Sub-clinical left and right ventricular dysfunction in patients with COPD

SummaryBackgroundCardiovascular manifestations in COPD include increased arterial stiffness, ischaemic heart disease, chronic heart failure and cor pulmonale. We hypothesised that sub-clinical right (RV) and left ventricular (LV) dysfunction occurs in patients with COPD, related to the severity of airflow obstruction, arterial stiffness and systemic inflammation.MethodsThirty six patients and 14 controls, all free of overt cardiovascular disease underwent tissue Doppler echocardiography, spirometry, measurement of aortic pulse wave velocity (PWV) and venous sampling for inflammatory markers.ResultsMean LV myocardial strain and strain rate were less in patients than controls, p<0.05. LV isovolumic relaxation time (IVRT) was prolonged in patients (125±15.2ms) compared with controls (98.2±21.1ms), p<0.01, indicating LV diastolic dysfunction. The RV free wall strain and strain rate were less in patients than controls, both p<0.05, indicating RV systolic dysfunction. Patients had sub-clinical pulmonary arterial hypertension with a greater RV myocardial relaxation time and Tei index, both p<0.01. Patients with mild airways obstruction had LV and RV dysfunction and evidence of increased RV afterload compared with controls. In multivariate analyses aortic PWV predicted LV IVRT, p<0.01, while FEV1 predicted RV Tei index and myocardial relaxation time, both p<0.01.ConclusionsPatients with COPD have sub-clinical left ventricular dysfunction related to arterial stiffness, and right ventricular dysfunction related to airways obstruction. Both right and left ventricular dysfunction are present in patients with mild airways obstruction suggesting that cardiac co-morbidities commence early in the development of COPD

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies.

Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner. The decrease in cell viability was due to an induction of apoptosis and cell cycle arrest. These results were recapitulated in in vivo studies where selinexor decreased tumor growth. Tumors treated with selinexor expressed lower levels of XPO1, cyclin A, cyclin B, and CDK2 and increased levels of RB and CDK inhibitor p27, a result that is consistent with growth arrest. Cells expressing wildtype RB, a potent tumor suppressor that promotes growth arrest and apoptosis, were most susceptible to selinexor. Cell fractionation and immunofluorescence studies showed that selinexor treatment increased nuclear RB levels and mechanistic studies revealed that RB ablation curtailed the response to the drug. Conversely, limiting CDK4/6 dependent RB phosphorylation by palbociclib was additive with selinexor in reducing bladder tumor cell viability, confirming that RB activity has a role in the response to XPO1 inhibition. These results provide a rationale for XPO1 inhibition as a novel strategy for the treatment of bladder malignancies

Interface Fluctuations under Shear

Coarsening systems under uniform shear display a long time regime characterized by the presence of highly stretched and thin domains. The question then arises whether thermal fluctuations may actually destroy this layered structure. To address this problem in the case of non-conserved dynamics we study an anisotropic version of the Burgers equation, constructed to describe thermal fluctuations of an interface in the presence of a uniform shear flow. As a result, we find that stretched domains are only marginally stable against thermal fluctuations in $d=2$, whereas they are stable in $d=3$.Comment: 3 pages, shorter version, additional reference

Cortical Inactivation by Cooling in Small Animals

Reversible inactivation of the cortex by surface cooling is a powerful method for studying the function of a particular area. Implanted cooling cryoloops have been used to study the role of individual cortical areas in auditory processing of awake-behaving cats. Cryoloops have also been used in rodents for reversible inactivation of the cortex, but recently there has been a concern that the cryoloop may also cool non-cortical structures either directly or via the perfusion of blood, cooled as it passed close to the cooling loop. In this study we have confirmed that the loop can inactivate most of the auditory cortex without causing a significant reduction in temperature of the auditory thalamus or other subcortical structures. We placed a cryoloop on the surface of the guinea pig cortex, cooled it to 2°C and measured thermal gradients across the neocortical surface. We found that the temperature dropped to 20–24°C among cells within a radius of about 2.5 mm away from the loop. This temperature drop was sufficient to reduce activity of most cortical cells and led to the inactivation of almost the entire auditory region. When the temperature of thalamus, midbrain, and middle ear were measured directly during cortical cooling, there was a small drop in temperature (about 4°C) but this was not sufficient to directly reduce neural activity. In an effort to visualize the extent of neural inactivation we measured the uptake of thallium ions following an intravenous injection. This confirmed that there was a large reduction of activity across much of the ipsilateral cortex and only a small reduction in subcortical structures

