bluuebunny/crossref_metadata_2025 huggingface dataset:
The Future (R)evolution of Preimplantation Genetic Diagnosis/Human Leukocyte Antigen Testing: Ethical Reflections
Authors: de Wert Guido , Liebaers Inge , Van de Velde Hilde
Published: May 2007

There has been increasing support for combining preimplantation genetic diagnosis (PGD) for specific diseases with a test for human leukocyte antigens (HLA) because the generation of HLA-matched umbilical cord blood cells may save the life of a diseased sibling. To date, this procedure has taken place in the context of conceiving another child—PGD/HLA testing type 1. However, it may well become possible to perform PGD/HLA testing outside this context, that is, to select matched embryos from which embryonic stem cells could be derived and used in cell therapy—PGD/HLA testing type 2. A proactive ethical analysis is needed and is presented in this article. Although PGD/HLA testing type 1 can be morally justified, the risks, pitfalls, and practical limitations of this procedure make it necessary to develop alternative strategies. PGD/HLA testing type 2 may provide an alternative strategy. From an ethical point of view, the controversial issue is that this procedure creates embryos purely for instrumental use. However, given the dominant view that the preimplantation embryo has only limited moral value, this alternative may be as morally justified as PGD/HLA testing type 1.

Disclosure of potential conflicts of interest is found at the end of this article.
Initiate Insulin by Aggressive Titration and Education (INITIATE)
Authors: Yki-Järvinen Hannele , Juurinen Leena , Alvarsson Michael , Bystedt Tord , Caldwell Ian , Davies Melanie , Lahdenperä Sanni , Nijpels Gil , Vähätalo Markku
Published: May 2007

OBJECTIVE—Insulin is often postponed for years because initiation is time-consuming. We sought to compare initiation of insulin individually and in groups with respect to change in A1C and several other parameters in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS—A randomized (1:1), multicenter, two-arm, parallel design study with a recruiting period of up to 14 weeks and a 24-week treatment period. Either in groups of 4–8 or individually, using the same personnel and education program, 121 insulin-naive type 2 diabetic patients with an A1C of 7.0–12.0% were randomized to initiate bedtime insulin glargine. The patients visited the treatment center before and at the time of insulin initiation and at 6, 12, and 24 weeks. Patients self-adjusted the insulin dose to achieve a fasting plasma glucose 4.0–5.5 mmol/l.

RESULTS—At 24 weeks, mean ± SE A1C had decreased from 8.7 ± 0.2 to 6.9 ± 0.1% in those treated individually and from 8.8 ± 0.2 to 6.8 ± 0.1% in those in groups (not significant [NS]). Insulin doses averaged 62 ± 5 IU and 56 ± 5 IU at 24 weeks (NS), respectively. The frequency of hypoglycemia was similar. The total time (visits and phone calls) spent in initiating insulin in the patients in groups (2.2 ± 0.1 h) was 48% less than in those treated individually (4.2 ± 0.2 h). Diabetes treatment satisfaction improved significantly in both sets of patients.

CONCLUSIONS—Similar glycemic control and treatment satisfaction can be achieved by initiating insulin in groups and individually. Starting insulin in groups takes one-half as much time as individual initiation.
Interindividual Variability and Intra-Individual Reproducibility of Glycemic Index Values for Commercial White Bread
Authors: Vega-López Sonia , Ausman Lynne M. , Griffith John L. , Lichtenstein Alice H.
Published: May 2007

OBJECTIVE—We sought to assess the intra- and interindividual variability of glycemic index value determinations for white bread using glucose as the reference food.

RESEARCH DESIGN AND METHODS—A total of 23 healthy adults (aged 20–70 years) completed up to three sets of two visits per set. Each pair of visits assessed the glycemic response to 50 g available carbohydrates from commercial white bread and glucose, administered in random order. Glycemic index values were calculated by dividing the 2-h incremental area under the serum glucose response curve after each commercial white bread challenge by the mean area under the curve (AUC) for glucose.

RESULTS—The mean ± SE ratio of the AUC after white bread intake by the AUC after glucose intake for the first set of determinations was 78 ± 15 (n = 23; coefficient of variation [CV] 94%). When using glycemic index values calculated with the subset of participants who completed three sets of tests (n = 14), glycemic index values for each of the three sets of determinations were 78 ± 10, 60 ± 5, and 75 ± 10, respectively. CVs were 50, 28, and 50%, respectively. The mean glycemic index value of these three sets was 71 ± 6, with a CV of 30%. When an ANOVA approach was applied to these data, the interindividual CV was 17.8%, and the intra-individual variation was 42.8%.

CONCLUSIONS—These data suggest that in response to a challenge of white bread relative to glucose, within-individual variability is a greater contributor to overall variability than among-individual variability. Further understanding of all the sources of variability would be helpful in better defining the utility of glycemic index values.
Plasma Resistin, Associated With Single Nucleotide Polymorphism −420, Is Correlated With Insulin Resistance, Lower HDL Cholesterol, and High-Sensitivity C-Reactive Protein in the Japanese General Population
Authors: Osawa Haruhiko , Tabara Yasuharu , Kawamoto Ryuichi , Ohashi Jun , Ochi Masaaki , Onuma Hiroshi , Nishida Wataru , Yamada Kazuya , Nakura Jun , Kohara Katsuhiko , Miki Tetsuro , Makino Hideichi
Published: May 2007

OBJECTIVE—Resistin, secreted from adipocytes, causes insulin resistance in rodents. We previously reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at −420 increases type 2 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP −420 genotype or factors related to insulin resistance.

