The utility and cost-effectiveness of D-dimer measurements in the diagnosis of deep vein thrombosis

BACKGROUND AND OBJECTIVE: The potential utility of D-dimer measurements for the diagnosis of deep vein thrombosis became evident soon after the development of reliable commercial assays. The purpose of this review is to outline some critical aspects affecting cost-effectiveness of D-dimer measurements in the diagnosis of deep vein thrombosis (DVT). METHODS: The authors have been working in this field contributing original papers whose data have been used for this study. In addition, the material analyzed in this article includes papers published in the journals covered by the Science Citation Index and Medline. RESULTS: D-dimer levels are very sensitive to the process of fibrin formation/dissolution occurring with ongoing thrombosis. However, they may not be highly specific for venous thromboembolism as they are influenced by the presence of comorbid conditions potentially elevating plasma D-dimer (cancer, surgery, infectious diseases). In addition, commercially available ELISA assays, although quantitative and reproducible, cannot be used under emergency conditions because they are time-consuming and suited for batch-processing of plasma samples. Recently, new assays have been introduced which permit fast and quantitative D-dimer estimations in individual patients. We have evaluated the utility of two new rapid assays (LPIA D-dimer. Mitsubishi, and VIDAS D-DIMER, bio-Merieux) in combination with compression real-time-B-mode ultrasonography for the detection of deep vein thrombosis in asymptomatic patients following elective hip replacement and in patients with clinically suspected deep vein thrombosis. In both settings, we identified cut-off values with optimal sensitivity which allow exclusion of deep vein thrombosis in a considerable percentage of patients, with substantial sparing of economic resources. In fact, based on a cost-effectiveness analysis, a diagnostic algorithm combining D-dimers measurement and compression ultrasonography would result in cost-savings ranging from 5% to 55% in patients with high or low clinical pretest probability respectively. However, the specificity of D-dimer measurements for deep vein thrombosis was much higher in symptomatic than in asymptomatic patients. Choice of the cut-off value proved to be dependent on the method as well as on the patient populations studied. CONCLUSIONS: The cost-effectiveness of D-dimers measurement in the diagnosis of asymptomatic DVT remains questionable. Conversely, our data strongly support the utility of D-dimers determinations in the diagnosis of symptomatic DVT. In terms of sparing economic resources, the introduction in the clinical laboratory of the rapid quantitative assays would be highly convenient, because they avoid a source of bias in the interpretation of D-dimers results, are easy to perform and do not require dedicated personnel or instrumentation. Prospective management studies validating the utility of D-dimer measurement in the diagnosis of deep vein thrombosis are urgently needed.     

Controllability of One Spin and Two Interacting Spins

Mathematics of Control, Signals, and Systems - ?We consider the problem of steering control for the systems of one spin ½ particle and two interacting spin ½ particles in an...     

On the properties of the realizations of linear dynamical systems

Summary This paper is concerned with the problem of finding realizations for dynamical systems, with the properties of minimality, stability and boundedness.In particular the paper considers the problems of the existence and uniqueness, within suitable equivalence relations, of these realizations, as well as the problems of the invariance of listed properties.Using a general procedure, the problems of invariance and uniqueness are solved in the case of subsets of minimal and stable (uniformly stable, restrictively stable, asymptotically and exponentially stable) realizations. The same problems are solved in the case of restrictively stable, bounded and minimal realizations.This work was partially supported by C.N.R. and by Fondazione U. Bordoni, Rome, Italy.This paper is a revised version of a contribution bearing the same title which the authors presented at the IFAC Symposium (System Engineering Approach to Computer Control) held at Kyoto in 1970. It contains some results they mentioned in the course of the discussion, as well as others that were subsequently established.     

