth processes andlead to rates of survival to birth. The speculation arisingfrom this and the experimental manipulation of the sex ratiois that the physiological component most likely to be involvedwould be the lipid compartment with its strong sex difference.     

Integration of target and effector information in human posterior parietal cortex for the planning of action

Recently, using event-related functional MRI (fMRI), we located a bilateral region in the human posterior parietal cortex (retIPS) that topographically represents and updates targets for saccades and pointing movements in eye-centered coordinates. To generate movements, this spatial information must be integrated with the selected effector. We now tested whether the activation in retIPS is dependent on the hand selected. Using 4-T fMRI, we compared the activation produced by movements, using either eyes or the left or right hand, to targets presented either leftward or rightward of central fixation. The majority of the regions activated during saccades were also activated during pointing movements, including occipital, posterior parietal, and premotor cortex. The topographic retIPS region was activated more strongly for saccades than for pointing. The activation associated with pointing was significantly greater when pointing with the unseen hand to targets ipsilateral to the hand. For example, although there was activation in the left retIPS when pointing to targets on the right with the left hand, the activation was significantly greater when using the right hand. The mirror symmetric effect was observed in the right retIPS. Similar hand preferences were observed in a nearby anterior occipital region. This effector specificity is consistent with previous clinical and behavioral studies showing that each hand is more effective in directing movements to targets in ipsilateral visual space. We conclude that not only do these regions code target location, but they also appear to integrate target selection with effector selection.     

Computed tomography scanning with simultaneous patient translation

This paper deals with methods of reducing the total time required to acquire the projection data for a set of contiguous computed tomography (CT) images. Normally during the acquisition of a set of slices, the patient is held stationary during data collection and translated to the next axial location during an interscan delay. We demonstrate using computer simulations and scans of volunteers on a modified scanner how acceptable image quality is achieved if the patient translation time is overlapped with data acquisition. If the concurrent patient translation is ignored, structured artifacts significantly degrade resulting reconstructions. We present a number of weighting schemes for use with the conventional convolution/backprojection algorithm to reduce the structured artifacts through the use of projection modulation using the data from individual and multiple slices. We compare the methods with respect to structured artifacts, noise, resolution and to patient motion. Review of preliminary results by a panel of radiologists indicates that the residual image degradation is tolerable for selected applications when it is critical to acquire more slices in a patient breathing cycle than is possible with conventional scanning.