Associations between specific plasma ceramides and severity of coronary-artery stenosis assessed by coronary angiography.

AIM: Recent prospective studies have identified distinct plasma ceramides as strong predictors of major adverse cardiovascular events in patients with established or suspected coronary artery disease (CAD). Currently, it is uncertain whether higher levels of distinct plasma ceramides are associated with greater angiographic severity of coronary-artery stenoses in this patient population. METHODS: We measured six previously identified high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD, who underwent urgent or elective coronary angiography. RESULTS: Approximately 77% of patients had a significant stenosis (≥50%) in one or more of the main coronary arteries, the majority of whom (∼60%) had a significant stenosis in the left anterior descending (LAD) artery. Of the six measured plasma ceramides, higher levels of plasma Cer(d18:1/20:0) (adjusted-odds ratio 1.39, 95%CI 1.0-1.99), Cer(d18:1/22:0) (adjusted-odds ratio 1.57, 95%CI 1.08-2.29) and Cer(d18:1/24:0) (adjusted-odds ratio 1.59, 95%CI 1.08-2.32) were significantly associated with the presence of LAD stenosis≥50%, after adjustment for age, sex, smoking, pre-existing CAD, hypertension, diabetes, dyslipidaemia, lipid-lowering therapy, estimated glomerular filtration rate and plasma C-reactive protein levels. Almost identical results were found even after excluding patients (n=15) with acute ST-elevation myocardial infarction. Similar results were also found when patients were categorized according to the Gensini severity score. CONCLUSION: Our cross-sectional study shows for the first time that higher levels of specific plasma ceramides are independently associated with a greater severity of coronary-artery stenoses in the LAD artery in patients who had suspected or established CAD.

Adherence to alendronic or risedronic acid treatment, combined or not to calcium and vitamin D, and related determinants in Italian patients with osteoporosis.

PURPOSE: Osteoporosis is a chronic disease and an important health and social burden due to its worldwide prevalence. Literature and clinical experience report incomplete adherence to the therapy. This retrospective observational study aimed at assessing the adherence to first-line antiosteoporosis drugs (AODs; reimbursed by the National Health System, according to the Italian Medicine Agency recommendation number 79), alendronate or risedronate, with or without calcium and/or vitamin D supplements, in a real, Italian clinical setting. PATIENTS AND METHODS: Analyses were carried out on data present in the ARNO Observatory, a population-based patient-centric Italian database. From a population of 5,808,832 inhabitants with available data, a cohort of 3.3 million of patients aged ≥40 years was selected. New users of first-line AODs as monotherapy (accrual period, 2007-2009) were followed up over 3 years to assess adherence at 6, 12, and 36 months to AODs and to supplements and related determinants. RESULTS: Approximately 40,000 new users were identified: mostly women, aged on average (standard deviation) 71±10 years. Alendronate was the most prescribed (38.2% of patients), followed by risedronate (34.9%) and alendronate with colecalciferol as a fixed-dose combination (25.8%). Adherence at the 6-month follow-up was 54%, and this constantly and significantly decreased after 1 year to 46%, and after 3 years to 33% (P<0.01). Adherence to the fixed-dose combination was higher than to plain alendronate throughout the follow-up period. Similarly, adherence to supplements constantly decreased with the duration of treatment. Women and patients aged >50 years were more likely to adhere to treatment regimen (P<0.001). The use of drugs for peptic ulcer and gastroesophageal reflux disease and of corticosteroids for systemic use were significantly associated with high adherence at different times. Polytherapy (>5 drugs), cardiovascular, and neurological therapies were significantly associated with low adherence throughout the follow-up period. CONCLUSION: In a huge clinical practice sample, this study highlights suboptimal adherence to first-line AODs and to supplements and important determinants, such as concomitant therapies.

Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator-stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry.

