bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Endoplasmic Reticulum Stress in the Progression of Atherosclerosis
Authors: Tabas Ira
Published: September 2010

Prolonged activation of the endoplasmic reticulum (ER) stress pathway known as the unfolded protein response (UPR) can lead to cell pathology and subsequent tissue dysfunction. There is now ample evidence that the UPR is chronically activated in atherosclerotic lesional cells, particularly advanced lesional macrophages and endothelial cells. The stressors in advanced lesions that can lead to prolonged activation of the UPR include oxidative stress, oxysterols, and high levels of intracellular cholesterol and saturated fatty acids. Importantly, these arterial wall stressors may be especially prominent in the settings of obesity, insulin resistance, and diabetes, all of which promote the clinical progression of atherosclerosis. In the case of macrophages, prolonged ER stress triggers apoptosis, which in turn leads to plaque necrosis if the apoptotic cells are not rapidly cleared. ER stress–induced endothelial cell apoptosis may also contribute to plaque progression. Another potentially important proatherogenic effect of prolonged ER stress is activation of inflammatory pathways in macrophages and, perhaps in response to atheroprone shear stress, endothelial cells. Although exciting work over the last decade has begun to shed light on the mechanisms and in vivo relevance of ER stress–driven atherosclerosis, much more work is needed to fully understand this area and to enable an informed approach to therapeutic translation.
Discursive positioning and planned change in organizations
Authors: Bisel Ryan S , Barge J Kevin
Published: September 2010

This study uses discursive positioning theory to explore how planned change messages influence organizational members’ identity and the way they experienced organizational change. Based on an in-depth case study of a home healthcare and hospice organization that engaged in a multiyear planned change process, our analysis suggests that workers experienced salient change messages as constituting unfavorable identities, which were associated with the experiences of violation, recitation, habituation, or reservation. Our study also explores the way discursive and material contexts enabled and constrained the governing board’s change messages as they responded to external and internal audiences. We highlight the importance of viewing messaging as a process of information transfer as well as discursive construction, which has important implications for the way change agents approach issues of sense making, emotionality, resistance, and materiality during planned change processes.
The antecedents of a ‘chilly climate’ for women faculty in higher education
Authors: Maranto Cheryl L , Griffin Andrea EC
Published: September 2010

The literature on women’s under-representation in academia asserts that faculty women face a ‘chilly climate’, but there are few theoretically based studies examining this proposition. Relational demography, organizational justice, and social network theories all identify possible antecedents of ‘chilly climate’. Using survey data of faculty at a private Midwestern US university, we test whether the perception of exclusion (chilly climate) is influenced by demographic dissimilarity, and perceptions of fairness and gender equity. We find that faculty women perceive more exclusion from academic departments with a low representation of women, consistent with relational demography. Perceptions of procedural fairness and gender equity are powerful factors that foster inclusion and warm the climate for both men and women. The ‘chilly climate’ for women faculty is a complex phenomenon with multiple causes. Policies that fail to address these multiple causes are unlikely to be effective.
Histopathology of Grossly Normal Mesenteric Lymph Nodes of New Zealand Farmed Red Deer (Cervus elaphus) Including Identification of Lipopigment
Authors: Hunnam J. C. , Wilson P. R. , Heuer C. , Mackintosh C. G. , West D. M. , Clark R. G.
Published: September 2010

This article describes the histopathology of grossly normal mesenteric lymph nodes (MLNs) of New Zealand farmed red deer ( Cervus elaphus). Eighty MLNs were sourced from 10 deer from 5 North Island herds and 5 South Island herds classified as low risk and high risk of Mycobacterium avium subspecies paratuberculosis (MAP) infection, respectively. Fixed sections were stained with hematoxylin and eosin; Ziehl-Neelsen; and, selectively, periodic acid–Schiff, Perl’s, and Sudan black. Positive Ziehl-Neelsen stain, follicular hyperplasia, capsular eosinophil infiltration, focal granulomas, foci of macrophages containing lipopigment, parasitic granulomas, and calcified foci are described and severity graded where appropriate. Animal age, sex, and herd of origin are variably associated with the presence of one or more features. Trabecular fibrosis and dilated edema-filled sinusoids are described. These observations allow differentiation between likely nonpathologic histologic features in deer MLNs and features possibly attributable to infection with a pathogen such as MAP.
Mobility and fractionation of arsenic, chromium and copper in thermally treated soil
Authors: Nordmark Désirée , Kumpiene Jurate , Andreas Lale , Lagerkvist Anders
Published: September 2010

Thermal treatment is used to remediate soil co-contaminated with organic and inorganic contaminants. It destroys organic contaminants, but the remaining inorganic contaminants require further treatment. In this study the effects of thermal treatment on the mobility, speciation and chemical fractionation of As, Cr and Cu in a CCA-polluted soil were evaluated by leaching tests, As speciation assays and a sequential extraction procedure. The soil was sieved into four size fractions (<0.125, 0.125—0.250, 0.250—0.500 and 0.500—1.0 mm), each of which was treated at 800°C and analysed in comparison with the untreated soil. The leaching of As and Cr increased by factors of 18—40 and 2—23, respectively, while the mobility of Cu decreased 12—14-fold after treatment. The concentration of As(V) in pore water of the finest soil fraction increased 19-fold, whereas that of As(III) remained constant. The treatment reduced As, Cr and Cu associated with the reducible soil fraction. In addition, it increased the proportions of As and Cr (slightly) associated with the exchangeable and acid-soluble soil fractions, and the proportions of Cu and Cr (substantially) associated with the residual fraction.
Predictors of Mortality in Older Hip Fracture Inpatients Admitted to an Orthogeriatric Unit in Oslo, Norway
Authors: Holvik Kristin , Ranhoff Anette Hylen , Martinsen Mette Irene , Solheim Ludvig Fjeld
Published: September 2010

