Early diagnosis of persons infected with human immunodeficiency virus (HIV) through diagnostic testing and screening is a critical priority for individual and public health. Emergency departments ...(EDs) have an important role in this effort. As EDs gain experience in HIV testing, it is increasingly apparent that implementing testing is conceptually and operationally complex. A wide variety of HIV testing practice and research models have emerged, each reflecting adaptations to site‐specific factors and the needs of local populations. The diversity and complexity inherent in nascent ED HIV testing practice and research are associated with the risk that findings will not be described according to a common lexicon. This article presents a comprehensive set of terms and definitions that can be used to describe ED‐based HIV testing programs, developed by consensus opinion from the inaugural meeting of the National ED HIV Testing Consortium. These definitions are designed to facilitate discussion, increase comparability of future reports, and potentially accelerate wider implementation of ED HIV testing.
Beta2-adrenoreceptor agonists (beta2-agonists) are primarily bronchodilators, targeting airway smooth muscle and providing critical symptomatic relief in conditions such as bronchial asthma and ...chronic obstructive pulmonary disease. These agents also possess broad-spectrum, secondary, anti-inflammatory properties. These are mediated largely, though not exclusively, via interactions with adenylyl cyclase-coupled beta2-adrenoreceptors on a range of immune and inflammatory cells involved in the immunopathogenesis of acute and chronic inflammatory disorders of the airways. The clinical relevance of the anti-inflammatory actions of beta2-agonists, although often effective in the experimental setting, remains contentious. The primary objectives of the current review are: firstly, to assess the mechanisms, both molecular and cell- associated, that may limit the anti-inflammatory efficacy of beta2-agonists; secondly, to evaluate pharmacological strategies, several of which are recent and innovative, that may overcome these limitations. These are preceded by a consideration of the various types of beta2-agonists, their clinical applications, and spectrum of anti-inflammatory activities, particularly those involving adenosine 3',5'-cyclic adenosine monophosphate-activated protein kinase-mediated clearance of cytosolic calcium, and altered gene expression in immune and inflammatory cells. Keywords: adenylyl cyclase, corticosteroids, cyclic AMP, muscarinic receptor antagonists, neutrophils, phosphodiesterase inhibitors
Departments of 1 Medicine and 2 Physiology and 3 Center for Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio; and 4 Department of Electrical and Computer ...Engineering, University of Texas at Austin, Austin, Texas
Submitted 7 June 2005
; accepted in final form 23 February 2006
Conductance measurements for generation of an instantaneous left ventricular (LV) volume signal in the mouse are limited, because the volume signal is a combination of blood and LV muscle, and only the blood signal is desired. We have developed a conductance system that operates at two simultaneous frequencies to identify and remove the myocardial contribution to the instantaneous volume signal. This system is based on the observation that myocardial resistivity varies with frequency, whereas blood resistivity does not. For calculation of LV blood volume with the dual-frequency conductance system in mice, in vivo murine myocardial resistivity was measured and combined with an analytic approach. The goals of the present study were to identify and minimize the sources of error in the measurement of myocardial resistivity to enhance the accuracy of the dual-frequency conductance system. We extended these findings to a gene-altered mouse model to determine the impact of measured myocardial resistivity on the calculation of LV pressure-volume relations. We examined the impact of temperature, timing of the measurement during the cardiac cycle, breeding strain, anisotropy, and intrameasurement and interanimal variability on the measurement of intact murine myocardial resistivity. Applying this knowledge to diabetic and nondiabetic 11- and 20- to 24-wk-old mice, we demonstrated differences in myocardial resistivity at low frequencies, enhancement of LV systolic function at 11 wk and LV dilation at 2024 wk, and histological and electron-microscopic studies demonstrating greater glycogen deposition in the diabetic mice. This study demonstrated the accurate technique of measuring myocardial resistivity and its impact on the determination of LV pressure-volume relations in gene-altered mice.
gene-altered mouse; diabetes; left ventricular volume; dual-frequency conductance method; myocardial resistivity
Address for reprint requests and other correspondence: M. D. Feldman, Rm. 5.642 U, Univ. of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900 (e-mail: feldmanm{at}uthscsa.edu )
Mutations in the vitamin D receptor (VDR) cause hereditary vitamin D-resistant rickets (HVDRR), an autosomal recessive disease resulting in target organ resistance to 1,25-dihydroxyvitamin D3 ...1,25(OH)2D3. In this report, we describe the clinical case and molecular basis of HVDRR in an Asian boy exhibiting the typical clinical features of the disease including alopecia. Using cultured dermal fibroblasts from the patient, 1,25(OH)2D3 resistance was demonstrated by a shift in the dose response required for 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) mRNA induction. Western blot showed that the cells express a normal size VDR but contained reduced levels of receptor compared to normal cells. At 24°C, the affinity of the patient's VDR for 3H1,25(OH)2D3 was 50-fold lower than the VDR in normal fibroblasts. Sequence analysis identified a unique T to G missense mutation in exon 6 that changed phenylalanine to cysteine at amino acid 251 (F251C). The recreated F251C mutant VDR showed reduced transactivation activity using a 24-hydroxylase promoter-luciferase reporter. Maximal transactivation activity exhibited by the WT VDR was not achieved by the mutant VDR even when the cells were treated with up to 10−6 M 1,25(OH)2D3. However, the transactivation activity was partially rescued by addition of RXRα. In the yeast two-hybrid system and GST-pull-down assays, high concentrations of 1,25(OH)2D3 were needed to promote F251C mutant VDR binding to RXRα, indicating defective heterodimerization. In conclusion, a novel mutation was identified in the VDR LBD that reduces VDR abundance and its affinity for 1,25(OH)2D3 and interferes with RXRα heterodimerization resulting in the syndrome of HVDRR.
