The effect of a 6-month cardiac rehabilitation programme on serum lipoproteins and apoproteins A1 and B and lipoprotein a

One hundred and forty-two cardiac rehabilitation patients were followed up over a p.eriod of 6 months and the percentage change over time was recorded for various lipid fractions including apoprotein AI (apo AI), apoprotein B (apo B) and lipoprotein a (Lp(a)). Data were analysed to see if improvement in peak oxygen consumption (V2) or changes in body weight were related to any of the above. A significant percentage change was found for peak Vo2, ventilatory threshold, highdensity lipoprotein cholesterol (HDLC) and triglyceride levels, total cholesterol (TC)/HDL ratio, apo AI, apo A/apo B ratio and Lp(a). Multiple regression analysis showed that alterations in the lipid fractions were not related to changes in physical fitness except in the case of TC levels which dropped independently of other measures. On multivariate analysis, Lp(a) correlated positively with both the Broca index and the use of drugs ofthe fibrate series.S Afr Med J1993; 83: 315-31

Redox linked flavin sites in extracellular decaheme proteins involved in microbe-mineral electron transfer

Extracellular microbe-mineral electron transfer is a major driving force for the oxidation of organic carbon in many subsurface environments. Extracellular multi-heme cytochromes of the Shewenella genus play a major role in this process but the mechanism of electron exchange at the interface between cytochrome and acceptor is widely debated. The 1.8 Å x-ray crystal structure of the decaheme MtrC revealed a highly conserved CX8C disulfide that, when substituted for AX8A, severely compromised the ability of S. oneidensis to grow under aerobic conditions. Reductive cleavage of the disulfide in the presence of flavin mononucleotide (FMN) resulted in the reversible formation of a stable flavocytochrome. Similar results were also observed with other decaheme cytochromes, OmcA, MtrF and UndA. The data suggest that these decaheme cytochromes can transition between highly reactive flavocytochromes or less reactive cytochromes, and that this transition is controlled by a redox active disulfide that responds to the presence of oxygen

MRI for assessment of anal fistula

Magnetic resonance imaging (MRI) is the best imaging modality for preoperative assessment of patients with anal fistula. MRI helps to accurately demonstrate disease extension and predict prognosis. This in turn helps make therapy decisions and monitor therapy. The pertinent anatomy, fistula classification and MRI findings will be discussed

The C-Terminal Domain of the Arabinosyltransferase Mycobacterium tuberculosis EmbC Is a Lectin-Like Carbohydrate Binding Module

The D-arabinan-containing polymers arabinogalactan (AG) and lipoarabinomannan (LAM) are essential components of the unique cell envelope of the pathogen Mycobacterium tuberculosis. Biosynthesis of AG and LAM involves a series of membrane-embedded arabinofuranosyl (Araf) transferases whose structures are largely uncharacterised, despite the fact that several of them are pharmacological targets of ethambutol, a frontline drug in tuberculosis therapy. Herein, we present the crystal structure of the C-terminal hydrophilic domain of the ethambutol-sensitive Araf transferase M. tuberculosis EmbC, which is essential for LAM synthesis. The structure of the C-terminal domain of EmbC (EmbCCT) encompasses two sub-domains of different folds, of which subdomain II shows distinct similarity to lectin-like carbohydrate-binding modules (CBM). Co-crystallisation with a cell wall-derived di-arabinoside acceptor analogue and structural comparison with ligand-bound CBMs suggest that EmbCCT contains two separate carbohydrate binding sites, associated with subdomains I and II, respectively. Single-residue substitution of conserved tryptophan residues (Trp868, Trp985) at these respective sites inhibited EmbC-catalysed extension of LAM. The same substitutions differentially abrogated binding of di- and penta-arabinofuranoside acceptor analogues to EmbCCT, linking the loss of activity to compromised acceptor substrate binding, indicating the presence of two separate carbohydrate binding sites, and demonstrating that subdomain II indeed functions as a carbohydrate-binding module. This work provides the first step towards unravelling the structure and function of a GT-C-type glycosyltransferase that is essential in M. tuberculosis. Author Summary Top Tuberculosis (TB), an infectious disease caused by the bacillus Mycobacterium tuberculosis, burdens large swaths of the world population. Treatment of active TB typically requires administration of an antibiotic cocktail over several months that includes the drug ethambutol. This front line compound inhibits a set of arabinosyltransferase enzymes, called EmbA, EmbB and EmbC, which are critical for the synthesis of arabinan, a vital polysaccharide in the pathogen's unique cell envelope. How precisely ethambutol inhibits arabinosyltransferase activity is not clear, in part because structural information of its pharmacological targets has been elusive. Here, we report the high-resolution structure of the C-terminal domain of the ethambutol-target EmbC, a 390-amino acid fragment responsible for acceptor substrate recognition. Combining the X-ray crystallographic analysis with structural comparisons, site-directed mutagenesis, activity and ligand binding assays, we identified two regions in the C-terminal domain of EmbC that are capable of binding acceptor substrate mimics and are critical for activity of the full-length enzyme. Our results begin to define structure-function relationships in a family of structurally uncharacterised membrane-embedded glycosyltransferases, which are an important target for tuberculosis therapy

