bluuebunny/crossref_metadata_2025 huggingface dataset:
Review: Blood pressure in haemodialysis patients: The importance of the relationship between the renin-angiotensin-aldosterone system, salt intake and extracellular volume
Authors: Doulton Timothy WR , MacGregor Graham A
Published: May 2007

This review outlines the major mechanisms for control of blood pressure (BP) in individuals with renal failure on haemodialysis. Dietary salt stimulates thirst and, thereby, greater fluid intake with excessive fluid gain between dialysis sessions and chronic expansion of extracellular volume. At the same time, this volume expansion often fails to suppress the renin-angiotensin system (RAS) appropriately and this inevitably leads to high BP in the majority of individuals on haemodialysis.

A greater understanding of the mechanisms involved leads to more rational treatment and better BP control. This can be achieved by careful measurement of BP before and after dialysis, allowing time for the equilibration of extracellular fluid shifts that occur after dialysis, combined with measurements of plasma renin activity. It is relatively easy to then decide how the high BP should be treated either by removal of excess volume by gradual ultrafiltration combined with restriction of salt intake to help prevent thirst and excessive fluid gain between dialyses, or by inhibition of the RAS, or by a combination of both.

In those individuals who are unable to adequately reduce their dietary salt intake and still continue to gain large amounts of weight between dialysis, and are resistant to reducing their pre-dialysis weight, calcium antagonists may help to lower BP, either alone or in combination with RAS blockade. However, the BP often remains resistant to treatment unless they can be persuaded to reduce their salt intake.
Neurohumoral mechanism in the natriuretic action of intracerebroventricular administration of renin
Authors: Zavala Lida , Barbella Yarisma , Israel Anita
Published: May 2007

Introduction Intracerebroventricular (IVT) administration of renin (R) decreases urinary volume and increases urinary sodium excretion. We investigated whether IVT-R-induced natriuresis could be associated with the release of atrial natriuretic peptide (ANP), its interaction with renal ANP-A receptors (ANPR-A) and the subsequent increase of urinary cyclic 3'-5' guanosine monophosphate (cGMP).

Methods In IVT cannulated rats, the left carotid artery was catheterised with PE-50 tubing for blood collection, renin was injected IVT and arterial blood samples were collected at 0, 2, 5, 10 and 15 minutes of injection, and urinary sodium and cGMP excretion at 1-, 3- and 6-hour periods of urine collection. Plasma ANP levels and urinary cGMP were determined by radioimmunoassay, and each urine sample was analysed for sodium concentration using a flame photometer.

Results Our results demonstrate that IVT-R administration increases plasma ANP levels after two minutes of injection and urinary cGMP concentration at 1-, 3-and 6 hour period of urine collection. The natriuretic action induced by IVT-R was blunted by peripheral administration of anantin, an ANPR-A antagonist. We assessed the role of brain angiotensin II (Ang II) AT1-receptors on the IVT-induced antidiuresis, natriuresis and cGMP urinary excretion, the last as an indirect index of ANP secretion. Blockade of brain Ang II AT 1-receptors with losartan (LOS; 120 µg/3 µl, IVT), inhibited the antidiuretic action and blocked the increased urinary sodium and cGMP excretion induced by IVT-R (7.14 mGU/5 µl). The increase in urinary cGMP was independent of nitric oxide synthase stimulation, since L-NAME pre-treatment did not alter the renal actions induced by IVT-R.

Conclusions Our results suggest that there is a link between the brain and the kidney. The activation of brain angiotensinergic neurons and stimulation of AT1 receptors may stimulate the release of ANP to the circulation. The released ANP circulates to the kidneys where it acts through renal ANPR-As and the consequent increase in cGMP to produce natriuresis.
Oligomerisation of angiotensin receptors: novel aspects in disease and drug therapy
Authors: Barki-Harrington Liza
Published: May 2007

The concept that 7 transmembrane receptors (7TMRs) exist and function as independent monomers has facilitated a therapeutic approach of selective targeting of receptors. However, oligomerisation of 7TMRs is now being recognised as an important biological phenomenon that adds a level of complexity to their signalling. In vitro, many 7TMR heterodimers display altered binding, signalling, and trafficking properties compared to their constituent monomeric units. This review discusses an emerging concept regarding the role of 7TMR heterodimerisation in vivo , and its significance to drug therapy. Studies of angiotensin receptor signalling indicate a pivotal role for heterodimerisation in the pathogenesis of human disorders. Furthermore, the occurrence of angiotensin receptor heterodimers has profound effect on the responsiveness to treatment with 7TMR blockers. Global assessment of the prevalence of different heterodimers during disease and their responsiveness to drug therapy is likely to optimise patient treatment and reduce side-effects associated with 7TMR blockers.
Review: The utility of BNP in clinical practice
Authors: Sharp Andrew , Mayet Jamil
Published: May 2007

Brain natriuretic peptide (BNP) is a cardiac neurohormone of increasing interest over recent years, with research applications expanding at a rapid rate and new data published on a monthly basis. Initially developed as a diagnostic aid for those with acute shortness of breath, clinical applications are now increasing, and this article reviews these clinical applications of BNP and the evidence for effectiveness of the synthetic BNP analogue nesiritide.
A putative placebo comparison of the SCOPE and LIFE trials
Authors: Meredith Peter A , Murray Lilian S , McMurray John JV
Published: May 2007

