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

The 5′ Leader of the mRNA Encoding the Mouse Neurotrophin Receptor TrkB Contains Two Internal Ribosomal Entry Sites that Are Differentially Regulated

A single internal ribosomal entry site (IRES) in conjunction with IRES transactivating factors (ITAFs) is sufficient to recruit the translational machinery to a eukaryotic mRNA independent of the cap structure. However, we demonstrate that the mouse TrkB mRNA contains two independent IRESes. The mouse TrkB mRNA consists of one of two 5′ leaders (1428 nt and 448 nt), both of which include the common 3′ exon (Ex2, 344 nt). Dicistronic RNA transfections and in vitro translation of monocistronic RNA demonstrated that both full-length 5′ leaders, as well as Ex2, exhibit IRES activity indicating the IRES is located within Ex2. Additional analysis of the upstream sequences demonstrated that the first 260 nt of exon 1 (Ex1a) also contains an IRES. Dicistronic RNA transfections into SH-SY5Y cells showed the Ex1a IRES is constitutively active. However, the Ex2 IRES is only active in response to retinoic acid induced neural differentiation, a state which correlates with the synthesis of the ITAF polypyrimidine tract binding protein (PTB1). Correspondingly, addition or knock-down of PTB1 altered Ex2, but not Ex1a IRES activity in vitro and ex vivo, respectively. These results demonstrate that the two functionally independent IRESes within the mouse TrkB 5′ leader are differentially regulated, in part by PTB1

Synthesis of two SAPAP3 isoforms from a single mRNA is mediated via alternative translational initiation

In mammalian neurons, targeting and translation of specific mRNAs in dendrites contribute to synaptic plasticity. After nuclear export, mRNAs designated for dendritic transport are generally assumed to be translationally dormant and activity of individual synapses may locally trigger their extrasomatic translation. We show that the long, GC-rich 5′-untranslated region of dendritic SAPAP3 mRNA restricts translation initiation via a mechanism that involves an upstream open reading frame (uORF). In addition, the uORF enables the use of an alternative translation start site, permitting synthesis of two SAPAP3 isoforms from a single mRNA. While both isoforms progressively accumulate at postsynaptic densities during early rat brain development, their levels relative to each other vary in different adult rat brain areas. Thus, alternative translation initiation events appear to regulate relative expression of distinct SAPAP3 isoforms in different brain regions, which may function to influence synaptic plasticity

Assembling Neurospheres: Dynamics of Neural Progenitor/Stem Cell Aggregation Probed Using an Optical Trap

Optical trapping (tweezing) has been used in conjunction with fluid flow technology to dissect the mechanics and spatio-temporal dynamics of how neural progenitor/stem cells (NSCs) adhere and aggregate. Hitherto unavailable information has been obtained on the most probable minimum time (∼5 s) and most probable minimum distance of approach (4–6 µm) required for irreversible adhesion of proximate cells to occur. Our experiments also allow us to study and quantify the spatial characteristics of filopodial- and membrane-mediated adhesion, and to probe the functional dynamics of NSCs to quantify a lower limit of the adhesive force by which NSCs aggregate (∼18 pN). Our findings, which we also validate by computational modeling, have important implications for the neurosphere assay: once aggregated, neurospheres cannot disassemble merely by being subjected to shaking or by thermal effects. Our findings provide quantitative affirmation to the notion that the neurosphere assay may not be a valid measure of clonality and “stemness”. Post-adhesion dynamics were also studied and oscillatory motion in filopodia-mediated adhesion was observed. Furthermore, we have also explored the effect of the removal of calcium ions: both filopodia-mediated as well as membrane-membrane adhesion were inhibited. On the other hand, F-actin disrupted the dynamics of such adhesion events such that filopodia-mediated adhesion was inhibited but not membrane-membrane adhesion

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011

Six months of Sildenafil therapy improves heart rate recovery in patients with heart failure

Previous research has demonstrated an increase in large vessel stiffness in patients with heart failure (HF). Furthermore, heart rate recovery (HRR) may be negatively impacted by increased arterial stiffness secondary to altered baroreceptor discharge. The purpose of the present study was to determine if chronic phosphodiesterase 5 (PDE5) inhibition with Sildenafil, previously shown to improve arterial stiffness, favorably impacts HRR in patients with HF. Forty male subjects (age: 65.3 ± 7.3 years, baseline ejection fraction: 37.1 ± 7.4%, 15 non-ischemic HF/25 ischemic HF) participated in this study. Subjects received Sildenafil (25 mg, 3 times/day) for six months. Symptom-limited exercise testing was performed at baseline and six months with a lower extremity ergometer. Heart rate recovery was defined as HR at maximal exercise minus HR at 1 min recovery. No adverse effects were reported throughout the study period. Paired t-testing revealed that HRR was significantly improved following six months of Sildenafil therapy (baseline: 17.5 ± 3.5 bpm vs. Post: 20.6 ± 3.2 bpm). The results of the present study indicate that chronic Sildenafil therapy significantly increases HRR, an important prognostic marker, in patients with HF. A plausible mechanism for the improvement of HRR is the previously demonstrated impact Sildenafil has on arterial stiffness and therefore baroreceptor functio