Objectives: To identify to which degree patient-related factors (age, gender, place of residence, general health condition, comorbidity) and hospital-related factors (waiting time for surgery, type of surgery, in-hospital complications, length of stay) may predict 1-year mortality in elderly hip fracture patients in an orthogeriatric unit, to optimize treatment and care. Method: In-hospital patient information was routinely collected by multidisciplinary staff and entered into a database. Information about mortality was obtained for 567 patients aged 65 and above. Multivariate logistic regression was performed. Results: Overall mortality was 23.5%, but there was a large variation in mortality according to age, gender, comorbidity, and place of residence. Independent predictors of mortality were admittance from nursing home (risk ratio [RR] = 3.24, 95% confidence interval [CI] = 2.37-4.43 compared with home dwellers) and a higher American Society of Anesthesiologists (ASA) score (RR = 1.75 and 95% CI = 1.24-2.46, for ASA ≥ 3 compared with ASA ≤ 2). Male gender, increasing age, increasing number of comorbid conditions, and having fallen indoors were indicators, but not independent predictors, of higher mortality. Discussion: Almost one fourth of older hip fracture patients in this unit died within a year. The most important predictor was admittance from nursing home, which was associated with comorbidity and frailty. More attention to patients from nursing homes is needed in the health care system.
Variations in Body Mass Index Among Older Americans: The Roles of Social and Lifestyle Factors
Authors: Ahn SangNam , Sharkey Joseph R. , Smith Matthew Lee , Ory Marcia G. , Phillips Charles D.
Published: September 2010

Objectives: To investigate the correlates of body mass index (BMI) among a national sample of older adults in the United States. Method: Data used in these analyses were part of the 2003-2004 National Health and Nutrition Examination Survey (NHANES). Generalized ordered logistic regression was used to analyze difference between normal weight, overweight, moderately obese, and severely obese adults ( n = 1,143) above the age of 65 years. Results: A higher BMI was more common among those with greater activities of daily living (ADL) limitations, greater use of prescription medicines (≥7), greater number of cardiovascular-related disorders (1 or ≥2), and those aged 65 to 74 years. Discussion: The findings acknowledge relationships between health characteristics, disability, and BMI among a national sample of older adults. These results suggest that prevention and management of health conditions, basic ADL, and BMI may be reasonable targets for intervention.
Factors Associated With Loneliness of Noninstitutionalized and Institutionalized Older Adults
Authors: Prieto-Flores Maria-Eugenia , Forjaz Maria João , Fernandez-Mayoralas Gloria , Rojo-Perez Fermina , Martinez-Martin Pablo
Published: September 2010

Objectives: First, to seek if sociodemographic and health factors contribute differentially to the explanation of loneliness in institutionalized and noninstitutionalized older adults; and second, to analyze the influence of institutionalization on loneliness. Method: This work was based on two surveys of older adults aged 60 years or more in Spain. A group of 234 community-dwelling people and 234 nursing homes residents were selected ( n = 468). Logistic regression models were applied using the six-item De Jong Gierveld Loneliness Scale as dependent variable. Results: Depression was associated with loneliness in both populations. Sex and marital status contributed to explain loneliness among those living at home, whereas gathering with family, friends, and neighbors showed a significant effect in the institutionalized group. Institutionalization per se showed a strong effect on loneliness. Discussion: Findings have potential implications for targeting older adults at risk for loneliness.
Are you SLiM? Developing an instrument for civic scientific literacy measurement (SLiM) based on media coverage
Authors: Rundgren Carl-Johan , Rundgren Shu-Nu Chang , Tseng Yuen-Hsien , Lin Pei-Ling , Chang Chun-Yen
Published: September 2010

The purpose of this study is to develop an instrument to assess civic scientific literacy measurement (SLiM), based on media coverage. A total of 50 multiple-choice items were developed based on the most common scientific terms appearing in media within Taiwan. These questions covered the subjects of biology (45.26%, 22 items), earth science (37.90%, 19 items), physics (11.58%, 6 items) and chemistry (5.26%, 3 items). A total of 1034 students from three distinct groups (7th graders, 10th graders, and undergraduates) were invited to participate in this study. The reliability of this instrument was 0.86 (KR 20). The average difficulty of the SLiM ranged from 0.19 to 0.91, and the discrimination power was 0.1 to 0.59. According to participants’ performances on SLiM, it was revealed that 10th graders (Mean = 37.34±0.23) performed better than both undergraduates (Mean = 33.00±0.33) and 7th graders (Mean = 26.73±0.45) with significant differences in their SLiM.
Justice, community knowledge, and waste facility siting in Taiwan
Authors: Fan Mei-Fang
Published: September 2010

