Multiphoton fluorescent images with a spatially varying background signal: a ML deconvolution method.

By means of multiphoton laser scanning microscopy, neuroscientists can look inside the brain deeper than has ever been possible before. Multiphoton fluorescent images, as all optical images, suffer from degradation caused by a variety of sources (e.g. light dispersion and absorption in the tissue, laser fluctuations, spurious photodetection and staining deficiency). From a modelling perspective, such degradations can be considered the sum of stochastic noise and a background signal. Among the methods proposed in the literature to perform image deconvolution in either confocal or multiphoton fluorescent microscopy, Vicidomini et al. (2009) were the first to incorporate models for noise (a Poisson process) and background signal (spatially constant) in the context of regularized inverse problems. Unfortunately, the so-called split-gradient deconvolution method (SGM) they used did not consider possible spatial variations in the background signal. In this paper, we extend the SGM by adding a maximum-likelihood estimation step for the determination of a spatially varying background signal. We demonstrate that the assumption of a constant background is not always valid in multiphoton laser microscopy and by using synthetic and actual multiphoton fluorescent images, we evaluate the face of validity of the proposed method, and compare its accuracy with the previously introduced SGM algorithm.

[Heart failure in chronic kidney disease: from epidemiology to therapy]. / Lo scompenso cardiaco nel paziente con insufficienza renale cronica: dall'epidemiologia alla terapia.

Many patients affected by chronic kidney disease (CKD) die before reaching endstage renal disease because of cardiovascular disease (CVD). Recent guidelines and position statements have therefore defined CKD as a cardiovascular risk equivalent, and patients in all stages of CKD are considered in the highest risk group for development of CVD. Heart failure (HF) is the main cardiovascular complication that occurs in renal patients and its incidence increases proportionally with the reduction of glomerular filtration rate. In fact, pressure and volume overload, that are inherent to the abnormalities of homeostasis typical of CKD, lead to concentric/eccentric left ventricular hypertrophy (LVH). Initially, LVH is adaptative because energy is spared by maintaining stable wall stress. However, in the long term, LVH becomes maladaptative, inducing systolic and/or diastolic dysfunction that, in turn, lead to symptomatic left ventricular failure. Nowadays, it is well established that several classes of drugs, including reninangiotensin system antagonists, beta blockers and aldosterone antagonists, improve survival in patients with HF. In fact, all major guidelines on HF recommend such drugs as standard therapy. The problem for nephrologists is that the general approach and recommendations for the management of HF in the general population may not be completely safe in renal patients with HF. This review is conducted with the purpose to provide more information on the efficacy and safety of HF therapy in renal patients.

Prospective crossover comparison of carvedilol and metoprolol in patients with chronic heart failure.

OBJECTIVES: This study investigates the effects of a change of beta-adrenergic blocking agent treatment from metoprolol to carvedilol and vice versa in patients with heart failure (HF). BACKGROUND: Beta-blockers improve ventricular function and prolong survival in patients with HF. It has recently been suggested that carvedilol has more pronounced effects on left ventricular ejection fraction (LVEF) compared with metoprolol. It is uncertain whether a change from one beta-blocker to the other is safe and leads to any change of left ventricular function. METHODS: Forty-four patients with HF due to ischemic (n = 17) or idiopathic cardiomyopathy (n = 27) that had responded well to long-term treatment with either metoprolol (n = 20) or carvedilol (n = 24) were switched to an equivalent dose of the respective other beta-blocker. Before and six months after crossover of treatment, echocardiography, radionuclide ventriculography and dobutamine stress echocardiography were performed. RESULTS: Six months after crossover of beta-blocker treatment, LVEF had further improved with both carvedilol and metoprolol (carvedilol: 32 +/- 3% to 36 +/- 4%; metoprolol: 27 +/- 4% to 30 +/- 5%; both p < 0.05 vs. baseline), without interindividual differences. There were no changes in either New York Heart Association functional class or any other hemodynamic parameters at rest. Dobutamine stress echocardiography revealed a more pronounced increase of heart rate after dobutamine infusion in metoprolol- compared with carvedilol-treated patients. After dobutamine infusion, LVEF increased in the carvedilol- but not in the metoprolol-treated group. CONCLUSIONS: When switching treatment from one beta-blocker to the other, improvement of LVEF in patients with HF is maintained. Despite similar long-term effects on hemodynamics at rest, beta-adrenergic responsiveness is different in both treatments.