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial and the Study on Cognition and Prognosis in the Elderly (SCOPE) superficially produced comparable outcomes, with effects on stroke greater than those anticipated from blood pressure (BP) lowering alone. This, however, ignores important features of both studies. It ignores firstly the disparate comparator agents — atenolol in LIFE and predominantly hydrochlorthiazide in SCOPE, secondly the small, but potentially important BP differential between the treatment arms in SCOPE and finally the small, statistically non-significant increase in coronary heart disease (CHD) in both trials. This analysis compares the major cardiovascular outcomes in these trials with reference to placebo. Two alternative reference populations were employed to calculate the imputed placebo, firstly the MRC Trial in Elderly Hypertensives and secondly a meta-analysis of trials in the elderly, which included comparisons between diuretic- and β-blocker-based regimens. Overall, the choice of `comparator placebo' did not substantially influence the derived results. Accounting for BP difference and based on the meta-analysis, both trials demonstrated statistically significant reductions in fatal/non-fatal stroke compared with placebo — relative risks (95% confidence intervals [CI]) of 0.53 (0.39, 0.73) and 0.56 (0.41, 0.76) for SCOPE and LIFE, respectively. For fatal/non-fatal MI, there were greater discrepancies between the studies, but with neither achieving statistical significance compared with placebo — relative risks of 0.85 (0.59, 1.24) and 1.08 (0.80, 1.46) for SCOPE and LIFE, respectively. This analysis clearly demonstrates that both candesartan in SCOPE and losartan in LIFE are associated with reductions in stroke events compared with placebo, greater than that observed in the well-established meta-analysis of placebo-controlled hypertensive trials. However, the CIs are such that it is not possible to suggest definitively that this is a benefit beyond BP reduction alone. Neither trial is sufficiently `powered' to demonstrate a benefit in CHD outcomes, but with SCOPE there was a trend towards benefit with a point estimate compatible with the major meta-analysis.
Macroarray analysis in the hypertrophic left ventricle of renin-dependent hypertensive rats: identification of target genes for renin
Authors: Kurdi Mazen , Cerutti Catherine , Randon Jacques , McGregor Lilian , Bricca Giampiero
Published: May 2007

Introduction The aim of this work was to identify new renin target genes in left ventricular hypertrophy during hypertension.

Materials and methods We compared left ventricle gene expression from four transgenic TGR(mRen2)27 (TG+/-) rats and four non-transgenic littermates (TG-/-) using cDNA macroarray. Hybridisation signals were quantified with a phosphorimager, and normalised to an external scale. Data analysis was performed with Statistical Analysis for Microarrays (SAM 1.21) software. The mRNA levels of candidate genes were determined by semi-quantitative RT-PCR in three different hypertensive rats: TG+/-, spontaneously hypertensive (SHR) and genetically Lyon hypertensive (LH) rats, compared to their respective controls (TG-/-, Wistar-Kyoto, Lyon low blood pressure rats).

Results Out of 1,200 genes present on the macroarray, 233 were reliably measured and only three were overexpressed (Biglycan, β1-adenosine monophosphate-activated protein kinase [AMPK] and amyloid precursor like protein 2 [APLP2]) and 19 were underexpressed in the left ventricle of TG+/compared with TG-/-. APLP2 is a member of the amyloid precursor protein (APP) family. APLP2 and APP mRNA levels were increased in TGR(mRen2)27 but significantly decreased in LH rats, while only APP was increased in SHR rats.

Conclusions We report new genes associated with renin-dependent left ventricular hypertrophy. Moreover, this work shows for the first time that the APP family gene expression could be altered in response to high renin activity and this effect is independent of cardiac remodelling and hypertension.
Losartan may prevent the elevation of plasma glucose, corticosterone and catecholamine levels induced by chronic stress
Authors: Üresin Yağiz , Erbas Bahar , Özek Mehmet , Özkök Elif , Gürol Ali Osman
Published: May 2007

Introduction

Stress is a stimulus that activates the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Increased activity of the SNS causes to increment or impairment in blood pressure, heart rate, body temperature and plasma glucose and adrenocorticotrophic hormone (ACTH) levels. Angiotensin II (Ang II), which is a product of the renin-angiotensin system (RAS), is an important factor affecting the activity of the SNS and responses to stress. We suggest that the blockade of Ang II may be worthwhile in the prevention and treatment of diabetes mellitus and cardiovascular diseases affected by stress. Therefore, we investigated the effects of immobilisation stress on blood glucose, norepinephrine (NE), epinephrine (E) and corticosterone levels and the effects of an Ang II receptor antagonist, losartan, on these parameters.

Materials and methods

The rats were kept in small cylindrical cages for 60 min/day for 10 consecutive days to perform chronic immobilisation stress. Losartan (10 mg/kg) was given daily by gavage to Losartan (L) and Losartan + Chronic Stress (L+CS) groups. Control (C) and Chronic Stress (CS) P groups received an equal volume of saline daily by gavage for 10 days. After the last stress regimen, blood samples were collected for plasma glucose, NE, E and corticosteroid measurements.

Results

Plasma glucose, NE, E and corticosterone levels in the CS Group increased significantly compared with the C group. In Group L+CS, the plasma glucose, NE, E and corticosterone levels decreased significantly vs. Group CS. In Group L there was no significant difference vs. Group C.