This article examines justice in the context of a controversial industrial waste facility siting in a Hakka (a minority ethnic group) town in Taiwan. It provides analysis of local perceptions of disproportionate risk, community knowledge claims, and the challenges of citizens to the controversial environmental impact assessment process. It explores knowledge disputes among regulators, developers, and local activists; it considers the struggle of local actors for recognition and inclusion in decision-making; and it argues for the development of institutional procedures that promote dialogue among stakeholders in order to avoid the preemption of debate, the control of the frame by the government and experts, and the centralization of power.
Reflections on Methodological Approaches and Conceptual Contributions in a Program of Caregiving Research: Development and Testing of Wuest’s Theory of Family Caregiving
Authors: Wuest Judith , Hodgins Marilyn J.
Published: September 2010

Caregiving by family members, particularly women, is a societal expectation that is intensifying in the context of an aging population and health care restructuring. Our program of caregiving research spans two decades, moving from inductive theory development using grounded theory methods to deductive theory testing. In this article, we reflect on the serendipitous development of this program of research methodologically and conceptually. We summarize the key conceptual contributions that the program has made to caregiving knowledge, particularly with respect to the past relationship between care recipient and caregiver, obligation to care, caregiver agency, and relationships between caregivers and the health care system.
The NEO Five-Factor Inventory: Latent Structure and Relationships With Dimensions of Anxiety and Depressive Disorders in a Large Clinical Sample
Authors: Rosellini Anthony J. , Brown Timothy A.
Published: September 2010

The present study evaluated the latent structure of the NEO Five-Factor Inventory (NEO FFI) and relations between the five-factor model (FFM) of personality and dimensions of DSM-IV anxiety and depressive disorders (panic disorder, generalized anxiety disorder [GAD], obsessive—compulsive disorder, social phobia [SOC], major depressive disorder [MDD]) in a large sample of outpatients ( N = 1,980). Exploratory structural equation modeling (ESEM) was used to show that a five-factor solution provided acceptable model fit, albeit with some poorly functioning items. Neuroticism demonstrated significant positive associations with all but one of the disorder constructs whereas Extraversion was inversely related to SOC and MDD. Conscientiousness was inversely related to MDD but demonstrated a positive relationship with GAD. Results are discussed in regard to potential revisions to the NEO FFI, the evaluation of other NEO instruments using ESEM, and clinical implications of structural paths between FFM domains and specific emotional disorders.
Internet Administration of Paper-and-Pencil Questionnaires Used in Couple Research
Authors: Brock Rebecca L. , Barry Robin A. , Lawrence Erika , Dey Jodi , Rolffs Jaci
Published: September 2010

This study examined the psychometric equivalence of paper-and-pencil and Internet formats of key questionnaires used in couple research. Self-report questionnaires assessing interpersonal constructs (relationship satisfaction, communication/conflict management, partner support, emotional intimacy) and intrapersonal constructs (individual traits, psychological symptoms, contextual influences) were administered to young adults in committed dating relationships. The same measures were administered twice via paper-and-pencil and/or Internet methods over a 2-week period. Method order was counterbalanced among participants, and temporal stability was controlled. Intrapersonal and interpersonal measures generally remained reliable when administered online and demonstrated quantitative and qualitative equivalence across methods. The implications of online administration of questionnaires are discussed, and specific recommendations are made for researchers who wish to transition to online data collection.
The effects of variable soil damping on soil-structure dynamics
Authors: Mott Grant , Wang Judith
Published: September 2010

This study examines the effects of variable dynamic dissipative and elastic soil characteristics on the dynamic response of a soil-structure system. Three equivalent linear modeling techniques (linear hysteretic and Kelvin-Voight constitutive models and weighted modal time history analysis) are used to incorporate the soil and structure’s unique dissipative characteristics. The soil’s critical viscous damping ratio and shear modulus are iteratively determined based upon experimentally observed, upper and lower bound strain-dependent stiffness degradation and damping curves. It is found that the three techniques produce consistent results: as the shear modulus increases, so does the primary natural frequency of the response; as the damping ratio of the soil increases, the magnitude of the response decreases. It is also found that variations in response due to using different values for a soil’s dynamic characteristics are dependent upon the equivalent linear modeling technique used. The impact of soil damping variability is seen to be as influential upon the dynamic response of a structure as shear modulus variability, because dissipative variations have a direct impact on the magnitudes of the displacement responses. The effects of variable soil damping should therefore be considered in addition to stiffness parameters as part of the dynamic characteristics of a system when determining a system’s dynamic performance.
WY-14 643, a Selective PPARα Agonist, Induces Proinflammatory and Proangiogenic Responses in Human Ocular Cells
Authors: Zhang Jin-Zhong , Ward Keith W.
Published: September 2010