RESEARCH DESIGN AND METHODS—We cross-sectionally analyzed 2,078 community-dwelling Japanese subjects attending a yearly medical checkup. The SNP −420 genotype was determined by TaqMan analysis. Fasting plasma resistin was measured using an enzyme-linked immunosorbent assay kit.

RESULTS—Plasma resistin was associated with the SNP −420 genotype (P < 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly individuals, female subjects, nondrinkers, and subjects with high blood pressure (P < 0.001, 0.003, <0.001, and 0.001, respectively). Simple regression analysis revealed that age, female sex, homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, low HDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP) were positively correlated with plasma resistin (P < 0.001, 0.003, <0.001, 0.004, <0.001, and 0.003, respectively). Multiple regression analysis adjusted for age, sex, and BMI revealed that plasma resistin was an independent factor for HOMA-IR, low HDL cholesterol, and hs-CRP (P = 0.001, <0.001, and 0.006, respectively).

CONCLUSIONS—Plasma resistin was associated with SNP −420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population.
The Underuse of Screening Services Among Elderly Women With Diabetes
Authors: McBean A. Marshall , Yu Xinhua
Published: May 2007

OBJECTIVE—To determine whether the use of nondiabetes-related preventive services (mammography, colorectal cancer screening, and bone density testing) among elderly diabetic women is different from the use among nondiabetic women.

RESEARCH DESIGN AND METHODS—Using a representative sample of the U.S. elderly female population and the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare files, we identified women with or without diabetes who were ≥67 years of age on 1 January 1999. All women with a prior history of cancer were excluded. Bivariate and multivariate analyses were used to compare the rates of preventive service use and to understand the factors influencing their use in the next 2–4 years.

RESULTS—Women with diabetes were less likely to have a mammogram (odds ratio [OR] 0.83 [95% CI 0.78–0.88]), colorectal cancer screening (0.79 [0.70–0.88]), and bone density testing (0.63 [0.58–0.69]). Women with diabetes seen by endocrinologists had significantly higher rates of bone density testing than women seen by primary care physicians. Women seen by obstetrician/gynecologists had the highest rates of use of all three services.

CONCLUSIONS—Elderly women with diabetes are less likely to receive cancer and osteoporosis screening than women without diabetes. Physicians treating these patients need to assure that they receive all recommended preventive services appropriate for their age. Additional national guidelines, practice-based improvements, and patient education targeting those at greatest risk of not receiving these services may be needed to achieve parity.
Normalization of the IGF-IGFBP Axis by Sustained Nightly Insulinization in Type 1 Diabetes
Authors: Ekström Klas , Salemyr Jenny , Zachrisson Ingmar , Carlsson-Skwirut Christine , Örtqvist Eva , Bang Peter
Published: May 2007

OBJECTIVE—We sought to test the hypothesis that start of insulin glargine with sustained nightly insulin action results in changes in circulating concentrations of IGF-I and IGF binding proteins (IGFBPs) in adolescents with type 1 diabetes—changes that may support improvement of A1C.

RESEARCH DESIGN AND METHODS—Twelve pubertal adolescents with type 1 diabetes and initially on NPH insulin were studied during 12 weeks of intensified treatment with glargine.

RESULTS—Subnormal IGF-I SD scores on NPH (−1.8 ± 0.4) rapidly increased and remained 54 ± 9% elevated (P < 0.001) after 12 weeks on glargine. A1C decreased from 8.3 ± 0.6% to a nadir of 6.9 ± 0.3% (P = 0.002) at 6 weeks and correlated with changes in IGF-I (r = −0.64, P < 0.05). The increase in IGF-I did not suppress the mean overnight growth hormone (GH) secretion at 6 weeks. The mean overnight IGFBP-1 levels decreased (P = 0.035), supporting the hypothesis that the nightly hepatic insulin action was increased. Circulating IGF-I increased in the absence of changes in both GH secretion and GH receptor numbers (assessed by growth hormone binding protein), indicating that postreceptor mechanisms are involved. IGFBP-3 proteolysis was decreased.

CONCLUSIONS—Increased hepatic insulin action after start of glargine was evident from a decrease in night time IGFBP-1 concentrations. This may improve GH postreceptor signaling, resulting in increased circulating IGF-I. We suggest that even in the absence of changes in GH, increased IGF-I and decreased IGFBP-1 support the improvement of metabolic control.
Accelerated Loss of Skeletal Muscle Strength in Older Adults With Type 2 Diabetes
Authors: Park Seok Won , Goodpaster Bret H. , Strotmeyer Elsa S. , Kuller Lewis H. , Broudeau Robert , Kammerer Candace , de Rekeneire Nathalie , Harris Tamara B. , Schwartz Ann V. , Tylavsky Frances A. , Cho Yong-wook , Newman Anne B. ,   for the Health, Aging, and Body Composition Study
Published: May 2007

OBJECTIVE—It has been shown that adults with either long-standing type 1 or type 2 diabetes had lower skeletal muscle strength than nondiabetic adults in cross-sectional studies. The aim of the study was to investigate longitudinal changes of muscle mass and strength in community-dwelling older adults with and without type 2 diabetes.

RESEARCH DESIGN AND METHODS—We examined leg and arm muscle mass and strength at baseline and 3 years later in 1,840 older adults aged 70–79 years in the Health, Aging, and Body Composition Study. Regional muscle mass was measured by dual energy X-ray absorptiometry, and muscle strength was measured using isokinetic and isometric dynamometers.

