Biomedical subjects

L Benedetti

Publications and source records attributed to L Benedetti.

At least 19 recordsLinked to original sources

PubMed2006

Prevalence and characteristics of peripheral neuropathy in hepatitis C virus population.

OBJECTIVE: To assess the prevalence of peripheral neuropathy (PN) and its correlation with cryoglobulinemia (CG) in an unselected, untreated referral hepatitis C virus (HCV) population. PATIENTS AND METHODS: Two hundred and thirty four patients (120 women and 114 men) with untreated HCV infection were consecutively enrolled by seven Italian centres. Clinical neuropathy was diagnosed when symptoms and signs of peripheral sensory or motor involvement were present. Median, ulnar, peroneal, and sural nerves were explored in all patients and distal symmetric polyneuropathy was diagnosed when all explored nerves or both lower limb nerves were affected. Mononeuropathy and mononeuropathy multiplex were diagnosed when one nerve or two non-contiguous nerves with asymmetrical distribution were affected. Screening for CG was done in 191 unselected patients. RESULTS: Clinical signs of PN were observed in 25 of the 234 patients (10.6%). Electrophysiological PN was found in 36 (15.3%). CG was present in 56/191 patients (29.3%). The prevalence of CG increased significantly with age (p<0.001) and disease duration (p<0.05). PN was present in 12/56 (21%) patients with CG and 18/135 (13%) without CG (p=NS). PN increased significantly with age (p<0.001) and logistic regression analysis confirmed age as the only independent predictor of PN (OR 1.10 for each year; 95% CI 1.04 to 1.15; p<0.001). CONCLUSIONS: Electrophysiological examination detected subclinical neuropathy in 11 patients (4.7%). Statistical analysis showed that CG was not a risk factor for PN whereas PN prevalence increased significantly with age.

Adolescent↗

PubMed2006

Distributed virtual experiments in water quality management.

Since the complexity of virtual experiments (VEs) and their underlying models is constantly increasing, computational performance of monolithic software solutions is rapidly becoming insufficient. Examples of VEs are probabilistic design, model calibration, optimal experimental design and scenario analysis. In order to tackle this computational bottleneck, a framework for the distributed execution of VEs on a potentially heterogeneous pool of work nodes has been implemented. This framework was named WDVE (WEST distributed virtual experimentation) and is built on top of technologies such as C++, XML and SOAP. It was designed for stability, expandability, performance, platform-independence and ease of use. Complex VEs are most often composed of mutually independent sub-experiments, which can be run concurrently. With WDVE, a complex VE that is executed on a so-called Master machine will therefore attempt to execute its sub-experiments on Slave machines that have previously registered with the Master. The process of submitting requests for the execution of sub-experiments is transparent and involves the transfer of a description of the experiment to be executed, and the resources that are needed for the execution (i.e., model and input data). WDVE is in many ways similar to the Grid Computing paradigm, which is currently receiving widespread attention. However, WDVE is more geared towards application within the scope of water quality management.

Calibration↗

PubMed2006

Estimating costs and benefits of advanced control for wastewater treatment plants--the MAgIC methodology.

This paper discusses a methodology to estimate the costs and benefits of advanced control for wastewater treatment plants. The methodology has been applied to four wastewater treatment plants, representing four standard types of plants built in Flanders, Belgium. The paper outlines the methodology and illustrated results from one of the four design cases. General results are shown and contrasted with full-scale experience. The methodology appears to give realistic results and will be used for further refinement of default control algorithms for certain types of plants. A preliminary analysis indicates that on-line control can become cost-effective for plant sizes above 50,000 population equivalents.

Automation↗

PubMed2006

Assessment of WWTP design and upgrade options: balancing costs and risks of standards' exceedance.

Numerical models can be used to evaluate design and upgrade scenarios of urban wastewater systems on the basis of their ecological consequences. The objective of this paper is to illustrate a systematic procedure of system design/upgrade. This procedure consists of the following steps: (1) data collection and data reconstruction; (2) model building and calibration; (3) evaluation of scenarios; (4) uncertainty assessment. In contrast to conventional practice, this approach allows to choose the most appropriate trade-off between cost of measures and risk of non-compliance with regulatory limits. An example of its application dealing with the assessment of WWTP design and upgrade options is provided. Results show that by reducing the tank volumes compared to conventional design procedures, costs can be reduced sensibly while the risk of not meeting legislative requirements are only slightly increased.

