Contribution of the genes of the renin-angiotensin system to interindividual differences in blood pressure levels in Caucasians from Rochester, Minnesota

The Renin-Angiotensin system (RAS) regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. The genes encoding the four major components of the RAS, angiotensinogen, renin, angiotensin I-converting enzyme (ACE), and angiotensin II receptor type 1 (AT1), have been investigated as candidate genes in the pathogenesis of essential hypertension. However, studies have primarily focused on small samples of diseased individuals, and, therefore, have provided little information about the determinants of interindividual variation in blood pressure (BP) in the general population.^ Using data from a large population-based sample from Rochester, MN, I have evaluated the contribution of variation in the region of the RAS genes to interindividual variation in systolic, diastolic, and mean arterial pressure in the population-at-large. Marker genotype data from four polymorphisms located within or very near these genes were first collected on 3,974 individuals from 583 randomly ascertained three-generation pedigrees. Haseman-Elston regression and variance component methods of linkage analysis were then carried out to estimate the proportion of interindividual variance in BP attributable to the effects of variation at these four measured loci.^ A significant effect of the ACE locus on interindividual variation in mean arterial pressure (MAP) was detected in a sample of siblings belonging to the youngest generation. After allowing for measured covariates, this effect accounted for 15-25% of the interindividual variance in MAP, and was even greater in a subset with a positive family history of hypertension. When gender-specific analyses were carried out, this effect was significant in males but not in females. Extended pedigree analyses also provided evidence for an effect of the ACE locus on interindividual variation in MAP, but no difference between males and females was observed. Circumstantial evidence suggests that the ACE gene itself may be responsible for the observed effects on BP, although the possibility that other genes in the region may be at play cannot be excluded.^ No definitive evidence for an effect of the renin, angiotensinogen, or AT1 loci on interindividual variation in BP was obtained in this study, suggesting that the impact of these genes on BP may not be great in the Caucasian population-at-large. However, this does not preclude a larger effect of these genes in some subsets of individuals, especially among those with clinically manifest hypertension or coronary heart disease, or in other populations. ^

Design and implementation of a multicriteria medical decision support system for diagnosis and treatment

Health care providers face the problem of trying to make decisions with inadequate information and also with an overload of (often contradictory) information. Physicians often choose treatment long before they know which disease is present. Indeed, uncertainty is intrinsic to the practice of medicine. Decision analysis can help physicians structure and work through a medical decision problem, and can provide reassurance that decisions are rational and consistent with the beliefs and preferences of other physicians and patients. ^ The primary purpose of this research project is to develop the theory, methods, techniques and tools necessary for designing and implementing a system to support solving medical decision problems. A case study involving “abdominal pain” serves as a prototype for implementing the system. The research, however, focuses on a generic class of problems and aims at covering theoretical as well as practical aspects of the system developed. ^ The main contributions of this research are: (1) bridging the gap between the statistical approach and the knowledge-based (expert) approach to medical decision making; (2) linking a collection of methods, techniques and tools together to allow for the design of a medical decision support system, based on a framework that involves the Analytic Network Process (ANP), the generalization of the Analytic Hierarchy Process (AHP) to dependence and feedback, for problems involving diagnosis and treatment; (3) enhancing the representation and manipulation of uncertainty in the ANP framework by incorporating group consensus weights; and (4) developing a computer program to assist in the implementation of the system. ^

An evaluation of the personal response system program for the elderly in Harris County, Texas