RESULTS—Older adults with type 2 diabetes (n = 305) showed greater declines in the leg muscle mass (−0.29 ± 0.03 vs. −0.23 ± 0.01 kg, P < 0.05) and strength (−16.5 ± 1.2 vs. −12.4 ± 0.5 Nm, P = 0.001) compared with older adults without diabetes. Leg muscle quality, expressed as maximal strength per unit of muscle mass (Newton meters per kilogram), also declined more rapidly in older adults with diabetes (−1.6 ± 0.2 vs. −1.2 ± 0.1 Nm/kg, P < 0.05). Changes in arm muscle strength and quality were not different between those with and without diabetes. Rapid declines in leg muscle strength and quality were attenuated but remained significant after controlling for demographics, body composition, physical activity, combined chronic diseases, interleukin-6, and tumor necrosis factor-α.

CONCLUSIONS—In older adults, type 2 diabetes is associated with accelerated loss of leg muscle strength and quality.
Effect of BMI on Lifetime Risk for Diabetes in the U.S.
Authors: Narayan K.M.V. , Boyle James P. , Thompson Theodore J. , Gregg Edward W. , Williamson David F.
Published: May 2007

OBJECTIVE—At birth, the lifetime risk of developing diabetes is one in three, but lifetime risks across BMI categories are unknown. We estimated BMI-specific lifetime diabetes risk in the U.S. for age-, sex-, and ethnicity-specific subgroups.

RESEARCH DESIGN AND METHODS—National Health Interview Survey data (n = 780,694, 1997–2004) were used to estimate age-, race-, sex-, and BMI-specific prevalence and incidence of diabetes in 2004. U.S. Census Bureau age-, race-, and sex-specific population and mortality rate estimates for 2004 were combined with two previous studies of mortality to estimate diabetes- and BMI-specific mortality rates. These estimates were used in a Markov model to project lifetime risk of diagnosed diabetes by baseline age, race, sex, and BMI.

RESULTS—Lifetime diabetes risk at 18 years of age increased from 7.6 to 70.3% between underweight and very obese men and from 12.2 to 74.4% for women. The lifetime risk difference was lower at older ages. At 65 years of age, compared with normal-weight male subjects, lifetime risk differences (percent) increased from 3.7 to 23.9 percentage points between overweight and very obese men and from 8.7 to 26.7 percentage points for women. The impact of BMI on diabetes duration also decreased with age.

CONCLUSIONS—Overweight and especially obesity, particularly at younger ages, substantially increases lifetime risk of diagnosed diabetes, while their impact on diabetes risk, life expectancy, and diabetes duration diminishes with age.
Heterobimetallic complexes containing iron (II) and hexa-coordinated organosilicon
Authors: Malhotra Rajesh , Mehta Jyoti , Puri J.
Published: May 2007

Heterobimetallic complexes of the type R2Si(HL)Cl2 and R2SiL2 (where R = Me, Et, Ph; L = ferrocenyl aroylhydrazone) have been synthesized at 40 °C to 50 °C and at room temperature (25 °C), respectively, and characterized by elemental analysis, molar conductance, infrared and NMR (1H, 13C and 29Si) spectral data. The ligands behave as bidentate, coordinating through the azomethine nitrogen and the oxygen in the amidic and the imidic acid forms of the ligand at low temperature and at room temperature, respectively. The ligands and their organosilicon complexes have been evaluated for the antifungal activity against Alternaria alternata, Fusarium oxysporum and Rhizoctonia solani, as well as antibacterial activity against gram negative, Escherichia coli and gram positive, Bacillus subtilis, at 28 °C. Organosilicon complexes of ferrocenyl aroylhydrazone were found to be more potent than the parent ligands.
Grosser Wert und wenig Geld? Über die Honorierung von Waldleistungen | Highly Valuable But Hardly Remunerative? On Compensating Forest Benefits
Authors: Kissling-Näf Ingrid
Published: May 2007

Forests provide people with a variety of services and products (protection against avalanches, walking trails, etc.). Most forest services and products are not provided by markets and the extent of their availability is often guaranteed by public funding. In this context, the question arises whether the high benefits derived from forests could not be converted into cash more easily. Looking at various explanations for the market failure (externalities, public goods, property rights) possible marketing strategies for forest products and services and how they could optimize social welfare are investigated. Although general compensation criteria are not available, economic concepts (type of externality, scarcity, etc.) provide a first clue as to the necessity of compensation. However, mention must be made that compensation is always the result of a social agreement, and financial compensation as well as property rights are subject to social change. From a political and an economic perspective the payment of compensation for forest benefits is limited.
Holzprodukte in vergleichenden Ökobilanzen | Wood Products in Comparative Life Cycle Assessment Studies
Authors: Werner Frank , Künniger Tina , Richter Klaus
Published: May 2007

Life Cycle Assessment (LCA) quantifies the potential environmental impacts of a product system throughout its life cycle. LCA methods are discussed taking into account the exceptional position of forestry and wood products. The results of three studies are presented where wood products are being compared to alternative products.
Jahrringforschung und Klimawandel in den borealen Wäldern | Annual ring research and climate change in boreal forests
Authors: Schweingruber Fritz H.
Published: May 2007

For a climatological interpretation of annual-ring sequences we used the northern hemispheric tree-ring network collected by the WSL for the boreal zone and subalpine areas. Ring width and maximum densities point to climatological events of short duration triggered by volcanic eruptions, as well as decennial and centennial changes of summer temperatures over the past 8000 years. The current warm period roughly corresponds to that which occurred around AD 1000.
The involvement of AT2-receptor in the antithrombotic effect of losartan in renal hypertensive rats
Authors: Chabielska Ewa , Matys Tomasz , Kucharewicz Iwona , Pawlak Dariusz , Rólkowski Roland , Buczko Wlodzimierz
Published: May 2007

