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Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart's contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality. [ABSTRACT FROM AUTHOR]

A 2011 randomized controlled trial compared the effectiveness of two brief motivation-enhancing therapy (MET) models among alcohol-positive adolescents in an urban emergency department: adolescent MET-only versus MET + Family Check-Up (FCU), a parent MET model. Results indicated that among the 97 adolescents completing the 3-month assessment, both conditions were associated with reduced drinking and MET+FCU was associated with lower rates of high volume drinking than adolescent MET-only. The goal of this study was to identify predictors and moderators of high volume drinking in the original trial. Seven candidate variables were evaluated as moderators across three domains: demographic characteristics, psychological factors, and socio-contextual factors. Analyses of covariance models identified one significant predictor and one significant moderator of outcome. Older adolescents had significantly worse drinking outcomes than younger adolescents regardless of MET condition. Adolescents whose parents screened positive for problematic alcohol use at baseline had significantly worse drinking outcomes in the MET+FCU condition than the MET-only condition. Results indicate that alcohol-positive adolescents presenting to the emergency department may respond better to MET models if they are under the age of 16. Involving parents who have problematic alcohol use in a parent-focused MET may have negative effects on adolescent high volume drinking. [ABSTRACT FROM AUTHOR]

Many potential therapeutic options are now available for patients with pulmonary arterial hypertension. Interest has emerged in using therapies in various combinations. Retrospective experience has suggested that this approach is common and can be efficacious. Data are emerging supporting the benefit of combination therapy; however, limitations and questions remain about this strategy. This report reviewed the rationale for combination therapy and summarized the results from clinical trials. [ABSTRACT FROM AUTHOR]

Background: Overaggressive fluid resuscitation in elderly patients requiring pancreatectomy can delay recovery and increase morbidity. Despite advancements, no accurate and reproducible methods exist to evaluate effective intravascular volume status in the postoperative setting. We hypothesized that sequential measurement of currently available serum proteins will indicate fluid balance. Study Design: Clinicopathologic (n = 44) and echocardiogram (echo) data (n = 18) were collected on patients receiving pancreatectomy or diagnostic laparoscopy (n = 5). Measured fluid balance, serum BUN, creatinine (CR), and brain natriuretic peptide (BNP) levels were recorded on postoperative days (POD) 1 to 7 (only POD1 for diagnostic laparoscopy). ANOVA and bivariate random effect models examined the correlation between BNP and BUN/CR and fluid balance. Linear mixed-effect models examined the correlation between factors associated with vascular stiffness and BNP, BUN/CR, and fluid balance. Results: On POD1 after diagnostic laparoscopy, the fluid balance was positive by 3,265 mL and was accompanied by a >300-point increase in BNP (p = 0.0083). After pancreatectomy, a similar increase in BNP (250 pg/mL) and fluid balance (4,492 mL) on POD1 was observed. During the return to euvolemia, the change in serum BNP levels correlated with fluid balance changes during POD 1 to 3 (p = 0.039), and BUN/CR levels correlated with fluid balance during POD 4 to 7. Patients with risk factors associated with cardiovascular stiffness or echo evidence of poor compliance experienced higher BNP during the postoperative period. Conclusions: Fluid loading at surgery is accompanied by an increase in serum BNP, and return to a balanced fluid state after pancreatectomy is paralleled by changes in BNP and BUN/CR levels. [Copyright &y& Elsevier]

