Stroke and Bleeding Risk in Atrial Fibrillation: Navigating the Alphabet Soup of Risk‐Score Acronyms (CHADS2, CHA2DS2‐VASc,R2CHADS2, HAS‐BLED,ATRIA, and More)

Stroke prevention is central to the management of patients with atrial fibrillation (AF). As effective stroke prophylaxis essentially requires oral anticoagulants, an understanding of the risks and benefits of oral anticoagulant therapy is needed. Although AF increases stroke risk 5‐fold, this risk is not homogeneous. Many stroke risk factors also confer an increased risk of bleeding. Various stroke and bleeding risk‐stratification schemes have been developed to help inform clinical decision‐making. These scores were derived and validated in different study cohorts, ranging from highly selected clinical‐trial cohorts to real‐world populations. Thus, their performance and classification accuracy vary depending on their derivation cohort(s). In the present review, we provide an overview of currently available stroke and bleeding risk‐stratification schemes. We particularly focus on the CHA₂DS₂‐VASc and HAS‐BLED schemes, as these are recommended by the latest European guidelines on AF management. Other risk‐stratification schemes (eg, CHADS₂, R₂CHADS₂, ATRIA, HEMORR₂HAGES, QStroke) and their place in the decision‐making are also considered.     

Endothelial CD44H mediates adhesion of a melanoma cell line to quiescent human endothelial cells in vitro

A critical step in the metastatic spread of tumour cells is the interaction of circulating tumour cells with the vascular endothelium. We have investigated the role of CD44 and its variants in the adhesion of a human melanoma cell line (RPMI-7951) and a breast adenocarcinoma cell line (MDA-MB-231) to quiescent human umbilical vein endothelial cells (HUVEC) in vitro. Both tumour cell lines express CD44H, CD44A and CD44v9, while HUVEC express only CD44H. Pre-treatment of endothelial cell monolayers with a blocking monoclonal antibody against CD44H (MAb 5A4) reduced the adhesion of RPMI-7951 cells but not that of MDA-MB-231. In contrast, pre-treatment of both tumour cell lines with the same antibody had no effect on adhesion. Digestion of the CD44 ligand hyaluronic acid (HA) on RPMI-7951 cells significantly reduced adhesion to endothelial monolayers, while digestion of HUVEC HA had no effect. We conclude that CD44H expressed on the surface of quiescent endothelial monolayers mediates in part the adhesion of the metastatic melanoma cell line RPMI-7951 but not that of a breast adenocarcinoma line. It does so by acting as a receptor for HA on the tumour cell surface. Tumour cell CD44H and variants CD44A and CD44v9 do not appear to be involved in adhesion to endothelial cells. © 1996 Wiley-Liss, Inc.     

Comparison between urinary diaries completed with and without intensive patient instructions

The evaluation of the incontinent patient relies on accurate assessment of urinary symptoms. Although the 7 day urinary diary is a reproducible method of data collection, the optimal means of implementing this diary is unknown. The urinary diary is usually employed after the initial clinical pathophysiologic evaluation has been performed and the patient has received intensive instructions on the correct method of diary completion. This study aims to determine if a urinary diary provided to the patient prior to the initial clinical evaluation along with minimal instructions will provide symptom data comparable with that obtained by conventional methods. Two hundred seventy-eight women were recruited to participate in one of three clinical trials for urinary incontinence treatment. All subjects completed a diary prior to the initial clinical evaluation, the Minimal Instruction Diary, and a second diary after clinical evaluation, the Intensive Instruction Diary. The Minimal and the Intensive Instruction Diaries were compared for number of episodes of diurnal and nocturnal voluntary micturition and incontinence. Pearsons' correlation coefficients ranged from 0.67 to 0.78 for each of the urinary symptoms. Intra-subject comparison indicated a decline in reports of nocturnal voluntary micturitions from the Minimal to the Intensive Instruction Diary. No demographic or urodynamic parameters could account for the difference. The 7 day urinary diary is a reliable tool to assess urinary symptoms, which can be utilized prior to the initial clinical evaluation. Its ease of use and practicality make this diary promising for use in a wider patient population. © 1996 Wiley-Liss, Inc.     

