Cholesterol lowering treatment restores blood global DNA methylation in chronic kidney disease (CKD) patients.

BACKGROUND AND AIMS: Chronic kidney disease (CKD) is characterized by increased oxidative stress (OS). In consideration of the well-known link between OS and DNA methylation we assessed DNA methylcytosine (mCyt) concentrations in CKD patients at baseline and during cholesterol lowering treatment. METHODS AND RESULTS: DNA methylation and OS indices (malonyldialdehyde, MDA; allantoin/uric acid ratio, All/UA) were measured in 30 CKD patients randomized to three cholesterol lowering regimens for 12 months (simvastatin 40 mg/day, ezetimibe/simvastatin 10/20 mg/day, or ezetimibe/simvastatin 10/40 mg/day) and 30 age- and sex-matched healthy controls. DNA methylation was significantly lower in CKD patients vs. controls (4.06 ± 0.20% vs. 4.27 ± 0.17% mCyt, p = 0.0001). Treatment significantly increased mCyt DNA concentrations in all patients (4.06 ± 0.04% at baseline; 4.12 ± 0.03% at 4 months; 4.17 ± 0.03% at 8 months; and 4.20 ± 0.02% at 12 months, p = 0.0001 for trend). A trend for a greater effect on DNA methylation was observed with combined treatment ezetimibe/simvastatin 10/40 mg/day (+5.2% after one year treatment). The treatment-associated mCyt increase was significantly correlated with the concomitant reduction in MDA concentrations and All/AU ratios. CONCLUSION: Our results demonstrate that CKD patients have a lower degree of DNA methylation and that cholesterol lowering treatment restores mCyt DNA concentrations to levels similar to healthy controls. The treatment-associated increase in DNA methylation is correlated with a concomitant reduction in OS markers. The study was registered at clinicaltrials.gov (NCT00861731).

Impact of cholesterol lowering treatment on plasma kynurenine and tryptophan concentrations in chronic kidney disease: relationship with oxidative stress improvement.

BACKGROUND AND AIM: Tryptophan (Trp) degradation via indoleamine (2,3)-dioxygenase (IDO), with consequent increased in kynurenine (Kyn) concentrations, has been proposed as marker of immune system activation. Oxidative stress (OS) might contribute to the pro-inflammatory state in chronic kidney disease (CKD) through the activation of NF-kB, with consequent activation and recruitment of immune cells. METHODS AND RESULTS: Serum concentrations of Trp and Kyn, oxidative stress indices malondialdehyde (MDA) and allantoin/uric acid (All/UA) ratio and anti-oxidant amino acid taurine were measured in 30 CKD patients randomized to 40 mg/day simvastatin (group 1), ezetimibe/simvastatin 10/20 mg/day (group 2) or ezetimibe/simvastatin 10/40 mg/day (group 3) and treated for 12 months. Baseline Kyn and Kyn/Trp ratio were higher in CKD patients vs. healthy controls (1.67 ± 0.62 µmol/L vs 1.25 ± 0.40 µmol/L, p < 0.01 and 0.036 ± 0.016 vs 0.023 ± 0.010, p < 0.001 respectively). Both Kyn and Kyn/Trp ratio significantly decreased after cholesterol lowering treatment, to values comparable with healthy controls after one year treatment (1.67 ± 0.62 µmol/L vs 1.31 ± 0.51 µmol/L, p < 0.0001 and 0.036 ± 0.016 vs 0.028 ± 0.012 p < 0.0001, respectively). This was paralleled by a significant decrease in MDA (218 ± 143 nmol/L vs 176 ± 123 nmol/L, p < 0.01) and All/UA ratio (1.47 ± 0.72 vs 1.19 ± 0.51, p < 0.01) in CKD patients. CONCLUSIONS: Amelioration of both oxidative and inflammation status after cholesterol lowering treatment in CKD might be mediated by restoration of antioxidant taurine concentrations during therapy (from 51.1 ± 13.3 µmol/L at baseline to 63.1 ± 16.4 µmol/L, p < 0.001 by ANOVA), suggesting that improvement of both oxidative and inflammation status in CKD patients could be explained, at least partly, by the cholesterol lowering effects.

A meta-regression study of the clinical significance of serum aminotransferases in COVID-19.

