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PubMed2005

Genetic studies in rat models: insights into cardiovascular disease.

PURPOSE OF REVIEW: Limited to 2003-2004 publications, this review focuses on 'big picture' concepts learned from rat genetic studies of cardiovascular disease. RECENT DEVELOPMENTS: Analysis reveals insights into pathogenic paradigms, as well as experimental perspectives into rat-based systems of analyses of complex cardiovascular disease. Key concepts are forwarded. Multiple susceptibility genes underlie several quantitative trait loci for blood pressure suggesting a 'quantitative trait loci cluster' concept; hypertension end-organ disease quantitative trait loci are distinct from blood pressure quantitative trait loci indicating differential susceptibility paradigms for hypertension and each complication (stroke, renal disease, cardiac hypertrophy); distinct blood pressure quantitative trait loci are found in males and females indicating gender-specific susceptibility; and genetic subtypes comprise polygenic hypertension in rat models suggesting a genetic basis for clinical heterogeneity of human essential hypertension. Gender specific genetic susceptibility plays a key role in coronary artery disease susceptibility; multiple distinct quantitative trait loci underlie hyperlipidemia and type-2 diabetes, indicating multiple susceptibilities in risk factors for cardiovascular disease. Studies in transgenic inbred rat-strain models demonstrate value for serial, complex, cardiovascular pathophysiological analyses within a genetic context. SUMMARY: Cognizant of the limitations of animal model studies, observations from rat genetic studies provide insight into respective modeled human cardiovascular diseases and risk factor susceptibility, as well as systematically dissect the multifaceted complexities apparent in human complex cardiovascular disease. Given the recapitulation of many features of human cardiovascular disease, the value of rat model-based genetic studies for complex cardiovascular disease is unequivocal, thus mandating the expansion of resources for maximization of rat-based genetic studies.

Animals↗
PubMed2006

Perceived conflict in the couple and chronic illness management: preliminary analyses from the Quebec Health Survey.

BACKGROUND: The quality of the relationship with the spouse/partner appears crucial among patients with multiple chronic conditions where illness management is complex and multifaceted. This study draws on data from the Quebec Health Survey (QHS) to examine, among patients with one or more chronic conditions, the relation between marital status, the perceived conflict with the spouse/partner, and what the patients do to manage their illness as well as how they perceive their health. METHODS: Data from the QHS 1998 were used. The sample included 7547 coupled adults who had one or more chronic health problems lasting more than 6 months. Independent variables included marital status, perceived conflict with the spouse/partner, and the number of chronic conditions. Illness management was defined broadly as a measure of the patient's efforts at self-care and an illness status indicator, including visits to the generalist and the specialist, the use of telephone health line in the last 12 months, self-rated general health, mental health, and a measure of psychological distress. Linkages between the independent variables and illness management were assessed for males and females separately with logistic regressions, while accounting for the survey sampling design and household clustering. RESULTS: Female patients who did not live with their partner and had never been married were more likely to report a negative perception of their general health and a higher psychological distress than those who were married. Perceived conflict with the partner was linked to a negative perception of mental health and a higher psychological distress among both men and women. Compared to patients with only one chronic condition, males who reported more than one chronic condition were more likely to have consulted a generalist prior to the survey and used the telephone health line, whereas females were more likely to have consulted a specialist. Both males and females with more than one chronic condition were more likely to have a negative perception of their general health and mental health. CONCLUSION: The study provides a useful preliminary measure of the importance of living arrangements and the quality of the couple relationship in chronic illness management broadly conceived as a measure of the patient's efforts at self-care and an illness status indicator. Results of this study prod us to examine more closely, within longitudinal designs, the influence of living arrangements and the presence of conflict in the couple on chronic illness management as well as the modifying effect of gender on these associations.

Adult↗
PubMed1998

Isolation and characterization of a cDNA encoding a potential morphogen from the marine sponge Geodia cydonium that is conserved in higher metazoans.

