FDG PET-derived parameters as prognostic tool in progressive malignant pleural mesothelioma treated patients.

PURPOSE: The value of FDG PET-derived parameters in predicting overall survival (OS), local relapse-free survival (LRFS) and distant relapse-free survival (DRFS) in treated patients with malignant pleural mesothelioma (MPM) was evaluated. METHODS: This retrospective evaluation included 55 MPM patients treated between March 2006 and February 2015 with FDG PET/CT-guided salvage helical tomotherapy (HTT) after previous surgery plus chemotherapy. Univariate Cox regression analysis was performed to assess the impact of the following FDG PET-derived parameters: biological target volume (BTV), mean and maximum standardized uptake values (SUVmean/max), metabolic tumour volume (MTV) and total lesion glycolysis (TLG), measured using different uptake thresholds (40%, 50% and 60%). Logistic regression was then performed to identify the best FDG PET-derived parameters for selecting patients with poorer survival. RESULTS: The median OS was 9.1 months (range 0.0 - 69.6 months) after the end of HTT; 54/55 patients were dead at the last follow-up. BTV and TLG40, TLG50 and TLG60 were the most significant predictors of OS (p < 0.005). The median OS was 4.8 months in patients with MTV60 >5 cm3 and TLG40 >334.4, compared with 13.8 months and 16.1 months in patients with smaller values, respectively. The median LRFS and DRFS were 6.2 months (range 1.2 - 39.4 months) and 6.5 months (0.0 - 66.4 months), respectively. TLG40, TLG50 and TLG60 were significantly correlated with LRFS (p < 0.015). Median DRFS was 6.4 months in patients with MTV40 >39.6 cm3 and 6.2 months in patients with TLG40 >334.4, compared with 17 months and 18.8 months in patients with smaller values. BTV, TLG40 and MTV40 were also found to be good predictors in patients with poor OS/LRFS/DRFS (median survival times less than the median values). CONCLUSION: FDG PET-derived parameters effectively discriminated patients with a poor prognosis and may be helpful in the selection of MPM patients for salvage HTT.

Desmopressin after cardiac surgery in bleeding patients. A multicenter randomized trial.

BACKGROUND: Previous studies showed that desmopressin decreases post-operative blood loss in patients undergoing cardiac surgery. These studies were small and never studied the effect of desmopressin in patients with active bleeding. Objective of the study was to determine whether desmopressin reduces red blood cells transfusion requirements in patients with active bleeding after cardiac surgery who had been pre-treated with tranexamic acid. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study randomized elective patients with bleeding after cardiac surgery despite pre-treatment with tranexamic acid, to receive placebo (saline solution) or a single administration of desmopressin (0.3 µg/kg in saline solution). The primary endpoint was the number of patients requiring red blood cells transfusion after randomization and during hospital stay. Secondary end points were: blood loss from chest tubes during the first 24 h after study drug administration, hours of mechanical ventilation, intensive care unit stay, and in-hospital mortality. RESULTS: The study was interrupted after inclusion of 67% of the planned patients for futility. The number of patients requiring red blood cells transfusion after randomization was 37/68 (54%) in desmopressin group and 33/67 (49%) in placebo group (P = 0.34) with no difference in blood loss: 575 (interquartile 422-770) ml in desmopressin group and 590 (476-1013) ml in placebo group (P = 0.42), mechanical ventilation, intensive care unit stay or mortality. CONCLUSIONS: This multicenter randomized trial demonstrated that, in patients pre-treated with tranexamic acid, desmopressin should not be expected to improve treatment of patients who experience bleeding after cardiac surgery.

A miRNA Signature in Human Cord Blood Stem and Progenitor Cells as Potential Biomarker of Specific Acute Myeloid Leukemia Subtypes.

