Mechanisms of Impaired Exercise Capacity in Short Duration Experimental Hyperthyroidism

Abstract To investigate the mechanism of reduced exercise tolerance in hyperthyroidism, we characterized cardiovascular function and determinants of skeletal muscle metabolism in 18 healthy subjects aged 26±1 yr (mean±SE) before and after 2 wk of daily ingestion of 100 pg of triiodothyronine (T3). Resting oxygen uptake, heart rate, and cardiac output increased and heart rate and cardiac output at the same submaximal exercise intensity were higher in the hyperthyroid state (P < 0.05). However, maximal oxygen uptake decreased after T3 administration (3.08±0.17 vs. 2.94±0.19 l/min; P < 0.001) despite increased heart rate and cardiac output at maximal exercise (P < 0.05). Plasma lactic acid concentration at an equivalent submaximal exercise intensity was elevated 25% (P < 0.01) and the arteriovenous oxygen difference at maximal effort was reduced (P < 0.05) in the hyperthyroid state. These effects were associated with a 21-37% decline in activities of oxidative (P < 0.001) and glycolytic (P < 0.05) enzymes in skeletal muscle and a 15% decrease in type 11A muscle fiber cross-sectional area (P < 0.05). Lean body mass was reduced (P < 0.001) and the rates of whole body leucine oxidation and protein breakdown were enhanced (P < 0.05). Thus, exercise tolerance is impaired in short duration hyperthyroidism because of decreased skeletal muscle mass and oxidative capacity related to accelerated protein catabolism but cardiac pump function is not reduced. (J. Clin

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Planck 2013 results. XXII. Constraints on inflation

We analyse the implications of the Planck data for cosmic inflation. The Planck nominal mission temperature anisotropy measurements, combined with the WMAP large-angle polarization, constrain the scalar spectral index to be ns = 0:9603 _ 0:0073, ruling out exact scale invariance at over 5_: Planck establishes an upper bound on the tensor-to-scalar ratio of r < 0:11 (95% CL). The Planck data thus shrink the space of allowed standard inflationary models, preferring potentials with V00 < 0. Exponential potential models, the simplest hybrid inflationary models, and monomial potential models of degree n _ 2 do not provide a good fit to the data. Planck does not find statistically significant running of the scalar spectral index, obtaining dns=dln k = 0:0134 _ 0:0090. We verify these conclusions through a numerical analysis, which makes no slowroll approximation, and carry out a Bayesian parameter estimation and model-selection analysis for a number of inflationary models including monomial, natural, and hilltop potentials. For each model, we present the Planck constraints on the parameters of the potential and explore several possibilities for the post-inflationary entropy generation epoch, thus obtaining nontrivial data-driven constraints. We also present a direct reconstruction of the observable range of the inflaton potential. Unless a quartic term is allowed in the potential, we find results consistent with second-order slow-roll predictions. We also investigate whether the primordial power spectrum contains any features. We find that models with a parameterized oscillatory feature improve the fit by __2 e_ _ 10; however, Bayesian evidence does not prefer these models. We constrain several single-field inflation models with generalized Lagrangians by combining power spectrum data with Planck bounds on fNL. Planck constrains with unprecedented accuracy the amplitude and possible correlation (with the adiabatic mode) of non-decaying isocurvature fluctuations. The fractional primordial contributions of cold dark matter (CDM) isocurvature modes of the types expected in the curvaton and axion scenarios have upper bounds of 0.25% and 3.9% (95% CL), respectively. In models with arbitrarily correlated CDM or neutrino isocurvature modes, an anticorrelated isocurvature component can improve the _2 e_ by approximately 4 as a result of slightly lowering the theoretical prediction for the ` <_ 40 multipoles relative to the higher multipoles. Nonetheless, the data are consistent with adiabatic initial conditions