Conclusion

It can be speculated that chronic blockade of RAS may decrease the excess sympathetic responses to stress in cardiovascular diseases and prevent the likely development of Type II diabetes mellitus.
Current guidelines in the pharmacological management of chronic heart failure
Authors: Metra Marco , Nodari Savina , Cas Livio Dei
Published: May 2007

Treatment of heart failure has undergone major changes in the last two decades. European and US guidelines have absorbed these major changes and set the new standards. It is therefore mandatory that treatment of heart failure is based on this knowledge. According to these guidelines, patients with chronic symptomatic heart failure should be treated with a diuretic and sometimes digoxin and vasodilators, to relieve symptoms, in addition to an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker (ARB) and a β-blocker to improve prognosis. An aldosterone antagonist should be added in patients with more advanced heart failure. Prevention of heart failure has also become a major goal.

We summarise here the major issues regarding the pharmacological treatment of chronic heart failure as indicated by the European and US guidelines.
Aldosterone blockade in heart failure
Authors: Struthers Allan D
Published: May 2007

Aldosterone plays a key role in the pathophysiology of heart failure. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers may not suppress aldosterone production in the long term. This allows aldosterone to exert its effects on myocardial fibrosis and cardiac remodelling, endothelial function, electrolytes and baroreceptor response.

The Randomized Aldactone Evaluation Study (RALES) tested spironolactone against placebo in patients with severe heart failure. The study found a 30% reduction in the risk of death among patients treated with spironolactone and a 31% reduction in the risk of death from cardiac causes. Patients in the spironolactone group had significantly lower risks of death from progression of heart failure and sudden cardiac death.

The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) investigated the effects of eplerenone against placebo in patients with myocardial infarction complicated by left ventricular dysfunction. Compared to placebo, the relative risk of death from any cause was 0.85 in eplerenone-treated patients, and the relative risk of death or hospitalisation for cardiovascular events was 0.87. The reduction in the risk of sudden death from cardiac causes was statistically significant.

In conclusion, aldosterone blockade should form part of optimal therapy for patients with heart failure.
Effect of bestatin on angiotensin I-, II- and III-induced collagen gel contraction in cardiac fibroblasts
Authors: Lijnen Paul , Petrov Victor , Diaz-Araya Guillermo , Fagard Robert
Published: May 2007

Objective

The purpose of this investigation was to determine whether the aminopeptidase inhibitor with broad specificity, bestatin, affects angiotensin I (Ang I)-, angiotensin II (Ang II)- or angiotensin III (Ang III)-stimulated collagen gel contraction in cardiac fibroblasts.

Design and methods

Cardiac fibroblasts (from normal male adult rats) were cultured to confluency in Dulbecco's modified Eagle's medium (DMEM) with 10% foetal bovine serum (FBS). These fibroblasts (100,000 cells) were then further incubated in a floating collagen gel lattice with the test products Ang I (1 µmol/L), Ang II (100 nmol/L), Ang III (100 nmol/L) and bestatin (100 µmol/L) for three days in DMEM without FBS. The area of the collagen gels embedded with cardiac fibroblasts was determined by a densitometric analysis. Aminopeptidase activity was estimated by spectrophotometric determination of the liberation of p-nitroaniline from alanine- or arginine-p-nitroanilide, Results p-nitroaniline from alanine- or arginine-p-nitroanilide.

Results

Ang I, II and III stimulated (p <0.05) collagen gel contraction by 30.4±4.8 (SEM)%, 27.1±3.1% and 15.4±3.6% respectively. Ang I- and II-induced stimulation of collagen gel contraction was of the same order but more pronounced (p<0.05) than Ang III-stimulated collagen gel contraction. The Ang I-, II- and III-stimulated collagen contraction was reduced by bestatin. Bestatin, however, did not affect basal collagen gel contraction in cardiac fibroblasts. Bestatin dose-dependently inhibited the hydrolysis of arginine- and alanine-p-nitroanilide in cardiac fibroblasts. When a neutralising antibody to transforming growth factor TGF-β 1 was added to the collagen gel simultaneously with the angiotensins, the stimulated collagen contraction was not affected. Beta-aminoproprionitrile, an inhibitor of lysyl oxidase, completely abolished basal as well as Ang I-, II- and III-stimulated collagen contraction in cardiac fibroblasts.

Results

Our data suggest that aminopeptidases are involved in the Ang I-, II- and III-induced stimulation of collagen contraction in cardiac fibroblasts.
Do Losartan and Atenolol have Differential Effects on BNP and Central Haemodynamic Parameters?
Authors: Davies Justine , Carr Elaine , Band Margaret , Morris Andrew , Struthers Allan
Published: May 2007

Introduction. It has been suggested that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have a differential effect on brachial and aortic haemodynamics. This is why they seem to have beneficial effects that are beyond brachial blood pressure (BP) lowering. We aimed to investigate if this was the case with losartan when compared to atenolol. We also investigated the differential effect of losartan and atenolol on the prognostic marker, brain type natriuretic peptide (BNP).

Methods. We studied 17 patients who were similar to those in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Patients were randomised to receive four months of losartan and atenolol in a crossover fashion. Main outcome measures were BNP and Augmentation index (AIx), which gives an indication of central haemodynamics. Brachial pulse wave velocity (PWV) and time to reflected wave (Tr) were measured as an indication of vascular stiffness.

Results. BNP was significantly lower on losartan than atenolol (p=0.007). AIx was lower on losartan than atenolol (p=0.03), however, this result was not significant when heart rate was considered as a covariate (p=0.09). Heart rate was significantly lower on atenolol than losartan (p=0.03). There was no difference between treatments for both brachial PWV and Tr (p=0.2 and p=0.99, respectively).

