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Neuromyelitis optica spectrum disorder (NMOSD) is associated with various comorbidities, including non-autoimmune and autoimmune conditions. The burden and cost of illness for NMOSD are unclear, particularly in the context of comorbidities.Claims data from IBM MarketScan Commercial and Medicare Supplemental Databases between 2014 and 2018 were analyzed. Patients with NMOSD were specified as having inpatient or outpatient claims for NMOSD diagnosis or specific NMOSD symptoms claims and no subsequent claims for multiple sclerosis (MS) or use of MS disease-modifying therapy (DMT). Continuous enrollment ≥ 6 months before and ≥ 1 year after the first claim (index date) was required for study inclusion. Total costs stratified by comorbidities within 12 months post-index date were calculated per patient and compared 1:5 with matched non-NMOSD controls.A total of 162 patients with NMOSD and 810 non-NMOSD controls were evaluated. A significantly higher proportion of NMOSD patients had comorbidities than non-NMOSD controls (66.7% vs 41.5%; P 0.001). Concomitant autoimmune disease occurred in 19.1% vs 4.9% (P 0.001) of patients with NMOSD vs non-NMOSD controls. NMOSD patients incurred significantly higher total median (interquartile range) healthcare costs per patient ($68,386.48 [$23,373.54-$160,862.70]) than matched non-NMOSD controls with autoimmune disease ($17,215.13 [$6715.48-$31,441.93]; P 0.001) or patients with NMOSD without autoimmune comorbidity ($23,905.42 [$8632.82-$67,251.54]; P = 0.022). Similarly, patients with NMOSD and non-autoimmune comorbidities incurred higher median healthcare costs than matched controls.Patients with NMOSD experience significant disease burden and cost that are amplified by comorbidities. Effective therapies are needed, particularly for patients with concomitant autoimmune disease.

Background Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system that often leads to severe disability. Patients with highly active NMOSD have approximately a 10-times higher hospital inpatient admission rate compared with patients without NMOSD. Accurate assessments of the impact of NMOSD treatments on the burdens of illness require quantitative metrics of these burdens, including costs of care. Methods This study evaluated claims data from the IBM MarketScan Commercial and Medicare Supplemental Databases between 2014 and 2018. Patients were included based on inpatient or outpatient claims meeting criteria defined for NMOSD. Non-NMOSD controls were matched 5:1 to patients with NMOSD. Total costs of healthcare services in consumer price index–adjusted 2019 US dollars during the 1-year postindex follow-up period were calculated for patients and controls. Results Patients with NMOSD required more healthcare services and incurred significantly greater costs for inpatient hospitalizations (annual mean [SD] cost: $29,054 [$144,872] vs controls $1521 [$10,759]), outpatient services ($24,881 [$35,463] vs $4761 [$26,447]), and emergency department (ED) visits ($2400 [$7771] vs $408 [$2579]). Almost 12% of patients with NMOSD were further burdened with plasma exchange or intravenous immunoglobulin G treatments, costing an annual median (interquartile range) of $1684 ($566–$3817) and $24,353 ($5425–$42,975), respectively. Conclusions Compared with controls, patients with NMOSD had significantly higher costs associated with hospitalizations, ED visits, and prescriptions. These results highlight the considerable economic burden of NMOSD, which may be favorably impacted by disease-modifying therapies that are regulatory-approved to be safe and effective.

Background: Recent scientific reports have shown that older persons treated with antipsychotics for dementia-related behavioural symptoms have increased mortality. However, the impact of these drugs prescribed during hospitalization has rarely been assessed. We aimed to investigate whether antipsychotics are associated with an increased risk of mortality during hospitalization and at 3-month follow-up in elderly inpatients. Methods: We analyzed data gathered during two waves (2010 and 2012) by the REPOSI (Registro Politerapie Società Italiana Medicina Interna). All new prescriptions of antipsychotic drugs during hospitalization, whether maintained or discontinued at discharge, were collected, and logistic regression models were used to analyze their association with in-hospital and 3-month mortality. Covariates were age, sex, the Short Blessed Test (SBT) score, and the Cumulative Illness Rating Scale. Results: Among 2703 patients included in the study, 135 (5%) received new prescriptions for antipsychotic drugs. The most frequently prescribed antipsychotic during hospitalization and eventually maintained at discharge was haloperidol (38% and 36% of cases, respectively). Patients newly prescribed with antipsychotics were older and had a higher Cumulative Illness Rating Scale comorbidity index both at admission and at discharge compared to those who did not receive a prescription. Of those prescribed antipsychotics, 71% had an SBT score ≥10 (indicative of dementia), 12% had an SBT score of 5-9 (indicative of questionable dementia); and 17% had an SBT score

Background The simultaneous measurement of multiple cytokines in parallel by using multiplex proteome arrays (MPA) is of great interest to understanding the inflammatory response following myocardial infarction; however, since cytokines are pleiotropic and redundant, increase of information throughput (IT) attained by measuring multiple cytokines remain to be determined. We aimed this study to assess the IT of an MPA system designed to assess 8 cytokines – commercially available at the time of the study – serum levels, before (control state) and after experimental myocardial cryoinjury (activated state) in rats. Methods By assuming that redundant information do not generally increase the IT, we derived Entropy ( H ) and Redundancy ( R ) of information by using formulas of Shannon modified accordingly, where a high IT (high H and low R ) corresponds to a low level of correlation between cytokines and vice versa for a low IT. The maximum theoretical level of IT and the contribution of each cytokine were also estimated. Results In control state, no significant correlations were found between cytokines showing high IT; on the contrary, in activated state, several significant correlations were found supporting a complex cross-talk pattern between cytokines with low IT. Using as reference the maximum theoretical level of IT, in activated state, H was reduced of 67.0% and R was increased of 77.4% supporting a reduction of IT. Furthermore, the contribution of individual cytokines to H value of MPA was variable: in control state, IL-2 gave the most contribution to H value, conversely during activated state IL-10 gave most contribution. Finally during activated state, IL-1β was the only cytokine strongly correlated with values of all other cytokines, suggesting a crucial role in the inflammatory cascade. Conclusions Paradoxically, by analyzing an MPA system designed for redundant analytes such as cytokines, translating the Shannon's information theory from the field of communication to biology, the IT system in our model deteriorates during the activation state by increasing its redundancy, showing maximum value of entropy in the control conditions. Finally, the study of the mutual interdependence between cytokines by the contribution to the IT may allow formulating alternative models to describe the inflammatory cascade after myocardial infarction.

Background and objectives Information on ambulatory blood pressure monitoring (ABPM) in children is scarce. While in adults office BP (OBP) is higher than ABP and the difference increases as OBP increases, information in children suggests that at this young age ABP is no lower and often higher than OBP. This study was aimed at describing OBP-ABP differences in a cohort of children of different ages and BPs, and investigating whether OBP-ABP differences are dependent on age or OBP level. Methods We retrospectively compared OBP and 24-h, daytime and night-time ABP in 433 children and adolescents aged 4-18 years, referred to our hospital clinic. Results OBP was found to be significantly lower than 24-h and daytime ABP in the low age tertile (4-10 years) but not in the medium and high tertiles. OBP was also lower than ABP in normotensive patients (n = 182), but higher than ABP in untreated hypertensive patients (n = 92) despite similar ages. Continuous analyses showed a weak correlation of OBP-ABP differences with age, and a much stronger correlation with OBP so that 24-h ABP was higher than OBP at OBP values less than 117/73 mmHg and lower than OBP at higher OBP values. Logistic regression analysis indicates that also in children OBP accounts for most of the OBP-ABP difference. Conclusion There is a common relation both in children and adults between OBP and ABP. It is only because high OBP is common in the elderly, and the lowest OBP is usually found in young children that large positive OBP-ABP differences have been associated with old age, and negative differences with childhood. OBP-ABP differences, often defined as white-coat effect, can have different directions and are likely to be largely due to regression to the mean.