The Personal Response System Program at Huffington Center on Aging, Baylor College of Medicine, provides emergency call systems for elderly people living independently in Houston, Texas. The goal of the project was to complete a formative evaluation of the Personal Response System Program. The specific aims of the evaluation were three-fold. One aim was to evaluate participant health status and level of disability. The second aim was to develop a health care cost estimation strategy. Finally, a preliminary cost-effectiveness analysis was completed to evaluate the program's impact on health care costs and health status among the elderly target population. ^ The evaluation was a longitudinal, randomized experimental design. After the screening of 120 volunteers for eligibility, clients were asked to complete a written questionnaire and a monthly health service contact diary. Volunteers were contacted by telephone interviewers to collect health status information from 100 eligible clients (83%) on three occasions during the six months of follow-up. ^ Initially, volunteers were randomized to two experimental groups. The two groups were found to be comparable at the beginning of the study. No significant differences were detected related to health status, level of disability, or history of physician visits at baseline. However, the group with the Personal Response System (PRS) device had more adverse health events, higher IADL scores, more frequent use of walkers, lower average health status scores, and fewer community volunteers hours than the usual care comparison group. ^ The health care costs were estimated based on an algorithm adapted from the American Medical Association guidelines. Average total health care costs for the group with the PRS device ($912) were greater than the usual care group ($464). However, median health care values for the PRS group ($263) were similar to the usual care comparison group ($234). The preliminary findings indicated that the use of the PRS device was not associated with health care cost savings. ^ In the preliminary cost-effectiveness analysis, use of the personal response system was found to be associated with increased mental health status among elderly clients. The cost-effectiveness evaluation indicated that the associated cost for six months was $710 per unit increase in mental component score when the $150 PRS subscription was included. However, clients with the PRS device were found to have a greater decline in physical health status during the six-month follow-up. The beneficial effect on mental health status was found to be in contrast to negative findings associated with changes in physical health status. The implications for future research relate to the need to identify risk factors among geriatric populations to better target groups that would most likely benefit from PRS Program enrollment. ^

The transformation of a health care system: An ecology perspective

Beginning in the early 1980s, the health care system experienced momentous realignments. Fundamental changes in structures of traditional health care organizations, shifts in authority and relationships of professionals and institutions, and the increasing influence of managed care contributed to a relatively stable industry entering into a state of turbulence. The dynamics of these changes are recurring themes in the health services literature. The purpose of this dissertation was to examine the content of this literature over a defined time period and within the perspective of a theory of organizational change. ^ Using a theoretical framework based upon the organizational theory known as Organizational Ecology, secondary data from the period between 1983 and 1994 was reviewed. Analysis of the literature identified through a defined search methodology was focused upon determining the manner in which the literature characterized changes that were described. Using a model constructed from fundamentals of Organizational Ecology with which to structure an assessment of content, literature was summarized for the manner and extent of change in specific organizational forms and for the changes in emphasis by the environmental dynamics directing changes in the population of organizations. Although it was not the intent of the analysis to substantiate causal relationships between environmental resources selected as the determinants of organizational change and the observed changes in organizational forms, the structured review of content of the literature established a strong basis for inferring such a relationship. ^ The results of the integrative review of the literature and the power of the appraisal achieved through the theoretical framework constructed for the analysis indicate that there is considerable value in such an approach. An historical perspective on changes which have transformed the health care system developed within a defined organizational theory provide a unique insight into these changes and indicate the need for further development of such an analytical model. ^

HUMAN PROPHASE CHROMOSOME UNIQUE BAND SEQUENCES; DEFINITION, CHARACTERIZATION, AND APPLICATION (CYTOGENETICS, IMAGE PROCESSING)

Extensive experience with the analysis of human prophase chromosomes and studies into the complexity of prophase GTG-banding patterns have suggested that at least some prophase chromosomal segments can be accurately identified and characterized independently of the morphology of the chromosome as a whole. In this dissertation the feasibility of identifying and analyzing specified prophase chromosome segments was thus investigated as an alternative approach to prophase chromosome analysis based on whole chromosome recognition. Through the use of prophase idiograms at the 850-band-stage (FRANCKE, 1981) and a comparison system based on the calculation of cross-correlation coefficients between idiogram profiles, we have demonstrated that it is possible to divide the 24 human prophase idiograms into a set of 94 unique band sequences. Each unique band sequence has a banding pattern that is recognizable and distinct from any other non-homologous chromosome portion.^ Using chromosomes 11p and 16 thru 22 to demonstrate unique band sequence integrity at the chromosome level, we found that prophase chromosome banding pattern variation can be compensated for and that a set of unique band sequences very similar to those at the idiogram level can be identified on actual chromosomes.^ The use of a unique band sequence approach in prophase chromosome analysis is expected to increase efficiency and sensitivity through more effective use of available banding information. The use of a unique band sequence approach to prophase chromosome analysis is discussed both at the routine level by cytogeneticists and at an image processing level with a semi-automated approach to prophase chromosome analysis. ^

