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The secular evolution of the Earth's crust is marked by a profound change in average crustal chemistry between 3.2 and 2.5 Ga. A key marker for this change is the transition from Archaean sodic granitoid intrusions of the tonalite-trondhjemite-granodiorite (TTG) series to potassic (K) granitic suites, akin (but not identical) to I-type granites that today are associated with subduction zones. It remains poorly constrained as to how and why this change was initiated and if it holds clues about the geodynamic transition from a pre-plate tectonic mode, often referred to as stagnant lid, to mobile plate tectonics. Here, we combine a series of proposed mechanisms for Archaean crustal geodynamics in a single model to explain the observed change in granitoid chemistry. Numeric modelling indicates that upper mantle convection drives crustal flow and subsidence, leading to profound diversity in lithospheric thickness with thin versus thick proto-plates. When convecting asthenospheric mantle interacts with lower lithosphere, scattered crustal drips are created. Under increasing P-T conditions, partial melting of hydrated meta-basalt within these drips produces felsic melts that intrude the overlying crust to form TTG. Dome structures, in which these melts can be preserved, are a positive diapiric expression of these negative drips. Transitional TTG with elevated K mark a second evolutionary stage, and are blends of subsided and remelted older TTG forming K-rich melts and new TTG melts. Ascending TTG-derived melts from asymmetric drips interact with the asthenospheric mantle to form hot, high-Mg sanukitoid. These melts are small in volume, predominantly underplated, and their heat triggered melting of lower crustal successions to form higher-K granites. Importantly, this evolution operates as a disseminated process in space and time over hundreds of millions of years (greater than 200 Ma) in all cratons. This focused ageing of the crust implies that compiled geochemical data can only broadly reflect geodynamic changes on a global or even craton-wide scale. The observed change in crustal chemistry does mark the lead up to but not the initiation of modern-style subduction.This article is part of a discussion meeting issue 'Earth dynamics and the development of plate tectonics'.

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Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).

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After successful resuscitation from cardiac arrest, it is important to identify whether the event has been triggered by a myocardial infarction, since this determines subsequent investigations and management. Previous studies have shown that biochemical indices of infarction become elevated after resuscitation in patients without myocardial infarction. This can lead to overdiagnosis of myocardial infarction in the post-arrest setting. The cause of the elevated enzyme levels is not known, but may involve electrical or mechanical injury to the heart during resuscitation. In this study we aimed to identify the effects of isolated direct current shock on serum levels of creatine kinase (CK), MB creatine kinase mass (MB-CK), and troponin T, and examined the relationships between enzyme levels and the dose of electrical energy used. Thirteen patients were studied who underwent DC cardioversion for atrial fibrillation. Serum was obtained for CK, MB-CK and troponin T estimation before and 10 min after cardioversion, at hourly intervals for 8 h, and 18 h after cardioversion. Total serum CK became significantly elevated after only 3 h and rose to a peak of 1294.4 IU l(-1) (P < 0.02) at 18 h. Post-shock CK levels were strongly correlated with total shock energy (r = 0.8, P < 0.01). Serum MB-CK was significantly elevated at 18 h among patients receiving total shock energies greater than 1000 J than in those receiving lower doses, reflecting a positive correlation (r = 0.64, P < 0.05) between shock energy and peak MB-CK level. Troponin T levels were not significantly elevated after cardioversion. In conclusion, total serum CK levels become significantly elevated early after cardioversion, suggesting rapid wash-out from injured skeletal muscle. MB-CK levels become significantly elevated in individuals receiving high energy shocks, probably due to release of small quantities of the CK-MB isoform from skeletal muscle. The negligible troponin T levels seen after high energy cardioversion indicate that significant myocardial injury does not occur. Electrical injury is not likely to account for the elevated troponin T levels seen after out-of-hospital resuscitation in patients without myocardial infarction.

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BACKGROUND: diagnosis of precipitating myocardial infarction is essential for management of victims of out-of-hospital cardiac arrest, since investigations and treatment are determined by the underlying cause. Skeletal muscle and myocardial damage from external cardiac massage and defibrillation may complicate biochemical diagnosis of myocardial infarction. OBJECTIVES: (a) to examine the relationship between cumulative defibrillation energy and serum levels of cardiac troponin T and MB creatine kinase (MB-CK) mass in out-of-hospital cardiac arrest survivors without electrocardiographic evidence of myocardial infarction; (b) to reassess diagnostic thresholds for myocardial infarction using MB-CK mass and troponin T in this setting. METHODS: 77 victims of out-of-hospital cardiac arrest were studied. Serum was obtained for MB-CK mass, CK and troponin T estimation on the first 4 days of admission. Patients were divided into three groups using electrocardiographic criteria: group 1, myocardial infarction; group 2, no evidence of infarction; and group 3, equivocal electrocardiograms. Correlation coefficients were calculated for highest recorded levels of the biochemical markers versus defibrillation energy. Receiver-operating characteristic plots were used to determine optimum biochemical diagnostic thresholds for subjects in groups 1 and 2. RESULTS: using predefined criteria, 27 patients had myocardial infarction, 34 did not have myocardial infarction and 16 had equivocal electrocardiograms. Significant correlations were found for defibrillation energy versus log troponin T (r = 0.42, P < 0.05), log MB-CK mass (r = 0.51, P < 0.01) and total CK (r = 0.68, P < 0.001) in group 2. Within groups 1 and 2, MB-CK mass and troponin T provided additional diagnostic value over MB-CK fraction (P < 0.001). Diagnostic accuracy was not improved by adjusting for shock energy. The optimum threshold value was 4 ng/ml for troponin T (sensitivity 88%, specificity 95%), 60 ng/ml for MB-CK mass (sensitivity 88%, specificity 88%) and 8% of total CK for MB-CK fraction (sensitivity 74%, specificity 82%). These values should be interpreted with caution, since this study is limited by the exclusion of patients with uncertain electrocardiographic diagnoses into group 3. CONCLUSIONS: skeletal muscle and myocardial damage occurs in survivors of out-of-hospital cardiac arrest and is related to the duration of resuscitation. This complicates biochemical diagnosis of underlying myocardial infarction. Specific high diagnostic threshold values for MB-CK and troponin T are needed to optimise diagnostic accuracy. The use of MB-CK fraction leads to greater diagnostic error because of the variability of muscle CK release after resuscitation.

