Search

Purpose Italian expenditure for vitamin D greatly increased in the last few years, reaching €314 million ($376.8 million) in 2019. In Italy, the main cause of the increase in public spending for vitamin D is the marketing of high-cost medicines. At national and regional levels, some interventions have been performed to reduce expenditure, but spending has continued to increase. The aim of this work is to propose a new saving strategy determined by an analysis of a significant sample of the market. Methods Data on the use of vitamin D formulations, including data for the different active substances that represent its pharmaceutical analogue and composition of groups of equivalence, were extrapolated from the Italian Medicines Agency transparency lists and from the Farmadati database. Data on pharmaceutical expenditure were obtained from the Data Warehouse of Liguria Region; the composition of this expenditure was analyzed in detail, focusing on the characteristics of the pharmaceutical preparations and their cost (price per defined daily dose). Findings Vitamin D expenditure paralleled that of cholecalciferol, the most used active ingredient, which in Liguria increased from €643,352 ($772,022.4) in 2010 to €8,006,574 ($9,607,888.8) in 2019 (increase of 1144%). Spending focused on high-cost formulations, exceeding 90% of total cholecalciferol cost in 2019. We simulated a possible optimization of the expense for cholecalciferol by applying a revised price to all the cholecalciferol consumptions in high-cost products because these formulations do not have an added therapeutic value, finding that the saving would be at least 60%. National data on the detailed expenditure composition for vitamin D are not available, but we found a strong resemblance between total cholecalciferol expenditure time series in Italy and the Liguria Region. Implications The expense of cholecalciferol and consequently the expense of vitamin D could be optimized by modifying the reimbursement of high-cost formulations. At a national level, savings should be proportional to that estimated for the Liguria Region. On the basis of the 2019 data, Italian savings with respect to total cholecalciferol expenditure should be €170.65 million ($204.78 million); per capita cholecalciferol expenditure would shift from €4.66 ($5.59) to €1.84 ($2.21).

A solution for in-process monitoring of part warpage in fused filament fabrication is presented, based on real-time measurement of the upwards-oriented repulsive force acting on the extruder during deposition. The force signal is processed with the help of simulation software implementing a mechanical model which incorporates the stiffness of the machine and the compliance of the part as it is fabricated. The model acts as a digital twin, where compliance is constantly updated while part geometry evolves through the creation of new layers. The incorporation of stiffness/compliance simulation helps the monitoring system in the interpretation of the force signal, leading to a better isolation of warpage events. The proposed monitoring solution is validated through the implementation of a sensorised hardware prototype and the execution of experiments involving the fabrication of test parts. The results indicate warpage detection performance with 92.9% accuracy, 91.5% specificity and 95.7% sensitivity, and demonstrate that it is possible to use a relatively affordable, quick and non-destructive sensing solution (that is, measuring the repulsive force acting on the extruder) as an effective means to detect part warpage. However, the developed solution highlights the challenge of developing accurate digital twins for the prediction of part compliance, essential for the correct interpretation of the force signal.

Introduction Cardiomyopathies are diseases of the heart muscle, with frequent genetic component, characterized by a strong heterogeneity concerning clinical presentation and echocardiographic profile. Diastolic dysfunction can affect all forms of cardiomyopathy, often being an expression of a more advanced state of the disease. Objectives To analyze the role of diastolic dysfunction in cardiomyopathies. Conclusions Echo-Doppler analysis is therefore very helpful, as it may give important information concerning the clinical stage of disease progression and could provide a prognostic stratification tool in order to orient the clinician toward early specific treatment.

INTRODUCTION: High prevalence of coeliac disease (CD) has been reported among patients with idiopathic dilated cardiomyopathy (DCM). We evaluated the feasibility and diagnostic accuracy of screening for CD by rapid test of anti-transglutaminase antibodies in the cardiology outpatients' clinic. MATERIAL AND METHODS: We screened the blood samples of 104 patients with DCM, 44 of their first-degree relatives, 63 diseased controls and 101 healthy controls for the presence of anti-transglutaminase antibodies in a drop of whole blood using a rapid assay. This test was compared to the enzyme-linked immunosorbent assay and the anti-endomysium antibody test. RESULTS: Our rapid test was positive in three (2.9%) DCM patients, in one (2%) relative and in one (1%) healthy control. These subjects were positive at both control assays. Two DCM patients had iron-deficient anaemia. The healthy relative was asymptomatic, while the healthy control experienced extreme asthenia. The relative refused intestinal biopsy, while the others showed histological evidence of CD. During the gluten-free diet, the patient with the worst left ventricular ejection fraction (LVEF) underwent heart transplant, and LVEF values improved in the other two. Anaemia and tiredness resolved in all patients. CONCLUSION: Early detection of CD in a cardiological setting allows prompt treatment with a gluten-free diet of gluten-dependent complaints with potential benefits for the course of DCM.

