Mohammed Al-Omran

Enteral versus parenteral nutrition for acute pancreatitis

BACKGROUNDnAcute pancreatitis creates a catabolic stress state promoting a systemic inflammatory response and nutritional deterioration. Adequate supply of nutrients plays an important role in recovery. Total parenteral nutrition (TPN) has been standard practice for providing exogenous nutrients to patients with severe acute pancreatitis. However, recent data suggest that enteral nutrition (EN) is not only feasible, but safer and more effective.Therefore, we sought to update our systematic review to re-evaluate the level of evidence.nnnOBJECTIVESnTo compare the effect of TPN versus EN on mortality, morbidity and length of hospital stay in patients with acute pancreatitis.nnnSEARCH STRATEGYnTrials were identified by computerized searches of The Cochrane Controlled Trials Register, MEDLINE, and EMBASE. Additional studies were identified by searching Scisearch, bibliographies of review articles and identified trials. The search was undertaken in August 2000 and updated in September 2002, October 2003, November 2004 and November 2008. No language restrictions were applied.nnnSELECTION CRITERIAnRandomized clinical trials comparing TPN to EN in patients with acute pancreatitis.nnnDATA COLLECTION AND ANALYSISnTwo reviewers independently abstracted data and assessed trial quality. A standardized form was used to extract relevant data.nnnMAIN RESULTSnEight trials with a total of 348 participants were included. Comparing EN to TPN for acute pancreatitis, the relative risk (RR) for death was 0.50 (95% CI 0.28 to 0.91), for multiple organ failure (MOF) was 0.55 (95% CI 0.37 to 0.81), for systemic infection was 0.39 (95% CI 0.23 to 0.65), for operative interventions was 0.44 (95% CI 0.29 to 0.67), for local septic complications was 0.74 (95% CI 0.40 to 1.35), and for other local complications was 0.70 (95% CI 0.43 to 1.13). Mean length of hospital stay was reduced by 2.37 days in EN vs TPN groups (95% CI -7.18 to 2.44). Furthermore, a subgroup analysis for EN vs TPN in patients with severe acute pancreatitis showed a RR for death of 0.18 (95% CI 0.06 to 0.58) and a RR for MOF of 0.46 (95% CI 0.16 to 1.29).nnnAUTHORS CONCLUSIONSnIn patients with acute pancreatitis, enteral nutrition significantly reduced mortality, multiple organ failure, systemic infections, and the need for operative interventions compared to those who received TPN. In addition, there was a trend towards a reduction in length of hospital stay. These data suggest that EN should be considered the standard of care for patients with acute pancreatitis requiring nutritional support.

Effects of Nitric Oxide on Cell Proliferation: Novel Insights

Nitric oxide (NO) has been suggested to be a pathophysiological modulator of cell proliferation, cell cycle arrest, and apoptosis. In this context, NO can exert opposite effects under diverse conditions. Indeed, several studies have indicated that low relative concentrations of NO seem to favor cell proliferation and antiapoptotic responses and higher levels of NO favor pathways inducing cell cycle arrest, mitochondria respiration, senescence, or apoptosis. Here we report the effects of NO on both promotion and inhibition of cell proliferation, in particular in regard to cardiovascular disease, diabetes, and stem cells. Moreover, we focus on molecular mechanisms of action involved in the control of cell cycle progression, which include both cyclic guanosine monophosphate-dependent and -independent pathways. This growing field may lead to broad and novel targeted therapies against cardiovascular diseases, especially concomitant type 2 diabetes, as well as novel bioimaging NO-based diagnostic tools.

CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy

Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1α at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via down-regulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression.

BRCA1 is an essential regulator of heart function and survival following myocardial infarction

The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure.

Endothelial progenitor cells as therapeutic agents in the microcirculation: An update

This review evaluates novel beneficial effects of circulating endothelial progenitor cells (EPCs) as shown by several preclinical studies and clinical trials carried out to test the safety and feasibility of using EPCs. There are 31 registered clinical trials (and many others still ongoing) and 19 published studies. EPCs originate in the bone marrow and migrate into the bloodstream where they undergo a differentiation program leading to major changes in their antigenic characteristics. EPCs lose typical progenitor markers and acquire endothelial markers, and two important receptors, (VEGFR and CXCR-4), which recruit circulating EPCs to damaged or ischemic microcirculatory (homing to damaged tissues) beds. Overall, therapeutic angiogenesis will likely change the face of regenerative medicine in the next decade with many patients worldwide predicted to benefit from these treatments.

