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To evaluate the long-term effect of simultaneous treatment of hypertension and hypercholesterolemia with angiotensin-converting enzyme (ACE) inhibitors and statins on the incidence of major cardiovascular events (MACE) and other clinical outcomes.We considered data from a subset of Brisighella Heart Study (BHS) participants who were consecutively evaluated in three epidemiological surveys between 2012 and 2020. We excluded normotensive subjects and individuals with a low calculated 10-year CVD risk, hypertensive patients treated with antihypertensive drugs different from ACE inhibitors and patients who changed antihypertensive medications during follow-up. The remaining participants were divided into four groups depending on whether they were treated with (I) perindopril ± amlodipine without statin treatment (N. 132), (II) perindopril ± amlodipine and atorvastatin (N. 132), (III) an ACE inhibitor other than perindopril ± a calcium-channel blocker without statin therapy (N. 133), (IV) an ACE inhibitor other than perindopril ± a calcium-channel blocker and statin therapy (N. 145). The long-term (8 years) effects of the different combined treatment were compared among the pre-defined groups. Over the follow-up period of 8 years, the proportion of subjects who developed MACE, type 2 diabetes mellitus and hyperuricemia, and the proportion of subjects needing for the intensification of antihypertensive treatment to improve blood pressure control were statistically different among the predefined groups (P 0.05).Combined treatment with ACE inhibitors and statins (especially atorvastatin) in hypertensive patients seems to significantly reduce the risk of developing CVD in comparison with treatment with ACE inhibitors alone.

Objective: Sensory deficits are important risk factors for delirium but have been investigated in single-center studies and single clinical settings. This multicenter study aims to evaluate the association between hearing and visual impairment or bi-sensory impairment (visual and hearing impairment) and delirium. Design: Cross-sectional study nested in the 2017 "Delirium Day" project. Setting and participants: Patients 65 years and older admitted to acute hospital medical wards, emergency departments, rehabilitation wards, nursing homes, and hospices in Italy. Methods: Delirium was assessed with the 4AT (a short tool for delirium assessment) and sensory deficits with a clinical evaluation. We assessed the association between delirium, hearing and visual impairment in multivariable logistic regression models, adjusting for: Model 1, we included predisposing factors for delirium (ie, dementia, weight loss and autonomy in the activities of daily living); Model 2, we added to Model 1 variables, which could be considered precipitating factors for delirium (ie, psychoactive drugs and urinary catheters). Results: A total of 3038 patients were included; delirium prevalence was 25%. Patients with delirium had a higher prevalence of hearing impairment (30.5% vs 18%; P < .001), visual impairment (24.2% vs 15.7%; P < .01) and bi-sensory impairment (16.2% vs 7.5%) compared with those without delirium. In the multivariable logistic regression analysis, the presence of bi-sensory impairment was associated with delirium in Model 1 [odds ratio (OR) 1.5, confidence interval (CI) 1.2-2.1; P = .00] and in Model 2 (OR 1.4; CI 1.1-1.9; P = .02), whereas the presence of visual and hearing impairment alone was not associated with delirium either in Model 1 (OR 0.8; CI 0.6-1.2, P = .36; OR 1.1; CI 0.8-1.4; P = .42) or in Model 2 (OR 0.8, CI 0.6-1.2, P = .27; OR 1.1, CI 0.8-1.4, P = .63). Conclusions and implications: Our findings support the importance of routine screening and specific interventions by a multidisciplinary team to implement optimal management of sensory impairments and hence prevention and the management of the patients with delirium.

BACKGROUND Children with cerebral palsy (CP) often present a loss of effectiveness of the plantarflexors/knee-extensors couple that leads to crouch gait. When treating a child with crouch gait by means of ankle foot orthoses, preserving or restoring push off power is a key issue. AIM To compare carbon-fiber spring (Carbon Ankle Seven® [CAFO], Ottobock® HealthCare, Duderstadt, Germany) and hinged ankle-foot orthoses (HAFO) effectiveness in improving functionality and walking ability in children with diplegic CP and crouch gait. DESIGN Randomized crossover trial. SETTING Hospital center. POPULATION Ten children with diplegic CP and crouch gait, 5 males and 5 females, aged 11 (4) years. METHODS The gait of each child was evaluated by means of instrumental gait analysis with both CAFO and HAFO, in a randomized order and after a 4-week adaptation period. The primary outcome measure was the change in ankle power generation. As secondary outcome measures, knee joint kinematics, stride length, walking speed, Observational Gait Scale, and preferred orthosis were considered. RESULTS The median of the energy produced in stance was superior with CAFO (+2.2 J/kg, IQR 4.7, P=0.006), and the energy absorbed inferior (-3.3 J/kg, IQR 4.3, P=0.011). No statistically significant difference was found for any other parameter. Preference of the children was equally distributed between the two orthoses. CONCLUSIONS No evident superiority of CAFO with respect to HAFO was found in improving gait performance of children with CP and crouch gait. Nevertheless, the results suggest the possibility that CAFO permits an energy saving and reduction of the more compromising deficits. CLINICAL REHABILITATION IMPACT The final choice of the participants indicates that CAFOs are preferred by older and heavier children, but the preference does not correlate with the performance of the orthoses during gait.

