Background and Purpose— Recombinant tissue plasminogen activator (rtPA) is an effective treatment for acute ischemic stroke but is associated with an increased risk of intracranial hemorrhage (ICH). We sought to identify the risk factors for ICH with a systematic review of the published literature. Methods— We searched for studies of rtPA-treated stroke patients that reported an association between a variable measured before rtPA infusion and clinically important ICH (parenchymal ICH or ICH associated with clinical deterioration). We calculated associations between baseline variables and ICH with random-effect meta-analyses. Results— We identified 55 studies that measured 43 baseline variables in 65 264 acute ischemic stroke patients. Post-rtPA ICH was associated with higher age (odds ratio, 1.03 per year; 95% confidence interval, 1.01–1.04), higher stroke severity (odds ratio, 1.08 per National Institutes of Health Stroke Scale point; 95% confidence interval, 1.06–1.11), and higher glucose (odds ratio, 1.10 per mmol/L; 95% confidence interval, 1.05–1.14). There was approximately a doubling of the odds of ICH with the presence of atrial fibrillation, congestive heart failure, renal impairment, previous antiplatelet agents, leukoaraiosis, and a visible acute cerebral ischemic lesion on pretreatment brain imaging. Little of the variation in the sizes of the associations among different studies was explained by the source of the cohort, definition of ICH, or degree of adjustment for confounding variables. Conclusions— Individual baseline variables were modestly associated with post-rtPA ICH. Prediction of post-rtPA ICH therefore is likely to be difficult if based on single clinical or imaging factors alone. These observational data do not provide a reliable method for the individualization of treatment according to predicted ICH risk.
BackgroundPlasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa.MethodsSeven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed.ResultsCounterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa.ConclusionsCriminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.
Diagnosing stroke is not always straightforward. Stroke mimics such as Todd's paresis or hemiplegic migraine account for between a fifth and a quarter of suspected strokes (depending on the setting in which they are assessed). Stroke chameleons can arise when the tempo of symptom onset is not apoplectic or if the loss of function is not clearly consistent with a deficit within an arterial territory. Thrombolysis and secondary prevention have much to offer patients with stroke chameleons, though those with stroke mimics may be harmed by these treatments and have more to gain from other therapies.
6-Phosphofructokinase-1-kinase (PFK) tetramers catalyse the phosphorylation of fructose 6-phosphate (F6P) to fructose 1,6-bisphosphate (F16BP). Vertebrates have three PFK isoforms (PFK-M, PFK-L, and PFK-P). This study is the first to compare the kinetic, structural, and transcript levels of recombinant human PFK isoforms. Under the conditions tested PFK-M has the highest affinities for F6P and ATP (K0.5ATP 152μM; K0.5F6P 147μM), PFK-P the lowest affinities (K0.5ATP 276μM; K0.5F6P 1333μM), and PFK-L demonstrates a high ATP affinity and low F6P affinity (K0.5ATP 160μM; K0.5F6P 1360μM). PFK-M is more resistant to ATP inhibition compared to PFK-L and PFK-P (respectively, 23%, 31%, 50% decreases in specificity constants). GTP is an alternate phospho donor. Interface 2, which regulates the inactive dimer to active tetramer equilibrium, differs between isoforms, resulting in varying tetrameric stability. PFK-M is less sensitive to fructose 2,6-bisphosphate (F26BP) allosteric modulation than PFK-L or PFK-P (allosteric constants [K0.5ATP+F26BP/K0.5ATP] 1.10, 0.92, 0.54, respectively). Structural analysis of two allosteric sites reveals one may be specialised for AMP/ADP and the other for smaller/flexible regulators (citrate or phosphoenolpyruvate). Correlations between PFK-L and PFK-P transcript levels indicate that simultaneous expression may expand metabolic capacity for F16BP production whilst preserving regulatory capabilities. Analysis of cancer samples reveals intriguing parallels between PFK-P and PKM2 (pyruvate kinase M2), and simultaneous increases in PFK-P and PFKFB3 (responsible for F26BP production) transcript levels, suggesting prioritisation of metabolic flexibility in cancers. Our results describe the kinetic and transcript level differences between the three PFK isoforms, explaining how each isoform may be optimised for distinct roles.
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