Isolated office hypertension and end-organ damage.

BACKGROUND: Patients with elevated blood pressure levels in the doctor's office but normal blood pressures at other times have recently been described as having 'isolated office hypertension' (IOH). There is debate concerning whether this condition is really benign and thus not in need of treatment. Most of the previous studies on this topic included patients who had already been administered antihypertensive treatment, which unavoidably alters their cardiovascular profile. OBJECTIVE: To evaluate whether recently discovered and never-treated patients with isolated office hypertension have structural or functional abnormalities in comparison with normotensive controls. METHODS: Patients included in the study underwent 24 h ambulatory blood pressure monitoring, M-mode echocardiography and high-resolution echography of carotid arteries. Parameters of lipid and carbohydrate metabolism were also determined. RESULTS: We investigated 76 patients (20 with IOH and 56 with sustained hypertension) who had recently been diagnosed hypertensive but never been administered antihypertensive treatment and 32 matched controls. No changes were detected in left ventricular mass (LVM h2.7, 41.5 +/- 11, 44.5 +/- 10 and 41.5 +/- 10 g/cm2.7 in IOH, sustained hypertension and controls, respectively) and in intimal-medial thickness (IMT, 0.54 +/- 0.13, 0.59 +/- 0.14 and 0.55 +/- 0.16 mm, respectively). However, the left ventricular diastolic function was significantly different (E/A = 1.08 +/- 0.3, 1.04 +/- 0.3 and 1.43 +/- 0.3, respectively, P = 0.02) and the carotid diameter significantly lower than that expected from the pressure-diameter relationship for normotensives. CONCLUSIONS: These results, at variance with those of others, suggest that IOH affects the cardiovascular system even during the early phases of the disease and indicate the need for prospective clinical trials to evaluate the benefit from early treatment of IOH patients.

Influence of cardiovascular risk factors on relation between angiotensin converting enzyme-gene polymorphism and blood pressure in arterial hypertension.

BACKGROUND: The angiotensin-converting enzyme gene insertion (I)/deletion (D) polymorphism might be involved in the development of several cardiovascular diseases, but its role in humans remains controversial. OBJECTIVE: To investigate the relation between the angiotensin converting enzyme gene polymorphism and extent of blood pressure elevation in arterial hypertension, taking into account the influence of cardiovascular risk factors. METHODS: We studied 171 patients (aged 49 +/- 9 years, 61 women) with abnormal clinic and 24 h ambulatory blood pressures, after a 3-week wash-out. RESULTS: We found no significant difference in clinic and ambulatory blood pressures among homozygotic D (DD), heterozygotic D (ID) and homozygotic I (II) angiotensin converting enzyme genotypes and between homozygotic D (DD) and pooled heterozygotic D (ID) plus homozygotic I (II) (non-DD) angiotensin converting enzyme genotypes. At least one additional cardiovascular risk factor (smoking, hypercholesterolaemia or diabetes) was present for 103 patients (33 DD and 70 non-DD). Non-DD subjects (n = 43) without additional cardiovascular risk factors exhibited lower values of 24 h, daytime systolic and pulse blood pressures than did members of all other groups (all P < 0.04). In the presence of risk factors, DD and non-DD subjects exhibited similar systolic and pulse ambulatory blood pressures, in that we found higher values in non-DD genotype subjects with risk factors than we did for non-DD subjects without additional risk factors. In multivariate analysis, the combination of non-DD genotype and absence of cardiovascular risk factors was associated with the lowest values of systolic and pulse blood pressures. CONCLUSIONS: Angiotensin converting enzyme insertion allele appears clustered with lower ambulatory systolic and pulse blood pressures in hypertensive patients when the potential interference of additional cardiovascular risk factors is eliminated. A high prevalence of cardiovascular risk factors in population studies might blunt a possible biological association of blood pressure with DD genotype by contributing to raising of blood pressures also in subjects with non-DD genotypes.

