Prolonged P wave duration is associated with right atrial dimensions, but not atrial arrhythmias, in middle-aged endurance athletes.

BACKGROUND: Atrial arrhythmias occur at a higher than expected prevalence amongst endurance athletes. Few studies have examined both atrial structure and arrhythmias in middle-aged endurance athletes. We examined the relationship between P-wave duration, atrial dimensions, and the presence of atrial ectopy in long-standing, middle-aged endurance athletes. METHODS: Middle-aged athletes with a minimum of 10 years of competitive endurance sport history and no history of structural heart disease or clinical atrial arrhythmias, had 12-lead ECGs to assess P-wave duration, signal-averaged ECGs (SAECG) to assess filtered P-wave duration, a 24 h Holter monitor to assess atrial ectopy, and echocardiography and cardiac magnetic resonance imaging to assess atrial structural characteristics. RESULTS: Amongst endurance athletes (n = 104; mean age = 54 ±â€¯5 years; 63% male), filtered P-wave duration on SAECG was correlated with P-wave duration on 12-lead ECG (r = 0.36, p, 0.0001), as well as with larger CMR-derived RA areas (r = 0.30, p = 0.01) and volumes (r = 0.24, p < 0.05). There was no correlation between filtered P-wave duration and any LA measures on imaging (p > 0.05). There was no correlation between the incidence of atrial ectopy (premature atrial contractions or atrial tachycardia) and any electrocardiographic or structural measures. CONCLUSION: Longer filtered P-wave duration was associated with larger RA areas and volumes, without an increase in atrial ectopy.

Doubling the power of DP4 for computational structure elucidation.

A large-scale optimisation of density functional theory (DFT) conditions for computational NMR structure elucidation has been conducted by systematically screening the DFT functionals and statistical models. The extended PyDP4 workflow was tested on a diverse and challenging set of 42 biologically active and stereochemically rich compounds, including highly flexible molecules. MMFF/mPW1PW91/M06-2X in combination with a 2 Gaussian, 1 region statistical model was capable of identifying the correct diastereomer among up to an upper limit of 32 potential diastereomers. Overall a 2-fold reduction in structural uncertainty and a 7-fold reduction in model overconfidence have been achieved. Tools for rapid set-up and analysis of computational and experimental results, as well as for the statistical model generation, have been developed and are provided. All of this should facilitate rapid and reliable computational NMR structure elucidation, which has become a valuable tool to natural product chemists and synthetic chemists alike.

Quality of life and psychosocial measures influenced by exercise modality in patients with coronary artery disease.

BACKGROUND: The optimal approach to prescribing resistance training (RT) combined with aerobic training (AT) for psychosocial and health-related quality of life (HRQOL) is unclear. AIM: To compare the effects of AT combined with RT (1 versus 3 sets) versus AT alone on HRQOL and psychosocial outcomes. DESIGN: Subjects (N.=72) were randomized to AT (5 d∙wk-1) or AT (3 d∙wk-1) with either 1 set (AT/RT1) or 3 sets (AT/RT3) of RT performed 2 d∙wk-1. SETTING: Outpatient Cardiac Rehabilitation Program. POPULATION: Subjects with coronary artery disease. METHODS: HRQOL and psychosocial parameters were assessed before and after 29 weeks of training by questionnaire. RESULTS: Fifty-three subjects (mean±SD age 60.6±10.6 years) completed training. There was a group effect for change in self-efficacy of lower body physical activity tasks (P=0.03) with significantly greater improvement for AT/RT3 than AT alone (17.5±16.6% vs. 3.2±12.8% respectively, p=0.04). Lower body self-efficacy improved for AT/RT1 (15.5±13.8%, p<0.001) but not for AT alone (P=0.2). Self-efficacy for upper body tasks improved with AT/RT3 (18.2±19.9%, P=0.003) and AT/RT1 training (12.6±15.8%, P=0.005) but not with AT alone (8.3±16.1%, P=0.1). AT/RT3 and AT/RT1 training yielded improvements in depression score (-4.0±7.7, P=0.04 and -3.0±5.1, P=0.02 respectively) but not with AT alone (-0.5±4.7, P=0.71). The improvement from baseline in physical HRQOL score (MOS, SF-36) averaged 8.2±11.2% for AT (P=0.04), 10.4±11.9% for AT/RT1 (P=0.006) and 12.0±12.9% for AT/RT3 (P=0.004). CONCLUSIONS: Both AT+RT groups with either 1 or 3 sets (AT 3 d∙wk-1and RT 2 d∙wk-1) each yield more pronounced psychosocial and HRQOL adaptations than AT alone (5 d∙wk-1). RT prescription beyond 1 set may further augment selected parameters in cardiac patients. CLINICAL REHABILITATION IMPACT: These results provide further rationale to develop combined AT+RT regimens for individuals with coronary artery disease.