Toenail selenium concentrations and bladder cancer risk in women and men

Prediagnostic selenium concentrations measured in archived toenails were inversely associated with bladder cancer risk in women (P for trend=0.02), but not in men, in a nested case–control study of 338 cases and 341 matched controls. These findings may be due to chance and more studies are needed to determine whether associations between selenium and bladder cancer risk differ by sex

Prevalence of pre- and postpartum depression in Jamaican women

BACKGROUND: Maternal depression during pregnancy has been studied less than depression in postpartum period. The aims of this study were to find out the prevalence of prepartum and postpartum depression and the risk factors associated in a cohort of Afro-Jamaican pregnant women in Jamaica. METHODS: The Zung self-rating depression scale instrument was administered to 73 healthy pregnant women at 28 weeks gestation and at 6 weeks postpartum for quantitative measurement of depression. Blood samples were collected at 8, 28, 35 weeks gestation and at day 1 and 6 weeks postpartum to study the thyroid status. RESULTS: Study demonstrated depression prevalence rates of 56% and 34% during prepartum and postpartum period, respectively. 94% women suffering depression in both periods were single. There were significant variations in both FT(3 )and TT(4 )concentrations which increased from week 8 to week 28 prepartum (p < 0.05) and then declined at the 35(th )week (p < 0.05 compared with week 28) and 1 day post delivery study (p < 0.05 compared with week 35). The mean values for TSH increased significantly from week 8 through week 35. The mean values at 1 day postpartum and 6 week postpartum were not significantly different from the 35 week values. For FT(3), TT(4 )and TSH there were no significant between group differences in concentrations. The major determinants of postpartum depression were moderate and severe prepartum depression and change in TT(4 )hormone concentrations. CONCLUSION: High prevalence of depression was found during pre- and postpartum periods. Single mothers, prepartum depression and changes in TT(4 )were factors found to be significantly associated with postpartum depression

Rationale and study design for a randomised controlled trial to reduce sedentary time in adults at risk of type 2 diabetes mellitus: project stand (Sedentary Time ANd diabetes)

<p>Abstract</p> <p>Background</p> <p>The rising prevalence of Type 2 Diabetes Mellitus (T2DM) is a major public health problem. There is an urgent need for effective lifestyle interventions to prevent the development of T2DM. Sedentary behaviour (sitting time) has recently been identified as a risk factor for diabetes, often independent of the time spent in moderate-to-vigorous physical activity. Project STAND (<it>Sedentary Time ANd Diabetes</it>) is a study which aims to reduce sedentary behaviour in younger adults at high risk of T2DM.</p> <p>Methods/Design</p> <p>A reduction in sedentary time is targeted using theory driven group structured education. The STAND programme is subject to piloting and process evaluation in line with the MRC framework for complex interventions. Participants are encouraged to self-monitor and self-regulate their behaviour. The intervention is being assessed in a randomised controlled trial with 12 month follow up. Inclusion criteria are a) aged 18-40 years with a BMI in the obese range; b) 18-40 years with a BMI in the overweight range plus an additional risk factor for T2DM. Participants are randomised to the intervention (n = 89) or control (n = 89) arm. The primary outcome is a reduction in sedentary behaviour at 12 months as measured by an accelerometer (count < 100/min). Secondary outcomes include physical activity, sitting/lying time using the ActivPAL posture monitor, fasting and 2 h oral glucose tolerance test, lipids, inflammatory biomarkers, body weight, waist circumference, blood pressure, illness perceptions, and efficacy beliefs for behaviour change.</p> <p>Conclusions</p> <p>This is the first UK trial to address sedentary behaviour change in a population of younger adults at risk of T2DM. The results will provide a platform for the development of a range of future multidisciplinary interventions in this rapidly expanding high-risk population.</p> <p>Trial registration</p> <p>Current controlled trials <a href="http://www.controlled-trials.com/ISRCTN08434554">ISRCTN08434554</a>, MRC project 91409.</p