Volcanogenic fluorine in rainwater around active degassing volcanoes: Mt. Etna and Stromboli Island,Italy

Many studies have assessed the strong influence of volcanic activity on the surrounding environment. This is particularly true for strong gas emitters such as Mt. Etna and Stromboli volcanoes. Among volcanic gases, fluorine compounds are potentially very harmful. Fluorine cycling through rainwater in the above volcanic areas was studied analysing more than 400 monthly bulk samples. Data indicate that only approximately 1% of fluorine emission through the plume is deposited on the two volcanic areas by meteoric precipitations. Although measured bulk rainwater fluorine fluxes are comparable to and sometimes higher than in heavily polluted areas, their influence on the surrounding vegetation is limited. Only annual crops, in fact, show some damage that could be an effect of fluorine deposition, indicating that long-living endemic plant species or varieties have developed some kind of resistance.     

The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems

Polyphenols in dietary and botanical matrices are usually present as simple and complex O-glycosides. In fermented dietary materials, the glycosidic moiety is removed and accompanied in some cases by more complex changes to the polyphenol. As for most xenobiotics, polyphenols undergo phase II conjugation in the intestinal wall during their absorption from the gut. In contrast, a few polyphenols, such as puerarin in the kudzu vine, are C-glycosides and are stable in the gut and during absorption, distribution and excretion. Large bowel bacteria reduce polyphenol aglycones, causing opening of the heterocyclic B-ring and ring cleavage. The products are mostly absorbed and enter the bloodstream. Phase I and II metabolism events occur in the intestine and the liver - most polyphenols predominantly circulate as β-glucuronides and sulfate esters with very little as the aglycones, the presumed active forms. In addition, metabolism can occur in non-hepatic tissues and cells including breast tumor cells that have variable amounts of cytochrome P450s, sulfatase and sulfotransferase activities. Inflammatory cells produce chemical oxidants (HOCl, HOBr, ONO(2)(-)) that will react with polyphenols. The isoflavones daidzein and genistein and the flavonol quercetin form mono- and dichlorinated products in reaction with HOCl. Genistein is converted to 3'-nitrogenistein in the lung tissue of lipopolysaccharide-treated rats. Whereas polyphenols that can be converted to quinones or epoxides react with glutathione (GSH) to form adducts, chlorinated isoflavones do not react with GSH; instead, they are converted to β-glucuronides and are excreted in bile. Analysis of polyphenols and their metabolites is routinely carried out with great sensitivity, specificity and quantification by LC-tandem mass spectrometry. Critical questions about the absorption and tissue uptake of complex polyphenols such as the proanthocyanins can be answered by labeling these polyphenols with (14)C-sucrose in plant cell culture and then purifying them for use in animal experiments. The (14)C signature is quantified using accelerator mass spectrometry, a technique capable of detecting one (14)C atom in 10(15) carbon atoms. This permits the study of the penetration of the polyphenols into the interstitial fluid, the fluid that is actually in contact with non-vascular cells.     

Quantitative analysis of CEA expression in colorectal adenocarcinoma and serum: lack of correlation

Tissues and sera from 110 patients diagnosed with colorectal primary carcinoma, 20 patients with benign colorectal diseases and 31 healthy donors were subjected to quantitative CEA analysis. Multiple samples from tumor lesions and autologous histologically normal mucosa (10 cm from the tumor) were obtained at the time of surgery (cancer patients) or endoscopy (benign patients and healthy volunteers). CEA content was measured in protein extracts obtained from these tissues using a quantitative RIA method. A limit of normality for CEA content was established as 300 ng/mg of protein. When this was taken as cut-off, 104 of 110 (94.5%) tumor lesions and 51 of 110 (46.4%) autologous histologically normal colonic mucosa from cancer patients had elevated CEA levels. No correlation with stage of disease was found, while a correlation was observed with degree of tumor differentiation. A statistically significant difference between CEA content in tumor lesions and in histologically normal mucosa from cancer patients was observed (p = -0.001). Moreover, CEA content was statistically higher in the normal mucosa from cancer patients than in that from healthy donors (p = 0.005). CEA content in tissue specimens from benign lesions differed significantly from that in tissue from healthy donors (p = 0.005) and in carcinoma lesions (p < 0.001). The highest CEA content was observed in benign lesions with severe dysplasia. No statistical correlation between CEA content in carcinoma tissues and serum CEA levels (r = 0.195, p = .13) was found. Therefore, in considering diagnosis or therapy with anti-CEA MAbs for colorectal-carcinoma patients, or potential therapies with anti-CEA recombinant vaccines, serum CEA levels should not be taken as indicating CEA expression in tumor lesions.     