Aims Familial screening of patients with dilated cardiomyopathy (DCM) allows an early diagnosis of the disease in family members. It is unclear if familial forms (FDC) have a different long-term outcome compared with sporadic DCM. Our aim was to compare the long-term prognosis of FDC and sporadic forms in order to assess the role of familial screening. Methods and results Between 1988 and 2007, 637 DCM patients were consecutively enrolled. Of these, 130 patients (20.4%) had FDC, including 82 (12.9%) probands and 48 (7.5%) non-proband FDC patients (NP-FDC), identified by family screening. We compared the 48 NP-FDC patients with a sample of 96 patients with sporadic DCM, who were randomly matched by year of enrolment in a 2:1 ratio. At enrolment the NP-FDC patients were younger (40 ± 16 vs. 48 ± 13 years, P = 0.002), less symptomatic [New York Heart Association, (NYHA) III–IV: 8 vs. 28%, P = 0.006], had higher left ventricular ejection fraction (35 ± 10 vs. 30 ± 9%, P = 0.005) and were less intensively treated with evidence-based drugs than the sporadic DCM patients. Survival free from heart transplant at 2, 5 and 10 years was 93, 91 and 82%, respectively, in NP-FDC patients compared with 86, 76 and 62% in sporadic forms (P = 0.04). After stratification for NYHA classes, no difference in survival was observed between sporadic and NP-FDC patients. Conclusion Our study demonstrates that family screening can effectively identify DCM patients at an earlier stage of disease and can improve survival. The possibility of changing the prognosis of DCM needs to be verified in patients intensively treated with tailored medical treatment. Family screening should be recommended for all DCM patients.

The aims of this study were to investigate the clinical outcomes of patients with low-gradient aortic stenosis despite preserved left ventricular ejection fraction and to assess reliable prognostic clinical-instrumental features in patients experiencing or not experiencing aortic valve replacement (AVR). Clinical-laboratory and echocardiographic data from 167 patients (median age 78 years, interquartile range 69 to 83) with aortic valve areas 70 years showed a trend toward being a prognostic predictor (p = 0.082). In conclusion, in patients with low-gradient aortic stenosis despite a preserved left ventricular ejection fraction, AVR was strongly correlated with a better prognosis. Patients with atrial fibrillation associated with advanced New York Heart Association class had the worst prognosis if treated medically but at the same time a relative better benefit from surgical intervention.

Cardiomyopathies (CMP) are defined as disorders of the heart muscle unexplained by coronary artery disease, hypertension, valvular disease, or congenital heart disease. All forms of CMP can be caused by genetic and nongenetic mechanisms. Whereas differences exist in the classification schema, CMP have historically been broken down into several major phenotypic categories: hypertrophic, dilated, arrhythmogenic, and restrictive. Phenotype overlap is common and increases the challenge in diagnostic accuracy. Some genetic and nongenetic subtypes can be identified using a step-by-step strategy, including history, physical examination, electrocardiography, echocardiography, laboratory, and a CMP-focused approach to interpreting cardiac and noncardiac investigations, not only in the patient but also in the familial history. Genetic testing is most informative if directed to a specific diagnosis suspected on the basis of the clinical assessment, and it is becoming an important tool for a personalized medical approach to CMP.

Infiltrative/storage cardiomyopathies (CMP) are diseases characterized by the deposition of pathological substances in the heart muscle. In particular, the term infiltrative refers to intercellular infiltration, whereas storage refers to intracellular deposition within the myocardium. As the infiltration/storage usually involves multiple organs, these CMP should be considered part of a systemic disorder. Despite variable etiology and pathological mechanisms, this group of CMP shares some common features, such as myocardial hypertrophy and progressive myocardial stiffness, with diastolic and systolic dysfunction. Heart failure is the main clinical manifestation, but arrhythmias and conduction defects are common. Accurate clinical evaluation is therefore crucial for correctly targeting further examinations. Moreover, cardiac imaging plays a major role not only in differential diagnosis but also in prognostic stratification. The impact of identifying cardiac involvement and the underlying pathology reflects upon treatment and prognosis.

