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Heparin and heparan sulphate (H/HS) are important members of the glycosaminoglycan family of sugars that regulate a substantial number of biological processes. Such biological promiscuity is underpinned by hetereogeneity in their molecular structure. The degree of O-sulfation, particularly at the 6-position of constituent D-GlcN units, is believed to play a role in modulating the effects of such sequences. Synthetic chemistry is essential to be able to extend the diversity of HS-like fragments with defined molecular structure, and particularly to deconvolute the biological significance of modifications at O6. Here we report a synthetic approach to a small matrix of protected heparin-type oligosaccharides, containing orthogonal D-GlcN O-6 protecting groups at programmed positions along the chain, facilitating access towards programmed modifications at specific sites, relevant to sulfation or future mimetics.

BACKGROUND: Many long-term studies have reported on associations of plasma fibrinogen concentration with cardiovascular disease, but few have been large enough to provide reliable estimates in different circumstances. Moreover, most published prospective studies have related disease risk only to baseline values of plasma fibrinogen (which can lead to substantial underestimation of any risk relationships) and have corrected only for baseline values of possible confounding factors (which can lead to residual biases). OBJECTIVES: By appropriate combination of data from individual participants from all relevant prospective studies in a systematic 'meta-analysis', with correction for regression dilution, the Fibrinogen Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age- and sex-specific associations of plasma fibrinogen with coronary heart disease (and, where data are sufficient, with other vascular diseases). It will also help to determine to what extent such associations are independent of possible confounding factors. METHODS: A central database has been established containing data on plasma fibrinogen, sex and other potential confounding factors, age at baseline fibrinogen measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of fibrinogen and potential confounding factors is being sought to allow study-specific correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available prospective studies of plasma fibrinogen will yield information on more than 10000 incident cardiovascular deaths and events among the approximately 200000 total participants who have been monitored, on average, for about 10 years.

In understanding the genetics of polygenic disorders, the modifying effects of the different environmental factors experienced by individuals are particularly important. We have detected such an interaction between environmental modulation of the effect of two mutations in the lipoprotein lipase gene which alter amino acids (D9N and N291S) to result in a moderate reduction in the lipoprotein lipase activity and mass secreted from COS cells in transient expression assays. Each mutation occurs at a frequency of 2%-3% in the general population, and carriers for these mutations have slightly elevated plasma triglyceride and lower high-density lipoprotein cholesterol levels, as expected from the role of lipoprotein lipase in lipoprotein metabolism. However, when these individuals also are obese, the effect on plasma lipid levels is marked, such that the individuals are predicted to be at a significant risk of atherosclerosis. This increase in risk may be because obesity promotes overproduction of triglyceride-rich lipoproteins from the liver, which overwhelms the already partially deficient lipoprotein lipase in the adipose and muscle. Individuals with the lipoprotein lipase S291 variant have significantly greater postprandial lipemia, in support of this mechanism, and carriers of such mutations may have a distinct response to changes in dietary fat. An understanding of the mechanisms of these effects will help to identify individuals who may be particularly responsive to small dietary changes and to identify potential therapeutic targets.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154 012 participants in 31 cohorts.† Copyright © 2009 John Wiley & Sons, Ltd.