Early evaluation of cardiovascular (CV) risk in hypertensive patients is of primary importance and studies of retinal vessels can be helpful. The aim of this study is to assess the correlation between retinal vessel changes and target organ damage (TOD), expressed as left ventricular remodelling (LVR) or hypertrophy (LVH). We evaluated 60 treated hypertensive individuals (mean age 60.9±13.3 years). On the basis of echocardiographic results, we divided the subjects showing the presence of TOD and subjects without TOD into Groups A and B, respectively. Both groups underwent a non-mydriatic digital retinography. The obtained vessel images were analysed using dedicated software in order to calculate AVR (arteriovenular ratio), index of the retinal arteriolar narrowing. The data analyses confirmed a mean AVR value of 0.86 in Group B and a mean value of 0.77 in Group A. AVR index was also analysed in a subgroup of A with evidence of LVR, and mean value was 0.76. The same procedure was carried out with subgroup of A with LVH and AVR index resulted 0.77. In all comparisons, P-value was statistically significant (P

Objectives Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA).\ud \ud Methods Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12.\ud \ud Results 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% (p=0.011), 53.8% (p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP

Heart rate variability (HRV) is the temporal beat-to-beat variation in successive RR intervals on an electrocardiographic (ECG) recording and it reflects the regulation of the heart rate (HR) by the autonomic nervous system (ANS). HRV analysis is a noninvasive tool for the assessment of autonomic function that gained momentum in the late 1980s when its clinical relevance as a predictor of mortality was established by a milestone study by Kleiger et al. in patients with postacute myocardial infarction. In the last few decades, the increasing availability of commercial ECG devices offering HRV analysis has made HRV a favorite marker for risk stratification in the setting of cardiovascular disease. The rapid aging of the world population and the growing popularity of HRV have also fueled interest for the prognostic value of HRV in the elderly, outside a specific cardiological context. However, the discussion of HRV measures in the elderly is still very much centered on the rather reductionistic model of sympathovagal balance, with the orthosympathetic and parasympathetic limbs of the ANS exercising opposing effects on the heart via autonomic tone. The expanding application of nonlinear dynamics to medicine has brought to the forefront the notion of system complexity, embedded in the mathematical concepts of chaos theory and fractals, and provides an opportunity to suggest a broader interpretation for the prognostic significance of HRV, especially in the elderly. Although the use of novel indices of HRV may be hampered by practical issues, a more holistic approach to HRV may still be safeguarded if traditional time- and frequency-domain measures are viewed in terms of autonomic modulation. This review focuses on HRV in geriatric populations. It considers studies on the prognostic value of HRV in elderly subjects, discussing the potential confounding effect of erratic rhythm, and concentrates on the conceptual distinction between autonomic tone and autonomic modulation. It also briefly addresses the question of the practicality of ECG recordings and identifies a promising area for future research in the effects of common noncardioactive drugs on HRV.

Erectile dysfunction (ED) is often associated with cardiovascular disease (CVD) and the risk of sildenafil-induced orthostatic hypotension (OH) in subjects with CVD is a matter of concern. We describe our experience in using the tilt test (TT) with continuous plethysmography to evaluate the occurrence of OH in patients with CVD and ED after a test dose of sildenafil. When sildenafil was added on top of their usual pharmacological treatment two patients out of 32 (6.2%) developed asymptomatic OH, with a maximum blood pressure fall of 40/20 mm Hg. The low prevalence and modest clinical relevance of OH in our high-risk population coupled with the known high sensitivity and reproducibility of the TT seem to suggest that sildenafil is haemodynamically safer than is generally believed even when added on top of vasoactive treatment. These findings should be put into perspective against the growing wealth of evidence that PDE5 inhibitors may have therapeutic potential for a number of CV conditions.

Myocardial fibrosis is commonly observed in left ventricular (LV) hypertrophied heart during Arterial Hypertension. This pathological change coupled with vascular stiffening with aging and diabetes may reduce the cardiovascular system elasticity contributing to the functional impairment. Both the LV adaptive response to the increasing blood pressure and the oxidative damage contribute to myocardial fibrosis; in particular, reactive oxygen species (ROS) induce the formation of reactive electrophilic carbonyl species by reacting with lipids and sugars which in turn react with proteins forming irreversible adducts (AGEs, ALEs and EAGLEs) and cross-links. The vascular wall matrix then becomes less distensible, as the formation of the adducts induces greater capacity in collagen to resist normal turnover. Therefore, monitoring cardiac fibrosis and markers of collagen synthesis, degradation and non-enzymatic cross-linking and the use of drugs that revert collagen accumulation and/or prevent/repair non-enzymatic cross-linking might represent a novel opportunity to alter the natural history of hypertensive heart disease. Recent evidences have suggested to target the excess of collagen cross-links; initial evidence seems to show that fibrosis is not affected to the same degree by all anti-hypertensive agents. ACEI and ARBs appear particularly effective. Finally, agents acting as cross-link breakers on AGEs or preventing AGEs formation or affecting the TTG activity are emerging.

Cardiac performance after myocardial infarction is compromised by ventricular remodeling, which represents a major cause of late infarct-related chronic heart failure and death. In recent years, the scientists' interest has focused on the hypothesis that the administration of bone marrow progenitors, following myocardial infarction, could ameliorate left ventricular remodeling by continuing to differentiate along the haematopoietic lineage. This approach has been developed minding to the consolidated use of transfusions to restore lost or depleted blood components and, therefore, as an enriched dose of various progenitors, generally autologous, injected peripherally or directly in the infarcted area. Since the safety of this therapy was not yet established, for ethical reasons pioneering researchers involved in these studies used animal models as surrogate of the human biologic system. Herein this hypothesis of therapy resulted in an increased use of living animals and in the reappraisal of models of myocardial damage with limited discussion on the theoretical basis of animal models applied to cell-based therapies. Recently, the European Union and its commission for surveillance of laboratory animals advanced a new proposal to restrict the use of living animals. This review will focus on the history of models utilization in biomedicine, with particular attention to animal models, and delineate an operative comparison between the two best known models of myocardial injury, namely coronary ligation and cryodamage, in the perspective of adult stem cell research applied to cardiovascular regenerative medicine.