Cities↗

PubMed2006

Benchmarking of WWTP design by assessing costs, effluent quality and process variability.

Process choice and dimensioning of WWTPs is a particularly sensitive step to cost-efficiently comply with regulatory standards. This step accounts only for a small fraction of the upfront costs, but it can lead to substantial savings. This paper illustrates the results of a systematic methodology to evaluate system design/upgrade options. In contrast to conventional practice, this approach allows the choice between the most appropriate trade-off between cost of measures and effluent quality, and to assess the reliability of a process layout. It is therefore a flexible instrument to cope with the flexibility and complexity of integrated water management regulations. Results show good agreement of the simulations with extensiv benchmarking studies on actual plants. For that reason, the suggested methodology can provide valuable support also to such practices.

Benchmarking↗

PubMed2005

Continuity-based interfacing of models for wastewater systems described by Petersen matrices.

In this paper the Petersen and composition matrices that modellers are now familiar with are used as a basis to construct interfacing models between subsystems considered in wastewater treatment. Starting from continuity considerations and a set of transformation reactions between components used in the two models of the subsystems to be interfaced, a set of linear algebraic equations needs to be solved. The theoretical development is illustrated using a simplified integrated model of an activated sludge system coupled to an anaerobic digester. Continuity-guaranteed interfacing of subsystems will facilitate optimization studies of the within-the-fence process units of a wastewater treatment plant or of the integrated urban wastewater system.

Bacteria, Anaerobic↗

PubMed2005

Systems analysis of urban wastewater systems--two systematic approaches to analyse a complex system.

This work was aimed at performing an analysis of the integrated urban wastewater system (catchment area, sewer, WWTP, receiving water). It focused on analysing the substance fluxes going through the system to identify critical pathways of pollution, as well as assessing the effectiveness of energy consumption and operational/capital costs. Two different approaches were adopted in the study to analyse urban wastewater systems of diverse characteristics. In the first approach a wide ranged analysis of a system at river basin scale is applied. The Nete river basin in Belgium, a tributary of the Schelde, was analysed through the 29 sewer catchments constituting the basin. In the second approach a more detailed methodology was developed to separately analyse two urban wastewater systems situated within the Ruhr basin (Germany) on a river stretch scale. The paper mainly focuses on the description of the method applied. Only the most important results are presented. The main outcomes of these studies are: the identification of stressors on the receiving water bodies, an extensive benchmarking of wastewater systems, and the evidence of the scale dependency of results in such studies.

Belgium↗

PubMed2004

Novel SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay type.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset familial disease with prominent myelinated fibers in the optic fundus. ARSACS is frequent in the Charlevoix-Saguenay region of Quebec but rare elsewhere. Mutations in SACS, encoding sacsin, a protein of unknown function, are associated with ARSACS. The authors identified three new SACS mutations in two Italian patients whose phenotype closely matches that of Quebec cases, but without retinal striation.

Adult↗

PubMed2001

Fast, simultaneous simulation of the integrated urban wastewater system using mechanistic surrogate models.

The urban wastewater system components (sewer, treatment plant, and river) are often modelled using complex mechanistic models. Mechanistic surrogate models are introduced here as simplified models that still contain some physical knowledge. Surrogate models are faster, but are less but still sufficiently accurate, and require more data to be calibrated. The possibilities of replacing actual field data by virtual data generated with a complex mechanistic model for calibration of the surrogate model are examined. As an example, a series of tanks with variable volume is shown to approximate sufficiently well the flow propagation in the river Zwalm (Belgium) as predicted by the "de Saint-Venant" equations. The three surrogate models can be implemented in the WEST simulator, which makes a simultaneous simulation of the system possible. In this work a connection is made between the ASM1 and the new IWA River Model No. 1 (RWOM1) by using a translator between the models in such a way that both mass and elemental balances remain closed for the overall system. This approach is illustrated with a case study on the river Lambro (Italy). The dispersion process in this river with steady flow could be modelled by using a tanks in series model, while the water quality in the river was predicted to improve substantially with an increase in hydraulic capacity of the treatment plant. The simulation results with the upgraded plant still need to be checked by field data.

Belgium↗

PubMed2000

Cooperative signaling between alpha(6)beta(4) integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase-dependent invasion.

