Release dynamics of nanodiamonds created by laser-driven shock-compression of polyethylene terephthalate.

Laser-driven dynamic compression experiments of plastic materials have found surprisingly fast formation of nanodiamonds (ND) via X-ray probing. This mechanism is relevant for planetary models, but could also open efficient synthesis routes for tailored NDs. We investigate the release mechanics of compressed NDs by molecular dynamics simulation of the isotropic expansion of finite size diamond from different P-T states. Analysing the structural integrity along different release paths via molecular dynamic simulations, we found substantial disintegration rates upon shock release, increasing with the on-Hugnoiot shock temperature. We also find that recrystallization can occur after the expansion and hence during the release, depending on subsequent cooling mechanisms. Our study suggests higher ND recovery rates from off-Hugoniot states, e.g., via double-shocks, due to faster cooling. Laser-driven shock compression experiments of polyethylene terephthalate (PET) samples with in situ X-ray probing at the simulated conditions found diamond signal that persists up to 11 ns after breakout. In the diffraction pattern, we observed peak shifts, which we attribute to thermal expansion of the NDs and thus a total release of pressure, which indicates the stability of the released NDs.

Associations of smoking with alterations in renal hemodynamics may depend on sex--investigations in potential kidney donors.

BACKGROUND/AIMS: Cigarette smoking is a risk factor for renal damage, but little is known about subclinical effects of smoking on renal hemodynamics and parameters of renal function in humans. We examined the associations of smoking with systemic and renal hemodynamics and renal function parameters in healthy individuals. METHODS: Data from 196 potential living kidney donors were analysed retrospectively. Mean arterial blood pressure (MAP), effective renal plasma flow (ERPF) and creatinine clearance had been measured. We additionally calculated parameters of renal hemodynamics. Data were analyzed for the effects of smoking and sex dependent on age and MAP. RESULTS: Systemic and renal hemodynamic parameters did not differ between smokers and non-smokers. In non-smokers of both sexes MAP was negatively correlated with ERPF, and higher MAP was associated with increased renal vascular resistance and with afferent arteriolar resistance, with glomerular pressure (PG) remaining constant. However, in male, but not in female smokers, ERPF and PG increased with MAP. A correlation of age with a steeper decline in ERPF in male smokers was lost in multiple regression analysis. CONCLUSIONS: As compared to women, smoking men may exhibit an increased glomerular hydrostatic pressure, which is a known promoter of kidney damage.

Endogenous retrotransposons cause catastrophic deoxyribonucleic acid damage in human trophoblasts.

OBJECTIVE: To determine the mechanistic role of mobile genetic elements in causing widespread DNA damage in primary human trophoblasts. DESIGN: Experimental ex vivo study. SETTING: Hospital-affiliated University. PATIENT(S): Trophoblasts from a patient with unexplained recurrent pregnancy loss and patients with spontaneous and elective abortions (n = 10). INTERVENTION(S): Biochemical and genetic analysis and modification of primary human trophoblasts. MAIN OUTCOME MEASURE(S): To phenotype and systematically evaluate the underlying pathogenic mechanism for elevated DNA damage observed in trophoblasts derived from a patient with unexplained recurrent pregnancy loss, transcervical embryoscopy, G-band karyotyping, RNA sequencing, quantitative polymerase chain reaction, immunoblotting, biochemical and siRNA assays, and whole-genome sequencing were performed. RESULT(S): Transcervical embryoscopy revealed a severely dysmorphic embryo that was euploid on G-band karyotyping. RNA sequencing was notable for markedly elevated LINE-1 expression, confirmed with quantitative polymerase chain reaction, and that resulted in elevated expression of LINE-1-encoded proteins, as shown by immunoblotting. Immunofluorescence, biochemical and genetic approaches demonstrated that overexpression of LINE-1 caused reversible widespread genomic damage and apoptosis. CONCLUSION(S): Derepression of LINE-1 elements in early trophoblasts results in reversible but widespread DNA damage.

Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide.

