Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.

Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient and reproducible in vivo gene techniques must be established to efficiently transfer transgenes globally to the myocardium. We have been testing the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor (beta-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human beta2-AR (Adeno-beta2AR), to the myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-beta2AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 x 10(11) viral particles of Adeno-beta2AR reproducibly produced 5- to 10-fold beta-AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function compared with control rabbits that received an empty adenovirus. Several physiological parameters, including dP/dtmax as a measure of contractility, were significantly enhanced basally and showed increased responsiveness to the beta-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of beta-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.

Accessibility, availability and affordability of anti-malarials in a rural district in Kenya after implementation of a national subsidy scheme.

BACKGROUND: Poor access to prompt and effective treatment for malaria contributes to high mortality and severe morbidity. In Kenya, it is estimated that only 12% of children receive anti-malarials for their fever within 24 hours. The first point of care for many fevers is a local medicine retailer, such as a pharmacy or chemist. The role of the medicine retailer as an important distribution point for malaria medicines has been recognized and several different strategies have been used to improve the services that these retailers provide. Despite these efforts, many mothers still purchase ineffective drugs because they are less expensive than effective artemisinin combination therapy (ACT). One strategy that is being piloted in several countries is an international subsidy targeted at anti-malarials supplied through the retail sector. The goal of this strategy is to make ACT as affordable as ineffective alternatives. The programme, called the Affordable Medicines Facility - malaria was rolled out in Kenya in August 2010. METHODS: In December 2010, the affordability and accessibility of malaria medicines in a rural district in Kenya were evaluated using a complete census of all public and private facilities, chemists, pharmacists, and other malaria medicine retailers within the Webuye Demographic Surveillance Area. Availability, types, and prices of anti-malarials were assessed. There are 13 public or mission facilities and 97 medicine retailers (registered and unregistered). RESULTS: The average distance from a home to the nearest public health facility is 2 km, but the average distance to the nearest medicine retailer is half that. Quinine is the most frequently stocked anti-malarial (61% of retailers). More medicine retailers stocked sulphadoxine-pyramethamine (SP; 57%) than ACT (44%). Eleven percent of retailers stocked AMFm subsidized artemether-lumefantrine (AL). No retailers had chloroquine in stock and only five were selling artemisinin monotherapy. The mean price of any brand of AL, the recommended first-line drug in Kenya, was $2.7 USD. Brands purchased under the AMFm programme cost 40% less than non-AMFm brands. Artemisinin monotherapies cost on average more than twice as much as AMFm-brand AL. SP cost only $0.5, a fraction of the price of ACT. CONCLUSIONS: AMFm-subsidized anti-malarials are considerably less expensive than unsubsidized AL, but the price difference between effective and ineffective therapies is still large.

Reduced length of hospital stay in colorectal surgery after implementation of an enhanced recovery protocol.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital. METHODS: Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates. RESULTS: There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02). DISCUSSION: Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals.

The influence of hepatic function on prostate cancer outcomes after radical prostatectomy.

Prostate growth is dependent on circulating androgens, which can be influenced by hepatic function. Liver disease has been suggested to influence prostate cancer (CaP) incidence. However, the effect of hepatic function on CaP outcomes has not been investigated. A total of 1181 patients who underwent radical prostatectomy (RP) between 1988 and 2008 at four Veterans Affairs hospitals that comprise the Shared Equal Access Regional Cancer Hospital database and had available liver function test (LFT) data were included in the study. Independent associations of LFTs with unfavorable pathological features and biochemical recurrence were determined using logistic and Cox regression analyses. Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were elevated in 8.2 and 4.4% of patients, respectively. After controlling for CaP features, logistic regression revealed a significant association between SGOT levels and pathological Gleason sum > or =7(4+3) cancer (odds ratio=2.12; 95% confidence interval=1.11-4.05; P=0.02). Mild hepatic dysfunction was significantly associated with adverse CaP grade, but was not significantly associated with other adverse pathological features or biochemical recurrence in a cohort of men undergoing RP. The effect of moderate-to-severe liver disease on disease outcomes in CaP patients managed non-surgically remains to be investigated.

Outcomes After Total Ankle Replacement in Association With Ipsilateral Hindfoot Arthrodesis.

BACKGROUND: Ipsilateral hindfoot arthrodesis in combination with total ankle replacement (TAR) may diminish functional outcome and prosthesis survivorship compared to isolated TAR. We compared the outcome of isolated TAR to outcomes of TAR with ipsilateral hindfoot arthrodesis. METHODS: In a consecutive series of 404 primary TARs in 396 patients, 70 patients (17.3%) had a hindfoot fusion before, after, or at the time of TAR; the majority had either an isolated subtalar arthrodesis (n = 43, 62%) or triple arthrodesis (n = 15, 21%). The remaining 334 isolated TARs served as the control group. Mean patient follow-up was 3.2 years (range, 24-72 months). RESULTS: The SF-36 total, AOFAS Hindfoot-Ankle pain subscale, Foot and Ankle Disability Index, and Short Musculoskeletal Function Assessment scores were significantly improved from preoperative measures, with no significant differences between the hindfoot arthrodesis and control groups. The AOFAS Hindfoot-Ankle total, function, and alignment scores were significantly improved for both groups, albeit the control group demonstrated significantly higher scores in all 3 scales. Furthermore, the control group demonstrated a significantly greater improvement in VAS pain score compared to the hindfoot arthrodesis group. Walking speed, sit-to-stand time, and 4-square step test time were significantly improved for both groups at each postoperative time point; however, the hindfoot arthrodesis group completed these tests significantly slower than the control group. There was no significant difference in terms of talar component subsidence between the fusion (2.6 mm) and control groups (2.0 mm). The failure rate in the hindfoot fusion group (10.0%) was significantly higher than that in the control group (2.4%; p < 0.05). CONCLUSION: To our knowledge, this study represents the first series evaluating the clinical outcome of TARs performed with and without hindfoot fusion using implants available in the United States. At follow-up of 3.2 years, TAR performed with ipsilateral hindfoot arthrodesis resulted in significant improvements in pain and functional outcome; in contrast to prior studies, however, overall outcome was inferior to that of isolated TAR. LEVEL OF EVIDENCE: Level II, prospective comparative series.

