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1.
Oxf Open Neurosci ; 2: kvad010, 2023.
Article in English | MEDLINE | ID: mdl-38596242

ABSTRACT

Pigs are an important large animal model for translational clinical research but underutilized in behavioral neuroscience. This is due, in part, to a lack of rigorous neurocognitive assessments for pigs. Here, we developed a new automated T-maze for pigs that takes advantage of their natural tendency to alternate. The T-maze has obvious cross-species value having served as a foundation for cognitive theories across species. The maze (17' × 13') was constructed typically and automated with flanking corridors, guillotine doors, cameras, and reward dispensers. We ran nine pigs in (1) a simple alternation task and (2) a delayed spatial alternation task. Our assessment focused on the delayed spatial alternation task which forced pigs to wait for random delays (5, 60, 120, and 240 s) and burdened spatial working memory. We also looked at self-paced trial latencies, error types, and coordinate-based video tracking. We found pigs naturally alternated but performance declined steeply across delays (R2 = 0.84). Self-paced delays had no effect on performance suggestive of an active interference model of working memory. Positional and head direction data could differentiate subsequent turns on short but not long delays. Performance levels were stable over weeks in diverse strains and sexes, and thus provide a benchmark for future neurocognitive assessments in pigs.

3.
J Thromb Thrombolysis ; 52(3): 848-853, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33649980

ABSTRACT

Multiple myeloma (MM) is associated to an increased incidence of venous thromboembolism (VTE). IMPEDE-VTE score constitutes a valuable risk assessment tool for VTE prediction in first-line MM patients. Nevertheless, refinement of the primary thromboprophylaxis category of this score (which pools aspirin and heparin) seems desirable. To investigate the role of the type of thromboprophylaxis, within IMPEDE-VTE score, for VTE prediction in MM patients. Retrospective analysis of a single-center cohort of 438 MM patients receiving first-line antimyeloma treatment (1991-2020). IMPEDE-VTE score was calculated. Primary thromboprophylaxis was additionally stratified into aspirin- and heparin-based regimen subgroups. VTE risk was analyzed by Cox regression. Median follow-up during first-line antimyeloma treatment was 6.0 months (IQR 4.1-9.0 months). Twenty-three patients developed VTE (5.3%, 95%CI 3.4-7.8%). IMPEDE-VTE score showed a notable predictive value (area under the ROC curve: 0.70, 95%CI 0.60-0.80). Cox analysis confirmed that 1-point increase in the score resulted in a 1.3-fold increase in VTE risk (HR 1.30, 95%CI 1.13-1.53, p < 0.001). In the multivariable analysis, the type of primary thromboprophylaxis (heparin versus aspirin) was an independent predictive factor (HR 0.15, 95% CI 0.05-0.47, p = 0.001). The combined model showed a higher goodness-of-fit (Akaike Information Criterion [AIC]: 99) than IMPEDE-VTE separately (AIC:235). Our analysis contributes to the external validation of IMPEDE-VTE score for the prediction of VTE in MM. But more interestingly, our results demonstrate that among those patients receiving thromboprophylaxis, the type of regimen (heparin versus aspirin) adds independent predictive value and should be explored for a more accurate risk assessment.


Subject(s)
Multiple Myeloma , Venous Thrombosis , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Heparin/adverse effects , Humans , Multiple Myeloma/complications , Multiple Myeloma/drug therapy , Retrospective Studies , Risk Factors , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
4.
Osteoporos Int ; 31(10): 1837-1851, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32500301

ABSTRACT

Decision aids (DAs) are evidence-based tools that support shared decision-making (SDM) implementation in practice; this study aimed to identify existing osteoporosis DAs and assess their quality and efficacy; and to gain feedback from a patient advisory group on findings and implications for further research. We searched multiple bibliographic databases to identify research studies from 2000 to 2019 and undertook an environmental scan (search conducted February 2019, repeated in March 2020). A pair of reviewers, working independently selected studies for inclusion, extracted data, evaluated each trial's risk of bias, and conducted DA quality assessment using the International Patient Decision Aid Standards (IPDAS). Public contributors (patients and caregivers with experience of osteoporosis and fragility fractures) participated in discussion groups to review a sample of DAs, express preferences for a new DA, and discuss plans for development of a new DA. We identified 6 studies, with high or unclear risk of bias. Across included studies, use of an osteoporosis DA was reported to result in reduced decisional conflict compared with baseline, increased SDM, and increased accuracy of patients' perceived fracture risk compared with controls. Eleven DAs were identified, of which none met the full set of IPDAS criteria for certification for minimization of bias. Public contributors expressed preferences for encounter DAs that are individualized to patients' own needs and risk. Using a systematic review and environmental scan, we identified 11 decision aids to inform patient decisions about osteoporosis treatment and 6 studies evaluating their effectiveness. Use of decision aids increased accuracy of risk perception and shared decision-making but the decision aids themselves fail to comprehensively meet international quality standards and patient needs, underpinning the need for new DA development.