MicroRNAs (miRNAs) are important regulators of several cellular processes. During hematopoiesis, specific expression signatures have been reported in different blood cell lineages and stages of hematopoietic stem cell (HSC) differentiation. Here we explored the expression of miRNAs in umbilical cord blood stem (HSC) and progenitor cells (HPC) and compared it to unilineage granulocyte and granulo-monocyte differentiation as well as to primary blasts from patients with acute myeloid leukemia (AML). CD34 + CD38- ad CD34 + CD38 + cells were profiled using a global array consisting of about 2000 miRNAs. An approach combining bioinformatic prediction of miRNA targets with mRNA expression profiling was used to search for putative biologically enriched functions and networks. At least 15 miRNAs to be differentially expressed between HSC and HPC cell population, a cluster of 7 miRNAs are located in the q32 region of human chromosome 14 (miR-377-3p, -136-5p, 376a-3p, 495-3p, 654-3p, 376c-3p and 381-3p) whose expression decreased during the early stages of normal myelopoiesis but were markedly increased in a small set of AML. Interestingly, miR-4739 and -4516, two novel microRNA whose function and targets are presently unknown, showed specific and peculiar expression profile during the hematopoietic stem cells differentiation into unilineages and resulted strongly upregulated in almost all AML subsets. miR-181, -126-5p, -29b-3p and -22-3p resulted dis-regulated in specific leukemias phenotypes. This study provides the first evidence of a miRNA signature in human cord blood stem and progenitor cells with a potential role in hematopoietic stemness properties and possibly in leukemogenesis of specific AML subtypes.

Forecasting temporal world recovery in air transport markets in the presence of large economic shocks: The case of COVID-19.

This paper estimates the relationship between the strength of economic shocks and temporal recovery in the world air transport industry. Our results show that world recovery of passenger demand to pre-COVID-19 levels is estimated to take 2.4 years (recovery by late-2022), with the most optimistic estimate being 2 years (recovery by mid-2022), and the most pessimistic estimate 6 years (recovery in 2026). Large regional differences are detected, Asia Pacific has the shortest estimated average recovery time 2.2 years, followed by North America 2.5 years and Europe 2.7 years. For air freight the results show a shorter average world recovery time of 2.2 years compared to passenger demand. At the regional level, Europe and Asia Pacific are comparable with average recovery times of 2.2 years while North America is predicted to recover faster in 1.5 years. The results show that the strength of economic shocks of various origins impacts the linear growth of passenger and freight traffic and the temporal recovery of the industry in a predictable transitory way. Hence, the impact of the COVID-19 recession will represent a temporary, although long-lasting, correction to previous growth levels.

Structural stability of Sclerotium rolfsii ATCC 201126 beta-glucan with fermentation time: a chemical, infrared spectroscopic and enzymatic approach.

AIMS: Sclerotium rolfsii ATCC 201126 exopolysaccharides (EPSs) recovered at 48 h (EPS I) and 72 h (EPS II) of fermentation, with differences in rheological parameters, hydrogel topography, salt tolerance, antisyneresis, emulsifying and suspending properties, were subjected to a polyphasic characterization in order to detect structural divergences. METHODS AND RESULTS: Fermenter-scale production led to productivity (P(r)) and yield (Y(P/C)) values higher at 48 h (P(r) = 0.542 g l(-1) h(-1); Y(P/C) = 0.74) than at 72 h (P(r) = 0.336 g l(-1) h(-1); Y(P/C) = 0.50). Both EPSs were neutral glucose-homopolysaccharides with a beta-(1,3)-glycosidic backbone and single beta-(1,6)-glucopyranosyl sidechains regularly attached every three residues in the main chain, as revealed by chemical analyses. The infra-red diagnostic peak at 890 cm(-1) confirmed beta-glycosidic linkages, while gentiobiose released by beta-(1,3)-glucanases confirmed single beta-1,6-glycosidic branching for both EPSs. CONCLUSIONS: The true modular repeating unit of S. rolfsii ATCC 201126 scleroglucan could be resolved. Structural stability was corroborated and no structural differences could be detected as to account for the variations in EPSs behaviour. SIGNIFICANCE AND IMPACT OF THE STUDY: Recovery of S. rolfsii ATCC 201126 scleroglucan at 48 h might be considered based on better fermentation kinetic parameters and no detrimental effects on EPS structural features.

Oxytocin stimulates migration and invasion in human endothelial cells.