Primary Prevention of Atherosclerosis A Clinical Challenge for the Reversal of Epigenetic Mechanisms

Innovative advances in understanding the pathogenesis of atherosclerosis have been achieved over the past 25 years. Although elevated levels of serum low-density lipoprotein cholesterol (LDL-C) are the major cause of onset of the disease, as established by a large number of superb epidemiological, clinical, and experimental studies, important novel factors have entered the arena of the atherogenic process. Besides the historical oxidative hypothesis that states that oxidized LDL, by escaping the homeostatic mechanism, strongly accelerates plaque formation, more recent evidence has given credit to vascular inflammation and apoptosis as crucial players in the progression of atherosclerosis.1–3 The disease has also been linked to the subintimal infiltration of immune cells and endothelial dysfunction induced by cardiovascular risk factors. Currently, endothelial dysfunction is considered one of the first stages of vascular damage and an early event in atherogenesis.1–3 Etiologic and pathogenetic factors, of both genetic and environmental origin, act together to promote local and systemic effects that lead to the onset, progression, and final outcome of the atherosclerotic disease. The clinical sequelae of atherosclerosis, myocardial infarction, stroke, and peripheral arterial disease depend on the affected vascular district, which in turn depends on complex gene-environment interplay.nnDespite the sudden occurrence of clinical symptoms, however, the evolution of atherosclerosis is very slow, which provides an opportunity for early diagnosis. In fact, a breakthrough in the field has been to recognize that although atherosclerosis generates severe diseases that most frequently affect middle-aged to old people, atherogenesis begins very early in life, even at the fetal stage.4,5 Primary prevention of any disease is more effective if started sooner. Therefore, it is of paramount importance to identify high-risk individuals and to initiate primary prevention in a timely manner, especially for atherosclerosis, which can begin its slow but relentless …

BRCA1 is a novel target to improve endothelial dysfunction and retard atherosclerosis

OBJECTIVEnBRCA1, a tumor suppressor gene implicated in breast and ovarian cancers, exerts multiple effects on DNA repair and affords resistance against cellular stress responses. We hypothesized that BRCA1 limits endothelial cell apoptosis and dysfunction, and via this mechanism attenuates atherosclerosis.nnnMETHODSnLoss and gain of function were achieved in cultured endothelial cells by silencing and overexpressing BRCA1, respectively. Inxa0vivo loss and gain of function were performed by generating endothelial cell-specific knockout (EC-BRCA1(-/-)) mice and administering a BRCA1 adenovirus. Well-established cell and animal models of angiogenesis and atherosclerosis were used.nnnRESULTSnBRCA1 is basally expressed in endothelial cells. BRCA1 overexpression protected and BRCA1 silencing exaggerated inflammation- and doxorubicin-induced endothelial cell apoptosis. Key indices of endothelial function were modulated in a manner consistent with an effect of BRCA1 to limit endothelial cell apoptosis and improve endothelial function. BRCA1 overexpression strongly attenuated the production of reactive oxygen species and upregulated endothelial nitric oxide synthase, phosphorylated endothelial nitric oxide synthase, phosphorylated Akt, and vascular endothelial growth factor-a expression. BRCA1 overexpression also improved capillary density and promoted blood flow restoration in mice subjected to hind-limb ischemia. BRCA1-overexpressing ApoE(-/-) mice fed a Western diet developed significantly less aortic plaque lesions, exhibited reduced macrophage infiltration, and generated less reactive oxygen species. Lung sections and aortic segments from EC-BRCA1(-/-) mice demonstrated greater inflammation-associated apoptosis and impaired endothelial function, respectively. BRCA1 expression was attenuated in the plaque region of human atherosclerotic carotid artery samples compared with the adjacent plaque-free area.nnnCONCLUSIONSnThese data collectively highlight a previously unrecognized role of BRCA1 as a gatekeeper of inflammation-induced endothelial cell function and a target to limit atherosclerosis. Translational studies evaluating endothelial function and atherosclerosis in individuals with BRCA1 mutations are suggested.