UNLABELLED: ESSENTIALS: The reliability of platelet tests as markers of the variable bioavailability of clopidogrel is not yet defined. Kinetics of clopidogrel active metabolite (CAM) and platelet response were studied in ischemic heart disease. CAM plasma maximum concentration (Cmax ) predicted vasodilator-stimulated phosphoprotein (VASP-P). Timely performed VASP-P, not an aggregation-based test, may be a surrogate for clopidogrel bioavailability. BACKGROUND: The high inter-individual variability in the inhibition of platelet function by clopidogrel is mostly explained by high variability in its transformation to an active metabolite (CAM). Objective We investigated the relations between pharmacokinetics and pharmacodynamics of CAM by comparing two methods of platelet function. METHODS: We enrolled 14 patients undergoing percutaneous coronary interventions for non-ST-segment elevation acute coronary syndrome or inducible myocardial ischemia. Plasma concentrations of clopidogrel and CAM, phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P), expressed as a platelet reactivity index (PRI) and whole-blood platelet aggregation (multiple electrode aggregometer, MEA) were measured before and after a 600-mg clopidogrel loading dose (nine time-points) and before and after 75-mg maintenance doses on days 2, 7 and 30. RESULTS: Plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax ) (median, 110.8 nm; range, 41.9-484.8) 0.5-2 h after the loading dose. A sigmoid dose-response curve defined the relations between CAMCmax and PRI after 3 to 24 h (IC50 , 459.6 nm; 95% confidence interval, 453.4-465.7; R(2) = 0.82). PRI was unchanged from baseline in patients with the lowest CAMCmax (< 83 nm, n = 7), indicating low sensitivity of VASP-P. PRI values were also predicted by CAMCmax at days 2, 7 and 30. Platelet aggregation measured by MEA did not show significant relations with either PRI or with CAM pharmacokinetics at any time-point. CONCLUSIONS: After 600 mg clopidogrel, VASP-P, but not whole-blood platelet aggregation measured by MEA, is almost entirely predicted by CAMCmax . VASP-P could be useful in studies aimed at investigating relations between CAM bioavailability and clinical events.

Atherosclerotic ischemic renal disease.

AIM: Atherosclerotic ischemic renal disease is a frequent cause of end-stage renal failure leading to dialysis among the elderly; its prevalence is inferred from autopsy or retrospective arteriographic studies. Screening investigation for ischemic nephropathy on large cohorts, based on non invasive diagnostic techniques, have not so far been published. This study has been conducted on 269 subjects over 50 with hypertension and/or chronic renal failure, unrelated to other known causes of renal disease. METHODS: All 269 patients were studied either by color-flow duplex sonography (n=238) or by renal scintigraphy (n=224), and 199 of the 269 patients were evaluated using both of these techniques. Forty patients, found to have renal artery stenosis, were subjected to 3D-contrast enhancement magnetic resonance angiography (MRA) and/or digital selective angiography (DSA). An additional 23 cases, negative both to scintigraphy and to ultrasound study, underwent renal angiography (MRA and/or DSA). RESULTS: Color-duplex sonography, carried out in 238 patients, revealed 49 cases of renal artery stenosis. MR or DSA was carried out in 35 of these 49 patients, and confirmed the diagnosis in 33. Color-duplex sonography was 91.7% sensitive and 90.9% specific, with positive predictive value of 94.2% and negative predictive value of 86.9%. Specificity and sensitivity of renal scintigraphy, carried out in 224 patients, was significantly lower. Patients with renal artery stenosis showed a higher degree of renal insufficiency compared to non stenotic patients while there were no differences in the extent of proteinuria between the two groups. Renal artery stenosis, based on color-duplex sonography studies, was present in 11% of patients in the age group 50-59, 18% in the 60-69 and 23% at age 70 and above. CONCLUSION: A relatively large percentage of the elderly population with renal insufficiency and/or hypertension is affected by renal artery stenosis and is at risk of developing end-stage renal failure. Color-duplex ultrasonography is a valid routine method of investigation of population at risk for renal artery stenosis.

Parathyroidectomy in chronic renal failure: short- and long-term results on parathyroid function, blood pressure and anemia.