State of the Antarctic and Southern Ocean Climate System

This paper reviews developments in our understanding of the state of the Antarctic and Southern Ocean climate and its relation to the global climate system over the last few millennia. Climate over this and earlier periods has not been stable, as evidenced by the occurrence of abrupt changes in atmospheric circulation and temperature recorded in Antarctic ice core proxies for past climate. Two of the most prominent abrupt climate change events are characterized by intensification of the circumpolar westerlies (also known as the Southern Annular Mode) between similar to 6000 and 5000 years ago and since 1200-1000 years ago. Following the last of these is a period of major trans-Antarctic reorganization of atmospheric circulation and temperature between A. D. 1700 and 1850. The two earlier Antarctic abrupt climate change events appear linked to but predate by several centuries even more abrupt climate change in the North Atlantic, and the end of the more recent event is coincident with reorganization of atmospheric circulation in the North Pacific. Improved understanding of such events and of the associations between abrupt climate change events recorded in both hemispheres is critical to predicting the impact and timing of future abrupt climate change events potentially forced by anthropogenic changes in greenhouse gases and aerosols. Special attention is given to the climate of the past 200 years, which was recorded by a network of recently available shallow firn cores, and to that of the past 50 years, which was monitored by the continuous instrumental record. Significant regional climate changes have taken place in the Antarctic during the past 50 years. Atmospheric temperatures have increased markedly over the Antarctic Peninsula, linked to nearby ocean warming and intensification of the circumpolar westerlies. Glaciers are retreating on the peninsula, in Patagonia, on the sub-Antarctic islands, and in West Antarctica adjacent to the peninsula. The penetration of marine air masses has become more pronounced over parts of West Antarctica. Above the surface, the Antarctic troposphere has warmed during winter while the stratosphere has cooled year-round. The upper kilometer of the circumpolar Southern Ocean has warmed, Antarctic Bottom Water across a wide sector off East Antarctica has freshened, and the densest bottom water in the Weddell Sea has warmed. In contrast to these regional climate changes, over most of Antarctica, near-surface temperature and snowfall have not increased significantly during at least the past 50 years, and proxy data suggest that the atmospheric circulation over the interior has remained in a similar state for at least the past 200 years. Furthermore, the total sea ice cover around Antarctica has exhibited no significant overall change since reliable satellite monitoring began in the late 1970s, despite large but compensating regional changes. The inhomogeneity of Antarctic climate in space and time implies that recent Antarctic climate changes are due on the one hand to a combination of strong multidecadal variability and anthropogenic effects and, as demonstrated by the paleoclimate record, on the other hand to multidecadal to millennial scale and longer natural variability forced through changes in orbital insolation, greenhouse gases, solar variability, ice dynamics, and aerosols. Model projections suggest that over the 21st century the Antarctic interior will warm by 3.4 degrees +/- 1 degrees C, and sea ice extent will decrease by similar to 30%. Ice sheet models are not yet adequate enough to answer pressing questins about the effect of projected warming on mass balance and sea level. Considering the potentially major impacts of a warming climate on Antarctica, vigorous efforts are needed to better understand all aspects of the highly coupled Antarctic climate system as well as its influence on the Earth's climate and oceans.