Background: Dihydropyridine calcium antagonists are largely employed for the treatment of hypertension, coronary heart disease, and heart failure. Objective: The aim of our study was to compare the antihypertensive effect of the dihydropyridine calcium antagonists barnidipine and amlodipine. Methods: This was a 24-week, randomized, open-label, pilot study. Consecutive treatment-naive patients with grade I or II essential hypertension (office sitting systolic blood pressure [BP] of 140–179 mm Hg and diastolic BP of 90–109 mm Hg) were enrolled. The primary end points were the effect of treatment with either barnidipine 10 mg or amlodipine 5 mg once daily on office and ambulatory BP, left ventricular mass index (LVMI), and markers of cardiac damage, serum procollagen type I C-terminal propeptide, and plasma amino-terminal pro-B-type natriuretic peptide concentrations. Patients were assessed at enrollment, and 12 and 24 weeks. During each visit, the prevalence of adverse events (AEs) was also monitored using spontaneous reporting, patient interview, and physical examination, the relationship to study drug being determined by the investigators. Compliance with treatment was assessed at each study visit by counting returned tablets. Results: Thirty eligible patients (20 men, 10 women; mean [SD] age, 47 [12] years) were included in the study; all patients completed the 24 weeks of study treatment. Twelve weeks after randomization, 6 patients in the amlodipine group had their dose doubled to 10 mg due to inadequate BP control. Mean BP reductions at study end were not significantly different between the barnidipine and amlodipine groups (office BP, −10.3/−9.4 vs −16.6/−9.1 mm Hg; ambulatory BP, 9.4/6.4 vs 8.1/5.1 mm Hg). Reductions in LVMI and markers of cardiac damage were not significantly different between the 2 groups. Significantly more patients in the amlodipine group reported drug-related AEs compared with those in the barnidipine group (9 [60%] vs 2 [13%]; P < 0.05). Conclusion: In this small sample of treatment-naive hypertensive patients, the antihypertensive effect of barnidipine 10 mg once daily was not significantly different from that of amlodipine 5 to 10 mg once daily.

Objective To determine the safety and efficacy of additional courses of rituximab in patients with rheumatoid arthritis (RA). Methods An open-label extension analysis of RA patients previously treated with rituximab was conducted. Patients who had participated in any of 3 double-blind trials were eligible for additional courses (2 infusions of 1,000 mg given 2 weeks apart) if they exhibited a swollen joint count and tender joint count of ≥8 with ≥16 weeks elapsing after the previous course. Safety was assessed in patients receiving all or a portion of a rituximab course. Efficacy was assessed 24 weeks after each course, using the American College of Rheumatology 20% criteria for improvement (ACR20), ACR50, ACR70, European League Against Rheumatism (EULAR) response criteria, Disease Activity Score in 28 joints, the disability index of the Health Assessment Questionnaire, and Short Form 36 scores, stratified according to prior tumor necrosis factor (TNF) inhibitor exposure. Results A total of 1,039 patients received ≥1 course of rituximab. Of these, 570 received 2 courses, 191 received 3 courses, and 40 received 4 courses, for a total of 1,669 patient-years. Irrespective of prior TNF inhibitor exposure, ACR20 responses were comparable at week 24 after course 1 and at week 24 after course 2 (65% versus 72%), as were ACR50 and ACR70 responses. EULAR moderate/good responses were also comparable in course 2 relative to course 1 (88% versus 79%), with EULAR remission occurring in a 2-fold higher proportion of patients after course 2 than after course 1 (13% versus 6%). The most common adverse events, which were mild-to-moderate acute infusion-related events, decreased with each course. The serious infection rate after course 1 (5.1 per 100 patient-years) remained stable through additional courses. The proportion of patients with circulating IgM and IgG levels below the lower limit of normal (LLN) increased with subsequent courses; however, serious infection rates in these patients (5.6 per 100 patient-years in patients with low IgM levels and 4.8 per 100 patient-years in patients with low IgG levels were comparable with those in patients with immunoglobulin levels above the LLN (4.7 per 100 patient-years). Patients with human antichimeric antibody (9.2%) did not exhibit decreasing efficacy or present additional safety concerns. Conclusion These findings indicate that patients treated with repeated courses of rituximab have sustained clinical responses with no new adverse events.

Objective. To describe the prevalence of advanced retinal microvascular lesions and their associations with cardiac and extracardiac signs of target organ damage (TOD) in a large selected hypertensive population. Methods. A total of 2172 non-diabetic untreated and treated uncomplicated essential hypertensives consecutively attending for the first time our hospital outpatient hypertension clinic and included in the Evaluation of Target Organ Damage in Hypertension (ETODH), an observational ongoing registry of hypertension-related TOD, were considered for this analysis. Advanced hypertensive retinopathy was defined by the presence of any of the following lesions: flame-shaped haemorrhages, soft exudates or cotton wool spots and papilloedema. Left ventricular hypertrophy (LVH), carotid structural abnormalities, such as plaques and intima media (IM) thickening, and microalbuminuria were diagnosed according to the 2003 ESH/ESC guidelines criteria. Results. Among the whole study population, 33 patients (1.5%) were found to have advanced hypertensive retinopathy. Patients with these retinal lesions were similar to those without for age, body mass index, known duration of hypertension, smoking habit, total serum cholesterol, fasting blood glucose and prevalence of antihypertensive treatment; whereas mean systolic and diastolic blood pressures were higher in the former group. The prevalence rates of LVH, carotid plaques, carotid IM thickening and microalbuminuria in patients with and without retinopathy were 57%, 67%, 69%, 19% and 25%, 47%, 44%, 12%, respectively. In a multivariate logistic regression analysis, advanced retinopathy was significantly associated with LVH (OR=4.0), carotid IM thickening (OR=2.9), carotid plaques (OR=2.8), but not with microalbuminuria. Conclusions. Our study indicates that: (i) advanced retinopathy is a rare finding in non-diabetic hypertensive patients seen in a specialist setting; (ii) a strong relation exists between retinal microvascular lesions and cardiac and macrovascular markers of TOD. © 2005 Taylor & Francis Group Ltd.

Background and purpose: The clinical and prognostic significance of initial retinal alterations in hypertensive patients remains controversial. Therefore, we assessed the relationship of microvascular abnormalities with prognostically validated markers of target organ damage (TOD), such as left ventricular mass (LVM), carotid intimamedia thickness (IMT) and microalbuminuria, in early stages of untreated essential hypertension. Methods: A total of 437 consecutive, never-treated patients with grade 1 or 2 essential hypertension, referred to our outpatient clinic, underwent the following procedures: (1) clinical and routine laboratory examinations, (2) 24-h ambulatory blood pressure monitoring, (3) 24-h urine collection for microalbuminuria, (4) echocardiography, (5) carotid ultrasonography, (6) non-mydriatic retinography. Patients were divided into group I, with either a normal retinal pattern (n = 65, 14.9%) or arteriolar narrowing (n = 185, 42.4%) and group II with arteriovenous crossings (n = 187, 42.70/0). Results: The two groups were similar for gender, body mass index, smoking habit, heart rate, clinic and ambulatory blood pressure (BP) values, while mean age was slightly but significantly higher in group II than in group I (47.6 ± 10.7 versus 44.5 ± 12.5 years, P = 0.008). No differences occurred between the two groups in LVM index (101.8 ± 18.5 versus 99.9 ± 20.4 g/m2), carotid IMT (0.67 ± 0.12 versus 0.66 ± 0.20 mm), urinary albumin excretion rate (14.4 ± 27.7 versus 13.3 ± 27.7 mg/24 h) as well as in the prevalence of LV hypertrophy (14.3 versus 14.0%), IM thickening and/or plaques (26.5 versus 27.2%) (both defined according to 2003 ESH-ESC guidelines) and microalbuminuria (10.1 versus 8.7%). Furthermore, the three different retinal artery patterns were similarly distributed among tertiles of LV mass index, IMT and urinary albumin excretion rate. Conclusions: These results show that: (1) a very large fraction (more than 80%) of untreated, recently diagnosed hypertensive patients have initial retinal microvascular abnormalities detectable by non-mydriatic retinography, (2) the presence of arteriovenous crossings is not associated with more prominent cardiac and extracardiac TOD, (3) fundoscopic examination has a limited clinical value to detect widespread organ involvement in early phases of grade 1 and 2 hypertension. © 2004 Lippincott Williams & Wilkins.