Supplemental Material - Pharmaceutical Industry Perspective on the Non-Clinical Evaluation of Novel Excipients: Results From an Industry Survey Conducted by the IQ Novel Excipient Working Group

Supplemental Material for Pharmaceutical Industry Perspective on the Non-Clinical Evaluation of Novel Excipients: Results From an Industry Survey Conducted by Paul S. Giffen, Lorrene A. Buckley, and Jason Pinkstaff in International Journal of Toxicology</p

Neuromuscular electrical stimulation and inspiratory muscle training as potential adjunctive rehabilitation options for patients with heart failure

Aerobic and resistance exercise training programs produce an abundance of physiologic and clinical benefits in patients with heart failure (HF). Improved maximal aerobic capacity, submaximal aerobic endurance, muscle force production, perceived quality of life, and skeletal muscle characteristics are among the more established outcomes resulting from these rehabilitation techniques. Moreover, both aerobic and resistance exercise training appear to portend a low risk to patients with HF when appropriate exercise prescription methods are followed. While the aforementioned training techniques will undoubtedly continue to be at the center of a well-formulated rehabilitation program, other adjunctive interventions, which are presently underutilized in clinical practice, may prove beneficial in patients with HF. Specifically, both neuromuscular electrical stimulation (NMES) and inspiratory muscle training (IMT) appear to significantly improve several physiologic, exercise, symptomatologic, and quality-of-life parameters. NMES targets skeletal muscle abnormalities, whereas IMT primarily targets the weakened respiratory musculature, both often encountered in patients with HF. A PubMed search using relevant key words identified 19 original investigations examining the impact of NMES (13 studies) and IMT (6 studies) training programs in patients with HF. The resultant review (1) provides a summary of the original research outcomes of both NMES and IMT in patients with HF; (2) addresses current research gaps, providing a direction for future investigations; and (3) provides clinical scenarios where NMES and IMT may prove to be beneficial during the rehabilitation of patients with HF. Copyrigh

Improvement in ventilatory efficiency and dyspnea on exertion are related to reduced pulmonary pressure in heart failure patients undergoing chronic phosphodiesterase-5 inhibition

Chronic phosphodiesterase-5 inhibition with Sildenafil has been shown to improve peak oxygen consumption (VO2), ventilatory efficiency (VE/VCO2 slope) and pulmonary artery pressure (PAP) in patients with heart failure (HF). The impact of Sildenafil on dyspnea on exertion (DOE) or the relationship between changes in the exercise response and pulmonary hemodynamics following use of this pharmacologic agent are unknown. We addressed the hypothesis that DOE would be reduced and improvements in the exercise response would be correlated with pulmonary hemodynamics following three months of treatment with Sildenafil. Forty male patients with HF (age: 65.3 \ub17.3 years; ejection fraction 37.1 \ub17.4%) underwent cardiopulmonary exercise testing and right heart catheterization prior to and following three months of treatment with Sildenafil at the dose of 50 mg three times per day, while maintaining standard pharmacologic management. The 0\u201310 Borg scale was used to assess DOE at maximal exercise. Three-months of Sildenafil treatment resulted in a significant (p<0.001 for all) increase in peak VO2 (mean change: 1.3 \ub10.78 mlO2\ub7kg\u20131\ub7min\u20131; range: 0\u20133 mlO2\ub7kg\u20131\ub7min\u20131) and a significant reduction in the VE/VCO2 slope (mean change: 2.2 \ub11.6; range: \u20131 to 6), DOE at maximal exercise (mean change: 0.98 \ub10.83; range: \u20131 to 2) and mean PAP (mean change: 5.2 \ub14.5 mmHg; range: \u20131 to 18 mmHg). The correlations between the change in mean PAP and both the change in the VE/VCO2 slope (Pearson\u2019s r = 0.57, p<0.001) and DOE at maximal exercise (Spearman\u2019s r = 0.49, p=0.001) were significant. The correlation between change in mean PAP and change in peak VO2 (Pearson\u2019s r = \u20130.02, p=0.90) was, however, not significant. The results of the present study are consistent with previous findings demonstrating a significant improvement in aerobic capacity, ventilatory efficiency and pulmonary hemodynamics after chronic administration of Sildenafil in HF. The findings presented here expand upon this area by demonstrating that: 1) DOE at maximal exercise, an important subjective measure, is significantly reduced and 2) The degree of improvement in mean PAP is reflected by the degree of improvement in the VE/VCO2 slope and DOE, but not peak VO2