Clinic-daytime blood pressure difference and cardiovascular damage.

OBJECTIVE: To investigate whether the clinic-daytime blood pressure difference can provide information on vascular reactivity to stress comparable to that of simple noninvasive stimuli such as a cold pressor test and isometric exercise, and whether there is any relationship between this blood pressure difference and noninvasive measurements of the left ventricular mass and carotid arterial wall. DESIGN: Patients with newly discovered, never-treated, sustained hypertension were included in the study after a 1 month run-in, during which time their blood pressure was measured three times at 2 week intervals. METHODS: Blood pressure was measured by a noninvasive procedure at rest and during a cold pressor test and an isometric exercise. The difference was calculated for systolic, diastolic and mean blood pressure as resting minus daytime ambulatory blood pressure. Parameters of the posterior wall and septal thickness of the left ventricle, aortic root and left atrium were studied by M-mode echocardiography. Carotid wall thickness and diameter were measured using ultrasound. RESULTS: The 90 patients enrolled in the study were divided into tertiles of clinic-daytime blood pressure difference. The composition of the groups differed in sex, since the majority of women were in the highest tertile, but was comparable for age, body mass index, renin-aldosterone axis and lipid and carbohydrate metabolism. Blood pressure responses to cold and isometric exercise were more pronounced in patients in the lowest tertile of blood pressure difference. No intergroup differences were detected in echocardiographic parameters of ventricular (left ventricular mass, tertiles I-III: 46.5 +/- 10, 42.3 +/- 8, 44.8 +/- 13 g/m2.7, respectively) and carotid (intima-media thickness, tertiles I-III 0.58 +/- 0.1, 0.54 +/- 0.1, 0.62 +/- 0.1 mm, respectively) structure. CONCLUSIONS: The present study indicates that the clinic-daytime blood pressure difference provides different information on cardiovascular reactivity compared with that obtained from the cold pressor test and isometric exercise. Moreover, it does not seem to have any relationship with ventricular hypertrophy and/or carotid wall thickening.

Early abnormalities of cardiac function in non-insulin-dependent diabetes mellitus and impaired glucose tolerance.

The aim of this study was to evaluate the role of diabetes and minor abnormalities of glucose homeostasis, such as impaired glucose tolerance, as determinants of cardiac function and structure in a working population. We studied a population-based sample of 64 telephone company employees (both sexes, mean age 58 years): 25 with normoglycemia, 15 with impaired glucose tolerance, and 24 with non-insulin-dependent diabetes mellitus (NIDDM) diagnosed by oral glucose tolerance test according to the recommendations of the World Health Organization. Subjects with myocardial ischemia were excluded. Left ventricular end-systolic dimension, indexed to body surface area, was greater in those with NIDDM (p < 0.05) and in those with impaired glucose tolerance (p < 0.05) with respect to normoglycemic persons. The ratio of the peak early diastolic velocity wave to the late diastolic wave was lower in those with NIDDM (p < 0.05) and in those with impaired glucose tolerance (p < 0.05) than in participants with normoglycemia. Body mass index and blood pressure were similar in the 3 groups. These results clearly indicate that early abnormalities of cardiac structure and function are observed not only in patients with NIDDM, but also in those with impaired glucose tolerance, independent of the confounding role of myocardial ischemia, body weight, and blood pressure.

Inappropriate left ventricular mass in normotensive and hypertensive patients.

We evaluated cardiovascular features of normotensive and hypertensive adults with left ventricular (LV) mass values exceeding levels predicted for given stroke work, gender, and height, termed "inappropriate" LV mass. Inappropriate LV mass is associated with overweight, concentric LV geometry, and low myocardial systolic function not only in hypertensive subjects, but also in normotensive subjects.

Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension.