BACKGROUND: The selective homing of peripherally injected marrow MNCs (MMNCs) has recently been demonstrated in a model of cryodamaged heart. However, the mechanism underlying this phenomenon is still unknown. In the hypothesis that this process is related to the necrotic area extension, the infarcted area was correlated with the number of homed MMNCs in a model of experimental cryodamaged heart. STUDY DESIGN AND METHODS: A total of 12 donor and 12 recipient inbred isogenic adult (4 weeks old) Fisher rats were used to mimic autologous transplantation. Myocardial damage was obtained in recipient rats by cryoinjury. MMNCs were purified, labeled with PKH26 (a red fluorescent cell dye), and infused 7 days after the injury through the femoral vein of recipient rats. One week after peripheral administration, the number of homed MMNCs was assessed and the infarct size was correlated with the number of cells present in the target. RESULTS: Labeled cells were found only in the injured myocardium of the treated animals (n = 6), where a mean of 12 ± 3 PKH26+ cells per section examined were found; a significant correlation was found between the infarct size and the estimated number of cells (p = 0.008) CONCLUSION: These data indicate that the homing of MMNCs is related to the extent of the myocardial injury, suggesting that cellular therapy for regeneration of damaged myocardium should be individualized by taking into consideration the extension of the area to repair.

Objective: The aim of the study was to evaluate the prevalence of left ventricular hypertrophy (LVH) in treated patients with good blood pressure (BP) control during multiple home BP (HBP) measurements and during 24-h ambulatory BP monitoring (ABPM), but with unsatisfactory BP control in the clinic. These patients were compared with treated hypertensives whose BP was well controlled under the three circumstances. Methods: Seventy-two treated consecutive patients (group I, age 56 ± 10 years) with clinic BP values ≥ 140/90 mmHg, and a difference between clinic and self-measured HBP > 10 mmHg for diastolic blood pressure (DBP) and/or > 20 mmHg for systolic blood pressure (SBP), underwent the following procedures: (1) clinic BP measurement; (2) routine diagnostic work-up; (3) HBP monitoring; (4) 24-h ABPM; (5) echocardiography. Thirty-five hypertensive patients with satisfactory BP control according to clinic (< 140/90 mmHg), HBP (≤ 131/82 mmHg) and ABP criteria (≤ 125/79 mmHg) were included as the control group (group II, age 55 ± 9 years). Results: In group I, 33 subjects out of the 72 (46%) with clinic BP > 140/90 mmHg had BP values controlled outside the clinic (23 according to HBP criteria and 22 according to ABP criteria). The prevalence of LVH (LV mass index > 134 g/m2 in men and > 110 g/m2 in women) was significantly higher in these patients (15.1 versus 2.8%, P < 0.01) than in group II (BP also controlled in the clinic), despite the fact that HBP and ABP were reduced to similar levels in the two groups. Conclusions: Our data provide evidence that treated hypertensive patients with good BP control at home or during ambulatory monitoring, but incomplete BP control in the clinic, have more pronounced cardiac alterations than patients with both clinic and out of the clinic BP control. This finding offers a new piece of information about the diagnostic value of BP measurement in the clinic to assess BP control during antihypertensive treatment. © 2003 Lippincott Williams & Wilkins.

To investigate whether in recently diagnosed essential hypertensives a reduced nocturnal fall in blood pressure (BP), established on the basis of two 24-h ambulatory blood pressure monitorings (ABPM) is related to a greater cardiovascular damage. In all, 355 consecutive, recently diagnosed, never-treated essential hypertensives referred for the first time to our outpatient clinic were included in the study. Each patient underwent the following procedures: (1) two 24-h ABPMs performed within 3 weeks, (2) 24-h urinary collection for microalbuminuria, (3) nonmydriatic photography of ocular fundi, (4) echocardiography, (5) carotid ultrasonography. We defined nondipping profile as a night-day systolic and diastolic fallor =10 % (mean of two ABPMs). A dipper BP profile was found in 238 patients, whereas in 117 patients a nondipper profile was present. The two groups were similar for age, gender, body mass index, smoking habit, clinic BP, 48-h BP and heart rate, while, by definition, night-time systolic and diastolic BP were significantly higher in nondippers than in dippers (130/81 vs 121/74 mmHg, P0.0001).The prevalence of left ventricular hypertrophy (LVH) defined by four different criteria: (a) LV mass index (LVMI)or = 125 g/m(2) in both genders; (b) LVMIor = 134 gm(2) in men andor = 110 in women; (c) LVMIor = 125 g/m(2) in men andor = 110 g/m(2) in women; (d) LVMIor = 51 g/m(2.7) in men andor = 47 g/m(2.7) in women was significantly higher in nondippers than in dippers (a: 12 vs 7%, P0.05; b: 16 vs 7%, P0.01; c: 20 vs 11%, P0.01; d: 35 vs 23% P0.02) and this finding was associated with a significant increase in aortic root and left atrium dimensions. There were no differences between the two groups in the prevalence of carotid and retinal changes and microalbuminuria. In conclusion our findings suggest that never-treated hypertensives with a reduced BP fall in the night time, defined on the basis of two ABPMs, have a higher prevalence of TOD than dippers, in terms of echocardiographic LVH. In this population setting, cardiac structural alterations are a more sensitive marker of the impact of the nocturnal BP load on cardiovascular system than other extracardiac signs of TOD.

OBJECTIVE Ultrasonic tissue characterization of epi-aortic vessels may be useful to define the composition of atherosclerotic plaques. Videodensitometry provides a histogram representing the frequency distribution of gray levels corresponding to different compositions of the carotid wall. However, lack of standardization limits the clinical application of this technique. In the present study, the echoreflectivity (ER) pattern of atherosclerotic plaques in vivo was compared with their histological pattern after surgical removal, and the reproducibility of measurement was tested. DESIGN AND METHODS We studied 19 hypertensive patients with a carotid artery stenosis >or= 70%, eligible for carotid thromboendarterectomy (TEA). Before TEA, all patients underwent standard high-resolution B-mode carotid ultrasound. ER parameters (mean gray level, broad band, skewness, and kurtosis) were obtained in a region of interest selected along the whole plaque, between the intima-blood and the media-adventitia interfaces. The plaques removed during TEA were examined by a histologist and classified into three groups on the basis of fibrous tissue (FT) content: lipidic (FT 50%). Discriminant function analysis was used to evaluate classification efficacy of different histological groups based on ER parameters. RESULTS Histologically, five lesions were classified as lipidic, six as fibrolipidic and eight as fibrous. Analysis of variance showed significant between group differences in all ER parameters. The combined use of all ER parameters provided correct classification of plaques in 94.73% of cases (P < 0.0001), improving the classification made using single parameters. Intra-observer and inter-observer variabilities (Bland-Altman method) of mean gray level measurements were small. CONCLUSIONS Videodensitometry can discriminate between tissue composition of carotid lesions and complement the quantitative assessment of intima-media thickness by additionally providing a well-reproducible semiquantitative evaluation of vascular wall constituents.