OBJECTIVE: The aim of the study was to appraise the capacity of serum aminotransferases to discriminate between hepatic and other extra-pulmonary COVID-19-related manifestations and, potentially, to serve as predictors of poor clinical outcomes. MATERIALS AND METHODS: Ninety-eight studies were identified (79% from China), including 43,554 patients (57% males), 9,983 (62% males) with poor outcomes and 33,571 (50% males) with favorable outcomes. After splitting studies depending on whether serum alanine aminotransferase (ALT) concentrations were statistically different between patients with poor vs. favorable outcomes, the 35 'hepatic involvement' articles (p<0.05) included 28,510 patients (51% males), 5,279 (66% males) and 23,231 subjects (48% males) with poor and favorable outcomes, respectively. The 63 'extra-hepatic involvement' studies (p>0.05) included 15,044 patients (54% males), 4,704 (60% males) with poor outcomes and 10,340 (51% males) with favorable outcomes. RESULTS: The meta-analysis shows that serum aspartate aminotransferase (AST) concentrations were significantly higher in patients with poor outcomes than those with favorable outcomes (WMD 12.5 UI/L, 95% CI 10.9 to 14.1 p<0.001). Similarly, AST concentrations were significantly higher in the 'hepatic involvement' studies (WMD 16.3 UI/L, 95% CI 13.4 to 19.2 p<0.001) and in the 'extra-hepatic involvement' studies (WMD 10.3 UI/L, 95% CI 8.6 to 12.0 p<0.001). CONCLUSIONS: The different association of serum AST concentrations with some clinical, demographic, and biochemical factors in the two clusters suggests that in COVID-19 patients, serum AST elevation is not necessarily linked to real liver damage.

Acute effects of 5-methyltetrahydrofolate on endothelial function and asymmetric dimethylarginine in patients with chronic heart failure.

BACKGROUND AND AIMS: Folic acid enhances endothelial function in vascular disease states but its effects in chronic heart failure (CHF) are largely unknown. We studied the acute effects of i.v. methyltetrahydrofolate (5MTHF), the active metabolite of folic acid, on endothelial function and asymmetric dimethylarginine (ADMA) in CHF patients. METHODS AND RESULTS: Twenty two CHF patients and 22 controls received one of the following three-step infusions (1h per each step) in a randomized, parallel group, placebo-control study: (1) active treatment (saline, 5MTHF, and 5MTHF+the endothelial nitric oxide inhibitor N(G)-monomethyl l-arginine, LNMMA); or (2) placebo (salinex3). Endothelium-dependent vasodilatation was assessed by pulse-wave analysis (salbutamol-mediated changes in augmentation index, AIx). 5MTHF did not exert any significant effects on endothelium-dependent vasodilatation both in controls [DeltaAIx post-salbutamol baseline -7.6% (-24.8/-4.1) vs. 5MTHF -5.5% (-16.7/-3.6), medians and interquartile range, and CHF patients [-1.8% (-17.3/+1.3) vs. -2.4% (-3.8/-1.2)]. However, a significant reduction in ADMA concentrations was observed in both groups [controls baseline 0.68micromol/L (0.64/0.77) vs. 5MTHF 0.65 (0.57/0.74); CHF baseline 0.76 (0.63/0.82) vs. 5MTHF 0.69 (0.66/0.71), P=0.05 for both vs. baseline and placebo. These effects persisted during co-infusion with LNMMA. CONCLUSION: 5MTHF did not affect endothelial function but significantly reduced serum ADMA concentrations both in CHF patients and controls. This suggests a direct effect of 5MTHF on ADMA metabolism.

Hypoalbuminaemia and impaired renal function are associated with increased anticholinergic drug prescribing.

BACKGROUND: A higher anticholinergic risk score (ARS) is associated with an increased risk of anticholinergic adverse effects in elderly patients. It is unknown whether factors other than the use of anticholinergic drugs determine the ARS. METHODS: A comprehensive medical record review was conducted in 155 consecutive hospitalised patients (median age 79.0 years, interquartile range 66.0-86.0). Information was collected on: demographics; clinical characteristics (including medications and their doses); history of anticholinergic-induced adverse effects; and biochemical markers of hepatic and renal function (serum albumin concentrations and estimated glomerular filtration rate, eGFR). The ARS was calculated for each patient using a standard scoring approach and Poisson regression was used for identifying variables associated with the ARS. RESULTS: Patients with an ARS >or= 3 had a lower eGFR (p = 0.012) and were receiving more non-anticholinergic drugs (p < 0.001) than patients with an ARS < 3. In addition to being prescribed more anticholinergic drugs, patients with ARS >or= 3 were prescribed high doses of these drugs more often than patients with ARS < 3 (41.3% vs. 26.9%, p = 0.034). A higher number of non-anticholinergic drugs (p < 0.001), a lower serum albumin concentration (p = 0.014), and a lower eGFR (p = 0.012) were independently associated with a higher ARS. CONCLUSIONS: Polypharmacy, hypoalbuminaemia and low eGFR are independently associated with the ARS. Patients with a higher ARS are also prescribed higher doses of anticholinergic medications than those with lower ARS.

