Transcriptome Alteration in the Diabetic Heart by Rosiglitazone: Implications for Cardiovascular Mortality

BACKGROUND: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse. METHODS AND FINDINGS: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes. CONCLUSIONS: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment

Surgical complications in 275 HIV-infected liver and/or kidney transplantation recipients

BackgroundIn this report, we examine the surgical safety and complications (SC) among 125 liver (L) and 150 kidney (K) HIV+ transplantation (TX) recipients in a prospective nonrandomized U.S. multicenter trial.MethodsSubjects were required to have CD4+ T-cell counts >200/100 cells/mm3 (K/L) and undetectable plasma HIV-1 RNA (Viral Load [VL]) (K) or expected posttransplantation suppression (L). Impact of SCs (N ≥ 7) was evaluated by use of the proportional hazards models. Baseline morbidity predictors for SCs (N ≥ 7) were assessed in univariate proportional hazards models.ResultsAt median 2.7 (interquartile range 1.9-4.1) and 2.3 (1.0-3.7) years after TX, 3-month and 1-year graft survival were [K] 96% (95% CI 91%-98%) and 91% (95% CI 85%-94%) and [L] 91% (95% CI 85%-95%) and 77% (95% CI 69%-84%), respectively. A total of 14 K and 28 L graft losses occurred in the first year; 6 K and 11 L were in the first 3 months. A total of 26 (17%) K and 43 (34%) L experienced 29 and 62 SCs, respectively. In the liver multivariate model, re-exploration was marginally associated (hazard ratio [HR] 2.8; 95% CI 1.0-8.4; P = .06) with increased risk of graft loss, whereas a greater MELD score before transplantation (HR 1.07 per point increase; 95% CI: 1.01-1.14; P = .02), and detectable viral load before TX (HR 3.6; 95% CI 0.9-14.6; P = .07) was associated with an increased risk of wound infections/dehiscence.ConclusionThe rates and outcomes of surgical complications are similar to what has been observed in the non-HIV setting in carefully selected HIV-infected liver and kidney TX recipients

Design and validation of a medication assessment tool for cancer pain management

A clinical tool to examine prescribing in cancer pain management may provide a means to help establish acceptable standards of adherence to treatment guidelines. The study aim was to design and validate a Medication Assessment Tool for Cancer Pain Management (MAT-CP). The MAT-CP was designed from guideline criteria based on a previously developed method. The tool was validated by peer review before and during field-testing on a study sample of cancer patients experiencing pain. The final tool comprised 36 criteria covering six different aspects of cancer pain management: (1) pain assessment and information transfer, (2) start of strong opioid therapy; (3) current continuous analgesia; (4) current intermittent analgesia; (5) follow-up of therapy, and; (6) other care issues. The tool was tested on 109 cancer patients experiencing pain (57 males), mean (SD) age 60.8 (11.5) years. Guideline adherence overall was 61% (n = 1704 applicable criteria). The field-testing informed the modification of the MAT-CP to optimise its clarity and utility when applied to patients' clinical documentation. Good inter- and intra-rater reliability (Cohen's kappa κ = 0.86 and κ = 0.95, respectively) were demonstrated in the application. The preliminary application of the tool during field-testing has highlighted the following for further study: (a) Low adherence (75%) to standards of prescribing of continuous analgesia. A clinical tool to examine prescribing in cancer pain management has been designed. Face and content validity have been informed by field-testing. The tool requires further study among palliative care specialists as part of the validation required before it can be recommended for clinical use

Implicit sequence learning in dyslexia : a within-sequence comparison of first- and higher-order information

The present study examines implicit sequence learning in adult dyslexics with a focus on comparing sequence transitions with different statistical complexities. Learning of a 12-item deterministic sequence was assessed in 12 dyslexic and 12 non-dyslexic university students. Both groups showed equivalent standard reaction time decrements when the sequence was unexpectedly changed suggesting learning of the sequence took place. However, a novel analysis comparing transitions of differing complexity within the learning blocks indicated that dyslexic participants were impaired only for higher-order but not first-order sequence learning. No difference was found in the explicit awareness contribution between two groups and this was found not to correlate with reaction time performance. This result suggests that statistical complexity of the sequence may account for intact and impaired learning performance in dyslexia