BACKGROUND: Diuretics are recommended as first-line agents for the treatment of hypertension. This randomized, double-blind, multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension. METHODS AND RESULTS: After a 2- to 4-week placebo run-in, 1124 patients (mean sitting diastolic blood pressure [BP] 95 to 109 mm Hg) were randomized to aliskiren 150 mg (n=459), hydrochlorothiazide 12.5 mg (n=444), or placebo (n=221) once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method. BP reductions (mean sitting systolic BP/mean sitting diastolic BP) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 (-20.3/-14.2 versus -18.6/-13.0 mm Hg; P<0.05) and were also greater at week 52 (-22.1/-16.0 versus -21.2/-15.0 mm Hg; P<0.05 for mean sitting diastolic BP). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP (-17.4/-12.2 versus -14.7/-10.3 mm H; P<0.001). Adverse event rates were similar with aliskiren- (65.2%) and hydrochlorothiazide-based therapy (61.5%). Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy (17.9% versus 0.9%; P<0.0001). CONCLUSIONS: Aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective hydrochlorothiazide regimens. Aliskiren-based therapy was well tolerated. Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension.

Candesartan improves blood pressure control and reduces proteinuria in renal transplant recipients: results from SECRET.

BACKGROUND: Hypertension is a risk factor for the two leading causes of death in renal transplant recipients: cardiovascular disease (CVD) and graft failure. Despite this, the optimum medication for post-transplant hypertension is unclear. METHODS: The Study on Evaluation of Candesartan Cilexetil after Renal Transplantation (SECRET) was an international multicentre, double-blind, randomized investigation of the angiotensin II type 1 receptor blocker (ARB) candesartan cilexetil versus placebo in renal allograft recipients originally designed to study 700 patients for 3 years. The candesartan dose was escalated from 4 to 16 mg daily, followed by addition of co-medication, if needed, with the aim of achieving a diastolic blood pressure (BP) <85 mmHg. The primary efficacy variable was a composite of all-cause mortality, cardiovascular morbidity and graft failure. RESULTS: SECRET was stopped prematurely as the primary event rate was much lower than expected. At that point, 502 patients were enrolled; 255 received candesartan and 247 placebo. Thirteen primary events had occurred in each group. Control of both systolic and diastolic BP was better in the candesartan group. Urinary protein excretion and protein/creatinine ratio decreased on candesartan but increased on placebo. Serum creatinine and potassium were increased in candesartan patients, but these changes were generally small. CONCLUSIONS: SECRET provides insights into the design and conduct of studies in this area and evidence for the utility of candesartan, which showed good safety and tolerability, improved BP control and decreased proteinuria in renal transplant recipients.

Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor.

AIM: This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor. METHODS: Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) ). RESULTS: Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively. CONCLUSIONS: Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

Avosentan reduces albumin excretion in diabetics with macroalbuminuria.

Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory, antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER 0.2 to 5.6 mg/min), and BP <180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo, in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean relative UAER (-16.3 to -29.9%) compared with placebo (35.5%). Median relative UAER decreased with all avosentan dosages (-28.7 to -44.8%) compared with placebo (12.1%). Creatinine clearance and BP were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (>/=25 mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%) patients experienced adverse events that led to withdrawal from study medication. In summary, the endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER in patients with diabetic nephropathy and macroalbuminuria.

Coronary artery bypass surgery and acute kidney injury--impact of the off-pump technique.

BACKGROUND: Acute kidney injury (AKI) is a serious and frequent complication after coronary artery bypass grafting (CABG). Cardiopulmonary bypass (CPB) was identified as a major AKI risk factor after CABG. Our aim was to assess the impact of the off-pump coronary artery bypass (OPCAB) compared to the on-pump coronary artery bypass (ONCAB) technique on the rate and severity of AKI, while taking other risk factors for AKI into account. METHODS: An observational study of 201 consecutive adult patients was conducted; 100 were operated by the OPCAB and 101 by the ONCAB technique. All patients in each group were operated by a single, experienced surgeon. Fifteen pre-, intra- and postoperative variables that were repeatedly identified in previous studies as independent AKI risk factors were included in this analysis. AKI was defined as an increase of serum creatinine >/=50% or >/=0.3 mg/dL within 48 h and AKI severity was classified, according to current AKIN definitions. RESULTS: Significantly fewer OPCAB patients developed AKI compared to ONCAB (14.0 versus 27.7%; P = 0.03). OPCAB was associated with milder stages of AKI, whereas ONCAB patients had more severe AKI. Congestive heart failure and chronic kidney disease were independent risk factors for AKI. The OPCAB technique for CABG was identified as the only independent factor associated with lower incidence of AKI. CONCLUSIONS: Using current AKI definitions and classifications, the OPCAB technique for CABG, which avoids CPB; was associated with a significantly lower rate and less severe AKI compared to ONCAB. The OPCAB technique was identified as the only modifiable and potentially protective factor against postoperative AKI.