Conclusion. The benefits seen when losartan was compared to atenolol in the LIFE trial may be due to a reduction in BNP. We failed to detect a differential effect in central compared to peripheral haemodynamics when losartan was compared to atenolol.
Review: From Hypertension to Heart Failure — Are There Better Primary Prevention Strategies?
Authors: Meredith Peter A , Östergren Jan
Published: May 2007

Although in the developed world the incidence of and mortality from coronary heart disease (CHD) and stroke have been declining over the last 15 years, heart failure is increasing in incidence, prevalence and overall mortality, despite advances in the diagnosis and management of the condition. Hypertension, alone or in combination with CHD, precedes the development of heart failure in the majority of both men and women. Whilst there have been improvements in the overall management of hypertension, as reflected in rates of diagnosis, awareness, treatment and control of blood pressure (BP), there are still many patients with hypertension who remain undiagnosed or untreated and of those who do receive treatment many fail to achieve current targets for BP control. Placebo controlled trials in hypertension, largely based on diuretic and beta-blocker-based regimens, have unequivocally demonstrated that the treatment of hypertension can significantly reduce the incidence of heart failure. Newer treatment strategies offer theoretical and proven practical advantages over established antihypertensive therapy. In particular, AT1-receptor blockers appear to provide benefits beyond BP control and are effective in the treatment of both hypertension and heart failure. Thus, the primary prevention of heart failure in hypertensive patients should be based upon strategies that provide tight and sustained BP control necessitating the use of multiple drugs. However, there is now compelling evidence to suggest that this therapy should include an antihypertensive agent that inhibits the reninangiotensin-aldosterone system (RAAS).
Influence of Gender and Genetic Variability on Plasma Angiotensin Peptides
Authors: Reyes-Engel Armando , Morcillo Luis , Aranda Francisco Javier , Ruiz Maximiliano , Gaitan Maria Jesús , Mayor-Olea Álvaro , Aranda Pedro , Ferrario Carlos Maria
Published: May 2007

Introduction. We analysed the influence of three polymorphisms of the renin-angiotensin system (RAS) (I/D from angiotensin-converting enzyme [ACE], M235T from angiotensinogen gene [ATG] and A1166C from AT1 receptors) on plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)].

Materials and Methods. The study population consisted of a homogeneous group of 93 healthy subjects (43 men and 50 women, mean age: 20.67±2.75 years). The mean blood pressure (BP) was 126±7/76±5 (SD) mmHg and the mean body mass index (SD) mmHg and the mean body mass ' (BMI) was 22.4±2.5 kg/m2. Angiotensin peptides were separated by high performance liquid chromatography (HPLC) and quantified by radio immuno assay (RIA). Genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme analysis.

Results. Mean peptide levels were 92.48±102.12 pg/ml for Ang I, 22.35±10 pg/ml for Ang II, and 31.65±27.46 pg/ml for Ang-(1-7). Men had significantly higher levels of Ang-(1-7) (37.76±36.47 pg/ml) than women (26.04±13.98 pg/ml) (p<0.05). Among genotypes of each polymorphism, men with the T allele showed higher Ang-(1-7) levels compared with those with the MM genotype (p<0.05). Genotype analysis in women showed that higher Ang I levels were related with the DD genotype. When both genders were compared according to genotype, higher values of Ang-(1-7) levels and its molar ratios were found in men, and there was significantly greater Ang I levels in DD genotypes in women than men (136.72±112.43 vs. 65.36±46.83 pg/mL).

Conclusions. Significant correlations were found between Ang I and Ang II as well as between Ang II and Ang-(1-7) in the different study group distributions. No correlation was found between levels of Ang I and Ang-(1- 7). Certain genotypes exert an influence on angiotensin peptide plasma levels which can only be seen when the population is divided according to gender.
Clinical Evidence for the Cardiovascular Benefits of Angiotensin Receptor Blockers
Authors: Nickenig Georg , östergren Jan , Struijker-Boudier Harry
Published: May 2007

Targeting the renin-angiotensin-aldosterone system (RAAS), specifically the effector peptide angiotensin II (Ang II), represents a major opportunity for slowing the progression of cardiovascular disease (CVD) and, in turn, reducing the risk of morbidity and mortality. Inhibition of angiotensin-converting enzyme (ACE) and selective blockade of Ang II AT1 receptors are two approaches through which the pathophysiological effects of Ang II can be targeted. Numerous clinical studies have established the benefits of ACE inhibitors (ACE-Is) in lessening the morbidity and mortality burden of CVD. There are, however, tolerability concerns associated with ACE-Is, such as angioedema and dry cough.