Every year 0.5-2% of women undergo non-obstetric surgery in pregnancy. Hypoxic events with short-term and long-term consequences are one of the most frequent complications in surgery. There is only limited data available regarding the impact of these events. This review aims to analyze the current literature on hypoxic events occurring in non-obstetric abdominal surgery in pregnant women, focused on maternal and fetal outcomes.We performed a non-systematic review of the literature, through a PubMed search using the key words "hypoxemia", "non-obstetric surgery", "surgical procedures", "pregnancy", "pregnant women" and "outcome".There is little data available regarding maternal and fetal outcomes after hypoxic episodes during non-obstetric surgery in pregnancy. In these cases, conservative intrauterine resuscitation maneuvers or immediate delivery should be taken into account. Perimortem cesarean section can be lifesaving for both mother and fetus when maternal collapse is non responsive to resuscitation procedures. Inaccurate information regarding maternal and fetal outcomes is due to the lack of robust data and the heterogeneity of the causes underlying maternal respiratory complications during surgery.Non-obstetric surgery during pregnancy must be performed when indicated. An expert multidisciplinary team, composed of obstetricians, surgeons, and anesthesiologists need to be included, giving appropriate attention to the physiological changes of respiratory, cardiovascular, and gastrointestinal system that occur during pregnancy. The shortest operative time and peri-operative assistance should be ensured. Complications, such as hypoxic events in pregnant patients need adequate assistance. Multidisciplinary cooperation, continuous training and simulation for anesthesiology and resuscitative procedures can guarantee this.

Summary Background Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.

Diplegia is a specific subcategory of the wide spectrum of motion disorders gathered under the name of cerebral palsy. Recent works proposed to use gait analysis for diplegia classification paving the way for automated analysis. A clinically established gait-based classification system divides diplegic patients into 4 main forms, each one associated with a peculiar walking pattern. In this work, we apply two different deep learning techniques, namely, multilayer perceptron and recurrent neural networks, to automatically classify children into the 4 clinical forms. For the analysis, we used a dataset comprising gait data of 174 patients collected by means of an optoelectronic system. The measurements describing walking patterns have been processed to extract 27 angular parameters and then used to train both kinds of neural networks. Classification results are comparable with those provided by experts in 3 out of 4 forms.

Endometrial cancer (EC) is a complex gynecological neoplasm with several clinical, histopathological and genetic features. Different hormonal, metabolic and biochemical axes are involved in pathogenesis. Obesity is a well-known risk factor for this disease and the role of local and systemic effects of adipose tissue, especially in the promotion of subclinical chronic inflammation, is an important issue. Indeed, inflammation is related to the pathogenesis of different tumors, including EC. This review aims to remark the role of obesity and inflammation in the pathogenesis of EC cancer through an exploration of the current literature.We performed a comprehensive review of the literature through a PubMed search using key words and including English language papers looking at this topic.Only few authors analyzed the role of inflammatory cytokines released by adipose tissue in visceral abdominal fat depots. Tumor Necrosis Factor-α, Interleukin-6, Interleukin-1 Receptor Antagonist, Nuclear Factor-kB, Leptin, Adiponectin and C Reactive Protein were studied for cancer risk prediction models, risk stratification or targeted therapies. Furthermore, genetic studies evaluated the effect of inflammatory cytokines secreted by visceral adipocytes in the modulation of angiogenesis and signaling pathways such as PI3K/AKT/mTOR, that result altered in the pathogenesis of EC.The identification of inflammatory biomarkers released by adipose tissue, in the pathogenesis of EC, could be useful in improving diagnostic accuracy, identifying targets of therapy, suggesting useful lifestyle behaviors. A deeper knowledge of the genetic background of alterations in inflammatory pathway genes could better define the population exposed to a higher susceptibility to EC due to genetic polymorphisms. Future studies are needed to better understand this field.

Background: The prevalence of senile dementia is increasing worldwide, especially in the developed countries. Nevertheless, drug therapy isn’t often enough to treat this condition. Researchers are evaluating the possible impact of a preventive approach, based on an improvement of lifestyle and the intake of micronutrients. Moreover, there is an increasing interest for combined nutraceuticals that can act as memory and learning enhancers, with a significant and beneficial potential on the cognitive disorders. Objective: To evaluate the effects of a rational assemblage of nutraceuticals on cognitive functions in a sample of 30 elderly subjects. Design: Double bind, cross-over designed trial versus placebo Setting: outpatient clinical practice Participants: 30 elderly subjects with basal Mini-Mental State Examination score between 20 and 27 and self-perceived cognitive decline. Intervention: Treatment with a combination of nutraceuticals based on Bacopa monnieri, L-theanine, Crocus sativus, copper, folate and vitamins of B and D group. After2 months of treatment or placebo. Measurements: Patients were evaluated with Mini-Mental State Examination (MMSE), Perceived Stress Questionnaire (PSQ) and Index and Self-Rating Depression Scale (SRDS). Results: MMSE and PSQ Index significantly improved in the active treatment arm, both versus baseline and versus the parallel arm. Both groups experienced a significant improving in the SRDS scores. Conclusions: We obtained a good and significant improvement of the cognitive functions tested with the MMSE, PSQ-Index and SRDS score, after 2 months of combined therapy of nutraceuticals. Further confirmation will be needed to verify these observations on the middle and long term in a larger number of subjects.

Objective: In this study anxiety and depressive disorders were evaluated in patients admitted to an emergency department (ED) or to a medical department (MD). Methods: The General Health Questionnaire-30 (GHQ-30) was administered to screen all patients (n = 719) consecutively admitted to an ED (n = 556) and to MD (n = 163) in a 120 day period. All GHQ-30 positive (score>4) underwent the Mini International Neuropsychiatric Interview, a structured interview to diagnose mental disorders according to DSM-IV criteria. Results: Subjects positive to GHQ-30 were 264 (47%) in ED and 88 (54%) in MD. A mental disorder was diagnosed in 233 ED patients (42%) and in 77 MD patients (47%) (p = 0.70). The most frequent disorders were anxiety disorders in ED patients (18.1%) and depressive disorders in MD patients (21%) (p = 0.04). Conclusions: Anxious patients more frequently seek attention at ED, whereas patients with depressive disorders are more often observed in medical units. The improvement of quality of care, the waste of healthcare resources through unnecessary medical care, and the well known efficacy of appropriate treatments in patients with anxiety and depressive disorders make the diagnosis of these patients particularly important.