Since a fraction of ingested ethanol (EtOH) is metabolized by gastric mucosa, different amounts of alcohol should reach the liver, when the same dose is administered by oral or intravenous route. Accordingly, we demonstrated that the hepatic depletion of glutathione induced by EtOH is lower when it is administered orally rather than intraperitoneally (i.p.). In the present study we investigated, after EtOH load, the time-course of common serum liver damage tests and of α-glutathione-S-transferase (αGST) levels as a new indicator of hepatocellular injury in rats. The tests were also performed in Cimetidine-treated rats. Oral EtOH administration was followed by a less pronounced decrease and by a quicker recovery of hepatic glutathione than after i.p. route. After oral EtOH load, Cimetidine, a potent inhibitor of gastric alcohol-dehydrogenase, produced a decrease of hepatic glutathione significantly (P

The management of refractory recurrent pericarditis is challenging. Previous clinical reports have noted a beneficial effect of high-dose intravenous human immunoglobulins (IvIgs) in isolated and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our clinical experience with IvIg therapy in a series of clinical cases of pericarditis refractory to conventional treatment. We retrospectively analyzed 9 patients (1994 to 2010) with refractory recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine treatment was not discontinued during IvIg treatment. No patients had a history of autoimmune or connective tissue diseases. During an average period of 11 months from the first recurrence, patients had experienced a mean of 5 relapses before the first IvIg treatment. In 4 cases, patients showed complete clinical remission with no further relapse after the first IvIg cycle. Two patients experienced a single minor relapse, responsive to short-term nonsteroidal anti-inflammatory drugs. In 2 patients, we performed a second cycle of IvIg after a recurrence of pericarditis, with subsequent complete remission. One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No major adverse effect was observed in consequence of IvIg administration in all the cases. In conclusion, although IvIg mode of action is still poorly understood in this setting, this treatment can be considered as an option in patients with recurrent pericarditis refractory to conventional medical treatment and, in our small series, has proved to be effective in 8 of 9 cases.

Left ventricular non-compaction (LVNC) is characterized by a pseudohypertrophic “spongy” left ventricle with deep trabeculations. It is considered to be a rare cardiomyopathy (CMP), with a prevalence of approximately 1:2,000 to 1:7,000 individuals. The condition shows excessive and unusually trabeculated myocardium within the mature heart muscle in the apical and midlateral/inferior portions of the left ventricle, which is usually hypokinetic (Fig. 8.1). LVNC represents a developmental failure of the heart to form the fully compact myocardium during the later stages of cardiac development.

In patients with a hypertrophic cardiomyopathy (HCM) phenotype, study of the electrocardiogram (ECG) can sometimes suggest a specific diagnosis (Table 5.1). For example, an ECG pattern of ventricular pre-excitation can be found in storage diseases, such as those characterized by abnormalities of muscle glycogen.

Since some H2-receptor antagonists, like cimetidine or ranitidine, affect ethanol metabolism by interference with gastric and/or hepatic alcohol dehydrogenase (ADH) it was investigated whether omeprazole has a similar effect and its effects were compared with those of cimetidine, an inhibitor of gastric ADH. The first-pass metabolism (FPM), quantified by measuring the difference between areas under the curve (AUC) of ethanol blood concentrations after oral intake or intravenous administration of the same amount (0.3 g kg−1 b.w.) of ethanol (EtOH), was studied before and after 1 week of omeprazole (20 mg daily) or cimetidine (800 mg daily) administration in 10 normal male volunteers. ADH activity was determined in gastric mucosal samples, collected during endoscopy, before and after 1 month of omeprazole treatment. The effect of the drugs on gastric and hepatic ADHs was studied in vitro in both rat and man. No significant effect of omeprazole was found on AUCs of the blood EtOH concentrations. The ADH activity in antral mucosa before and after omeprazole therapy did not show significant differences. In vitro, omeprazole reduced the activity of the low Km gastric ADH with a Ki of 5.6 mm in rat and the hepatic ADH activity with a Ki of 2.4 mm in man, whereas the drug did not show any effect on hepatic ADH in rat and gastric ADH in man. On the contrary, cimetidine increased the AUCs of EtOH blood concentrations after both gastric and intravenous route and, in the in vitro assay, inhibited gastric and hepatic ADH in both man and rat. These results indicate that omeprazole does not affect EtOH metabolism in man and seems to be safer than cimetidine in subjects unable to reduce ethanol intake during the therapy for peptic ulcer or other hypersecretory conditions.

In recent years, outstanding progress has been made in the diagnosis and treatment of cardiomyopathies. Genetics is emerging as a primary point in the diagnosis and management of these diseases. However, molecular genetic analyses are not yet included in routine clinical practice, mainly because of their elevated costs and execution time. A patient-based and patient-oriented clinical approach, coupled with new imaging techniques such as cardiac magnetic resonance, can be of great help in selecting patients for molecular genetic analysis and is crucial for a better characterisation of these diseases. This article will specifically address clinical, magnetic resonance and genetic aspects of the diagnosis and management of cardiomyopathies.