Diagnostic Accuracy of Anticarbamylated Protein Antibodies in Established Rheumatoid Arthritis: A Monocentric Cross-Sectional Study.

OBJECTIVE: To evaluate the diagnostic accuracy of anticarbamylated protein antibodies (CarP), alone and in combination with traditional biomarkers (rheumatoid factor [RF] and anticitrullinated peptide antibodies [ACPA]), in established rheumatoid arthritis (RA). METHODS: A commercially available enzyme-linked immunosorbent assay (ELISA) kit was used to assess CarP concentrations in serum samples of 200 established RA and 206 controls (115 healthy donors and 55 patients with other rheumatic diseases). Main outcome measures were sensitivity, specificity, and area under the curve (AUC; 95% confidence interval [CI]). Difference in accuracy was evaluated by comparison of the respective AUCs. RESULTS: A serum CarP cut-off of 1.47 ng/ml or more differentiated patients with RA from controls with 30% sensitivity, 97.1% specificity, and good accuracy (AUC[95%CI] = 0.83[0.79-0.86], P < 0.0001). However, it showed moderate diagnostic accuracy in seronegative RA patients: sensitivity 17.9%, specificity 96.9%, and AUC (95% CI) = 0.69 (0.63-0.75). The diagnostic accuracy of CarP_ACPA and CarP_RF combinations was significantly superior to that of ACPA and RF alone (P < 0.0001 and P = 0.015, respectively), but not to that of ACPA_RF combination (P = 0.089) In addition, the CarP_ACPA_RF combination did not improve the diagnostic accuracy of the ACPA_RF combination (AUC mean difference [95% CI] = 0.006 [-0.001 to 0.015], P = 0.10). The number of positive autoantibodies (0, 1, 2, or 3) was not significantly associated with moderate-severe disease (Disease Activity Score-28 [DAS-28] > 3.2) in adjusted multiple regression analysis. CONCLUSION: CarP has good diagnostic accuracy in established RA but not in seronegative RA. The addition of CarP to ACPA and RF alone or in combination does not significantly enhance the diagnostic accuracy of ACPA_RF combination.

ACE inhibitor-based treatment and antihypertensive effects in patients with type 2 diabetes.

AIM: The presence of hypertension significantly increases cardiovascular risk in diabetic patients. Different classes of antihypertensive drugs, by targeting different pathophysiological mechanisms and therapeutic targets, might provide different antihypertensive effects. The authors speculated that drugs specifically targeting the renin-angiotensin-aldosterone system provide better antihypertensive control than other therapeutic agents. METHODS: Fifty consecutive type 2 diabetic patients with hypertension (M:F 29:21) were followed for 3-9 yrs. Antihypertensive treatment was stable for the last 12 months and included angiotensin convertying enzyme (ACE) inhibitors (ACEI) alone in 8 patients (group IA), ACEI combined with other drugs in 11 patients (group IB) and non-ACEI treatment in 31 patients (group II), 23 of whom were treated with Ca-channel blockers and 8 were treated with beta-blockers alone or with diuretics. During the last month of the study a 3-7 days antihypertensive drugs wash-out was performed. Measurements were performed in sitting position in the same ambulatory conditions, in supine position after 20 min of absolute rest, and in motionless standing station after quickly rising up from sitting rest. RESULTS: Groups IA, IB, and II had similar blood pressure values during antihypertensive therapy within the last year. However, blood pressure values after antihypertensive drug wash-out were significantly higher in groups IA and IB vs. group II (SBP and DBP resting sitting position, P=0.039 and P=0.014 respectively; SBP and DBP in standing position, P=0.001 and P=0.016, respectively). CONCLUSION: These data show that the underlying condition in terms of pathophysiologic mechanisms is more severe in groups IA and IB, including a greater increase of peripheral resistance. Thus we may conclude that the antihypertensive effect of ACEI is greater than other classes of antihypertensive drugs.