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.     

International Multicenter Evaluation of the DiversiLab Bacterial Typing System for Escherichia coli and Klebsiella spp.

Successful multidrug-resistant clones are increasing in prevalence globally, which makes the ability to identify these clones urgent. However, adequate, easy-to-perform, and reproducible typing methods are lacking. We investigated whether DiversiLab (DL), an automated repetitive-sequence-based PCR bacterial typing system (bioMérieux), is suitable for comparing isolates analyzed at different geographic centers. A total of 39 Escherichia coli and 39 Klebsiella species isolates previously typed by the coordinating center were analyzed. Pulsed-field gel electrophoresis (PFGE) confirmed the presence of one cluster of 6 isolates, three clusters of 3 isolates, and three clusters of 2 isolates for each set of isolates. DL analysis was performed in 11 centers in six different countries using the same protocol. The DL profiles of 425 E. coli and 422 Klebsiella spp. were obtained. The DL system showed a lower discriminatory power for E. coli than did PFGE. The local DL data showed a low concordance, as indicated by the adjusted Rand and Wallace coefficients (0.132 to 0.740 and 0.070 to 1.0 [E. coli] and 0.091 to 0.864 and 0.056 to 1.0 [Klebsiella spp.], respectively). The central analysis showed a significantly improved concordance (0.473 to 1.0 and 0.290 to 1.0 [E. coli] and 0.513 to 0.965 and 0.425 to 1.0 [Klebsiella spp.], respectively). The misclassifications of profiles for individual isolates were mainly due to inconsistent amplification, which was most likely due to variations in the quality and amounts of the isolated DNA used for amplification. Despite local variations, the DL system has the potential to indicate the occurrence of clonal outbreaks in an international setting, provided there is strict adherence to standardized, reproducible DNA isolation methods and analysis protocols, all supported by a central database for profile comparisons.     

Endothelial dysfunction in hypertension in pregnancy: associations between circulating endothelial cells,circulating progenitor cells and plasma von Willebrand factor

Background  

Endothelial damage/dysfunction has been related to hypertension in pregnancy, with implications in pregnancy outcomes. We hypothesised abnormal levels of circulating endothelial cells (CECs), circulating progenitor cells (CPCs) and plasma von Willebrand factor (vWf, a marker of endothelial damage/dysfunction) in pregnant women with hypertension, when compared to pregnant normotensives and non pregnant healthy controls.     

Cognitions and alcohol-influenced performance: the impact of reinforcement contingencies

The effects of different reinforcement conditions on self-reported cognitions and task performance under the influence of alcohol were examined. Four groups of male university students attended a series of four drinking sessions. During the sessions, the groups performed a visual tracking task under different reinforcement conditions which influence the speed of acquisition of behavioural tolerance to the impairing effects of alcohol. At the end of each session, subjects completed a questionnaire intended to elicit any thoughts, feelings, ideas or images they experienced during the session. Their responses were scored in categories related to alcohol effects, task performance and motivation. The groups differed significantly on numbers of self-reported cognitions related to general alcohol effects and to alcohol effects on task performance; these differences corresponded to differences in the speed of tolerance development. In the group that acquired tolerance most rapidly, several aspects of task performance were significantly correlated with cognitions. These data provide support for the suggestion that cognitive activity may be an important factor in individuals' responses to alcohol and other drugs.     

Enhancement characteristics of papillary renal neoplasms revealed on triphasic helical CT of the kidneys.