Subject(s)
Decision Support Techniques , Osteoporosis , Decision Making , Humans , Osteoporosis/diagnosis , Osteoporosis/drug therapy , Patient Participation
5.
QJM ; 112(3): 183-188, 2019 Mar 01.
Article in English | MEDLINE | ID: mdl-30380132

ABSTRACT

BACKGROUND: The clinical effect of peri-operative bridging therapy in atrial fibrillation (AF) patients remains unclear given that it may increase bleeding risk without providing significant benefits. We aimed to investigate peri-procedural events in relation to peri-operative use of bridging therapy in AF patients under Vitamin K Antagonists (VKAs). METHODS: We included AF patients stable the previous 6 months on VKAs. During a median follow-up of 6.5 years (IQR 4.3-7.9), we recorded all invasive procedures and the peri-operative clinical management. All peri-procedural events (ischaemic stroke/transient ischaemic attack/systemic embolism, clinically relevant non-major bleeding and major bleeding) and severe peri-procedural events (ischaemic stroke/transient ischaemic attack/systemic embolism and major bleeding) suffered until the 30-days post-intervention period were recorded. RESULTS: We included 1361 patients (48.7% male, median age 76 [IQR 71-81] years). There were 1100 (70.9%) procedures performed using bridging therapy. The rate of any (4.5% vs. 0.7%, P < 0.001) and severe (2.3% vs. 0.0%, P = 0.002) peri-procedural events were higher in patients receiving bridging therapy. Adjusted logistic regressions demonstrated that the bleeding risk of the procedure was related with higher risk of severe peri-procedural events (OR 3.51, 95% CI 1.54-8.01) and peri-procedural events (OR 2.77, 95% CI 1.56-4.91). Importantly, the use of bridging therapy was also independently associated with higher risk of any peri-procedural events (OR 4.32, 95% CI 1.28-14.51). CONCLUSIONS: In this study including AF patients under VKA therapy, the use of bridging therapy as part of the clinical management during an invasive procedure was independently associated with higher risk of any peri-procedural event.


Subject(s)
Atrial Fibrillation/therapy , Heparin, Low-Molecular-Weight/adverse effects , Perioperative Care , Vitamin K/antagonists & inhibitors , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Female , Hemorrhage/epidemiology , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Logistic Models , Male , Prevalence , Risk Factors , Spain/epidemiology , Stroke/prevention & control , Thromboembolism/epidemiology , Thromboembolism/prevention & control
6.
J Intern Med ; 283(3): 282-292, 2018 03.
Article in English | MEDLINE | ID: mdl-29044861

ABSTRACT

BACKGROUND: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. OBJECTIVES: To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. METHODS: HAS-BLED, ORBIT, ATRIA and HEMORR2 HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. RESULTS: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P < 0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P = 0.0019), ATRIA (P < 0.001) and HEMORR2 HAGES (P < 0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P = 0.0607). CONCLUSIONS: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.


Subject(s)
Atrial Fibrillation/drug therapy , Dabigatran/adverse effects , Hemorrhage/chemically induced , Risk Assessment/methods , Stroke/prevention & control , Warfarin/adverse effects , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antithrombins/adverse effects , Antithrombins/therapeutic use , Atrial Fibrillation/complications , Dabigatran/therapeutic use , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Global Health , Hemorrhage/epidemiology , Humans , Incidence , Male , Stroke/etiology , Time Factors , Warfarin/therapeutic use
7.
Haemophilia ; 23(6): e488-e496, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28960694