Suboptimal use of statin therapy in elderly patients with atherosclerosis: A population-based study

BACKGROUNDnCurrent evidence suggests that statin use plays an important role in improving adverse cardiovascular outcomes in patients with atherosclerosis. However, limited population-based data are available on use of statin therapy in these patients in Canada. We sought to study trends in statin use to treat these patients in Ontario during a 10-year period.nnnMETHODSnWe conducted a population-based cross-sectional time series analysis between April 1, 1995, and March 31, 2004, using health care data from Ontario, Canada.nnnRESULTSnDuring the study period, 343,154 elderly patients with atherosclerosis were identified. Of these, 235,615 (68.7%) had coronary artery diseases (CAD), 115,012 (33.5%) had cerebrovascular disease (CVD), and 23,886 (7.0%) had peripheral arterial disease (PAD). About 46% were women, and mean patient age was 77.1 (SD, 7.5) years. During the study period, the percentage of patients treated with a statin in each group increased considerably, from 9.8% to 55.3% in all atherosclerotic patients (P < .01), from 11.8% to 61.2% in CAD patients (P < .01), from 5.3% to 41.2% in CVD patients (P < .01), and from 6.8% to 43.3% in PAD patients (P < .01). During the entire study period, the percentage of statin users was lowest among PAD and CVD patients, followed by patients with both a history of PAD and CVD.nnnCONCLUSIONnThe use of statin therapy in elderly patients with symptomatic atherosclerosis has increased substantially during the past decade, but many patients remain untreated. The suboptimal use is greatest among patients with PAD or CVD, or both, and lowest in patients with CAD. Given the heightened risk of cardiovascular adverse outcomes in patients with atherosclerosis, these data have important and immediate implications.

Potential benefits of cell therapy in coronary heart disease

Cardiovascular disease is the leading cause of morbidity and mortality in the world. In recent years, there has been an increasing interest both in basic and clinical research regarding the field of cell therapy for coronary heart disease (CHD). Several preclinical models of CHD have suggested that regenerative properties of stem and progenitor cells might help restoring myocardial functions in the event of cardiac diseases. Here, we summarize different types of stem/progenitor cells that have been tested in experimental and clinical settings of cardiac regeneration, from embryonic stem cells to induced pluripotent stem cells. Then, we provide a comprehensive description of the most common cell delivery strategies with their major pros and cons and underline the potential of tissue engineering and injectable matrices to address the crucial issue of restoring the three-dimensional structure of the injured myocardial region. Due to the encouraging results from preclinical models, the number of clinical trials with cell therapy is continuously increasing and includes patients with CHD and congestive heart failure. Most of the already published trials have demonstrated safety and feasibility of cell therapies in these clinical conditions. Several studies have also suggested that cell therapy results in improved clinical outcomes. Numerous ongoing clinical trials utilizing this therapy for CHD will address fundamental issues concerning cell source and population utilized, as well as the use of imaging techniques to assess cell homing and survival, all factors that affect the efficacy of different cell therapy strategies.

Osteosarcoma cells induce endothelial cell proliferation during neo‐angiogenesis

Understanding the mechanisms inducing endothelial cell (EC) proliferation following tumor microenvironment stimuli may be important for the development of antiangiogenic therapies. Here, we show that cyclin‐dependent kinase 2 and 5 (Cdk2, Cdk5) are important mediators of neoangiogenesis in in vitro and in vivo systems. Furthermore, we demonstrate that a specific Yin Yang 1 (YY1) protein‐dependent signal from osteosarcoma (SaOS) cells determines proliferation of human aortic endothelial cells (HAECs). Following tumor cell stimuli, HAECs overexpress Cdk2 and Cdk5, display increased Cdk2 activity, undergo enhanced proliferation, and form capillary‐like structures. Moreover, Roscovitine, an inhibitor of Cdks, blunted overexpression of Cdk2 and Cdk5 and Cdk2 activity induced by the YY1‐dependent signal secreted by SaOS cells. Furthermore, Roscovitine decreased HAEC proliferation and angiogenesis (the latter by 70% in in vitro and 50% in in vivo systems; Pu2009<u20090.01 vs. control). Finally, the finding that Roscovitine triggers apoptosis in SaOS cells as well as in HAECs by activating caspase‐3/7 indicates multiple mechanisms for the potential antitumoral effect of Roscovitine. Present work suggests that Cdk2 and Cdk5 might be pharmacologically accessible targets for both antiangiogenic and antitumor therapy. J. Cell. Physiol. 228: 846–852, 2013.