BACKGROUND AND PURPOSE: It has recently been reported that oxytocin is produced by some tumour cell types, and that oxytocin receptors, belonging to the G-protein-coupled receptor (GPCR) family, are expressed in a variety of cell types. Among these, human umbilical vein endothelial cells (HUVECs) respond to oxytocin with an increased proliferation, suggesting a possible role for the hormone in the regulation of angiogenesis. EXPERIMENTAL APPROACH: We employed chemotaxis and chemoinvasion assays to characterize the effect of oxytocin on HUVEC motility, and immunoblot analysis to study its molecular mechanisms of action. KEY RESULTS: We showed that oxytocin stimulates migration and invasion in HUVECs via oxytocin receptor activation. Searching for the molecular mechanism(s) responsible for oxytocin's pro-migratory effect, we identified the Gq coupling of oxytocin receptors and phospholipase C (PLC) as the main effectors of oxytocin's action in HUVECs. We also found that oxytocin stimulates the phosphorylation of endothelial nitric oxide synthase (eNOS) via the phosphatidylinositol-3-kinase (PI-3-K)/AKT pathway, and that the activation of PI-3-K and formation of nitric oxide (NO) are required for the pro-migratory effect of oxytocin. CONCLUSIONS AND IMPLICATIONS: The ability of oxytocin to stimulate HUVEC motility and invasion suggests that the hormone can participate in physiopathological processes where activation of endothelial cells plays an important role, for example, in angiogenesis. Interestingly, both the AKT and eNOS phosphorylation induced by oxytocin receptor activation depended on PLC activity, thus suggesting the existence of a still undefined mechanism connecting PLC to the PI-3-K/AKT pathway, upon oxytocin stimulation.

The use of desmopressin in open-heart surgery.

Desmopressin (l-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of the antidiuretic hormone vasopressin. Like the natural antidiuretic hormone, desmopressin increases the plasma levels of factor VIII and von Willebrand factor (vWF), with the advantage, compared to vasopressin, that it produces little or no vasoconstriction, no increase in blood pressure, and no contraction of the uterus or gastrointestinal tract, so that it is well tolerated when administered to humans. In 1977, desmopressin was used for the first time in patients with mild hemophilia A and von Willebrand disease (vWD) for the prevention and treatment of bleeding, first during dental extractions and then during major surgical procedures. The clinical indications for desmopressin rapidly expanded beyond hemophilia and vWD. The compound was shown to be efficacious even in bleeding disorders not involving a deficiency or dysfunction of factor VIII or vWF, including congenital and acquired defects of platelet function and such frequent abnormalities of hemostasis as those associated with chronic kidney and liver diseases. Desmopressin has also been used prophylactically in patients undergoing surgical operations characterized by large blood loss and transfusion requirements.

Rare bleeding disorders.

During the haemostatic response, the formation of a primary platelet plug limits bleeding and provides a surface for clotting factors to assemble and become activated. The initial platelet plug is stabilized by fibrin monomers, covalently cross-linked by FXIII, forming a platelets-fibrin thrombus. Defects in platelets as well as inherited deficiencies of coagulation factors including fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI and FXIII deficiencies, generally lead to lifelong bleeding disorders, whose severity of bleeding symptoms is heterogeneous in platelets abnormalities but generally inversely proportional to the degree of the factor deficiency in rare bleeding disorders (RBDs). The prevalence of platelet defects among the general population has not been established, whereas for RBDs it ranges from approximately 1 in 2 million to 1 in 500,000, being higher in countries where consanguineous marriages are diffused. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not well established. In this review the main features, diagnosis, available treatment options and treatment complications of the platelet disorders, caused by abnormalities in platelet receptors for adhesive proteins, platelet receptors for soluble agonists, platelet granules, signal transduction pathways, or procoagulant phospholipids will be discussed by Dr Cattaneo, whereas fibrinogen deficiency and FXIII deficiency will be described by Dr Inbal and Dr de Moerloose, respectively. Finally, the update of the Rare Bleeding Disorders Database will be presented by Dr Spreafico.

Antibiotic resistant bacteria in urban sewage: Role of full-scale wastewater treatment plants on environmental spreading.

The presence of antibiotic resistant bacteria (ARB) in wastewater was investigated and the role of wastewater treatment plants (WWTPs) in promoting or limiting antibiotic resistance was assessed. Escherichia coli (E. coli) and total heterotrophic bacteria (THB) resistance to ampicillin, chloramphenicol and tetracycline was monitored in three WWTPs located in Milan urban area (Italy), differing among them for the operating parameters of biological process, for the disinfection processes (based on sodium hypochlorite, UV radiation, peracetic acid) and for the discharge limits to be met. Wastewater was collected from three sampling points along the treatment sequence (WWTP influent, effluent from sand filtration, WWTP effluent). Antibiotic resistance to ampicillin was observed both for E. coli and for THB. Ampicillin resistant bacteria in the WWTP influents were 20-47% of E. coli and 16-25% of THB counts. A limited resistance to chloramphenicol was observed only for E. coli, while neither for E. coli nor for THB tetracycline resistance was observed. The biological treatment and sand filtration led to a decrease in the maximum percentage of ampicillin-resistant bacteria (20-29% for E. coli, 11-21% for THB). However, the conventionally adopted parameters did not seem adequate to support an interpretation of WWTP role in ARB spread. Peracetic acid was effective in selectively acting on antibiotic resistant THB, unlike UV radiation and sodium hypochlorite. The low counts of E. coli in WWTP final effluents in case of agricultural reuse did not allow to compare the effect of the different disinfection processes on antibiotic resistance.