Homoarginine and inhibition of human arginase activity: kinetic characterization and biological relevance.

The inhibition of arginase, resulting in higher arginine (ARG) availability for nitric oxide synthesis, may account for the putative protective effect of homoarginine (HOMOARG) against atherosclerosis and cardiovascular disease. However, uncertainty exists regarding the significance of HOMOARG-induced arginase inhibition in vivo. A novel UPLC-MS method, measuring the conversion of ARG to ornithine (ORN), was developed to determine arginase 1 and arginase 2 inhibition by HOMOARG, lysine (LYS), proline (PRO), agmatine (AG), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and NG-Monomethyl-L-arginine (L-NMMA). Plasma HOMOARG, ARG and ORN concentrations were further measured in 50 healthy older adults >65 years (27 males and 23 females). HOMOARG inhibited arginase 1 with IC50 and Ki values of 8.14 ± 0.52 mM and 6.1 ± 0.50 mM, and arginase 2 with IC50 and Ki values of 2.52 ± 0.01 mM and 1.73 ± 0.10 mM, respectively. Both arginase isoforms retained 90% activity vs. control when physiological HOMOARG concentrations (1-10 µM) were used. In partial correlation analysis, plasma HOMOARG was not associated with ARG (P = 0.38) or ARG/ORN ratio (P = 0.73) in older adults. Our results suggest that arginase inhibition is unlikely to play a significant role in the reported cardio-protective effects of HOMOARG.

Sex Differences in the Associations between L-Arginine Pathway Metabolites, Skeletal Muscle Mass and Function, and their Responses to Resistance Exercise, in Old Age.

OBJECTIVES: The current study was designed to explore the associations between L-arginine metabolites and muscle mass and function in old age, which are largely unknown. DESIGN: The study used a randomised, double-blind, placebo-controlled design. SETTING: The study was carried out in a laboratory setting. PARTICIPANTS: 50 healthy older adults [median age 70 years (IQR 67-73); 27 males]. INTERVENTION: Participants undertook an 18-week resistance exercise program, and a nutritional intervention (fish oil vs. placebo). MEASUREMENTS: Serum homoarginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA), NG-monomethyl-L-arginine (L-NMMA), and symmetric dimethylarginine (SDMA), maximal voluntary contraction (MVC) and isokinetic torque of the knee extensors at 30° s-1 (MIT), muscle cross sectional area (MCSA) and quality (MQ) were measured at baseline and after the intervention. RESULTS: No significant exercise-induced changes were observed in metabolite concentrations. There were significant sex differences in the associations between metabolites and muscle parameters. After adjusting for age, glomerular filtration rate and fish oil intervention, citrulline (P=0.002) and ornithine (P=0.022) were negatively associated with MCSA at baseline in males but not females. However, baseline citrulline was negatively correlated with exercise-induced changes in MVC (P=0.043) and MQ (P=0.026) amongst females. Furthermore, amongst males, baseline homoarginine was positively associated with exercise-induced changes in MVC (P=0.026), ADMA was negatively associated with changes in MIT (P=0.026), L-NMMA (p=0.048) and ornithine (P<0.001) were both positively associated with changes in MCSA, and ornithine was negatively associated with changes in MQ (P=0.039). CONCLUSION: Therefore, barring citrulline, there are significant sex differences in the associations between L-arginine metabolites and muscle mass and function in healthy older adults. These metabolites might enhance sarcopenia risk stratification, and the success of exercise programs, in old age.

Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance.