Applying an Empirical Hydropathic Forcefield in Refinement May Improve Low-Resolution Protein X-Ray Crystal Structures

BACKGROUND: The quality of X-ray crystallographic models for biomacromolecules refined from data obtained at high-resolution is assured by the data itself. However, at low-resolution, >3.0 Å, additional information is supplied by a forcefield coupled with an associated refinement protocol. These resulting structures are often of lower quality and thus unsuitable for downstream activities like structure-based drug discovery. METHODOLOGY: An X-ray crystallography refinement protocol that enhances standard methodology by incorporating energy terms from the HINT (Hydropathic INTeractions) empirical forcefield is described. This protocol was tested by refining synthetic low-resolution structural data derived from 25 diverse high-resolution structures, and referencing the resulting models to these structures. The models were also evaluated with global structural quality metrics, e.g., Ramachandran score and MolProbity clashscore. Three additional structures, for which only low-resolution data are available, were also re-refined with this methodology. RESULTS: The enhanced refinement protocol is most beneficial for reflection data at resolutions of 3.0 Å or worse. At the low-resolution limit, ≥4.0 Å, the new protocol generated models with Cα positions that have RMSDs that are 0.18 Å more similar to the reference high-resolution structure, Ramachandran scores improved by 13%, and clashscores improved by 51%, all in comparison to models generated with the standard refinement protocol. The hydropathic forcefield terms are at least as effective as Coulombic electrostatic terms in maintaining polar interaction networks, and significantly more effective in maintaining hydrophobic networks, as synthetic resolution is decremented. Even at resolutions ≥4.0 Å, these latter networks are generally native-like, as measured with a hydropathic interactions scoring tool

Crystal Structure of a Novel Esterase Rv0045c from Mycobacterium tuberculosis

There are at least 250 enzymes in Mycobacterium tuberculosis (M. tuberculosis) involved in lipid metabolism. Some of the enzymes are required for bacterial survival and full virulence. The esterase Rv0045c shares little amino acid sequence similarity with other members of the esterase/lipase family. Here, we report the 3D structure of Rv0045c. Our studies demonstrated that Rv0045c is a novel member of α/β hydrolase fold family. The structure of esterase Rv0045c contains two distinct domains: the α/β fold domain and the cap domain. The active site of esterase Rv0045c is highly conserved and comprised of two residues: Ser154 and His309. We proposed that Rv0045c probably employs two kinds of enzymatic mechanisms when hydrolyzing C-O ester bonds within substrates. The structure provides insight into the hydrolysis mechanism of the C-O ester bond, and will be helpful in understanding the ester/lipid metabolism in M. tuberculosis

Bioinformatics in crosslinking chemistry of collagen with selective cross linkers

<p>Abstract</p> <p>Background</p> <p>Identifying the molecular interactions using bioinformatics tools before venturing into wet lab studies saves the energy and time considerably. The present study summarizes, molecular interactions and binding energy calculations made for major structural protein, collagen of Type I and Type III with the chosen cross-linkers, namely, coenzyme Q₁₀, dopaquinone, embelin, embelin complex-1 & 2, idebenone, 5-O-methyl embelin, potassium embelate and vilangin.</p> <p>Results</p> <p>Molecular descriptive analyses suggest, dopaquinone, embelin, idebenone, 5-O-methyl embelin, and potassium embelate display nil violations. And results of docking analyses revealed, best affinity for Type I (- 4.74 kcal/mol) and type III (-4.94 kcal/mol) collagen was with dopaquinone.</p> <p>Conclusions</p> <p>Among the selected cross-linkers, dopaquinone, embelin, potassium embelate and 5-O-methyl embelin were the suitable cross-linkers for both Type I and Type III collagen and stabilizes the collagen at the expected level.</p