Regional point prevalence study of healthcare-associated infections and antimicrobial use in acute care hospitals in Liguria, Italy.

BACKGROUND: Given the importance of monitoring healthcare-associated infections (HCAIs) and the consumption of antibiotics, a regional point prevalence survey was conducted in Liguria between March and April 2016. AIM: To measure the overall prevalence of HCAI and describe the use of antibiotics in all public hospitals. METHODS: Data on risk factors and use of antibiotics were collected for each hospitalized patient. To define the variables significantly associated with HCAI, univariate and multivariate analyses were conducted. Standardized infection ratio and standardized antimicrobial use ratio were measured for each participating hospital. FINDINGS: A total of 3647 patients were enrolled. In all, 429 HCAIs were diagnosed in 376 patients, giving a prevalence of HCAI of 10.3%. Respiratory tract (21.7%) and urinary tract (20%) were the most frequent sites of infection. High rates of meticillin-resistant Staphylococcus aureus (47.4%) and Enterobacteriaceae resistant to carbapenems (26.3%) were isolated. Forty-six percent of patients received at least one antibiotic. Combinations of penicillins including ß-lactamase inhibitors (24.1%) were the most widely used; the main indication (46.7%) was the treatment of a community-acquired infection. CONCLUSION: There was an increase in HCAI prevalence compared to a similar survey conducted in 2007; however, the performance of overlapping investigations will enable more reliable considerations. Nevertheless, data on antimicrobial resistance and use of antibiotics are consistent with the national trend. Despite methodological limitations, prevalence studies are useful to monitor HCAI over time and encourage greater awareness of the problem by all stakeholders.

Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection.

The definition 'resistance to antiplatelet drugs' should be limited to situations in which failure of the drug to hit its pharmacological target has been documented by specific laboratory tests. Aspirin resistance, as determined by specific tests (e.g. serum thromboxane B(2)), appears to be rare (1-2%) and, in most instances, is caused by poor compliance. In contrast to aspirin, studies that used specific tests to measure the pharmacological effect of thienopyridines [e.g. vasodilator-stimulated phosphoprotein (VASP)] showed a wide variability of responses to these drugs, with significant proportions of subjects (15-30%) who are very poor responders. Inter-individual differences in the extent of metabolism of thienopyridines to their active metabolites is the most plausible mechanism for the observed inter-individual variability in platelet inhibition. The demonstration that some patients may be 'resistant' or 'poor responders' to the pharmacological effect of antiplatelet drugs, has prompted the need of laboratory monitoring of antiplatelet therapy. However, many published studies have been performed using unspecific tests of platelet function, which identify patients on antiplatelet treatment with high residual platelet reactivity, which is not necessarily because of resistance to antiplatelet drugs. Despite this drawback, identification of patients with high residual platelet reactivity may be useful to predict their risk of atherothrombotic events. However, many studies still need to be carried out to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring antiplatelet therapy can be recommended in the clinical practise. Until then, monitoring of antiplatelet therapy should be considered for investigational purposes only.

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin.

BACKGROUND: Activation of two receptors for adenosine diphosphate (ADP), P2Y(1) and P2Y(12), is necessary for ADP-induced platelet aggregation (PA). It is generally believed that the antithrombotic effects of drugs inhibiting P2Y(12), such as clopidogrel, are uniquely mediated by inhibition of P2Y(12)-dependent PA. However, as P2Y(12) is negatively coupled to adenylyl cyclase (AC), its inhibition may also exert antithrombotic effects through the potentiation of prostacyclin (PGI(2)), which inhibit PA by stimulating AC. OBJECTIVES: To test whether inhibition of P2Y(12) potentiates the antiplatelet effects of PGI(2). METHODS: We measured the effects of PGI(2) (0.01-10 microm) on PA of washed human platelets induced by thrombin (0.5 U mL(-1)) in the presence or absence of ARC69931MX (anti-P2Y(12)) or MRS2500 (anti-P2Y(1)). RESULTS: PGI(2) inhibited PA in the presence of anti-P2Y(12), but not in the presence of anti-P2Y(1) or in the absence of inhibitors. In contrast, dibutyryl-cyclicAMP inhibited PA both in the presence and absence of anti-P2Y(1) or anti-P2Y(12). PGI(2) increased platelet cyclicAMP levels only in the absence of thrombin or in the presence of thrombin plus anti-P2Y(12). CONCLUSIONS: PGI(2) did not inhibit PA induced by thrombin, because its effect on AC was prevented by released ADP interacting with P2Y(12). Anti-P2Y(12) drugs, by rescuing AC activity, potentiate the antiplatelet effect of PGI(2), which may contribute to their antithrombotic effect.

Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: comparison with the bleeding time.

BACKGROUND: Global tests of hemostasis that are used to screen patients with clinical suspicion of bleeding disorders should help the physician to identify the phase of the hemostatic system that is abnormal and guide further diagnostic workup. PATIENTS AND METHODS: We compared the performance of Platelet Function Analyzer-100 (PFA-100) closure time (CT) with bleeding time (BT), both of which are screening tests for primary hemostasis, in the diagnostic workup of 128 consecutive patients who were screened for bleeding disorders. The sensitivities of BT and PFA-100 CT for known defects of hemostasis were evaluated; in addition, we calculated their correlation with the levels of severity of the bleeding symptoms, which were recorded using a standardized questionnaire. RESULTS: The sensitivity of PFA-100 testing was 71% for von Willebrand disease (VWD) [with both collagen-adenosine diphosphate (C-ADP) and collagen-epinephrine (C-EPI) cartridges]; 58% (C-EPI) and 8% (C-ADP) for platelet function disorders (PFDs); and the sensitivity of BT was 29% (VWD) and 33% (PFD). C-EPI CT was also prolonged in about 20% of patients with abnormalities of coagulation or fibrinolysis. Only the C-EPI CT was significantly associated with the levels of severity of the patients' bleeding scores. CONCLUSIONS: BT and C-EPI are insufficiently sensitive to be recommended as hemostasis screening tests. The C-ADP cartridge, which is sensitive to VWD only, might prove useful in further diagnostic workup of defects of primary hemostasis. The association of C-EPI CT with the severity of bleeding symptoms as a useful predictor of risk of bleeding in clinical practise should be tested in properly designed studies.

Clinical, haematological, biochemical and economic impacts of Trichinella spiralis infection in pigs.

The purpose of this work was to assess the clinical, haematological and biochemical responses of pigs experimentally inoculated with Trichinella spiralis. Groups of three pigs were inoculated per os with 100, 500 and 5000 T. spiralis muscle larvae, two pigs were used as control. Clinical evaluation of disease in pigs included daily examination, rectal temperature measurements and cardiac and respiration rates. Haematological studies included: hematocrit (%), hemoglobin (g/dl), and white cell, neutrophil, lymphocyte and eosinophil counts. Blood biochemistry included: bun (mg/dl), creatinine (mg/dl), AST (UI/l), ALT (UI/l), CPK (UI/l) and ALP (UI/l). No significant differences were observed in rectal temperature and in cardiac and respiration rates between inoculated animals and the control group (p> or =0.05). Significant differences were detected (p< or =0.05) in the values of % hemoglobin, and eosinophils, as well as in the values of CK, ALP, AST and ALT. The variations observed in some cases were related to the number of T. spiralis larvae inoculated and varied with the number of days post-infection. Inoculated pigs showed significant differences (p< or =0.05) in weight gain when compared with uninoculated controls. This study has clinical, haematological, and enzyme alterations in Trichinella infected pigs provides a better understanding of acute and chronic trichinellosis in pigs.

[Project, natural lighting and comfort indoor]. / Illuminazione naturale e benessere indoor: valutazione ed aggiornamento degli strumenti normativi locali.