By blocking Ang II at the AT1 receptor lever, Ang II receptor blockers (ARBs) provide a more specific and complete blockade of the deleterious effects of Ang II and tend to have more favourable tolerability. A number of clinical trials have shown that ARBs are not only associated with positive outcomes across the CVD continuum but may also have a role in the prevention or delay of diabetes (a major cardiovascular risk factor). Ongoing trials are aiming to define the place of such agents in lessening morbidity and mortality from CVD.
Review: Relationship between Erythropoietin Administration and Alterations of Renin-Angiotensin-Aldosterone
Authors: Rosario Reinaldo , Epstein Murray
Published: May 2007

The effect of erythropoietin (EPO) administration on the responsiveness of the renin-angiotensin-aldosterone system (RAAS) has not been established. Because patients with chronic kidney disease (CKD) require EPO for their management as CKD progresses, it is important to ascertain whether EPO treatment alters the RAAS. If EPO administration stimulates renin-angiotensin or aldosterone (ALDO) this intervention would mediate cardiovascular and renal injury, and consequently promote cardiovascular events and/or exacerbate the progression of renal disease.We reviewed the available publications investigating the effects of EPO on the RAAS. In CKD patients following EPO administration plasma renin activity (PRA) was unchanged in all three and ALDO was not altered in the two studies in which it was determined. In end-stage renal disease (ESRD) patients undergoing dialysis following EPO administration, four studies reported a decrease in PRA levels whereas the remaining nine disclosed no change in PRA levels.The changes in ALDO levels after EPO administration in ESRD patients were discrepant with two studies reporting an increase, two reporting a decrease and the remaining three disclosing no change.
Aldosterone Antagonism in an Inflammatory State: Evidence for Myocardial Protection
Authors: Ramires Felix JA , Salemi Vera MC , Ianni Barbara M , Fernandes Fábio , Martins Daniel G , Billate Angelina , Cunha Edécio , Mady Charles
Published: May 2007

Introduction. Chagas' disease is one of the most important causes of dilated cardiomyopathy in South and Central America. It is an inflammatory cardiomyopathy. We wanted to investigate whether it could have the same response to aldosterone antagonism as demonstrated before in other dilated cardiomyopathies.

Objective. To evaluate the role of spironolactone in myocardial remodelling in a Chagas' cardiomyopathy model.

Material and Methods. We studied 60 Sirius Hamsters divided into: control (C) infected (Inf) and Inf plus spironolactone (Infsp, 40 mg/kg/day) groups, for 11 months. Echocardiography with colour doppler was performed. Left ventricular end diastolic diameter (LVEDD), fractional shortening (FS) and corrected isovolumic relaxation time (IRT) were evaluated, as well as interstitial collagen volume fraction (ICVF) and myocardial inflammation.

Result. The results demonstrated that survival was improved by use of spironolactone in the chronic phase (p<0.04). Body weight (BW) was C:190 g, Inf:167 g*, Infsp:198 g (*p<0.05, compared to C and Infsp), LVEDD/BW was C:0.31, Inf: 0.35*, Infsp: 0.29 (*p<0.05, compared to C and Infsp), FS was C:38, Inf: 35.5, Infsp: 38 (with no statistical difference) and IRT was C: 23 msec, Inf: 26 msec*, Infsp: 22 msec (p<0.05, compared to C and Infsp). ICVF (%) was attenuated at LV (C: 0.34±0.1, Inf: 1.75±0.7*†, Infsp: 0.95±0.2*; *p<0.05, †p<0.05).

Conclusion. Spironolactone attenuated the myocardial remodelling in Chagas' cardiomyopathy, reduced mortality during the chronic phase and reduced inflammatory infiltration.
Achieving the goal of optimised renin system suppression: Predirical experience with a direct renin inhibitor
Authors: Luft Friedrich C
Published: May 2007

Aliskiren is the first orally available direct rennin inhibitor and is a highly potent and specific inhibitor of human renin. The high specificity for human renin has resulted in considerable challenges in utilising animal models in preclinical studies. Both marmoset and spontaneously hypertensive rat models demonstrate the safety and efficacy of aliskiren in reducing blood pressure, although both models have drawbacks. The former are difficulty to study, while the latter feature a renin that is less amenable to inhibition by a human-renin specific drug. However, a double transgenic rat (dTGR) model has been shown to be extremely valuable in preclinical studies of aliskiren. These rats are designed to express genes for human renin and angiotensinogen. Preclinical studies in dTGR demonstrate the efficacy and safety of aliskiren, both as monotherapy and in combination with ACE inhibitors and ARBs in the treatment of hypertension. Direct renin inhibition with aliskiren improves kidney function and reduces left ventricular hypertrophy, and may have the potential to provide end-organ protection.
Regression of left ventricular hypertrophy by a candesartan-based regimen in clinical practice The VIPE study
Authors: Barrios Vivencio , Escobar Carlos , Calderon Alberto , Pablo Tomás Juan , Ruiz Soledad , Moya Jose Luis , Megias Alicia , Vegazo Onofre , Fernandez Raul
Published: May 2007

The VIPE study was a prospective, non-comparative, open-label clinical evaluation of 97 hypertensive patients (69.1% female; 68.9±9.5 years; mean blood pressure (BP) 160±12/90±9 mmHg) with echocardiographic evidence of left ventricular hypertrophy (LVH). Patients were treated for six months with a candesartan-based regimen (8 mg/16 mg + HCTZ 12.5 mg + additional drugs to lower BP < 140/90 mmHg). After six months, systolic/diastolic BP was decreased by 19.3±8/9.4±5 mmHg (p<0.001 for both), and left ventricular mass index (LVMI) decreased 17.01 g/m2 (95%CI: -13.2 to -20.99; p<0.001). During treatment with the candesartan-based regimen all echocardiographic parameters related to LVMI were significantly reduced and 28% achieved a target LVMI [< 134 g/m2 (men) and < 110 g/m2 (women) ]. No significant changes were observed in ejection fraction, shortening fraction or LV diastolic function. Univariate analysis showed that both age (p=0.03) and diabetes (p=0.029) were predictive of LVH regression.