ABSTRACT

INTRODUCTION: Factor XI (FXI) deficiency is a rare disorder with molecular heterogeneity in Caucasians but relatively frequent and molecularly homogeneous in certain populations. AIM: To characterize FXI deficiency in a Spanish town of 60 000 inhabitants. METHODS: A total of 324 764 APTT tests were screened during 20 years. FXI was evaluated by FXI:C and by Western blot. Genetic analysis of F11 was performed by sequencing, multiplex ligation-dependent probe amplification and genotyping. RESULTS: Our study identified 46 unrelated cases and 170 relatives with FXI deficiency carrying 12 different genetic defects. p.Cys56Arg, described as founder mutation in the French-Basque population, was identified in 109 subjects from 24 unrelated families. This mutation was also identified in 2% of the general population. p.Cys416Tyr, c.1693G>A and p.Pro538Leu were identified in 7, 6 and 2 unrelated families, respectively. NGS analysis of the whole F11 gene revealed a common haplotype for each of the four recurrent mutations, suggesting a founder effect. The analysis of plasma FXI of four p.Pro538Leu homozygous carriers revealed that this variant was not activated by FXIIa. We identified four mutations previously described in other Caucasian subjects with FXI deficiency (p.Lys536Asn; p.Thr322Ile, p.Arg268Cys and c.325G>A) and four new gene defects: p.(Cys599Tyr) potentially causing a functional deficiency, p.(Ile426Thr), p.(Ile592Thr) and the first worldwide duplication of 1653 bp involving exons 8 and 9. Bleeding was rare and mild. CONCLUSIONS: Our population-cohort study supplies new evidences that FXI deficiency in Caucasians is more common than previously thought and confirmed the wide underlying genetic heterogeneity, caused by both recurrent and sporadic mutations.


Subject(s)
Factor XI Deficiency/genetics , Factor XI/genetics , Gene Duplication , Mutation , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Factor XI Deficiency/blood , Factor XI Deficiency/epidemiology , Female , Gene Frequency , Genotype , Haplotypes , Humans , Incidence , Male , Middle Aged , Pedigree , Sequence Analysis, DNA , Spain/epidemiology
9.
J Thromb Haemost ; 14(8): 1549-60, 2016 08.
Article in English | MEDLINE | ID: mdl-27214821

ABSTRACT

UNLABELLED: Essentials We investigated the molecular base of antithrombin deficiency in cases without SERPINC1 defects. 27% of cases presented hypoglycosylation, transient in 62% and not restricted to antithrombin. Variations in genes involved in N-glycosylation underline this phenotype. These results support a new form of thrombophilia. Click here to listen to Dr Huntington's perspective on thrombin inhibition by the serpins SUMMARY: Background Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than antithrombin deficiency. Objective To identify new thrombophilic mechanisms. Patients/methods We studied 30 patients with antithrombin deficiency but no defects in the gene encoding this key anticoagulant (SERPINC1). Results A high proportion of these patients (8/30: 27%) had increased hypoglycosylated forms of antithrombin. All N-glycoproteins tested in these patients (α1-antitrypsin, FXI and transferrin) had electrophoretic, HPLC and Q-TOF patterns indistinguishable from those of the congenital disorders of glycosylation (rare recessive multisystem disorders). However, all except one had no mental disability. Moreover, intermittent antithrombin deficiency and hypoglycosylation was recorded in five out of these eight patients, all associated with moderate alcohol intake. Genetic analysis, including whole exome sequencing, revealed mutations in different genes involved in the N-glycosylation pathway. Conclusions Our study provides substantial and novel mechanistic insights into two disease processes, with potential implications for diagnosis and clinical care. An aberrant N-glycosylation causing a recessive or transient antithrombin deficiency is a new form of thrombophilia. Our data suggest that congenital disorders of glycosylation are probably underestimated, especially in cases with thrombosis as the main or only clinical manifestation.


Subject(s)
Antibodies/chemistry , Antithrombin III/genetics , Antithrombins/chemistry , Thrombophilia/genetics , Adolescent , Adult , Aged , Anticoagulants/chemistry , Antithrombin III/chemistry , Chromatography, High Pressure Liquid , Exome , Female , Genetic Variation , Genotype , Glycoproteins/chemistry , Glycosylation , Humans , Male , Middle Aged , Mutation , Spain , Thrombophilia/immunology , Thrombophilia/therapy , Thrombosis , Young Adult
10.
Thromb Res ; 136(3): 634-41, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26186963