Proton pump inhibitor (PPI)-induced inhibition of dimethylarginine dimethylaminohydrolase 1 (DDAH1), with consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), might explain the increased cardiovascular risk with PPI use. However, uncertainty exists regarding whether clinical PPI concentrations significantly inhibit DDAH1 under linear initial rate conditions, and whether PPI-induced DDAH1 inhibition significantly increases ADMA in humans. DDAH1 inhibition by esomeprazole, omeprazole, pantoprazole, lansoprazole and rabeprazole was determined by quantifying DDAH1-mediated L-citrulline formation in vitro. Plasma ADMA was measured in PPI users (n = 134) and non-users (n = 489) in the Hunter Community Study (HCS). At clinical PPI concentrations (0.1-10 µmol/L), DDAH1 retained >80% activity vs. baseline. A significant, reversible, time-dependent inhibition was observed with lansoprazole (66% activity at 240 min, P = 0.034) and rabeprazole (25% activity at 240 min, P < 0.001). In regression analysis, PPI use was not associated with ADMA in HCS participants (beta 0.012, 95% CI -0.001 to 0.025, P = 0.077). Furthermore, there were no differences in ADMA between specific PPIs (P = 0.748). At clinical concentrations, PPIs are weak, reversible, DDAH1 inhibitors in vitro. The lack of significant associations between PPIs and ADMA in HCS participants questions the significance of DDAH1 inhibition as a mechanism explaining the increased cardiovascular risk reported with PPI use.

Co-Culture of Plant Beneficial Microbes as Source of Bioactive Metabolites.

In microbial cultures the production of secondary metabolites is affected by experimental conditions, and the discovery of novel compounds is often prevented by the re-isolation of known metabolites. To limit this, it is possible to cultivate microorganisms by simulating naturally occurring interactions, where microbes co-exist in complex communities. In this work, co-culturing experiments of the biocontrol agent Trichoderma harzianum M10 and the endophyte Talaromyces pinophilus F36CF have been performed to elicit the expression of genes which are not transcribed in standard laboratory assays. Metabolomic analysis revealed that the co-culture induced the accumulation of siderophores for both fungi, while production of M10 harzianic and iso-harzianic acids was not affected by F36CF. Conversely, metabolites of the latter strain, 3-O-methylfunicone and herquline B, were less abundant when M10 was present. A novel compound, hereby named harziaphilic acid, was isolated from fungal co-cultures, and fully characterized. Moreover, harzianic and harziaphilic acids did not affect viability of colorectal cancer and healthy colonic epithelial cells, but selectively reduced cancer cell proliferation. Our results demonstrated that the co-cultivation of plant beneficial fungi may represent an effective strategy to modulate the production of bioactive metabolites and possibly identify novel compounds.

Peripheral blood CD8+ T-cell profiles in patients with psoriatic arthritis: a cross-sectional case-control study.

OBJECTIVE: While CD4+ T-cells are traditionally regarded as the main pathogenic T-cell subpopulation in psoriatic arthritis (PsA), the role of circulating CD8+ T-cells remains poorly characterized. We evaluated the differential representation of CD8+ T-cell subpopulations in peripheral blood (PB) of PsA patients. PATIENTS AND METHODS: CD8+IL-17+, CD8+IFNγ+ and CD8+IL-17-IL-22+ T-cells were evaluated by flow-cytometry in 25 consecutive PsA patients, 7 rheumatoid arthritis (RA) patients, 16 patients with psoriasis, and 26 healthy controls (HC). RESULTS: We observed a significant expansion of circulating IFN-γ producing CD8+ T-cells in PsA when compared to psoriasis [21.2 (6.9-55.8)% vs. 3.8 (0.7-11.8)%, p < 0.0001] and HC samples [21.2 (6.9-55.8)% vs. 4.05 (0.44-19.8)%, p < 0.0001]. A frequency of circulating IFN-γ producing CD8+T-cells ≥ 9% distinguished PsA from psoriasis patients with a specificity of 84% and a sensitivity of 87.5% [AUC = 0.9 (0.80-0.99), p < 0.0001]. In addition, we found a significant expansion of circulating IL-17 producing CD8+ T cells in RA patients when compared to PsA, psoriasis and HC samples. By contrast, there were no significant between-group differences in the prevalence of circulating IL-22 producing CD8+ T-cells. In PsA patients there was a significant correlation between number of swollen joints and frequency of circulating IFN-γ producing CD8+ T-cells, and between extent and severity of psoriasis and frequency of circulating IL-17 producing CD8+ T-cells. CONCLUSIONS: Circulating IFNγ-producing CD8+ T-cells are raised in PsA when compared to psoriasis, suggesting a potential pathogenetic involvement of CD8+ T-cells and IFNγ production in chronic joint inflammation and damage. The significant enrichment of circulating IL-17 producing CD8+ T-cells in RA when compared to PsA warrants functional characterization and confirmation in larger studies. We found no significant enrichment of circulating IL-22 producing CD8+ T-cells in PsA, RA and psoriasis.