In previous studies, we have shown that losartan possesses nitric oxide-dependent antithrombotic properties in various models of hypertension in rats. It was demonstrated that stimulation of AT2-receptors plays an important role in the pharmacological effects of AT1-receptor antagonists. Thus, in this study, we examine the participation of AT2-receptors in the antithrombotic action of losartan in renal hypertensive rats on venous thrombosis induced by a two-hour ligation of the vena cava. Losartan administration (30 mg/kg, p.o.) resulted in a marked decrease in thrombus weight (by 85%, p<0.001). PD123319, an AT2-receptor antagonist (10 mg/kg, i.v.), administered concomitantly with losartan, abolished its antithrombotic effect, whilst it had no influence on thrombus weight when given alone. A significant decrease in systolic blood pressure was observed in animals given losartan. PD123319 administration did not abolish this action of losartan and did not alter blood pressure when given alone. No changes in prothrombin time, activated partial thromboplastin time, or euglobulin clot lysis time were observed in animals administered losartan and/or PD123319. Similarly, primary haemostatics evaluated by bleeding time and platelet count did not change in any group of rats. In conclusion, we have shown that AT2receptor stimulation is involved in the antithrombotic action of losartan in renal hypertensive rats.
The antithrombotic effect of angiotensin-(1—7) closely resembles that of losartan
Authors: Kucharewicz Iwona , Chabielska Ewa , Pawlak Dariusz , Matys Tomasz , Rólkowski Roland , Buczko Wlodzimierz
Published: May 2007

Angiotensin-(1-7) [Ang-(1-7)] is the bioactive peptide which may be responsible for some of the pharmacological effects of losartan. Our previous study has demonstrated the antithrombotic action of losartan in a model of experimental thrombosis. In the present study, we compared the antithrombotic action of losartan and Ang-(1-7).

Acute (10 mg/kg, p.o.) and chronic (10 mg/kg, p.o., three weeks) losartan administration to spontaneously hypertensive rats (SHR) induced a decrease in thrombus weight (1.6±0.6 mg and 1.2±0.3 mg respectively vs. control 2.9±0.8 mg; p<0.05, p<0.05). A similar reduction was observed in two-kidney, one-clip hypertensive rats (2K-1C) receiving acute losartan administration (1.39±0.29 mg vs. 3.25±0.62 mg; p<0.01). Infusion of Ang-(1-7) to 2K-1C rats also reduced the thrombus weight (1.01±0.34 mg, 1.23±0.38 mg and 2.17±0.36 mg for 1, 10, 100 pmol/kg/min, respectively vs. 3.58±0.6 mg control; p<0.01, p<0.01, p<0.05). Losartan produced a decrease in systolic blood pressure (BP) in SHR as well as in 2K-1C rats, while Ang-(1-7) infusion had no effect on BP. Acute losartan dosing to 2K-1C rats decreased platelet adhesion to fibrillar collagen (24.9±1.0% vs. control 31.5±1.1%, p<0.001). The incubation of platelet samples with Ang-(1-7) (10-6 and 10 —5 M) also reduced adhesion to fibrillar collagen (38.4±0.1% and 33.8±0.8% respectively vs. control 40.0±0.6%; p<0.05, p<0.001). There were no apparent changes in prothrombin time, activated partial thromboplastin time and euglobulin clot lysis time in losartan and Ang-(1-7)-treated groups. We conclude that, like losartan, Ang-(1-7) is able to act as an antithrombotic agent.
Saving lives: Long-term morbidity and mortality trials with selective angiotensin receptor blocker therapy
Authors: McInnes Gordon T
Published: May 2007

Prospective randomised trials have demonstrated convincingly the benefits of drug treatment of hypertension. Treatment with conventional antihypertensive agents reduces the incidence of cardiovascular events by about that which would be expected from epidemiological data for the achieved difference in blood pressure. Newer agents, such as angiotensin II receptor blockers, have potential for benefits beyond blood pressure reduction. This rationale is under evaluation in a number of long-term morbidity and mortality trials which will report over the next few years, with the largest, VALUE, due to provide results in 2004. The findings from these trials will be decisive in determining the future role of this important new class of drugs.
New basic science initiatives with the angiotensin II receptor blocker valsartan
Authors: de Gasparo Marc
Published: May 2007

Angiotensin II (Ang II) plays a key role in the regulation of blood pressure and fluid homeostasis. Valsartan is a highly selective Ang II receptor blocker that specifically and selectively blocks Ang II at the AT1-receptor. In animal models, valsartan has shown positive effects on vasoconstriction, proliferation, remodelling, endothelial function and thrombogenesis, inflammation and atherosclerosis. These data are likely to be confirmed by the results of current clinical trials and valsartan is set to provide improved cardiovascular therapy in the future.
Transforming growth factor-β1 induces angiotensin-converting enzyme synthesis in rat cardiac fibroblasts during their differentiation to myofibroblasts
Authors: Petrov Victor V , Fagard Robert H , Lijnen Paul J
Published: May 2007

Objectives Appearance of angiotensin-converting enzyme (ACE) in fibrotic tissue can be the result of the action either of one particular growth factor or of cross-talk between multiple factors. Transforming growth factor-β1 (TGF-β 1) is an effective inducor of the differentiation of cultured fibroblasts to myofibroblasts, which are heterogeneous cells with different phenotypes. The present study investigated whether TGF-β1 is able to induce, in vitro, the differentiation of cultured fibroblasts to myofibroblasts with a phenotype containing ACE.