Left ventricular (LV) concentric remodelling is an adaptive change in cardiac geometry frequently observed in arterial hypertension. This study was addressed to investigate the extent of extracardiac target organ damage (TOD) in patients with LV concentric remodelling. Two groups of never-treated essential hypertensives, 31 with normal LV geometry (group I, relative wall thickness: 0.39) and 31 with LV concentric remodelling (group II, relative wall thickness: 0.47) matched for age, sex, body mass index and mean 24-h systolic blood pressure (BP), were included in the study. They underwent clinical and laboratory examination, 24-h ambulatory BP monitoring (ABPM), 24-h urinary collection for microalbuminuria, non-mydriatic photography of ocular fundi, echocardiography and carotid ultrasonography. In both groups age (I: 51 +/- 11 years; II: 51 +/- 11 years), body mass index (I: 25 +/- 3 kg/m(2); II: 26 +/- 3 kg/m(2)), clinic and 24-h ABPM values (I: 149 +/- 11/95 +/- 8, 142 +/- 11/91 +/- 7 mm Hg; II: 150 +/- 11/98 +/- 9, 142 +/- 12/92 +/- 9 mm Hg) were similar by design. There were no differences between patients with normal LV geometry and with LV concentric remodelling in LVM index (97 +/- 16 vs 99 +/- 16), carotid intima-media thickness (0.7 +/- 0.02 vs 0.7 +/- 0.02) and carotid plaques prevalence (35% vs 35%). Furthermore, no significant differences among the two groups were found in the prevalence of retinal changes and microalbuminuria. These results suggest that in hypertensive patients with similar BP and LVMI levels, LV concentric remodelling is not associated with more prominent TOD.

Objective: To investigate in a selected population of patients with a recently diagnosed essential hypertension the short-term intrasubject variability of diurnal changes in blood pressure (BP). Methods: Two hundred and eight consecutive, recently diagnosed, never treated essential hypertensives (119 men, 89 women, 46 ± 12 years) underwent 24-h ambulatory BP monitoring (ABPM) twice within 3 weeks. Dipping pattern was defined as a reduction in average systolic and diastolic BP at night greater than 10% compared to average daytime values. Results: 177 subjects (85%) showed no change in their diurnal variations in BP. Of the 159 subjects who had a dipping pattern on first ABPM, 134 (90.6%) confirmed this type of profile on the second ABPM, while 15 (9.4%) showed a non-dipping pattern. Of the 59 subjects who had a non-dipping pattern on the first ABPM, 43 (72.2%) confirmed their initial profile on the second ABPM, while 16 (28.8%) did not. Conclusion: These findings indicate that short-term reproducibility of diurnal changes in BP in early phases of untreated essential hypertension, characterized by a large prevalence of dipping pattern, is overall satisfactory. However, our study underlines that also in this particularly selected population of hypertensives the definition of non-dipping status on the basis of a single ABPM remains unreliable in about one-third of patients.

Background: The aim of the present study was to evaluate the association between heart failure (HF) and chronic kidney disease (CKD) in tertiary care centers using the clinical records of patients enrolled in internal medicine departments.Patients and methods: We used the clinical records of 1380 elderly patients to identify patients with a history of HF and CKD using admission ICD codes and glomerular filtration rate (GFR) formulas. Magnitude and strength of such associations were investigated by univariable and multivariable analysis.Results: Of the 1380 patients enrolled, 27.9% had HF (age 80 ± 7, BMI 27 ± 6 kg/m2) and 17.4% CKD (age 81 ± 7, BMI 26.8 ± 6 kg/m2). Both groups were significantly older (P

Here we report the case of an 86-year-old woman with advanced dementia addressed to our service for routinary ECG Holter Monitoring (EHM) for bradycardia in AV block type I. Several day-time episodes of fall-asleep while sitting had been previously reported by the nurse and generally attributed to the dementia itself, without taking into consideration the hypothesis of an AV block. The EHM reading reported several and often subsequent pauses (561), many of them critical, the longest lasting 15,9 s with no changes in clinical condition of the patient. The results of the EHM were reported to the physicians in charge for the patient and subsequently the woman was referred to the arrhythmology unit for pace-maker device implantation. Generalizing our experience, we suggest that advanced dementia, often associated with episodes of fall-asleep, could mask a conduction disturbance causing critical pauses with syncope; therefore we suggest screening those patients for possible arrhythmic disorders. Finally, we remark that in our patient the pauses weren’t associated with a worsening of the patient as seen in the follow-up, and this fact supports the hypothesis that vascular dementia could increase cerebral ischaemic tolerance.

Objective Acromegaly is frequently associated with an increase in left ventricular mass, even in the absence of systemic hypertension. Pathological studies on acromegalic hearts have shown an extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy. The aim of this study was to assess left ventricular wall structure in acromegaly by ultrasonic tissue characterization. Design and methods We studied 10 untreated acromegalic patients and 10 age-matched healthy control subjects. The echo patterns of two-dimensional long-axis end-diastolic echocardiograms were assessed by colour-scale analysis of the interventricular septum, with estimates of the mean colour scale value, the broad band (Bb) and the derived collagen volume fraction (dCVF). We also measured electrocardiographic QT interval dispersion (QTd) as a marker of dyshomogeneous ventricular repolarization. Results Seven patients had left ventricular hypertrophy according to the sex-independent criteria; of these, two had arterial hypertension. None of our patients had echocardiographic evidence of diastolic or systolic dysfunction. All patients showed significantly increased myocardial echoreflectivity (Bb = 106.4 ± 12.1 versus 79.3 ± 6.5; dCVF% = 2.78 ± 0.53 versus 1.58 ± 0.29; P

Muir-Torre syndrome (MTS) is an autosomal dominant disorder characterized by the presence of at least one sebaceous gland tumour and a minimum of one visceral malignant tumour. Recently, microsatellite instability (MSI) has been detected in the tumours of patients with MTS and germline mutations of the hMSH2 and hMLH1 mismatch repair genes have been detected in some patients with this syndrome. To determine if the tumours of patients with MTS have widespread genomic instability and whether loss of heterozygosity (LOH) in the chromosomal regions containing hMSH2 and hMLH1 is detectable, MSI and LOH were examined at 10 dinucleotide repeats on chromosomes 2p, 3p, 5q, 9p, 17p and 18q. Data were obtained from six sebaceous gland tumours and two adenocarcinomas of the colon from three patients of two Muir-Torre families. MSI was detected at more than half of the loci tested in all sebaceous tumours examined. In addition, there was LOH at D2S119 in one sebaceoma and one sebaceous carcinoma from one patient. The colon carcinomas from two patients showed MSI at five of the 10 loci analysed. These results show that widespread MSI is a feature of tumours in patients with MTS. In addition, the finding of LOH at D2S119, a marker located in the vicinity of hMSH2, in sebaceous tumours of one patient indicates that this gene may have a pathogenetic role in this patient.