Species belonging to the lowest metazoan phylum, the sponges (Porifera), exhibit a surprisingly complex and multifaceted Bauplan (body plan). Recently, key molecules have been isolated from sponges which demonstrate that the cells of these animals are provided with characteristic metazoan adhesion and signal transduction molecules, allowing tissue formation. In order to understand which factors control the spatial organization of these cells in the sponge body plan, we screened for a cDNA encoding a soluble modulator of the behaviour of endothelial cells. A cDNA encoding a putative protein, which is highly similar to the human and mouse endothelial monocyte-activating polypeptide (EMAP) II has been isolated from a library of the marine sponge Geodia cydonium. The sponge EMAP-related polypeptide (EMAPR) has been termed EMAPR1_GC. The full-length cDNA clone, GCEMAPR1, has a size of 592 nucleotides (nt) and contains a 447 nt-long potential open reading frame; the molecular weight (MW) of the deduced amino acid sequence, 16,499 Da, is close to that of mature mammalian EMAP II (ca. 18 kDa). The sponge polypeptide is also closely related to a deduced polypeptide from the cosmid clone F58B3 isolated from Caenorhabditis elegans. A phylogenetic analysis revealed that the sponge and the nematode EMAPR molecules form a cluster which is significantly separated from the corresponding mammalian EMAP molecules. The function of the first cloned putative soluble modulator of endothelial cells in sponges remains to be determined.

Amino Acid Sequence↗
PubMed2005

Missing clinical information during primary care visits.

CONTEXT: The coordinating function of primary care is information-intensive and may be impeded by missing clinical information. However, missing clinical information has not been explicitly investigated in the primary care setting. OBJECTIVE: To describe primary care clinicians' reports of missing clinical information. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional survey conducted in 32 primary care clinics within State Networks of Colorado Ambulatory Practices and Partners (SNOCAP), a consortium of practice-based research networks participating in the Applied Strategies for Improving Patient Safety medical error reporting study. Two hundred fifty-three clinicians were surveyed about 1614 patient visits between May and December 2003. For every visit during 1 half-day session, each clinician completed a questionnaire about patient and visit characteristics and stated whether important clinical information had been missing. Clinician characteristics were also recorded. MAIN OUTCOME MEASURES: Reports of missing clinical information frequency, type, and presumed location; perceived likelihood of adverse effects, delays in care, and additional services; and time spent looking for missing information. Multivariate analysis was conducted to assess the relationship of missing information to patient, visit, or clinician characteristics, adjusting for potential confounders and effects of clustering. RESULTS: Clinicians reported missing clinical information in 13.6% of visits; missing information included laboratory results (6.1% of all visits), letters/dictation (5.4%), radiology results (3.8%), history and physical examination (3.7%), and medications (3.2%). Missing clinical information was frequently reported to be located outside their clinical system but within the United States (52.3%), to be at least somewhat likely to adversely affect patients (44%), and to potentially result in delayed care or additional services (59.5%). Significant time was reportedly spent unsuccessfully searching for missing clinical information (5-10 minutes, 25.6%; >10 minutes, 10.4%). After adjustment, reported missing clinical information was more likely when patients were recent immigrants (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.06-2.99), new patients (OR, 2.39; 95% CI, 1.70-3.35), or had multiple medical problems compared with no problems (1 problem: OR, 1.09; 95% CI, 0.69-1.73; 2-5 problems: OR, 1.87; 95% CI, 1.21-2.89; >5 problems: OR, 2.78; 95% CI, 1.61-4.80). Missing clinical information was less likely in rural practices (OR, 0.52; 95% CI, 0.29-0.92) and when individual clinicians reported having full electronic records (OR, 0.40; 95% CI, 0.17-0.94). CONCLUSIONS: Primary care clinicians report that missing clinical information is common, multifaceted, likely to consume time and other resources, and may adversely affect patients. Additional research on missing information is needed to focus on validating clinicians' perceptions and on conducting prospective studies of its causes and sequelae.

Communication↗
PubMed2004

Quality of care for patients with type 2 diabetes mellitus in the Netherlands and the United States: a comparison of two quality improvement programs.

