John Radcliffe Hospital

About: John Radcliffe Hospital is a healthcare organization based out in Oxford, Oxfordshire, United Kingdom. It is known for research contribution in the topics: Population & Antigen. The organization has 14491 authors who have published 23670 publications receiving 1459015 citations.

Pharmacokinetics and Pharmacodynamics of Lumefantrine (Benflumetol) in Acute Falciparum Malaria

Abstract: The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting The population absorption half-life of lumefantrine was 45 h The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 62 (025 and 148) microgram/ml after regimen A, 9 0 (11 and 198) microgram/ml after regimen B, and 8 (14 and 174) microgram/ml after regimen C During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%) The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 00001) The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 microgram/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 00001]) and higher cure rates Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC

Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial

Abstract: OBJECTIVES :T his prespeci fied subgroup analysis examined the effect of diabetes on left main coronary disease (LM) and/or three-vessel disease (3VD) in patients treated with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in the SYNTAX trial. METHODS: Patients (n= 1800) with LM and/or 3VD were randomized to receive either PCI with TAXUS Express paclitaxel-eluting stents or CABG. Five-year outcomes in subgroups with (n= 452) or without (n= 1348) diabetes were examined: major adverse cardiac or cerebrovascular events (MACCE), the composite safety end-point of all-cause death/stroke/myocardial infarction (MI) and individual MACCE components death, stroke, MI and repeat revascularization. Event rates were estimated with Kaplan–Meier analyses. RESULTS: In diabetic patients, 5-year rates were significantly higher for PCI vs CABG for MACCE (PCI: 46.5% vs CABG: 29.0%; P< 0.001) and repeat revascularization (PCI: 35.3% vs CABG: 14.6%; P< 0.001). There was no difference in the composite of all-cause death/stroke/ MI (PCI: 23.9% vs CABG: 19.1%; P= 0.26) or individual components all-cause death (PCI: 19.5% vs CABG: 12.9%; P= 0.065), stroke (PCI: 3.0% vs CABG: 4.7%; P= 0.34) or MI (PCI: 9.0% vs CABG: 5.4%; P= 0.20). In non-diabetic patients, rates with PCI were also higher for MACCE (PCI: 34.1% vs CABG: 26.3%; P= 0.002) and repeat revascularization (PCI: 22.8% vs CABG: 13.4%; P< 0.001), but not for the composite end-point of all-cause death/stroke/MI (PCI: 19.8% vs CABG: 15.9%; P= 0.069). There were no differences in all-cause death (PCI: 12.0% vs CABG: 10.9%; P= 0.48) or stroke (PCI: 2.2% vs CABG: 3.5%; P= 0.15), but rates of MI (PCI: 9.9% vs CABG: 3.4%; P< 0.001) were significantly increased in the PCI arm in non-diabetic patients. CONCLUSIONS: In both diabetic and non-diabetic patients, PCI resulted in higher rates of MACCE and repeat revascularization at 5 years. Although PCI is a potential treatment option in patients with less-complex lesions, CABG should be the revascularization option of choice for patients with more-complex anatomic disease, especially with concurrent diabetes.

The functional organization of mitochondrial genomes in human cells

Abstract: We analyzed the organization and function of mitochondrial DNA in a stable human cell line (ECV304, which is also known as T-24) containing mitochondria tagged with the yellow fluorescent protein. Mitochondrial DNA is organized in ~475 discrete foci containing 6–10 genomes. These foci (nucleoids) are tethered directly or indirectly through mitochondrial membranes to kinesin, marked by KIF5B, and microtubules in the surrounding cytoplasm. In living cells, foci have an apparent diffusion constant of 1.1 × 10-3 μm2/s, and mitochondria always split next to a focus to distribute all DNA to one daughter. The kinetics of replication and transcription (monitored by immunolabelling after incorporating bromodeoxyuridine or bromouridine) reveal that each genome replicates independently of others in a focus, and that newly-made RNA remains in a focus (residence half-time ~43 min) long after it has been made. This mitochondrial RNA colocalizes with components of the cytoplasmic machinery that makes and imports nuclear-encoded proteins – that is, a ribosomal protein (S6), a nascent peptide associated protein (NAC), and the translocase in the outer membrane (Tom22). The results suggest that clusters of mitochondrial genomes organize the translation machineries on both sides of the mitochondrial membranes. Then, proteins encoded by the nuclear genome and destined for the mitochondria will be made close to mitochondrial-encoded proteins so that they can be assembled efficiently into mitochondrial complexes.