PATE 2000 Sorrento: a modern, effective instrument for defining haemorrhoids. A multicentre observational study conducted in 930 symptomatic patients

In 2000, the Italian Society of Coloproctology and the UCP (Coloproctology Units) devised a new haemorrhoid classification system, named PATE 2000 Sorrento, which is capable of defining all the main characteristics of the disease. Any new system should be able to predict the real extent of hemorrhoids by means of a specific index in order to help physicians in choosing the best therapeutic option. The authors present the results of a national multicentre study of 930 patients with symptomatic haemorrhoids. Nineteen patients (2%) could not be classified with the old haemorrhoid classification, while PATE 2000 Sorrento proved successful in classifying all patients. The difference was statistically significant. The new classification enables us to establish a specific score for the disease. In order to better evaluate the clinical impact of the scores obtained with PATE 2000 Sorrento, the authors analyzed the correlation between the score itself and the therapy chosen by each individual centre. The highest scores always corresponded to the choice of surgical hemorrhoidectomy, while in the case of lower values each centre seemed to be in doubt between medical therapy and other less invasive procedure such as sclerotherapy or rubber band ligation. These data were statistically significant (P < 0.0001). On the basis of our findings, PATE 2000 Sorrento seems to confirm its scientific and clinical relevance and could be a useful tool for the choice of the best treatment for each individual patient.     

The usefulness of adenosine 99mTc tetrofosmin SPECT for the diagnosis of left anterior descending coronary artery disease in patients with chest pain and left bundle branch block

OBJECTIVES: The aim of this study was to assess the usefulness of 99mTc tetrofosmin single photon emission computed tomography (SPECT) for the diagnosis of left anterior descending (LAD) coronary artery disease in 60 subjects with left bundle branch block (LBBB) admitted for chest pain. METHODS AND RESULTS: Adenosine 99mTc tetrofosmin SPECT, transthoracic echocardiogram and coronary angiography were performed, by protocol, in 60 non-infarcted consecutive patients. The mean left ventricular ejection fraction (LVEF) was 41.6 +/- 10.8%. A significant angiographic disease of the LAD was found in 15 (25%) patients. The sensitivity and the specificity of SPECT was found to be 75% and 89%, respectively; the positive predictive value (PPV) was 70% with a negative predictive value (NPV) of 91%. During the adenosine infusion the QRS complex width reduced from 131.3 +/- 29.6 ms to 125.5 +/- 28.6 ms in the patients without LAD involvement (P = 0.008) but remained unchanged in LAD disease patients (P = 0.1). Combining SPECT information and QRS analysis the sensitivity increased to 87% with unchanged specificity, the PPV was 74% and the NPV resulted 95%. At 2-year follow-up 13 (22%) patients experienced a cardiac event. Using Kaplan-Meier analysis, an LVEF of < or = 35% was the only predictor of cardiac events (P = 0.01, log-rank 6.2). CONCLUSIONS: A quarter of patients with LBBB complaining of chest pain had LAD coronary disease. The highly negative predictive value of adenosine SPECT could help in the exclusion of LAD disease, especially when the SPECT image is combined with the QRS analysis.     

3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides as a new class of synthetic histone deacetylase inhibitors. 2. Effect of pyrrole-C2 and/or -C4 substitutions on biological activity

