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Concept: Blood tests

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Persicarin and isorhamnetin were isolated from Oenanthe javanica and their anticoagulant activities were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of cell-based thrombin and activated factor X (FXa). In addition, the effects of persicarin and isorhamnetin on the expressions of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were tested in tumor necrosis factor-α (TNF-α) activated human umbilical vein endothelial cells (HUVECs). The data obtained showed that persicarin and isorhamnetin both prolonged aPTT and PT significantly and inhibited the activities of thrombin and FXa. In addition, they both inhibited the generations of thrombin and FXa in HUVECs. In accordance with these anticoagulant activities, persicarin and isorhamnetin prolonged in vivo bleeding time and inhibited TNF-α induced PAI-1 production. Furthermore, PAI-1/t-PA ratio was significantly decreased by persicarin. Interestingly, the anticoagulant and profibrinolytic effects of persicarin were greater than those of isorhamnetin, which suggest that the sulfonate group of persicarin positively regulates its anticoagulatory function. Accordingly, our results suggest persicarin and isorhamnetin possess antithrombotic activities and that they could provide bases for the development of new anticoagulant agents.

Concepts: Coagulation, Fibrinolysis, Warfarin, Tissue plasminogen activator, Blood tests, Thrombin, Prothrombin time, Partial thromboplastin time

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BACKGROUND: Thromboelastography (TEG®) is a point of care monitor of whole blood coagulation and has previously demonstrated hypercoagulability in both pregnant and obese populations. However, the individual and combined contribution of pregnancy and obesity on coagulation status has not been defined. We carried out a study to assess the effect of both pregnancy and body mass index (BMI) on blood coagulation using laboratory tests of coagulation and thromboelastography. METHODS: This was a prospective study of 96 women divided into four equal groups; non-pregnant lean (NPL) BMI <25kg/m2, pregnant lean (PL) BMI <25kg/m2, non-pregnant obese (NPO) BMI >35kg/m2 and pregnant obese (PO) BMI >35kg/m2. Women were of either >36weeks of gestation presenting for elective caesarean delivery; non-pregnant women with BMI >35kg/m2 presenting for bariatric surgery; or non-pregnant volunteers with BMI <25kg/m2. Eligible women were then allocated to a group based on BMI and pregnancy status. TEG® analysis, full blood count and coagulation profiles were performed on all patients. The main outcome measures were TEG® profile (including r time, k time, α angle, maximum amplitude and coagulation index), platelet count, activated partial thromboplastin time, prothrombin time, and fibrinogen levels. RESULTS: The coagulation index was significantly higher in the obese patient groups compared with the lean groups (NPL -4.5 vs. NPO 1.9, P<0.001; PL -4.3 vs. PO 2.5, P<0.001). However, comparisons between the pregnant and non-pregnant groups when matched for BMI demonstrated no significant difference in coagulation. CONCLUSIONS: The combined effect of pregnancy and obesity on coagulation has not previously been investigated. Thromboelastographic comparison of pregnant and non-pregnant females separated into low or high BMI cohorts in the current study suggests that obesity correlates more with a hypercoagulable state than with pregnancy, particularly in pregnant patients at the extremes of low and high body weight.

Concepts: Childbirth, Blood, Obesity, Coagulation, Platelet, Body mass index, Blood tests, Prothrombin time

48

Previous literature indicates that pre-diagnostic diabetes and blood glucose levels are inversely related to glioma risk. To replicate these findings and determine whether they could be attributed to excess glucose consumption by the preclinical tumour, we used data from the Apolipoprotein MOrtality RISk (AMORIS) (n = 528,580) and the Metabolic syndrome and Cancer project (Me-Can) cohorts (n = 269,365). We identified individuals who were followed for a maximum of 15 years after their first blood glucose test until glioma diagnosis, death, emigration or the end of follow-up. Hazard ratios (HRs), 95% confidence intervals (CIs) and their interactions with time were estimated using Cox time-dependent regression. As expected, pre-diagnostic blood glucose levels were inversely related to glioma risk (AMORIS, P trend = 0.002; Me-Can, P trend = 0.04) and pre-diagnostic diabetes (AMORIS, HR = 0.30, 95% CI 0.17 to 0.53). During the year before diagnosis, blood glucose was inversely associated with glioma in the AMORIS (HR = 0.78, 95% CI 0.66 to 0.93) but not the Me-Can cohort (HR = 0.99, 95% CI 0.63 to 1.56). This AMORIS result is consistent with our hypothesis that excess glucose consumption by the preclinical tumour accounts for the inverse association between blood glucose and glioma. We discuss additional hypothetical mechanisms that may explain our paradoxical findings.