The Adjuvant Activity and Mechanisms of Action for Mastoparan 7 Peptide After Intranasal Immunization in Mice

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Variation in Inpatient Rehabilitation Utilization After Hospitalization for Burn Injury in the United States.

Approximately 45,000 individuals are hospitalized annually for burn treatment. Rehabilitation after hospitalization can offer a significant improvement in functional outcomes. Very little is known nationally about rehabilitation for burns, and practices may vary substantially depending on the region based on observed Medicare post-hospitalization spending amounts. This study was designed to measure variation in rehabilitation utilization by state of hospitalization for patients hospitalized with burn injury. This retrospective cohort study used nationally collected data over a 10-year period (2001 to 2010), from the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SIDs). Patients hospitalized for burn injury (n = 57,968) were identified by ICD-9-CM codes and were examined to see specifically if they were discharged immediately to inpatient rehabilitation after hospitalization (primary endpoint). Both unadjusted and adjusted likelihoods were calculated for each state taking into account the effects of age, insurance status, hospitalization at a burn center, and extent of burn injury by TBSA. The relative risk of discharge to inpatient rehabilitation varied by as much as 6-fold among different states. Higher TBSA, having health insurance, higher age, and burn center hospitalization all increased the likelihood of discharge to inpatient rehabilitation following acute care hospitalization. There was significant variation between states in inpatient rehabilitation utilization after adjusting for variables known to affect each outcome. Future efforts should be focused on identifying the cause of this state-to-state variation, its relationship to patient outcome, and standardizing treatment across the United States.

Peace and war: trajectories of posttraumatic stress disorder symptoms before, during, and after military deployment in Afghanistan.

In the study reported here, we examined posttraumatic stress disorder (PTSD) symptoms in 746 Danish soldiers measured on five occasions before, during, and after deployment to Afghanistan. Using latent class growth analysis, we identified six trajectories of change in PTSD symptoms. Two resilient trajectories had low levels across all five times, and a new-onset trajectory started low and showed a marked increase of PTSD symptoms. Three temporary-benefit trajectories, not previously described in the literature, showed decreases in PTSD symptoms during (or immediately after) deployment, followed by increases after return from deployment. Predeployment emotional problems and predeployment traumas, especially childhood adversities, were predictors for inclusion in the nonresilient trajectories, whereas deployment-related stress was not. These findings challenge standard views of PTSD in two ways. First, they show that factors other than immediately preceding stressors are critical for PTSD development, with childhood adversities being central. Second, they demonstrate that the development of PTSD symptoms shows heterogeneity, which indicates the need for multiple measurements to understand PTSD and identify people in need of treatment.

Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment.

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.

The reappearance hypothesis revisited: recurrent involuntary memories after traumatic events and in everyday life.

Recurrent involuntary memories are autobiographical memories that come to mind with no preceding retrieval attempt and that are subjectively experienced as being repetitive. Clinically, they are classified as a symptom of posttraumatic stress disorder. The present work is the first to systematically examine recurrent involuntary memories outside clinical settings. Study 1 examines recurrent involuntary memories among survivors of the tsunami catastrophe in Southeast Asia in 2004. Study 2 examines recurrent involuntary memories in a large general population. Study 3 examines whether the contents of recurrent involuntary memories recorded in a diary study are duplicates of, or differ from, one another. We show that recurrent involuntary memories are not limited to clinical populations or to emotionally negative experiences; that they typically do not come to mind in a fixed and unchangeable form; and that they show the same pattern regarding accessibility as do autobiographical memories in general. We argue that recurrent involuntary memories after traumas and in everyday life can be explained in terms of general and well-established mechanisms of autobiographical memory.

Preoperative pain level and patient expectation predict hospital length of stay after total hip arthroplasty.

The purpose of this study was to identify preoperative predictors of length of stay after primary total hip arthroplasty in a patient population reflecting current trends toward shorter hospitalization and using readily obtainable factors that do not require scoring systems. A retrospective review of 112 consecutive patients was performed. High preoperative pain level and patient expectation of discharge to extended care facilities (ECFs) were the only significant multivariable predictors of hospitalization extending beyond 2 days (P=0.001 and P<0.001 respectively). Patient expectation remained significant after adjusting for Medicare's 3-day requirement for discharge to ECFs (P<0.001). The study was adequately powered to analyze the variables in the multivariable logistic regression model, which had a concordance index of 0.857.

Patient expectation is the most important predictor of discharge destination after primary total joint arthroplasty.

The purpose of this study was to identify preoperative predictors of discharge destination after total joint arthroplasty. A retrospective study of three hundred and seventy-two consecutive patients who underwent primary total hip and knee arthroplasty was performed. The mean length of stay was 2.9 days and 29.0% of patients were discharged to extended care facilities. Age, caregiver support at home, and patient expectation of discharge destination were the only significant multivariable predictors regardless of the type of surgery (total knee versus total hip arthroplasty). Among those variables, patient expectation was the most important predictor (P < 0.001; OR 169.53). The study was adequately powered to analyze the variables in the multivariable logistic regression model, which had a high concordance index of 0.969.