Association of elevated pretransplant sCD30 levels with graft loss in 206 patients treated with modern immunosuppressive therapies after renal transplantation.

BACKGROUND: Recent reports suggest that high pretransplant serum levels of soluble CD30 (sCD30) are a risk factor for rejections after kidney transplantation. The aim of our study was to elucidate the predictive value of pretransplant sCD30 levels for kidney transplantation outcome in a single-center patient cohort that has been treated with modern immunosuppressive therapies after transplantation. METHODS: We retrospectively analyzed sCD30 in multiple pretransplant sera from 206 patients, of whom 174 were transplanted with a cadaveric kidney and 32 patients received an allograft from a living donor. Renal function after transplantation was estimated by measuring serum creatinine and by rejection diagnosis. RESULTS: We could demonstrate a statistically significant association between increased pretransplant sCD30 values and graft failures (P=0.005). Receiver operating curve analysis revealed a cutoff value of 124 U/mL pretransplant sCD30. A multivariate analysis confirmed pretransplant sCD30 values >124 U/mL (P=0.011) and rejection episodes (P<0.0001) as independent risk factors for graft loss. CONCLUSION: Our study revealed a strong correlation between pretransplant sCD30 levels and the incidence of graft failure, but we could not confirm that the development of rejection episodes is correlated with pretransplant sCD30 values.

Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension.

BACKGROUND: Patients with hypertension may require combination therapy to attain the blood pressure targets recommended by US and European treatment guidelines. Combination therapy with a calcium channel blocker and an angiotensin II-receptor blocker would be expected to provide enhanced efficacy. OBJECTIVES: Two studies were conducted to compare the efficacy of various combinations of amlodipine and valsartan administered once daily with their individual components and placebo in patients with mild to moderate essential hypertension (mean sitting diastolic blood pressure [MSDBP] >/=95 and < 110 mm Hg). A secondary objective was to evaluate safety and tolerability. METHODS: The 2 studies were multinational, multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group trials. In study 1, patients were randomized to receive amlodipine 2.5 or 5 mg once daily, valsartan 40 to 320 mg once daily, the combination of amlodipine 2.5 or 5 mg with valsartan 40 to 320 mg once daily, or placebo. In study 2, patients were randomized to receive amlodipine 10 mg once daily, valsartan 160 or 320 mg once daily, the combination of amlodipine 10 mg with valsartan 160 or 320 mg once daily, or placebo. The primary efficacy variable in both studies was change from baseline in MSDBP at the end of the study. Secondary variables included the change in mean sitting systolic blood pressure (MSSBP), response rate (the proportion of patients achieving an MSDBP <90 mm Hg or a >/= 10-mm Hg decrease from baseline), and control rate (the proportion of patients achieving an MSDBP <90 mm Hg). Safety was assessed in terms of adverse events (spontaneously reported or elicited by questioning), vital signs, and laboratory values. RESULTS: A total of 1911 patients were randomized to treatment in study 1 (1022 amlodipine + valsartan; 507 valsartan; 254 amlodipine; 128 placebo); 1250 were randomized to treatment in study 2 (419, 415, 207, and 209, respectively). In all treatment groups in both studies, the majority of patients were white (79.5% study 1, 79.4% study 2) and male (53.5% and 50.3%, respectively). The overall mean age was 54.4 years in study 1 and 56.9 years in study 2. The mean weight of patients in study 1 was higher than that in study 2 (88.8 vs 79.7 kg). The overall baseline mean sitting BP was 152.8/99.3 mm Hg in study 1 and 156.7/99.1 mm Hg in study 2. With the exception of a few combinations that included amlodipine 2.5 mg, the combination regimens in both studies were associated with significantly greater reductions in MSDBP and MSSBP compared with their individual components and placebo (P < 0.05). A positive dose response was observed for all combinations. The highest response rate in study 1 was associated with the highest dose of combination therapy (amlodipine 5 mg + valsartan 320 mg: 91.3%). Amlodipine 5 mg, valsartan 320 mg, and placebo were associated with response rates of 71.9%, 73.4%, and 40.9%, respectively. In study 2, the 2 doses of combination therapy were associated with similar response rates (amlodipine 10 mg + valsartan 160 mg: 88.5%; amlodipine 10 mg + valsartan 320 mg: 87.5%). Amlodipine 10 mg was associated with a response rate of 86.9%; valsartan 160 and 20 mg were associated with response rates of 74.9% and 72.0%, respectively; and placebo was associated with a response rate of 49.3%. Control rates followed a similar pattern. The incidence of peripheral edema with combination therapy was significantly lower compared with amlodipine monotherapy (5.4% vs 8.7%, respectively; P = 0.014), was significantly higher compared with valsartan monotherapy (2.1%; P < 0.001), and did not differ significantly from placebo (3.0%). CONCLUSIONS: In these adult patients with mild to moderate hypertension, the combination of amlodipine + valsartan was associated with significantly greater blood pressure reductions from baseline compared with amlodipine or valsartan monotherapy or placebo. The incidence of peripheral edema was significantly lower with combination therapy than with amlodipine monotherapy.