Thus, a candesartan-based regimen for six months significantly reduced echocardiographic LVH in hypertensive patients in general practice. The drug was very well tolerated and no serious adverse events were reported.
Is writing affected by spelling performance and beliefs about spelling?
Authors: Rankin Joan L. , Bruning Roger H. , Timme Vicky L. , Katkanant Chanida
Published: May 2007

This study examined relations between self‐efficacy and outcome expectancy beliefs and spelling and writing performance. Perceptions about spelling and writing were assessed in 258 collegeage participants. Spelling performance was measured through a 50‐item spelling test and writing performance by a holistically scored writing sample. The most highly correlated variables included spelling outcome expectancy and writing outcome expectancy, spelling selfefficacy and writing self‐efficacy, spelling performance and spelling self‐efficacy, and spelling and writing performance. A causal model relating perceptions, spelling performance, and writing performance was proposed and its appropriateness estimated. Direct effects on spelling were found for spelling self‐efficacy, while spelling self‐efficacy had indirect effects on writing performance and spelling had a direct effect on writing performance. The causal model was discussed in terms of changing conceptions of writing instruction and traditional views of the role of spelling as a necessary component of good writing.
Candidate gene analysis of 21q22: Support for S100B as a susceptibility gene for bipolar affective disorder with psychosis
Authors: Roche S. , Cassidy F. , Zhao C. , Badger J. , Claffey E. , Mooney L. , Delaney C. , Dobrin S. , McKeon P.
Published: May 2007

A genome‐wide scan in 60 bipolar affective disorder (BPAD) affected sib‐pairs (ASPs) identified linkage on chromosome 21 at 21q22 (D21S1446, NPL = 1.42, P = 0.08), a BPAD susceptibility locus supported by multiple studies. Although this linkage only approaches significance, the peak marker is located 12 Kb upstream of S100B, a neurotrophic factor implicated in the pathology of psychiatric disorders, including BPAD and schizophrenia. We hypothesized that the linkage signal at 21q22 may result from pathogenic disease variants within S100B and performed an association analysis of this gene in a collection of 125 BPAD type I trios. S100B single nucleotide polymorphisms (SNPs) rs2839350 (P = 0.022) and rs3788266 (P = 0.031) were significantly associated with BPAD. Since variants within S100B have also been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history of psychosis, a phenotype in common between the two disorders. SNPs rs2339350 (P = 0.016) and rs3788266 (P = 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level. Interestingly, SNP rs3788266 is located within a consensus‐binding site for Six‐family transcription factors suggesting that this variant may directly affect S100B gene expression. Fine‐mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 Mb upstream of S100B, as a possible BPAD susceptibility gene at 21q22. We also performed a family‐based association analysis of TRPM2 which did not reveal any evidence for association of this gene with BPAD. Overall, our findings suggest that variants within the S100B gene predispose to a psychotic subtype of BPAD, possibly via alteration of gene expression. © 2007 Wiley‐Liss, Inc.
Study of the interaction of poly(acrylic acid) and poly(acrylic acid‐poly acrylamide) complex with bone powders and hydroxyapatite by using TGA and DSC
Authors: Moharram M. A. , Allam Mousa A.
Published: May 2007

The thermo gravimetric analysis (TGA) and differential scanning calorimetric analysis (DSC) were used to study the thermal degradation of poly(acrylic acid) PAA and poly(acrylamide) PAAm as well as the compound obtained from their interactions. The examination of the thermal curves revealed that the characteristics of the curves of the compound resulting from the cooperative interactions are different from those of the constituent polymers. The differences in the characteristics of the thermal curves were attributed to the formation of an interpolymer complex resulting from the interaction of PAA with PAAm at low pH value. These two thermal techniques were also used to investigate the thermal behavior of the compounds obtained from the interaction of PAA and (PAA‐PAAm) mixture with bone powders (BP) and hydroxyapatite (HA). It was found that the TGA, DTG, and DSC curves do not show the peak of formation and degradation of PAA anhydride which provided strong evidence for the consumption of PAA in the reaction between the polymer and BP. The interaction between PAA and the thermally treated BPs and HA was investigated. Moreover the interaction between the mixture of PAA and PAAm at different pH values and the BPs and HA was discussed. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Flame retarding glass fibers reinforced polyamide 6 by melamine polyphosphate/polyurethane‐encapsulated solid acid
Authors: Wang Zhang‐Yu , Feng Zhi‐Qiang , Liu Yuan , Wang Qi
Published: May 2007

Melamine polyphosphate and thermal‐plastic polyurethane (TPU)‐encapsulated solid acid were applied for flame retardant glass fibers reinforced polyamide 6 (GFPA6). The introduction of TPU would change the interfacial property between glass fibers (GFs) and polyamide 6 (PA6), weakening the “candlewick effects” of GFs in PA6. Serving as a synergist, solid acid containing sulfur (CAS) played the role of a strong acid source, which could promote the system to form much more condensed and closed char layers. Macromolecular charring agent, TPU, was able to accelerate the charring process. In addition, TPU encapsulating on the unstable solid acid could isolate CAS from PA6 resin, preventing the chemical interaction between them, which would cause the degradation of material. This established technology provided an effective approach to prepare halogen‐free flame retardant GFPA6 with UL94‐1.6 mm V0 rating and good mechanical performance, showing a promise in the future commercial application. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Sink or swim? Bone density as a mechanism for buoyancy control in early cetaceans
Authors: Gray Noel‐Marie , Kainec Kimberly , Madar Sandra , Tomko Lucas , Wolfe Scott
Published: May 2007