The present research aims at analyzing the relationship between the project, the natural lighting, and the residential indoor environments. The reasons that lead to this research are to be found in the complex relationship between natural lighting, sunlight, and health in indoor environments and in the oncoming research of project and technological solutions in order to guarantee an adequate level of indoor health while preserving the environment. After describing the physical and hygienic characteristics of the natural lighting, the various laws (in particular the Italian ones) were taken into account according to the definition of the minimal performance and project requirements concerning the natural lighting of the indoor residential environments. The minimal requirements for the Coefficient of Daily Lighting--CDL (illumination levels on horizontal surface inside the room/illumination levels on the same horizontal surface situated outside, closed to the windows) were satisfied on average during the project phase with a lighting ratio (area of the windows hole/floor area) more than 12.5% (1/8) for every habitable rooms. An analysis based on CDL was then performed, since it is able to estimate the level of lighting of different indoor environments for dimensional and geometric aspects, for specific characteristics of each window opening and for the context situation of the building. During the analysis, the CDL of some rooms (42) was taken and analyzed according to the specific features of the indoor environment in order to evaluate the appropriateness of the current laws on the subject, which are too often recognized as only prescriptive. In conclusion, the current laws, considering the complex reciprocity between natural lighting and indoor environments, are not very adequate in orienting the architect towards more innovative quality and performance oriented choices. According to these deficiencies, it was proposed to integrate those laws with more adequate indications for the computation of the windows surface, and to write a document on the project phase in order to support the architect in her architectonic choices. Such instrument, coming from work in depth of analysis and observation of the behaviour of the natural light in order to better understand the factors able to condition its penetration into the indoor environments, could then be used along with the legislative instruments in order to improve those aspects of indoor health related to natural lighting.

Prediction of high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndromes.

BACKGROUND: About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like 'structure' information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients. METHODS: A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score >14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1month, compared to TSMs. RESULTS: ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59-66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1month). CONCLUSIONS: Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype.

Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function.

BACKGROUND: Closure time (CT), measured by platelet function analyzer (PFA-100) device, is now available to the clinical laboratory as a possible alternative or supplement to the bleeding time test. AIM: On behalf of the Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH-SSC), a working Group was formed to review and make recommendations on the use of the PFA-100 CT in the evaluation of platelet function within the clinical laboratory. METHODS: The Medline database was searched to review the published information on the PFA-100 CT in the evaluation of platelet disorders and platelet function. This information, and expert opinion, was used to prepare a report and generate consensus recommendations. RESULTS: Although the PFA-100 CT is abnormal in some forms of platelet disorders, the test does not have sufficient sensitivity or specificity to be used as a screening tool for platelet disorders. A role of the PFA-100 CT in therapeutic monitoring of platelet function remains to be established. CONCLUSIONS: The PFA-100 closure time should be considered optional in the evaluation of platelet disorders and function, and its use in therapeutic monitoring of platelet function is currently best restricted to research studies and prospective clinical trials.

Nicotine stimulates a serotonergic autocrine loop in human small-cell lung carcinoma.

Small-cell lung carcinoma cells express different plasma membrane nicotinic acetylcholine receptor subtypes. We have now found that interacting with these receptors (-)-nicotine induces a dose-dependent and stereoselective release of [3H]serotonin which is dependent on external calcium and blocked by the specific ganglionic nicotinic antagonist mecamylamine. With the same potency (-)-nicotine stimulates tumor cell proliferation, an effect also blocked by mecamylamine. Serotonin itself stimulates cell proliferation in a dose-dependent manner, an effect blocked by the selective serotonergic receptor antagonists methiotepine and metergoline. These data suggest that nicotine might affect proliferation of small-cell lung carcinoma cells by inducing the release of hormones (such as serotonin) with autocrine capabilities and place both the nicotinic and the serotonergic receptors at key positions in the biological and, possibly, pharmacological approach to this human lung cancer.

Current and emerging approaches for evaluating platelet disorders.

Platelets play a central role in physiological hemostasis and also in pathological thrombosis. It is well established that congenital or acquired abnormalities of platelet function are associated with a heightened risk of bleeding of variable severity and excessive hemorrhage after surgery or trauma. Several kinds of different platelet function tests have been developed over the years to identify or diagnose platelet function disorders. The use of these tests for the assessment of thrombotic risk or for monitoring the effects of drugs inhibiting platelet function is not well established. Light transmission aggregometry (LTA) is the gold standard for the study of patients with defects of platelet function. Its results are affected by several pre-analytical and analytical variables. The Subcommittee on Platelet Physiology of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis published official guidelines for the standardization of the variables affecting LTA, which should be followed to harmonize the procedures across different laboratories worldwide. The lumi-aggregometer, a modification of LTA that measures platelet secretion in parallel with aggregation, is preferable to LTA for diagnosing inherited defects of platelet function, because it is more sensitive to the most common disorders, which are characterized by abnormalities of platelet secretion. LTA (or lumi-aggregometry) is useful as a first screening test of patients with the clinical suspicion of defects of platelet function, because it helps to provide an interim diagnostic hypothesis, which can then be confirmed or discounted using appropriate and specific tests.