New 1,2,3-triazolo[1,5-a]quinoxalines: synthesis and binding to benzodiazepine and adenosine receptors. II

On pursuing research about 1,2,3-triazolo[1,5-a]quinoxalines, in this paper we report synthesis and binding assays toward the benzodiazepine and A(1) and A(2A) adenosine receptors, of a new series of derivatives, bearing some structural changes (introduction of fluorine and trifluoromethyl in the seventh position, amino substituents in the fourth position, benzyl group in the fifth position and aroyl substituents in the third position). The biological tests have shown that only the 7-fluorosubstituted compounds 3a and 4a and the N-benzyl derivative 7 have a good affinity toward the benzodiazepine receptors, while only the 7-trifluoromethyl substituted compound 3b presents a moderate affinity with low selectivity toward the A(1) adenosine receptors. The other structural modifications strongly decreased biological activity.     

Biotechnological engineering of heparin/heparan sulphate: a novel area of multi-target drug discovery

Heparin is a sulphated glycosaminoglycan currently used as an anticoagulant and antithrombotic drug. It consists largely of 2-O-sulphated IdoA not l&r arrow N, 6-O-disulphated GlcN disaccharide units. Other disaccharides containing unsulphated IdoA or GlcA and N-sulphated or N-acetylated GlcN are also present as minor components. This heterogeneity is more pronounced in heparan sulphate (HS), where the low-sulphated disaccharides are the most abundant. Heparin/HS bind to a variety of biologically active polypeptides, including enzymes, growth factors and cytokines, and viral proteins. This capacity can be exploited to design multi-target heparin/HS-derived drugs for pharmacological interventions in a variety of pathologic conditions besides coagulation and thrombosis, including neoplasia and viral infection. The capsular K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor N-acetyl heparosan. The possibility of producing K5 polysaccharide derivatives by chemical and enzymatic modifications, thus generating heparin/HS-like compounds, has been demonstrated. These K5 polysaccharide derivatives are endowed with different biological properties, including anticoagulant/antithrombotic, antineoplastic, and anti-AIDS activities. Here, the literature data are discussed and the possible therapeutic implications for this novel class of multi-target "biotechnological heparin/HS" molecules are outlined.     

Second Biopsy of Axillary Sentinel Lymph Node for Reappearing Breast Cancer After Previous Sentinel Lymph Node Biopsy

Background Sentinel lymph node biopsy (SLNB) is a safe and accurate axillary staging procedure for patients with primary operable breast cancer. An increasing proportion of these patients undergo breast-conserving surgery, and 5% to 15% will develop local relapses that necessitate reoperation. Although a previous SLNB is often considered a contraindication for a subsequent SLNB, few data support this concern. Methods Between January 2000 and June 2004, 79 patients who were previously treated at our institution with breast-conserving surgery and who had a negative SLNB for early breast cancer developed, during follow-up, local recurrence that was amenable to reoperation. Eighteen of these patients were offered a second SLNB because of a clinically negative axillary status an average of 26.1 months after the primary event. Results In all 18 patients (7 with ductal carcinoma-in-situ and 11 with invasive recurrences), preoperative lymphoscintigraphy showed an axillary sentinel lymph node, with a preoperative identification rate of 100%, and 1 or more SLNs (an average of 1.3 per patient) were surgically removed. Sentinel lymph node metastases were detected in two patients with invasive recurrence, and a complete axillary dissection followed. At a median follow up of 12.7 months, no axillary recurrences have occurred in patients who did not undergo axillary dissection. Conclusions Second SLNB after previous SLNB is technically feasible and likely effective in selected breast cancer patients. A larger population and longer follow-up are necessary to confirm these preliminary data.     

Monitoring of chemical elements and oxidative damage in patients affected by Alzheimer's disease

The haematic concentration of 26 metals and the oxidative damage in 60 patients (20 males and 40 females) affected by Alzheimer's disease and 44 healthy individuals (33 males and 11 females) were compared. In patients, the following significant (p < or = 0.05) discrepancies were found: i) increment of Ca, Cd, Hg, Mg, Si and Sn, and decrement of Al, Co, Fe and Zn in serum; ii) higher concentrations of Cu, Li, Mn, Sn and Zr and lower of Fe, Hg, Mo in blood; iii) overproduction of oxidant species (SOS) and decrease of the anti-oxidant capacity (SAC) (p < or = 0.001, for both). Variables that, joined, better discriminated between patients and controls resulted to be Si, SOS, SAC, Co, Ca, Al in serum (94% of cases correctly classified) and Cu, Zr, Mo and Fe in blood (90% of cases properly categorized).     

The network of the Italian laboratories: a proficiency test on the quantification of trace elements in serum

A proficiency test on the quantification of Al, Cu, Mn, Se and Zn in serum was carried out to verify the performance of about 30 regional laboratories of the network of Italian laboratories. The exercise consisted of four runs in which the laboratories were free in choosing analytical methods to determine trace elements in freeze-dried animal serum. Laboratories performances were evaluated by the study of statistical functions as Coefficients of Variation (CV), Youden plot and Z-score value. As for Al, the results were generally characterized by good accuracy and precision, in spite of the low levels of the element (5-7 microg l(-1)). Copper determination had some problems only at low concentration (about 160 microg l(-1)--first run), in which an elevated number of anomalous data were found. Better data were achieved for Zn, for which anomalous values were mainly stragglers than outliers. Due to the low number of data for Mn (concentrations from 0.6 to 60 microg l(-1)) and Se (concentration from 45 to 106 microg l(-1)), a restricted statistical treatment was applied; for these elements high CV values were found (range from 30 to 80%). The results of this trial confirmed that participation in a proficiency test represents a benefit for all analytical laboratories. In fact, with few exceptions, most of the participants improved their performances in terms of Z-score values.     

