Citations

Background: Coronary heart disease (CHD) poses a major health burden in the Gulf countries. Knowledge of novel genetic and proteomic markers of CHD will provide more precise estimates of risk while defining the pathways important in individual patients, revealing new targets for intervention, and ultimately enabling an individualized approach to care. We describe design of a biorepository with linkage to medical records to facilitate discovery of biomarkers for CHD. Methods: The goal of the Qatar Cardiovascular Biorepository (QCBio) is to archive plasma and DNA of 1000 Qatari patients with CHD and 1000 age, gender, and ethnicity-matched controls who have no history of CHD. Cases will include patients needing percutaneous intervention for symptomatic CHD or admitted with an acute coronary syndrome (myocardial infarction or unstable angina). Controls will be identified from the blood bank as adults who have no history of CHD. Relevant risk factors and comorbid conditions will be ascertained by electronic medical record (EMR)-based electronic phenotyping algorithms that included diagnosis and procedure codes, medication use and laboratory data. We will include processes to promote use of the biorepository by Qatari investigators by facilitating access to the repository for biomarker research, while maintaining the highest ethical standards with emphasis on patient confidentiality and stewardship of the biospecimens. Results: Thus far, we have a) created a patient questionnaire in Arabic to obtain information on demographic factors, cardiovascular disease risk factors, and family history; b) hired the technologist for sample processing, aliquoting, and DNA extraction; c) hired and trained the study coordinators who will recruit patients; d) developed consent forms in Arabic; e) put in place a Laboratory Information Management System (LIMS) for sample tracking; and f) set up a website for the study. We have obtained approval from the Hamad Medical Center IRB and recruitment is about to begin. We will present the progress made at various seminars and conferences of the Cardiology Department to increase awareness of QCBio.

We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC) tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival, whereas HE4-V0 levels positively correlate with age. HE4 variants exhibit tissue-specific expression, suggesting that each variant may exert distinct functions in normal and malignant cells. HE4 levels appear to correlate with EC patient survival in a variant-specific manner. When using HE4 as a biomarker for EC management, the effects of age should be considered.

Amyloid deposits that characteristically form in the pancreatic islets of patients with non-insulin-dependent diabetes mellitus (NIDDM) and in insulinomas are both derived from islet amyloid polypeptide (IAPP). Evidence from previous studies has suggested that deposition of IAPP-derived amyloid is related to inherent amyloidogenic sequences present within normal human IAPP, together with an increased production and local concentration of IAPP. However, whether the aggregation of IAPP to form amyloid fibrils is primarily an intra- or extracellular event is not clear. To address this question, we studied 20 human insulinomas by light and electron microscopy. By light microscopy, amyloid deposits were demonstrated in 13 of 20 (65%) human insulinomas. Furthermore, evaluation of Congo red-stained tumor sections showed small, globular or irregular, congophilic amyloid deposits within the cytoplasm of many tumor cells in 10 of 13 (77%) amyloid-containing insulinomas. Dense, punctate areas of IAPP immunoreactivity within tumor cells corresponded with the congophilic intracellular deposits. Ubiquitin immunoreactivity also was observed as punctate intracellular labeling and within large extracellular amyloid deposits. Among the 10 insulinomas available for electron microscopic evaluation, pathological IAPP-immunoreactive (immunogold) deposits were found in 3 of 5 insulinomas in which amyloid was demonstrated by light microscopy and in none of 5 tumors found negative for amyloid by light microscopy. Morphology of IAPP-immunoreactive deposits varied from those with the classical distinct 7- to 10-nm diameter nonbranching fibrils to those with distinct but faint fibrillarity to those without discernable fibrils. In each of the 3 tumors with ultrastructurally demonstrable amyloid deposits, intracellular aggregates of IAPP-immunoreactive amyloid fibrils were observed either free in the cytoplasmic matrix or in membrane-bound structures. Intracellular IAPP-immunoreactive deposits were up to 10 urn in the greatest dimension. Free intracellular aggregates of amyloid fibrils sometimes contained degenerating secretory vesicles and fragments of membranous organelles. These observations suggest that IAPP-derived amyloid deposits are initially formed intracellularly and are subsequently released to the extracellular space by exocytosis of the membrane-bound structures and/or after necrosis of the tumor cells. Our observations raise the possibility that IAPP-derived islet amyloid deposits (characteristically present in NIODM patients) also may be initially formed within the cytoplasm of β-cells, thus leading to β-cell necrosis and a reduction of β-cell mass as seen in NIDDM.

The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD+/+) and manganese SOD heterozygous haploinsufficient (MnSOD+/−) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16ink4a, a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD+/+ and MnSOD+/− mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD+/+ and MnSOD+/− mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD+/+ mice but significantly impaired endothelial function in MnSOD+/− mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.