We previously demonstrated that beta(4) integrin subunit overexpression increases in vitro invasiveness of NIH3T3 cells that have been transformed by ErbB-2 oncogene. We used this model to identify domains within the large beta(4) cytoplasmic domain that are involved in the interaction of alpha(6)beta(4) with ErbB-2, invasion, and phosphatidylinositol 3-kinase (PI3K) activation. For this purpose, we expressed deletion mutants of beta(4) that lacked either all or portions of the beta(4) cytoplasmic domain in NIH3T3/ErbB-2 cells. We also used an ecto-domain mutant in which most of the extracellular domain of beta(4) was replaced with a c-Myc tag. These transfectants were examined for their ability to invade Matrigel and their ability to activate PI3K, as well as for the ability of alpha(6)beta(4) to co-immunoprecipitate with ErbB-2. The results obtained revealed that a region of the beta(4) cytoplasmic domain between amino acids 854 and 1183 is critical for the ability of alpha(6)beta(4) integrin to increase invasion. Interestingly, the extracellular domain of beta(4) is not necessary for alpha(6)beta(4) to stimulate invasion. The association of alpha(6)beta(4) with ErbB-2 is dependent upon the beta(4) cytoplasmic domain and can occur in the absence of alpha(6)beta(4) heterodimerization. Finally, we observed strong activation of PI3K with beta(4) wild type and with those beta(4) deletion mutants that were able to stimulate invasion upon the expression in NIH3T3/ErbB-2 cells. In conclusion, our results establish that there is cooperation between alpha(6)beta(4) and ErbB-2 in promoting PI3K-dependent invasion and implicate a specific region of the beta(4) cytoplasmic domain (amino acids 854-1183) in this event.

3T3 Cells↗

PubMed1997

Characterization of the retinoid binding properties of the major fusion products present in acute promyelocytic leukemia cells.

The bcr1- and bcr3- promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) are the two major fusion proteins expressed in acute promyelocytic leukemia (APL) patients. These proteins, which are present in different lengths of PML (amino acids 1-552 and 1-394, respectively), contain most of the functional domains of PML and RAR alpha, bind all-trans-retinoic acid (t-RA), and act as t-RA-dependent transcription factors. T-RA is an effective inducer of clinical remission only in patients carrying the t(15;17) and expressing the PML/RAR alpha products. However, in APL patients achieving complete remission with t-RA therapy the bcr3-PML/RAR alpha product has been found associated with a poorer prognosis than bcr1-PML/RAR alpha. In the present study we have investigated the structural and functional properties of the bcr3-PML/RAR alpha in comparison to the previously characterized bcr1-PML/RAR alpha. In particular, we have measured the binding properties of the two endogenous ligands t-RA and 9-cis-RA to both of these isoforms. T-RA binding analysis of nuclear and cytosolic extracts prepared from bcr3-PML/RAR alpha APL patients and from bcr3-PML/RAR alpha COS-1 transfected cells indicates that this protein is present only as high-molecular-weight nuclear complexes. Using saturation binding assays and Scatchard analyses we found that t-RA binds with slightly less affinity to the bcr3-PML/RAR alpha receptor than to bcr1-PML/RAR alpha or RAR alpha (Kd = 0.4 nmol/L, 0.13 nmol/L or 0.09 nmol/L, respectively). Moreover, two different high-affinity 9-cis-RA binding sites (Kd = 0.45 and 0.075 nmol/L) were detectable in the bcr3-PML/RAR alpha product but not in the bcr1-PML/RAR alpha product (Kd = 0.77 nmol/L). By competition binding experiments we showed that 9-cis-RA binds with higher specificity to the bcr3-PML/RAR alpha isoform than to the bcr1-PML/RAR alpha or RAR alpha. Consistent with these data, the binding of 9-cis-RA to the bcr3-PML/RAR alpha product resulted in increased transcriptional activation of the RA-responsive element (RARE) TRE, but not of the betaRARE, in transiently transfected COS-1 cells. These results provide evidence indicating that preferential retinoid binding to the different PML/RAR alpha products can be measured.

Alitretinoin↗

PubMed1997

A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RAR alpha mutation.