To evaluate the long-term results of parathyroidectomy (PTX) on parathyroid function, blood pressure and anemia, data of 45 patients with secondary Hyperparathyroidism in dialysis who had undergone PTX were collected retrospectively from 8 different dialysis units. The patients, 25 M and 20 F, mean age 56 +/- 11 years, who were followed up for an average period of 3.3 +/- 2.3 years, were divided into four groups according to the surgical procedure: 19 patients had had a subtotal PTX; 10 patients had undergone total PTX with autotransplantation (AT); 10 patients had had total PTX without AT, and 6 patients had undergone partial PTX. Taking a reduction in intact PTH > 50% as sign of successful PTX, only 5 patients did not attain this result. Considering values of PTH between 20 and 200 pg/ml at the mid-term observation (1-2 years) as the optimal result, values under 20 pg/ml as an expression of permanent hypoparathyroidism, and those above 200 pg/ml as indicating persistent/recurrent hyperparathyroidism, 65.5% of patients operated with subtotal PTX and total PTX + AT had a therapeutic success, versus 31.2% of patients in the other two groups, due to excess permanent hypoparathyroidism and persistent/recurrent hyperparathyroidism; 20 of 45 patients with preoperative hypertension experienced a statistically and clinically significant decrease in blood pressure levels. An increase in serum hemoglobin was also observed, despite a reduction of administered erythropoietin. In conclusion, the results of PTX obtained from this multicenter study are comparable to those reported by single leading centers. Recommended surgical procedures are subtotal PTX and total PTX with AT. The fall in blood pressure in hypertensive patients is clinically significant, and improvement in anemia is also observed with a reduction in erythropoietin dosage.

Histomorphometric assessment of bone turnover in uraemic patients: comparison between activation frequency and bone formation rate.

AIMS: The histomorphometric assessment of bone formation rate (BFR/BS) in bone biopsies from uraemic patients is of crucial importance in differentiating low from high turnover types of renal osteodystrophy. However, since BFR/BS relies on osteoblasts, activation frequency (Ac.f), encompassing all remodelling phases, has recently been preferred to BFR/BS. This study was carried out to consider whether estimation of Ac.f is superior, in practical terms, to that of BFR/BS in distinguishing between different rates of bone turnover in uraemic patients. METHODS AND RESULTS: Bone biopsies from 27 patients in predialysis (20 men and seven women; mean age 53 +/- 12 years) and 37 in haemodialysis (22 men and 15 women; mean age 53 +/- 12 years) were examined. The types of renal osteodystrophy were classified on the basis of morphology. Bone formation rate and Ac.f were evaluated according to standardized procedures. The Ac.f was calculated both as a ratio between BFR/BS and wall thickness (W.Th) and as a reciprocal of erosion, formation and quiescent periods (EP, FP and QP). Patients were affected by renal osteodystrophy with predominant hyperparathyroidism (two predialysis and 16 dialysis), predominant osteomalacia (three predialysis and seven dialysis) or that of advanced (nine predialysis and five dialysis) or mild (seven predialysis and four dialysis) mixed type or adynamic type (six predialysis and five dialysis). Activation frequency, which with either formula requires the measurement of W.Th, i.e. the thickness of bone structural units (BSUs), was not calculated in three dialysis patients with severe hyperparathyroidism and in one predialysis and four dialysis patients with severe osteomalacia, because only incomplete BSUs were found. In dialysis, EP was higher in the adynamic than in the other types of osteodystrophy. During both predialysis and dialysis, FP was higher in osteomalacia than in the other forms of osteodystrophy, and in adynamic osteopathy than in hyperparathyroidism or in advanced and mild mixed osteodystrophy. During predialysis and dialysis, QP was higher in the adynamic than in the other forms of osteodystrophy. Correlations were found between BFR/BS and Ac.f, during predialysis (r=0.97) and dialysis (r=0.95). CONCLUSIONS: The superiority of Ac.f in assessing bone turnover, in comparison to BFR/BS, is conceptual rather than practical. The highest values for FP in osteomalacia and for QP in adynamic bone allow a clearer characterization of these low turnover conditions.

Urinary deoxypyridinoline excretion for the evaluation of bone turnover in chronic renal failure.