Abstract: sBackground: : The availability of rapid-acting insulin analogues and inhaled insulin gives clinicians additional treatmentoptions in the management of patients with diabetes mellitus (DM). Combining rapid-acting insulin analogues with basal insulin can more closely mimic physiologic insulin release to maximize glycemic control. Objective: : The objective of this article was to discuss the role of rapid-acting insulin analogues and inhaled insulin inthe treatment of patients with type 2 DM. Methods: : Materials for this article were obtained through an online search of MEDLINE/PubMed and Google(1996-2006) using the search terms bolus insulin, postprandial, rapid-acting insulin analogues, titration, hypoglycemia, glycemic control, inhaled insulin, and insulins lispro, aspart, and glulisine. Results: : Glycosylated hemoglobin (A1C) levels and number of all hypoglycemic episodes were similar in patients withtype 2 DM taking either mealtime rapid-acting insulin analogues or regular human insulin (RHI). Rapid-acting insulins have been successfully used in basal-bolus regimens with a variety of long- and intermediate-acting insulins, as well as with oral hypoglycemic agents. Injectable rapid-acting insulin analogues markedly decreased postprandial glucose (PPG) levels compared with RHI. Better reduction in PPG levels may be key to achieving target A1C levels in some patients, but long-term outcome studies are needed to assess whether lowering PPG levels decreases cardiovascular risk in patients with type 2 DM. Inhaled insulin may be an option for patients who cannot inject insulin, but route of administration and dosing issues limit its use in many patients. The effect of inhaled insulin on PPG is unclear at this time. Conclusions: : Although rapid-acting insulin analogues are effective in the management of patients with type 2 DM, the limited numbers of studies have yet to demonstrate that these agents have any significant long-term advantage compared with RHI. In addition, they cost more than RHI. Further studies are needed to compare the efficacy of the rapid-acting insulin analogues, to compare the different dosing regimens used with mealtime insulin administration, and to ascertain if the decrease in PPG levels seen with the use of rapid-acting insulin analogues translates into improved glycemic control and perhaps even a reduction in cardiovascular risk in patients with type 2 DM. (Insulin. 2007;2:61-67) Copyright 2007 Excerpta Medica, Inc. [Copyright &y& Elsevier]

Background & Aims: Tumor necrosis factor blockade has been shown to be an effective treatment strategy in Crohn’s disease (CD). Adalimumab is a human immunoglobulin G1 (IgG1) monoclonal antibody targeting tumor necrosis factor (TNF). A randomized, double-blind, placebo-controlled, dose-ranging trial was performed to evaluate the efficacy of adalimumab induction therapy in patients with CD. Methods: A total of 299 patients with moderate to severe CD naive to anti–TNF therapy were randomized to receive subcutaneous injections at weeks 0 and 2 with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The primary endpoint was demonstration of a significant difference in the rates of remission at week 4 (defined as a Crohn’s Disease Activity Index score <150 points) among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups. Results: The rates of remission at week 4 in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18% (P = .36), 24% (P = .06), and 36% (P = .001), respectively, and 12% in the placebo group. Adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions, which were more common in adalimumab-treated patients. Conclusions: Adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn’s disease naive to anti–TNF therapy. The optimal induction dosing regimen for adalimumab in this study was 160 mg at week 0 followed by 80 mg at week 2. Adalimumab was well tolerated. [Copyright &y& Elsevier]

Molecular motors that make up the intracellular transport system are akin to subway cars and trains that ply the rails of cities. The inner workings of these extraordinarily complicated systems are being explicated at the atomic level at a phenomenal rate, and it is becoming apparent that we are on the verge of bioengineering these motors for specialized applications. These systems might be the key to yet unsolved biomedical applications that include non-viral gene therapy and interneuron drug delivery. [Copyright &y& Elsevier]

Recombinant human growth hormone post-renal transplantation in children: A randomized controlled study of the NAPRTCS. Background. Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken. Methods. Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment. Results. After one year, the delta SDS (standardized height) was +0.49 ± 0.10 in the treatment group (N = 30) compared to -0.10 ± 0.08 in the control group ( N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups. Conclusion. In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events. [ABSTRACT FROM AUTHOR]

Cancer cells display lysosome hypertrophy, secreting lysosomal hydrolases for tumor progression. Hypertrophy renders lysosomes fragile, increasing lysosomal membrane permeabilization (LMP) tendency. In this issue of Cancer Cell, Petersen and colleagues show that lysosomal sphingomyelin content determines LMP and cationic drugs displace acid sphingomyelinase from lysosomal membranes, increasing tumor LMP and death. [ABSTRACT FROM AUTHOR]

Background Polymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the diversity in clinical response. The aim of the analysis was to model the exposure–response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs. Method The population pharmacokinetic–pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n = 36), visceral pressure (n = 54) and skin pinch (n = 34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters. Results None of the selected SNPs were associated with analgesic response of oxycodone at P < 0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P < 0.001). Simulations indicated that large differences in drug response between genotypes (> 50% for similar population sizes) or large populations (n > 200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability. Conclusion A population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified. [ABSTRACT FROM AUTHOR]