30 pags., 17 figs., 12 tabs. 4 apps., We present a new compilation of Type Ia supernovae (SNe Ia), a new data set of low-redshift nearby-Hubble-flow SNe, and new analysis procedures to work with these heterogeneous compilations. This >Union> compilation of 414 SNe Ia, which reduces to 307 SNe after selection cuts, includes the recent large samples of SNe Ia from the Supernova Legacy Survey and ESSENCE Survey, the older data sets, as well as the recently extended data set of distant supernovae observed with the Hubble Space Telescope (HST). A single, consistent, and blind analysis procedure is used for all the various SN Ia subsamples, and a new procedure is implemented that consistently weights the heterogeneous data sets and rejects outliers. We present the latest results from this Union compilation and discuss the cosmological constraints from this new compilation and its combination with other cosmological measurements (CMB and BAO). The constraint we obtain from supernovae on the dark energy density is ¿¿ = 0.713+ 0.027¿0.029(stat)+ 0.036¿0.039(sys) , for a flat, ¿CDM universe. Assuming a constant equation of state parameter, w, the combined constraints from SNe, BAO, and CMB give w = ¿ 0.969+ 0.059¿0.063(stat)+ 0.063¿0.066(sys) . While our results are consistent with a cosmological constant, we obtain only relatively weak constraints on a w that varies with redshift. In particular, the current SN data do not yet significantly constrain w at z > 1. With the addition of our new nearby Hubble-flow SNe Ia, these resulting cosmological constraints are currently the tightest available., This work was supported in part by the Director, Office of Science, Office of High Energy and Nuclear Physics, US Department of Energy, through contract DE-AC02-05CH11231. This research used resources of the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the US Department of Energy under contract DEAC02- 05CH11231. The use of Portuguese time for the YALO telescope was supported by Fundacao para a Ciencia e Tecnologia, Portugal, and by Project PESO/ESO/P/PRO/1257/98. M. K. acknowledges support from the Deutsche Forschungsgemeinschaft (DFG). P. E. N. acknowledges support from the USDepartment of Energy Scientific Discovery throughAdvanced Computing program under contract DE-FG02-06ER06-04. A.M. M. acknowledges financial support from Fundacao para a Ciencia e Tecnologia (FCT), Portugal, through project PESO/P/PRO/ 15139/99.

A near-threshold He-4(gamma, n) cross-section measurement has been performed at MAX-lab. Tagged photons from 23 < Ey < 42 MeV were directed toward a liquid He-4 target, and neutrons were detected by time-of-flight in two liquid-scintillator arrays. Seven-point angular distributions were measured for eight photon energies. The results are compared to experimental data measured at comparable energies and Recoil-Corrected Continuum Shell Model, Resonating Group Method, and recent Hyperspherical-Harmonic Expansion calculations. The angle-integrated cross-section data are peaked at a photon energy of about 28 MeV, in disagreement with the value recommended by Calarco, Berman, and Donnelly in 1983. (c) 2005 Elsevier B.V. All rights reserved.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

We present optical spectra of the peculiar Type Ia supernova (SN Ia) 1999ac. The data extend from -15 to +42 days with respect to B-band maximum and reveal an event that is unusual in several respects. Prior to B-band maximum, the spectra resemble those of SN 1999aa, a slowly declining event, but possess stronger SiII and CaII signatures (more characteristic of a spectroscopically normal SN). Spectra after B-band maximum appear more normal. The expansion velocities inferred from the Iron lines appear to be lower than average; whereas, the expansion velocity inferred from Calcium H and K are higher than average. The expansion velocities inferred from SiII are among the slowest ever observed, though SN 1999ac is not particularly dim. The analysis of the parameters v_10, R(SiII), dv(SiII)/dt, and d_m15 further underlines the unique characteristics of SN 1999ac. We find convincing evidence of CII 6580 in the day -15 spectrum with ejection velocity v > 16,000 km/s, but this signature disappears by day -9. This rapid evolution at early times highlights the importance of extremely early-time spectroscopy., 40 pages, 24 figures, accepted for publication in The Astronomical Journal