The sensitivity of the IRMA method is limited by the specific activity (SA) of the conventionally employed radioisotropic label and high sensitivity radioimmunoassay should theoretically be attained by the use of short-lived radiometallic nuclides. Our group have achieved radiolabeling of high SA IgG by using the radiometal, gallium-67 (67Ga) with a short half-life (T1/2 = 78 h) and deferoxamine (DF), a bifunctional chelating agent bound through a multispacer (dialdehyde starch, DAS) as the linker (J Nucl Med 32:825, 1991). In the present work, the application of the approach is attempted by employing a two-site IRMA for human growth hormone (hGH); the monoclonal antibody to hGH (MAB2) is bound to DF via DAS and the coupled DF-DAS-MAB2 is radiolabeled with 67Ga. The 67Ga-DF-DAS-MAB2 of high SA (4,884 MBq/mg versus 370-518 MBq/mg calculated for radioiodinated MAB2) was thus used for the two site 'sandwich' 67Ga-IRMA. Excellent correlation with the 125I-IRMA was registered, and higher detection capability obtained by using 67Ga over the 125I in the hGH IRMA offered a good basis for the exploitation of short-lived radio-nuclides in the IRMA system.

Background: Sex hormones and adipokines seem to differently interact in both genders at different ages. Aim: To comparatively evaluate the serum level of adipokines and sex hormones in healthy non-pharmacologically treated premenopausal women, post-menopausal women, and elderly women, and in age-matched men. Subjects: From the historical cohort of the Brisighella Heart Study we selected 199 adult healthy subjects (males: 89; females: 110), aged 62.5 +/- 12.4 yr. Men and women included in the age-class subgroups were matched for body mass index (BMI), waist circumference, blood pressure, heart rate, fasting plasma glucose, plasma lipids. Results: Leptin did not differ among various age classes in men, while pre-menopausal women displayed significantly lower serum leptin than post-menopausal women (-6.7 +/- 2.2 pg/ml, p=0.036). Post-menopausal women had significantly greater serum leptin when compared with age-matched men (+13.1 +/- 2.0 pg/ml, p

The lack of a correct diagnostic and therapeutic planning of vestibular diseases is still often observed, and some difficulties are still to deal with in clinical practice, even when treating acute hearing problems, although the needed competence is more easily identified as otologic. A review of the international literature confirms the existence of such a problem, and permits to underline the scarcity of connections between otology and neurotology, on one hand, and principles of basic sciences and general and internal medicine, on the other hand: this can explain some therapeutic contradictions in treating inner ear disorders, their frequent labelling as idiopathic and the persisting uncertainties concerning a correct diagnostic and therapeutic management. In order to overcome the difficulties deriving to insufficient interdisciplinary cooperation, the institution of hospital audiovestibular services with a strictly linked net of cooperation with internal medicine units could represent a progress. This could help prevent clinically and economically inadequate management, contributing to minimize the possibility of expensive and/or health-threatening mistakes; moreover, it could represent an example to easily improve the practical aspects of both pre graduate and postgraduate curricula, and to form more open-minded clinicians, starting both from an ear. Nose and throat (ENT)/audiological and from an Internal Medicine extraction.

This work is aimed at comparing mucinous colorectal adenocarcinomas (MUC) and non-mucinous colorectal adenocarcinomas (non-MUC), and at verifying the existence of two different subgroups of MUC, in terms of clinicopathological features, chromosomal alterations, and outcome, in a geographical area where mucinous colorectal cancer resulted as being very frequent. One hundred and fifty-six unselected patients who underwent curative colorectal resection for sporadic colorectal cancer over a 4-year period were evaluated for histological classification as to MUC and non-MUC subtype, for microsatellite instability (MSI) using six microsatellite markers, and for the presence of p27, Fhit, and cyclooxygenase-2 (Cox-2). Molecular data, immunohistochemical results, recurrence frequency, and patient survival were analyzed statistically in relation to histological subtypes. MUC accounted for 38.5% of all colorectal carcinomas. Compared to non-MUCs, MUCs were more frequently located in the proximal colon (p

The introduction of perfluoro-based contrast agents such as SonoVue together with sensitive realtime scanning modes such as cadence contrast pulse sequences (CPS) have made possible significant advances in the management of patients with pathology affecting large vessels. This has been particularly valuable in aortic graft procedures where the lack of nephrotoxicity allows multiple repeat studies for follow-up of leaks. It has also proved valuable in situations where the flow is very slow and undetectable on conventional Doppler

We sought to investigate the effect of angiotensin-converting enzyme (ACE) inhibition9 h after myocardial infarction (MI) on left ventricular (LV) dilation in patients receiving thrombolysis.The ACE inhibitors reduce mortality after MI. Attenuation of LV dilation has been suggested as an important mechanism.The data of 845 patients with three-month echocardiographic follow-up after MI were combined from three randomized, double-blind, placebo-controlled studies. The criteria for these studies included: 1) thrombolytic therapy; 2) ACE inhibition within 6 to 9 h; and 3) evaluation of LV dilation as the primary objective.The ACE inhibitor was started 3.2+/-1.7 h after the patients' first (mainly, 85%) anterior MI. After three months, LV dilation was not significantly attenuated by very early treatment with an ACE inhibitor. The diastolic volume index was attenuated by 0.5 ml/m2 (95% confidence interval [CI] -1.5 to 2.5, p = 0.61), and the systolic volume index by 0.5 ml/m2 (95% CI -1.0 to 1.9, p = 0.50). Subgroup analysis demonstrated that LV dilation was significantly attenuated by ACE inhibitor treatment for patients in whom reperfusion failed. In contrast, LV dilation was almost unaffected by ACE inhibitor treatment in successfully reperfused patients.We could not demonstrate attenuation of LV dilation in patients receiving thrombolysis by ACE inhibitor treatment within 6 to 9 h after MI. We speculate that very early treatment with an ACE inhibitor has a beneficial effect on LV remodeling only in patients in whom reperfusion failed. Other mechanisms may be responsible for the beneficial effects of ACE inhibitors in successfully reperfused patients after MI.