BACKGROUND: The urinary excretion of deoxypyridinoline (DPD) was evaluated in predialysis chronic renal failure (CRF), together with intact PTH and several classic markers of bone turnover in order to assess whether urine free and total DPD excretion are equivalent parameters of bone turnover in CRF, and to evaluate the relationship between urine DPD excretion, PTH and the other bone markers. METHODS: The study was carried out in 94 patients with different degrees of renal failure due to various kidney diseases. Besides urinary DPD expressed as free DPD, total DPD, free/total DPD, free DPD/Cr and total DPD/Cr, the following determinations were made: intact PTH, bone alkaline phosphatase (BALP), total alkaline phosphatase (AP), osteocalcin (BGP), serum C-terminal telopeptide of collagen type I (ICTP) and hydroxyproline (OHpro). The patients were divided into 3 groups according to the increasing severity of renal failure (Ccr >40, 40-20, <20 ml/min). RESULTS: The ratio free/total DPD decreased (NS) with advancing renal failure, and was inversely correlated with total DPD excretion. While PTH increased progressively to about four times the values observed in the Ccr >40 group, there was a parallel increase only in BGP and ICTP, parameters retained in the serum with decreasing renal function, while AP, BALP, total DPD and OHpro did not change. However, significant correlations between total DPD/Cr and PTH, BALP, BGP and ICTP were also found. CONCLUSIONS: In CRF free DPD is an unreliable index of bone turnover due to a probable interference in its production from the peptide-bound DPD. Total DPD or total DPD/Cr are better used. In spite of the significant correlations observed in advanced renal failure between PTH and most of the parameters examined, a resistance of bone tissue to PTH action in CRF must be considered.

Calcitriol per os once, twice or three times a week: effect of different schedules of administration in hemodialysis patients.

Administration of a single dose of 1,25-OH(2)D(3) can lower PTH levels for up to 4 days in chronic hemodialysis patients. Our purpose was to verify the effects of the same weekly dose of calcitriol per os given in one, two or three administrations, to patients on dialysis with secondary hyperparathyroidism. Thirty patients were studied, divided in to three groups each of 10 patients. Calcitriol therapy in group A was given as a single weekly dose of 0.08 microg/kg b.w. In group B the same total weekly dose was divided in two equal doses. In group C the same total weekly dose was divided in three times. Treatment lasted 2 months. After 8 weeks of therapy the fall in intact PTH was statistically significant in each group, respectively with one-way ANOVA: p<0.02 (A); p<0.002 (B); p<0.001 (c). Two-way ANOVA for comparison of PTH % variation among the three groups was statistically significant p<0.003. Significance was due to difference between group A and groups B and C. The present study confirms the efficacy of single dose in suppressing significantly intact PTH. However, when the same weekly dose is divided into two or in three time-spaced administrations, the suppressive effects are definitely increased.

Bone markers in the diagnosis of low turnover osteodystrophy in haemodialysis patients.

BACKGROUND: Renal osteodystrophy includes a number of low and high turnover bone histologic patterns which require a bone biopsy for their full identification. The role of intact PTH and several classical and more recent bone markers in the non-invasive diagnosis of renal bone disease in patients with CRF in HD requires further definition since available published data are limited. METHODS: In addition to intact PTH, alkaline phosphatase (AP) and osteocalcin (BGP), bone alkaline phosphatase isoenzyme (BALP), tartrate resistant acid phosphatase (TRAP), C-terminal cross-linked peptide of collagen type 1 (ICTP) and deoxypyridinoline (DPD) were measured in the serum of 41 patients on haemodialysis, subjected at the same time to transiliac bone biopsy for histomorphometric, histodynamic and aluminium histochemical examination. Histodynamic evaluation following double tetracycline label, was carried out in 37 patients. The patients had no evidence of active cytolytic and cholestatic liver disease and a history of very limited aluminium exposure. RESULTS: The patients had differing degrees of hyper-parathyroidism, with intact PTH ranging from normal to very elevated levels. Serum values of the markers BGP, ICTP and DPD, normally excreted through the kidneys, were on average very high. The correlation coefficients of the humoral parameters vs dynamic variables, such as BFR/BS, were high. The highest values were: intact PTH 0.798, AP 0.900, BALP 0.891, ICTP 0.807. The patients, grouped in low turnover osteodystrophy (LTO; 9), mixed osteodystrophy (MO; 9) and prevalent hyperparathyroidism (HP; 23), showed significant difference in the levels of most humoral and static and dynamic parameters (ANOVA). Bone aluminium histochemistry was negative in all cases. Discrimination of LTO patients from the other groups by humoral parameters, at the highest value of accuracy, showed 100% sensitivity and 93.7% specificity with a cut-off of 12.9 ng/ml for BALP; 88.9% sensitivity and 93.7% specificity with a cut-off of 21.5 ng/ml for DPD, and 88.9% sensitivity and 90.6% specificity with a cut-off of 79.7 pg/ml for intact PTH. The other markers had lower values. A standardized z-score approach for evaluation of all humoral parameters was also carried out. Using all variables, a correct classification of MO/HP and of LTO was possible in 93.8 and 88.9% of the cases, respectively. Predictive power was 96.8 and 80%, respectively for MO/HP and LTO. When the only variables used were intact PTH and BALP, a correct classification of MO/HP and LTO was possible in 90.6% and 88.9%, respectively. Predictive value of MO/HP was 96.7% and for LTO 72.7%. Predictive values using PTH and AP were 96.3% and 57.2%, respectively. CONCLUSION: Intact PTH and several relatively new bone markers are of certain value in the non-invasive diagnosis of renal osteodystrophy. However some of the humoral markers carry the same quality of information and the use of intact PTH and BALP may be adequate in the discrimination of bone histologic patterns. In cases exempt from liver disease, PTH and AP may be used as a less costly alternative. Bone biopsy could be chiefly limited to cases with borderline humoral values and to all those with a suspected aluminium overload.