OBJECTIVE: The purpose of this study was to determine whether renal tumor enhancement or heterogeneity on triphasic helical CT scans is predictive of the papillary cell subtype or nuclear grade of renal cell carcinoma. MATERIALS AND METHODS: We reviewed the CT scans of 90 consecutive patients with renal masses who had undergone triphasic renal helical CT before a complete or partial nephrectomy (12 with papillary renal cell carcinomas, 66 with nonpapillary renal cell carcinomas, and 12 with benign lesions). Three radiologists who were unaware of the patients' diagnoses retrospectively and independently measured the attenuation of each patient's tumor, abdominal aorta, and normal renal parenchyma on the scans obtained during all three phases. Ratios of tumor-to-aorta enhancement and tumor-to-normal renal parenchyma enhancement were calculated for both of the phases performed after contrast material had been administered. Tumor heterogeneity was calculated as the difference between the highest and lowest attenuation values divided by the value of the enhancement of the aorta. Values were correlated with cell type and nuclear grade found at surgical pathology. RESULTS: Low tumor-to-aorta enhancement and low tumor-to-normal renal parenchyma enhancement ratios on the vascular phase scans significantly correlated (p < 0.001) with papillary renal cell type carcinoma. Homogeneity and tumor-to-parenchyma enhancement ratios on the parenchymal phase scans also significantly correlated (p < 0.001) with papillary renal cell type carcinoma. Heterogeneity and tumor enhancement ratios did not correlate with the nuclear grade of the carcinoma. CONCLUSION: Papillary renal cell carcinomas are typically hypovascular and homogeneous. A high tumor-to-parenchyma enhancement ratio (> or = 25%) essentially excludes the possibility of a tumor being papillary renal cell carcinoma. A low tumor-to-aorta enhancement ratio or tumor-to-normal renal parenchyma enhancement ratio is more likely to indicate papillary renal cell carcinoma.     

Calcineurin inhibitor minimization in pediatric liver allograft recipients

Abstract:  The use of CNI in pediatric LTx has dramatically improved the outcome for children with end-stage liver disease by significantly reducing the rate of acute and chronic rejection. Long-term concerns about CNI-induced nephrotoxicity and other adverse effects remain an issue, particularly as the emphasis moves from short-term survival to long-term quality of life. This review summarizes lessons learnt from pediatric and adult solid organ transplantation in minimizing CNI use in immunosuppression protocols in children following LTx. There are three models for CNI minimization: dose reduction, withdrawal or avoidance, supplemented by the use of IL-2 receptor blocking antibodies in the peri-transplant period, and early transition to alternate drugs such as MMF or SRL. Prospective studies evaluating reduction or withdrawal protocols in adult and pediatric LTx indicate that rejection rates are comparable with traditional CNI-based immunosuppression and that two and five yr patient and graft survival are similar, with recovery in renal function. There are few studies evaluating complete avoidance of CNI, apart from that in renal transplantation, although the benefits of long-term reduction in cardiovascular, metabolic, and possibly neoplastic side effects may justify this approach. It is not clear yet how CNI minimization will affect the development of tolerance but experimental and preliminary clinical studies indicate that CNI and steroid avoidance or minimization in the peri-operative period may favor the development of long-term graft tolerance. In summary, CNI minimization may be safe and effective in the short term but large-scale pediatric randomized studies are required to evaluate the long-term efficacy of these regimes in the development of chronic rejection, PTLD, and graft tolerance.     

Do sex-role appropriate materials influence the piagetian task performance of older adults?

The intent of this study was to assess the influence of sex-role appropriate materials on the utilization of logical competence among older persons, and to determine how such materials interact with subject's sex-role identity to affect cognitive performance. Thirty male and 30 female Ss (mean age = 71.3 years) were administered the Short Form of the Bern Sex-Role Inventory and either a male-oriented, a female-oriented, or a traditional version of two concrete operational and two formal operational Piagetian tasks. Gender was found to influence performance on one of the concrete tasks, task orientation influenced performance on one of the formal tasks, and sex-role classification interacted with task orientation to influence performance on both of the formal operational tasks. The pattern of results suggested that subjects may perform best on those versions of the formal operational tasks that do not match their own sex type. Possible explanations for these findings are discussed.