A positive history of arterial hypertension (HBP) is present in as many as 30% of patients with acute myocardial infarction (AMI) and their clinical outcome could be greatly improved by drugs enhancing blood pressure control and preserving ventricular function. The aim of the present study was to evaluate the importance of a history of HBP on the clinical efficacy of early treatment with the angiotensin-converting enzyme (ACE) inhibitor zofenopril in patients with anterior AMI. We summarize the results of a post-hoc analysis of data from the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study, which randomly evaluated the efficacy of zofenopril given within 24 h of symptom onset to patients with anterior AMI not undergoing thrombolysis. Of 1441 patients who entered the study, 565 (39.2%) had a history of HBP. The mean follow-up time was 12 months and the main outcome measures were 6-week combined occurrence of death and severe congestive heart failure (CHF) and 1-year mortality. After 6-week of treatment with zofenopril the relative risk of death or severe CHF was 0.60 (95% confidence interval [CI]: 0.45-0.81; 2P.05) in the hypertensive group and 0.89 (0.74-1.08; 2P = .62) for normotensive patients, whereas the 1-year risk of death was 0.61 (95% CI: 0.23,0.89; 2P.05) and 0.77 (95% CI: 0.52-1.17; 2P = .22), respectively. The 6-week prevalence of mild-to-moderate CHF was also significantly reduced by zofenopril in the hypertensive population (14.1% v 9.4%; 2P.05). The present data suggest that treatment with zofenopril started within 24 h of the onset of anterior AMI could be highly beneficial in patients with a history of HBP.

The FAMIS (Fosinopril in Acute Myocardial Infarction Study) was a multicenter, placebo-controlled, double-blind trial designed to evaluate the safety and the efficacy of fosinopril in reducing left ventricular enlargement after acute anterior myocardial infarction. We evaluated the echocardiographic examinations performed during the trial in order to assess the trend of the remodeling process over time and to evaluate the role of infarct size in identifying patients at risk of progressive left ventricular dilation.A complete echocardiographic examination was performed on admission, before discharge and three months later. Patients undergoing coronary bypass surgery or PTCA had a further examination prior to the procedure. The echocardiograms were analyzed at a central laboratory, and the end-diastolic and end-systolic left ventricular volumes were computed by using a modified Simpson's rule technique. Regional wall motion was evaluated using the centerline method, analyzing the left ventricular boundary along 100 chords perpendicular to the centerline constructed midway between the end-diastolic and the end-systolic contours. A quantitative infarct-size index was then computed according to the number of chords with a fractional shortening equal to or less than 5%.Left ventricular end-diastolic and end-systolic volume index significantly increased over time (p0.0001); as a result, the stroke volume increased (p0.0001) but the ejection fraction did not change. Patients were then divided according to the three-month infarct-size index. For both end-diastolic and end-systolic volume, not only did larger infarcts had higher volumes, but there was also a greater increase from baseline to 3 months. Moreover, larger infarcts had a lower ejection fraction, with a further reduction over the three months, while smaller infarcts had higher values and an increase over time. An infarct-size index of 25 or larger allowed prospective identification at the baseline examination of patients at risk of subsequent left ventricular dilation.In conclusion, patients at greatest risk of left ventricular dilation, namely those with larger infarct size, constitute a group that is worth considering for any therapeutic effort for reducing the remodeling process. These patients could in fact benefit from therapeutic strategies aimed at the reduction of left ventricular remodeling and should be studied in clinical trials.

Hormone replacement therapy (HRT) in post-menopausal or ovariectomized women reduces mortality due to cardiovascular diseases, lowers morbidity due to osteoporosis and improves vasovagal symptoms. Long-term therapy, however, increase the risk of side-effects. HRT may decrease mammographic sensitivity, markedly increasing glandular density. Enlargement of pre-existing cysts and fibroadenomas has also been reported after HRT. The correlation between HRT and breast cancer is highly controversial. We examined 650 women: 550 of them (84.6%) received HRT (157 estrogens and 393 estrogens-progestins) and 100 (15.4%) refused treatment and were thus considered as a control group. All patients underwent mammography and DEXA before HRT and, during treatment, were followed-up yearly with mammography, often combined with US, and DEXA. Fisher's test was used for data analysis (confidence interval: 95%). The statistical analysis showed a significant difference between the HRT group and the control group only for the lumbar spine. Mammographic changes (Tab. II) were shown in 150 of 550 HRT patients. Increased breast density was the most frequent finding. Benign lesions arising de novo or increasing in size and/or number were observed in 41 of 150 patients (27.3%) in the HRT group, where 3 breast carcinomas were detected, versus 1 breast cancer only in the control group. HRT had a marked positive effect on bone mineral content (BMC) at 2 years' follow-up, but it remains debated if it reduces breast cancer risk. In conclusion, our results indicate that a yearly mammography is mandatory in long-term HRT subjects and US may be also needed in particularly dense breasts.

Acute myocardial infarction, major cause of death in Western society, has been the focus of many clinical investigations over the past decade. As the result of randomized trials involving hundreds of thousands of infarct patients worldwide, the life-saving potential of several pharmacologic interventions has been validated, and the usefulness of other commonly used treatments has been disproven or brought into question. Much of the innovative therapy has been targeted toward limiting myocardial damage by eradicating the occlusive thrombus or otherwise restoring flow through the infarct-related artery, reducing oxygen demands in the injured ventricle, and altering vascular dynamics to limit the process of ventricular remodeling. Data have accumulated showing substantially lower mortality of acute myocardial infarction with simple pharmacological interventions such as intravenous thrombolytic therapy, aspirin, beta-blockers and ACE-inhibitors. In particular, ACE-inhibitors have recently proven to be effective in infarcted patients, especially in high-risk subjects with acute anterior infarction not treated with thrombolytic agents or patients with left ventricular dysfunction. ACE-inhibitors may limit the process of ventricular remodeling after a large infarction, lessening the risk of sudden death and heart failure. Intravenous heparin has a role in maintaining patency of infarct-related vessel after rt-PA, and it seems that this combination offers some benefits with respect to streptokinase plus subcutaneous heparin. Recent studies have also demonstrated the importance of lipid-lowering agents for secondary prevention after myocardial infarction. Several previously recommended therapies (routine intravenous lidocaine, calcium channel blockers, magnesium, nitrates) have not been proven to be life-saving.