Design Adult rat cardiac ventricular fibroblasts were obtained from hearts perfused with collagenase. Cells from second passage were always used. Rat cardiac ventricular fibroblasts were incubated with TGF-β1 (10 ng/ml) for seven days.

Cell characterisation was performed using light microscopy and indirect immunostaining. Presence of vimentin, desmin, factor VIII, α-smooth muscle actin, and ACE was checked with both immunostaining and Western blotting. ACE activity was measured fluorometrically with hippuryl-histidyl-leucine as substrate. Synthesis of DNA was measured as 3H-thymidine incorporation.

Results Fibroblasts contained two types of activity of hip-his-leu degradation, namely a lisinopril-dependent activity (ACE activity) and a lisinopril-independent activity (`ACE-like' activity) which is performed by peptidase(s) other than ACE. The ACE activity constituted approximately 30% of the total activity. TGF-β1 induced an increase in both ACE activity and ACE protein (detected by immunoblotting) by 4.5 ± 0.9- and 6.9 ± 2.0-fold, respectively (p<0.05). This induction of ACE was accompanied by a profound modification of the fibroblasts phenotype, which consisted of a change in cell morphology, an enlargement of cell volume and an increase in cell protein content. TGF-β1 profoundly inhibited 3H-thymidine incorporation and the number of cells in growing cultures. The induction of α-smooth muscle actin by TGF-β 1 (6.8 ± 2.8-fold increase, p<0.05) simultaneously with these modifications in cell morphology and proliferation indicates the appearance of myofibroblasts. These myofibroblasts did not contain desmin.

Conclusion TGF-β 1 is able to induce the appearance of ACE in cultures of adult rat cardiac ventricular fibroblasts. The appearance of the enzyme is accompanied by the differentiation of fibroblasts to myofibroblasts.
Effects of the mineralocorticoid fludrocortisone on fibrinolytic function in healthy subjects
Authors: Lottermoser Katja , Hertfelder Hans-Jörg , Wehling Martin , Schiermeyer Beate , Vetter Hans , Düsing Rainer
Published: May 2007

Recent evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the regulation of fibrinolytic function. Angiotensin II (Ang II) is the primary candidate to mediate this inter-relationship, since this peptide is capable of stimulating plasminogen activator inhibitor-1 (PAI-1) in vitro and in vivo. It has been suggested that aldosterone may also modulate fibrinolysis, possibly by interacting with Ang II. The present study therefore investigates the effect of short-term treatment with the synthetic mineralocorticoid fludrocortisone (F) on fibrinolytic function. Ten healthy male volunteers, aged 25 to 30 years, on a constant intake of 160—180 mmol Na+ and 60—80 mmol K+, were studied on a control day (C1), after two days of oral administration of F (0.1 mg b.d.), and again three days after cessation of F (C2). F was associated with a marked decrease in plasma renin activity (PRA) from 0.91 ± 0.45 ng ml-1 h -1 to 0.34 ± 0.29 ng ml-1 h-1 (p=0.005), which returned to the baseline range at C2 (0.65 ± 0.45 ng ml-1 h -1; p=0.032). The experimental protocol was not associated with significant changes in the activity or antigen concentration of tissue plasminogen activator (t-PA). PAI-1 exhibited a circadian rhythm with highest values at 0800 hours (41.8 ± 9.1 ng/ml), decreasing by 1230 hours (22.6 ± 5.9 ng/ml), with a further decrease at 1630 hours (12.3 ± 3.1 ng/ml). At all three time points, PAI-1 remained unchanged by the mineralocorticoid. Our results therefore do not support a major mineralocorticoid effect on PAI-1. However, our study does not exclude a modulatory role of F, since unchanged PAI-1 could be observed in spite of a marked suppression of the RAAS.
Evaluation of the safety and efficacy of telmisartan and enalapril, with the potential addition of frusemide, in moderate-renal failure patients with mild-to-moderate hypertension
Authors: Hannedouche Thierry , Chanard Jacques , Baumelou Bertrand , French Collaborative Telmisartan Study Group
Published: May 2007

The effect on renal function and efficacy of the angiotensin II AT1-receptor blocker (ARB), telmisartan, were compared with those of the angiotensin-converting enzyme inhibitor, enalapril, for the treatment of mild-to-moderate hypertension (diastolic blood pressure [DBP] 95—114 mmHg) in the presence of moderate renal failure (creatinine clearance [Ccr] 30—80 ml/minute). The study was multicentre, double-blind, double-dummy and active-controlled in design, with patients randomised in a 2:1 ratio to receive telmisartan or enalapril. After a two-week placebo run-in period, the 71 eligible patients received either telmisartan, 40 mg, or enalapril, 10 mg, once-daily for four weeks. Thereafter, doses were titrated to telmisartan 80 mg or enalapril 20 mg once-daily if supine trough DBP was still ≥90 mmHg. After a further four weeks, dose titration was again performed, as required, to telmisartan, 80 mg, or enalapril, 20 mg, or frusemide was given in addition if the double dose was already being administered. Mean Ccr decreases of 4.6% for telmisartan and 2.8% for enalapril were not clinically significant. Adverse events occurred in 12 (26.7%) telmisartan-treated patients and in 12 (46.2%) patients receiving enalapril. The mean reduction in supine trough DBP from baseline to the last available value was 12.5 mmHg for telmisartan, compared with 11.9 mmHg for enalapril. A full (reduction of ≥10 mmHg) or partial (reduction of 7—9 mmHg) response occurred in 78% of telmisartan patients and 65% of enalapril patients. In the enalapril group, 43% of patients required frusemide, compared with 29% of those in the telmisartan group. In conclusion, telmisartan lacks detrimental effect on renal function, is effective in the treatment of mild-to-moderate hypertension in patients with moderate renal failure, and is comparable to enalapril.
Interaction of ACE inhibitors and AT1-receptor blockers on maximum blood pressure response in spontaneous hypertensive rats
Authors: Morgan Trefor , Griffiths Cory , Delbridge Lea
Published: May 2007