The effect of haem in red and processed meat on the endogenous formation of N-nitroso compounds in the upper gastrointestinal tract.

Red and processed meat (PM) consumption increases the risk of large bowel cancer and it has been demonstrated that haem in red meat (RM) stimulates the endogenous production of N-nitroso compounds (NOCs) within the human intestine. To investigate whether N-nitrosation occurs in the upper gastrointestinal tract, 27 ileostomists were fed diets containing no meat, or 240 g RM or 240 g PM in a randomly assigned crossover intervention design carried out in a volunteer suite. Endogenous NOC were assessed as apparent total N-nitroso compounds (ATNC) in the ileostomy output. ATNC concentration in the diets was 22 microg ATNC/kg (RM) and 37 microg ATNC/kg (PM), and 9 microg ATNC/kg in the no meat diet. Levels significantly increased to 1175 microg ATNC/kg SEM = 226 microg ATNC/kg) following the RM (P=0.001) and 1832 microg ATNC/kg (SEM=294 microg ATNC/kg) following PM (P<0.001) compared to the no meat diet (283 microg ATNC/kg, SEM=74 microg ATNC/kg). ATNC concentrations in the ileal output were equivalent to those measured in faeces in similarly designed feeding studies. Supplementation with either 1 g ascorbic acid or 400 IU alpha-tocopherol had no effect on the concentration of ATNC detected in the ileal output. In in vitro experiments, N-nitrosomorpholine (NMor) was formed in the presence of nitrosated haemoglobin, at pH 6.8 but not in the absence of nitrosated haemoglobin. These findings demonstrate that haem may facilitate the formation of NOC in the absence of colonic flora in the upper human gastrointestinal tract.

Experimental data checker: better information for organic chemists.

An experimental data checker has been developed that reads, analyses, and cross-correlates experimental information copied and pasted from authors' manuscripts, which will be useful for authors, referees, editors and readers of papers reporting new molecular information, and which makes possible a quantification of the accuracy of journals' data.

Alcohol oxidase and dihydroxyacetone synthase, the abundant peroxisomal proteins of methylotrophic yeasts, assemble in different cellular compartments.

Alcohol oxidase (AO) and dihydroxyacetone synthase (DHAS) constitute the bulk of matrix proteins in methylotrophic yeasts, model organisms for the study of peroxisomal assembly. Both are homooligomers; AO is a flavin-containing octamer, whereas DHAS is a thiamine pyrophosphate-containing dimer. Experiments in recent years have demonstrated that assembly of peroxisomal oligomers can occur before import; indeed the absence of chaperones within the peroxisomal matrix calls into question the ability of this compartment to assemble proteins at all. We have taken a direct pulse-chase approach to monitor import and assembly of the two major proteins of peroxisomes in Candida boidinii. Oligomers of AO are not observed in the cytosol, consistent with the proteins inability to undergo piggyback import. Indeed, oligomerization of AO can be followed within the peroxisomal matrix, directly demonstrating the capacity of this compartment for protein assembly. By contrast, DHAS quickly dimerizes in the cytosol before import. Binding and import was slowed at 15 degrees C; the effect on AO was more dramatic. In conclusion, our data indicate that peroxisomes assemble AO in the matrix, while DHAS undergoes dimerization prior to import.

Site-specific examination of secondary structure and orientation determination in membrane proteins: the peptidic (13)C=(18)O group as a novel infrared probe.

