Homozygous parent affected sib pair method for detecting disease predisposing variants: application to insulin dependent diabetes mellitus

For complex genetic diseases involving incomplete penetrance, genetic heterogeneity, and multiple disease genes, it is often difficult to determine the molecular variant(s) responsible for the disease pathogenesis. Linkage and association studies may help identify genetic regions and molecular variants suspected of being directly responsible for disease predisposition or protection, but, especially for complex diseases, they are less useful for determining when a predisposing molecular variant has been identified. In this paper, we expand upon the simple concept that if a genetic factor predisposing to disease has been fully identified, then a parent homozygous for this factor should transmit either of his/her copies at random to any affected children. Closely linked markers are used to determine identity by descent values in affected sib pairs from a parent homozygous for a putative disease predisposing factor. The expected deviation of haplotype sharing from 50%, when not all haplotypes carrying this factor are in fact equally predisposing, has been algebraically determined for a single locus general disease model. Equations to determine expected sharing for multiple disease alleles or multiple disease locus models have been formulated. The recessive case is in practice limiting and therefore can be used to estimate the maximum proportion of putative susceptibility haplotypes which are in fact predisposing to disease when the mode of inheritance of a disease is unknown. This method has been applied to 27 DR3/DR3 parents and 50 DR4/DR4 parents who have at least 2 children affected with insulin dependent diabetes mellitus (IDDM). The transmission of both DR3 and DR4 haplotypes is statistically different from 50% (P < 0.05 and P < 0.001, respectively). An upper estimate for the proportion of DR3 haplotypes associated with a high IDDM susceptibility is 49%, and for DR4 haplotypes 38%. Our results show that the joint presence of non-Asp at DQ beta position 57 and Arg at DQ alpha position 52, which has been proposed as a strong IDDM predisposing factor, is insufficient to explain the HLA component of IDDM predisposition.     

Women Engineers: A Study of Educational Preparation and Professional Success

In an effort to better understand the educational experiences and professional issues facing women in these fields, a survey of women alumnae was conducted. Respondents seemed fairly pleased with the education they received and were heavily influenced by personal aspects of the campus. Relationships with faculty members were described as their most beneficial and detrimental experiences. They particularly liked opportunities to apply their technical knowledge but did not believe there were enough opportunities for application. The need for more female role models and importance of involvement in student organizations were cited by many of the respondents. Self-confidence and good communication skills were rated as the most important qualities for professional success and advancement. Alumnae have pursued training experiences since graduation, but would like to see more opportunities to enhance communication and personal management skills and apply theoretical knowledge built into the undergraduate experience. The findings are discussed in relationship to previous research studies and recommendations are made to improve the technically oriented college environment.     

Comparison of magnetic resonance volume flow rates, angiography, and carotid Dopplers. Preliminary results

BACKGROUND AND PURPOSE: We compared the results of conventional angiography, carotid Doppler, and magnetic resonance angiography volume flow rates to determine the clinical utility of volume flow rate assessment of blood flow to the anterior circulation in patients with carotid occlusive disease. METHODS: From 11 symptomatic patients, a total of 22 extracranial carotid arteries were studied with all three techniques. The studies were independently read, and regression analysis was used to compare the measurements. RESULTS: Carotid Doppler measurements of the distal extracranial carotid arteries were proportional to the inverse of the extracranial carotid volume flow rate (r = .53, R2 = 29%, P < .01), volume flow rates were proportional to the inverse of measured percent stenosis on angiography (r = .84, R2 = 71%, P < .01), and Dopplers were proportional to angiography (r = .94, R2 = 90%, P < .01). Symptomatic Doppler systolic velocity was significantly higher (P < .002), symptomatic measured stenosis was significantly higher (P < .002), and symptomatic volume flow rate was significantly lower (P < .01) than their respective asymptomatic-side values. These preliminary observations, however, may well change once a large data set, especially one in which more patients with high-grade carotid stenosis are included, is studied. CONCLUSIONS: Assessment of carotid volume flow rates by magnetic resonance angiography quantifies flow reduction secondary to atherosclerotic occlusive disease. The easily obtained flow data add both documentation of arterial flow characteristics related to internal carotid stenosis and information regarding the adequacy of collateral pathways.     