OBJECTIVE: To assess differences in diabetes care and patient outcomes by comparing two multifaceted quality improvement programs in two different countries, and to increase knowledge of effective elements of such programs. STUDY SETTING: Primary care in the ExtraMural Clinic (EMC) of the Department of General Practice of the Vrije Universiteit in Amsterdam, the Netherlands, and the Group Health Cooperative (GHC), a group-model health maintenance organization (HMO) in western Washington State in the United States. Data were collected from 1992 to 1997. STUDY DESIGN: In this observational study two diabetes cohorts in which a quality improvement program was implemented were compared. Both programs included a medical record system, clinical practice guidelines, physician educational meetings, audit, and feedback. Only the Dutch program (EMC) included guidelines on the structure of diabetes care and a recall system. Only the GHC program included educational outreach visits, formation of multidisciplinary teams, and patient self-management support. DATA COLLECTION: Included were 379 EMC patients, and 2,119 GHC patients with type 2 diabetes mellitus. Main process outcomes were: annual number of diabetes visits, and number of HbA1c and blood lipid measurements. Main patient outcomes were HbA1c and blood lipid levels. Multilevel analysis was used to adjust for dependency between repeated observations within one patient and for clustering of patients within general practices. PRINCIPAL FINDINGS: In the EMC process outcomes and glycemic control improved more than at GHC, however, GHC had better baseline measures. There were no differences between programs on blood lipid control. During follow-up, intensification of pharmacotherapy was noted at both sites. Differences noted between programs were in line with differences in diabetes guidelines. CONCLUSIONS: Following implementation of guidelines and organizational improvement efforts, change occurred primarily in the process outcomes, rather than in the patient outcomes. Although much effort was put into improving process and patient outcomes, both complex programs still showed only moderate effects.

Aged↗
PubMed2006

Reducing door-to-antibiotic time in community-acquired pneumonia: Controlled before-and-after evaluation and cost-effectiveness analysis.

BACKGROUND: Practice guidelines suggest that all patients hospitalised with community-acquired pneumonia (CAP) should receive antibiotics within 4 h of admission. An audit at our hospital during 1999-2000 showed that this target was achieved in less than two thirds of patients with severe CAP. METHODS: An experienced multidisciplinary steering group designed a management pathway to improve the early delivery of appropriate antibiotics to patients with CAP. This was implemented using a multifaceted strategy. The effect of implementation was evaluated using a controlled before-and-after study design over two winter seasons (November-April 2001-2 and 2002-3). Cost-effectiveness analyses were performed from the hospital's perspective. RESULTS: The proportion of patients receiving appropriate antibiotics within 4 h of admission to hospital increased from 33% to 56% at the intervention site, and from 32% to 36% at the control site (absolute change adjusted for differences in severity of illness 17%, p = 0.035). The cost per additional patient receiving appropriate antibiotics within 4 h was 132 pound with no post-implementation evaluation, and 456 pound for a limited post-implementation evaluation. Simple modelling from the results of a large observational study suggests that the cost per death prevented could be 3003 pound with no post-implementation evaluation, or 16,632 pound with a limited post-implementation evaluation. CONCLUSIONS: The intervention markedly improved door-to-antibiotic time, albeit at considerable cost. It might still be a cost-effective strategy, however, to reduce mortality in CAP. Uncertainty about the cost effectiveness of such interventions is likely to be resolved only by a well-designed, cluster randomised trial.

Aged↗
PubMed2006

Impact, distress and HRQoL among Malaysian men and women with a mobility impairment.