Previous SAR studies (Part 1: Mai, A.; et al. J. Med. Chem. 2003, 46, 512-524) performed on some portions (pyrrole-C4, pyrrole-N1, and hydroxamate group) of 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1a) highlighted its 4-phenylacetyl (1b) and 4-cynnamoyl (1c) analogues as more potent compounds in inhibiting maize HD2 activity in vitro. In the present paper, we investigated the effect on anti-HD2 activity of chemical substitutions performed on the pyrrole-C2 ethene chains of 1a-c, which were replaced with methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds 2). Biological results clearly indicated the unsubstituted ethene chain as the best structural motif to get the highest HDAC inhibitory activity, the sole exception to this rule being the introduction of the 1,3-butadienyl moiety into the 1a chemical structure (IC50(2f) = 0.77 microM; IC50(1a) = 3.8 microM). IC50 values of compounds 3, prepared as 1b homologues, revealed that between benzene and carbonyl groups at the pyrrole-C(4) position a hydrocarbon spacer length ranging from two to five methylenes is well accepted by the APHA template, being that 3a (two methylenes) and 3d (five methylenes) are more potent (2.3- and 1.4-fold, respectively) than 1b, while the introduction of a higher number of methylene units (see 3e,f) decreased the inhibitory activities of the derivatives. Particularly, 3a (IC50 = 0.043 microM) showed the same potency as SAHA in inhibiting HD2 in vitro, and it was 3000- and 2.6-fold more potent than sodium valproate and HC-toxin and was 4.3- and 6-fold less potent than trapoxin and TSA, respectively. Finally, conformationally constrained forms of 1b,c (compounds 4), prepared with the aim to obtain some information potentially useful for a future 3D-QSAR study, showed the same (4a,b) or higher (4c,d) HD2 inhibiting activities in comparison with those of the reference drugs. Molecular modeling and docking calculations on the designed compounds performed in parallel with the chemistry work fully supported the synthetic effort and gave insights into the binding mode of the more flexible APHA derivatives (i.e., 3a). Despite the difference of potency between 1b and 3a in the enzyme assay, the two APHA derivatives showed similar antiproliferative and cytodifferentiating activities in vivo on Friends MEL cells, being that 3a is more potent than 1b in the differentiation assay only at the highest tested dose (48 microM).     

Rivastigmine in vascular dementia

Patients with vascular dementia (VaD) show cholinergic deficits that may result in characteristic clinical syndromes for different subtypes of the condition. Subcortical VaD is characterised by executive dysfunction and behavioural problems, reflecting deterioration of the frontal lobe. Based on limited open-labelled controlled studies of rivastigmine in VaD, this article aims to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effects on the typical symptoms of subcortical VaD. Long-term rivastigmine treatment is safe and effective. Improvements in domains that characterise subcortical VaD were observed, indicating that rivastigmine may have provided targeted treatment in areas of the brain that are particularly affected in this patient population. A large, double-blind study of rivastigmine in patients with VaD is clearly warranted.     

Anti-IgE monoclonal antibody (omalizumab) in the treatment of atopic asthma and allergic respiratory diseases

Since the discovery of immunoglobulin E (IgE) antibodies thirty-six years ago, our understanding of the mechanisms of allergy has improved to such an extent that we can now better differentiate allergy from non-allergic hypersensitivity, and allergic/atopic from intrinsic/non-atopic bronchial asthma. IgE antibodies are crucial immune mediators of airway inflammation in allergic atopic asthma and IgE-mediated hypersensitivity reactions are the likely mechanisms of allergen-induced airway obstruction. In addition, IgE may cause chronic airway inflammation in asthma through effector cells activated via high-affinity (Fcepsilon RI) or low-affinity (Fcepsilon RII) IgE receptors. Therapeutic anti-IgE antibodies able to reduce free IgE levels and to block the binding of IgE to Fcepsilon RI without cross-linking IgE and triggering degranulation of IgE-sensitised cells have been developed. This non-anaphylactogenic anti-IgE monoclonal antibody (rhuMAb-E25; omalizumab) binds IgE at the same site as these antibodies bind Fcepsilon RI and Fcepsilon RII. As a consequence, omalizumab inhibits IgE effector functions by blocking IgE binding to high-affinity receptors on IgE effector cells and does not cause mast cell or basophil activation because it cannot bind to IgE on cell surfaces where the Fcepsilon R1 receptor already masks the anti-IgE epitope. Studies in patients with atopic asthma demonstrated that omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen. In several clinical controlled trials omalizumab resulted to be able to reduce asthma-related symptoms, to decrease corticosteroid use and to improve quality of life of asthmatic patients.The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis and food allergies), a favourable side-effect profile and a twice-monthly dosing frequency.     