Ischemic nephropathy in an elderly nephrologic and hypertensive population.

BACKGROUND: Atherosclerotic renovascular disease is a frequent cause of end-stage renal failure leading to dialysis in the elderly population. Its prevalence is known from autopsy or retrospective arteriographic investigations. This prospective study was conducted in 133 subjects with the inclusion criteria of hypertension and/or chronic renal failure starting after 50 years of age. Renal failure was unrelated to other known causes of renal disease. METHODS: The patients were subjected to echo-color doppler ultrasonography of renal arteries (104) and/or to renal scintigraphy (112). Thirteen of 27 patients with positivity using one or both noninvasive techniques were subjected to digital selective angiography. RESULTS: All the patients with positivity of echo-color doppler technique were true positives, with a consequent predictive value reaching 100%. Renal scintigraphy was of markedly lower predictive value. Based on the echo-color doppler investigation, percentage positivity for hemodynamically significant stenosis (> 50%) was 3.2 (16.3% had mild nonsignificant stenosis of renal arteries) in the 50- to 59-year-old group, 20% (plus 12.5% with nonsignificant stenosis) in the 60- to 69-year-old group and 25% (plus 17.8% nonsignificant stenosis) in the > 70-year age group. Patients with significant stenosis also had a significantly higher degree of renal insufficiency and received a higher number of hypotensive drugs (p < 0.013). The percentage of hypertensive patients was not different in the stenotic and nonstenotic groups. CONCLUSIONS: A large percentage of the elderly population is affected by renal vascular obstructive disease and is at risk of developing end-stage renal failure. Considering the wide number of cases with foreseeable renal arterial stenosis in the vast population meeting the selection criteria, it is possible to conclude that not all cases evolve to renal failure due to different rates of progression or to untimely nonrenal death.

Epidemiology of hemopoietic system neoplasms in Argentina.

The mortality caused by blood neoplasms in Argentina shows great irregularity. This was found to be caused in certain ways by (a) differences in the sexes and ages of the populations studied; (b) differences in available health services; and (c) environmental factors. Thus high rates and clusters of lymphomas and multiple mylomas were observed in zones with arsenical water, for example.In rural districts, the rates are lower, especially among old-aged people.Lower rates of leukemias were also observed among Spaniards compared to Italians (p=0.001) residing in Argentina. Turkish, Syrian, and Lebanese showed higher rates than Argentinians, Spaniards, or Italians.The results of a case-control study are given in which the following were observed: (a) Among the ancestors of cases HSN there are fewer Spaniards (not significant) and Latin-Americans (p=0.03) and more people who were born in Central or Eastern Europe (p=0.01). (b) In case group, there was more frequent contact with animals, especially dogs; and a greater exposure to petroleum and its products, and to insecticides.