Objective: To examine trends in the number of cases of primary vesicoureteral reflux managed by ureteral reimplantation nationally over the last decade. Substantial changes have occurred in management of vesicoureteral reflux (VUR) over time, but trends in use of ureteral reimplantation have yet to be investigated on a national scale with annualized data.Materials and Methods: Using the Premier Healthcare Database, we extracted hospital discharge data for pediatric patients (age ≤ 18 years) with a procedure code for ureteroneocystostomy (International Classification of Diseases, Ninth Revision, 56.74) between January 1, 2003 and December 31, 2013. We excluded patients with secondary VUR. The presence of a temporal trend in reimplantation was examined via regression using generalized estimating equations.Results: In 4301 cases of primary VUR (23,602 weighted), there was a substantial decrease in the number of reimplantations performed, with an estimated decline in the rate of 0.239 cases per attending per year (P = .006). Average patient age declined 1.2 months in each year (P < .0001) due largely to a decline in reimplantation in those over age 2, which fell by 0.15 reimplantations per attending per year (P = .026). There was no difference between rates of decline in reimplantation for children with and without reflux nephropathy (P = .21) CONCLUSION: Nationally there has been a marked decrease in the incidence of ureteral reimplantation among children with primary VUR. The potential factors contributing to this are broad, including changes in diagnostic patterns, treatment recommendations, and the rise of endoscopic intervention. [ABSTRACT FROM AUTHOR]

Background Delirium is a common, morbid, and costly postoperative complication. We aimed to identify blood-based postoperative delirium markers in a nested case-control study of older surgical patients using a proteomics approach followed by enzyme-linked immunosorbent assay (ELISA) validation. Methods The Successful Aging after Elective Surgery study enrolled dementia-free adults ≥70 years old undergoing major scheduled noncardiac surgery ( N = 566; 24% delirium). Plasma was collected at four time points: preoperative, postanesthesia care unit, postoperative day 2, and 1 month postoperative. Matched pairs were selected for the independent discovery (39 pairs) and replication cohorts (36 pairs), which were subsequently combined into the pooled cohort (75 pairs). Isobaric tags for relative and absolute quantitation–based relative quantitation mass spectrometry proteomics were performed to identify the strongest delirium-related protein, which was selected for ELISA validation. Using the ELISA results, statistical analyses using nonparametric signed rank tests were performed in all cohorts examining the association between the identified protein and delirium. Results C-reactive protein emerged from the proteomics analysis as the strongest delirium-related protein. Validation by ELISA confirmed that compared with controls, cases had significantly higher C-reactive protein levels in the discovery, replication, and pooled cohorts at the preoperative (median paired difference [MPD] 1.97 mg/L [ p < .05], 0.29 mg/L, 1.56 mg/L [ p < .01]), postanesthesia care unit (MPD 2.83 mg/L, 2.22 mg/L [ p < .05], 2.53 mg/L [ p < .01]) and postoperative day 2 (MPD 71.97 mg/L [ p < .01], 35.18 mg/L [ p < .05], 63.76 mg/L [ p < .01]) time points, but not 1 month postoperative (MPD 2.72 mg/L, −0.66 mg/L, 1.10 mg/L). Conclusions Elevated preoperative and postoperative plasma levels of C-reactive protein were associated with delirium, suggesting that a preinflammatory state and heightened inflammatory response to surgery are potential pathophysiologic mechanisms of delirium. [ABSTRACT FROM AUTHOR]

Study objective: Widespread chest CT use in trauma evaluation may increase the diagnosis of minor sternal fracture (SF), making former teaching about SF obsolete. We sought to determine: (1) the frequency with which SF patients are diagnosed by CXR versus chest CT under current imaging protocols, (2) the frequency of surgical procedures related to SF diagnosis, (3) SF patient mortality and hospital length of stay comparing patients with isolated sternal fracture (ISF) and sternal fracture with other thoracic injury (SFOTI), and (4) the frequency and yield of cardiac contusion (CC) workups in SF patients. Methods: We analyzed charts and data of all SF patients enrolled from January 2009 to May 2013 in the NEXUS Chest and NEXUS Chest CT studies, two multi-centre observational cohorts of blunt trauma patients who received chest imaging for trauma evaluation. Results: Of the 14,553 patients in the NEXUS Chest and Chest CT cohorts, 292 (2.0%) were diagnosed with SF, and 94% of SF were visible on chest CT only. Only one patient (0.4%) had a surgical procedure related to SF diagnosis. Cardiac contusion was diagnosed in 7 (2.4%) of SF patients. SF patient mortality was low (3.8%) and not significantly different than the mortality of patients without SF (3.1%) [mean difference 0.7%; 95% confidence interval (CI) 1.0 to 3.5%]. Only 2 SF patient deaths (0.7%) were attributed to a cardiac cause. SFOTI patients had longer hospital stays but similar mortality to patients with ISF (mean difference 0.8%; 95% CI 4.7% to 12.0). Conclusions: Most SF are seen on CT only and the vast majority are clinically insignificant with no change in treatment and low associated mortality. Workup for CC in SF patients is a low-yield practice. SF diagnostic and management guidelines should be updated to reflect modern CT-driven trauma evaluation protocols. [ABSTRACT FROM AUTHOR]