ABSTRACT

INTRODUCTION: ß-antithrombin, the minor antithrombin glycoform in plasma, is probably the major thrombin inhibitor in vivo because of its high heparin affinity. The levels and variability of this glycoform in general population and its relevance in thromboembolic diseases is unknown since there is no specific method to measure this glycoform in clinical samples. METHODS: Plasma and recombinant α- and ß-antithrombins were purified by heparin affinity chromatography. An anti-FXa chromogenic method in presence of pentassacharide was used with two NaCl concentrations (15mM and 1.1M). This method was applied to plasma samples from 97 healthy subjects and 117 consecutive patients with ischemic cerebrovascular disease during the acute event and one year later. SERPINC1 sequencing was done in cases with antithrombin deficiency. RESULTS: High salt concentrations specifically restricted the pentassacharide-induced activation of antithrombin to the ß glycoform. ß-antithrombin displayed a normal distribution in the general population (89.5%-103.5%), with no significant variations according to age or sex. In patients, whole antithrombin values remained within the normal range. Only five cases had antithrombin deficiency during the thrombotic event, one carrying the L99F mutation in SERPINC1. Interestingly, both ß-antithrombin and the ß/whole antithrombin ratio were significantly higher in patients during the acute event but normalized after one year. CONCLUSIONS: We have developed a rapid, simple, sensitive and specific method to quantify ß-antithrombin activity using 1µL of plasma. ß-antithrombin significantly increases in patients with ischemic cerebrovascular disease during the acute event, probably by its release from the vasculature.


Subject(s)
Antithrombins/blood , Immunoassay/methods , Stroke/blood , Stroke/diagnosis , Adult , Aged , Aged, 80 and over , Animals , Antithrombins/classification , Antithrombins/immunology , Biomarkers/blood , Female , Humans , Male , Middle Aged , Reproducibility of Results , Sensitivity and Specificity , Stroke/immunology , Up-Regulation
12.
Int J Clin Pract ; 68(4): 434-43, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24372915

ABSTRACT

Atrial fibrillation (AF) confers a raised risk of stroke and death, and this risk of adverse events is increased by the coexistence of other cardiovascular risk factors. The pathophysiology of AF is complex, involving the role of inflammation, structural remodelling with apoptosis, inflammation or fibrosis. These changes confer a prothrombotic or hypercoagulable state in this arrhythmia. Despite being easy to use for decision-making concerning oral anticoagulant therapy in AF, clinical risk scores used for stratification have shown modest capability in predicting thromboembolic events, and biomarkers may improve our identification of 'high risk' patients. Biomarkers, whether measured in the peripheral blood, urine or imaging-based may improve our knowledge of the pathophysiology of AF. Importantly these biomarkers could help in the assessment of AF prognosis. The aim of this review was to summarise the published data about biomarkers studied in AF, with focus on data from randomised prospective clinical trials and large community-based cohorts. We will also review the application of these biomarkers to prognosis on the main schemes used to help stratify risk in AF.


Subject(s)
Atrial Fibrillation/diagnosis , Atrial Fibrillation/blood , Atrial Fibrillation/etiology , Biomarkers/blood , Humans , Prognosis , Risk Factors
13.
Thromb Haemost ; 109(5): 956-60, 2013 May.
Article in English | MEDLINE | ID: mdl-23572113

ABSTRACT

Chronic Kidney Disease (CKD) constitutes an adverse risk factor in chronic anticoagulated atrial fibrillation (AF) patients, being related to adverse cardiovascular events, mortality and major bleeds. It is unclear if CKD adds independent prognostic information to stroke risk stratification schemes, as the risk factor components of the CHADS2 and CHA2DS2-VASc scores are themselves related to renal dysfunction. The aim of our study was to determine if CKD independently improves the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification scores in AF. We recruited consecutive patients (n=978) patients (49% male; median age 76) with permanent or paroxysmal AF on oral anticoagulants with acenocoumarol, from our out-patient anticoagulation clinic. After a median follow-up of 875 (IQR 706-1059) days, we recorded stroke/transient ischaemic attack (TIA), peripheral embolism, vascular events (acute coronary syndrome, acute heart failure and cardiac death) and all-cause mortality. During follow-up, 113 patients (4.82%/year) experienced an adverse cardiovascular event, of which 39 (1.66%/year) were strokes, 43 (1.83%/year) had an acute coronary syndrome and 32 (1.37%/year) had acute heart failure. Also, 102 patients (4.35%/year) died during the following up, 31 of them (1.32%/year) as a result of a thrombotic event. Based on c-statistics and the integrated discrimination improvement (IDI), CKD did not improve the prediction for stroke/systemic embolism, thrombotic events and all-cause mortality using the CHADS2 and CHA2DS2-VASc scores. In conclusion, evaluating renal function in AF patients is important as CKD would confer a poor overall prognosis in terms of thromboembolic events and all-cause mortality. Adding CKD to the CHADS2 and CHA2DS2-VASc stroke risk scores did not independently add predictive information.


