Testing concordance of clinical characteristics in familial studies with application to inflammatory bowel diseases

The etiology of chronic Inflammatory Bowel Diseases (IBD) remains unknown, with both genetic and environmental risk factors having been implicated. A recent collaborative study of IBD provides clinical data from families with three or more affected first-degree relatives. The scientific question is whether specific clinical characteristics aggregate among affected individuals within families. Gastroenterological researchers have examined the number of concordant familial pairs in familial aggregation studies, but methods and results have been discrepant. This article investigates concepts of concordance and gives a comprehensive statistical treatment for testing concordance of various clinical traits in familial studies. For dichotomous traits, the distribution of this statistic under the null hypothesis of no familial aggregation is obtained by three methods: asymptotic, probability generating function, and permutation. The permutation method is extended to analyze aggregation for non-dichotomous traits and co-aggregations between two traits. We apply the permutation method to analyze the aforementioned multiply-affected IBD family data. Evidence is found for familial clustering of various traits, some of which are not revealed in existing studies. Such analyses provide a basis for investigating the dependence of trait aggregation upon genetic or environmental risk factors.     

A de novo reciprocal t(2;18) translocation with regular trisomy 21

A 4-year-old girl with Down syndrome exhibited an autosomal translocation t(2;18) in addition to trisomy 21. An evaluation of GTG-banded metaphases revealed the karyotype 47,XX,t(2;18),21 that was confirmed by using fluorescent in situ hybridization (FISH) probes. This case represents a very rare coincidence of an autosomal aneuploidy and a structural rearrangement. Her parents showed a normal chromosome complement. The translocation must have been an apparently "balanced" one as the proband presented with typical features of Down syndrome alone. The mechanism of origin of this rearrangement along with a nondisjunctional error and its significance are discussed.     

Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging

The extracellular matrix (ECM), once thought to solely provide physical support to a tissue, is a key component of a cell’s microenvironment responsible for directing cell fate and maintaining tissue specificity. It stands to reason, then, that changes in the ECM itself or in how signals from the ECM are presented to or interpreted by cells can disrupt tissue organization; the latter is a necessary step for malignant progression. In this review, we elaborate on this concept using the mammary gland as an example. We describe how the ECM directs mammary gland formation and function, and discuss how a cell’s inability to interpret these signals—whether as a result of genetic insults or physicochemical alterations in the ECM—disorganizes the gland and promotes malignancy. By restoring context and forcing cells to properly interpret these native signals, aberrant behavior can be quelled and organization re-established. Traditional imaging approaches have been a key complement to the standard biochemical, molecular, and cell biology approaches used in these studies. Utilizing imaging modalities with enhanced spatial resolution in live tissues may uncover additional means by which the ECM regulates tissue structure, on different length scales, through its pericellular organization (short-scale) and by biasing morphogenic and morphostatic gradients (long-scale). Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Does perceived financial strain predict depression among young women? Longitudinal findings from the Southampton Women's Survey

Background Social and financial environment has an influence on the incidence of depression. We studied perceived financial strain as a risk factor for development of depression among a large cohort of young women in Southampton, UK.Methods We recruited a large number of young women in Southampton in the Southampton Women's Survey, a longitudinal study looking at factors influencing the health of women and their offspring. Women were asked to complete a baseline questionnaire, which included the GHQ-12 (an assessment of mental health), as well as questions on perceived financial strain and past history of depression. They were followed up two years later through their general practitioner (GP) records for evidence of incident mental illness.Results A total of 7020 women completed the baseline questionnaire including the GHQ-12. Of these, 5237 (74.6%) had records available for follow-up. Among those developing depression, there was a higher proportion receiving benefits, and a higher level of perceived financial strain. There were also modest elevations in perceived stress, and poorer levels of educational attainment. Among women not depressed at baseline, and with no previous history of depression, those in receipt of state benefits at baseline had a significantly elevated risk of developing the disorder - hazard ratio 1.61 (95% confidence interval (CI) 1.13-2.3). The risk associated with perceived financial strain was 2.16 (95% CI 1.14-4.11), but this did not remain statistically significant after adjustment was made for receipt of benefits, educational qualification, and perceived stress.Conclusion Financial hardship as evidenced by receipt of benefits is a strong independent predictor for the development of depression. Although perception of financial strain is also a predictor for incident depression, the risk associated with this subjective characteristic does not remain significantly elevated after adjustment. Future studies of the aetiology of depression should incorporate ascertainment of actual financial status.     