Objective: To assess the association of matrix metalloproteinases (MMP) genetic polymorphism (PM) with plaques vulnerability and clinical outcome of acute vascular events. Methods: MMP-1 (-1607 G in/del), MMP-3 (-1171 A in/del), and MMP-9 microsatellite (13–26 CA repeats around -90) PMs have been determined (i) in 204 patients with cerebrovascular disease to assess the association with features of vulnerability in carotid plaques and prevalence of stroke, (ii) in 208 patients with UA/NSTEMI to assess the association with in-hospital clinical outcome. Results: Plaques from carriers of MMP-1 G insertion showed significantly smaller plaques and thicker fibrous cap. In CVD patients carrying such variant, Odds Ratio for previous stroke was 0.27 (95% C.I. 0.13–0.56, P = 0.0002) and, in UA/NSTEMI patients, the risk of Major Adverse Cardiac Events (MACE, persistent angina, NSTEMI, and vascular death) was 0.22 (95% C.I. 0.11–0.44, P < 0.0001).Novariants inMMP-3 PM were associated to differences in either plaque features or clinical outcome. Carriers of MMP-9≥22 repeats in the microsatellite had larger plaques and lipid core. In CVD patients with such variant, Odds Ratio for stroke was 2.2 (95% C.I. 1.1–4.4) and, in UA/NSTEMI patients, MACE risk was 4.1 (95% C.I. 2.3–7.4, P < 0.0001). Persistent angina and NSTEMI separately provided comparable results. Conclusions: Carriers of MMP-1 G insertion show smaller and more stable plaques, as well as better prognosis in acute vascular events, while patients with ≥22 repeats in MMP-9 have larger necrotic core and worse prognosis in UA/NSTEMI.

To investigate the short term effects of Doxycycline on MMP-2 and MMP-9.Short term effects of Doxycycline (100 mg B.I.D.) on plasma levels of MMP-2 and MMP-9 were investigated in 20 healthy subjects; the effects of Doxy, Acetylsalicylic acid, Nitrates, and Enalapril on MMP-9 release from were assessed in isolated polymorphonuclear cells.In plasma, MMP-9 activity was reduced (-22\%, 95\% CI -32/-11; P = 0.002) starting at 12 h after doxy; in vitro, MMP-9 released from stimulated neutrophils was reduced by Doxy (-28\%, 95\% CI -43/-14; P = 0.001), inhibiting degranulation, and by nitrates (-52\%, 95\% CI -76/-28 P = 0.005), increasing three times both pro- and active-MMP-9 bound to neutrophils (P = 0.007 and 0.040, respectively).Doxy decreases MMP-9 plasma levels by around 20\%, within the first 12 h. The mechanism leading to such reduction seems due to the inhibition of PMN degranulation.

We report a case of a 57 year-old woman with Starr- Edwards model 6120 mitral valve replacement and Kay- Shiley bioprosthetic tricuspid valve replacement in 1968 at Niguarda Hospital in Milan. The mitral caged-ball has proved its excellent durability and its good hemodynamic performance in many patients, even if subject to high tendency to thrombosis. In literature there is no evidence of durability of this prosthesis longer than 35 years. Our patient after 39 years from mitral valve replacement lives a happy and fulfilling life (NYHA II), with no evidence of hemolysis, ball variance, symptomatic embolization or major bleeding.

The use of low molecular weight heparin sometimes leads to major life threatening complications, such as acute abdominal haemorrhages. We report two cases of major haematoma of rectus abdominis. Computed tomography was very helpful to confirm the diagnosis in these cases.

Alcoholic beverages are known to exert a protective effect on atherosclerotic disease. This study aimed to assess the in vivo and in vitro effects of alcohol on matrix metalloproteinase (MMP) -2 and -9, known to determine atherosclerosis progression. Eighteen healthy volunteers, regular drinkers (two standard alcohol servings/day, on average) at first examination (baseline) were asked to abstain from any alcoholic beverage for one week (abstention), and then to assume two standard alcohol servings of beer daily for 1 week (re-exposure). Activity of MMP-2 and -9, total antioxidant activity (AOA), glutathione (GSH) plasma levels were carried out at baseline, at the end of abstention, and after 1 week of re-exposure. To validate the in vivo results, MMP-2 activity and expression, AOA, and GSH, were determined in human smooth muscle cells treated for 96 h with increasing concentrations (12.5-100 mM) of ethanol. MMP-2, but not MMP-9 plasma activity was higher at abstention than at baseline or re-exposure (P

