Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 x 10(-5)), and at chromosome 1p (MLod = 2.65, P = 2.4 x 10(-4)) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 x 10(-4)), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly among Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC.     

The astrocytic response to afferent activity blockade in chick nucleus magnocellularis is independent of synaptic activation, age, and neuronal survival

Astrocytes in nucleus magnocellularis (NM) of the chick respond to afferent activity blockade with increased immunoreactivity for glial fibrillary acidic protein (GFAP). NM neurons respond to the same manipulations with reduced protein synthesis, ribosomal dissociation, and subsequent death of a subset of these neurons. In the present study, we sought to evaluate the relationship between these neuronal and glial responses and to determine if similar activity-dependent mechanisms mediate them. We first examined the anatomical relationship between NM neurons and astrocytic processes by electron microscopy and GFAP immunostaining. Both methods showed that NM neurons deprived of activity for 6 hr were apposed by more glial processes than active NM neurons. However, we found no preferential positioning of GFAP-immunoreactive processes near neurons of the dying or surviving populations, and there were no differences in glial process apposition to dying versus surviving neurons at the EM level. To determine whether the astrocytic response is similar to the neuronal response in age dependence, GFAP immunoreactivity was analyzed in adult chickens following unilateral afferent activity blockade. Unlike the neuronal response to activity blockade, the astrocytic response is equally strong in adult animals. These results imply an independence of the neuronal and astrocytic responses to activity blockade, raising the possibility that these two cell types may be responding to different activity-related signals. This possibility was tested using an in vitro slice preparation. Unilateral stimulation of NM was provided in three ways: orthodromically, antidromically, and orthodromically in a low-calcium medium. The regulation of astrocytic GFAP immunoreactivity by these manipulations of activity was then analyzed. The results of these experiments show that, unlike neuronal protein synthesis, astrocytic GFAP immunoreactivity can be suppressed by either presynaptic or postsynaptic neuronal activity. Therefore, the astrocytes and neurons are regulated by different activity-dependent signals and, by the present measures, their responses to activity blockade appear independent of one another.     

Systemic and cellular calcium metabolism and hypertension

The calcium status of humans with essential hypertension and genetic animal models of hypertension is characterized by low serum ionized calcium concentration, increased urinary calcium excretion, and increased parathyroid hormone (PTH) concentration. Calcitriol metabolism and bone mineralization are also altered in hypertension. These alterations in systemic calcium metabolism may be linked to factors responsible for the elevated blood pressure. Cytosolic free calcium tends to be increased in most cells that have been studied from hypertensive humans and animals. Changes in cellular calcium metabolism may be partly mediated by calcium-regulating hormones that tend to be elevated in essential hypertension such as PTH and calcitriol. Administration of supplemental dietary calcium tends to suppress PTH, calcitriol, and intracellular free calcium. Further research is need concerning the observed association among systemic markers of calcium metabolism, cellular calcium metabolism, and arterial blood pressure regulation.     

Sequence and temperature effect on hydrogen bond disruption in DNA determined by a statistical analysis

Multiple closely related, yet distinct, isoforms exist for each of the cardiac contractile proteins. The isoform composition of the heart changes in response to developmental and physiologic cues. This paper reviews the molecular basis for cardiac contractile protein isoform diversity and the functional consequences of isoform shifts.     

Effect of low dose UVB irradiation on the migratory properties and functional capacities of human skin dendritic cells

We recently described the 'spontaneous' migration of skin dendritic cells out of human split skin during culture. Since newly infiltrating cells from the circulation are excluded, this in vitro model is very suitable for studying the effect of UVB irradiation on the migratory properties, phenotype and functional capacities of skin cells. In the present study, we show that UVB irradiation of the skin before the culture period results in a significantly lower number of migrated cells that could be obtained compared with untreated skin. Relatively more dendritic cells of the population that migrated from UVB-irradiated skin were of dermal origin, as indicated by a higher percentage of CD1b+ cells. These data imply that UVB irradiation inhibits migration, especially of the epidermal Langerhans cells. Ultrastructural analysis of the irradiated skin revealed that the UVB dose used did not cause any directly visible damage to the cells. However, the cell population that had migrated from UVB-irradiated skin showed a significantly lower capacity to stimulate allogeneic T cells. This was not due to a lower expression of MHC class II on these cells. The percentage of cells expressing B7.1, B7.2 and LFA-3 was decreased in the population migrated from irradiated skin. The possible mechanism underlying the UVB-induced suppression is discussed.     