Satellite-Derived Variability in Chlorophyll, Wind Stress, Sea Surface Height, and Temperature in the Northern California Current System

Satellite-derived data provide the temporal means and seasonal and nonseasonal variability of four physical and biological parameters off Oregon and Washington ( 41 degrees - 48.5 degrees N). Eight years of data ( 1998 - 2005) are available for surface chlorophyll concentrations, sea surface temperature ( SST), and sea surface height, while six years of data ( 2000 - 2005) are available for surface wind stress. Strong cross-shelf and alongshore variability is apparent in the temporal mean and seasonal climatology of all four variables. Two latitudinal regions are identified and separated at 44 degrees - 46 degrees N, where the coastal ocean experiences a change in the direction of the mean alongshore wind stress, is influenced by topographic features, and has differing exposure to the Columbia River Plume. All these factors may play a part in defining the distinct regimes in the northern and southern regions. Nonseasonal signals account for similar to 60 - 75% of the dynamical variables. An empirical orthogonal function analysis shows stronger intra-annual variability for alongshore wind, coastal SST, and surface chlorophyll, with stronger interannual variability for surface height. Interannual variability can be caused by distant forcing from equatorial and basin-scale changes in circulation, or by more localized changes in regional winds, all of which can be found in the time series. Correlations are mostly as expected for upwelling systems on intra-annual timescales. Correlations of the interannual timescales are complicated by residual quasi-annual signals created by changes in the timing and strength of the seasonal cycles. Examination of the interannual time series, however, provides a convincing picture of the covariability of chlorophyll, surface temperature, and surface height, with some evidence of regional wind forcing.

A Low-Flow Self-Cleaning Drainage System for Fish Rearing Tanks

A float-stopper mechanism was designed to drain fish holding tanks directly from the bottom. Unlike traditional, top-drawn standpipe systems, it allows continuous flushing of settled solid waste. It also prevents the accumulation of these wastes between the two standpipes that are used in bottom-drawn, double-walled standpipe systems. When suspended solids are forced upward between the outer and inner standpipes of such systems, a minimum velocity must be maintained to prevent sediment accumulation. This minimum velocity determines the minimum flow rate through the tank. The system described in this report flushes well over a wide range of flow rates.

Phytoplankton Scales of Variability in the California Current System: 1. Interannual and Cross-Shelf Variability

In the California Current System, strong mesoscale variability associated with eddies and meanders of the coastal jet play an important role in the biological productivity of the area. To assess the dominant timescales of variability, a wavelet analysis is applied to almost nine years (October 1997 to July 2006) of 1-km-resolution, 5-day-averaged, Sea-viewing Wide Field-of-view Sensor (SeaWiFS) chlorophyll a (chl a) concentration data. The dominant periods of chlorophyll variance, and how these change in time, are quantified as a function of distance offshore. The maximum variance in chlorophyll occurs with a period of similar to 100-200 days. A seasonal cycle in the timing of peak variance is revealed, with maxima in spring/summer close to shore (20 km) and in autumn/winter 200 km offshore. Interannual variability in the magnitude of chlorophyll variance shows maxima in 1999, 2001, 2002, and 2005. There is a very strong out-of-phase correspondence between the time series of chlorophyll variance and the Pacific Decadal Oscillation (PDO) index. We hypothesize that positive PDO conditions, which reflect weak winds and poor upwelling conditions, result in reduced mesoscale variability in the coastal region, and a subsequent decrease in chlorophyll variance. Although the chlorophyll variance responds to basin-scale forcing, chlorophyll biomass does not necessarily correspond to the phase of the PDO, suggesting that it is influenced more by local-scale processes. The mesoscale variability in the system may be as important as the chl a biomass in determining the potential productivity of higher trophic levels.

The ovine cerebral venous system: comparative anatomy, visualization, and implications for translational research.

