190 research outputs found
PREDICTION OF OPTIMAL WARFARIN MAINTENANCE DOSE USING ADVANCED ARTIFICIAL NEURAL NETWORKS
No full textIntroduction. The individual response to vitamin K antagonists (VKA) is highly variable, being influenced by clinical factors and genetic variants of enzymes that are involved in the metabolism of VKA (CYP2C)) and vitamin K (VKORC1). Currently, the dose of VKA is adjusted based on measurements of the prothrombin time. In the last years, mathematical algorithms were developed for estimating the appropriate VKA dose, based on different mathematical approaches working on clinical and genetic data. Artificial Neural Networks (ANN) are computerized algorithms resembling interactive processes of the human brain, which allow to study very complex non-linear phenomena like biological systems. Aim. To evaluate the performance of new generation ANN on a large data base of patients on chronic VKA treatment. Methods. Clinical and genetic data from 377 patients (186 m; 191 f) treated with a VKA (warfarin) average weekly maintenance dose (WMD) of 23.7 mg (11.5 SD) were used to create a dose algorithm. Forty-eight variables, including demographic, clinical and genetic data (5 CYP2C9 and 3 VKORC1 genetic variants) were entered into Twist® system, which can select fundamental variables during their evolution in search for the best predictive model. The final model, based on 23 variables expressed a functional approximation of the actual dose within a validation protocol based on a tripartite division of the data set (training, testing, validation). Results. In the validation cohort, the pharmacogenetic algorithm reached high accuracy, with an average absolute error of 5.7 mg WMD. In the subset of patients requiring ≤21 mg (45 % of the cohort) and 21-49 mg (51 % of the cohort) the absolute error was 3.86 mg and 5.45 with a high percentage of subjects being correctly identified (72%, 74% respectively). Conclusion. ANN can be applied successfully for VKA maintenance dose prediction and represent a robust basis for a prospective multicentre clinical trial of the efficacy of genetically informed dose estimation for patients who require VKA
Cholesterol metabolism in primary biliary cirrhosis during simvastatin and UDCA administration
No full textLittle is known about the effects of cholesterol-lowering agents in hypercholesterolemic patients with primary biliary cirrhosis (PBC). The aim of this study was to compare the changes induced by simvastatin and ursodeoxycholic acid (UDCA) on cholesterol metabolism in patients with PBC and preserved liver function. Six patients with PBC were administered simvastatin (40 mg/day) for 30 days and, after a washout period of 30 days, ursodeoxycholic acid (600 mg/day) for 30 days. Serum levels of lathosterol, campesterol, 7 alpha-hydroxycholesterol, and 27-hydroxycholesterol were measured by gas chromatography-mass spectrometry. During simvastatin administration, reduction of cholesterol levels (34% in 30 days) was paralleled by the decrease of lathosterol (55%), whereas concentrations of campesterol and of the two hydroxysterols were not substantially modified. During ursodeoxycholic acid administration, a trend toward a decrease of serum cholesterol concentrations was observed after only one year of treatment, and these changes were paralleled by the decrease of campesterol serum levels. Both simvastatin and UDCA were well tolerated, and a reduction of serum liver enzyme levels occurred with the latter. Simvastatin proved to be safe and effective in reducing serum cholesterol levels in patients with PBC by an inhibitory effect on cholesterol synthesis occurring within 24 h. --Del Puppo, M., M. Galli Kienle, A. Crosignani, M. L. Petroni, B. Amati, M. Zuin, and M. Podda. Cholesterol metabolism in primary biliary cirrhosis during simvastatin and UDCA administration. J. Lipid Res. 2001. 42: 437--441
Effects of fenofibrate on biliary lipids and bile acid pool size in patients with type IV hyperlipoproteinemia
No full textLipid-lowering drugs, notably clofibrate, may induce a supersaturation of bile with cholesterol, thus favouring the development of cholelithiasis. In order to see whether or not fenofibrate, a clofibrate analogue, has any influence on biliary cholesterol saturation, we determined the lipid composition of gallbladder bile and the bile acid pool size in 15 patients with type IV hyperlipoproteinemia before and after 6-8 weeks of treatment with a daily dose of 300 mg of the drug. At the end of treatment plasma triglycerides were markedly decreased, whereas no detectable influence on liver cell integrity or bile excretory function could be demonstrated in any patient by comparing the pre- and post-treatment serum levels of liver enzymes, bilirubin and bile acids. The mean bile cholesterol saturation index did not significantly change and cholic acid was the only bile acid to increase significantly. In the 3 patients with an initial saturation index of less than 1, bile became supersaturated with cholesterol. However, in no case were the limits of the metastable phase for cholesterol solubility in bile exceeded. Though only long-term prospective studies may give a definitive answer about the lithogenic potential of fenofibrate, our data on gallbladder bile composition in patients with type IV hyperlipoproteinemia indicate that it is not very likely that fenofibrate administration will increase the risk of gallstone formation in severely hyperlipidemic patients