Concepts: Scientific method, Nutrition, Diabetes mellitus, Blood sugar, Glucose tolerance test, Prediction interval, Blood tests, Hyperglycemia

39

BACKGROUND: The increasing prevalence of type 2 diabetes poses a major public health challenge. Population-based screening and early treatment for type 2 diabetes could reduce this growing burden. However, uncertainty persists around the benefits of screening for type 2 diabetes. We assessed the effect of a population-based stepwise screening programme on mortality. METHODS: In a pragmatic parallel group, cluster-randomised trial, 33 general practices in eastern England were randomly assigned by the method of minimisation in an unbalanced design to: screening followed by intensive multifactorial treatment for people diagnosed with diabetes (n=15); screening plus routine care of diabetes according to national guidelines (n=13); and a no-screening control group (n=5). The study population consisted of 20 184 individuals aged 40-69 years (mean 58 years), at high risk of prevalent undiagnosed diabetes, on the basis of a previously validated risk score. In screening practices, individuals were invited to a stepwise programme including random capillary blood glucose and glycated haemoglobin (HbA(1c)) tests, a fasting capillary blood glucose test, and a confirmatory oral glucose tolerance test. The primary outcome was all-cause mortality. All participants were flagged for mortality surveillance by the England and Wales Office of National Statistics. Analysis was by intention-to-screen and compared all-cause mortality rates between screening and control groups. This study is registered, number ISRCTN86769081. FINDINGS: Of 16 047 high-risk individuals in screening practices, 15 089 (94%) were invited for screening during 2001-06, 11 737 (73%) attended, and 466 (3%) were diagnosed with diabetes. 4137 control individuals were followed up. During 184 057 person-years of follow up (median duration 9·6 years [IQR 8·9-9·9]), there were 1532 deaths in the screening practices and 377 in control practices (mortality hazard ratio [HR] 1·06, 95% CI 0·90-1·25). We noted no significant reduction in cardiovascular (HR 1·02, 95% CI 0·75-1·38), cancer (1·08, 0·90-1·30), or diabetes-related mortality (1·26, 0·75-2·10) associated with invitation to screening. INTERPRETATION: In this large UK sample, screening for type 2 diabetes in patients at increased risk was not associated with a reduction in all-cause, cardiovascular, or diabetes-related mortality within 10 years. The benefits of screening might be smaller than expected and restricted to individuals with detectable disease. FUNDING: Wellcome Trust; UK Medical Research Council; National Health Service research and development support; UK National Institute for Health Research; University of Aarhus, Denmark; Bio-Rad.

Concepts: Epidemiology, Insulin, Diabetes mellitus, Medical statistics, Blood sugar, Glucose tolerance test, Insulin resistance, Blood tests

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Aim: To develop and characterize Gymnema sylvestre extract-loaded niosomes using nonionic surfactants, and to evaluate their antihyperglycemic efficacy in comparison with the parent extract. Materials & methods: Nonionic surfactant-based G. sylvestre extract-loaded niosomes were prepared using the thin-film hydration method. The optimized formulation was screened for entrapment efficiency of the constituents, as well as other parameters such as release kinetics, vesicle size, zeta-potential and stability studies. The parent extract and optimized niosomal formulation were evaluated for their antihyperglycemic potential in an alloxan-induced diabetic animal model. Results: Niosomes prepared using Span™ 40 (SD Fine Chemicals Ltd, Mumbai, India) provided sterically stable vesicles 229.5 nm in size with zeta-potential and entrapment efficiency of 150.86 mV and 85.3 ± 4.5%, respectively. The surface morphology of vesicles was confirmed to be spherical by scanning electron microscopy studies. An in vitro release study demonstrated 77.4% of phytoconstituents release within 24 h. The niosome formulation demonstrated significant blood glucose level reduction in an oral glucose tolerance test, and increased antihyperglycemic activity compared with the parent extract in an alloxan-induced diabetic model. Conclusion: This study reveals the merits of G. sylvestre extract-loaded niosomes, and justifies the potential of niosomes for improving the efficacy of G. sylvestre extract as antidiabetic. Original submitted 30 March 2012; Revised submitted 29 August 2012.

Concepts: Electron, Enzyme, Insulin, Diabetes mellitus, Blood sugar, Glucose tolerance test, Blood tests, Gymnema sylvestre

27

Septic arthritis is an emergency. In 1999 Kocher et al. identified four clinical criteria to distinguish hip septic arthritis from transient synovitis in children (nonweightbearing, erythrocyte sedimentation rate ≥ 40 mm/L, white blood cell count > 12 × 10(9)/L, temperature > 38.5°C). Subsequent authors evaluating the same criteria produced conflicting results. This calls into question the use of such diagnostic algorithms. The reasons for the differences remain unclear.

