Exaggerated blood pressure response to dynamic exercise despite chronic refractory hypotension : results of a human case study

BACKGROUND: Chronic refractory hypotension is a rare but significant mortality risk in renal failure patients. Such aberrant physiology usually deems patient unfit for renal transplant surgery. Exercise stimulates the mechano-chemoreceptors in the skeletal muscle thereby modulating the sympathetic effects on blood pressure regulation. The haemodynamic response to dynamic exercise in such patients has not been previously investigated. We present a case with severe chronic hypotension who underwent exercise testing before and after renal transplantation, with marked differences in blood pressure response to exercise. CASE PRESENTATION: A 40-year old haemodialysis-dependent patient with a 2 year history of refractory hypotension (≤80/50 mmHg) was referred for living donor renal transplantation at our tertiary centre. Each dialysis session was often less than 2 h and 30 min due to symptomatic hypotension. As part of the cardiovascular assessment, she underwent haemodynamic evaluation with cardiopulmonary exercise testing. Blood pressure normalized during unloaded pedalling but was exaggerated at maximal workload whereby it rose from 82/50 mmHg to a peak of 201/120 mmHg. Transthoracic echocardiography, tonometric measure of central vascular compliance and myocardial perfusion scan were normal. She subsequently underwent an antibody-incompatible renal transplantation and was vasopressor reliant for 14 days during the post-operative period. Eight weeks following transplant, resting blood pressure was normal and a physiological exercise-haemodynamic response was observed during a repeat cardiopulmonary exercise testing. CONCLUSION: This case highlights the potential therapeutic role of unloaded leg cycling exercise during dialysis session to correct chronic hypotension, allowing patients to have greater tolerance to fluid shift. It also adds to existing evidence that sympathetic dysfunction is reversible with renal transplant. Furthermore chronic hypotension with preserved exercise-haemodynamic response and cardiovascular reserve should not preclude these patients from renal transplant surgery

Statistical Inference in a Directed Network Model with Covariates

Networks are often characterized by node heterogeneity for which nodes exhibit different degrees of interaction and link homophily for which nodes sharing common features tend to associate with each other. In this paper, we propose a new directed network model to capture the former via node-specific parametrization and the latter by incorporating covariates. In particular, this model quantifies the extent of heterogeneity in terms of outgoingness and incomingness of each node by different parameters, thus allowing the number of heterogeneity parameters to be twice the number of nodes. We study the maximum likelihood estimation of the model and establish the uniform consistency and asymptotic normality of the resulting estimators. Numerical studies demonstrate our theoretical findings and a data analysis confirms the usefulness of our model.Comment: 29 pages. minor revisio

Systems-Based Design of Bi-Ligand Inhibitors of Oxidoreductases: Filling the Chemical Proteomic Toolbox

Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases

Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background: There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods: Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results: There were 70 participants (age 41.7614.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p,0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiveroperating- characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions: To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Theory-Motivated Benchmark Models and Superpartners at the Tevatron

Recently published benchmark models have contained rather heavy superpartners. To test the robustness of this result, several benchmark models have been constructed based on theoretically well-motivated approaches, particularly string-based ones. These include variations on anomaly and gauge-mediated models, as well as gravity mediation. The resulting spectra often have light gauginos that are produced in significant quantities at the Tevatron collider, or will be at a 500 GeV linear collider. The signatures also provide interesting challenges for the LHC. In addition, these models usually account for electroweak symmetry breaking with relatively less fine-tuning than previous benchmark models.Comment: 44 pages, 4 figures; some typos corrected. Revisions reflect published versio