Effect of phosphodiesterase-5 inhibition on apoptosis and Aβ load in aged mice
No full textAge-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aβ) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aβ production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aβ42 production and the increase of the Aβ42:Aβ40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging
Effect of different doses of ursodeoxycholic acid in chronic liver disease
No full textRecent clinical studies have indicated that ursodeoxycholic acid (ursodiol), administered at dosages ranging between 10 and 15 mg/kg/day, improves liver function indices in both cholestatic and inflammatory chronic liver diseases. These dosages would be considered high for the use of ursodiol in gallstone dissolution therapy. To investigate the dose-response relationship to ursodiol administration, we planned a few studies in patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and chronic hepatitis (CH). Patients with PBC were subdivided into two groups on the basis of their serum bilirubin values, with 2 mg/dl as the dividing line. Ursodiol was given at dosages of 250, 500, and 750 mg/day for consecutive periods of two months, the order of treatment being randomly assigned to each patient. The enrichment with ursodiol of biliary bile acids was similar in both PBC and CH and, within the PBC group, in both anicteric and icteric patients. Highly significant decreases in serum enzyme levels were observed in all groups with the 250 mg/day dose, corresponding to about 4-5 mg/kg/day. The two higher doses induced further improvements in serum enzyme levels, especially in patients with PBC, but no significant differences were found between the 500 and the 750 mg/day doses. The improvements were roughly proportional to the enrichment of conjugated biliary bile acids with ursodiol. Serum bilirubin levels, an important prognostic factor in PBC, were also significantly reduced by ursodiol administration in patients with initial serum levels higher than 2 mg/dl. The present study indicated that ursodiol is a potentially useful drug for chronic liver disease.(ABSTRACT TRUNCATED AT 250 WORDS
Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose-response study
No full textTauroursodeoxycholic acid, a highly hydrophilic bile acid, may be of therapeutic value for chronic cholestatic liver diseases. We performed a dose-response study on 24 patients with primary biliary cirrhosis who were randomly assigned to receive 500, 1000, or 1500 mg daily of tauroursodeoxycholic acid for six months. Biliary enrichment with ursodeoxycholic acid ranged from 15% to 48% and was not related with the dose. Serum liver enzyme levels decreased significantly after the first month of treatment with all the three doses. No significant difference among the three doses was found, although further reduction over time occurred with 1000 and 1500 mg daily. Plasma total and HDL cholesterol significantly decreased in patients administered the two higher doses. Diarrhea was the only side effect. In conclusion, a dose of about 10 mg/kg body wt/day of tauroursodeoxycholic acid should be used for long-term studies in patients with primary biliary cirrhosis
Stream water chemistry in the arsenic-contaminated Baccu Locci mine watershed (Sardinia, Italy) after remediation
No full textThe abandoned Pb-As Baccu Locci mine represents the first and only case of mine site remediation in Sardinia, Italy. Arsenic is the most relevant environmental concern in the Baccu Locci stream watershed, with concentrations in surface waters up to and sometimes over 1 mg/L. The main remediation action consisted in creation of a "storage site", for the collection of contaminated materials from different waste-rock dumps and most of tailings piles occurring along the Baccu Locci stream. This paper reports preliminary results on the level of contamination in the Baccu Locci stream after the completion of remediation measures. Post-remediation stream water chemistry has not substantially changed compared to the pre-remediation situation. In particular, dissolved As maintains an increasing trend along the Baccu Locci stream, with a concentration of about 400 μg/L measured at a distance of 7 km from the storage site. Future monitoring will provide fundamental information on the effectiveness of remediation actions conducted and their applicability to other mine sites in Sardinia. At the stage of mine site characterisation of future remediation plans, it is recommended to pay more attention to the understanding of mineralogical and geochemical processes responsible for pollution. Moreover, mixing of materials with different composition and reactivity in a storage site should require careful consideration and long-term leaching tests
Unlocking Strategic and Critical Raw Materials: Assessment of Zinc and REEs Enrichment in Tailings and Zn-Carbonate in a Historical Mining Area (Montevecchio, SW Sardinia)
No full textMining wastes are often both a potential source of Strategic and Critical Raw Materials (SRMs and CRMs) and a threat to the environment. This study investigated the potential of mining wastes from the Montevecchio district of Sardinia, Italy, as a source of SRMs and CRMs. The tailings from Sanna mine processing plant were characterized by X-ray diffraction,
Scanning Electron Microscopy, and Plasma Mass Spectometry, showing contents of 1.2 wt% of lead, 2.6 wt% of zinc, and about 600 mg/kg of Rare Earth Elements (REEs). White patinas formed in the riverbed, composed