Detailed site-specific information can be exceptionally useful in structural studies of macromolecules in general and proteins in particular. Such information is usually obtained from spectroscopic studies using a label/probe that can reflect on particular properties of the protein. A suitable probe must not modify the native properties of the protein, and should yield interpretable structural information, as is the case with isotopic labels used by Fourier transform infrared (FTIR) spectroscopy. In particular, 1-(13)C=(18)O labels have been shown to relay site-specific secondary structure and orientational information, although limited to small peptides. The reason for this limitation is the high natural abundance of (13)C and the lack of baseline resolution between the main amide I band and the isotope-edited peak. Herein, we dramatically extend the utility of isotope edited FTIR spectroscopy to proteins of virtually any size through the use of a new 1-(13)C=(18)O label. The double-isotope label virtually eliminates any contribution from natural abundance (13)C. More importantly, the isotope-edited peak is further red-shifted (in accordance with ab initio Hartree-Fock calculations) and is now completely baseline resolved from the main amide I band. Taken together, this new label enables determination of site specific secondary structure and orientation in proteins of virtually any size. Even in small peptides 1-(13)C=(18)O is far preferable as a label in comparison to 1-(13)C=(18)O since it enables analysis without the need for any deconvolution or peak fitting procedures. Finally, the results obtained herein represent the first stage in the application of site-directed dichroism to the structural elucidation of polytopic membrane proteins.

Theoretical evaluation of the origin of the regio- and stereoselectivity in the Diels-Alder reactions of dialkylvinylboranes: studies on the reactions of vinylborane, dimethylvinylborane, and vinyl-9-BBN with trans-piperylene and isoprene.

Ab initio and DFT calculations have been performed to study the origin of the regio- and stereoselectivity of the Diels-Alder reactions of dialkylvinylboranes with substituted dienes. B3LYP/6-31G energies of the transition structures for the reactions of dimethylvinylborane and vinyl-9-BBN with trans-piperylene and isoprene yielded calculated ratios which are in very good agreement with experimental values. Nonclassical carbon-boron [4+3] secondary orbital interactions seem to account for the high endo stereoselectivity of these reactions. However, C-B interactions become less important when the bulkiness of the alkyl groups attached to boron increases. Both endo and exo transition structures for the reactions of dimethylvinylborane and vinyl-9-BBN adopt classical [4+2] character. This study also extends Singleton's investigation on butadiene to regioselectivity. FMO theory has been used to rationalize the lack of regioselectivity in the reactions of dimethylvinylborane. The anomalous meta regioselectivity of the Diels-Alder reaction of vinyl-9-BBN with trans-piperylene is mainly caused by steric effects.

Left ventricular performance during prolonged exercise: absence of systolic dysfunction.

We assessed left ventricular systolic and diastolic performance during and after prolonged exercise under controlled conditions in a group of healthy, trained men. Previous studies have examined the effects of prolonged effort on left ventricular function, yet it remains unclear whether or not left ventricular dysfunction (e.g. cardiac fatigue) can be produced under such conditions. We studied 15 healthy men, aged 27+/-1 years (mean+/-S.E.M.). Subjects exercised on bicycles at a constant work rate (60% of maximum oxygen uptake per min) for 150 min. Measurements of gas exchange, blood pressure and haematocrit were obtained, concurrent with the assessment of left ventricular function using equilibrium radionuclide angiography, at rest, during exercise (every 30 min) and after 30 min of recovery. Fluid replacement was provided and monitored during the exercise period. The baseline resting and exercise ejection fractions were 66+/-2% and 78+/-2% respectively. During exercise, subjects consumed 1816+/-136 ml of fluid, and the haematocrit had increased at 120 min of exercise (from 47.2%+/-0.6 to 49.9+/-0.8%; P<0.05). There was no change in either systolic or diastolic blood pressure throughout the exercise period, but heart rate drifted upwards from 141+/-2 beats/min after 30 min to 154+/-3 beats/min after 150 min (P<0.05). There was a small decline (8%; P<0.05) in end-diastolic volume at 150 min. No changes were observed in left ventricular ejection fraction, the pressure/volume ratio or end-systolic volume. After 30 min of sitting in recovery, heart rate was still higher than the pre-exercise value (84+/-3 compared with 69+/-2 beats/min; P<0.05), as were measures of peak filling rate and time to peak filling (P<0.05). The ejection fraction in the post-exercise recovery period was similar to the pre-exercise value. The results indicate that prolonged exercise of moderate duration may not induce abnormal left ventricular systolic function or cardiac fatigue during exercise.