Retinoids induce fibroblast growth factor-2 production in endothelial cells via retinoic acid receptor alpha activation and stimulate angiogenesis in vitro and in vivo.

The effect of retinoic acid (RA) on endothelial cells is still controversial and was examined in the present study. In bovine aortic endothelial cells (BAECs), all-trans RA (ATRA) and 9-cis RA (9CRA), but not 13-cis RA (13CRA), induced fibroblast growth factor-2 (FGF-2) production and exhibited a biphasic dose-dependent effect to enhance BAEC proliferation and differentiation into tubular structures on reconstituted basement membrane proteins (Matrigel); both processes were inhibited by FGF-2-neutralizing antibody. The pan RA receptor (RAR)-selective ligand (E)-4-[2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphtalenyl)-1-propenyl] benzoic acid and the RARalpha-selective ligand 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphtyl)-ethenyl] benzoic acid stimulated the production of FGF-2, whereas the addition of the RARalpha-antagonist RO 41-5253 inhibited this effect. In BAECs, the forced expression of RARalpha, but not RARbeta or RARgamma, enhanced FGF-2 production, whereas the RARalpha-dominant negative, Delta403, blocked this effect. Furthermore, RARalpha overexpression directly stimulated BAEC differentiation on Matrigel and potentiated the effects of ATRA in this assay. Finally, ATRA-treated BAECs coinjected with Matrigel subcutaneously in mice induced neovascularization within the Matrigel plug, and ATRA also enhanced angiogenesis in the chicken chorioallantoic membrane assay. In conclusion, RA can stimulate endothelial cell proliferation and differentiation in vitro via enhanced RARalpha-dependent FGF-2 production, and it can also induce angiogenesis in vivo. The full text of this article is available at http://www.circresaha.org.

Predictors of impaired blood pressure homeostasis during acute and sustained orthostasis in patients with type 2 diabetes.

AIM: Sympathetic failure with acute postural hypotension is a common feature of advanced autonomic neuropathy in type 2 diabetes. It is unknown, however, whether: a) the presence of sympathetic autonomic neuropathy is also a powerful predictor of postural blood pressure changes during sustained orthostasis and b) other factors affecting baroreceptor and neuro-hormonal control might play a role. METHODS: Systolic blood pressure (SBP) was measured during supine rest and after 2, 5, and 20 min of active orthostasis in 45 males with type 2 diabetes (age 56.4+/-8.2 years, mean+/-SD) and different degrees of autonomic neuropathy (absence of neuropathy, n=26, parasympathetic neuropathy, n=9, and sympathetic neuropathy, n=10). Eight healthy subjects (50.1+/-11.6 years) served as controls. A multiple backward regression analysis was performed to identify independent predictors of SBP changes during orthostasis. The regression model included presence/absence of sympathetic autonomic neuropathy, age, diabetes duration, presence/absence of hypertension, baseline SBP and neuro-hormonal parameters (plasma adrenaline, noradrenaline, plasma renin activity, and aldosterone). RESULTS: Sympathetic autonomic neuropathy (P=0.005), baseline SBP (P=0.001), and adrenaline (P=0.003) independently predicted SBP changes after 2 min (R2=0.64); sympathetic autonomic neuropathy (P<0.001), baseline adrenaline (P=0.008), and plasma renin activity (P=0.006) predicted SBP changes after 5 min (R2=0.58); whereas sympathetic autonomic neuropathy (P<0.001) and baseline SBP (P<0.001) predicted SBP changes after 20 min orthostasis (R2=0.65). CONCLUSIONS: The presence of sympathetic autonomic neuropathy and higher supine SBP values remain strong and independent predictors of SBP fall not only during the acute transition from supine to standing position but also during sustained orthostasis in type 2 diabetes. Lower baseline plasma adrenaline concentrations and plasma renin activity are also involved, though to a lesser extent, in the genesis of this haemodynamic response.

Effect of methionine loading on pulse wave analysis in elderly volunteers.