Previous analyses have shown that secondarily aquatic tetrapods, including whales, exhibit osteological adaptations to life in water as part of their complex buoyancy control systems. These structural specializations of bone span hyperostosis through osteoporosis. The past 15 years of paleontological effort has provided an unprecedented opportunity to examine the osteological transformation of whales as they make their transition to an obligate aquatic lifestyle over a 10‐million‐year period. It is hypothesized that whales manifest their osteological specialization in the same manner as extant semiaquatic and fully aquatic mammals. This study presents and analysis of the microstructural features of bone in early and late archaic cetaceans, and in a comparative sample of modern terrestrial, semiaquatic, and aquatic mammals. Bone histology was examined from the ribs of 10 fossilized individuals representing five early cetacean families, including Pakicetidae, Ambulocetidae, Protocetidae, Remintonocetidae, and Basilosauridae. Comparisons were then made with rib histology from nine genera of extant mammals including: Odocoileus (deer), Bos (cow), Equus (horse), Canis (dog), Lutra (river otter), Enhydra (sea otter), Choeropsis (pygmy hippo), Trichechus (sea cow), and Delphinus (dolphin). Results show that the transition from terrestrial, to semiaquatic, to obligate aquatic locomotion in archaeocetes involved a radical shift in bone function achieved by means of profound changes at the microstructural level. A surprising finding was that microstructural change predates gross anatomical shift in archaeocetes associated with swimming. Histological analysis shows that high bone density is an aquatic specialization that provides static buoyancy control (ballast) for animals living in shallow water, while low bone density is associated with dynamic buoyancy control for animals living in deep water. Thus, there was a shift from the typical terrestrial form, to osteopetrosis and pachyosteosclerosis, and then to osteoporosis in the first quarter of cetacean evolutionary history. Anat Rec, 290:638–653, 2007. © 2007 Wiley‐Liss, Inc.
Vertebral anatomy in the Florida manatee, Trichechus manatus latirostris: A developmental and evolutionary analysis
Authors: Buchholtz Emily A. , Booth Amy C. , Webbink Katherine E.
Published: May 2007

The vertebral column of the Florida manatee presents an unusual suite of morphological traits. Key among these are a small precaudal count, elongate thoracic vertebrae, extremely short neural spines, lack of a sacral series, high lumbar variability, and the presence of six instead of seven cervical vertebrae. This study documents vertebral morphology, size, and lumbar variation in 71 skeletons of Trichechus manatus latirostris (Florida manatee) and uses the skeletons of Trichechus senegalensis (west African manatee) and Dugong dugon (dugong) in comparative analysis. Vertebral traits are used to define morphological, and by inference developmental, column modules and to propose their hierarchical relationships. A sequence of evolutionary innovations in column morphology is proposed. Results suggest that the origin of the fluke and low rates of cervical growth originated before separation of trichechids (manatees) and dugongids (dugongs). Meristic reduction in count is a later, trichechid innovation and is expressed across the entire precaudal column. Elongation of thoracic vertebrae may be an innovative strategy to generate an elongate column in an animal with a small precaudal count. Elimination of the lumbus through both meristic and homeotic reduction is currently in progress. Anat Rec, 290:624–637, 2007. © 2007 Wiley‐Liss, Inc.
Breaking symmetry: The marine environment, prey size, and the evolution of asymmetry in cetacean skulls
Authors: Macleod C.D. , Reidenberg J.S. , Weller M. , Santos M.B. , Herman J. , Goold J. , Pierce G.J.
Published: May 2007

Skulls of odontocetes (toothed whales, including dolphins and porpoises) are typified by directional asymmetry, particularly in elements associated with the airway. Generally, it is assumed this asymmetry is related to biosonar production. However, skull asymmetry may actually be a by‐product of selection pressure for an asymmetrically positioned larynx. The odontocete larynx traverses the pharynx and is held permanently in place by a ring of muscle. This allows prey swallowing while remaining underwater without risking water entering the lungs and causing injury or death. However, protrusion of the larynx through the pharynx causes a restriction around which prey must pass to reach the stomach. The larynx and associated hyoid apparatus has, therefore, been shifted to the left to provide a larger right piriform sinus (lateral pharyngeal food channel) for swallowing larger prey items. This asymmetry is reflected in the skull, particularly the dorsal openings of the nares. It is hypothesized that there is a relationship between prey size and skull asymmetry. This relationship was examined in 13 species of odontocete cetaceans from the northeast Atlantic, including four narrow‐gaped genera (Mesoplodon, Ziphius, Hyperoodon, and Kogia) and eight wide‐gaped genera (Phocoena, Delphinus, Stenella, Lagenorhynchus, Tursiops, Grampus, Globicephala, and Orcinus). Skulls were examined from 183 specimens to assess asymmetry of the anterior choanae. Stomach contents were examined from 294 specimens to assess prey size. Results show there is a significant positive relationship between maximum relative prey size consumed and average asymmetry relative to skull size in odontocete species (wide‐gape species: R2 = 0.642, P = 0.006; narrow‐gape species: R2 = 0.909, P = 0.031). This finding provides support for the hypothesis that the directional asymmetry found in odontocete skulls is related to an aquatic adaptation enabling swallowing large, whole prey while maintaining respiratory tract protection. Anat Rec, 290:539–545, 2007. © 2007 Wiley‐Liss, Inc.
Use of tusks in feeding by dugongid sirenians: Observations and tests of hypotheses
Authors: Domning Daryl P. , Beatty Brian L.
Published: May 2007