Chronic congestive heart failure (CHF) is a common disease responsible for a high mortality and morbidity whose clinical course can be improved by angiotensin-converting-enzyme (ACE) inhibition. However, limited data are available on the effects of ACE inhibitors on the onset and progression of CHF in patients with acute myocardial infarction (AMI). The present study was performed as a substudy of the Survival of Myocardial Infarction Long-term Evaluation trial and involved 1,146 patients with anterior wall AMI not undergoing thrombolysis with the exclusion of patients with prior history or clinical signs of CHF on admission. Patients were randomly allocated to treatment with zofenopril (7.5 to 30 mg twice daily) or placebo for a cumulative period of 6 weeks. The prevalence of CHF, either mild to moderate or severe, has been the main objective and has been evaluated 6 weeks and 1 year after AMI. The overall prevalence of CHF was not reduced by zofenopril after both 6 weeks and 12 months. Conversely the prevalence of severe CHF (1.6% vs 2.6%: risk reduction 55.5%; 95% confidence interval 9 to 63; p = 0.0325) and the combined occurrence of death or severe CHF (4.8% vs 8.2%: risk reduction 59%; 95% confidence interval 11 to 71; p = 0.024) were reduced after 6 weeks of treatment with zofenopril. Moreover, the percentage of patients experiencing a deterioration to severe CHF after 1 year was significantly reduced with zofenopril (11.0% vs 24.3%; p = 0.001). In conclusion, the early administration of zofenopril to patients with AMI attenuates the progression of the clinical symptoms of CHF and its clinical consequences, suggesting that ACE inhibitors should be regarded as a suitable strategy for the prevention and treatment of CHF in patients with AMI.

The results of the large randomized trials in which antihypertensive drugs have been compared to placebo demonstrated that antihypertensive therapy reduces cardiovascular and cerebrovascular mortality and morbidity. Nowadays, however, it is not enough to lower blood pressure; the goal of the treatment should be to prevent progression of the underlying atherosclerotic disease, reduce major and minor complications and improve survival and quality of life. Furthermore, primary prevention and risk reduction in hypertensives are dependent not only on the antihypertensive effect of the chosen agent, but also on improved detection and management of the other cardiovascular risk factors. The potential ability of antihypertensive treatment to exert an effect on global cardiovascular risk profile has become one of the most important considerations in the selection of an antihypertensive treatment. Thus, in patients at risk for coronary events it seems important to choose a drug or drug combination with a documented effect on coronary events. In addition, both prevention of cardiovascular events and prevention of organ damage and organ disease have to be considered essential goals of antihypertensive therapy. The prevention of organ damage associated with hypertension has also been facilitated by the development of effective antihypertensive drugs. These agents have been shown to have a beneficial influence on organ damage in hypertensive patients through an effective, continuous, smooth control of blood pressure and through specific effects on some of the functional and structural alterations induced by hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

In this review, we evaluate the efficacy of ACE-inhibitors for the treatment of acute myocardial infarction (AMI). Our information is based on published material and personal experience derived from extensive revision of the SMILE study. All trials with a randomized experimental design, irrespective of their primary research objective, have been included. Results are presented in terms of either hemodynamic or clinical benefit. The available evidence indicates that the mortality rate of AMI patients who undergo short- and long-term treatment with ACE-inhibitors is significantly reduced. This reduction is more evident in high risk patients, such as subjects with asymptomatic left ventricular dysfunction, congestive heart failure on admission, anterior location of the infarction. ACE-inhibitors also limit the development and progression of congestive heart failure after myocardial infarction, the onset of clinical manifestations of coronary artery disease (reinfarction, need for revascularization) and the occurrence of ventricular arrhythmias, probably by means of mechanisms involving a specific effect of these compounds. In conclusion, the available data indicate that administration of ACE-inhibitors to patients with AMI is associated with significant clinical benefit.

Left ventricular dilatation and neuroendocrine activation are common after acute anterior myocardial infarction. Long-term treatment with an angiotensin-converting-enzyme (ACE) inhibitor may improve outcome by attenuating these processes. We investigated whether the ACE inhibitor zofenopril, administered for six weeks after anterior myocardial infarction, could improve both short-term and long-term outcome.A total of 1556 patients were enrolled within 24 hours after the onset of symptoms of acute anterior myocardial infarction, and they were randomly assigned in a double-blind fashion to receive either placebo (784 patients) or zofenopril (772 patients) for six weeks. At this time we assessed the incidence of death or severe congestive heart failure. The patients were reexamined after one year to assess survival.The incidence of death or severe congestive heart failure at six weeks was significantly reduced in the zofenopril group (55 patients, 7.1 percent), as compared with the placebo group (83 patients, 10.6 percent); the cumulative reduction in the risk of death or severe congestive heart failure was 34 percent (95 percent confidence interval, 8 to 54 percent; P = 0.018). The reduction in risk was 46 percent (95 percent confidence interval, 11 to 71 percent; P = 0.018) for severe congestive heart failure and 25 percent (95 percent confidence interval, -11 to 60 percent; P = 0.19) for death. After one year of observation, the mortality rate was significantly lower in the zofenopril group (10.0 percent) than in the placebo group (14.1 percent); the reduction in risk was 29 percent (95 percent confidence interval, 6 to 51 percent; P = 0.011).Treatment with zofenopril significantly improved both short-term and long-term outcome when this drug was started within 24 hours after the onset of acute anterior myocardial infarction and continued for six weeks.