Echocardiographic image texture has been demonstrated to reflect the physical properties of the tissue under examination. To evaluate the role of collagen in determining the echo pattern of the left ventricular wall, we studied nine hypertensive patients with left ventricular hypertrophy (left ventricular mass index > 125 gm/m2) and biopsy-proven different degrees of myocardial fibrosis by analyzing the echocardiographic examinations performed before the biopsy. Myocardial tissue was sampled under fluoroscopy and two-dimensional echo guidance in the interventricular septum. Collagen volume fraction (CVF; normal range up to 2%) was taken as an index of fibrosis. The echo patterns were assessed by analyzing standard two-dimensional parasternal long-axis echocardiograms recorded on videotape. Images were color-coded at 256 levels (0 = yellow, 256 = black) and digitized off-line onto a personal computer. The region of analysis was set using a selection tool (20 x 10 mm) in the general area of septum where the specimen was taken. For each selection a color-level histogram, representing the frequency distribution, was derived with estimates of the average pixel intensity (mCS), skewness (SK), kurtosis (K), and the broad band (Bb) of the echoes about the distribution. Echo-derived parameters in each patient were compared with corresponding CVF values. CVF was out of range in all patients, ranging from 2.6% to 7.6% (mean 4.3% +/- 1.6%). No correlation was found between CVF and mCS, whereas a significant correlation was found at end diastole between CVF and the parameters describing histogram morphology, respectively, SK (r = 0.73), K (r = 0.69), Bb (r = 0.72). These findings for the first time demonstrate in vivo in hypertensive patients with left ventricular hypertrophy an agreement between echo amplitude and histologically assessed collagen volume. Thus in our studied patients collagen content appears to be the major determinant of regional echo intensity, its increase resulting in a significant and progressive wider asymmetrical left shift (yellow) of the color histogram.

We analyzed microsatellite instability (MSI) and loss of heterozygosity (LOH) at 17 microsatellite markers located on chromosomes 2p, 3p, 5q, 6q, 9p, 9q, 17p and 18q in 19 randomly selected keratoacantomas (KAS), in one cutaneous lesion that histologically could not unequivocally be differentiated from squamous cell carcinoma, and in one patient with multiple KAs of longstanding duration. The goals of our study were to determine whether, in a similar manner to some visceral carcinomas, genomic instability could be detected in KAs and to clarify whether molecular analysis might be useful to further characterize KA. MSI was observed in 2 of 21 cases (9.5%) at 5 of 17 loci examined. In one patient with a solitary KA, the presence of MSI and a family history of visceral malignant tumours suggested that the patient might have belonged to a family with Muir-Torre syndrome. In one other MSI+ KA, a definite differential diagnosis in relation to squamous cell carcinoma could not be established. In addition, one sample displayed LOH at 2 of 17 loci analysed whereas in the patient with multiple KAs, LOH at one locus was the only alteration found. In conclusion, the low frequency of MSI and LOH detected in our study suggests that these genetic events are uncommon in KA unless it is associated with a familial disease (e.g. Muir-Torre syndrome) or it has more aggressive histological features.

The origin and the meaning of life on the earth was traditionally attributed to an intelligent creator as an independent act until 1859 when Charles Darwin compiled the book The Origin of Species (Darwin, 1859). In this book Darwin introduced the theory of evolution by natural selection (Figure 1, central panel) opening a new perspective to read what looks like the largest experiment on earth called biological life. This new perspective has proposed a reversal of the traditional view where the intelligence is placed above the experiment by introducing the concept of transformation or evolution (Dennett, 2009). In this upside down view intelligence is not excluded but, rather, is within the experiment and drives the so called "struggle for life" in a dynamic planet where habitats are continuously destroyed and created.

The Authors illustrate the results derived from a data base of a thoracic and cardiovascular Department, comprehensive of 1001 patients (464 M and 537 F, average age 71, minimum age 18 and maximum age 101). The conducted analysis results in several considerations: the cause of patient's hospitalization was not relevant to the direct expertise of the Department in the 27,5% of the cases and the profile of the typical-patient is of an elderly person (73% of the cases over 65 years old), basically overweight or obese (35% of the cases with BMI25) and with medium-low cultural level (70% of the cases not over middle school); moreover our patients, although under poly-therapy before hospitalization, were discharged with a number of prescribed medicines even more plentiful. The data base of the Department proved to be a useful tool both to instantaneously monitor the departmental activity and also to rationalize the pharmacological therapies.

Heart rate variability (HRV) is the temporal beat-to-beat variation in successive RR intervals on an electrocardiographic (ECG) recording and it reflects the regulation of the heart rate (HR) by the autonomic nervous system (ANS). HRV analysis is a noninvasive tool for the assessment of autonomic function that gained momentum in the late 1980s when its clinical relevance as a predictor of mortality was established by a milestone study by Kleiger et al. in patients with postacute myocardial infarction. In the last few decades, the increasing availability of commercial ECG devices offering HRV analysis has made HRV a favorite marker for risk stratification in the setting of cardiovascular disease. The rapid aging of the world population and the growing popularity of HRV have also fueled interest for the prognostic value of HRV in the elderly, outside a specific cardiological context. However, the discussion of HRV measures in the elderly is still very much centered on the rather reductionistic model of sympathovagal balance, with the orthosympathetic and parasympathetic limbs of the ANS exercising opposing effects on the heart via autonomic tone. The expanding application of nonlinear dynamics to medicine has brought to the forefront the notion of system complexity, embedded in the mathematical concepts of chaos theory and fractals, and provides an opportunity to suggest a broader interpretation for the prognostic significance of HRV, especially in the elderly. Although the use of novel indices of HRV may be hampered by practical issues, a more holistic approach to HRV may still be safeguarded if traditional time- and frequency-domain measures are viewed in terms of autonomic modulation. This review focuses on HRV in geriatric populations. It considers studies on the prognostic value of HRV in elderly subjects, discussing the potential confounding effect of erratic rhythm, and concentrates on the conceptual distinction between autonomic tone and autonomic modulation. It also briefly addresses the question of the practicality of ECG recordings and identifies a promising area for future research in the effects of common noncardioactive drugs on HRV.

Inferior acute myocardial infarction (IAMI) is often associated with right ventricle involvement (RVAMI). Echocardiogram (Echo) shows the ischemic involvement of the right ventricle with an initial dilatation (RVD) and segmental cinetic abnormalities (RVSCS). During RVAMI the normal convexity of the interatrial septum (IAS) toward right atrium is inverted (IASI). 53 patients with IAMI were studied with ECG, echo and hemodinamic monitoring by a Swan-Ganz catheter. Echo was early performed and patients were subdivided into three groups: 1. IAMI with RVSCS and/or RVD with IASI (12 patients); 2. IAMI with RVSCS and/or RVD without IASI (8 patients); 3. IAMI without VSCS, RVD IASI (33 patients). ECG showed RV involvement only in A and B groups (ST-T segment elevation more than 2 mm in V3 r - V5 r). Echo-Doppler showed no statistically differences between the two groups on RV protodiastolic pression; no hemodinamic differences between the two groups (p = n.s.); no statistically differences in central venous pressure, right ventricular pressure, cardiac output, wedge pressure. Complications (arrhytmias, heart failure, ipotension, pericarditis, 3rd A-V block) were so subdivided: group A: 6 patients (50%); group B: 2 patients (24%); group C: 4 patients (12%) with statistical significance (p0.03) between all three groups. Coronarography showed that in group A significative lesions were localized in the proximal tract of the right coronary and/or in the proximal tract of the circumflex coronary; on the contrary in B and C groups the lesions were localized in medium and distal tract of the two vessels. Mortality at six months was 41 % in group A (5 patients); 20 % in group B (2 patients); 6 % in group C (2 patients), with p0.01 between all three groups. Echo after six months showed IASI only in two patients of group A. Patients with IASI revealed complications (residual angina, ventricular ipercinetic arrytmias).IASI in patients with IAMI and RVAMI seems to identify a group with higher risk in developing complications and with a more adverse prognosis.

