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The possibility that population admixture has distorted the strength of the pooled estimate of association remains. Family-based studies using transmission disequilibrium testing to account for population admixture have not yet examined the association of the PAI-1 polymorphism with pre-eclampsia. A major limiting factor in determining the validity and applicability of the findings of any systematic review and meta-analysis is the quality of the included studies. However, unlike the quality assessment of randomised controlled trials, empirical evidence to determine the degree to which different genetic association study characteristics introduce bias is lacking. Furthermore, the methods used in many genetic association studies are reported variably and incompletely. The potential methodological design weakness in genetic association studies include imprecise phenotype definition, inappropriate control selection, and lack of blinding of laboratory genotyping staff to the clinical status of cases and controls. We specifically excluded studies in which participants included women with gestational hypertension in order to improve the homogeneity of phenotype between studies. The absence of statistical heterogeneity in the metaanalyses is reassuring and may reflect the a priori requirement for studies to have used an internationally-accepted case definition. Furthermore, only studies in which controls were women who had a pregnancy uncomplicated by pre-eclampsia were eligible for inclusion. This inclusion criterion reduces the risk that any observed association is due to another unrelated or unknown factor. Only two studies included in this review reported blinding of genotyping. Some of the older genotyping techniques are more subjective than the modern methods and knowing the clinical status of the case or the control may have influenced the interpretation of the genotyping result. We have managed this problem to some extent by excluding studies in which the genotype distribution within the controls deviated substantially form Hardy Weinberg equilibrium. The underlying pathophysiology in most cases of ischemic stroke involves thrombotic or thromboembolic arterial occlusion. Platelets play a role in the development of atherosclerotic lesions and in thrombus formation following plaque rupture or erosion, and antiplatelet therapy is recommended to reduce the risk of recurrent stroke and other cardiovascular events in patients with noncardioembolic ischemic stroke or transient ischemic attack. The results of a recent randomized trial, the second Cilostazol Stroke Prevention Study, indicated that a phosphodiesterase 3 inhibitor cilostazol is superior to acetylsalicylic acid for secondary stroke prevention. K- 134 was identified as a more selective PDE3 inhibitor than cilostazol, and shown to more potently inhibit human platelet aggregation and thrombus formation. Thus, K-134 is also expected to prevent brain infarction, and it is of interest to compare the effects of K-134 with those of cilostazol. In non-clinical studies, cilostazol has been shown to attenuate brain injury induced by middle cerebral artery occlusion. The pathophysiological mechanism of photothrombotic stroke model is more similar to that of human cerebral infarction than mechanical occlusion models, because photothrombotic MCA occlusion is induced by platelet-rich thrombi following Propyl gallate photochemical reaction of rose bengal that causes endothelial damage. In fact, Umemura et al. reported that preadministration of clopidogrel, which is a potent inhibitor of ADP-induced platelet activation, prolonged the time to produce thrombotic occlusion of the MCA and induced a significant reduction in the size of ischemic cerebral damage in this model. To date, little is known about whether K-134 shows more potent antithrombotic activity in in vivo thrombotic models and beneficial effects on the photothrombotic stroke model compared to cilostazol. Hence, the aim of the present study was to further evaluate and compare the effects of oral preadministration of K-134 and cilostazol on MCA occlusion and infarct volume in the photothrombotic stroke model. K-134 exerts a similar dose-dependent vasodilatory effects on rat femoral arteries contracted by KCl in vitro compared with cilostazol, and both drugs increases both pre- and posttreadmill exercise hindlimb blood flow after 1 week of treatment to a similar extent in a rat experimental peripheral artery disease model. In contrast, anti-platelet activities of K-134 are more potent than cilostazol. K-134 is currently being developed for treating intermittent claudication associated with peripheral arterial diseases and the beneficial effects of PDE3 inhibitors on peripheral arterial disease are attributable to not only antiplatelet activity but also vasodilatory activity or some chronic unknown effects, as no studies have shown a benefit of other antiplatelet drugs such as acetylsalicylic acid and clopidogrel.

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