A double ring closing metathesis reaction in the rapid, enantioselective synthesis of NK-1 receptor antagonists.

[structure: see text]. The NK-1 receptor antagonist 1 has been prepared in seven steps from phenylglycine methyl ester. The key steps are a double ring closing metathesis reaction of tetraene 7 to prepare spirocycle 6 and a reductive Heck reaction to introduce the aryl moiety. This latter reaction discriminates the olefins of compound 6 and proceeds in a highly regio- and stereoselective manner.

Discrete targeting signals direct Pmp47 to oleate-induced peroxisomes in Saccharomyces cerevisiae.

Pmp47 is a peroxisomal membrane protein consisting of six transmembrane domains (TMDs). We previously showed that the second matrix loop containing a basic cluster of amino acids is important for peroxisomal targeting, and similar basic targeting motifs have been found in other peroxisomal membrane proteins. However, this basic cluster by itself targets to peroxisomes very poorly. We have developed a sensitive quantitative localization assay based on the targeting of Pmp47-GFP fusion proteins to identify the important elements of the basic cluster and to search for other targeting information on Pmp47. Our data suggest that side-chain structure and position as well as charge are important for targeting by the basic cluster. Analysis of other regions of Pmp47 indicates that all TMDs except TMD2 can be eliminated or substituted without significant loss of targeting. TMD2 plus an adjacent cytoplasmic-oriented sequence is crucial for targeting. Cytoplasmic-oriented sequences from two other peroxisomal membrane proteins, ScPex15p and ScPmp22, could partially substitute for the analogous sequence in Pmp47. Targeting with high fidelity to oleate-induced peroxisomes required the following elements: the cytoplasmic-oriented sequence and TMD2, a short matrix loop containing a basic cluster, and a membrane-anchoring TMD.

Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase.

This paper concerns the design, synthesis, and evaluation of inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Initially study was made of the structures of the leishmanial and human enzyme active sites to see if there were significant differences which could be exploited for selective drug design. Then a series of compounds were synthesized based on 5-benzyl-2, 4-diaminopyrimidines. These compounds were assayed against the protozoan and human enzymes and showed selectivity for the protozoan enzymes. The structural data was then used to rationalize the enzyme assay data. Compounds were also tested against the clinically relevant forms of the intact parasite. Activity was seen against the trypanosomes for a number of compounds. The compounds were in general less active against Leishmania. This latter result may be due to uptake problems. Two of the compounds also showed some in vivo activity in a model of African trypanosomiasis.

Oxygen uptake kinetics during exercise in chronic heart failure: influence of peripheral vascular reserve.

Exercise performance in chronic heart failure is severely impaired, due in part to a peripherally mediated limitation. In addition to impaired maximal exercise capacity, the O(2) uptake (VO(2)) response during submaximal exercise may be affected, with a greater reliance on anaerobiosis leading to early fatigue. However, the response of VO(2) kinetics to submaximal exercise in chronic heart failure has not been studied extensively; in particular, the relationship between oxygen utilization and the peripheral response to exercise has not been studied. The present investigation examined the time-constant (tau, corresponding to 63% of the total response fitted from exercise onset) of the VO(2) kinetics on-response to submaximal exercise and its relationship to maximal peripheral blood flow in patients with chronic heart failure, and compared responses with those in healthy sedentary subjects. Subjects were 10 patients with chronic heart failure (NYHA class II/III). The mean age was 50+/-12 years, with a mean resting left ventricular ejection fraction of 25+/-9%. Controls were 10 age-matched healthy subjects. VO(2(max)) was first determined for all subjects. Repeated transitions from rest to exercise were performed on a cycle ergometer while measuring breath-by-breath responses of VO(2) at a fixed work rate of 50% of VO(2(max)) (heart failure patients and healthy controls) and at a work rate equivalent to the average in heart failure patients (65 W; healthy controls only). On a separate occasion, post-maximal ischaemic exercise calf blood flow was measured (strain-gauge plethysmography). Whereas heart failure subjects displayed a significantly prolonged VO(2) kinetics response at a similar absolute workload (i.e. 65 W), as indicated by a longer tau value (42 s, compared with 22 s in controls; P<0.01), there was no difference in tau at a similar relative work rate [50% of VO(2(max))]. In addition, heart failure subjects demonstrated a lower maximal calf blood flow (P<0.05) than control subjects. These results indicate that patients with heart failure have a prolonged VO(2) kinetics on-response compared with healthy subjects at a similar absolute work rate (i.e. 65 W), but not at a similar relative work rate [50% of VO(2(max))]. Thus, despite a reduced maximal calf blood flow response associated with heart failure, it does not appear that this contributes to an impairment of the submaximal exercise response beyond that explained by a reduced maximal exercise capacity [VO(2(max))].

Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis.

BACKGROUND: Schizophrenia is characterized by subcortical and cortical brain abnormalities. Evidence indicates that some nonpsychotic relatives of schizophrenic patients manifest biobehavioral abnormalities, including brain abnormalities. The goal of this study was to determine whether amygdala-hippocampal and thalamic abnormalities are present in relatives of schizophrenic patients. METHODS: Subjects were 28 nonpsychotic, and nonschizotypal, first-degree adult relatives of schizophrenics and 26 normal control subjects. Sixty contiguous 3 mm coronal, T1-weighted 3D magnetic resonance images of the brain were acquired on a 1.5 Tesla magnet. Cortical and subcortical gray and white matter and cerebrospinal fluid (CSF) were segmented using a semi-automated intensity contour mapping algorithm. Analyses of covariance of the volumes of brain regions, controlling for expected intellectual (i.e., reading) ability and diagnosis, were used to compare groups. RESULTS: The main findings were that relatives had significant volume reductions bilaterally in the amygdala-hippocampal region and thalamus compared to control subjects. Marginal differences were noted in the pallidum, putamen, cerebellum, and third and fourth ventricles. CONCLUSIONS: Results support the hypothesis that core components of the vulnerability to schizophrenia include structural abnormalities in the thalamus and amygdala-hippocampus. These findings require further work to determine if the abnormalities are an expression of the genetic liability to schizophrenia.

Dissociation of peak vascular conductance and V(O2) max among highly trained athletes.

Previously, a strong relationship has been found between whole body maximal aerobic power (VO(2 max)) and peak vascular conductance in the calf muscle (J. L. Reading, J. M. Goodman, M. J. Plyley, J. S. Floras, P. P. Liu, P. R. McLaughlin, and R. J. Shephard. J. Appl. Physiol. 74: 567-573, 1993; P. G. Snell, W. H. Martin, J. C. Buckley, and C. G. Blomqvist. J. Appl. Physiol. 62: 606-610, 1987), suggesting a matching between maximal exercise capacity and peripheral vasodilatory reserve across a broad range of aerobic power. In contrast, long-term training could alter this relationship because of the unique demands for muscle blood flow and cardiac output imposed by different types of training. In particular, the high local blood flows but relatively low cardiac output demand imposed by the type of resistance training used by bodybuilders may cause a relatively greater development in peripheral vascular reserve than in aerobic power. To examine this possibility, we studied the relationship between treadmill VO(2 max) and vascular conductance in the calf by using strain-gauge plethysmography after maximal ischemic plantar flexion exercise in 8 healthy sedentary subjects (HS) and 28 athletes. The athletes were further divided into three groups: 10 elite middle-distance runners (ER), 11 power athletes (PA), and 7 bodybuilders (BB). We found that both BB and ER deviate from the previously demonstrated relationship between VO(2 max) and vascular conductance. Specifically, for a given vascular conductance, BB had a lower VO(2 max), whereas ER had a higher VO(2 max) than did HS and PA. We conclude that the relationship between peak vascular conductance and aerobic power is altered in BB and ER because of training-specific effects on central vs. peripheral cardiovascular adaptation to local skeletal muscle metabolic demand.