OBJECTIVE: To test the hypothesis that an acute increase in plasma homocysteine produced by methionine is associated with an acute increase in pulse wave velocity. DESIGN: A double blind, cross over, placebo controlled design was used and pulse wave velocity, plasma homocysteine, total cholesterol: high density lipoprotein ratio, plasma triglyceride, oxidised low density lipoprotein cholesterol concentrations, apolipoproteins A1 and B, and C reactive protein were measured between 12.5 and 20 hours after methionine loading or placebo. RESULTS: Between 12.5 and 20 hours after exposure to a methionine loading test, arterial pulse wave velocity showed no significant difference compared with placebo. At 12 hours after exposure to the methionine loading test, in the presence of a controlled diet, triglyceride concentration significantly increased by 32.6% (p<0.02), cholesterol: high density lipoprotein ratio increased significantly by 22.5% (p<0.05) compared with placebo. Simultaneously, systolic blood pressure increased significantly by 4.9% (p<0.02). CONCLUSION: In elderly volunteers, acute hyperhomocysteinaemia induced by methionine loading resulted in no overall significant delayed reduction in peripheral arterial distensibility. A significant deterioration in the lipid profile and increased blood pressure was seen during acute hyperhomocysteinaemia.

HIV infection and drug use: influence on cognitive function.

OBJECTIVE: To examine the involvement of cognitive function in HIV-seropositive drug users (DU) in a pre-AIDS state. DESIGN: Fifty-six HIV-positive DU were prospectively evaluated. They belonged to groups II, III and IV (subgroups A, C2 and E) of the 1987 Centers for Disease Control and Prevention classification, with anamnesis negative for neurological pathology. HIV-negative DU (n = 19) and non-DU (n = 27) were used as controls. Infection with HIV and use of toxic drugs were considered variables of influence on cognitive function. METHOD: Subjects underwent neuropsychological evaluation by tests designed to explore cortical and subcortical function. RESULTS: HIV-positive DU showed worse performance scores at the psychometric tests than HIV-negative non-DU, but there was no difference when compared with HIV-negative DU. Ex-DU showed better performance than active DU. No difference with regard to degree of disease evolution was observed among HIV-positive individuals (i.e., groups II and III versus group IV). CONCLUSIONS: There was no evidence of cognitive deficits in HIV-positive individuals in non-AIDS phases to indicate early involvement by HIV at the cerebral level. Progression of the disease, prior to the AIDS phase, did not determine a worsening of intellectual performance. Instead, cognitive function was affected by the chronic and current use of toxic substances. In HIV-positive DU, a decline in cognitive function was found to be attributable to the chronic use of toxic substances rather than HIV infection.

Heart rate-dependent stiffening of large arteries in intact and sympathectomized rats.

In the anesthetized rat, acute increases in heart rate are accompanied by a reduction in arterial distensibility, which is a significant phenomenon in elastic-type vessels such as the common carotid but much less evident in muscle-type vessels such as the femoral artery. Because the sympathetic nervous system importantly reduces arterial distensibility, the present study aimed to determine whether sympathetic influences (1) are involved in the heart rate-dependent changes in arterial distensibility and (2) exert differential effects on elastic-type versus muscle-type arteries. To address this issue, 9 sympathectomized (6-hydroxydopamine) and 10 vehicle-treated, 12-week-old, pentobarbitone-anesthetized Wistar-Kyoto rats were subjected to atrial pacing via a transjugular catheter at 5 different randomly sequenced rates (280, 310, 340, 370, and 400 bpm). After each step, spontaneous sinus rhythm was allowed to return to normal. Common carotid and femoral artery diameters were measured by an echo Doppler device (NIUS 01), and blood pressure was measured via catheter inserted into the contralateral vessel. Arterial distensibility was calculated over the systolic-diastolic pressure range according to the Langewouters formula. In the common carotid artery, progressive increases in heart rate determined progressive and marked reductions of distensibility (range, 15% to 43%) in sympathectomized and intact rats. In the femoral artery, the stiffening effect of tachycardia was present in sympathectomized rats (range, 21% to 42%), at variance with the inconsistent changes observed in intact rats. In conclusion, our experiments support the notions (1) that in predominantly elastic-type arteries, the stiffening effect of tachycardia is exerted independently of sympathetic modulation of the vessel wall properties and (2) that in predominantly muscle-type arteries, removal of sympathetic influences unmasks the stiffening effect of tachycardia.

Effect of sympathectomy on mechanical properties of common carotid and femoral arteries.