Sixty-three patients suffering from benign prostatic hyperplasia (BPH) entered a double-blind, comparative, parallel-groups study lasting 3 weeks, carried out to compare the efficacy and safety of alfuzosin 2.5 mg tid (n = 32) vs serenoa repens 160 mg bid (n = 31) in BPH.Efficacy was assessed both on clinical symptoms (Boyarsky's scale, visual analogue scale, clinical global impression), urinary flow rates (uroflowmetry) and residual urinary volume (transabdominal ultrasound). Events and reported signs were recorded throughout the entire study.Statistically significant and clinically relevant differences were found between the two treatments in favour of alfuzosin for Boyarsky's total score (decrease from 9.6 +/- 3.0 to 5.9 +/- 3.0, 38.8% for alfuzosin and from 9.3 +/- 2.5 to 6.8 +/- 2.8, 26.9% for serenoa repens) and obstructive score (decrease from 4.9 +/- 2.1 to 3.0 +/- 1.9, 37.8% for alfuzosin; from 4.4 +/- 1.7 to 3.4 +/- 1.8, 23.1% for Serenoa repens; p = 0.01 for both). Clinically relevant differences were found between the two treatments for visual analogue scale and overall clinical impression at the end of the study. Furthermore, the increase in quality of micturition was better with alfuzosin. The proportion of responders (increase on day 21 in peak flow rate of at least 25% relative to the baseline values) was in favour of alfuzosin (71.8% and 48.4% for alfuzosin and Serenoa repens, respectively; p = 0.057). Both treatments were well tolerated. No patient treated with alfuzosin complained of any adverse event at any time during the study. One patient in the Serenoa group complained of mild pruritus which cleared spontaneously. Systolic, diastolic blood pressure and heart rate did not show any clinically relevant change during treatment with alfuzosin.The findings confirm the efficacy and safety of alfuzosin in symptomatic BPH and indicate the superiority of alfuzosin over Serenoa repens in the treatment of urinary signs and symptoms of BPH.

The participation of the cellular sodium content and renin-angiotensin-aldosterone system in the development of high blood pressure has been frequently suggested. To elucidate the role of a mechanism responsible for renal sodium reabsorption on the time-course of renin suppression, 16 young borderline hypertensive patients were studied by analyzing the relationship between the level of baseline activation of lymphocyte Na+:H+ exchange and the degree of plasma renin activity (PRA) suppression in response to saline loading. In the whole hypertensive population, a significant correlation (R = 0.64; p0.01) was found between the lymphocyte Na+:H+ exchange activity and the percentage degree of PRA suppression induced by saline loading. Urinary sodium excretion was enhanced in patients with lesser activation of lymphocyte Na+:H+ exchange and greater PRA suppression (3.5 +/- 5 vs. 2.4 +/- .1 umol/min/kg; p0.05). These findings suggest that a mechanism influencing renal sodium reabsorption as Na+:H+ exchange could also affect the control of plasma renin activity, and concur with the development of salt-sensitive high blood pressure.

The rationale, design, organization and outcome definitions of the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study are described in detail. The recruitment of a total of 1500 patients (750 per treatment group) has been planned for this multicenter, double-blind, randomized, placebo-controlled study to investigate the effects of oral treatment with zofenopril calcium (7.5-30 mg twice a day) on the combined short-term total mortality and occurrence of severe refractory congestive heart failure in patients with acute anterior myocardial infarction (AMI). Secondary end-points of the study include recurrent myocardial infarction, angina, progression of congestive heart failure as well as long-term mortality. Patients are initially treated in hospital within 24 hours from the onset of symptoms of AMI and their active follow-up continued for 6 weeks. In addition, the patients will be passively followed for a total of 12 months from the index AMI to assess their vital status and the occurrence of congestive heart failure. The study data will be analyzed on an intention to treat basis. An international independent Policy and Safety Monitoring Board is acting as the overall supervisory body and is responsible for the ethical conduction of the trial. A Scientific Committee is responsible for the scientific aspects of the trial and for the regular review of the progress of the study. We assume that the rationale and design of the SMILE trial will provide reliable information on the ability of ACE-inhibitors to reduce the occurrence of major cardiovascular events in patients with acute myocardial infarction.

The role of renin-angiotensin system in the development of atherosclerosis is not yet defined, even though several actions of angiotensin II have been suggested as contributing to the development of the atherosclerotic lesion. Local renin-angiotensin system may exert a variety of autocrine or paracrine influences on vascular tissue leading to important trophic and growth regulatory effects and participating to well known events in atherogenesis as control of smooth muscle cell growth and proliferation. The existence and the specific function of components of this system in blood vessels wall suggest its possible involvement in atherosclerotic process. On these bases, the antiatherogenic properties of ACE-inhibitors have been recently evaluated in animal models where a protective effect of ACE-inhibition over the development of experimental atherosclerotic lesions has been observed. This favorable effect could follow the antihypertensive action of ACE-inhibitors even whether other potential mechanisms, including prevention of angiotensin II-induced vascular proliferation and interference with sympathetic nervous system activity and insulin sensitivity, have to be considered. Despite some clear-cut experimental evidences, the clinical importance of such findings as well as the precise mechanisms by which ACE-inhibition is able to interfere with the pathogenesis of atherosclerosis is still matter of debate and need to be assessed in future investigations.