Concepts: Red blood cell, Rheumatoid arthritis, Hematology, Blood tests, Erythrocyte sedimentation rate, Septic arthritis, Transient synovitis

27

To create and validate an estimation formula for 2-h post-challenge plasma glucose (2-hPG) as an alternative to oral glucose tolerance test (OGTT) for impaired glucose tolerance (IGT) screening.

Concepts: Insulin, Diabetes mellitus, Blood sugar, Glucose tolerance test, Impaired fasting glycaemia, Impaired glucose tolerance, Blood tests

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BACKGROUND: Serologic tests are widely used for the diagnosis of syphilis. However, conventional methods require well-trained technicians to produce reliable results. We compared automated nontreponemal and treponemal tests with conventional methods. METHODS: The HiSens Auto Rapid Plasma Reagin (AutoRPR) and Treponema Pallidum Particle Agglutination (AutoTPPA) tests, which utilize latex turbidimetric immunoassay, were assessed. A total of 504 sera were assayed by AutoRPR, AutoTPPA, conventional VDRL and FTA-ABS. Among them, 250 samples were also tested by conventional TPPA. RESULTS: The concordance rate between the results of VDRL and AutoRPR was 67.5%, and 164 discrepant cases were all VDRL reactive but AutoRPR negative. In the 164 cases, 133 showed FTA-ABS reactivity. Medical records of 106 among the 133 cases were reviewed, and 82 among 106 specimens were found to be collected from patients already treated for syphilis. The concordance rate between the results of AutoTPPA and FTA-ABS was 97.8%. The results of conventional TPPA and AutoTPPA for 250 samples were concordant in 241 cases (96.4%). AutoRPR showed higher specificity than that of VDRL, while VDRL demonstrated higher sensitivity than that of AutoRPR regardless of whether the patients had been already treated for syphilis or not. Both FTA-ABS and AutoTPPA showed high sensitivities and specificities greater than 98.0%. CONCLUSIONS: Automated RPR and TPPA tests could be alternatives to conventional syphilis tests, and AutoRPR would be particularly suitable in treatment monitoring, since results by AutoRPR in cases after treatment became negative more rapidly than by VDRL.

Concepts: Sensitivity and specificity, Syphilis, Blood tests, Spirochaete, Treponema pallidum, Treponema, FTA-ABS, Rapid plasma reagin

26

The CS5100 analyzer (Sysmex) was validated for the determination of routine coagulation parameters. This fully automated coagulation analyzer uses multiple wavelength technology to perform coagulation (e.g., activated partial thromboplastin time - APTT, prothrombin time - PT, fibrinogen - FBG), chromogenic (e.g., antithrombin - AT) and immunological (e.g., D-dimers - DDi) assays.

Concepts: Coagulation, Warfarin, Blood tests, Factor XII, Thrombin, Prothrombin time, Disseminated intravascular coagulation, Partial thromboplastin time

26

The International Society on Haemostasis and Thrombosis (ISTH) and the British Committee for Standards in Haematology (BCSH) have recently updated their lupus anticoagulant (LA) detection guidelines. The Clinical and Laboratory Standards Institute (CLSI) subsequently will publish its first LA guideline. General agreement exists on issues such as sample preparation, the use of dilute Russell viper venom time (dRVVT) in diagnostic repertoires, the use of normalized ratios, calculations to demonstrate phospholipid dependence, calculations to demonstrate inhibition, and interpretive reporting. The ISTH recommendation to employ only dRVVT and activated partial thromboplastin time is not mirrored in the BCSH and CLSI documents. The potential for false negatives in mixing tests is acknowledged by all panels, yet they remain mandated by ISTH as there are occasions when they are crucial to diagnostic accuracy. BCSH indicates that a negative mixing test need not exclude the presence of a LA, and CLSI reprioritizes test order to screen-confirm-mix, the latter being considered unnecessary in specific circumstances. Opinions in the guidelines differ on setting cutoff levels (i.e., 97.5th vs. 99th percentile for normally distributed data). All guidelines cover testing of anticoagulated patients, more detail being given by BCSH and CLSI, who suggest that Taipan snake venom time is a useful adjunct test in patients receiving vitamin K antagonists. Although complete agreement is not apparent, the guidelines represent significant moves toward engendering common practices.

Concepts: Warfarin, Hematology, Anticoagulant, Blood tests, Daboia, Snake, Dilute Russell's viper venom time, Lupus anticoagulant