The last 20 years have seen impressive progress in the study of cardiomyopathies. The improved understanding of these diseases has made clear that cardiomyopathies are extremely complex entities that defy current classification standards. The 1980 and 1995 WHO/ISFC Task Forces, and very recently an American Heart Association (AHA) Scientific Statement expert panel, have systematically approached new advances as well as emerging problems. In spite of this effort and an increasingly growing understanding of myocardial disorders, several issues remain unresolved. Without a doubt, the identification of genetic defects responsible for many forms of cardiomyopathies has changed our perspective of myocardial diseases. In fact, in the last few years, we have seen that (1) clinically defined cardiomyopathies, previously considered single entities, are actually the result of mutations in different genes, (2) different mutations in the same gene may be the cause of different clinical entities and (3) in the group of cardiomyopathies, a large phenotypic and genetic heterogeneity exists that is expected to increase in the future. Genotype knowledge is a fundamental advance in medicine and in particular in the field of cardiomyopathies and is becoming increasingly more important in clinical practice for disease diagnosis and prevention, prognostic stratification and possible future therapies. Knowledge of the phenotype, including clinical, morphological and physiological features, however, continues to provide the clinical basis for diagnosis and classification of cardiomyopathies, prognostic evaluation and symptomatic treatment, and should not be abandoned.

The long-term beta-blockade strategy with carvedilol, metoprolol succinate or bisoprolol is now strongly recommended to reduce the rates of mortality and morbidity in patients with chronic heart failure (CHF). Although the benefits observed with such drugs are viewed as a class effect, theoretically, carvedilol might be superior to the other two agents, considering its unique pharmacological profile, which includes a more comprehensive antiadrenergic activity and potentially relevant ancillary properties. So far, carvedilol has been proven to be effective and safe in a broader range of CHF patients than metoprolol and bisoprolol. Moreover, a recent large clinical trial has shown a significantly greater survival benefit with carvedilol as directly compared with metoprolol tartrate. Therefore, carvedilol may be the preferred beta-blocking agent to treat patients with CHF.

We assessed whether the low sigma-alcohol dehydrogenase (ADH) activity in Japanese (compared with Caucasians) affects the first-pass metabolism of ethanol. ADH isozyme activities were determined in endoscopic biopsies of the gastric corpus from 24 Japanese and 41 Caucasian men by starch gel electrophoresis and by comparing the reduction of m-nitrobenzaldehyde (a preferred substrate of sigma-ADH) with that of acetaldehyde (a preferred substrate of gamma-ADH) and the glutathione-dependent formaldehyde oxidation (a specific reaction of chi-ADH). Alcohol pharmacokinetics was compared in 10 Japanese and 10 Caucasians after administration of ethanol (300 mg/kg of body weight) intravenously or orally, using 5 and 40% oral solutions. Japanese exhibited lower sigma-ADH activity than Caucasians, with no difference in the other gastric isozymes. With 5% ethanol, first-pass metabolism was strikingly lower in Japanese than in Caucasians. Blood alcohol levels were similar because of the high elimination rate in Japanese due to the hepatic beta 2-ADH variant. With 40% ethanol, the first-pass metabolism increased in both groups to comparable levels, suggesting an additional contribution by chi-ADH at high ethanol concentrations. These results indicate that sigma-ADH activity contributes significantly to gastric ethanol oxidation and its lower activity in Japanese is associated with lesser first-pass metabolism.

Objectives. As a close relationship has been established between mixed cryoglobulinaemia and hepatitis C virus (HCV) infection, the clinical, histological and virological findings of patients affected by mixed cryoglobulinaemia were determined. Design. Hepatitis C virus infection was investigated by the presence of anti-HCV antibodies and PCR amplification of the 5′ untranslated region (5′ UTR), and the genotype of HCV was also determined according to Okamoto. A bone marrow biopsy was performed in all patients and liver and kidney biopsies when indicated. Subjects. Eighty-two subjects affected by mixed cryoglobulinaemia were enrolled in this study. Results. The prevalence of anti-HCV antibodies was high (83%); PCR amplification of the 5′UTR region was performed in 52 subjects and in 44 of them (85%) the results were positive. In the same subjects, the Core region amplification was positive in 46 cases (88%). A high prevalence of genotype II was found (54%). Chronic liver disease was present in 55 patients (67%). Bone marrow biopsies showed the presence of low-grade non-Hodgkin's lymphomas in 11 cases (13%). Membrano-proliferative glomerulonephritis was found in seven subjects (8%). Conclusions. Mixed cryoglobulinaemia is associated with HCV infection in the nearly all cases. Several HCV genotypes are involved in the pathogenesis of this disease. Mixed cryoglobulinaemia is associated with a high prevalence of chronic liver disease, low-grade non-Hodgkin's lymphomas and membranoproliferative glomerulonephritis.