Nine non-obese males with non-insulin-dependent diabetes mellitus (NIDDM) were evaluated before and after 3 and 12 months (6 patients) treatment with the second generation hypoglycemic sulfonylurea: gliclazide. They underwent an oral glucose tolerance test, intravenous glucose and arginine tests measuring plasma insulin and C-peptide responses. Pre-hepatic insulin production and insulin delivery to peripheral tissues were calculated by deconvolution techniques and hepatic extraction of insulin estimated. An improvement was observed in the beta-cell function of the patients on gliclazide treatment: reduction of fasting plasma glucose associated with a progressive increase in C-peptide level but insulin levels decreased at 12 months, suggesting an increase in hepatic insulin extraction at this time. In the same way, while plasma glucose values after oral and i.v. glucose were greatly reduced at 3 and 12 months treatment, insulin did not change but C-peptide levels increased significantly at 12 month treatment. While the prehepatic insulin secretion rate increased progressively on gliclazide during all glucose challenges, the fractional hepatic insulin extraction fell after 3 and increased at 12 month treatment, with opposite changes in insulin delivered to peripheral tissues. Thus the insulinogenic effect of gliclazide could be masked during long-term administration by a concomitant effect of gliclazide which increases hepatic extraction of insulin. The maintenance of the responsiveness to the non-glucose secretagogue, arginine, as evaluated by the C-peptide levels, before and after correction of hyperglycemia, suggested improvement of beta-cell sensitivity to glucose after sulfonylurea treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of angiotensin-converting enzyme (ACE) inhibitors in acute myocardial infarction (AMI) is based on their capacity to limit ventricular enlargement and dysfunction. To date, the safety profile of administration of ACE inhibitors early in the course of AMI has not been established. In-hospital and long-term consequences of treatment with the ACE inhibitor zofenopril initiated within 24 hours of the onset of symptoms were compared with those of standard treatment in an open-label trial involving 204 patients with AMI who were not undergoing thrombolytic treatment. Zofenopril promptly blocked ACE activation. Blockade was almost complete (91 +/- 6%) after 72 hours and paralleled decreases in systolic blood pressure. Systemic blood pressure was acutely reduced by zofenopril, and severe but reversible hypotension occurred in 15% of hospitalized patients and in 3% of those treated over the long term. No adverse clinical or biochemical events were reported during the course of zofenopril therapy. Overall cardiovascular mortality was not significantly reduced by early zofenopril compared with placebo therapy (7.8% vs 10.7% [difference not significant]). The inhospital incidence of acute left ventricular failure and ventricular arrhythmias decreased by 63% and 39%, respectively, among zofenopril-treated patients, who also reported fewer anginal episodes both acutely (68% reduction) and over the long term (56% reduction) and did not require as much drug treatment (i.e., diuretics, digoxin, and/or anti-ischemic agents) during the follow-up phase. Left ventricular size decreased and ejection fraction (EF) increased in patients who received zofenopril, and the improvement was greater among patients with poorer ventricular function (EF less than 40%). Early administration of ACE inhibitors may therefore constitute a safe form of therapy for patients with AMI, particularly when the event is complicated by clinical signs or evidence of ventricular dysfunction.

A simple and rapid gas chromatographic/mass spectrometric method to determine plasma diclofenac was developed, which employs formation of the methyl ester with diazomethane. Methoxydiclofenac was used as the internal standard. Under the conditions used, the previously described partial cyclization of diclofenac to the indolone derivative was avoided. The limit of detection of plasma levels of diclofenac is 2 ng ml-1, which renders the method useful for clinical studies on oral, intravenous and rectal administration of the drug. The analysis is carried out by electron impact gas chromatography/mass spectrometry and can therefore be performed on the more common mass spectrometers. Linearity and reproducibility of the method were demonstrated by the high correlation coefficient of the calibration lines (r greater than 0.999) and from the low variation of their slopes (coefficient of variation 3%) determined on different days, respectively. Pharmacokinetic parameters (area under curve = 1.8 +/- 0.26 microgram h ml-1, tmax = 1.5 +/- 0.5 h, Cmax = 734 +/- 82 ng ml-1 and terminal half-life = 0.88 +/- 0.52 h) determined from the plasma decay of diclofenac in three healthy subjects given a single oral dose of diclofenac were in good agreement with those reported in the literature.

The purpose of this study was to record some clinical and psychological parameters in attempt to find out and to estimate patients with abnormal cardiovascular responses during dental therapy. On the basis of psychological questionnaires, used to value anxiety, resulted that patients who have self defined themselves anxious and therefore objectively nervous while in the dental chair, underwent cardiovascular responses significantly lower than those who were not anxious. Among the clinical parameters studied, blood pressure and the heart rate during basic conditions are not able to foresee hemodynamic responses during dental extraction. The only clinical situation able to relate to a corresponding regularity with an hemodynamic response during dental extraction, is the blood pressure determination during a provoked generic mental stress. These findings suggest that cardiovascular response during dental stress depends on the personal individual reaction of each individual.

In this study, the effects of epinephrine in the local anesthesia were valued. No significant differences were revealed to cardiovascular response when a group of patients under generic stress were given an anesthetic without epinephrine and a second group of patients underwent an anesthetic with epinephrine. In patients in which epinephrine was injected, a significant fall in diastolic blood pressure was recorded two minutes after the injection and it remained as such for ten minutes. The cardiovascular response during dental extraction has a significant result dissimilar in the two groups of patients. No significant correlation was revealed between the blood pressure and the heart rate in basic conditions and the same parameters during an extraction. There exists a significant correlation between pressure response during generic stress and pressure response during an extraction. These findings suggest that cardiovascular response during dental stress is not in relation with the use of epinephrine with an anesthetic, but rather depends on each individual reaction.

Renal tolerability of a guided incremental dose schedule of sulphinpyrazone was evaluated in an open study of 2-month duration, performed in twenty-one cardiovascular elderly azotemic patients (thirteen males, eight females; mean age: 79 years, S.D.: 7·3 years). Starting dosage was 200 mg per day; daily dosage was then increased, every 4 days, by 200 mg or kept constant for another 4 days, according to each patient's basal renal function, up to the maintenance dose: 800 mg/day. Eighty-one per cent of the patients followed a successful incremental pathway, 9% kept a constant daily dosage of 200 mg for 8 days, reaching then the maintenance daily dose without any problems. Nine per cent withdrew at 200 mg/day because renal function deteriorated at two consecutive visits. Renal function of the patients who completed the study significantly improved (two-way ANOVA, p < 0·01). General tolerability was good. The proposed incremental dose schedule of sulphinpyrazone can be successfully used in the treatment of cardiovascular elderly azotemic patients.

