Coupling the Deconfining and Chiral Transitions

The Polyakov loop and the chiral condensate are used as order parameters to explore analytically the possible phase structure of finite temperature QCD. Nambu-Jona-Lasinio models in a background temporal gauge field are combined with a Polyakov loop potential in a form suitable for both the lattice and the continuum. Three possible behaviors are found: a first-order transition, a second-order transition, and a region with both transitions.Comment: 4 pages, LaTeX, 4 Postscript Figures, uuencoded, Contribution to Lattice 95 Conference Proceeding

An analysis of 112 acute porphyric attacks in Cape Town, South Africa

Four forms of porphyria may present clinically with the acute attack, an episodic, severe, and potentially life-threatening manifestation characterized by abdominal and neurologic symptoms. We describe our experience with 112 consecutive attacks observed and treated in 25 patients with the 2 most common forms of acute porphyria in Cape Town, South Africa; 25 attacks in 10 patients with variegate porphyria and 87 attacks in 14 patients with acute intermittent porphyria. The remaining patient experienced more than 100 sequential, severe, and poorly remitting attacks, which are not included in our analysis. In our population, the relative risk of an acute attack in acute intermittent porphyria compared with that in variegate porphyria was 14.3 (confidence intervals, 6.3-32.7). Patients with variegate porphyria were significantly older (median age at first attack, 30 yr) than those with acute intermittent porphyria (median age at first attack, 23.5 yr; p < 0.0001), and demonstrated an equal sex ratio, whereas the male:female ratio in acute intermittent porphyria was 2:12 (p < 0.0001). There was a significant difference in the incidence of factors precipitating the acute attack. Drug exposure was a frequent precipitant of the acute attack in variegate porphyria, whereas hormonal factors were more important in acute intermittent porphyria (p < 0.00001). Patients with acute intermittent porphyria also showed a trend to earlier and more frequent recurrent acute attacks following the initial admission. Mean urine precursor levels, blood pressure, pulse rate, and heme arginate requirement were all significantly higher in patients with acute intermittent porphyria. No significant difference in the frequency of serious complications or in outcome could be shown. We describe our experience with treatment with heme arginate, and provide evidence that heme arginate results in a prompt and statistically significant improvement in symptoms. The incidence of serious complications and mortality in this series was low, confirming a trend to an increasingly good prognosis for patients with acute porphyria who receive expert treatment

Fifty years of porphyria at the University of Cape Town

The porphyrias are a group of disorders resulting from defective haem biosynthesis. One form, variegate porphyria, is common in South Africa as a result of a founder effect. Over the past 50 years, the University of Cape Town Faculty of Health Sciences has built and maintained an international reputation for excellence in the field of porphyria. The porphyria group is respected for its research and for its accumulated experience in the management of these disorders. Equally important has been the comprehensive and holistic care offered to patients with porphyria, and to their families

Variegate porphyria in South Africa, 1688 - 1996 - new developments in an old disease

Variegate porphyria, an autosomal dominant inherited trait resulting in decreased activity of protoporphyrinogen oxidase, the penuttimate haem biosynthetic enzyme, is characterised clinically by photosensitive skin disease and a propensity to acute neurovisceral crises. The disease has an exceptionally high frequency in South Africa,owing to a founder effect. The specific mutation in the protoporphynnogen oxidase gene sequence which represents this founder gene has been identified. Genetic diagnosis is therefore now possible in families in whom the gene defect is known. However, the exact nature and degree of activity of the porphyria can only be determined by detailed quantitative biochemical analysis of excreted porphyrins. The relative contributions of the acute attack and the skin disease to the total disease burden of patients with variegate porphyria is not static, and in South Africa there have been significant changes over the past 25 years, with fewer patients presenting with acute attacks, leaving a greater proportion to present with skin disease or to remain asymptomatic with the diagnosis being made in the laboratory. The most common precipitating cause of the acute attack of VP is administration of porphyrinogenic drugs. Specific suppression of haem synthesis with intravenous haem arginate is the most useful treatment of a moderate or severe acute attack. Although cutaneous lesions are limited to the sun-exposed areas, management of the skin disease of VP remains inadequate