The unique t(15;17) of acute promyelocytic leukemia (APL) fuses the PML gene with the retinoic acid receptor alpha (RAR alpha) gene. Although retinoic acid (RA) inhibits cell growth and induces differentiation in human APL cells, resistance to RA develops both in vitro and in patients. We have developed RA-resistant subclones of the human APL cell line, NB4, whose nuclear extracts display altered RA binding. In the RA-resistant subclone, R4, we find an absence of ligand binding of PML-RAR alpha associated with a point mutation changing a leucine to proline in the ligand-binding domain of the fusion PML-RAR alpha protein. In contrast to mutations in RAR alpha found in retinoid-resistant HL60 cells, in this NB4 subclone, the coexpressed RAR alpha remains wild-type. In vitro expression of a cloned PML-RAR alpha with the observed mutation in R4 confirms that this amino acid change causes the loss of ligand binding, but the mutant PML-RAR alpha protein retains the ability to heterodimerize with RXR alpha and thus to bind to retinoid response elements (RAREs). This leads to a dominant negative block of transcription from RAREs that is dose-dependent and not relieved by RA. An unrearranged RAR alpha engineered with this mutation also lost ligand binding and inhibited transcription in a dominant negative manner. We then found that the mutant PML-RAR alpha selectively alters regulation of gene expression in the R4 cell line. R4 cells have lost retinoid-regulation of RXR alpha and RAR beta and the RA-induced loss of PML-RAR alpha protein seen in NB4 cells, but retain retinoid-induction of CD18 and CD38. Thus, the R4 cell line provides data supporting the presence of an RAR alpha-mediated pathway that is independent from gene expression induced or repressed by PML-RAR alpha. The high level of retinoid resistance in vitro and in vivo of cells from some relapsed APL patients suggests similar molecular changes may occur clinically.

ADP-ribosyl Cyclase↗

PubMed1997

Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and complications.

BACKGROUND: Little is known about the clinical, diagnostic, and prognostic aspects of upper-extremity deep vein thrombosis (UEDVT). OBJECTIVES: To identify the clinical and laboratory parameters associated with this disease, to assess the diagnostic accuracy of ultrasonographic methods for its detection, and to establish the frequency of both early and late complications. PATIENTS AND METHODS: After a careful history was taken, 58 consecutive patients with signs and symptoms that were clinically suggestive of UEDVT underwent the determination of antithrombin III and protein C and S levels and resistance to activated protein C and lupuslike anticoagulants. Compression ultrasonography, color flow Doppler imaging, and Doppler ultrasonography were performed prior to venography. Patients with confirmed UEDVT underwent objective tests to detect a pulmonary embolism and were followed up prospectively to record recurrent thromboembolic events and postthrombotic sequelae. RESULTS: Findings from venography confirmed UEDVT in 27 patients (47%). Central venous catheters, thrombophilic states, and a previous leg vein thrombosis were statistically significantly associated with UEDVT. Sensitivity and specificity of compression ultrasonography (96% and 93.5%, respectively) and color flow Doppler imaging (100% and 93%, respectively) were comparable and better than those of Doppler ultrasonography (81% and 77%, respectively). Objective findings suggestive of a pulmonary embolism were recorded in 36% of the patients with UEDVT. After a mean follow-up of 2 years, 2 patients with UEDVT experienced recurrent thromboembolic events, and 4 had postthrombotic sequelae. CONCLUSIONS: Symptomatic UEDVT is associated with central venous catheters, thrombophilic states, and a previous leg vein thrombosis. Both compression ultrasonography and color flow Doppler imaging are accurate methods for its detection. A pulmonary embolism is a common complication of the disease. Finally, this disorder may recur and may be followed by postthrombotic sequelae.

Adult↗

PubMed1996

The PML/RAR alpha oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells.

Acute promyelocytic leukemia (APL) is characterized by the translocation, t(15;17) and the expression of a PML/RAR alpha fusion protein that is diagnostic of the disease. There is evidence that PML/RAR alpha protein acts as a dominant negative inhibitor of normal retinoid receptor function and myeloid differentiation. We now show that the PML/RAR alpha fusion product is directly downregulated in response to retinoic acid (tRA) treatment in the human APL cell line, NB4. tRA treatment induces loss of PML/RAR alpha at the protein level but not at the level of mRNA, as determined by Northern blots, by Western blots, and by ligand binding assays and in binding to RA-responsive DNA elements. We present evidence that this regulation is posttranslational. This evidence suggests that tRA induces synthesis of a protein that selectively degrades PML/RAR alpha. We further show that this loss of PML/ RAR-alpha is not limited to the unique APL cell line. NB4, because PML/RAR alpha protein is selectively downregulated by tRA when expressed in the transfected myeloid cell line U937. The loss of PML/RAR alpha may be directly linked to tRA-induced differentiation, because in a retinoid-resistant subclone of NB4, tRA does not decrease PML/RAR alpha protein expression. In NB4 cells, the specific downregulation of the fusion protein decreases the ratio of PML/RAR alpha to wild-type RAR alpha. Because the ratio of expression of PML/RAR alpha to wild-type RAR alpha and PML may be important in maintaining the dominant negative block of myelocytic differentiation, these data suggest a molecular mechanism for restoration by tRA normal myeloid differentiation in APL cells.