This study in spontaneous hypertensive rats (SHR) was designed to determine whether a greater fall in blood pressure (BP) could be achieved with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and an AT1-receptor blocking drug than with higher doses of either drug alone.

The peak effect of captopril occurred 3—4 hours post-dose and a plateau response was achieved with 10 mg/kg. The peak effect of losartan occurred 7—8 hours post-dose and a plateau response was achieved with 10 mg/kg. Increasing the dose of either drug caused no greater fall in BP, but increased the duration of the effect.

Captopril, 10 mg/kg, administered with losartan 10 mg/kg caused a greater fall in BP than captopril or losartan, 20 mg/kg. This was present after acute doses or after one week of daily therapy.

The combination of ACE-I and AT1-blocking drugs is more effective than either therapy alone and may be a useful combination to manage hypertension and/or cardiac failure.
Oxidative stress increases the expression of the angiotensin-II receptor type 1 in mouse peritoneal macrophages
Authors: Keidar Shlomo , Heinrich Ronit , Kaplan Marielle , Aviram Michael
Published: May 2007

Angiotensin II (Ang II) has been shown to accelerate atherogenesis, and the cellular Ang II type 1 (AT1) -receptor mediates most of Ang II-induced proatherogenic effects. In this study we have examined the effect of macrophage oxidative stress on cellular AT1-receptor expression.

Mouse peritoneal macrophages (MPM) from apolipoprotein-E deficient (E0) mice at increasing ages (1—6 months) demonstrated an age-dependent increase in cellular lipid-peroxides (PD) content. In parallel, the AT1-receptor mRNA and protein levels both increased by up to 3.7-fold and 1.7-fold, respectively, in MPM from 6-month old mice compared with 1-month old mice. Vitamin E supplementation to E0 mice significantly decreased the MPM PD content and macrophage AT1-receptor mRNA expression compared with placebo-treated mice. The role of oxidative stress in the cellular expression of AT1-receptors was further demonstrated by manipulation of macrophage glutathione content. Buthionine-sulfoximine, a glutathione synthesis inhibitor, increased MPM PD content and AT1receptor mRNA expression, whereas L-2-oxothiazolidine-4-carboxylic acid, that contributes to glutathione synthesis, reduced macrophage PD and AT1receptor mRNA expression. Incubation of MPM with oxidised low-density lipoproteins (LDL) led to a significant, dose-dependent and time-dependent increase in macrophage AT1-receptor mRNA and protein expression, compared with control cells. In contrast, native LDL or acetylated LDL did not significantly affect macrophage AT1-receptor mRNA expression.

In conclusion, our findings suggest that oxidative stress in macrophages induces AT1-receptor expression. This phenomenon can stimulate the interaction of Ang II with macrophages and hence accelerate macrophage foam cell formation and early atherogenesis.
Acute and long-term effects of ACE inhibition on renal haemodynamics in glomerular and interstitial nephropathies
Authors: Guidi Ettore , Minetti Enrico E , Cozzi Maria Grazia
Published: May 2007

Background Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice for the treatment of hypertension in patients with non-diabetic nephropathies. However, not every trial has reported better results with ACE inhibitors (ACE-I) than with other drugs. This study investigates whether the acute and chronic effects of ACE inhibition on renal and glomerular haemodynamics are similar in glomerular and interstitial nephropathies.

Methods We studied 20 hypertensive patients, on their usual diet, with mild-to-moderate chronic renal failure secondary to non-diabetic nephropathy. After a three-week wash out period, we determined plasma clearances of para-amino-hippurate and inulin before, and after acute oral administration of either enalapril or ramipril. This same test was carried out after one and two years of treatment with the same drug.

Results Acute ACE inhibition causes a decrease of renal perfusion, glomerular filtration and pressure with an increase of afferent resistances. Long-term ACE inhibition is associated only with a decrease in renal perfusion, with a non-significant tendency to higher filtration fraction and lower afferent resistances. All the renal haemodynamic modifications mentioned above are present only in patients with glomerular diseases.

Conclusions Renal and glomerular haemodynamic responses are not similar after acute and chronic ACE inhibition. Only patients with glomerular diseases show acute or long-term responses to ACE inhibition.
The renin-angiotensin system does not contribute to the endothelial dysfunction and increased infarct size in rats exposed to second hand smoke
Authors: Zhu Bo-qing , Sievers Richard E , Browne Amanda EM , Hillman Robert T , Chair Kamel , Lee Randall J , Chatterjee Kanu , Glantz Stanton A , Parmley William W
Published: May 2007

Introduction

Both second hand smoke (SHS) and the renin-angiotensin system (RAS) contribute to endothelial dysfunction and increased infarct size in a rat ischaemia-reperfusion model. However, the potential interaction between SHS and the RAS is unknown.