Peroxisome proliferator-activated receptor α (PPARα) agonism in ocular inflammation has not been thoroughly investigated. The objective of this investigation was to determine the effect of WY-14 643, a selective PPARα agonist, on inflammatory cytokine release in human ocular cells. Stimulation of primary human corneal epithelial cells, keratocytes, and retinal endothelial cells with 1 to 10 ng/mL interleukin 1β (IL-1β) resulted in a significant increase in numerous inflammatory cytokines, including IL-6, IL-8, and tumor necrosis factor α (TNF-α); and dexamethasone was able to significantly inhibit these effects. However, WY-14 643 did not effectively block IL-1β-induced cytokine release in ocular cells; rather, significant increases in IL-1β-induced inflammatory cytokines were observed in these cells but not in aortic smooth muscle cells. WY-14 643 also significantly upregulated vascular endothelial growth factor (VEGF) expression in corneal epithelial cells and keratocytes. These studies demonstrate for the first time that PPARα agonism may be proinflammatory and proangiogenic in a variety of ocular cells and suggest that therapeutic applications of such agents in ophthalmology may be limited.
Distinctions between non-peptide angiotensin II AT1-receptor antagonists
Authors: Vauquelin Georges , Fierens Frederik LP , Verheijen Ilse , Vanderheyden Patrick ML
Published: September 2010

A far-reaching understanding of the molecular action mechanism of AT1-receptor antagonists (AIIAs) was obtained by using CHO cells expressing transfected human AT 1-receptors. In this model, direct [3H]-antagonist binding and inhibition of agonist-induced responses (inositol phosphate accumulation) can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan) causes parallel shifts of the angiotensin II (Ang II) concentration-response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174,) to almost complete (95% for candesartan) reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan). Antagonist-bound AT1-receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long-lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT1-receptors. This recycling, or `rebinding' takes place because of the very high affinity of candesartan for the AT1-receptor.
Role of basic amino acids of the human angiotensin type 1 receptor in the binding of the non-peptide antagonist candesartan
Authors: Vauquelin Georges , Fierens Frederik LP , Gáborik Zsuzsanna , Le Minh Tam , De Backer Jean-Paul , Hunyady László , Vanderheyden Patrick ML
Published: September 2010

To explain the insurmountable/long-lasting binding of biphenyltetrazole-containing AT1-receptor antagonists such as candesartan, to the human angiotensin II type 1-receptor, a model is proposed in which the basic amino acids Lys199 and Arg 167 of the receptor interact respectively with the carboxylate and the tetrazole group of the antagonists. To validate this model, we have investigated the impact of substitution of Lys199 by Ala or Gln and of Arg167 by Ala on the binding properties of [3H]candesartan and on competition binding by candesartan, EXP3174, irbesartan, losartan, angiotensin II (Ang II) and [Sar1-Ile8]angiotensin. Our results indicate that both amino acids play an important role in the AT1-receptor ligand binding. Whereas the negative charge of Lys 199 is involved in an ionic bond with the end-standing carboxylate group of the peptide ligands, its polarity also contributes to the non-peptide antagonist binding. Substitution of Arg167 by Ala completely abolished [3H]Ang II, as well as [3H] candesartan, binding. Whereas these results are in line with the proposed model, it cannot be excluded that both amino acid residues are important for the structural integrity of the AT1-receptor with respect to its ligand binding properties.
Analysis of responses to angiotensin II in the mouse
Authors: Bivalacqua Trinity J , Champion Hunter C , Hyman Albert L , McNamara Dennis B , Kadowitz Philip J
Published: September 2010

Responses to angiotensin II (Ang II) were investigated in anaesthetised CD1 mice. Injections of Ang II caused dose-related increases in systemic arterial pressure that were antagonised by candesartan. Responses to Ang II were not altered by PD 123319. At the lowest dose studied (20 µg/kg i.v.), the inhibitory effects of candesartan were competitive, whereas at the highest dose (100 µg/kg i.v.), the dose-response curve for Ang II was shifted to the right in a non-parallel manner. The inhibitory effects of candesartan were selective and were similar in animals pretreated with enalaprilat to reduce endogenous Ang II production. Pressor responses to Ang II were not altered by propranolol, phentolamine or atropine, but were enhanced by hexamethonium. Increases in total peripheral resistance were inhibited by the AT1-receptor antagonist (ARB) but were not altered by AT2-receptor, alpha- or beta-receptor antagonists. These results suggest that pressor responses to Ang II are mediated by AT 1-receptors, are buffered by the baroreceptors, are not modulated by effects on AT2receptors, and that activation of the sympathetic nervous system plays little role in mediating rapid haemodynamic responses to the peptide in anaesthetised mice.
Improvement of endothelial dysfunction in experimental heart failure by chronic RAAS-blockade: ACE-inhibition or AT1-receptor blockade?
Authors: Wagenaar Lodewijk J , Buikema Hendrik , Pinto Yigal M , van Gilst Wiek H
Published: September 2010

Chronic heart failure (CHF) is associated with endothelial dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) is believed to be important in the deterioration of endothelial dysfunction in CHF through stimulation of oxidative stress. Whereas angiotensin-converting enzyme inhibitors (ACE-I) improve endothelial function in CHF, the effects of angiotensin II AT1-receptor blockers (ARB) are less well established. Therefore we compared the effects of the ACE-I lisinopril vs. the ARB candesartan on endothelial dysfunction in a rat model of CHF.

CHF was induced by myocardial infarction (MI) after coronary ligation. Two weeks after MI, daily treatment with lisinopril (2 mg/kg) or candesartan cilexetil (1.5 mg/kg) was started. After 13 weeks, rats were sacrificed and endothelial function was determined by measuring acetylcholine (ACh)-induced vasodilation in aortic rings, with selective presence of the nitric oxide synthase (NOS)-inhibitor NG-monomethyl-L-arginine (L-NMMA) to determine the contribution of nitric oxide (NO).