by Zn-bearing minerals (hydrozincite and zincite), also contain about 2900 mg/kg of REEs. Characterization of white patinas along the Rio Roia Cani evidenced that their precipitation from water also involves an uptake of Rare Earth Elements, enhancing their contents by an order of magnitude
compared with tailings. The process of REEs concentration in Zn-bearing minerals of white patinas is a candidate as a tool for the economic recovery of these elements. These findings suggest that mining wastes from the Montevecchio district could be considered a potential resource for extracting SRMs and CRMs
Primary Segmental Omental Torsion, mimicking acute appendicitis
No full textPrimary segmental omental torsion (PSOT) is a very rare cause of acute abdominal pain, and it may often imitate the clinical picture of acute appendicitis. In instances of acute abdominal pain without anorexia, nausea, and vomiting, omental torsion should be included in the differential diagnosis. Any misdiagnosis may lead to major complications such as intraabdominal abscesses and adhesions. A 63-year-old overweight man with a body mass index (BMI) of 41 Kg/m2 presented to the emergency department on a remote island with acute abdominal pain. His medical history included type 2 diabetes mellitus managed with insulin, essential hypertension, osteoarthritis, and no previous abdominal operations. He reported a sharp pain originating in the epigastrium and the right hypochondrium that started five days prior. Physical examination revealed rebound tenderness and guarding across the abdomen with a positive McBurney sign. However, the patient did not report vomiting and was not nauseous. Vital signs were as follows: blood pressure 116/56 mmHg, heart rate 98 beats/min, respiratory rate 19 breaths/min, and a temperature of 38.2 0C. Laboratory results showed a white blood cell count of 10.6, neutrophils of 8.11, C-reactive protein (CRP) 74 mg/l, haemoglobin11.6 g/dl, and hematocrit 36.9%. Due to the absence of a radiographer at the hospital during that period, no imaging investigations were conducted. Diagnostic laparoscopy demonstrated diffused hemoperitoneum and necrotic mass at the site of the hepatic flexure. Initially suspected to be an advanced colon cancer, the decision was made to proceed with open surgery. The necrotic segment of the omentum was found at the right superior point of attachment of the omentum to the hepatic flexure. Consequently, the necrotic segment of the omentum was resected. A thorough investigation of the abdominal cavity did not detect any other abnormalities or pathologies. The patient recovered uneventfully and was transferred to the surgical ward. Torsion of the omentum is a very rare cause of acute abdominal pain. This case highlights the necessity of considering PSOT in the differential diagnosis of acute abdominal pain, especially in cases where symptoms are suggestive of appendicitis but diagnostic findings are negative
Geochemistry of rare earth elements in water and solid materials at abandoned mines in SW Sardinia (Italy)
No full textThis study investigates the behavior of rare earth elements (REE) in near-neutral waters that drain abandoned mines in SW Sardinia (Italy). The REE, together with other major and minor components, were determined in waters (146 samples) and solid materials (13 samples). Research was performed to evaluate the main factors that control the geochemical behavior of REE in non-acidic mining environments. Zinc, cadmium and lead are the main contaminants in the study area, either in the processing residues or in the waters that drain the mine site. Contamination of stream waters extends several km downstream of the mine, till the Mediterranean Sea.
The mine tailing (MT) materials are the main REE source, with peak concentrations of 300 mg/kg ΣREE. PAAS-normalized patterns of MT are characterized by light REE (LREE) enrichment with respect to heavy REE (HREE). The waters flowing out of the MT heaps are near-neutral (6.2 to 7.0 pH), with Zn-sulfate dominant composition, and a mean concentration of 53 μg/l ΣREE. Drainages from MT and an adit flow in the Naracauli stream headwaters (mean 1.4 μg/l ΣREE). Concentrations of REE in the Naracauli stream decrease dramatically about 400 m downstream of source. The REE decrease matches Fe and Zn decrease in waters, probably because the REE are sorbed on freshly precipitated solid phases.
Sorption processes, and/or co-precipitation with secondary phases, appear to control the REE geochemistry in the studied waters under near-neutral conditions. Also, despite the non-acidic environment, it is worth to observe that small changes in pH seem to affect the mobility of REE at Naracauli.
The PAAS-normalized REE patterns in the waters generally reflect the PAAS-normalized REE patterns in the solid materials with which the water interacts, either MT or secondary phases such as Fe-hydroxide and bio-hydrozincite. As it is expected in waters under oxidizing conditions, patterns with negative Ce anomalies are developed due to the poor solubility of Ce+ 4 species, and its consequent scavenging in solid phases. However, there is an exception: Ce shows a poor affinity for the bio-hydrozincite mineral, probably reflecting the role of bacteria in the precipitation of the Naracauli hydrozincite
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