The normal cell is confined by its genetic program to a rather narrow range of morphofunctional characteristics within which it is nevertheless able to handle normal physiological demands (Kumar et al., 2011). A single cell, placed in an appropriate environment, contains, enclosed in its genome, sufficient information to generate a variety of differentiated cell types, whose spatial and temporal dynamics interact to form detailed morphological patterns (Geard and Wiles, 2005). Similarly, in multicellular organisms, it is the genetic program that establishes networks basics -including differentiation, functional hierarchy and interaction patternswith each level in the system representing an increase in organizational complexity. Indeed the emergence from a single or few stem cells of multicellular organisms with a complex organization must be seen as a necessity in evolution since it alone can ensure an optimal use of resources (Furusawa and Kaneko, 2000). From such evolutionary perspective, the development of a cardiovascular system in complex organisms fulfills the need for transport of nourishment, oxygen and metabolic waste as well as the need for communication between distant districts. All closed biological systems facing the external environment, whatever their level of complexity, are characterized by the ability to maintain a stable, constant condition by regulating themselves and the internal environment. In the early 19th century Cannon (Cannon, 1926) defined this property “homeostasis”, from the Greek: ὅμοιο┪, homoios, "similar" and ┫┬ά┫ι┪, stasis, "standing still". This condition of relative equilibrium grants the biological system a certain degree of independence from the environment and enables what we call life. Any change, either decremental or incremental, in the internal/external environment of the cell/organism such that it requires an active response from the cell/organism can be termed demand. In the case of complex organisms demands are met by the functional reserve of the cell/tissue/organ. The functional reserve is involved in the process of adaptation by which a cell/organism acquires morphofunctional features that allow it to better fit in with the changed environment and thus attain a new equilibrium (Figure 1). Adaptation is driven by the genetic program, via the activation of appropriate subsets of genes, and is influenced by the qualitative and quantitative characteristics of the demand such as its nature, intensity and duration. Adaptation can be considered to include both plasticity and adaptability. Plasticity is

Mavrilimumab is a fully human monoclonal antibody that binds to granulocyte-macrophage colony stimulating factor receptor α (GM-CSFRα) with high affinity and specificity and has potential application in various inflammatory diseases. The objective of this investigation was to develop a mechanistic population model to characterize the pharmacokinetics of mavrilimumab, the GM-CSFRα-mediated clearance, and receptor occupancy following single intravenous dosing to patients with rheumatoid arthritis. The internalization rate of mavrilimumab-GM-CSFRα complex was fixed to a value determined from quantitative confocal fluorescent imaging. The estimated typical first-order clearance and the central and peripheral distribution volumes were 3.79 mL/kg/d, 39.6 mL/kg, and 50.3 mL/kg, respectively. The systemic GM-CSFRα expression level was estimated to be 0.0782 nM, and the equilibrium dissociation constant (0.103 nM) was in good agreement with the monovalent affinity determined by surface plasmon resonance. By fitting to the observed pharmacokinetic data, the mechanistic model predicted that systemically greater than 90% GM-CSFRα blockade by mavrilimumab was achieved and maintained up to 4, 7, and 11 weeks following single 1-, 3-, and 10-mg/kg administrations, respectively. Posterior visual predictive check and bootstrapping suggest that the mechanistic model is reasonably robust and can be used to predict mavrilimumab exposure under various scenarios for future clinical trial design.

A 40-year-old man with amyotrophic lateral sclerosis undergoing home non-invasive ventilation, with no risk factors for coronary artery disease, was admitted with bilateral lung infiltrates. Given the lack of a favorable clinical response, transfer to our department was scheduled. During ambulance transport the patient experienced chest discomfort. Upon arrival at our department, a diagnosis of tako-tsubo syndrome was made. In this report, the clinical aspects are taken as a basis to highlight differences with common available findings, and an international registry is proposed to help piece together fractional information present in the literature.

The purpose of this experiment was to study the impact of simulated microgravity and of chronic removal of hydrostatic pressure gradients on blood pressure maturation and body growth in rats. A special device was developed in our laboratory to transfer prolonged "dry" water immersion (a technique that has been used for training astronauts under hypogravic conditions) to six Sprague-Dawley test rats (immersion-G group). The time course of heart rate, systolic blood pressure, urinary output, and body weight was monitored from weaning to maturity and then compared with those responses from six sex- and age-matched Sprague-Dawley rats grown in a gravity environment (group G). A downward shift in systolic blood pressure and body weight maturation curves was observed in immersion-G rats from the age of 60 days. Cessation of dry water immersion produced a gradual, significant rise in systolic blood pressure but not in body weight to control values. No marked changes in heart rate and urinary output between G and immersion-G rats were noticed throughout the investigation. Our results provide indirect evidence that an interference in the natural history of blood pressure maturation was introduced by immersion, which dissociated the effects of body weight increase during growth from the effects of ageing per se. It is concluded that the physiological increase in systolic blood pressure during growth is partly gravity-dependent.

Objective To compare the effects of the angiotensin II receptor antagonist candesartan with the angiotensin-converting enzyme inhibitor enalapril on myocardial fibrosis evaluated by echoreflectivity analysis. Methods Hypertensive patients (n = 196) with echocardigraphically documented left ventricular hypertrophy were randomized to candesartan 8-16 mg/day (n = 91) or enalapril 10-20 mg/day (n = 105) with possible addition of hydrochlorothiazide (12.5-25 mg/day) for 48 weeks. Echoreflectivity analysis was performed on ultrasound two-dimensional tracings of the midapex septum with a specifically designed and validated software. Colour histograms were obtained; the primary outcome variable was the treatment-related change in histogram width (broadband), previously shown to correlate with collagen volume on endomyocardial biopsy; changes in mean colour scale were secondary outcome variable. Results Echoreflectivity analysis was feasible in 84 patients (48 candesartan, 36 enalapril). Broadband decreased significantly in the candesartan (-8.0 colour levels) and in the enalapril group (-12.9 colour levels) with no significant difference between treatments (P = 0.409); no significant changes occurred in mean colour scale. Patients under monotherapy (n = 46) showed similar trends as the larger intention to treat cohort, without significant difference between treatments. Conclusion In hypertensive patients with left ventricular hypertrophy, both candesartan and enalapril induce a moderate but statistically significant reduction in an echoreflectivity index of myocardial fibrosis.

