Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure

Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance “strength”) rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain—consequent to increased chemosensitivity and delay—the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = −0.68) oscillations (P < 0.001 for all, both groups combined). Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population

Extraluminal Amyloidoma of the Pelvic Cavity Causing Large Bowel Obstruction

Amyloidosis is a group of diverse disorders that fall into several major categories: primary, secondary, dialysis-associated, and hereditary forms. Clinically, amyloidosis may be categorized as localized or systemic. The gastrointestinal tract is among the most common places for deposition of amyloid, but large, localized amyloid deposits are an uncommon occurrence and rarely cause extraluminal bowel compression resulting in obstruction as was seen in the case presented in this clinical scenario

Developing the Diagnostic Adherence to Medication Scale (the DAMS) for use in clinical practice

There is a need for an adherence measure, to monitor adherence services in clinical practice, which can distinguish between different types of non-adherence and measure changes over time. In order to be inclusive of all patients it needs to be able to be administered to both patients and carers and to be suitable for patients taking multiple medications for a range of clinical conditions. A systematic review found that no adherence measure met all these criteria. We therefore wished to develop a theory based adherence scale (the DAMS) and establish its content, face and preliminary construct validity in a primary care population

Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) γ Activators and Pan-PPAR Partial Agonists

Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8–C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products

Rapidity and Centrality Dependence of Proton and Anti-proton Production from Au+Au Collisions at sqrt(sNN) = 130GeV

We report on the rapidity and centrality dependence of proton and anti-proton transverse mass distributions from Au+Au collisions at sqrt(sNN) = 130GeV as measured by the STAR experiment at RHIC. Our results are from the rapidity and transverse momentum range of |y|<0.5 and 0.35 <p_t<1.00GeV/c. For both protons and anti-protons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y|<0.5. Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton(anti-proton) yields and transverse mass distributions the possibility of pre-hadronic collective expansion may have to be taken into account.Comment: 4 pages, 3 figures, 1 table, submitted to PR

Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding

Peroxisome proliferator activated receptors (PPARs δ, α and γ) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design

Knowledge about complementary, alternative and integrative medicine (CAM) among registered health care providers in Swedish surgical care: a national survey among university hospitals

<p>Abstract</p> <p>Background</p> <p>Previous studies show an increased interest and usage of complementary and alternative medicine (CAM) in the general population and among health care workers both internationally and nationally. CAM usage is also reported to be common among surgical patients. Earlier international studies have reported that a large amount of surgical patients use it prior to and after surgery. Recent publications indicate a weak knowledge about CAM among health care workers. However the current situation in Sweden is unknown. The aim of this study was therefore to explore perceived knowledge about CAM among registered healthcare professions in surgical departments at Swedish university hospitals.</p> <p>Method</p> <p>A questionnaire was distributed to 1757 registered physicians, nurses and physiotherapists in surgical wards at the seven university hospitals in Sweden from spring 2010 to spring 2011. The questionnaire included classification of 21 therapies into conventional, complementary, alternative and integrative, and whether patients were recommended these therapies. Questions concerning knowledge, research, and patient communication about CAM were also included.</p> <p>Result</p> <p>A total of 737 (42.0%) questionnaires were returned. Therapies classified as complementary; were massage, manual therapies, yoga and acupuncture. Alternative therapies; were herbal medicine, dietary supplements, homeopathy and healing. Classification to integrative therapy was low, and unfamiliar therapies were Bowen therapy, iridology and Rosen method. Therapies recommended by > 40% off the participants were massage and acupuncture. Knowledge and research about CAM was valued as minor or none at all by 95.7% respectively 99.2%. Importance of possessing knowledge about it was valued as important by 80.9%. It was believed by 61.2% that more research funding should be addressed to CAM research, 72.8% were interested in reading CAM-research results, and 27.8% would consider taking part in such research. Half of the participants (55.8%) were positive to learning such therapy. Communication about CAM between patients and the health care professions was found to be rare.</p> <p>Conclusion</p> <p>There is a lack of knowledge about CAM and research about it among registered health care professions in Swedish surgical care. However, in contrast to previous studies the results revealed that the majority perceived it as important to gain knowledge in this field.</p