Subject(s)
Atrial Fibrillation/complications , Decision Support Techniques , Ischemic Attack, Transient/etiology , Renal Insufficiency, Chronic/complications , Stroke/etiology , Acenocoumarol/administration & dosage , Administration, Oral , Aged , Aged, 80 and over , Atrial Fibrillation/blood , Atrial Fibrillation/drug therapy , Atrial Fibrillation/mortality , Female , Humans , Ischemic Attack, Transient/blood , Ischemic Attack, Transient/mortality , Ischemic Attack, Transient/prevention & control , Kidney/physiopathology , Male , Multivariate Analysis , Proportional Hazards Models , Renal Insufficiency, Chronic/mortality , Renal Insufficiency, Chronic/physiopathology , Risk Assessment , Risk Factors , Stroke/blood , Stroke/mortality , Stroke/prevention & control , Time Factors , Treatment Outcome
14.
J Agric Food Chem ; 60(45): 11331-42, 2012 Nov 14.
Article in English | MEDLINE | ID: mdl-23072624

ABSTRACT

The colonic microbial degradation of a polyphenol-rich black tea extract (BTE) and red wine/grape juice extract (RWGE) was compared in a five-stage in vitro gastrointestinal model (TWINSHIME). Microbial metabolism of BTE and RWGE polyphenols in the TWINSHIME was studied subsequently in single- and continuous-dose experiments. A combination of liquid or gas chromatography with mass spectrometry (LC-MS or GC-MS) and NMR-based metabolic profiling was used to measure selected parent polyphenols, their microbial degradation into phenolic acids, and the production of short-chain fatty acids (SCFAs) in different colon compartments. Acetate production was increased by continuous feeding of BTE but not RWGE. During RWGE feeding, gallic acid and 4-hydroxyphenylpropionic acid remained elevated throughout the colon, while during BTE feeding, they were consumed in the distal colon, while 3-phenylpropionic acid was strongly produced. Gut microbial production of phenolics and SCFAs is dependent on colon location and polyphenol source, which may influence potential health benefits.


Subject(s)
Bacteria/metabolism , Camellia sinensis/metabolism , Colon/metabolism , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/microbiology , Plant Extracts/metabolism , Polyphenols/metabolism , Vitis/metabolism , Wine/analysis , Camellia sinensis/chemistry , Colon/microbiology , Humans , Metagenome , Models, Biological , Plant Extracts/analysis , Species Specificity , Tea/metabolism , Vitis/chemistry
15.
J Thromb Haemost ; 10(8): 1500-7, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22681487

ABSTRACT

UNLABELLED: There are limited data on the prognostic role of biomarkers in anticoagulated patients with atrial fibrillation (AF). We evaluated the prognostic value of high sensitivity TnT (hsTnT) and high-sensitivity interleukin-6 (hsIL6) in a large cohort of AF patients taking oral anticoagulant therapy (OAC) as both biomarkers have been associated with adverse cardiovascular events. METHODS: We studied 930 patients (51% male; median age 76) with permanent/ paroxysmal AF who were stabilized (for at least 6 months) on OAC (INRs 2.0-3.0). Plasma hsTnT and hsIL6 levels were quantified by electrochemiluminescense immunoassay at baseline. Patients were followed-up for up to 2 years, and adverse events (thrombotic and vascular events, mortality and major bleeding) were recorded. RESULTS: At follow-up, 96 patients (3.97%/year) died whilst 107 had an adverse cardiovascular event (3.14%/year). On multivariate analysis, high hsTnT and high hsIL6 remained significantly associated with prognosis even after adjusting for CHADS2 score: HR 2.21 (1.46-3.35, P<0.001) for high hsTnT and 1.97 (1.29-3.02, P=0.002) for high hsIL6, for adverse cardiovascular events. For all-cause mortality, the HRs were 1.79 (1.13-2.83, P=0.013) and 2.48 (1.60-3.85, P<0.001), respectively. The integrated discrimination index (IDI) values of clinical scores (CHADS2 and CHA2 DS2-VASc) were improved by the addition of hsTnT and/or hsIL6 (all P<0.05). CONCLUSION: In a large 'real world' cohort of anticoagulated AF patients, both hsTnT and hsIL6 levels provided prognostic information that was complementary to clinical risk scores for prediction of long-term cardiovascular events and death, suggesting that these biomarkers may potentially be used to refine clinical risk stratification in AF.