Prognostic significance of nm23 gene product expression in patients with colorectal carcinoma treated with radical intent

Reports of the relationship between the putative metastasis suppressor NM23 and metastasis and/or survival in colorectal cancer patients are conflicting. This study aimed to investigate whether nm23 immunostaining is correlated with established prognostic variables (Dukes' stage, degree of tumour differentiation, T stage and nodal involvement) in colorectal carcinomas for the patients treated with radical intent using Kruskal chi(2) analysis. The rates of survival at five years were estimated with the use of the Kaplan-Meier product-limit method with 95% confidence intervals derived by Greenwood's formula and the curves were compared with the use of the log-rank test. Cox proportional-hazard regression model was used to identify multivariate predictors and the corresponding outcome. The staining was performed on 112 paraffin-embedded surgical specimens collected between 1989-1992 using a monoclonal anti-nm23 antibody. Follow-up of patients was until time of death or for at least 5 years. There was not a significant correlation between tumour staging, degree of tumour differentiation, nodal involvement and nm23 status. Furthermore, there was no significant association with overall 5-year survival, disease recurrence, tumour site, age or sex. Although nm23 may be involved in suppressing tumour metastasis, nm23 immunohistochemistry has no prognostic value in colorectal cancer. For these reasons nm23 does not contribute further to the prognostic information provided by established prognostic variables.     

Corticobasal degeneration: structural and functional MRI and single-photon emission computed tomography

We studied seven patients with corticobasal degeneration (CBD) from a clinical and imaging perspective. We describe the main morphological features of CBD and, using functional MRI, try to define the possible role of the parietal lobe in simple and complex learned motor sequences. We showed decreased activation of the parietal lobe contralateral to the more affected arm, when movements, simple or complex, are performed with that hand. Moreover we found that functional imaging can demonstrate parietal and motor cortex dysfunction before structural, and even single-photon emission computed tomography changes become evident.     

Prospective, randomized study of external jugular vein patch versus polytetrafluoroethylene patch during carotid endarterectomy: perioperative and long-term results

OBJECTIVES: The purpose of this study was to evaluate the relative risks and advantages of using external jugular vein (EJV) patch, compared with polytetrafluoroethylene (PTFE) patch, during carotid endarterectomy. The primary end point was the relevant neurologic complication rate (RNCR; fatal or disabling stroke) at any time during follow-up. Secondary end points included stroke-free survival, 30-day and long-term mortality, recurrent stenosis rate (> or =50%), occlusion, patch infection, aneurysm formation, and other local complications. METHODS: The study, a prospective randomized clinical trial carried out at a single center, was divided into two 3-year phases: December 1996 to March 1999, when patients were enrolled, and March 1999 to March 2002, which was the follow-up period. Inclusion criteria included an external jugular vein suitable for patching, defined as vein diameter 3 mm or larger and absence of collateral vessels noted on preoperative color duplex ultrasound scans. Patients were prospectively randomized 1:1 to receive either the EJV (n = 80; group A) or synthetic (n = 80; group B) patch. RESULTS: Carotid endarterectomy and patching was performed by one surgeon. At 30 months the RNCR-free rate, analyzed with the Kaplan-Meier method, was 98.7% for group A (1 ipsilateral lethal stroke) and 94.6% for group B (4 ipsilateral disabling strokes), and remained stable to 60 months. No statistical difference was observed with the log-rank test. Stroke-free survival rate was 100% for group A and 98.7% for group B at 1 year, 98.7% for group A and 93.6% for group B (1 ipsilateral minor stroke) at 30 months, and was unchanged at 60 months. Life table analysis demonstrated freedom from significant recurrent stenosis (> or =50%) of 97.5% for both groups at 6 months, 93.6% for group A and 92.2% for group B at 30 months, and 90.2% for group A and 86.7% for group B at 60 months. No statistical difference was observed with the log-rank test. In no patients was recurrent stenosis greater than 70%. No aneurysm formation was noted during follow-up. CONCLUSIONS: We can conclude, with the power limitation of the study, that carotid endarterectomy can be safely performed with either the EJV or PTFE patch. Advantages of the EJV for carotid angioplasty include no cost for material, low risk for graft infection, and preservation of the saphenous vein.