ACh-induced vasodilation was attenuated in untreated MI (-50%) compared with control rats. This was in part due to an impaired contribution of NO (-49%). Lisinopril and candesartan cilexetil fully normalised ACh-induced dilation, including the part mediated by NO.

Chronic RAAS-blockade with lisinopril and candesartan cilexetil normalised endothelial function in CHF in a comparable way. The effect of both treatments included the increase of the NO-mediated dilation, further indicating the important role of oxidative stress in the relationship between the RAAS and endothelial dysfunction in CHF.
Effects of low-dose candesartan on the rate of re-endothelialisation following vascular wound healing
Authors: Koshy Prakash , Self Amanda , Kadowitz Philip J , Fonseca Vivian A , McNamara Dennis B
Published: September 2010

The wound healing response of the vascular wall to injury involves re-endothelialisation of the denuded luminal surface and thickening of the intimal area (intimal hyperplasia), as expressed by the intimal-to-medial area ratio (I/M). Candesartan, at doses of 1 mg/kg/day or higher, has been reported to attenuate the intimal hyperplastic response. We tested the hypothesis that candesartan, at doses lower than those associated with attenuation of intimal hyperplasia, may affect re-endothelialisation. New Zealand White rabbits were subjected to balloon catheter injury to the thoracic aorta. Candesartan, at doses of 50, 100, and 500 µg/kg/day, was delivered via an Alzet pump placed in the abdomen one week prior to aortic injury. There was no attenuation of the hyperplastic response of the aortic wall. However, at 50 µg/kg/day the rate of reendothelialisation was significantly increased. These data suggest that candesartan may exhibit pleiotropic effects on vascular wound healing, in addition to the well-known effect of attenuating the development of intimal hyperplasia.
Blockade of angiotensin AT1-receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats reduces blood pressure and sympathetic nerve discharge
Authors: Allen Andrew M
Published: September 2010

Microinjections of angiotensin II (Ang II) into the rostral ventrolateral medulla (RVLM) induce a sympathetically-mediated increase in blood pressure (BP), through an interaction with AT1-receptors. Under basal conditions in anaesthetised animals, microinjections of AT 1-receptor antagonists into the RVLM have little, or no effect on BP, suggesting that the angiotensin input to this nucleus is not tonically active. In contrast, microinjections of AT1-receptor antagonists into the RVLM of sodium-deplete rats and TGR(mRen2)27 rats, induce a depressor response through sympatho-inhibition. This indicates that when the renin-angiotensin system is activated, angiotensin can act in the RVLM to support sympathetic nerve discharge and BP. This study examined whether angiotensin inputs to the RVLM are activated in the spontaneously hypertensive rat — a pathophysiological model which displays increases in both brain angiotensin levels and sympathetic nerve activity. Bilateral microinjections of the AT 1-receptor antagonist candesartan cilexetil, (1 nmol in 100 nl), into the RVLM of the spontaneously hypertensive rat induced a significant decrease in lumbar sympathetic nerve discharge (-18±2%) and BP (140±6 to 115±6 mmHg). In contrast, similar microinjections in the Wistar-Kyoto (WKY) rat had no effect on BP or sympathetic nerve discharge. These results are interpreted to suggest that Ang II inputs to the RVLM are activated in the spontaneously hypertensive rat to maintain an elevated level of sympathetic nerve discharge, even in the face of increased BP.
Development of salt-sensitive hypertension in a sensory denervated model: the underlying mechanisms
Authors: Wang Donna H , Yan Huang
Published: September 2010

We use a novel salt-sensitive hypertensive model recently developed in our laboratory. This model shows that neonatal degeneration of capsaicin-sensitive sensory nerves renders a rat responsive to a salt load with a significant rise in blood pressure (BP). To test the hypothesis that development of salt-sensitive hypertension in sensory denervated rats is mediated by abnormal regulation of both circulating and tissue renin-angiotensin systems (RAS), neonatal Wistar rats were given capsaicin, 50 mg/kg s.c., on the first and second days of life. Control rats were treated with vehicle solution. After the weaning period, male rats were divided into four groups and subjected to the following treatments for three weeks: control + high sodium diet (4%, CON-HS), capsaicin pretreatment + normal sodium diet (0.5%, CAP-NS), capsaicin pretreatment + high sodium diet (CAP-HS), and capsaicin pretreatment + high sodium diet + candesartan cilexetil (10 mg/kg/per day, CAP-HS-CAN). Radioimmunoassay shows that plasma renin activity (ng/ml/hr, PRA) was higher in CAP-NS (2.58±0.17) than in CON-HS (0.14±0.03) and CAP-HS (0.74±0.15), and it was higher in CAP-HS than in CON-HS (p<0.05). Western blot analysis shows that expression of the angiotensin II (Ang II) type 1 (AT1) receptor in both the renal cortex and outer medulla was higher in CAP-HS than in CON-HS and CAP-NS rats (p<0.05). Expression of the Ang II type 2 (AT2) receptor in the renal cortex was higher in both CAP-HS and CAP-NS than in CON-HS rats (p<0.05), but there was no difference in AT2-receptor expression in the renal medulla between CAP-HS, CAP-NS, and CON-HS rats. Likewise, there was no difference in AT1-receptor expression in mesenteric resistance arteries between CAP-HS, CAP-NS, and CON-HS rats. In contrast, mesenteric AT2-receptor expression was lower in CAP-HS than in CAP-NS and CON-HS rats (p<0.05). Tail-cuff systolic BP (mmHg) shows that blockade of the AT1-receptor with candesartan prevents the development of hypertension in CAP-HS rats (by the end of the experiment, CON-HS, 122±3; CAP-NS, 118±10; CAP-HS, 169±9; CAP-HS-CAN, 129±2, p<0.05). Thus, both circulating and tissue RAS in sensory-denervated rats are abnormally regulated in response to a high-salt intake, which may contribute to increased salt sensitivity and account for the effectiveness of candesartan in lowering BP in this model.
Candesartan decreases the sympatho-adrenal and hormonal response to isolation stress
Authors: Armando Ines , Carranza Andrea , Nishimura Yasuaki , Barontini Marta , Ito Takeshi , Saavedra Juan M
Published: September 2010