Most living and fossil sea cows of the subfamily Dugonginae (Dugongidae, Sirenia, Mammalia) are characterized by large upper incisor tusks, which are thought to play an important role (at least primitively) in feeding on seagrass rhizomes. Testing this hypothesis is difficult, because the only extant tusked sirenian (Dugong dugon) is morphologically and perhaps behaviorally aberrant. The tests attempted here involve examination of stomach contents of wild Recent dugongs, experiments using plastic replicas of diverse tusks to harvest seagrasses, gross anatomical observations on tusks and skulls, measurements of tusk tip geometry, and observations of microwear on tusks. We conclude that (a) male D. dugon (with erupted tusks) do not consume more rhizomes than females (without erupted tusks); (b) the tusks do not play a significant role in feeding in the modern dugong; (c) larger, more bladelike tusks are more effective at harvesting rhizomes, but the effect of shape was not experimentally separated from the effect of exposed tusk length; (d) some fossil dugongines show apparent cranial adaptations for downward and backward cutting motions of their large, bladelike tusks; (e) geometry of wear surfaces is consistent with use of at least the more bladelike tusks as cutting instruments; (f) preliminary observations of microwear in D. dugon do not indicate more than occasional use of the tusks in purposeful harvesting of rhizomes, and then only opportunistically by large adult males. The hypothesis of such tusk use by extinct dugongines (in contrast to the living species) is so far corroborated, but available data and tests do not suffice to establish this conclusively. Anat Rec, 290:523–538, 2007. © 2007 Wiley‐Liss, Inc.
Discovery of a low frequency sound source in Mysticeti (baleen whales): Anatomical establishment of a vocal fold homolog
Authors: Reidenberg Joy S. , Laitman Jeffrey T.
Published: May 2007

The mechanism of mysticete (baleen whale) vocalization has remained a mystery. Vocal folds (true vocal “cords”), the structures responsible for sound production in terrestrial mammals, were thought to be absent in whales. This study tests the hypothesis that the mysticete larynx possesses structures homologous to vocal folds and that they are capable of sound generation. Laryngeal anatomy was examined in 37 specimens representing 6 mysticete species. Results indicate the presence of a U‐shaped fold (U‐fold) in the lumen of the larynx. The U‐fold is supported by arytenoid cartilages, controlled by skeletal muscles innervated by the recurrent laryngeal nerve, is adjacent to a diverticulum (laryngeal sac) covered with mucosa innervated by the superior laryngeal nerve, and contains a ligament—conditions that also define the vocal folds of terrestrial mammals and, therefore, supports homology. Unlike the vocal folds of terrestrial mammals, which are perpendicular to airflow, the mysticete U‐fold is oriented parallel to airflow. U‐fold adduction/abduction and elevation/depression may control airflow, and vibration of its edges may generate sounds. The walls of the laryngeal sac can expand and contract, may serve as a resonant space, and may also propagate vibrations generated by movements of the supporting arytenoid cartilages. The extensive musculature surrounding the laryngeal sac may enable rapid and forceful expulsion of air from the lumen of the sac into other respiratory spaces, or maintain a constant sac volume despite the effects of ambient pressure (e.g., changes during diving or ascent). The size and complexity of the mysticete larynx indicates an organ with multiple functions, including protection during breathing/swallowing, regulation of airflow and pressures in the respiratory spaces, and sound generation. The presence of a vocal fold homolog offers a new insight into both the mechanism of sound generation by mysticetes and the divergent evolution of odontocete and mysticete cetaceans. Anat Rec, 290:745–759, 2007. © 2007 Wiley‐Liss, Inc.
Different Ca2+signalling cascades manifested by mastoparan in the prothoracic glands of the tobacco hornworm,Manduca sexta, and the silkworm,Bombyx mori
Authors: Dedos Skarlatos G. , Wicher Dieter , Kaltofen Sabine , Birkenbeil Heiner
Published: May 2007

Application of the tetradecapeptide mastoparan to the prothoracic glands (PGs) of the tobacco hornworm,Manduca sexta, and the silkworm,Bombyx mori, resulted in increases in intracellular Ca2+([Ca2+]i). InM. sexta, Gi proteins are involved in the mastoparan‐stimulated increase in [Ca2+]i. However, there is no involvement of Gi proteins in the mastoparan‐stimulated increase in [Ca2+]iin prothoracic gland cells fromB. mori. Unlike inM. sextaprothoracic glands, inB. moriprothoracic glands mastoparan increases [Ca2+]ieven in the absence of extracellular Ca2+. Pharmacological manipulation of the Ca2+signalling cascades in the prothoracic glands of both insect species suggests that inM. sextaprothoracic glands, mastoparan's first site of action is influx of Ca2+through plasma membrane Ca2+channels while inB. moriprothoracic glands, mastoparan's first site of action is mobilization of Ca2+from intracellular stores. InM. sexta, the combined results indicate the presence of mastoparan‐sensitive plasma membrane Ca2+channels, distinct from those activated by prothoracicotropic hormone or the IP3signalling cascade, that coordinate spatial increases in [Ca2+]iin prothoracic gland cells. We propose that inB. mori, mastoparan stimulates Ca2+mobilization from ryanodine‐sensitive intracellular Ca2+stores in prothoracic gland cells. Arch. Insect Biochem. Physiol. 65:52–64, 2007. © 2007 Wiley‐Liss, Inc.