In patients chronically treated with metoprolol, the demand of inotropic catecholamine support after coronary artery bypass grafting is determined by the Arg389Gly-beta 1-adrenoceptor polymorphism.

In vitro, the Arg389Gly-beta(1)-adrenoceptor (AR) polymorphism exhibits decreased receptor signaling. In vivo, dobutamine infusion evoked smaller heart rate and/or contractility increases in subjects carrying Gly389Gly-beta(1)AR vs subjects carrying Arg389Arg-beta(1)AR. The aim of this study was to find out whether the Arg389Gly-beta(1)AR polymorphism might also determine demand of catecholamine-induced inotropic support in patients with low cardiac index (CI) after coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB). For this purpose, we assessed in 82 patients, who were preoperatively chronically treated with metoprolol, after CABG surgery with CPB, the dose and duration of adrenaline-induced inotropic support in relation to the Arg389Gly-beta(1)AR genotype. Patients homozygous for the Arg389-beta(1)AR variant (n = 45) required, in comparison to patients homozygous for the Gly389-beta(1)AR variant (n = 9), lower adrenaline doses (53 +/- 24 vs 164 +/- 39 ng/kg body weight/min, p < 0.05) to reach a stable and comparable hemodynamic status and a CI >or= 3.0 l/min/m(2). Moreover, the time necessary for inotropic support tended to be shorter in patients homozygous for the Arg389-beta(1)AR than in patients homozygous for the Gly389-beta(1)AR (10.5 +/- 6 vs 20.5 +/- 12 h). Values for patients heterozygous for the Arg389Gly-beta(1)AR (n = 28) were in between. We conclude that the Arg389Gly-beta(1)AR polymorphism appears to be a determinant of cardiac responses to catecholamine stimulation. Thus, by assessment of the Arg389Gly-beta(1)AR polymorphism, it might be possible to predict demand of and therapeutic responses to beta AR agonist treatment.

Amlodipine and valsartan combined and as monotherapy in stage 2, elderly, and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies.

Patients with difficult to control hypertension typically require 2 or more agents to achieve goal blood pressure (BP) levels. Fixed-dose combination therapies with lower doses generally are well tolerated and more effective than higher-dose monotherapy. The authors performed prespecified and post hoc subgroup analyses of 2 double-blind, randomized, placebo-controlled trials that assessed the efficacy and safety of amlodipine and valsartan, alone and in combination, in patients with mild to moderate hypertension. Patients were randomized to amlodipine (study 1: 2.5 or 5 mg/d; study 2: 10 mg/d), valsartan (study 1: 40, 80, 160, or 320 mg/d; study 2: 160 or 320 mg/d), combination therapy across the same dose ranges, or placebo. Analyses were performed on changes from baseline in mean sitting systolic and diastolic BP and the occurrence of adverse events in specific subgroups of patients (ie, those with stage 2 hypertension [post hoc], the elderly [65 years or older], and blacks [both prespecified]). Amlodipine + valsartan combination therapy was associated with greater BP-lowering effects in the subgroups compared with each respective monotherapy and placebo. These findings were consistent with the primary efficacy analysis results from the overall study populations. Combination regimens were generally well tolerated by all patient subgroups.

[Hepatorenal syndrome. What's new in 2007?]. / Das hepatorenale Syndrom : Wo stehen wir im Jahr 2007?