A change from group housing to isolation in unfamiliar metabolic cages represents, for rodents, a significant emotional stress. We studied the effect of candesartan, a peripheral and central angiotensin II AT1-receptor antagonist, on the hormonal and sympathetic response to acute isolation. We pretreated rats with 1 mg/kg/day candesartan for 13 days via subcutaneously implanted osmotic minipumps, followed by 24-hour isolation in individual metabolic cages. We measured brain, pituitary and adrenal angiotensin II (Ang II) receptor binding by quantitative autoradiography and adrenal hormones and catecholamines by RIA and HPLC. Isolation increased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in the zona glomerulosa and AT2-receptor binding in the adrenal medulla. Candesartan pretreatment decreased adrenal catecholamines, aldosterone and corticosterone, AT1-receptor binding in adrenal zona glomerulosa and medulla, pituitary gland and the hypothalamic paraventricular nucleus, and AT2-receptor binding in adrenal medulla, but increased AT2-receptor binding in zona glomerulosa. We conclude that peripheral and central AT1-receptor blockade with candesartan decreases the sympatho-adrenal and hormonal response to acute stress. Our results indicate that Ang II is an important stress hormone and suggest that blockade of the physiologically active AT 1-receptors could influence stress-related disorders.
Cardioprotective effects of angiotensin II type 1 receptor blockade with candesartan after reperfused myocardial infarction: role of angiotensin II type 2 receptor
Authors: Jugdutt Bodh I , Yi Xu  , Balghith Mohammed , Menon Vijayan
Published: September 2010

To determine whether angiotensin II (Ang II) type 2 (AT2)-receptor activation associated with cardioprotection induced by Ang II type 1 (AT1)-receptor blockade during ischaemia-reperfusion (IR) might be reflected in increased AT 2-receptor, IP3-(1,4,5- inositol trisphosphate type 2) receptor and PKC-ε (protein kinase C-ε) proteins and tissue cGMP (cyclic guanosine monophosphate), we measured in vivo left ventricular (LV) systolic and diastolic function and remodelling (echocardiogram/Doppler) and haemodynamics, and ex vivo infarct size, AT1-/AT 2receptor, IP3-receptor and PKC-ε proteins (immunoblots) and cGMP (enzyme immunoassay) in dogs with reperfused anterior acute myocardial infarction (MI) (90-minute ischaemia, 120-minute reperfusion). Compared with controls (C, n=6) in vivo, candesartan (1 mg/kg i.v. over 30-minute pre-ischaemia, n=6) effectively inhibited the Ang II pressor response (Δ%, -14±22% vs. -80±11, p<0.003) and decreased preload (122±35 vs. -2±16%, p<0.01), improved LV systolic ejection fraction (-29±4 vs. -11±5, p<0.03) and diastolic function (E/A ratio, -25±7 vs. 33±13, p<0.004), decreased the extent of LV asynergy (26±20 vs. -31±10% LV, p<0.05) and limited acute LV remodelling (expansion index 19±6 vs. -3±5, p<0.05; thinning ratio -22±2 vs. -4±2, p<0.0003). Ex vivo, candesartan decreased infarct size (55±2 vs. 27±2% risk, p<0.001) and increased infarct zone (IZ) AT2 -receptor protein by 8-fold (but not AT1-receptor protein), IP3-receptor protein by 12-fold, PKC-ε protein by 5-fold and cGMP by 40%. Cardioprotective effects of AT1-receptor blockade on acute IR injury, LV function, and remodelling may also involve AT 2-receptor activation and downstream signalling via IP3-receptor, PKC-ε and cGMP.
The effect of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein excretion
Authors: Weinberg Marc S , Weinberg Adam J , Cord Raymond , Zappe Dion H
Published: September 2010