The phenolic recognition profiles of the Agrobacterium tumefaciens VirA protein are broadened by a high level of the sugar binding protein ChvE

The formation of crown gall tumors by Agrobacterium tumefaciens requires that the virulence (vir) genes be induced by chemical signals which consist of specific phenolic compounds and monosaccharides, synthesized at plant wound sites. Signal transduction in the activation of these genes is mediated by the VirA-VirG two-component regulatory system, together with ChvE, a glucose-galactose binding protein which interacts with VirA. We have previously presented genetic evidence that virA senses phenolic compounds directly (Y.-W. Lee, S. Jin, W.-S. Sim, and E. W. Nester, Proc. Natl. Acad. Sci. USA 92:12245-12249, 1995). The vir genes of strain KU12 can be induced by 4-hydroxyacetophenone, p-coumaric acid, and phenol, whereas these same phenolic compounds are weak inducers of the vir genes of strain A6. In this report, we show that a specific inducing sugar can broaden the specificity of the phenolic compound which VirA senses. 4-Hydroxyacetophenone and other related phenolic compounds function as inducing phenolic compounds with the virA gene of A6 if arabinose replaces glucose as the inducing sugar. We further demonstrate that this broadened specificity for phenolic inducers results from the increased level of ChvE through induction by arabinose via the regulatory protein GbpR. If high levels of ChvE are present, then poorly inducing phenolic compounds can induce the vir genes to high levels in combination with glucose. Comparing the induction response of the wild type and that of a VirA mutant with a mutation in its receiver domain revealed that the activity of the receiver domain is controlled by the periplasmic domain. We discuss these observations in terms of how VirA senses and transduces signals elicited by the two classes of plant signal molecules.     

More than 10 years of unrecognized nosocomial transmission of legionnaires' disease among transplant patients

OBJECTIVE: To investigate a cluster of cases of legionnaires' disease among patients at a hospital. SETTING: A university hospital that is a regional transplant center. DESIGN: Retrospective review of microbiology and serology data from the hospital laboratories and prospective surveillance via the radiology department; a case-control study and environmental sampling within the hospital and from nearby cooling towers. RESULTS: Diagnosis of seven cases of legionnaires' disease in the first 9 months of 1996 led to recognition of a nosocomial outbreak that may have begun as early as 1979. Review of charts from 1987 through September 1996 identified 25 culture-confirmed cases of nosocomial or possibly nosocomial legionnaires' disease, including 18 in bone marrow and heart transplant patients. Twelve patients (48%) died. During the first 9 months of 1996, the attack rate was 6% among cardiac and bone marrow transplant patients. For cases that occurred before 1996, intubation was associated with increased risk for disease. High-dose corticosteroid medication was strongly associated with the risk for disease, but other immunosuppressive therapy or cancer chemotherapy was not. Several species and serogroups of Legionella were isolated from numerous sites in the hospital's potable water system. Six of seven available clinical isolates were identical and were indistinguishable from environmental isolates by pulsed-field gel electrophoresis. Initial infection control measures failed to interrupt nosocomial acquisition of infection. After extensive modifications to the water system, closely monitored repeated hyperchlorinations, and reduction of patient exposures to aerosols, transmission was interrupted. No cases have been identified since September 1996. CONCLUSIONS: Legionella can colonize hospital potable water systems for long periods of time, resulting in an ongoing risk for patients, especially those who are immunocompromised. In this hospital, nosocomial transmission possibly occurred for more than 17 years and was interrupted in 1996, after a sudden increase in incidence led to its recognition. Hospitals specializing in the care of immunocompromised patients (eg, transplant centers) should prioritize surveillance for cases of legionnaires' disease. Aggressive control measures can interrupt transmission of this disease successfully.     

Spectral properties of fluorescein in solvent-water mixtures: applications as a probe of hydrogen bonding environments in biological systems

In a 4-year study we examined the longitudinal effects of deinstitutionalization programs on those who remain in institutions being downsized. Individual outcomes investigated were community access, social activities, community inclusion, family relationships, and choice. Effects of residential relocation on individual outcomes such as adaptive behavior were evaluated and total daily per-person expenditure on institutional services for participants was determined. Downsizing was associated with decreased community integration but no change in most other outcomes. Availability of therapy services fell over time, and individuals experienced many residential and day program moves within the institution. Per person expenditure on services increased substantially. Finally, no significant changes in adaptive behavior were associated with intrainstitutional moves.