Background Bone Marrow (BM) progenitor cells can target the site of myocardial injury, contributing to tissue repair by neovascolarization and/or by a possible direct paracrine effect on the inflammatory cascade. Angiotensin Converting Enzyme inhibitors (ACE-I) are effective in reducing mortality and preventing left ventricular (LV) function deterioration after myocardial infarction. Methods We investigated the short term effects of BM mononuclear cells (BMMNCs) therapy on the pro-inflammatory cytokines (pro-CKs) and on LV remodelling and compared these effects over a standard ACE-I therapy in a rat model of myocardial cryodamage. Forty two adult inbread Fisher-F344 rats were randomized into three groups: untreated (UT; n = 12), pharmacological therapy (ACE-I; n = 14, receiving quinapril), and cellular therapy (BMMNCs; n = 16, receiving BMMNCs infusion). Rats underwent to a standard echocardiogram in the acute setting and 14 days after the damage, before the sacrifice. Pro-CKs analysis (interleukin (IL)1β, IL-6, tumor necrosis factor (TNF)α was performed (multiplex proteome arrays) on blood samples obtained by direct aorta puncture before the sacrifice; a control group of 6 rats was considered as reference. Results Concerning the extension of the infarcted area as well as the LV dimensions, no differences were observed among the animal groups; treated rats had lower left atrial diameters and higher indexes of LV function. Pro-Cks were increased in infarcted-UT rats if compared with controls, and significantly reduced by BMMNCs and ACE-I ; TNFα inversely correlated with LV fractional shortening. Conclusion After myocardial infarction, both BMMNCs and ACE-I reduce the pattern of pro-Ck response, probably contributing to prevent the deterioration of LV function observed in UT rats.

Background Circulating Endothelial Precursors (PB-EPCs) are involved in the maintenance of the endothelial compartment being promptly mobilized after injuries of the vascular endothelium, but the effects of a brief normobaric hypoxia on PB-EPCs in healthy subjects are scarcely studied. Methods Clinical and molecular parameters were investigated in healthy subjects (n = 8) in basal conditions (T0) and after 1 h of normobaric hypoxia (T1), with Inspiratory Fraction of Oxygen set at 11.2% simulating 4850 mt of altitude. Blood samples were obtained at T0 and T1, as well as 7 days after hypoxia (T2). Results In all studied subjects we observed a prompt and significant increase in PB-EPCs, with a return to basal value at T2. The induction of hypoxia was confirmed by Alveolar Oxygen Partial Pressure (PAO2) and Spot Oxygen Saturation decreases. Heart rate increased, but arterial pressure and respiratory response were unaffected. The change in PB-EPCs percent from T0 to T1 was inversely related to PAO2 at T1. Rapid (T1) increases in serum levels of hepatocyte growth factor and erythropoietin, as well as in cellular PB-EPCs-expression of Hypoxia Inducible Factor-1α were observed. Conclusion In conclusion, the endothelial compartment seems quite responsive to standardized brief hypoxia, possibly important for PB-EPCs activation and recruitment.

In view of a potential clinical use we aimed this study to assess the selective homing to the injured myocardium and the definitive fate of peripherally injected labeled and previously cryopreserved Bone Marrow Mononuclear cells (BMMNCs). The myocardial damage (cryoinjury) was produced in 59 rats (45 treated, 14 controls). From 51 donor rats 4.4 x 10(9) BMMNCs were isolated and cryopreserved (slow-cooling protocols); the number of CD34+ and the viability of pooled cells was assessed by flow-cytometry analysis before and after cryopreservation and simulated delivery through a 23G needle. Seven days after injury, BMMNCs were thawed, labeled with PKH26 dye and peripherally injected (20 x 10(6) cells in 500 microl) in recipient rats. Two weeks after experimental injury, the heart, lungs, liver, kidneys, spleen and thymus were harvested to track transplanted cells. Except a small amount in the spleen, PKH26+ cells were found only in the infarcted myocardium of the treated animals. Typical vascular structures CD34+ were found in the infarcted areas of all animals; treated rats showed a significantly higher number of these structures if compared with untreated. Morphological ultra-structural examination of infarcted areas confirmed in treated rats the presence of early-stage PKH26+ vascular structures derived from injected BMMNCs. The estimated mean CD34+ cells loss due to the cryopreservation procedure and to the system of delivery was 0.24% and 0.1%, respectively, confirming the feasibility of the procedure. This study supports the possible therapeutic use of cryopreserved peripherally injecetd BMMNCs as a source of CD34+ independent vascular structures following myocardial damage.

The definitive fate of peripherally injected PKH26 labelled bone marrow mononuclear cells expressing the CD34+ antigen following experimental myocardial cryodamage in rats (n=10) has been examined by direct visualization on photoconverted light and electron microscopy images. One week after the injection in each rat of about 150,000 CD34+ cells early stage PKH26+ vascular structures were localized in the infarcted areas, suggesting that a potential benefit of this therapeutic approach consists in the regeneration of the vasculature.

The majority of clinical studies on endothelial progenitor cells (EPCs) focuses on the role of these cells in cardiovascular diseases and no systematic studies exist regarding their variations in healthy subjects. In order to define the burden of angiogenesis in physiological conditions we assessed the frequency of peripheral blood endothelial colonies (PB-ECs) and their relation with other factors possibly involved in their function such as high-sensitivity C-reactive protein (hs-CRP), endothelial cell-specific mitogen factor (VEGF) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in a highly selected healthy population. A PB sample was obtained from 37/47 healthy subjects (age 40.2+/-15.0yrs; M/F 15/22) without known cardiovascular risk factors. The serum level of hs-CRP, VEGF, TIMP-1, the frequency of PB-ECs by clonogenic assay, and the number of early EPCs and late EPCs by flow cytometry analysis were evaluated. PB-ECs were formed by 40.5% of studied subjects with a mean of 0.40+/-0.82 colonies/10(6) cells. The differences in the frequency of colony formation between genders were not statistically significant. The subjects with PB-ECs were characterized by higher values of hs-CRP, when compared with those not forming colonies, 0.276+/-0.230 vs 0.095+/-0.077 mg/l (p=0.003) respectively, and of VEGF, 328.3+/-162.9 vs 202.68+/-118.53 pg/ml (p=0.02). No significant differences were found in TIMP-1 values. The EPC clonogenic potential seems to be related to hs-CRP and VEGF levels even in healthy population supporting the concept that these mediators are involved in physiological ECs function.

OBJECTIVE: In the European Lacidipine Study on Atherosclerosis (ELSA), against a similar antihypertensive effect, a significantly greater effect of lacidipine was found on carotid intima-media thickness (IMT) progression, indicating a specific anti-atherosclerotic effect of lacidipine. However, not only the extent but also the composition of an atherosclerotic plaque is a determinant of subsequent events. DESIGN AND METHODS: Among the 2334 patients enrolled in ELSA, 420 with 4-year treatment were chosen, videodensitometric analysis of their ultrasound carotid scan was performed and the maximum wall lesion (Tmax) was classified as lipidic, fibrolipidic and fibrotic by means of software previously validated against histology. Of the 420 patients, 244 had scans suitable for videodensitometry. RESULTS: Excellent reproducibility of videodensitometry analysis was found using the Bland-Altman and other methods. At baseline, ELSA hypertensive patients had predominantly fibrolipidic walls (70%), with an echoreflectivity indicating a mean collagen content of 25%. After 4 years of antihypertensive treatment, little change in the frequency distribution of carotid lesions (fibrolipidic 73%) was found, with no significant differences between patients randomized to lacidipine or atenolol. CONCLUSIONS: Our study provides previously unavailable information that carotid wall composition changes to an extremely small extent during 4-year effective blood pressure lowering. With lacidipine, stable composition is associated with a lower IMT progression than with atenolol.