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OBJECTIVE: To investigate whether the measurement of maternal plasma creatine kinase concentration is of clinical value in the diagnosis of tubal ectopic pregnancy. DESIGN: A retrospective observational study covering a three month period. SETTING: The gynaecological emergency service of a UK teaching hospital. SUBJECTS: One hundred and twenty women presenting with clinical suspicion of an ectopic pregnancy such that plasma human chorionic gonadotrophin (hCG) concentration was measured. MAIN OUTCOME MEASURES: Plasma hCG and creatine kinase concentrations were measured. Pregnancies were classified as ectopic pregnancy, complete miscarriage, incomplete miscarriage or ongoing pregnancy. Pregnancies were further classified as uncertain diagnosis if the diagnosis was not clear after initial investigation. RESULTS: Twenty-one of the patients had an ectopic pregnancy. Diagnosis was classified as uncertain in 48% of pregnancies studied and in 54% of ectopic pregnancies during the study period. The mean plasma creatine kinase was higher in ectopic pregnancies than other pregnancies in the study group (P < 0.01) and remained higher in the subgroup of patients with uncertain diagnosis (P < 0.05) but there were significant overlaps in creatine kinase concentrations in all four clinical groups. When a cut-off point of 45 iu/l is used, the measurement of plasma creatine kinase activity has a sensitivity of 0.57 and a specificity of 0.67 for the diagnosis of ectopic pregnancy.

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DMP 323 is a potent inhibitor of the protease of human immunodeficiency virus (HIV), with antiviral activity against both HIV type 1 and HIV type 2. This compound is representative of a class of small, novel, nonpeptide cyclic urea inhibitors of HIV protease that were designed on the basis of three-dimensional structural information and three-dimensional database searching. We report here studies of the kinetics of DMP 323 inhibition of the cleavage of peptide and HIV-1 gag polyprotein substrates. DMP 323 acts as a rapidly binding, competitive inhibitor of HIV protease. DMP 323 is as potent against both peptide and viral polyprotein substrates as A-80987, Q8024, and Ro-31-8959, which are among the most potent inhibitors of HIV protease described in the literature to date. Incubation with human plasma or serum did not decrease the effective potency of DMP 323 for HIV protease, suggesting that plasma protein binding is of a low affinity relative to that of HIV protease. DMP 323 was also assessed for its ability to inhibit the mammalian proteases renin, pepsin, cathepsin D, cathepsin G, and chymotrypsin. No inhibition of greater than 12% was observed for any of these enzymes at concentrations of DMP 323 that were 350 to 40,000 times higher than that required to inhibit the viral protease 50%.

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The identification of the main dieneconjugated "free-radical marker" in human serum led to a study of free-radical activity in chronic alcoholics. 66 patients were investigated immediately after alcohol withdrawal and over 1-4 weeks' follow-up. The control groups were 76 normal subjects, 78 patients with liver disease, 30 patients on long-term antiepileptic drug treatment, 9 pregnant women, and 99 unselected hospital patients. 82% of chronic alcoholics had a significantly higher than normal level of phospholipid-esterified 9,11 linoleicacid isomer in blood collected within 24 h of their last alcoholic drink. The levels fell to normal over the next 2-4 days but continued to decline within the normal range for 2-3 weeks. There was no rise in the level of the isomer in normal controls after an acute alcohol load. The results suggest that chronic alcoholism may induce a specific detoxifying mechanism which is activated by alcohol and which entails or depends on greatly increased free-radical activity.

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A method is described for the measurement of a diene-conjugated derivative of linoleic acid, 18:2(9,11), in the phospholipid fraction of serum. The method is based on enzymatic hydrolysis, solid-phase sample preparation, and high-performance liquid chromatography (HPLC). Phospholipid esterified 18:2(9,11) can be detected in serum from normal individuals, and a provisional normal range is provided. The possible origins of 18:2(9,11) and the potential application of this method to the measurement of free radical damage to linoleic acid in vivo is discussed.

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The predominant diene conjugated acyl residue in triacylglycerols, cholesteryl esters and phospholipids in human serum was identified by high performance liquid chromatography and capillary gas chromatography-mass spectrometry. It is an octadeca -9,11-dienoic acid.

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Diene-conjugated lipids have been located by HPLC in serum, bile and duodenal juice. Whether esterified or not the same predominant fatty acid is responsible for most of the diene conjugation in all of these biological fluids. Initial attempts to generate this fatty acid in pure lipid by classical lipid peroxidation in vitro were unsuccessful. Ultraviolet irradiation of free fatty acids in the presence of protein produced diene-conjugated lipids similar to those found in vivo. The predominant diene-conjugated fatty acid in vivo is an isomerised C18:2 compound.

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Serial samples of bile or duodenal or pancreatic secretions from patients with and without pancreatic disease were examined for lipid-peroxidation (free-radical-oxidation) products. Peroxidation products were found in the phospholipid fraction of bile and the free-fatty-acid fraction of duodenal juice but not in pancreatic juice. There was a highly significant difference in the concentration and excretion pattern of these products between the group of patients with pancreatic disease and the control group of patients with miscellaneous abdominal disorders.

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