Lepton pairs from thermal mesons

We study the net dielectron production rates from an ensemble of thermal mesons, using an effective Lagrangian to model their interaction. The coupling between the electromagnetic and the hadronic sectors is done through the vector meson dominance approach. For the first time, a complete set of light mesons is considered. We include contributions from decays of the type V~(PS)~$\rightarrow$~PS~(V)~+~$e^+~e^-$, where V is a vector meson and PS is a pseudoscalar, as well as those from binary reactions PS~+~PS, V~+~V, and V~+~PS~$\rightarrow~e^+e^-$. Direct decays of the type V~$\rightarrow~e^+ e^-$ are included and shown to be important. We find that the dielectron invariant mass spectrum naturally divides in distinct regions: in the low mass domain the decays from vector and pseudoscalar mesons form the dominant contribution. The pion--pion annihilation and direct decays then pick up and form the leading signal in an invariant mass region that includes the $\rho - \omega$ complex and extends up to the $\phi$. Above invariant mass $M\ \approx$~1~GeV other two-body reactions take over as the prominent mechanisms for lepton pair generation. These facts will have quantitative bearing on the eventual identification of the quark--gluon plasma.Comment: In ReVTeX 3.0, 9 figs. available from above email address. McGill 93/8, TPI-MINN-93/19-

Fermion sea along the sphaleron barrier

In this revised version we have improved the treatment of the top and bottom quark mass. This leads to slight changes of the numerical results, especially of those presented in Fig.4. The discussion of the numerical procedure and accuracy has been extended.Comment: 39 pages (LaTex) plus 5 figures (uuencoded postscript files); RUB-TPII-62/93, to appear in Phys.Rev.

Crystal structure of protoporphyrinogen oxidase from Myxococcus xanthus and its complex with the inhibitor acifluorfen

Protoporphyrinogen IX oxidase, a monotopic membrane protein, which catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX in the heme/chlorophyll biosynthetic pathway, is distributed widely throughout nature. Here we present the structure of protoporphyrinogen IX oxidase from Myxococcus xanthus, an enzyme with similar catalytic properties to human protoporphyrinogen IX oxidase that also binds the common plant herbicide, acifluorfen. In the native structure, the planar porphyrinogen substrate is mimicked by a Tween 20 molecule, tracing three sides of the macrocycle. In contrast, acifluorfen does not mimic the planarity of the substrate but is accommodated by the shape of the binding pocket and held in place by electrostatic and aromatic interactions. A hydrophobic patch surrounded by positively charged residues suggests the position of the membrane anchor, differing from the one proposed for the tobacco mitochondrial protoporphyrinogen oxidase. Interestingly, there is a discrepancy between the dimerization state of the protein in solution and in the crystal. Conserved structural features are discussed in relation to a number of South African variegate porphyria-causing mutations in the human enzyme

Insight in Genome-Wide Association of Metabolite Quantitative Traits by Exome Sequence Analyses