Methods

Eighty-four rats were randomised into four groups: group C was a normal control; L was given 40 mg/kg/day of losartan in drinking water; SC and SL were exposed to SHS (smoking chamber) and given regular water or 40 mg/kg/day of losartan in drinking water, respectively. After six weeks of pre-treatment, rats were subjected to 17 minutes of left coronary artery occlusion and 2 hours of reperfusion with haemodynamic and ECG monitoring.

Results

Haemodynamics were not significantly different among the four groups. Losartan increased the threshold for ventricular fibrillation (p=0.0001) and reduced spontaneous ventricular arrhythmias (p=0.002) during ischaemia-reperfusion, while SHS did not (p=0.713, 0.110), and there was no interaction between losartan and SHS. The maximal endothelium-dependent vasorelaxation induced by a calcium ionophore (A23187) was increased by losartan (p=0.007). Myocardial infarct size was smaller in the losartan groups (p=0.032), larger in the SHS groups (p=0.0001), and there was no significant interaction.

Conclusion

In conclusion, losartan decreased infarct size and increased endothelium-dependent vasorelaxation. SHS exposure impaired endothelial function and increased infarct size. The effects of losartan and SHS were consistently independent of each other. These results suggest that the RAS does not contribute to the adverse effects of SHS.
Age-related increase of pulse pressure and gene polymorphisms in essential hypertension: a preliminary study
Authors: Mourad Jean-Jacques , Ducailar Guilhem , Rudnicki Annie , Lajemi Malika , Mimran Albert , Safar Michel E
Published: May 2007

Genes may modulate the changes of blood pressure (BP) with age; this possibility has never been studied for the age-related increase of pulse pressure (PP), although in older populations, PP is considered the stronger mechanical factor predicting cardiovascular mortality. In humans, the presence of the mutant allele C of the angiotensin II (Ang II) AT1-receptor or of the mutant allele T of the eNOS G298 T gene polymorphisms is associated with enhanced contractile properties of conduit arteries in response to vasoconstrictive agents. In this study, we evaluated, in subjects with untreated essential hypertension, whether the presence of these mutant alleles or their combination might influence the age-related increase of PP. Three main findings emerged from the study and were particularly observed in women: 1) the presence of the C and/or of the T mutant alleles or their combination were associated with a steeper slope of the age versus PP curve, compared with subjects without the mutant allele; 2) the slope was more significantly enhanced when the two mutant alleles were associated in the same genotype; and 3) no comparable age- and gender-related changes in systolic, diastolic or mean BP were found according to this genetic classification. In subjects with essential hypertension, genes may modulate the age-mediated increase of PP. This finding gives new insights in the interactions between genes, mechanical factors and cardiovascular risk.
Lack of rapid aldosterone effects on forearm resistance vasculature in health
Authors: Gunaruwan Prasad , Schmitt Matthias , Taylor Justin , Lee Leong , Struthers Allan , Frenneaux Michael
Published: May 2007

Objectives

Systemic infusions of aldosterone cause an acute increase in systemic vascular resistance (SVR) in healthy subjects. It is not clear whether this is due to a direct effect on the vasculature or the result of increased sympathetic tone. We investigated the short-term effects of locally infused aldosterone on the forearm resistance bed.

Methods

In this dose response study, we assessed the effects of incremental doses (10, 50, 100 ng/minute) of intrabrachial aldosterone on forearm blood flow (FBF), using conventional strain gauge plethysmography. Arterial blood pressure was monitored continuously, using finger photo-plethysmography. Forearm vascular resistance (FVR) was calculated. FBF and FVR were also measured in the non-infused arm. Changes in FBF and FVR in the infused arm were corrected for those occurring in the control arm.

Results

Plasma aldosterone levels in the venous effluent of the infused arm increased in a dose-dependent fashion, from 113.3±17.9 pg/ml at baseline to 297.8±51.8 pg/ml at 10 ng/minute (p=<0.01), 743.9±105.9 pg/ml at 50 ng/min (p=<0.001 vs. baseline) and 1230.6±73.7 pg/ml at 100 ng/min (p=<0.0005 vs. baseline). Plasma concentrations of aldosterone in the control arm did not change significantly vs. baseline. The corrected FBF (+4.1±10.3%) and corrected FVR (+4.3±11.3%) did not change significantly even at peak infusion rates.

Conclusions

Local intra-arterial infusion of aldosterone had no acute effect on forearm resistance vessels in healthy male volunteers.
Review: Developments in restenosis
Authors: Chan Philip
Published: May 2007

Restenosis is a major complication leading to the failure of vascular procedures, including surgery, angioplasty and stenting. Major efforts including over 100 clinical trials have been made to overcome this complication, with little success to date. Issues relating to trial rationale, design, measurement and biology are addressed in this review.
Transforming growth factor-β1-mediated collagen gel contraction by cardiac fibroblasts
Authors: Lijnen Paul , Petrov Victor , Fagard Robert
Published: May 2007

Objective

Myofibroblasts and transforming growth factor-β1 (TGF-β1) are key elements of cardiac tissue fibrosis development. The aim of this study was to determine whether the ability of TGF-β1 to affect the contractile activity of cardiac fibroblasts depends on their differentiation into myofibroblasts.

Methods

Cardiac fibroblasts (from male adult Wistar rats) from passage two were cultured to confluency and incubated on a hydrated collagen gel with and without TGF-β1 (0, 20, 40, 100, 200, 400 or 600 pmol/L) for one, two and three days in a Dulbecco's Modified Eagle's Medium without foetal bovine serum.