Cell Differentiation↗

PubMed1996

Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase.

All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RAR alpha for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.

Apoptosis↗

PubMed1996

Quantitative assessment of the tissue response to films of hyaluronan derivatives.

The aim of this study was to evaluate the in vivo response following implantation into a rat model of three innovative hyaluronan derivatives for clinical use: HYAFF 7, HYAFF 11 and HYAFF 11p75 (respectively, the 100% ethyl ester, 100% and 75% benzyl esters). The tissue reaction evoked by films of these new biomaterials implanted into the dorsolumbar musculature of rats was assessed quantitatively using a well established technique based upon an image analysis system. The number of inflammatory cells present and the patterns of cell distribution around the implant up to a distance of 642 microns were examined at different time periods after implantation. Since a well-delineated tissue-material interface was needed for this type of investigation, it was not possible to apply image analysis to sections once dissolution of the implanted materials had begun. Films of both the total esters, HYAFF 7 and HYAFF 11, were found to undergo a slow dissolution process and, after a month, films of these materials were still present at the site of implantation. Differences in response to the two materials were observed only during the first two weeks, particularly with respect to neutrophil distribution and total cellularity. HYAFF 7 was found to be more reactive, with higher numbers of neutrophils near the surface of the implant than HYAFF 11. Thereafter, the differences between the two materials were minimal and owing mainly to a faster dissolution of HYAFF 7 films. After 3 and 5 months, considerable degradation of films of both total esters had occurred. Significant quantities of material appeared inside numerous macrophages with an ED1-positive phenotype. Only a very thin layer of fibrous connective tissue, indicative of low reactivity, was found to surround the site of implantation, separating the dissolved material and the phagocytic cells from healthy muscular tissue. ED2-positive macrophages were primarily confined within the lining connective tissue. The partial benzyl ester, HYAFF 11p75, showed a different behaviour. In fact, evidence of film dissolution was already present a week after the implantation. After two weeks, the implanted films were completely dissolved and numerous ED1-positive macrophages phagocytosing the material were observed at the site of implantation. Therefore, in agreement with previous in vitro studies, which showed a greater susceptibility to degradation of hyaluronan derivatives with lower percentage of esterification, HYAFF 11p75 underwent resorption faster than the corresponding total ester.

Animals↗

PubMed1996

Deep venous thrombosis and lupus anticoagulant. A case-control study.

BACKGROUND: A definite evidence in favour of an association of deep-vein thrombosis (DVT) with lupus anticoagulant (LA) in patients free from systemic lupus erythematosus is still lacking. METHODS: In a case-control study, LA was determined in 176 consecutive outpatients who underwent phlebography because of the first episode of clinically suspected DVT of lower limbs. The association between DVT and LA was described using odds ratios (OR). RESULTS: Contrast venography confirmed the clinical suspicion in 59 patients (33.5%). LA was detected in 5 of the 59 patients with DVT (8.5%), and in none of the 117 subjects with normal venogram (P = 0.007). The OR for having an acute DVT in patients with LA was 10.7 (95% CI: 1.2-94.2). CONCLUSIONS: LA is significantly associated with DVT in symptomatic patients. Further studies are needed to establish the clinical implications of this association.

Adult↗

PubMed1996

Hyperhomocysteinemia and deep-vein thrombosis. A case-control study.

In a case-control study, fasting total homocysteinemia was determined in 208 consecutive outpatients who underwent phlebography because of the first episode of clinically suspected deep-vein thrombosis (DVT) of lower limbs. Contrast venography confirmed the clinical suspicion in 60 patients (28.8%). Hyperhomocysteinemia was detected in 15 of the 60 patients with DVT (25.0%), and in 17 of the 148 subjects without thrombosis (11.5%; p = 0.025). The OR for having an acute DVT in patients with hyperhomocysteinemia was 2.6 (95% CI: 1.1-5.9). It is concluded that high plasma homocysteine levels are significantly associated with DVT in symptomatic patients. Further studies are needed to clarify the clinical implications of this association.

Adult↗