Metabolite quantitative traits carry great promise for epidemiological studies, and their genetic background has been addressed using Genome-Wide Association Studies (GWAS). Thus far, the role of less common variants has not been exhaustively studied. Here, we set out a GWAS for metabolite quantitative traits in serum, followed by exome sequence analysis to zoom in on putative causal variants in the associated genes. 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy experiments yielded successful quantification of 42 unique metabolites in 2,482 individuals from The Erasmus Rucphen Family (ERF) study. Heritability of metabolites were estimated by SOLAR. GWAS was performed by linear mixed models, using HapMap imputations. Based on physical vicinity and pathway analyses, candidate genes were screened for coding region variation using exome sequence data. Heritability estimates for metabolites ranged between 10% and 52%. GWAS replicated three known loci in the metabolome wide significance: CPS1 with glycine (P-value  = 1.27×10−32), PRODH with proline (P-value  = 1.11×10−19), SLC16A9 with carnitine level (P-value  = 4.81×10−14) and uncovered a novel association between DMGDH and dimethyl-glycine (P-value  = 1.65×10−19) level. In addition, we found three novel, suggestively significant loci: TNP1 with pyruvate (P-value  = 1.26×10−8), KCNJ16 with 3-hydroxybutyrate (P-value  = 1.65×10−8) and 2p12 locus with valine (P-value  = 3.49×10−8). Exome sequence analysis identified potentially causal coding and regulatory variants located in the genes CPS1, KCNJ2 and PRODH, and revealed allelic heterogeneity for CPS1 and PRODH. Combined GWAS and exome analyses of metabolites detected by high-resolution 1H-NMR is a robust approach to uncover metabolite quantitative trait loci (mQTL), and the likely causative variants in these loci. It is anticipated that insight in the genetics of intermediate phenotypes will provide additional insight into the genetics of complex traits

Use of local anaesthetics and adjuncts for spinal and epidural anaesthesia and analgesia at German and Austrian University Hospitals: an online survey to assess current standard practice

<p>Abstract</p> <p>Background</p> <p>The present anonymous multicenter online survey was conducted to evaluate the application of regional anaesthesia techniques as well as the used local anaesthetics and adjuncts at German and Austrian university hospitals.</p> <p>Methods</p> <p>39 university hospitals were requested to fill in an online questionnaire, to determine the kind of regional anaesthesia and preferred drugs in urology, obstetrics and gynaecology.</p> <p>Results</p> <p>33 hospitals responded. No regional anaesthesia is conducted in 47% of the minor gynaecological and 44% of the urological operations; plain bupivacaine 0.5% is used in 38% and 47% respectively. In transurethral resections of the prostate and bladder no regional anaesthesia is used in 3% of the responding hospitals, whereas plain bupivacaine 0.5% is used in more than 90%. Regional anaesthesia is only used in selected major gynaecological and urological operations. On the contrary to the smaller operations, the survey revealed a large variety of used drugs and mixtures. Almost 80% prefer plain bupivacaine or ropivacaine 0.5% in spinal anaesthesia in caesarean section. Similarly to the use of drugs in major urological and gynaecological operations a wide range of drugs and adjuncts is used in epidural anaesthesia in caesarean section and spontaneous delivery.</p> <p>Conclusions</p> <p>Our results indicate a certain agreement in short operations in spinal anaesthesia. By contrast, a large variety concerning the anaesthesiological approach in larger operations as well as in epidural analgesia in obstetrics could be revealed, the causes of which are assumed to be primarily rooted in particular departmental structures.</p

LKB1 loss links serine metabolism to DNA methylation and tumorigenesis

Intermediary metabolism generates substrates for chromatin modification, enabling the potential coupling of metabolic and epigenetic states. Here we identify a network linking metabolic and epigenetic alterations that is central to oncogenic transformation downstream of the liver kinase B1 (LKB1, also known as STK11) tumour suppressor, an integrator of nutrient availability, metabolism and growth. By developing genetically engineered mouse models and primary pancreatic epithelial cells, and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation is fuelled by pronounced mTOR-dependent induction of the serine-glycine-one-carbon pathway coupled to S-adenosylmethionine generation. At the same time, DNA methyltransferases are upregulated, leading to elevation in DNA methylation with particular enrichment at retrotransposon elements associated with their transcriptional silencing. Correspondingly, LKB1 deficiency sensitizes cells and tumours to inhibition of serine biosynthesis and DNA methylation. Thus, we define a hypermetabolic state that incites changes in the epigenetic landscape to support tumorigenic growth of LKB1-mutant cells, while resulting in potential therapeutic vulnerabilities