Planck 2013 results. XX. Cosmology from Sunyaev-Zeldovich cluster counts

We present constraints on cosmological parameters using number counts as a function of redshift for a sub-sample of 189 galaxy clusters from the Planck SZ (PSZ) catalogue. The PSZ is selected through the signature of the Sunyaev--Zeldovich (SZ) effect, and the sub-sample used here has a signal-to-noise threshold of seven, with each object confirmed as a cluster and all but one with a redshift estimate. We discuss the completeness of the sample and our construction of a likelihood analysis. Using a relation between mass $M$ and SZ signal $Y$ calibrated to X-ray measurements, we derive constraints on the power spectrum amplitude $\sigma_8$ and matter density parameter $\Omega_{\mathrm{m}}$ in a flat $\Lambda$CDM model. We test the robustness of our estimates and find that possible biases in the $Y$--$M$ relation and the halo mass function are larger than the statistical uncertainties from the cluster sample. Assuming the X-ray determined mass to be biased low relative to the true mass by between zero and 30%, motivated by comparison of the observed mass scaling relations to those from a set of numerical simulations, we find that $\sigma_8=0.75\pm 0.03$, $\Omega_{\mathrm{m}}=0.29\pm 0.02$, and $\sigma_8(\Omega_{\mathrm{m}}/0.27)^{0.3} = 0.764 \pm 0.025$. The value of $\sigma_8$ is degenerate with the mass bias; if the latter is fixed to a value of 20% we find $\sigma_8(\Omega_{\mathrm{m}}/0.27)^{0.3}=0.78\pm 0.01$ and a tighter one-dimensional range $\sigma_8=0.77\pm 0.02$. We find that the larger values of $\sigma_8$ and $\Omega_{\mathrm{m}}$ preferred by Planck's measurements of the primary CMB anisotropies can be accommodated by a mass bias of about 40%. Alternatively, consistency with the primary CMB constraints can be achieved by inclusion of processes that suppress power on small scales relative to the $\Lambda$CDM model, such as a component of massive neutrinos (abridged).Comment: 20 pages, accepted for publication by A&

Planck 2015 results. V. LFI calibration

We present a description of the pipeline used to calibrate the Planck Low Frequency Instrument (LFI) timelines into thermodynamic temperatures for the Planck 2015 data release, covering four years of uninterrupted operations. As in the 2013 data release, our calibrator is provided by the spin-synchronous modulation of the cosmic microwave background dipole, but we now use the orbital component, rather than adopting the Wilkinson Microwave Anisotropy Probe (WMAP) solar dipole. This allows our 2015 LFI analysis to provide an independent Solar dipole estimate, which is in excellent agreement with that of HFI and within 1σ (0.3% in amplitude) of the WMAP value. This 0.3% shift in the peak-to-peak dipole temperature from WMAP and a general overhaul of the iterative calibration code increases the overall level of the LFI maps by 0.45% (30 GHz), 0.64% (44 GHz), and 0.82% (70 GHz) in temperature with respect to the 2013 Planck data release, thus reducing the discrepancy with the power spectrum measured by WMAP. We estimate that the LFI calibration uncertainty is now at the level of 0.20% for the 70 GHz map, 0.26% for the 44 GHz map, and 0.35% for the 30 GHz map. We provide a detailed description of the impact of all the changes implemented in the calibration since the previous data release

Planck 2015 results. VI. LFI mapmaking

This paper describes the mapmaking procedure applied to Planck Low Frequency Instrument (LFI) data. The mapmaking step takes as input the calibrated timelines and pointing information. The main products are sky maps of I, Q, and U Stokes components. For the first time, we present polarization maps at LFI frequencies. The mapmaking algorithm is based on a destriping technique, which is enhanced with a noise prior. The Galactic region is masked to reduce errors arising from bandpass mismatch and high signal gradients. We apply horn-uniform radiometer weights to reduce the effects of beam-shape mismatch. The algorithm is the same as used for the 2013 release, apart from small changes in parameter settings. We validate the procedure through simulations. Special emphasis is put on the control of systematics, which is particularly important for accurate polarization analysis. We also produce low-resolution versions of the maps and corresponding noise covariance matrices. These serve as input in later analysis steps and parameter estimation. The noise covariance matrices are validated through noise Monte Carlo simulations. The residual noise in the map products is characterized through analysis of half-ring maps, noise covariance matrices, and simulations