BACKGROUND: Although non-communicable and chronic disease now accounts for 47% of the global burden of disease, little is known of the everyday experiences and social aspects of disability and disablement in middle and low income countries. This article aims to address this gap by exploring the subjective experience of mobility impairment in Malaysia. Specifically, it examines health-related quality of life and the impact and distress related to impaired mobility, and investigates any gender differences in relation to the experience of disability. METHODS: The data were collected as part of an interdisciplinary, multi-country study known as RESILIENCE (Research into Social Inclusion, Locomotive Impairment and Empowerment through Networking, Collaboration and Education). Cluster sampling was used to administer the EQ-5D and the Perceived Impact of Problems Profile (PIPP) to 210 adults from Selangor state, west coast Peninsular Malaysia. RESULTS: The participants consisted of 94 males and 116 females, aged between 18-90 years (mean 60 years), with the majority being Malay. The majority of participants were also married, from rural areas and had primary education only. Very few participants lived alone. In addition, males were more likely to attribute their impaired mobility to an accident. The majority of participants with mobility impairment experienced a moderate to high level of pain/discomfort (79%) and anxiety/depression (72%), and at least some problems with performing usual activities (71%), as measured by the EQ-5D. In addition, using the Perceived Impact of Problems Profile (PIPP), participants also reported high levels of impact and distress related to participation in community life. In general, males reported higher impact and distress across several items, most significantly in regard to participation in community activities, moving around the neighbourhood, ability to live independently, and ability to assist their family members. CONCLUSION: This paper provides preliminary data regarding the health-related quality of life among Malaysians with impaired mobility, and highlights the multifaceted impact of disability and the importance of acknowledging the diverse cultural contexts in which disability can occur. It also raises questions regarding gender differences in the subjective experience of disability in Malaysia.

Activities of Daily Living↗
PubMed1998

Altered morning and nighttime pulsatile corticotropin and cortisol release in polycystic ovary syndrome.

An overdrive of the hypothalamic-pituitary-adrenal (HPA) axis has been postulated in patients with polycystic ovary syndrome (PCOS). However, little is known concerning the pulsatile modes of corticotropin (ACTH) and cortisol secretion in these patients. To further investigate this issue, spontaneous ACTH and cortisol release were evaluated in 16 normal-weight patients with PCOS and 16 control women. Nine PCOS patients and eight controls were studied between 8 AM and 12 AM (noon), and seven PCOS patients and eight controls between 11 PM and 3 AM. Venous blood samples were taken at 10-minute intervals. Cluster analysis was used to assess ACTH and cortisol pulse frequency and amplitude, deconvolution to calculate mean hormone secretion rates, and approximative entropy (ApEn) to measure the orderliness of ACTH and cortisol time-series data. PCOS patients compared with controls displayed increased ACTH and cortisol release (area under the curve [AUC] and mean plasma concentration) both in the morning and at night. This was not due to increased hormonal secretory burst frequency, but to higher hormonal interpeak valley concentrations and, in the case of ACTH, nighttime pulse amplitudes. Mean ACTH and cortisol secretion rates also were increased in PCOS patients. Further, both controls and PCOS patients exhibited significant (0 to 20 minutes lagged) concordance between individual daytime pulsatile ACTH and cortisol release episodes. As shown by increased ApEn values, PCOS patients had more disorderly daytime cortisol release. In addition, the normal daytime correlation between the amount of pulsatile ACTH and cortisol release as observed in the controls was lost in PCOS patients. Finally, cross-correlation analysis showed a more prominent negative correlation in PCOS patients versus controls between plasma cortisol and 40- to 120-minute delayed ACTH concentrations in the morning, indicating a more sustained negative feedback of cortisol on ACTH release in PCOS at this time. Taken together, these findings demonstrate the existence of multifaceted dysregulation of the HPA axis in PCOS.

Adolescent↗
PubMed2005

Pharmacogenomic profiling of an oxidative stress-mediated spongiform encephalopathy.

The majority of cellular superoxide is generated in the mitochondria as a by-product of normal oxidative metabolism. In the mitochondria, superoxide is detoxified by manganese superoxide dismutase (SOD2). Mice lacking SOD2 demonstrate a multifaceted neonatal lethal phenotype, including a spongiform encephalopathy that is preventable through antioxidant treatment. The molecular events behind the observed pathology in the cortex of these mice are unknown. We hypothesized that the lack of SOD2 would result in significant changes in cortical gene expression and that therapeutically beneficial antioxidant treatment would normalize the expression of some genes, providing insight into the mechanism by which mitochondrial oxidative stress results in neurodegeneration. We report the identification of gene expression profiles associated with this paradigm, which characterize the degree of response to the pharmacologic intervention. We have identified specific pathways targeted by endogenous oxidative stress, including glutathione metabolism, iron metabolism, and cell-survival pathways centering on the kinase AKT. The normalization of expression of some of these pathways by antioxidant treatment suggests approaches to treating disease in which endogenous oxidative stress plays a role.