Cerebrovascular diseases are significant causes of death and disability in humans. Improvements in diagnostic and therapeutic approaches strongly rely on adequate gyrencephalic, large animal models being demanded for translational research. Ovine stroke models may represent a promising approach but are currently limited by insufficient knowledge regarding the venous system of the cerebral angioarchitecture. The present study was intended to provide a comprehensive anatomical analysis of the intracranial venous system in sheep as a reliable basis for the interpretation of experimental results in such ovine models. We used corrosion casts as well as contrast-enhanced magnetic resonance venography to scrutinize blood drainage from the brain. This combined approach yielded detailed and, to some extent, novel findings. In particular, we provide evidence for chordae Willisii and lateral venous lacunae, and report on connections between the dorsal and ventral sinuses in this species. For the first time, we also describe venous confluences in the deep cerebral venous system and an 'anterior condylar confluent' as seen in humans. This report provides a detailed reference for the interpretation of venous diagnostic imaging findings in sheep, including an assessment of structure detectability by in vivo (imaging) versus ex vivo (corrosion cast) visualization methods. Moreover, it features a comprehensive interspecies-comparison of the venous cerebral angioarchitecture in man, rodents, canines and sheep as a relevant large animal model species, and describes possible implications for translational cerebrovascular research.

Electrochemical simulation of phase I metabolism for 21 drugs using four different working electrodes in an automated screening setup with MS detection.

BACKGROUND Electrochemical conversion of xenobiotics has been shown to mimic human phase I metabolism for a few compounds. MATERIALS & METHODS Twenty-one compounds were analyzed with a semiautomated electrochemical setup and mass spectrometry detection. RESULTS The system was able to mimic some metabolic pathways, such as oxygen gain, dealkylation and deiodination, but many of the expected and known metabolites were not produced. CONCLUSION Electrochemical conversion is a useful approach for the preparative synthesis of some types of metabolites, but as a screening method for unknown phase I metabolites, the method is, in our opinion, inferior to incubation with human liver microsomes and in vivo experiments with laboratory animals, for example.

The Memorbook of Nürnberg, containing the names of the Jews martyred in that city in the year 5109=1349 A.D. : from the unique manuscript preserved in the University Library Cambridge and marked: ADD. 1506

ed. by W. H. Lowe

Prospectus of the Library of Ephraim Deinard at New Orleans, Louisiana : also a list of Jewish antiquities, depicting the "history of religion", on exhibition at the Smithsonian Institution at Washington, D. C., and at New Orleans, Louisiana

Devir Efrayim

Expression, purification, and structural insights for the human uric acid transporter, GLUT9, using the Xenopus laevis oocytes system.

The urate transporter, GLUT9, is responsible for the basolateral transport of urate in the proximal tubule of human kidneys and in the placenta, playing a central role in uric acid homeostasis. GLUT9 shares the least homology with other members of the glucose transporter family, especially with the glucose transporting members GLUT1-4 and is the only member of the GLUT family to transport urate. The recently published high-resolution structure of XylE, a bacterial D-xylose transporting homologue, yields new insights into the structural foundation of this GLUT family of proteins. While this represents a huge milestone, it is unclear if human GLUT9 can benefit from this advancement through subsequent structural based targeting and mutagenesis. Little progress has been made toward understanding the mechanism of GLUT9 since its discovery in 2000. Before work can begin on resolving the mechanisms of urate transport we must determine methods to express, purify and analyze hGLUT9 using a model system adept in expressing human membrane proteins. Here, we describe the surface expression, purification and isolation of monomeric protein, and functional analysis of recombinant hGLUT9 using the Xenopus laevis oocyte system. In addition, we generated a new homology-based high-resolution model of hGLUT9 from the XylE crystal structure and utilized our purified protein to generate a low-resolution single particle reconstruction. Interestingly, we demonstrate that the functional protein extracted from the Xenopus system fits well with the homology-based model allowing us to generate the predicted urate-binding pocket and pave a path for subsequent mutagenesis and structure-function studies.