BACKGROUND: Hepatorenal syndrome (HRS) is a serious complication of end-stage liver disease that was associated with a fatal prognosis in the past. A clear definition of HRS and increased understanding of the pathogenesis have led to considerable progress in therapy outcome. PATHOGENESIS: The major pathogenetic factor is vasodilation of the mesenteric circulation with arterial underfilling and consecutive renal vasoconstriction. THERAPY AND CONCLUSION: Restoration of an effective arterial blood volume can be achieved by the combination of vasopressor therapy (terlipressin, norepinephrine), in combination with volume expansion (albumin) with a success rate of up to 75%. Restoration of the effective arterial blood volume may also be achieved by implantation of a transjugular intrahepatic portosystemic stent (TIPS). This has also been successful in up to 50% of patients in selected cohorts. Finally, extracorporeal liver support systems based on exchange or detoxification of albumin have been successfully employed in a number of patients. Liver transplantation remains the only principal therapy of HRS as this is the single measure with a curative intent. All other forms of therapy are palliative but may serve as a bridge to liver transplantation.

Transcervical embryoscopic and cytogenetic findings reveal distinctive differences in primary and secondary recurrent pregnancy loss.

OBJECTIVE: To assess the cytogenetic and embryoscopic characteristics of primary and secondary recurrent pregnancy loss. DESIGN: Clinical prospective descriptive study. SETTING: Tertiary care center. PATIENT(S): Nine hundred and eighty-four women affected by first-trimester pregnancy loss; 145 patients with recurrent pregnancy loss (RPL) and 839 patients with nonrecurrent pregnancy loss as controls. INTERVENTION(S): Transcervical embryoscopic examination of the embryo before uterine evacuation, and cytogenetic analysis of the chorionic villi by standard G-banding cytogenetic techniques. MAIN OUTCOME MEASURE(S): Aneuploidy frequency in the primary and secondary RPL group and the nonrecurrent pregnancy loss (non-RPL) control group. RESULT(S): Patients with RPL showed statistically significantly fewer aneuploid pregnancy losses (odds ratio [OR] 0.596; 95% confidence interval [CI], 0.40-0.88). Primary RPL was associated with lower aneuploidy rates compared with the non-RPL group (OR 0.423; 95% CI, 0.27-0.66) while secondary RPL was not (OR 1.414; 95% CI, 0.67-2.99). Patients with primary RPL had statistically significantly more morphologically normal embryos compared with non-RPL and secondary RPL. CONCLUSION(S): Patients' embryos after primary and secondary RPL show distinctive differences in aneuploidy and morphologic defect rates. These findings suggest different treatment approaches for the patients with primary and secondary RPL.

The angiotensin II receptor antagonist valsartan inhibits endothelin 1-induced vasoconstriction in the skin microcirculation in humans in vivo: influence of the G-protein beta3 subunit (GNB3) C825T polymorphism.

OBJECTIVE: We investigated the influence of angiotensin II receptor blockade on angiotensin II-induced, endothelin 1 (ET-1)-induced, and norepinephrine-induced vasoconstriction to further characterize interactions of the 3 major pressor systems. ET-1, angiotensin II, and norepinephrine act via G protein-coupled receptors with a possible involvement of the G-protein beta3 subunit (GNB3) C825T polymorphism. We studied the influence of this polymorphism on the responses to angiotensin II antagonism in the presence of ET-1, norepinephrine, and angiotensin II. METHODS: Twenty-five healthy men (mean age, 28.6 +/- 4 years; n = 14 CC, n = 9 CT, and n = 2 TT) were included in a double-blind, randomized, placebo-controlled crossover study. We used a laser Doppler imager to evaluate skin perfusion changes after injection of ET-1, angiotensin II, and norepinephrine (10(-18), 10(-16), and 10(-14) mol) after oral intake of the angiotensin II receptor antagonist valsartan (80 mg) or placebo. Data were analyzed with ANOVA or t test and are expressed as arbitrary perfusion units (PU) (mean +/- SEM). RESULTS: Valsartan abolished angiotensin II-induced vasoconstriction and, more importantly, also ET-1-induced vasoconstriction in the skin microcirculation (ET-1 placebo versus valsartan, - 33 +/- 10 PU versus +33 +/- 21 PU for CC [P = .02] and -71 +/- 25 PU versus +108 +/- 21 PU for CT/TT [P < .001]). For both ET-1 and angiotensin II, valsartan effects were greater in GNB3 835T-allele carriers (P = .007 and P = .03 for ET-1 and angiotensin II, respectively, for CC versus CT/TT). Norepinephrine-mediated constriction was not influenced by valsartan. These effects were independent of blood pressure. CONCLUSION: Our results indicate that the renin-angiotensin system may significantly contribute to ET-1-mediated microvascular responses. Valsartan inhibited local vasoconstriction to angiotensin II and ET-1 to a greater degree in carriers of the GNB3 825T allele, which adds to data from earlier studies implicating the C825T polymorphism as a pharmacogenetic marker for drug effects.