Animals↗
PubMed1991

Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.

Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.

Arteriosclerosis↗
PubMed1999

What is the place of genetics in the pathogenesis of pre-eclampsia?

It is most unlikely that there is a single 'pre-eclampsia (PE) gene'. We are probably looking for a cluster of polymorphisms which, possibly in conjunction with environmental factors, predispose to the development of the condition. Accurate phenotyping is vital for any genetic studies of PE, and since the disease is only clinically-detectable in the second half of pregnancy, is particularly difficult. It is increasingly likely that there is a fetal genetic contribution which can only be examined after birth. Candidate genes examined on the basis of displayed or hypothetical pathophysiological effects, but for which no evidence of association or linkage has been found have included HLA-DRbeta, HLA-G, and tumour necrosis factor alpha (chromosome 6), angiotensin-converting enzyme (chromosome 17) and CuZn superoxide dismutase (chromosome 21). Chromosomal exclusion mapping and a pedigree study suggest a role for genes on chromosomes 1, 3, 4, 9 or 18. Two genes concerned with clotting, those for factor 5 and methylenetetrahydrofolate reductase, lie on chromosome 1. Both have polymorphisms present in significantly higher frequency in women with PE, as well as showing functional abnormality. They probably predispose to the development of the condition, without being necessary for it. The angiotensinogen (Aogen) gene also lies on chromosome 1. The renin-angiotensin system may be activated during the early stages of PE and subsequently suppressed. In some populations, a relatively common polymorphism is present in raised frequency in women with PE, but it is also raised in non-pregnant hypertensive subjects. However, it is in partial linkage disequilibrium with another polymorphism which shows significantly distorted transmission from mother to fetus in PE pregnancies. Furthermore, its expression is significantly raised in the decidual spiral arteries; abnormal placentation is a feature of PE. We have also shown that a relatively common polymorphism in the angiotensin AT1 receptor gene (chromosome 3) is associated with raised density of the receptor. Thus far, studies of candidate genes have been on a small scale and have very much reflected the pathophysiological research interests of the investigators. The multifaceted nature of PE and the difficulties of accurate phenotyping require the accumulation of a large, very carefully phenotyped, database. It is hoped that funding will become available this year in the UK to allow the collection of such a database. The introduction of chip technology should allow genome scanning of the resource.

Angiotensinogen↗
PubMed2006

Community and cultivation analysis of arsenite oxidizing biofilms at Hot Creek.

At Hot Creek in California, geothermally derived arsenite is rapidly oxidized to arsenate. This process is mediated by microorganisms colonizing the surfaces of submerged aquatic macrophytes in the creek. Here we describe a multifaceted approach to characterizing this biofilm community and its activity. Molecular techniques were used to describe the community as a function of 16S-rRNA gene diversity. Cultivation-based strategies were used to enumerate and isolate three novel arsenite oxidizers, strains YED1-18, YED6-4 and YED6-21. All three strains are beta-Proteobacteria, of the genus Hydrogenophaga. Because these strains were isolated from the highest (i.e. million-fold) dilutions of disrupted biofilm suspensions, they represent the most numerically significant arsenite oxidizers recovered from this community. One clone (Hot Creek Clone 44) obtained from an inventory of the 16S rDNA sequence diversity present in the biofilm was found to be 99.6% identical to the 16S rDNA sequence of the isolate YED6-21. On the basis of most probable number (MPN) analyses, arsenite-oxidizing bacteria were found to account for 6-56% of the cultivated members of the community. Using MPN values, we could estimate an upper bound on the value of V(max) for the community of 1 x 10(-9)micromole arsenite min(-1) cell(-1). This estimate represents the first normalization of arsenite oxidation rates to MPN cell densities for a microbial community in a field incubation experiment.

Arsenites↗
PubMed2006

Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers.

BACKGROUND: Inadequate oxygen (hypoxia) triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF), plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1alpha protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1alpha RNA in renal cells, and it could be diminished by reducing HIF-1alpha expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis in breast and ovarian cancer.

Adult↗