We investigated the influence of major cardiovascular risk factors (smoking, hypercholesterolemia, diabetes mellitus) on the association between angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism and echocardiographic left ventricular mass in 225 patients with sustained hypertension, assessed by ambulatory blood pressure monitoring. When the study population was analyzed as a whole, the 3 ACE genotypes did not differ in left ventricular mass (II, 47 g/m2.7; ID, 49 g/m2.7; DD, 51 g/m2.7; p = NS). No difference was found in subjects (n = 135) in whom at least 1 major cardiovascular risk factor was present (II, 51 g/m2.7; ID, 51 g/m2.7; DD: 52 g/m2.7; p = NS). In contrast, in the absence of cardiovascular risk factors, DD subjects (n = 32) exhibited left ventricular mass index higher than non-DD (ID/II) subjects (n = 75; p <0.05). After controlling for age and sex, in the absence of cardiovascular risk factors, the risk of left ventricular hypertrophy was 3.8-fold higher in DD than in non-DD patients (odds ratio 3.8; 95% confidence interval 1.2 to 12.1, p <0.02). We conclude that in the present setting of patients with established sustained systemic hypertension, the absence of risk factors potentially affecting cardiovascular adaptation allows for the detection of a positive association between homozygosity for the D allele of the ACE gene and left ventricular hypertrophy.

Cardiovascular abnormalities in never-treated hypertensives according to nondipper status.

Ambulatory blood pressure monitoring allows a better understanding of blood pressure fluctuations over 24 h than simple clinic measurements. In this way the diagnosis of "white coat" versus "sustained" hypertension and that of "dipper" (patient with blood pressure fall during nighttime > 10% of daytime levels) versus "nondipper" status were made possible. This pilot study has been undertaken to investigate whether patients with recently discovered, never-treated, mild, sustained hypertension have cardiovascular abnormalities according to their dipper/nondipper status. Patients with long-standing (n = 123) and newly discovered (n = 56) sustained hypertension were classified according to their nighttime blood pressure fall, and compared with normotensive controls. Ambulatory blood pressure monitoring was performed noninvasively. Parameters of left ventricular structure, cardiac systolic and diastolic function, and carotid anatomy were determined noninvasively by echographic methods. Significant increases in parameters of cardiac structure as well as abnormalities in diastolic function were observed in patients with long-standing hypertension, regardless of their dipper status. In the group with newly discovered hypertension, left atrium (3.4+/-0.3, 3.7+/-0.5, 3.2+/-0.4 cm in dippers, nondippers, and controls, respectively), end-diastolic diameter index (2.9+/-0.3, 3.0+/-0.2, 2.8+/-0.2 cm/m), and atrial filling fraction (0.50+/-0.07, 0.52+/-0.05, 0.42+/-0.04) were significantly altered only in the nondipper subgroup, in comparison with controls. Significant changes in cardiac structure and diastolic function were observed in nondipper patients with recently discovered hypertension, who, at variance with dippers, show changes similar to those in patients with long-standing hypertension. Hypertensives with the observed abnormalities may benefit from active antihypertensive treatment, which appears, therefore, justified even in an early phase of mild hypertension, in terms of potential reduction of end-organ complications as well as cost-effectiveness.

Ketanserin alone and in combination with enalapril in the treatment of essential hypertension: assessment of the haemodynamic effects.

The antihypertensive and haemodynamic efficacies of ketanserin and ketanserin plus enalapril were compared. The monotherapy phase of the study involved the oral administration of 40 mg ketanserin twice daily or 20 mg enalapril once daily for 12 weeks to 25 hypertensive patients. Systolic and diastolic blood pressures were significantly reduced by both drugs. Left ventricular function both at rest and during effort improved significantly with either drug. This was due to a reduction of end-systolic volume; end-diastolic volume decreased only with the use of enalapril. Combination therapy, involving 16 patients and both drugs given at the original dosage schedule for 12 weeks, resulted in further reductions in systolic and diastolic blood pressures, and an improvement in left ventricular function; indices of diastolic function were not modified. In conclusion, ketanserin and enalapril showed comparable antihypertensive and haemodynamic activities. A combination of ketanserin and enalapril increased the favourable characteristics of both drugs.