The optimal doses of angiotensin-converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor blockers (ARBs) for maximal reduction in urinary protein excretion are not known. Moreover, beneficial effects from ARBs, such as tissue protection owing to a more complete blockade of the renin-angiotensin-aldosterone system (RAAS), may be independent of blood pressure-lowering by ARBs. In this investigation, we evaluated whether increasing the dose of candesartan cilexetil, in subjects already on the maximally-recommended FDA doses of 32 mg, would induce a further reduction in 24-hour urinary protein excretion in patients with heavy proteinuria (urinary protein excretion >1.5 g/day; mean 4.4±2 g/day). Ten patients were started on 16 or 32 mg of candesartan cilexetil daily. After 1—2 months of therapy, the dose was titrated upwards to 96 mg. In all subjects, there were further reductions in 24-hour urinary protein excretion when the dose was increased beyond the recommended 32 mg maximal dose. Increasing the dose of candesartan cilexetil to 96 mg was safe, as most subjects showed no changes in serum potassium and, as expected, only a slight increase (0.5—0.7 mg/dl) in serum creatinine. These data warrant further investigation, since some subjects may require higher doses of candesartan to achieve optimal regression of proteinuria.
Plumbing — vital to global health
Authors: Burgon Robert D
Published: September 2010

Robert D Burgon, Chairman of the World Plumbing Council, highlights the role that plumbing makes in protecting health
Blending skills for water gain
Authors: Gordon Colin
Published: September 2010

Colin Gordon, an International Development Executive at Cardonald College Glasgow, proposes an approach to improve water utilization for water-stressed countries that blends skills development with enterprise
Water and health: A forgotten connection?
Authors: Moss Gloria A.
Published: September 2010

There are frequent and doom-laden messages concerning impending water shortages but the consequential negative effects on the availability of waters for healing and the factors underlying the decline in the use of water therapies in some parts of the world are ignored. This article reviews the evidence for the medicinal uses of water, past and present, showing how ancient Egyptian, Greek, Roman, Celtic and Hebrew societies all used water for medicinal purposes, sometimes in conjunction with herbal medicine. Water treatments consisted of hydrotherapy (techniques of therapeutic bathing and use of water), balneotherapy (therapeutic bathing in medicinal and thermal springs) and thalassotherapy (the therapeutic use of ocean bathing and marine products) and these treatments continue to be used to the present day although their use in the Anglo-Saxon world is diminised. Factors in this decline are the lack of research funding and the availability of allopathic medicine. In ancient society, the factors underlying the efficacious healing properties of water may have been ignored and its benefits instead attributed to divine sources. Latterday science, however, from the 19th century to the present, has isolated those factors in water that have health-giving properties.
How health professionals can leverage health gains from improved water, sanitation and hygiene practices
Authors: Bartram Jamie , Platt Jennifer
Published: September 2010

Emerging evidence suggests that widespread failure in coordination and collaboration between the health and WaSH sectors contributes to the substantive disease burden associated with inadequate water, sanitation and hygiene (WaSH). This results in missed opportunities at every level starting with access to water and sanitation and adequate hygiene practices in primary health facilities. This paper describes the application of an established health system functions framework to the WaSH sector and summarizes examples of successful health system action including the roles played by diverse health professionals.
Improving Risk Assessment in Family Medicine Through the Family History
Authors: Bernard Matthew E. , Zabel Carrie A. , Rohrer James E.
Published: September 2010

The family history is used as a screening tool to identify persons who may be at risk for a heritable disorder. Primary care providers sometimes do not thoroughly gather and document the family history. This pilot study was undertaken to determine whether having a genetic counselor on site at our family medicine clinic 2 days a week for 3 months would improve the quality of the family history field in patient records. We compared 7 elements in the family history field for patients seen before and after the genetic counselor was on site. Documentation of 1 of the 7 elements (major disease) improved significantly after the intervention period ( P = .02). Changing provider behavior with regard to gathering and documenting family history of major disease may be facilitated by tools to help collect the family history and by using the increasing number of available genetic tests.
Population Attributable Risk Fraction for Selected Chronic Diseases in India
Authors: Arokiasamy Periyanayangam , Agrawal Gopal
Published: September 2010

Background: India’s current health transition stage poses a critical challenge of dealing with the unfinished agenda of communicable diseases and the steadily rising burden of noncommunicable diseases. A significant burden of chronic diseases in India is attributable to household and individual level health risk factors coupled with socioeconomic conditions. From this perspective, this article made a first time effort to assess disease burden attributable to health risk factors using cross-sectional population health survey data. Methods: Population attributable fractions (PAF) were estimated for a cluster of health risk factors that include unsafe water, lack of sanitation, exposure to cooking smoke, tobacco and alcohol use, physical inactivity, and socioeconomic conditions on a set of widely prevalent chronic diseases such as tuberculosis, malaria, diarrhea, diabetes, angina, and asthma. Data from the 2003 World Health Survey was used. Results: The analysis revealed evidence of a significant contribution of health risk factors to India’s escalating chronic disease burden. The contribution of health risk factors toward chronic disease burden varied by residence. Conclusion: Results suggest that promotional health care based policies to deal with health risks should be a major priority in policy agenda to combat with the challenge of emerging noncommunicable disease coupled with the persistent burden of communicable diseases. Disease burden in India could be halved by effectively modifying exposure to the risk factors through promotional health care.
Immigration, Drinking, and Frequent Mental Distress
Authors: Ade Julius , Rohrer James E. , Merchant Munira
Published: September 2010