Aerosol characterisation in Italian towns by IBA techniques

The composition of particulate matter in the atmosphere of four major Italian towns (Florence, Genoa, Milan and Naples) has been studied with the extensive application of IBA techniques. The aerosol has been collected simultaneously in the four towns during the first weeks of year 2001, by two-stage continuous streaker samplers, which provide the separation of the particulate matter in two fractions. The concentrations in air of about 20 elements, and the total particulate mass, have been extracted in the PM2.5 and PM10 fractions with hourly resolution by PIXE, PIGE and optical analyses of about 2700 samples. IBA analyses have been performed at the 3 MeV external proton beam of the INFN accelerator facility at the University of Florence.     

Laminin alpha 2-chain gene mutations in two siblings presenting with limb-girdle muscular dystrophy

We report two siblings, an 11-year-old boy and his 7-year-old sister, referred to us with a diagnosis of muscular dystrophy. The boy presented at 22 months with delay in walking. A very high serum creatine kinase (CK) level and a dystrophic muscle biopsy lead to a diagnosis of Duchenne muscular dystrophy prior to the identification of the dystrophin gene. Two years later his sister presented with similar problems. A diagnosis of limb-girdle muscular dystrophy was made when they were shown to have inherited different X-chromosomes and normal expression of dystrophin and all sarcoglycans. Their conditions remained static. Recently a slowing of the peripheral motor nerve conduction velocities and T2-weighted brain magnetic resonance imaging showed increased signal of the white matter, both of which are features of merosin-deficient congenital muscular dystrophy. Immunolabelling using a C-terminal laminin alpha 2 chain antibody showed a reduction in expression, while labelling with another antibody that recognises a 300-kDa fragment showed a very significant reduction. Mutational analysis of the LAMA2 gene showed two mutations: one was a G-->C point mutation at position -1 of intron 28 acceptor splicing site. This mutation induced activation of a cryptic splice at nucleotide 4429 of exon 29 and partial skipping of this exon, with conservation of the open reading frame. The other was a nonsense mutation due to a C_T transition at position 5525 of the cDNA sequence (exon 37), resulting in a stop codon. These data confirm that mutations of the LAMA2 gene that do not completely disrupt the production of the protein can give rise to phenotypes considerably milder than classical merosin-deficient congenital muscular dystrophy. Partial laminin alpha 2 deficiency should be considered in the differential diagnosis of limb-girdle muscular dystrophy.     

Exclusive radical radiotherapy of laryngeal tumors: 10-year experience

Exclusive irradiation is used to treat primary neoplasms localized to the larynx because it is known to be able to cure, or at least control, the disease in a high percentage of cases without affecting speech. We report our ten-year experience in the Radiotherapy Department of Chieti Hospital. From 1985 to 1994, exclusive radiotherapy was used to treat 87 patients bearing histologically proved epidermoid carcinomas of the larynx. The patients average age was 67 years. The primary site was the glottis in 64 cases and the supraglottic and subglottic areas in 21 and 2 cases, respectively. The lymph nodes were clinically positive in 8 patients (9%) and negative in 79 (91%). The minimum follow-up was 20 months. All the patients were treated with cobalt 60 beams; the daily dose was 2 Gy, fractionation was 5 days a week. Average tumor dose was 64 Gy (range: 55-70 Gy). Disease-free survival actuarial curves show 72% five-year survival for glottic cancer (75% for N0, 80% for T1 and 61% for T2-T3-T4 cases) and 21% for supraglottic cancer (25% for N0 cases). To conclude, irradiation is confirmed to be a useful tool to treat early laryngeal cancer, while new combinations of surgery, chemotherapy and irradiation are needed to treat locally advanced cancer.