Objective To test a multidisciplinary approach to reduce heart failure (HF) readmissions that tailors the intensity of care transition intervention to the risk of the patient using a suite of electronic medical record (EMR)-enabled programmes. Methods A prospective controlled before and after study of adult inpatients admitted with HF and two concurrent control conditions (acute myocardial infarction (AMI) and pneumonia (PNA)) was performed between 1 December 2008 and 1 December 2010 at a large urban public teaching hospital. An EMR-based software platform stratified all patients admitted with HF on a daily basis by their 30-day readmission risk using a published electronic predictive model. Patients at highest risk received an intensive set of evidence-based interventions designed to reduce readmission using existing resources. The main outcome measure was readmission for any cause and to any hospital within 30 days of discharge. Results There were 834 HF admissions in the pre-intervention period and 913 in the post-intervention period. The unadjusted readmission rate declined from 26.2% in the pre-intervention period to 21.2% in the post-intervention period (p=0.01), a decline that persisted in adjusted analyses (adjusted OR (AOR)=0.73; 95% CI 0.58 to 0.93, p=0.01). In contrast, there was no significant change in the unadjusted and adjusted readmission rates for PNA and AMI over the same period. There were 45 fewer readmissions with 913 patients enrolled and 228 patients receiving intervention, resulting in a number needed to treat (NNT) ratio of 20. Conclusions An EMR-enabled strategy that targeted scarce care transition resources to high-risk HF patients significantly reduced the risk-adjusted odds of readmission.

HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The effects of HE4 overexpression on cell growth and function were measured with the use of cell proliferation assay, matrigel invasion, and soft agar gel colony formation assays. HE4-induced cancer cell proliferation in vivo was examined in a mouse xenograft model. HE4 overexpression significantly enhanced EC cell proliferation, matrigel invasion, and colony formation in soft agar. Moreover, HE4 overexpression promoted tumor growth in the mouse xenograft model. HE4 overexpression enhanced several malignant phenotypes in cell culture and in a mouse model. These results are consistent with our previous observation that high levels of serum HE4 closely correlate with the stage, myometrial invasion and tumor size in patients with EC. This study provides evidence that HE4 overexpression directly impacts tumor progression in endometrial cancer.

AimTreatment of hepatitis C genotype 4 (HCV‐G4) with pegylated interferon (PEG IFN) has not been adequately studied and is considered to be challenging. The aim of this meta‐analysis is to systematically review and evaluate the effectiveness of 48 weeks of combined PEG IFN plus ribavirin (RBV) compared to standard interferon (IFN) plus RBV. The outcome of interest is sustained virological response (SVR).MethodsWe searched for eligible randomized controlled trials (RCT) through May 2012. Random effects meta‐analysis was used to pool the risk ratio (RR) of achieving SVR across trials.ResultsFive RCT enrolling 386 patients were included. The PEG IFN/RBV group had increased likelihood of achieving SVR (RR = 1.51, 95% confidence interval [CI] = 1.08–2.10). SVR was significantly higher in PEG IFN‐α‐2a compared to the ‐α‐2b group (P = 0.02). There was no statistically significant effect of ribavirin dosage on SVR (P = 0.55). The quality of evidence was moderate overall and limited by heterogeneity.ConclusionIn treatment‐naive patients with HCV‐G4, treatment with PEG IFN plus RBV achieves higher SVR rate than treatment with IFN plus RBV.

AbstractAimsPioglitazone, a thiazolidinedione, was approved for treatment of Type 2 diabetes. However, several observational studies suggest an association of pioglitazone with an increased risk of bladder cancer in patients with diabetes. Therefore, we sought to perform a systematic review and meta‐analysis to evaluate the magnitude of this association and the quality of the supporting evidence.MethodsElectronic databases were queried to identify controlled studies of pioglitazone that measured the risk of bladder cancer.ResultsSix studies involving 215 142 patients using pioglitazone were included, with a median period of follow‐up of 44 months. The hazard of developing bladder cancer was significantly higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09–1.39; I2 = 0%) compared with control groups. The risk of bias was moderate across the six studies. Considering an incidence rate of 20.8 per 100 000 person years, the number needed to harm was five additional cases of bladder cancer per 100 000 person years.ConclusionsPatients treated with pioglitazone have a slight increased risk of bladder cancer compared to general population. Patient involvement and weighing treatment benefits versus risks should be discussed with patient toward shared decision. Patients with type 2 diabetes with risk factors, such as family history, smoking, or exposure to certain forms of chemotherapy may need to consider other anti‐hyperglycemic agents. Also, pioglitazone should be discontinued in type 2 diabetes patients with newly diagnosed bladder cancer.