[A query system for the "SINTESI" database in scientific research and medical practice]. / II ruolo del modulo di interrogazione della banca dati "SINTESI" tra ricerca scientifica e pratica medica.

"SINTESI release 1.0" is an application for Windows that was designed to enable a practical approach to day-hospital evaluation and management of several metabolic and instrumental parameters. "SINTESI" provides electronic archives such as demographics, history, follow-up, laboratory, electrocardiogram, Doppler echocardiography, vascular echo-Doppler, Holter ECG, nuclear imaging, radiology, ergometric testing, ambulatory blood pressure monitoring, hemodynamics. We have improved the first release (1.0) with a new application that queries the database ("SINTESI release 2.0"). The new query application, developed in collaboration with experts of the Italian Group for the Study of Atherosclerosis and Metabolic Diseases, was designed with the central file displaying buttons that recall electronic archives, allowing to select the variables for the query. At the end of each operation, the user always returns to the central file, where it builds the query formula by "AND/OR" logic operators. Query formula and results can be recorded to be used whenever needed. The results of the query can be exported as DBF or ASCII files for analysis with statistical packages. This feature allows the use of the data bank for medical research.

Left ventricular geometry and arterial function in hypercholesterolemia.

AIMS: To investigate the effect of hypercholesterolemia on total arterial compliance and left ventricular (LV) geometry in the absence of arterial hypertension and diabetes. METHODS: One hundred and fifty-two normotensive, non-diabetic patients (109 men) aged 52 +/- 10 years with plasma cholesterol > 240 mg/100 mL, and 282 normotensive controls (154 men) aged 42 +/- 10 years (p < 0.0001) with plasma cholesterol < 200 mg/100 mL were studied by means of echocardiography. The stroke volume/pulse pressure ratio as a percentage of the value predicted by individual age, body weight and heart rate was used as a prognostically-validated index of total arterial compliance. Central pulse pressure (PP) was estimated using a regression equation obtained in a non-overlapping population. RESULTS: Although within the "normal" range, systolic pressure, PP and estimated central PP were higher in the hypercholesterolemic patients even after controlling for differences in age, body mass index (BMI) and race (all p < 0.0001). After controlling for differences in systolic pressure, age, BMI and race, LV mass and the prevalence of hypertrophy were comparable between the two groups, whereas relative diastolic wall thickness was greater (0.36 + 0.06 vs 0.33 + 0.05) and percent SV/PP (stroke volume/PP) lower in the hypercholesterolemic patients (96 +/- 19% vs 102 +/- 18%; both p < 0.005). After considering the covariates, there was still an independent negative correlation between relative wall thickness and percent SV/PP (r = -0.37, p < 0.0001). CONCLUSIONS: Hypercholesterolemia in normotensive non-diabetic adults is independently associated with a mildly concentric LV geometry and a reduced index of total arterial compliance.

[The SINTESI Project: software in cardiovascular prevention]. / "Progetto SINTESI": un software nella prevenzione cardiovascolare.

Coronary heart disease is the most important cause of mortality in adults. New approaches may reduce the cardiovascular risk in population. "SINTESI" is an original data base designed in collaboration with the Italian Group for the Study of Metabolism Disease and Atherosclerosis to improve the evaluation of the major risk factors in the population and to create a data bank for medical research. It runs in Windows. The software includes the following electronics archives: Demographics; History; Follow-up; ECG; Laboratory; Doppler-echocardiography; Stress test-ECT; Ambulatory blood pressure monitoring; Holter-ECG; Nuclear imaging; Vascular echo-Doppler; Hemodynamics; Radiology. We named the most important file "Main Working Area" (MWA). This displays all the most important information on the clinical status of the patients and represents the "console" for using the software. In fact, in MWA "buttons" are displayed to enter all the electronic archives. The software displays graphics and the flow-chart of clinical history. We implemented "routines" for automatic evaluation of several variables. We also simplify the statistical use of the data implementing functions for "query" that permit the management of data bank. The use of this software may facilitate the correct evaluation and stratification of the cardiovascular risk. In conclusion, "Progetto SINTESI" is an easy, synthetic organization of patient's clinical data and a complete data bank. It is our opinion that the use of this software may promote a standard way of collecting a large number of data to improve the stratification of cardiovascular risk.