The X-ray and mid-infrared luminosities in luminous type 1 quasars

Several recent studies have reported different intrinsic correlations between the active galactic nucleus (AGN) mid-IR luminosity (${L}_{\mathrm{MIR}}$) and the rest-frame 2–10 keV luminosity (L X) for luminous quasars. To understand the origin of the difference in the observed {L}_{{\rm{X}}}\mbox{--}{L}_{\mathrm{MIR}} relations, we study a sample of 3247 spectroscopically confirmed type 1 AGNs collected from Boötes, XMM-COSMOS, XMM-XXL-North, and the Sloan Digital Sky Survey quasars in the Swift/XRT footprint spanning over four orders of magnitude in luminosity. We carefully examine how different observational constraints impact the observed {L}_{{\rm{X}}}\mbox{--}{L}_{\mathrm{MIR}} relations, including the inclusion of X-ray-nondetected objects, possible X-ray absorption in type 1 AGNs, X-ray flux limits, and star formation contamination. We find that the primary factor driving the different {L}_{{\rm{X}}}\mbox{--}{L}_{\mathrm{MIR}} relations reported in the literature is the X-ray flux limits for different studies. When taking these effects into account, we find that the X-ray luminosity and mid-IR luminosity (measured at rest-frame $6\,\mu {\rm{m}}$, or ${L}_{6\mu {\rm{m}}}$) of our sample of type 1 AGNs follow a bilinear relation in the log–log plane: $\mathrm{log}{L}_{{\rm{X}}}=(0.84\pm 0.03)\times \mathrm{log}{L}_{6\mu {\rm{m}}}/{10}^{45}$ erg s−1 + (44.60 ± 0.01) for ${L}_{6\mu {\rm{m}}}\lt {10}^{44.79}$ erg s−1, and $\mathrm{log}{L}_{{\rm{X}}}=(0.40\pm 0.03)\times \mathrm{log}{L}_{6\mu {\rm{m}}}/{10}^{45}$ erg s−1 + (44.51 ± 0.01) for ${L}_{6\mu {\rm{m}}}\,\geqslant {10}^{44.79}$ erg s−1. This suggests that the luminous type 1 quasars have a shallower {L}_{{\rm{X}}}\mbox{--}{L}_{6\mu {\rm{m}}} correlation than the approximately linear relations found in local Seyfert galaxies. This result is consistent with previous studies reporting a luminosity-dependent {L}_{{\rm{X}}}\mbox{--}{L}_{\mathrm{MIR}} relation and implies that assuming a linear {L}_{{\rm{X}}}\mbox{--}{L}_{6\mu {\rm{m}}} relation to infer the neutral gas column density for X-ray absorption might overestimate the column densities in luminous quasars

The Massive and Distant Clusters of WISE Survey: MOO J1142+1527, a 10^(15) M_⊙ Galaxy Cluster at z = 1.19

We present confirmation of the cluster MOO J1142+1527, a massive galaxy cluster discovered as part of the Massive and Distant Clusters of WISE Survey. The cluster is confirmed to lie at z = 1.19, and using the Combined Array for Research in Millimeter-wave Astronomy we robustly detect the Sunyaev–Zel'dovich (SZ) decrement at 13.2σ. The SZ data imply a mass of M_(200m) = (1.1 ± 0.2) × 10^(15)M_⊙, making MOO J1142+1527 the most massive galaxy cluster known at z > 1.15 and the second most massive cluster known at z > 1. For a standard ΛCDM cosmology it is further expected to be one of the ~5 most massive clusters expected to exist at z ≥ 1.19 over the entire sky. Our ongoing Spitzer program targeting ~1750 additional candidate clusters will identify comparably rich galaxy clusters over the full extragalactic sky

Marine ecosystem response to the Atlantic Multidecadal Oscillation.

Against the backdrop of warming of the Northern Hemisphere it has recently been acknowledged that North Atlantic temperature changes undergo considerable variability over multidecadal periods. The leading component of natural low-frequency temperature variability has been termed the Atlantic Multidecadal Oscillation (AMO). Presently, correlative studies on the biological impact of the AMO on marine ecosystems over the duration of a whole AMO cycle (∼60 years) is largely unknown due to the rarity of continuously sustained biological observations at the same time period. To test whether there is multidecadal cyclic behaviour in biological time-series in the North Atlantic we used one of the world's longest continuously sustained marine biological time-series in oceanic waters, long-term fisheries data and historical records over the last century and beyond. Our findings suggest that the AMO is far from a trivial presence against the backdrop of continued temperature warming in the North Atlantic and accounts for the second most important macro-trend in North Atlantic plankton records; responsible for habitat switching (abrupt ecosystem/regime shifts) over multidecadal scales and influences the fortunes of various fisheries over many centuries