Abstract Objectives This study sought to evaluate the outcomes of the early experience of transcatheter mitral valve replacement (TMVR) with balloon-expandable valves in patients with severe mitral ...annular calcification (MAC) and reports the first large series from a multicenter global registry. Background The risk of surgical mitral valve replacement in patients with severe MAC is high. There are isolated reports of successful TMVR with balloon-expandable valves in this patient population. Methods We performed a multicenter retrospective review of clinical outcomes of patients with severe MAC undergoing TMVR. Results From September 2012 to July of 2015, 64 patients in 32 centers underwent TMVR with compassionate use of balloon-expandable valves. Mean age was 73 ± 13 years, 66% were female, and mean Society of Thoracic Surgeons score was 14.4 ± 9.5%. The mean mitral gradient was 11.45 ± 4.4 mm Hg and the mean mitral area was 1.18 ± 0.5 cm2 . SAPIEN valves (Edwards Lifesciences, Irvine, California) were used in 7.8%, SAPIEN XT in 59.4%, SAPIEN 3 in 28.1%, and Inovare (Braile Biomedica, Brazil) in 4.7%. Access was transatrial in 15.6%, transapical in 43.8%, and transseptal in 40.6%. Technical success according to Mitral Valve Academic Research Consortium criteria was achieved in 46 (72%) patients, primarily limited by the need for a second valve in 11 (17.2%). Six (9.3%) had left ventricular tract obstruction with hemodynamic compromise. Mean mitral gradient post-procedure was 4 ± 2.2 mm Hg, paravalvular regurgitation was mild or absent in all. Thirty-day all-cause mortality was 29.7% (cardiovascular = 12.5% and noncardiac = 17.2%); 84% of the survivors with follow-up data available were in New York Heart Association functional class I or II at 30 days (n = 25). Conclusions TMVR with balloon-expandable valves in patients with severe MAC is feasible but may be associated with significant adverse events. This strategy might be an alternative for selected high-risk patients with limited treatment options.
Adverse events (AEs) and serious adverse events (SAEs) are important outcomes of any intervention study yet are under-researched. Vague and variable definitions and substantial underreporting make ...comparisons of risk between studies difficult and evaluation of the safety of a particular intervention almost impossible. These realities may deter researchers from studying at-risk populations. Suicidal behavior is an adverse event in any study, and potentially a very serious one. Thus the issues of reporting and definition are particularly salient for researchers who work with populations at risk for suicidal behavior, especially when the suicidal behavior is the outcome of interest. We conducted a qualitative study with experienced suicide researchers and intervention experts to delineate the issues related to reporting serious adverse events faced by investigators conducting trials in suicide prevention. Participants from multiple sites were interviewed by phone, interviews transcribed and coded for definition and reporting issues and suggested solutions. A narrative synthesis was prepared and validated by all participants. Participants highlighted the difficulties in defining AEs and SAEs and stressed the importance and complexity of ensuring the AE was related to the study and reported properly, and were in agreement about the consequences of AEs to both institutions and individuals. Participants identified the need for the development of clear and consistent AE definitions and reporting requirements. Clear and consistently applied definitions of adverse and serious adverse events and reporting requirements would enhance the comparability of intervention studies in suicidal populations.
The use of phototherapy for psoriasis has declined because of inconvenience, managed care disincentives, and poor reimbursements. However, phototherapy is safer than other options, and the efficacy ...rates for different methods of phototherapy are among the highest of all available treatment options. Phototherapy is also one of the least costly treatments for moderate-to-severe psoriasis. We hypothesize that utilization management controls on phototherapy shift patients to more expensive and risky systemic treatments. Reducing disincentives on phototherapy will benefit both patients and payors, while increasing physicians' ability to manage this debilitating disease.
It has been hypothesized that because of its rapid heart rate, the intact murine heart functions near maximal contractility in the basal state. If this hypothesis is correct, then the fast and slow ...components of myocardial length-dependent activation should be blunted compared with larger mammals.
Mice (n=24) were anesthetized, and via an open chest, LV pressure-volume relationships were determined by a dual-frequency conductance catheter system. Baseline pressure-volume relationships were determined during transient occlusion of the inferior vena cava, and repeat measurements were made after 1 (n=10) and 7 (n=21) minutes of sustained aortic occlusion. Control experiments were performed in a subset of mice (n=3). For baseline to 1 minute, an increase in afterload (maximal pressure 95+/-9 to 126+/-7 mm Hg; P<0.001) and effective arterial elastance (5.9+/-3.1 to 9.2+/-3.9 mm Hg/microl; P<0.001) resulted in an increase in end-diastolic volume (31+/-8 to 35+/-9 microL; P<0.001). The result was maintenance of stroke volume (17+/-6 to 15+/-6; P=NS) owing to an increase in contractility (leftward shift in V100 the volume of end-systolic elastance at 100 mm Hg, 24+/-9 to 16+/-5 microL; P<0.001). No additional augmentation of systolic function was found at 7 minutes.
This study demonstrates that the fast phase of length-dependent activation is intact but not the slow phase, consistent with murine myocardium functioning near maximal contractility in the basal state.
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