Subject(s)
Anticoagulants/therapeutic use , Atrial Fibrillation/drug therapy , Interleukin-6/blood , Stroke/prevention & control , Thromboembolism/prevention & control , Troponin T/blood , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Atrial Fibrillation/blood , Atrial Fibrillation/mortality , Biomarkers/blood , Female , Hemorrhage/chemically induced , Hemorrhage/mortality , Humans , Immunoassay , International Normalized Ratio , Kaplan-Meier Estimate , Male , Multivariate Analysis , Proportional Hazards Models , Prospective Studies , Risk Assessment , Risk Factors , Spain , Stroke/blood , Stroke/mortality , Thromboembolism/blood , Thromboembolism/mortality , Time Factors , Treatment Outcome , Up-Regulation
17.
J Thromb Haemost ; 9(10): 1985-92, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21794077

ABSTRACT

BACKGROUND: Tissue factor (TF) is the main initiator of the coagulation cascade and elements that may upregulate its expression might provoke thrombotic events. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune diseases characterized by a high TF expression in monocytes. OBJECTIVES: To examine the role of microRNAs (miRNAs) in TF expression and to evaluate their levels in SLE and APS patients. METHODS: An in silico search was performed to find potential putative binding sites of miRNAs in TF mRNA. In vitro validation was performed transfecting cells expressing TF (THP-1 and MDA-MB-231) with oligonucleotide miRNA precursors and inhibitors. Additionally, reporter assays were performed to test for the binding of miR-20a to TF mRNA. Levels of miRNAs and TF were measured by quantitative (qRT-PCR) in patients with APS and SLE. RESULTS: Overexpression of miRNA precursors, but not inhibitors, of two of the members of cluster miR-17∼92, for example miR-19b and miR-20a, in cells expressing TF decreased TF mRNA, protein levels, and procoagulant activity between 30% and 60%. Reporter assays showed that miR-20a binds to TF mRNA. Finally, we measured levels of miR-19b and miR-20a in monocytes from patients with APS and SLE and observed significantly lower miRNAs levels in comparison with healthy subjects inversely correlated with the levels of TF. CONCLUSIONS: Down-regulation of miR-19b and miR-20a observed in patients with SLE and APS could contribute to increased TF expression and thus provoke the hypercoagulable state characteristic of these patients.


Subject(s)
Antiphospholipid Syndrome/metabolism , Lupus Erythematosus, Systemic/metabolism , MicroRNAs/physiology , Thromboplastin/metabolism , Adult , Aged , Blotting, Western , Case-Control Studies , Cell Line , Female , Humans , Male , MicroRNAs/genetics , Middle Aged , Real-Time Polymerase Chain Reaction
18.
Int J Clin Pract ; 65(3): 361-71, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21314873

ABSTRACT

Increasing number of patients presenting for ophthalmic surgery are using oral anti-coagulant and anti-platelet therapy. The current practice of discontinuing these drugs preoperatively because of a presumed increased risk of bleeding may not be evidence-based and could pose a significant risk to the patient's health. To provide an evidence-based review on the peri-operative management of ophthalmic patients who are taking anti-thrombotic therapy. In addition, we briefly discuss the underlying conditions that necessitate the use of these drugs as well as management of the operative field in anti-coagulated patients. A semi-systematic review of literature was performed. The databases searched included MEDLINE, EMBASE, database of abstracts of reviews of effects (DARE), Cochrane controlled trial register and Cochrane systematic reviews. In addition, the bibliographies of the included papers were also scanned for evidence. The published data suggests that aspirin did not appear to increase the risk of serious postoperative bleeding in any type of ophthalmic surgery. Topical, sub-tenon, peri-bulbar and retrobulbar anaesthesia appear to be safe in patients on anti-thrombotic (warfarin and aspirin) therapy. Warfarin does not increase the risk of significant bleeding in most types of ophthalmic surgery when the INR was within the therapeutic range. Current evidence supports the continued use of aspirin and with some exceptions, warfarin in the peri-operative period. The risk of thrombosis-related complications on disruption of anticoagulation may be higher than the risk of significant bleeding by continuing its use for most types of ophthalmic surgery.