Serum and tonsillary tissue levels of cefroxadine, a new broad-spectrum cephalosporin, proving to be effective in several infections, particularly in the ENT ones, were measured in patients scheduled for tonsillectomy. Twenty patients (12 males, 8 females) aged between 11 and 25 years (mean 18.0 years) were given cefroxadine for 2 days (500 mg every 12 h), and on the 3rd day 500 mg of the drug was given before surgical operation. Tonsillar tissues were taken 2 h after dosing and blood samples before, 1, 2, 4 and 6 h after the drug administration in 8 out of 20 enrolled patients. Cefroxadine concentrations were measured according to microbiological methods. Cefroxadine tonsillary levels were 1.13 +/- 1.73 micrograms/g, approaching the MIC for sensitive bacteria. The time course of plasma levels is superimposable to previous studies. These findings suggest a rapid penetration of cefroxadine in tonsillar tissue and seem to confirm the clinical efficacy of the drug in ENT infections.

The ability of plasma extracts to inhibit Na+-K+ ATPase in vitro (P.I.A.) was tested in 20 normotensives, 10 without (F-) and 10 with (F+) familial hypertension, in 20 borderlines (BL) and in 21 essential hypertensives (EH). In these subjects we also measured intralymphocytic sodium (ILSC) and potassium (ILKC) content, P.R.A. urinary aldosterone and Na+(Na+u), and blood pressure. P.I.A. of EH, BL and F+ subjects was significantly higher than that of F-. 60% of EH and BL and 40% of F+ had P.I.A. values greater than the highest found in F-. P.I.A. was significantly related to mean blood pressure (r = 0.63), to ILSC (r = 0.56), to ILKC (r = -0.56), to ILSC/ILKC ratio (r = 0.71) and to Na+u (r = 0.39) but not to P.R.A. or aldosterone. These data demonstrate that plasma extracts from young subjects prone to hypertension may inhibit sodium pump and that this inhibitor may affect blood pressure by altering the Na+/K+ intracellular ratio.

Two-hundred-and-three female patients (mean age: 58 yrs; SD: 8.2 yrs) suffering from osteoarthritis entered this late phase IV multicentre, stratified according to previous therapy (e.g. ketoprofen, naproxen, aspirin, indomethacin or indoprofen), randomized, double-blind, between within-patient trial of 2-week duration. Each patient received either diclofenac SR 100 mg/day (D), piroxicam 20 mg/day (P), or placebo (P1 by oral route. Clinical evaluation (functional class; pain assessment; osteoarthritic condition; joint motility and stiffness) was performed at entry, as well as after the first and the second week. Patient compliance and reported signs and symptoms were recorded after the first week and at the end of the trial. Patient preference, as regards previous therapy, and global evaluation (both by the physicians and the patients) were checked at the end of the trial. The clinical evaluation showed a superiority of D and P over P1. No difference was seen between the two active drugs. Placebo effect was very strong. Global evaluation was significantly in favour of D and P. Patient compliance was extremely good (greater than or equal to 95%). Diclofenac was preferred to naproxen, aspirin and indomethacin, while piroxicam and placebo were preferred only to aspirin. The tolerability of the two active drugs was good and comparable. A significantly lower number of patients complaining of unwanted effects (u.e.) was detected in the placebo group. The number of patients withdrawn for u.e. was similar in the three trial groups.

Forty-four essential hypertensive patients were studied during placebo and after 2 months of the following treatments: hydrochlorothiazide 25 mg once daily (group 1); captopril 50 mg twice daily (group 2); hydrochlorothiazide + captopril (group 3). Blood pressure, serum sodium and potassium (Nae, Ke) and intralymphocytic sodium and potassium (Nai, Ki) were measured before and after treatment. During placebo, diastolic blood pressure was directly related to Nai (r = -0.84) and inversely related to Ki (r = -0.81). The correlation was even greater when the Ki:Ke ratio was considered instead of Ki alone (r = -0.91). Hydrochlorothiazide reduced Nai, Ke and Ki. Captopril induced a decrease in Nai, an increase in Ki and no change in Nae or Ke. The association of the two drugs caused a reduction in Nae and Nai and an increase in Ki. All three treatments caused an increase in Ki:Ke ratio which was proportional to the decrease in the blood pressure. While the antihypertensive effect of hydrochlorothiazide seems to be more related to Nai:Nae reduction, the effect of captopril seems to be more related to the increase in Ki:Ke ratio. The results of our study suggest that hyperpolarization of arterial smooth muscle cells, induced by a Ki:Ke ratio increase, along with a reduction in Nai:Nae, might play a role in the antihypertensive effect of captopril and hydrochlorothiazide.

Clinical efficacy and safety of oxmetidine (400 mg b.i.d.), a new potent specific H2-receptor antagonist, and cimetidine (1 g/day) were compared in a double-blind randomized trial of 4 weeks duration that involved 39 outpatients with endoscopically proven active duodenal ulcer. The disappearance of the ulcer crater leading to complete reepithelization of the bulbs or to the presence of erosions occurred in 17 out of 19 (89.6%) patients treated with oxmetidine, and in 13 out of 20 (65.0%) patients treated with cimetidine (n.s.). Ulcer symptoms and antacid consumption were not different in two groups. No side effects or significant haematological or biochemical abnormalities were found. Both drugs failed to evoke significant changes in the basal levels of prolactin (PRL) and gonadotropins. The higher, though not significant, percentage of healing obtained with oxmetidine had no clinical relevance and needs to be demonstrated in a larger number of patients.