Planck 2013 results. IX. HFI spectral response

The Planck High Frequency Instrument (HFI) spectral response was determined through a series of ground based tests conducted with the HFI focal plane in a cryogenic environment prior to launch. The main goal of the spectral transmission tests was to measure the relative spectral response (including out-of-band signal rejection) of all HFI detectors. This was determined by measuring the output of a continuously scanned Fourier transform spectrometer coupled with all HFI detectors. As there is no on-board spectrometer within HFI, the ground-based spectral response experiments provide the definitive data set for the relative spectral calibration of the HFI. The spectral response of the HFI is used in Planck data analysis and component separation, this includes extraction of CO emission observed within Planck bands, dust emission, Sunyaev-Zeldovich sources, and intensity to polarization leakage. The HFI spectral response data have also been used to provide unit conversion and colour correction analysis tools. Verifications of the HFI spectral response data are provided through comparisons with photometric HFI flight data. This validation includes use of HFI zodiacal emission observations to demonstrate out-of-band spectral signal rejection better than 10^8. The accuracy of the HFI relative spectral response data is verified through comparison with complementary flight-data based unit conversion coefficients and colour correction coefficients. These coefficients include those based upon HFI observations of CO, dust, and Sunyaev-Zeldovich emission. General agreement is observed between the ground-based spectral characterization of HFI and corresponding in-flight observations, within the quoted uncertainty of each; explanations are provided for any discrepancies.Comment: 27 pages, 28 figures, one of the papers associated with the 2013 Planck data releas

Planck 2015 results. XXVII. The second Planck catalogue of Sunyaev-Zeldovich sources

We present the all-sky Planck catalogue of Sunyaev-Zeldovich (SZ) sources detected from the 29 month full-mission data. The catalogue (PSZ2) is the largest SZ-selected sample of galaxy clusters yet produced and the deepest systematic all-sky surveyof galaxy clusters. It contains 1653 detections, of which 1203 are confirmed clusters with identified counterparts in external data sets, and is the first SZ-selected cluster survey containing >103 confirmed clusters. We present a detailed analysis of the survey selection function in terms of its completeness and statistical reliability, placing a lower limit of 83% on the purity. Using simulations, we find that the estimates of the SZ strength parameter Y5R500are robust to pressure-profile variation and beam systematics, but accurate conversion to Y500 requires the use of prior information on the cluster extent. We describe the multi-wavelength search for counterparts in ancillary data, which makes use of radio, microwave, infra-red, optical, and X-ray data sets, and which places emphasis on the robustness of the counterpart match. We discuss the physical properties of the new sample and identify a population of low-redshift X-ray under-luminous clusters revealed by SZ selection. These objects appear in optical and SZ surveys with consistent properties for their mass, but are almost absent from ROSAT X-ray selected samples

Planck 2015 results. XX. Constraints on inflation

We present the implications for cosmic inflation of the Planck measurements of the cosmic microwave background (CMB) anisotropies in both temperature and polarization based on the full Planck survey. The Planck full mission temperature data and a first release of polarization data on large angular scales measure the spectral index of curvature perturbations to be n s = 0.968 ± 0.006 and tightly constrain its scale dependence to dn s /dlnk = −0.003 ± 0.007 when combined with the Planck lensing likelihood. When the high-ℓ polarization data is included, the results are consistent and uncertainties are reduced. The upper bound on the tensor-to-scalar ratio is r 0.002 <0.11 (95% CL), consistent with the B-mode polarization constraint r<0.12 (95% CL) obtained from a joint BICEP2/Keck Array and Planck analysis. These results imply that V(ϕ)∝ϕ 2 and natural inflation are now disfavoured compared to models predicting a smaller tensor-to-scalar ratio, such as R 2 inflation. Three independent methods reconstructing the primordial power spectrum are investigated. The Planck data are consistent with adiabatic primordial perturbations. We investigate inflationary models producing an anisotropic modulation of the primordial curvature power spectrum as well as generalized models of inflation not governed by a scalar field with a canonical kinetic term. The 2015 results are consistent with the 2013 analysis based on the nominal mission data