The impact of living-related kidney transplantation on the donor's life.

BACKGROUND: Living-donation kidney transplantation (LDKT) is increasingly performed for treatment of chronic renal failure. Recently, risks for the donor and problems in decision-making have been stressed. This study was conducted to illuminate the decision making-process and consequences of LDKT on family life, the financial and occupational situation. Moreover, quality of life (QOL) and mental distress were explored. METHODS: All German residents at Essen University, who donated their kidney between 1999 and 2003, were included in the study. Donors filled out the questionnaire of the European Multicenter Study of Transplantation Using Living Donors, the Short Form 36-Health Survey, and the Brief Symptom Inventory. RESULTS: Out of a total of 65 donors, 47 replied (72%) at an average 2.5 years postdonation. No fatalities occurred in the whole sample (n=65), medical complications were experienced by 28%. Most donors decided voluntarily (94%) and spontaneously (66%) to donate, after donation 96% stated that they would decide in the same way again. QOL was within the norm. On the other hand, 10% experienced family conflicts, every eighth donor suffered from clinically relevant distress, financial disadvantages were experienced by every fourth donor, with 25% not answering this question. CONCLUSION: Seen from the donor's perspective, LDKT is a relatively safe procedure. However, increased rates of donors with mental distress and intra-familial conflicts emphasize the need for a careful selection process. Regular postdonation psychosocial screening and provision of specific interventions to those in need are recommended. Donors should not suffer from financial and occupational disadvantages resulting from donation.

Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass.

OBJECTIVE: Pheochromocytomas are neoplasms generally characterized by the autonomous production of catecholamines. This study compared various biochemical parameters for the diagnosis of adrenal pheochromocytoma in patients with adrenal mass. DESIGN: One hundred and fifty subjects were studied, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas and 30 nonfunctioning adrenal masses, 16 patients with essential hypertension and 42 healthy normotensive volunteers. Spontaneous blood samples and 24-h urine samples were collected prospectively. METHODS: Plasma and urinary epinephrine and norepinephrine levels were measured by high performance liquid chromatography, whereas plasma and urinary metanephrine and normetanephrine levels were determined by radioimmunoassay (RIA). Putative ratio thresholds were calculated by receiver operating characteristic (ROC) analysis to balance between sensitivity and specificity. RESULTS: Plasma normetanephrine was found to be the best single parameter with the highest sensitivity (91.7%) and specificity (95.6%) using a threshold of 126 pg/ml. In combination, plasma normetanephrine and metanephrine had a higher sensitivity of 95.8% with lower specificity (79.4%). All other combinations of plasma and/or urinary parameters demonstrated a lower accuracy. CONCLUSION: Plasma metanephrines measured by RIA are reliable screening parameters for the diagnosis of pheochromocytoma.

Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients.

BACKGROUND: The posterior retroperitoneoscopic adrenalectomy is less popular than the laparoscopic transabdominal method. Due to the direct approach to the adrenal glands, however, the posterior retroperitoneal access is easy to use and may offer advantages not available with other endoscopic procedures for adrenalectomy. METHODS: Between July 1994 and March 2006, we performed 560 adrenalectomies (right side: n = 258; left side: n = 302) by the posterior retroperitoneoscopic approach in 520 patients (200 male, 320 female; age, 10 to 83 years). Of the 520 patients, 21 suffered from Cushing's disease, 499 patients had adrenal tumors (157 Conn's adenomas, 120 pheochromocytomas [13 bilateral], 110 Cushing's adenomas [6 bilateral], and 112 other tumors). Tumor size ranged from 0.5 to 10 cm (mean, 2.9 +/- 1.7 cm). The procedures were performed with the patients in the prone position usually with 3 trocars. RESULTS: Mortality was zero. Conversions to open or laparoscopic lateral surgery were necessary in 9 patients (1.7%). Major complications occurred in 1.3% of patients, minor complications in 14.4%. Mean operating time was 67 +/- 40 min and declined significantly (P < .001) from the early procedures (106 +/- 46 min) to the later operations (40 +/- 15 min). CONCLUSIONS: The posterior retroperitoneoscopic adrenalectomy is a safe and fast procedure. In experienced hands, this method represents the ideal approach in adrenal surgery.