Subject(s)
Eye Diseases/surgery , Fibrinolytic Agents/therapeutic use , Intraoperative Care/methods , Blood Loss, Surgical , Hemostasis, Surgical , Humans , Ophthalmologic Surgical Procedures/methods , Risk Factors , Thrombosis/etiology
19.
Zoo Biol ; 30(1): 65-70, 2011.
Article in English | MEDLINE | ID: mdl-20235106

ABSTRACT

The Greater Rhea (Rhea americana) is a characteristic bird of the Argentine Pampas. Despite the increasing farming interest of this ratite, their natural populations are progressively decreasing in size and range. The object of this study was to evaluate the status of captive populations as potential genetic reservoirs. Using Inter-Simple Sequence Repeats as molecular markers, levels of genetic variability of F1 individuals from two captive populations were estimated and compared with those of wild populations in the same region. The captive populations were polymorphic for 12.22 and 13.33% of the loci, with a genetic diversity of 0.050. Differences with wild populations were not significant (z=1.79; P>0.05). Therefore, captive populations of rheas in Argentina should not be overlooked as genetic reservoir and source of individuals for reinforcement of natural populations, through reintroduction and translocation.


Subject(s)
Genetic Variation , Rheiformes/genetics , Animals , Animals, Zoo , Argentina , Conservation of Natural Resources , Female , Genetic Markers , Male
20.
J Thromb Haemost ; 8(5): 1012-7, 2010 May.
Article in English | MEDLINE | ID: mdl-20149073

ABSTRACT

SUMMARY BACKGROUND: There is currently intense debate as to whether pharmacogenetic algorithms for estimating the initial dose of coumarins provide a more accurate dose than the fixed-dose approach. Recently, it has been suggested that the greatest benefit of pharmacogenetic algorithms is observed in patients with extreme dose requirements. OBJECTIVES: To identify clinical and genetic factors that better characterize patients who need extreme acenocoumarol doses for steady anticoagulation state. PATIENTS/METHODS: We reviewed 9538 patients with a steady acenocoumarol dose from three Spanish hospitals, selecting 83 who took or= 30.00 mg week(-1) (p95). We also selected patients matched by gender and age taking 13.50-14.00 mg week(-1) (p50). We genotyped VKORC1 (rs9923231), CALU (rs1043550), GGCX (rs699664), CYP2C9 (rs1799853; rs1057910), CYP4F2 (rs2108622) and F7 (rs5742910) single-nucleotide polymorphisms (SNPs). RESULTS: Comparison between p5 and p95 revealed five parameters with significant differences: body surface area (BSA) (P = 0.006), age, VKORC1, CYP2C9 and CYP4F2 genotypes (all P < 0.001). First VKORC1, and second, CYP2C9 SNPs played a strong effect by determining extreme doses, particularly in p95. Only one out of 203 p95 had the VKORC1 A-1639A genotype, but this subject was CYP2C9*1/*1. In contrast, nine out of 83 p5 carried the VKORC1 G-1639G genotype, although six of them were CYP2C9*3 homozygotes and another two were heterozygotes. Surprisingly, CYP4F2 V433M SNP displayed prevalences that suggest that its influence might only be evident when patients are treated with high doses. CONCLUSION: Two clinical data, age and BSA, and three SNPs in the VKORC1, CYP2C9 and CYP4F2 genes strongly predict outlier patients treated with acenocoumarol.


Subject(s)
Acenocoumarol/pharmacology , Anticoagulants/pharmacology , Pharmacogenetics , Acenocoumarol/administration & dosage , Adult , Aged , Anticoagulants/administration & dosage , Aryl Hydrocarbon Hydroxylases/genetics , Base Sequence , Cytochrome P-450 CYP2C9 , Cytochrome P-450 Enzyme System/genetics , Cytochrome P450 Family 4 , DNA Primers , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Mixed Function Oxygenases/genetics , Polymorphism, Single Nucleotide , Vitamin K Epoxide Reductases
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