Sympathetic stimulation is accompanied by a reduction of arterial distensibility, but whether and to what extent elastic and muscle-type arterial mechanics is under tonic sympathetic restraint is not known. We addressed this issue by measuring, in the anesthetized rat, the diameters of the common carotid and femoral arteries with an echo-Doppler device (NIUS 01). Blood pressure was measured by a catheter inserted contralaterally and symmetrically to the vessel where the diameter was measured. Arterial distensibility over the systolic-diastolic pressure range was calculated according to the Langewouters formula. Data were collected in 10 intact (vehicle pretreatment) and 9 sympathectomized (6-hydroxydopamine pretreatment) 3-month-old Wistar-Kyoto rats. Compared with the intact animals, sympathectomized rats showed a marked increase in arterial distensibility over the entire systolic-diastolic pressure range. When quantified by the area under the distensibility-pressure curve, the increase was 59% and 62% for the common carotid and femoral arteries, respectively (P<.01 for both). In the femoral but not in the common carotid artery, sympathectomy was accompanied also by an increase in arterial diameter (+18%, P<.05 versus intact). Therefore, in the anesthetized normotensive rat, sympathetic activity exerts a tonic restraint on large-artery distensibility. This restraint is pronounced in elastic vessels and even more pronounced in muscle-type vessels.

Combined effects of hypertension and hypercholesterolemia on radial artery function.

Compliance and distensibility of middle-sized conduit arteries are increased in hypertension and reduced in hypercholesterolemia. Despite their frequent association in the same individual, the combined effect of these two conditions on arterial mechanical properties is unknown. We studied four groups of age- and sex-matched subjects: 10 normotensive normocholesterolemic subjects, 10 mild hypertensive normocholesterolemic subjects, 10 mild hypercholesterolemic normotensive subjects, and 10 mild hypertensive and mild hypercholesterolemic subjects. We measured radial artery diameter by an echotracking device and beat-to-beat blood pressure from an ipsilateral finger. Compliance-pressure and distensibility-pressure curves were derived by Langewouters' formula. Between-group comparisons were made by calculating for both compliance and distensibility the integral of the area under the portion of the curve common to the four groups ("isobaric" compliance and distensibility). Blood pressure was similarly elevated in the two hypertensive groups, and serum cholesterol was similarly elevated in the two hypercholesterolemic groups. Compared with values in normotensive normocholesterolemic subjects, isobaric compliance and distensibility were greater in hypertensive normocholesteroclemic (+38% and 47%, respectively) and smaller in normotensive hypercholesterolemic (-6% and -23%) subjects. However, when both hypertension and hypercholesterolemia were present, isobaric compliance and isobaric distensibility were significantly reduced (-26% and -18%, P < .05). Therefore, hypercholesterolemia reverses the effect of hypertension on arterial compliance and causes arterial stiffening, as when present alone.

Angiotensin-converting enzyme inhibition and radial artery compliance in patients with congestive heart failure.

Congestive heart failure is characterized by a clear-cut impairment of arterial compliance of medium-sized arteries, but whether this alteration is irreversible or can be favorably affected by cardiovascular drugs currently used in congestive heart failure treatment is unknown. We studied 9 congestive heart failure patients (New York Heart Association class II; age, [mean +/- SEM] 60.7 +/- 3.3 years) receiving diuretic and digitalis treatment in whom arterial compliance was assessed at the level of the radial artery by an echotracking device capable of measuring the arterial diameter along the entire cardiac cycle. Beat-to-beat arterial blood pressure was concomitantly measured by a Finapres device that allowed diameter-pressure curves and compliance-pressure curves (Langewouters' formula) to be calculated for the entire systolic-diastolic blood pressure range. Arterial compliance was expressed as the area under the compliance-pressure curve normalized for pulse pressure (compliance index). Data were collected before and after 4 and 8 weeks of oral administration of benazepril (10 mg/day). Ten healthy subjects were studied before and after an observational period of 4 weeks (5 subjects) or 8 weeks (5 subjects), and 9 age-matched mildly essential hypertensive subjects studied before and after 4 to 12 weeks of benazepril administration served as control subjects. In congestive heart failure patients, baseline compliance index was significantly less than in normotensive and hypertensive subjects. However, the compliance index showed a marked increase after 4 weeks of benazepril administration (+95.7 +/- 24.9%, P < .05); the increase was also marked after 8 weeks of angiotensin-converting enzyme inhibitor treatment (+77.7 +/- 4.2%, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)