Background: Inhaled treprostinil improved functional capacity as add-on therapy in the short-term management of patients with pulmonary arterial hypertension (PAH). This study investigated the long-term effects of inhaled treprostinil in patients concurrently receiving oral background therapy. Methods: A total of 206 patients (81% women) completing the 12-week double-blind phase of the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study transitioned into an open-label extension. Patients were assessed every 3 months for changes in 6-minute walk distance (6MWD), Borg dyspnea score, New York Heart Association (NYHA) functional class, quality of life (QOL) scores, and signs and symptoms of PAH. Results: Patients were primarily NYHA class III (86%), with a mean baseline 6MWD of 349 ± 81 meters. A median change in 6MWD of 28, 31, 32, and 18 meters in patients continuing therapy was observed at 6, 12, 18, and 24 months, respectively. This effect was more prominent in those patients originally allocated to active therapy in the double-blind phase. Survival rates for patients remaining on therapy were 97%, 94%, and 91% at 12, 18, and 24 months, respectively. In addition, 82%, 74%, and 69% of patients maintained treatment benefit as evidenced by lack of clinical worsening at 12, 18, and 24 months. The most common adverse events were known effects of prostanoid therapy (headache [34%], nausea [21%], and vomiting [10%]) or were due to the route of administration (cough [53%], pharyngolaryngeal pain [13%], and chest pain [13%]). Conclusions: Long-term therapy with inhaled treprostinil demonstrated persistent benefit for PAH patients who remained on therapy for up to 24 months. [ABSTRACT FROM AUTHOR]

Recently, the use of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU) in combination with nucleoside analogs has gained attention as a potential strategy for anti-HIV-1 therapy. However, appeal for the long-term use of HU in HIV-1 infection may be limited by its propensity to induce hematopoietic toxicity. We report a comparison of the efficacy and bone marrow toxicity of HU (400 and 200 mg/kg/day) with the novel RR inhibitors and free radical-scavenging compounds didox (DX; 3,4-dihydroxybenzohydroxamic acid; 350 mg/kg/day) and trimidox (TX; 3,4,5-trihydroxybenzamidoxime; 175 mg/kg/day) in the murine AIDS (LPBM5 MuLV) model of retrovirus infection. Infected mice received daily drug treatment for 8 weeks. Efficacy was determined by measuring drug effects on retroviral-induced disease progression (i.e. development of splenomegaly and hypergammaglobulinemia) and by evaluating splenic levels of proviral DNA. Bone marrow toxicity was evaluated by measuring peripheral blood indices (WBC, hematocrit and reticulocyte counts), femoral cellularity and by determining the numbers of hematopoietic progenitor cells (CFU-GM, BFU-E) per femur and spleen. Compared to infected controls receiving no drug treatment, disease progression was significantly suppressed by TX, DX and HU. However, HU was associated with mortality and induced significant hematopoietic toxicity in a time- and dose-dependent manner. Conversely, TX and DX effectively inhibited retrovirus-induced disease but did not induce hematopoietic toxicity. These results suggest that due to their reduced hematopoietic toxicity and ability to inhibit disease progression in murine AIDS, TX and DX may offer effective alternatives to HU therapy in HIV-1 infection. [Copyright &y& Elsevier]

We present the case of a 9 year old boy with hemorrhagic cystitis and urinary clot retention in the setting of chemotherapy refractory pre-B cell acute lymphocytic leukemia. The patient was undergoing palliative care which was complicated by severe discomfort from urinary clot retention. The decision was made to perform a cutaneous vesicostomy for clot removal and urinary drainage given the goals of care. The patient tolerated the procedure well and was comfortable with no further urinary tract symptoms until he expired. Cutaneous vesicostomy should be considered as an effective surgical option for severe clot retention in children. [Copyright &y& Elsevier]