On the formation of the neural keel and neural tube in the zebrafishDanio (Brachydanio) rerio

Morphogenetic movements accompanying formation of the neural keel and neural tube in the zebrafishDanino (Brachydanio) rerio were studied by labelling single neural plate cells with fluoresceinated dextran (FDA) during late gastrula stages (95–100% epiboly) and localizing their progeny with an anti-fluorescein antibody on histological sections throughout neurulation. The mediolateral extent of the neural plate correlates directly with the dorso-ventral extent of the neural tube. That is to say, the progeny of cells located medially in the neural plate come to lie ventrally in the neural tube; cells located laterally in the neural plate give rise to progeny that populate dorsal levels in the neural tube. Fixation of labelled cells at various stages reveals that neural keel and nerve rod are organized as monostratified epithelia and that they maintain this organization during neurulation. These observations strongly suggest that the neural keel in the zebrafish forms by way of infolding of the neural plate and, therefore, utilizes a mechanism similar to primary neurulation in other vertebrates. The folding process juxtaposes the apical surfaces of both flanks of the neural plate at the midline. Mitoses occur preferentially in this zone, leading very frequently to formation of bilaterally symmetrical clones of progeny cells. The size of the clones that develop from injected cells suggests that neural plate cells divide an 1.5 times on average between late gastrula and the end of neurulation. Correspondence to: J.A. Campos-Ortega     

The linked conservation of structure and function in a family of high diversity: the monomeric cupredoxins

The monomeric cupredoxins are a highly divergent family of copper binding electron transport proteins that function in photosynthesis and respiration. To determine how function and structure are conserved in the context of large sequence differences, we have carried out a detailed analysis of the cupredoxins of known structure and their sequence homologs. The common structure of the cupredoxins is formed by a sandwich of two beta sheets which support a copper binding site. The structure of the deeply buried core is intimately coupled to the binding site on the surface of the protein; in each protein the conserved regions form one continuous substructure that extends from the surface active site and through the center of the molecule. Residues around the active site are conserved for functional reasons, while those deeper in the structure will be conserved for structural reasons. Together the two sets support each other.     

Differential effects of a heparin antagonist (hexadimethrine) or chlorate on amphiregulin,basic fibroblast growth factor,and heparin-binding EGF-like growth factor activity

Amphiregulin (AR) and heparin-binding EGF-like growth factor (HB-EGF) are two recently identified members of the EGF family. Both AR and HB-EGF share with EGF the ability to interact with the type-1 EGF receptor; however, AR and HB-EGF differ from EGF in that both of these mitogens bind to heparin while EGF does not. To determine whether interactions with heparin-like molecules on the cell surface influence binding of AR and HB-EGF with EGF receptors and the subsequent mitogenic activity exerted by these growth factors, murine AKR-2B and Balb/MK-2 cells were treated with either an inhibitor of proteoglycan sulfation (chlorate) or a heparin antagonist (hexadimethrine). As expected, neither treatment significantly altered the specific binding of ¹²⁵I-EGF on AKR-2B cells. Interestingly, treatment with either chlorate or hexadimethrine inhibited the ability of AR to compete with ¹²⁵I-EGF for cell surface binding and also attenuated AR-mediated DNA synthesis. Thus, as has been suggested for other heparin-binding growth factors such as basic fibroblast growth factor (bFGF), the interaction of AR with an EGF-binding receptor appears to be facilitated by interaction with cell-associated sulfated glycosami-noglycans or proteoglycans. Unexpectedly, however, neither chlorate nor hexadimethrine treatment caused an inhibition of HB-EGF-induced mitogenic activity. Chlorate treatment did not significantly alter the ability of HB-EGF to compete with ¹²⁵I-EGF for cell surface binding sites, however, heparin and hexadimethrine reduced the ability of HB-EGF to compete for ¹²⁵I-EGF binding. These results suggest that, in AKR-2B cells, HB-EGF may mediate its mitogenic response at least in part through a receptor which appears to be selective for HB-EGF and permits HB-EGF-mediated mitogenic responses in the presence of hexadimethrine or heparin. Finally, hexadimethrine inhibited the specific binding and mitogenic activity of bFGF, suggesting that this cationic polymer can function as an antagonist of heparin-binding mitogens other than AR. © 1995 Wiley-Liss, Inc.