Results

TGF-β1 dose-dependently increased the contraction of collagen gel mediated by cardiac fibroblasts, reaching a maximal effect at 100 pmol/L TGF-β1. TGF-β 1 also stimulated 3H-thymidine incorporation and total protein content in cardiac fibroblasts in the collagen gel lattice . TGF-β 1 dose-dependently induced an increase in αsmooth muscle actin, a marker of myofibroblasts. The TGF-β1-induced reduction of area of the collagen gel was negatively correlated to the TGF- R β 1-evoked appearance of α-smooth muscle actin in the collagen gel matrix.

Conclusion

Our data demonstrate that TGF-β1 increased the contractile activity of adult rat cardiac fibroblasts and their ability to differentiate into myofibroblasts. Because contractile activity was correlated with differentiation, the influence of TGF-β1 on cardiac fibroblast-induced collagen gel contraction might depend on the promotion of myofibroblast differentiation.
Biphasic effects of angiotensin (1-7) and its interactions with angiotensin II in rat aorta
Authors: Haulica Ion , Bild Walther , Mihaila Christian N , Ionita Teodor , Boisteanu Corneliu P , Neagu Bogdan
Published: May 2007

Using isolated rat aortic rings perfused with Krebs-Henseleit saline, the vascular effects of angiotensin (1-7) (Ang [1-7]) and its interactions with angiotensin II (Ang II) were investigated.

Ang (1-7) induced endothelium-dependent relaxation and vasodilating effects in preparations precontracted with phenylephrine. Without preconstriction, Ang (1-7) at high doses (10 -6—10-5 M) produced either a significant inhibition of Ang IIinduced vasoconstriction or a non-tachyphylactic vasopressor response. While losartan inhibited the vasoconstriction induced by Ang (1-7), A779 blocked only its relaxation. Unlike losartan, blockade of AT2-receptors with PD 123319 had no effect.

Taking into account the biphasic effects of angiotensin (1-7), we propose that it is one of the active components of the renin-angiotensin system, which is involved as a modulator both in the counter-regulatory actions of Ang II and in the self-regulation of its own vasodilating effects.
Review: Angiotensin II receptor blockers and cardiovascular outcomes: what does the future hold?
Authors: Weber Michael A
Published: May 2007

The ability of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) to lower blood pressure (BP) is well established. ACE inhibitors (ACE-Is) have also been shown to improve the prognosis of a broad range of patients at high cardiovascular risk, including those with heart failure, post-myocardial infarction (MI), and nephropathy. These benefits suggest that interrupting the reninangiotensin-aldosterone system (RAAS) with ACE-Is has a widespread vasculoprotective effect, provided that BP is also adequately controlled. Evidence that RAAS blockade by ARBs also improves long-term clinical outcomes in patients with cardiovascular disease has started to accumulate, and will be tested further during the coming years as a number of large-scale, prospective trials are completed. These trials are investigating the long-term protective effects of ARBs on morbidity and mortality in patients with hypertension, heart failure, diabetes mellitus, acute MI, or established vascular disease. The results should establish the extent to which ARBs exhibit the vasculoprotective properties demonstrated by ACE-Is in patients at high cardiovascular risk. If ARBs are found to provide benefits that are similar to , or even greater than ACE-Is, it may have important implications for drug selection, given the excellent tolerability of ARBs. Some studies are also investigating whether more extensive RAAS blockade using a combination of an ARB and an ACE-I will offer even greater protection than either agent alone.
Review: The renin-angiotensin-aldosterone system and Alzheimer's disease?
Authors: Kehoe Patrick G
Published: May 2007

Epidemiological studies from the last decade have begun to produce evidence that the perceived joint occurrence of vascular disease and Alzheimer's disease (AD), both common elderly disorders more often believed to occur by chance due to their high prevalence, may now actually have a more pathological significance. The following review discusses some of this evidence and the implications for cognitive decline and the development of AD and how a well-known cardiovascular risk factor gene, the apolipoprotein E (APOE) gene, plays a significant role in the molecular genetics of AD. It also introduces and discusses recent and compelling evidence for the involvement of another well-known cardiovascular risk factor gene, the angiotensin-converting enzyme (ACE1) gene, in the pathogenesis of AD. This role is suggested in terms of recent molecular genetic association evidence implicating the ACE1 insertion/deletion (indel) polymorphism, a more recent large haplotype study that greatly extends the ACE1 indel evidence and incorporates knowledge accrued from previous cardiovascular disease-focused ACE1 haplotype studies. Finally, this paper discusses very recent biological evidence that further supports a role for ACE1 and hypothesises a number of readily testable mechanisms by which the ACE1 enzyme and other components of the renin-angiotensin-aldosterone system may be implicated in increased risk and/or the progression of AD.
Angiotensin receptor blockers in heart failure
Authors: Östergren Jan , McMurray John JV
Published: May 2007

Collectively, a series of large, prospective randomised outcome trials has now shown that angiotensin receptor blockers (ARBs) are of clinical value in a broad spectrum of patients with symptomatic heart failure, regardless of background therapy and ventricular function. There is a clear benefit of ARBs in patients unable to tolerate an angiotensin-converting enzyme (ACE) inhibitor and this benefit is of a similar magnitude to that obtained with an ACE inhibitor (ACE-I). Both Val-HeFT and, particularly, CHARM-Added, also show that symptoms, morbidity and mortality are further reduced if an ARB is added to an ACE-I. This benefit is not only statistically significant but clinically important. CHARM-Preserved showed that candesartan can reduce hospital admission for heart failure in patients with preserved systolic function though more definitive outcome data are needed in this group.