To investigate the effect of age and gender on ethanol metabolism, first-pass metabolism (FPM) and gastric alcohol-dehydrogenase (ADH) activity were compared in 32 elderly and 30 young adult nonalcoholic subjects. The FPM was obtained from the difference between the area under the curve of ethanol blood concentration after intravenous or oral administration of ethanol 0.3 g/Kg b.w. The ADH activity was determined in samples of gastric mucosa obtained during diagnostic endoscopy. In the young adult group the FPM was higher in men than in women (3.3 +/- 2.3 vs 1.2 +/- 0.9 mmol/l/h, respectively, p < .01). In aged subjects FPM was found to be very low for men (1.1 +/- 0.8 mmol/l/h, p < .001); conversely, FPM was not significantly reduced in women (1.7 +/- 0.8 mmol/l/h, p = n.s.). The gastric ADH activity was significantly (p < .01) higher in young adult men than women, whereas in aged subjects the activities were low (p < .0001) in both sexes. Thus, gender-related FPM differences equalize in the elderly or are even reversed, most likely because of gastric mucosal atrophy, which occurs more in men than women.

The aim of the study was to assess the role of different viral strains of hepatitis C virus (HCV) in determining the outcome of the alpha-interferon (IFN) therapy. Fifty-seven patients (34 from Italy and 23 from Japan) with HCV-positive liver disease were enrolled in the study. The NS4 region of HCV was amplified in sera by “nested” polymerase chain reaction (PCR) using a primer pair synthesized according to the sequence of JK-1. The NS4 region was positive in 14 (41%) Italian and in 13 (56%) Japanese patients. In positive patients the sequence of the NS4 region was also obtained. Subsequently, HCV genotype was determined in all patients by PCR amplification of the core region. All patients received recombinant alpha2a-interferon (IFN), 6 million units 3 times a week for 1 month followed by 3 million units 3 times a week for 5 months. The patients were followed for 1 year after the end of treatment. At the end of the follow-up, 17 (30%) had sustained normal levels of serum alanine aminotransferase (ALT). The outcome of treatment was not correlated with race, age, sex, histology, and pretreatment ALT level, but was significantly (P < 0.00001) associated with the presence of both the NS4-JK-1 region and HCV type II. Among the 27 NS4-positive patients, only 1 patient (3.7%) achieved a complete response, whereas the remaining 26 patients (96.3%) either were non-responders or relapsed after IFN was discontinued. In contrast, among the 30 NS4-JK-1-negative patients, 15 (53%) had a sustained remission. HCV genotyping showed type I in 3 (6%), type II in 40 (74%), type III in 4 (7%), and type IV in 3 (6%) cases. Coinfection was present in 4 (7%), while in 3 cases amplification was not obtained. Patients with type II were all non-responders or relapsers, while a response to the treatment was oberved in 17 of 17 (100%) of the remaining patients. These data indicate that the presence of JK-1 variant of HCV or HCV type II is almost always predictive of a poor response rate Of IFN therapy. © 1995 Wiley-Liss, Inc.

As a fraction of ingested ethanol (EtOH) is metabolized by gastric mucosa, different amounts of alcohol reach the liver, when the same dose is administered by oral or intravenous route. In previous experiments, we demonstrated that the decrease of hepatic reduced glutathione (GSH) is less pronounced and is followed by a quicker recovery after oral than after intraperitoneal administration of the same amount of EtOH. Therefore, the time-course of hepatic GSH concentration seems to be an indirect assay of EtOH metabolism by the liver. On the basis of these findings, any condition causing a reduced function of gastric alcohol dehydrogenase (ADH) should show up as a more severe depletion of hepatic GSH. In the same rat experimental model we determined the effects of cimetidine and omeprazole administration on gastric ADH activity and on the time-course of hepatic GSH after EtOH load. Cimetidine was shown to inhibit gastric ADH with a Ki of 0.167 +/- 0.009 mmol l-1; accordingly, the pretreatment with this drug (20 mg kg-1 b.w. per day for 1 week) determined, after oral EtOH load, a marked reduction of hepatic GSH, likewise after intraperitoneal administration. Omeprazole exerted only a marginal inhibition on gastric ADH and this drug (0.3 mg kg-1 b.w. per day for 1 week) did not modify the time-course of hepatic GSH concentrations after EtOH load. This study indicates that the inhibition of gastric ADH, when associated with EtOH intake, induces depletion of the hepatic GSH concentration and, therefore, possible liver damage.