Role of different nocturnal monitorings in the evaluation of CPAP titration by autoCPAP devices

The aim of the study was to assess how the analysis of different signals recorded during application of automatic continuous positive airway pressure (autoCPAP) devices improves the evaluation of pressure titration in patients with obstructive sleep apnea syndrome (OSAS) naive to treatment. Seventy-two patients underwent nocturnal polysomnography during autoCPAP (Autoset T, ResMed, Sydney, Australia) application. Progressively more complex combinations of signals were analysed in consecutive steps. According to the analysis of oxyhemoglobin saturation (SaO(2)) alone, a fixed CPAP level suitable for treatment could not be identified in 3 subjects. When analysis of posture was added, titration was considered unsatisfactory in 1 more subject, due to a short time spent supine. Further, addition of flow and respiratory movements led to consider titration unsatisfactory in 1 more subject. Analysis of all polysomnographic signals demonstrated a not fully reliable titration in 9 subjects: 1 with short sleep duration, 2 without REM sleep, 4 with a short sleep time spent supine, and 3 subjects (already identified by SaO(2)) with insufficient correction of respiratory disorders even when a relatively high CPAP was administered. Mask leaks did not hamper titration. CPAP titration by automatic devices alone results in imperfect titration in >10% subjects naive to ventilatory treatment. Only polysomnographic recording ensures titration reliability in all patients. Further research is needed to identify simple and economic methods to reliably start the CPAP treatment.     

Plaque-removing effect of a toothbrush, dental floss, and a toothpick

The ability of three different oral hygiene devices to remove 2-day-old bacterial deposits was evaluated on 21 young adults with healthy periodontia. On buccal tooth surfaces, the cleaning effect of a multitufted nylon brush was superior to that of a wooden toothpick or unwaxed dental floss. On lingual surfaces, the toothpick was as effective as the brush. On the visible portions of proximal surfaces, all three devices were equally efficient. A combined cleaning exercise with all three instruments together yielded significantly better results than did the use of each single device. Eight subjects were able to remove all disclosable deposits.     

The "schola medica salernitana": the forerunner of the modern university medical schools

The schola medica salernitana is considered the oldest medical school of modern civilization. Salerno's long medical tradition began during the Greco-Roman period in a Greek colony named Elea, where Parmenides decided to found a medical school. The fame of the school became more and more important during the 10th century, and it was best known in the 11th century. In the middle of 12th century, the school was at its apogee, and Salerno provided a notable contribution to the formulation of a medical curriculum for medieval universities. The most famous work of the Salernitan School was the Regimen Sanitatis Saleritanum, a Latin poem of rational, dietetic, and hygienic precepts, many of them still valid today. The school also produced a physician's reference book, with advice on how to treat a patient, a sort of code of conduct to help the physician to respect the patient and his or her relatives. The first science-based surgery appeared on the scene of the discredited medieval practice in Salerno, thanks to Roger of Salerno and his fellows. He wrote a book on surgery, called Rogerina or Post Mundi Fabricam, in which surgery from head to toe is described, with surprising originality. The important contribution to the School of Salerno made by women as female practitioners is outlined, and among them, Trotula de Ruggiero was the most renowned. The period when the School of Salerno, universally recognized as the forerunner of the modern universities, became a government academy was when Frederick II reigned over the Kingdom of the Two Sicilies, as Emperor of the Holy Roman Empire.     

Octogenarians with contralateral carotid artery occlusion: a cohort at higher risk for carotid endarterectomy?

PURPOSE: Carotid angioplasty and stenting has been proposed as a treatment option for carotid occlusive disease in patients at high risk, including those 80 years of age or older or with contralateral carotid occlusion. We analyzed 30-day mortality and stroke risk rates of carotid endarterectomy (CEA) in patients aged 80 years or older with concurrent carotid occlusive disease. METHODS: From a retrospective review of 1000 patients undergoing 1150 CEA procedures to treat symptomatic and asymptomatic carotid lesions over 13 years, we identified 54 patients (5.4%) aged 80 years or older with concurrent contralateral carotid occlusion. These patients were compared with 38 patients (3.8%) aged 80 years or older with normal or diseased patent contralateral carotid artery and 81 patients (8.1%) younger than 80 years with contralateral carotid occlusion. All CEA procedures involved either standard CEA with patching or eversion CEA, and were performed by the same surgeon, with the patients under deep general anesthesia and cerebral protection involving continuous perioperative electroencephalographic monitoring for selective shunting. Shunting criteria were based exclusively on electroencephalographic abnormalities consistent with cerebral ischemia. RESULTS: The 30-day mortality and stroke rate in patients aged 80 years or older with concurrent contralateral carotid occlusion was zero. CONCLUSIONS: The concept of high-risk CEA needs to be revisited. Patients with two of the criteria considered high risk in the medical literature, that is, age 80 years or older and contralateral carotid occlusion, can undergo CEA with no greater risks or complications. Until prospective randomized trials designed to evaluate the role of carotid angioplasty and stenting have been completed, CEA should remain the standard treatment in such patients.