Angiotensin II receptor type 1 mRNA is upregulated in atria of patients with end-stage heart failure

There is increasing evidence that pathological changes in the myocardium during chronic heart failure (CHF) are partly regulated through the activation of the renin-angiotensin system (RAS), an effect mediated by the angiotensin II type 1 receptor (AT1R). We examined the expression of cardiac AT1R mRNA in normal (atria, n=7; ventricle, n=3) and end-stage CHF human hearts (atria, n=8; ventricle, n=14). Tissue was snap-frozen immediately after explantation during orthotopic cardiac transplantation; control specimens were obtained from healthy donor hearts rejected for technical reasons. Northern blots of purified total mRNA from each tissue were hybridized with a random primed radiolabeled probe for the coding sequence of AT1R. Stringent conditions were used for both hybridization (5X SSC, 65 degrees C) and washing (0.5X SSC, 0.1% SDS, 65 degrees C) of the membrane. Left and right atrial tissue showed low levels of AT1R mRNA expression in the controls, with statistically significant upregulation of expression in tissue from pathological hearts; CHF atria 1.28+/-0.86 optical density (OD) units, control atria 0.56+/-0.31 OD units, P=0.05 (mean+/-s.d.). There were undetectable levels in ventricles from either control (2/2) or dilated hearts (7/7). The results were independent of the etiology of the heart failure and suggest that increased levels of atrial AT1R mRNA may occur in response to elevated atrial pressures in heart failure.     

Knowing Good From Bad: The Paradox of Neuroticism, Negative Affect, and Evaluative Processing.

There are pragmatic benefits to trait-consistent mood states, especially when people are evaluating new objects within the environment (M. Tamir, M. D. Robinson, & G. L. Clore, 2002). The present studies, involving both naturally occurring (Studies 1 and 2) and manipulated (Study 3) mood states, demonstrated such trait-consistent interactions within the context of neuroticism and negative mood states. Individuals high in neuroticism were faster to make evaluations when in a negative mood state like sadness. By contrast, individuals low in neuroticism were faster to make evaluations when in a neutral mood state. The present studies demonstrate that although negative mood states are hedonically unpleasant, they can be beneficial in some ways for individuals high in neuroticism. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Electrical and optical feedback in an InGaAs/InP light-amplifyingoptical switch (LAOS)

A circuit model for optical and electrical feedback has been developed to investigate the cause of negative differential resistance (NDR) switching in a series connected heterojunction phototransistor (HPT) light-emitting diode (LED) device. The model considers optical feedback from the light generated in the LED, electrical feedback from the holes thermally emitted over the LED cladding layer, nonlinear gain of the HPT, the Early effect, and leakage resistance. The analysis shows that either electrical or optical feedback can be the dominant cause for the NDR, depending upon their relative strengths. The NDR observed in the devices was caused primarily by electrical feedback since the optical feedback is weak. For low input power, avalanche breakdown appears to initiate the NDR in the devices although avalanching alone cannot cause NDR     

A multimedia interactive conferencing application for personalworkstations

The multimedia interactive conferencing application (MICA), a personal-workstation application for multipoint visual teleconferencing, is described. MICA allows people at two or more locations to share visual material such as documents, photographs, and computer screens in a highly interactive way. It supports the distribution, storage, retrieval, and high-quality display of visuals, real-time interaction by pointing and annotation, and meeting services facilities. The context of multimedia teleconferencing and computer-supported cooperative work is established, relating earlier research to the design of MICA. The services MICA offers are outlined. The handling, compression, and display of multiple media, and the design of a suitable user interface for MICA are discussed