Anti-hypertensive effect of manidipine: 24 hours monitoring evaluation and Doppler-echocardiographic remarks.

In order to evaluate the antihypertensive effects of manidipine, at the dosage of 10 or 20 mg once daily, we studied 36 patients (12 males and 24 females, mean age 54.3 years) with mild hypertension. After a wash-out period of 2 weeks and another 2 week run-in period with placebo, all the patients were assigned to a treatment with manidipine 10 mg/ day. After 2 weeks of treatment, the non-normalized (diastolic BP > 90 mmHg) and the non-responders (BP fall < 10 mmHg) received an increase in dosage to 20 mg/day. The drug effects were assessed by casual blood pressure (BP) measurement at baseline and after 4, 8, 12, 24, 36 and 52 weeks. At baseline and after 1 year of treatment a 24-h BP monitoring and a Doppler echocardiogram were performed. Routine laboratory tests were performed at baseline, after 6 months and after 1 year of treatment. At the end of the observation period, both casual systolic (p < 0.01) and diastolic (p < 0.001) BP were significantly reduced; 24-h BP monitoring showed a significant decrease in systolic (p < 0.05) and diastolic (p < 0.01) pressure, systolic and diastolic (p < 0.001) daytime and night-time measurements. The peak to through ratio was 67%. No difference was found in heart rate. Reduced interventricular septum thickness (p < 0.05), increased fractional shortening (p < 0.02), reduced end-systolic stress (p < 0.005) and systemic vascular resistances (p < 0.001), and lower values of atrial filling fraction (AFF) (p < 0.001) after 1 year of treatment have been shown at the Doppler-Echo evaluation. A multilinear regression analysis showed a relation between delta %AFF and delta %24-h systolic BP (R = 0.74; F = 7.5: p < 0.05) and with delta % daytime systolic BP (R = 0.77; F = 9.2; p < 0.02). No abnormal changes were observed in laboratory tests. Three non-responder patients and three patients with adverse effects (1 flushing and 2 ankle oedema) dropped out and were excluded from the final analysis. In conclusion, manidipine at an individualized dose of 10 or 20 mg. was effective and safe in the management of arterial hypertension. Hemodynamic evaluations after 1 year of treatment confirmed an improvement of systolic and diastolic function, with an evident reduction of afterload.

[Absence of an association of the D allele of the ACE gene with arterial pressure in mild-moderate essential arterial hypertension]. / Assenza di associazione tra allele D del gene dell'ACE e pressione arteriosa nell'ipertensione arteriosa essenziale lieve-moderata.

To assess the relationship between the angiotensin converting enzyme (ACE) gene I/D polymorphism, blood pressure (BP) and family history of hypertension, 133 hypertensive subjects (mean age 50 +/- 9 years, 78 males, 55 females) were selected according to both casual supine BP > 140/90 mmHg and ambulatory BP > 134/88 mmHg. Drug treatment was discontinued 2 weeks before entering the study. Subjects with myocardial ischemia, as well as those with "white coat" hypertension, were excluded. The study population was subclassified according to age < or = 50 years. Polymerase chain reaction was used to detect the I/D polymorphism of the ACE gene, and the DD genotype was analysed twice. The frequencies of the I and D allele were 42 and 58%, and the distribution of the ID+ II and DD genotypes were 69 and 31% respectively. No significant relation was found among ACE genotypes (DD vs ID+ II) and casual systolic or diastolic BP as well as ambulatory BP, both in the whole study population and in the subpopulation < 50 years old. No difference was found also in the distribution of dippers and no dippers, as well as in the distribution of subjects with a positive family history in the whole sample and hypertensives < 50 years old.