As a fraction of ingested ethanol is metabolized by gastric mucosa, different amounts of alcohol should reach the liver when the same dose is administered by oral or intravenous route. Therefore, we investigated the time-course of hepatic reduced glutathione (GSH) concentrations after intra-peritoneal or intra-gastric load of the same amount of ethanol in the rat. The test was also performed in fasted and Cimetidine-treated rats. The oral ethanol administration was followed by a less pronounced decrease and by a quicker recovery of hepatic content of GSH than after intraperitoneal route. In the fasted rat, basal hepatic GSH significantly decreased; after alcohol administration the decrease of hepatic GSH was more severe and prolonged than in the fed rat. Cimetidine was shown to be a potent inhibitor of gastric ADH. Pre-treatment with Cimetidine did not change the basal levels of hepatic GSH, but after oral ethanol load, the decrease of the hepatic GSH content was significantly (p0.005) more pronounced than in controls. This study demonstrates the beneficial effects of gastric ethanol metabolism on the liver. The reduced gastric ethanol metabolism, induced by fasting or by Cimetidine resulted in a decreased content and delayed recovery of liver GSH content.

Background/Aims: The determination of HCV-RNA concentration in liver samples is likely to provide interesting insights for the study of disease progression and for evaluation of the efficacy of anti-viral therapy. Methods: a procedure was developed for the precise quantification of HCV-RNA in liver biopsies, based on the competitive reverse transcription-polymerase chain reaction technology. This competitive assay consists of the co-amplification of the target RNA with known amounts of a competitor RNA molecule containing the same sequence as the target plus an insertion in the middle, allowing resolution of the two amplification products by gel electrophoresis. Results: The amounts of HCV-genomic-RNA and β-actin mRNA (the latter being used as an internal standard to overcome the problem of reproducibility of quantitative RNA extraction) were evaluated in liver biopsies of 15 patients affected by hepatitis C virus-positive chronic liver disease at the time of diagnosis. All the patients underwent α-interferon therapy for 6 months and were subsequently followed for at least 1 further year after the end of treatment. Viral RNA concentration (which ranged from 2 to 2.7 × 10 5 HCV-RNA molecules per 10 16 β-actin molecules) directly correlated with the efficacy of treatment, indicating that low levels of viral replication in the liver are associated with a poor response to therapy. Conclusions: This study suggests that the determination of viral load in the liver is an important prognostic tool for the prediction of the efficacy of α-interferon therapy.

The presence of the “Japanese type” NS4 region was investigated in two series of patients (53 from Italy and 58 from Japan) with hepatitis C virus (HCV)-related chronic liver disease. The two populations were homogeneous as regard to age, male/female ratio, histological diagnosis, and serum aminotransferase activities. Genomic amplification was carried out by “nested” poly-merase chain reaction (PCR) with a pair of primers synthesized according to the sequence of JK-1 isolated in Japan. The presence of viral replication was confirmed further by PCR amplification of the 5′NC region. The NS4 region of the Japanese strain was detected in 24 sera (45%) from Italy and in 44 (71%) from Japan. NS4-posi-tive patients were significantly older and showed an ALT serum level significantly lower (P < 0.01) than NS4 negative cases in each group. Cirrhosis was significantly (P < 0.0007) more common in NS4-positive than in NS4-negative patients. The HCV genotype was subsequently obtained according to Okamoto. All the NS4-positive patients were infected by Type II, whereas in NS4-negative patients all four genotypes were present though Type II still constituted the majority. Cirrhosis was associated exclusively with Type II both in NS4-positive and -negative subjects. These data indicate that, although the pos-itivity for NS4 “Japanese” region seems to be associated with a more aggressive liver disease, the most prevalent Type II predicts more specifically those who are likely to develop cirrhosis. Since the same findings were obtained in two population from different areas of the world, the genotype of HCV appears to be one of the major determinants of the progression of chronic active hepatitis to cirrhosis. © 1994 Wiiey-Liss, Inc.