Objective: The objective of this study was to investigate the importance of immigration as a risk factor for self-reported frequent mental distress (FMD) among black respondents to an Internet survey. Method: Snowball sampling was used to obtain Internet survey responses from immigrant and non-immigrant black adults in the United States. Multiple logistic regression analysis was used to control for the effects of personal characteristics ( N = 301). Results: In this sample of black adults, 13.3% had FMD. Being an immigrant was not associated with FMD in this sample (adjusted odds ratio [OR] = 0.75, P = .53). However, more drinking days was an independent risk factor (OR = 1.07, P < .01). Conclusions: Being an immigrant was not an independent risk factor for FMD in this sample of black adults. However, drinking more days per month was a significant risk factor. Primary care providers should be alert for FMD and alcohol consumption in this population. Directing health education about hazardous drinking toward high-risk individuals should be considered.
Impacts of mutation effects and population size on mutation rate in asexual populations: a simulation study
Authors: Jiang Xiaoqian , Mu Baolin , Huang Zhuoran , Zhang Mingjing , Wang Xiaojuan , Tao Shiheng
Published: September 2010

Background

In any natural population, mutation is the primary source of genetic variation required for evolutionary novelty and adaptation. Nevertheless, most mutations, especially those with phenotypic effects, are harmful and are consequently removed by natural selection. For this reason, under natural selection, an organism will evolve to a lower mutation rate. Overall, the action of natural selection on mutation rate is related to population size and mutation effects. Although theoretical work has intensively investigated the relationship between natural selection and mutation rate, most of these studies have focused on individual competition within a population, rather than on competition among populations. The aim of the present study was to use computer simulations to investigate how natural selection adjusts mutation rate among asexually reproducing subpopulations with different mutation rates.

Results

The competition results for the different subpopulations showed that a population could evolve to an "optimum" mutation rate during long-term evolution, and that this rate was modulated by both population size and mutation effects. A larger population could evolve to a higher optimum mutation rate than could a smaller population. The optimum mutation rate depended on both the fraction and the effects of beneficial mutations, rather than on the effects of deleterious ones. The optimum mutation rate increased with either the fraction or the effects of beneficial mutations. When strongly favored mutations appeared, the optimum mutation rate was elevated to a much higher level. The competition time among the subpopulations also substantially shortened.

Conclusions

Competition at the population level revealed that the evolution of the mutation rate in asexual populations was determined by both population size and mutation effects. The most striking finding was that beneficial mutations, rather than deleterious mutations, were the leading force that modulated the optimum mutation rate. The initial configuration of the population appeared to have no effect on these conclusions, confirming the robustness of the simulation method developed in the present study. These findings might further explain the lower mutation rates observed in most asexual organisms, as well as the higher mutation rates in some viruses.
Comparative transcriptional profiling of the limbal epithelial crypt demonstrates its putative stem cell niche characteristics
Authors: Kulkarni Bina B , Tighe Patrick J , Mohammed Imran , Yeung Aaron M , Powe Desmond G , Hopkinson Andrew , Shanmuganathan Vijay A , Dua Harminder S
Published: September 2010

Background

The Limbal epithelial crypt (LEC) is a solid cord of cells, approximately 120 microns long. It arises from the undersurface of interpalisade rete ridges of the limbal palisades of Vogt and extends deeper into the limbal stroma parallel or perpendicular to the palisade. There are up to 6 or 7 such LEC, variably distributed along the limbus in each human eye.

Morphological and immunohistochemical studies on the limbal epithelial crypt (LEC) have demonstrated the presence of limbal stem cells in this region. The purpose of this microarray study was to characterise the transcriptional profile of the LEC and compare with other ocular surface epithelial regions to support our hypothesis that LEC preferentially harbours stem cells (SC).

Results

LEC was found to be enriched for SC related Gene Ontology (GO) terms including those identified in quiescent adult SC, however similar to cornea, limbus had significant GO terms related to proliferating SC, transient amplifying cells (TAC) and differentiated cells (DC). LEC and limbus were metabolically dormant with low protein synthesis and downregulated cell cycling. Cornea had upregulated genes for cell cycling and self renewal such as FZD7, BTG1, CCNG, and STAT3 which were identified from other SC populations. Upregulated gene expression for growth factors, cytokines, WNT, Notch, TGF-Beta pathways involved in cell proliferation and differentiation were noted in cornea. LEC had highest number of expressed sequence tags (ESTs), downregulated and unknown genes, compared to other regions. Genes expressed in LEC such as CDH1, SERPINF1, LEF1, FRZB1, KRT19, SOD2, EGR1 are known to be involved in SC maintenance. Genes of interest, in LEC belonging to the category of cell adhesion molecules, WNT and Notch signalling pathway were validated with real-time PCR and immunofluorescence.

Conclusions

Our transcriptional profiling study identifies the LEC as a preferential site for limbal SC with some characteristics suggesting that it could function as a 'SC niche' supporting quiescent SC. It also strengthens the evidence for the presence of "transient cells" in the corneal epithelium. These cells are immediate progeny of SC with self-renewal capacity and could be responsible for maintaining epithelial turn over in normal healthy conditions of the ocular surface (OS). The limbus has mixed population of differentiated and undifferentiated cells.