We present an extensive new time-series of spectroscopic data of the peculiar SN 1999aa in NGC 2595. Our data set includes 25 optical spectra between -11 and +58 days with respect to B-band maximum light, providing an unusually complete time history. The early spectra resemble those of a SN 1991T-like object but with a relatively strong Ca H&K absorption feature. The first clear sign of Si II 6355, characteristic of Type Ia supernovae, is found at day -7 and its velocity remains constant up to at least the first month after B-band maximum light. The transition to normal-looking spectra is found to occur earlier than in SN 1991T suggesting SN 1999aa as a possible link between SN 1991T-like and Branch-normal supernovae. Comparing the observations with synthetic spectra, doubly ionized Fe, Si and Ni are identified at early epochs. These are characteristic of SN 1991T-like objects. Furthermore, in the day -11 spectrum, evidence is found for an absorption feature which could be identified as high velocity C II 6580 or H-alpha. At the same epoch C III 4648.8 at photospheric velocity is probably responsible for the absorption feature at 4500 A. High velocity Ca is found around maximum light together with Si II and Fe II confined in a narrow velocity window. Implied constraints on supernovae progenitor systems and explosion hydrodynamical models are briefly discussed., 46 pages including 23 figures. Accepted for publication by AJ. For full-resolution figures see http://www.physto.se/~gabri/sn99aa/

Prune belly syndrome (PBS) has been recognized since 1950 as the triad of absent abdominal wall musculature, undescended testes, and urinary tract anomalies. The etiology, however, remains uncertain. Theories of mesenchymal maldevelopment, obstruction, and genetic origin have been proposed. To evaluate the role of lower urinary tract obstruction as it relates to prostatic development and PBS, we studied the lower urinary tract of 15 cases of PBS, 8 cases of posterior urethral valves (PUV), and 34 age-matched controls. It is generally accepted that prostatic growth and development are dependent on mesenchymal-epithelial interactions. We evaluated the mesenchymal and epithelial differentiation and relationships, and found distinctly different and consistent abnormalities between PBS and PUV as compared with one another and controls. The findings suggest that in PBS, prostatic growth and development are hindered because of destruction or absence of the appropriate primitive mesenchyme. Our studies could not definitely exclude very early obstruction as a cause of the findings because of lack of appropriate fetal material.

An indication of the degree of cadmium exposure and renal accumulation in an Australian population (Brisbane) has been obtained from cadmium determinations of urine from 98 patients and post-mortem kidney specimens from 91 patients. Urinary excretion of cadmium from normal or unexposed adults and lead exposed adults was consistent with normal values from other developed countries. There was no apparent relationship between cadmium and lead excretion levels for individual urine specimens. Renal cadmium concentrations were used to estimate the average total cadmium content for a "standard man" and renal cortex concentrations. The results were similar to reported studies from the United Kingdom and Europe, but lower than those from Japan. Daily intake of cadmium was estimated to be 30 to 50 mug, which compares favourably with the FAO/WHO1 "provisional tolerable weekly intake" of 0-4 to 0-5 mg cadmium per adult per week. It is concluded that Australian populations exposed to potential sources of industrial and environmental cadmium contamination should be investigated.

To improve intramedullary fixation with polymethylmethacrylate for use in pathologic bone, a new fixation system was developed. A fluted intramedullary rod was modified to allow injection of low-viscosity polymethylmethacrylate (PMMA) through the rod with retrograde filling of the void spaces between the rod and the medullary canal. This provided uniform distribution of the cement along the length of the rod and significantly improved fixation stability. Biomechanical testing using this system on simulated pathologic lesions of the femur showed a twofold increase in torsional strength over intramedullary methods previously used, with strength approaching that of the intact femur. In 16 patients, the device made mobilization possible immediately after the operation.

Nucleoside analogues have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers and viruses. Several such compounds, including Sofosbuvir and Gemcitabine are the go-to option in first line treatments. However, these compoundss do have limitations (poor cellular uptake, low conversion to the active triphosphate metabolite, rapid degradation or clearance and development of resistance profiles in certain cell types) and the development of next generation compounds remains a topic of significant interest and necessity. This project broadly involves the chemical synthesis of thionucleoside analogues, a class of molecules which act as antimetabolites and are known to have antiproliferative activity against numerous cancers, viruses and bacteria. The thionucleoside targets herein are inspired by current nucleoside analogue drugs on the market, and they have potential for both greater potency and improved metabolic stability in vivo.