Background: Peak oxygen consumption (VO2) an old-time classic parameter used to stratify HF patients (pts) was recently combined to VE/VCO2 slope, in order to improve heart transplant selection criteria. The lack of prognostic factors is particularly evident in the subgroup of pts with intermediate grade of risk (i.e. with a peak VO2 between 10 and 18 ml/kg/min).We sought to analyse the predictive role of aerobic indexes obtained during Cardiopulmonary Exercise Testing (CPET) in pts affected by idiopathic dilated cardiomyopathy (IDC) with a peak VO2 between 10 and 18 ml/kg/min. Methods:We analyzed 171 IDC pts enrolled in the Trieste Heart Muscle Disease Registry who underwent CPET from 1997 and 2005. Among these, 97 pts had a peak VO2 between 10 and 18 ml/kg/min (mean age 48±10 yrs, males 71%, NYHA class III-IV 20%, left ventricle ejection fraction (LVEF) 0.30±0.11, peak VO2 14±2 ml/kg/min, ACE-inhibitors 93%, beta-blockers 88%). Combined end-point was considered Cardiovascular Death/Major Ventricular Arrhythmias/Cardiovascular Hospitalizations at 1 year. Results: At univariate analysis, pts who satisfied the end point criteria at one-year, in comparison with those who did not, showed a trend towards more advanced functional NYHA class, lower LVEF and lower circulatory power. The only parameter significantly associated to our combined end-point resulted a higher VE/VCO2 slope (34±7 vs 29±4, p=0.003). At multivariate analysis VE/VCO2 slope was selected as an independent predictor of one-year cardiovascular endpoint (for a 2-unit increase: O.R.1.41, 95% I.C. 1.08-1.85, p=0.012) together with LVEF (for a 5point decrease: O.R.1.71, 95% I.C. 1.08-2.71, p=0.025). At ROC curves VE/VCO2 slope had an AUC of 0.694 for our study end-point with a cut-off value of 28. Conclusions: In pts classified at intermediate risk according to peak VO2, VE/VCO2 slope may add prognostic power to identify pts at higher risk of early heart transplant indication.

9±7 mmHg; pulmonary wedge pressure, 27±11 mmHg, peak VO2, 11.8±3.2 mL/kg/min, VE/VCO2 slope, 51±15. All the patients were treated with furosemide (89±12 mg/day) and enalapril (16±10 mg/day), 44 patients were on spironolactone (47±34 mg/day), 38 on carvedilol (29±16 mg/day) and 18 on metoprolol (87±52 mg/day). The 3, 6, 9, 12 and 24 months cumulative survival was of 96%, 89%, 86%, 86% and 86%, respectively, in the 28 patients who underwent Tx and of 97%, 94%, 79%, 73% and 39% in the 34 patients remaining in the waiting list (p

The role of polyamines in cartilage is not known: they may be somehow related to the mechanism of calcification. In epiphyseal cartilage from calf scapulas, they are more concentrated in the ossifying area, where calcification takes place, than in the resting region. Spermidine is present in greater amounts than spermine and putrescine. Since ornithine decarboxylase (EC 4.1.1.17) is measurable only in the resting region of the tissue, it is in this area that polyamine biosynthesis occurs, while they accumulate in the ossifying area. Immunohistochemical evidence is obtained that only in the ossifying zone is spermidine extracellular. It is at this level that the matrix is rearranged to become calcified, and proteoglycans are dissociated and partially removed. The effect of polyamines on solutions of proteoglycan subunits has been studied in vitro by following variations of turbidity and viscosity. While in the presence of putrescine the specific viscosity decreases to asymptotic values, in the presence of either 30 mM spermidine or 2.5-10 mM spermine, the decrement is more marked. At the same concentrations, increase of the turbidity of proteoglycan subunit solutions was observed. Only spermidine showed the capacity of displacing proteoglycan subunits from a column of Sepharose 4B-type II collagen: at 15 mM concentration, about 90% of proteoglycans were removed from the column. Alkaline phosphatase activity, which plays an important role in calcification, is enhanced by spermidine and spermine. These results obtained in vitro support the hypothesis that polyamines may be related to calcification of preosseous cartilage.

Twenty-four-hour intragastric acidity was measured continuously over five separate occasions in 15 patients with healed duodenal ulcers. They were randomized to receive either placebo, cimetidine 800 mg, ranitidine 150 mg, famotidine 20 mg, or nizatidine 150 mg, given at 2200 hr in double-blind fashion. All H2-receptor blockers were more effective than placebo in suppressing both circadian (P less than 0.05-P less than 0.01) and nocturnal (P less than 0.002) gastric acidity, while there was no significant differences between the effects of the four active drugs in the same time periods. The percentage of nocturnal acid inhibition (2300-0800 hr) over placebo in terms of H+ values was virtually 100% with all active treatments. The effect on daytime (0800-1700 hr) and evening (1700-2300 hr) acidity of both placebo and the four H2-receptor antagonists was similar. Therefore, in the above doses H2-receptor blockers guarantee overnight anacidity to a similar degree and cause the physiological buffering of daily meals on gastric acidity to be fully exploited. Furthermore, the reducing effect of daily meals on drug action can be prevented. Since strong acid suppression strictly confined to the nocturnal period has been shown to be closely correlated with the highest ulcer healing rates, it is suggested that single low bedtime doses of H2-receptor antagonist should be evaluated in the acute treatment of duodenal ulcer.