RNA interference in the cat flea, Ctenocephalides felis : Approaches for sustained gene knockdown and evidence of involvement of Dicer-2 and Argonaute2

This work was supported by a Knowledge Transfer Network BBSRC Industrial Case (# BB/L502467/1) studentship in association with Zoetis Inc. We acknowledge the expert help provided by Nikki Kernell (Zoetis Inc., Kalamazoo) during the feeding trials. Declarations of interest: none.Peer reviewedPublisher PD

The Influence of Hormonal Contraception on Vitamin D Supplementation on Serum 25(OH)D3 Status in Premenopausal Women: A Prospective Double-Blind Placebo Random Controlled Trial

Background: A number of cross-sectional studies have highlighted a potential benefit of estrogen-containing contraception on serum 25-hydroxyvitamin D (25(OH)D) levels. The purpose of the present prospective study was to determine whether oral vitamin D3 supplementation significantly increases serum 25(OH)D more for women taking the estrogen-containing oral contraception than those not taking this medication. Methods: Thirty-eight premenopausal adult females aged 18 - 45 years old were recruited from a university campus; exclusion criteria included those presently taking vitamin D supplementation, those who stopped or started taking oral contraception in last 6 months and those taking any other form of contraception. A prospective doubleblind placebo design was implemented; the dependent variable was serum 25(OH)D and the independent variables were using or not using oral estrogen-containing contraception, and vitamin D3 or placebo supplementation. Participants were tested 4 weeks apart, and blood samples were collected using a capillary blood spot sample method and analyzed by liquid chromatography-tandem mass spectrometry. An independent technician prepared the identical supplement bottles with either 100 placebo pills or 100 active vitamin D3 pills (1,000 IU per pill) and participants randomly selected a supplement bottle. Results: Baseline measurements of 25(OH)D were non-significantly 11% higher in those taking estrogen. ANOVA results revealed a significant two-way interaction between supplementation group (treatment vs. placebo) and treatment period (before vs. after) (P < 0.001), demonstrating a substantial rise in serum 25(OH)D for the treatment group compared with the placebo group. The results also identified a three-way interaction (P = 0.014) on serum 25(OH)D between the three independent variables, with the vitamin D oral contraception group having significantly greater serum 25(OH)D increases (from 45.9 to 98.3 nmol/L) compared with those not taking oral contraception (44.2 - 69.6 nmol/L) (P = 0.019). Conclusions: The estrogen-containing oral contraception increases serum 25(OH)D in premenopausal women with a magnified effect in those taking vitamin D supplementation. Future studies need to examine the relationship between estrogen, vitamin D supplementation, serum 25(OH)D, 1,25(OH)D, parathyroid hormone and other markers of bone metabolisms

Multi-Grid Monte Carlo. IV. One-Dimensional O(4)O(4)-Symmetric Nonlinear σ\sigma-Model

We study the dynamic critical behavior of the multi-grid Monte Carlo (MGMC) algorithm with piecewise-constant interpolation and a W-cycle, applied to the one-dimensional $O(4)$-symmetric nonlinear $\sigma$-model [= $SU(2)$ principal chiral model], on lattices from $L=128$ to $L=16384$. Our data for the integrated autocorrelation time $\tau_{int,{\cal M}^2}$ are well fit by a logarithmic growth. We have no idea why the critical slowing-down is not completely eliminated.Comment: 377866 bytes Postscript, 16 pages, includes figure

New Universality Classes for Two-Dimensional σ\sigma-Models

We argue that the two-dimensional $O(N)$-invariant lattice $\sigma$-model with mixed isovector/isotensor action has a one-parameter family of nontrivial continuum limits, only one of which is the continuum $\sigma$-model constructed by conventional perturbation theory. We test the proposed scenario with a high-precision Monte Carlo simulation for $N=3,4$ on lattices up to $512 \times 512$, using a Wolff-type embedding algorithm. [CPU time $\approx$ 7 years IBM RS-6000/320H] The finite-size-scaling data confirm the existence of the predicted new family of continuum limits. In particular, the $RP^{N-1}$ and $N$-vector models do not lie in the same universality class.Comment: 10 pages (includes 2 figures), 211176 bytes Postscript, NYU-TH-93/07/03, IFUP-TH 34/9