Recent Publications by CFE Educators

Integrins are transmembrane receptors that promote neurite growth and guidance. To identify regulators of integrin-dependent neurite outgrowth, here we used two loss of function genetic screens in SH-SY5Y neuroblastoma cells. First, we screened a genome-wide retroviral library of genetic suppressor elements (GSEs). Among the many genes identified in the GSE screen, we isolated the hematopoetic transcriptional factor MTGR1 (myeloid translocation gene-related protein-1). Treatment of SH-SY5Y cells with MTGR1 siRNA enhanced neurite outgrowth and concurrently increased expression of GAP-43, a protein linked to neurite outgrowth. Second, we transduced SH-SY5Y with a genome-wide GFP-labeled lentiviral siRNA library, which expressed 40,000 independent siRNAs targeting 8500 human genes. From this screen we isolated GFI1 (growth factor independence-1), which, like MTGR1, is a member of the myeloid translocation gene on 8q22 (MTG8)/ETO protein complex of nuclear repressor proteins. These results reveal novel contributions of MTGR1 and GFI1 to the regulation of neurite outgrowth and identify novel repressors of integrin-dependent neurite outgrowth.

BACKGROUND

There are many indications for hepatic retransplantation.

AIM

To identify factors influencing retransplantation needs and outcomes.

PATIENTS AND METHODS

Retransplantation records from January 1993 to March 2005 were analysed. Patient and disease characteristics and survival outcomes for retransplantation were compared between various groups.

RESULTS

Totally, 286 primary and 42 hepatic retransplantations were performed. Retransplantation indications included primary sclerosing cholangitis (PSC), primary biliary cirrhosis, chronic hepatitis C (HCV), chronic active hepatitis (CAH), and alcohol-related disease. Mean follow-up post-retransplantation was 31 +/- 9 months. Actuarial patient survival at 3 months, 1 year, 3 years, 5 years, and at the end of study was 71.4, 69, 59.5, 54.7, and 50%, respectively. Early and late retransplantation had 1-year survival of 73 and 68.5%, respectively. Retransplantation need was significantly higher for PSC, HCV, and CAH.

CONCLUSIONS

Hepatic retransplantation remains a successful salvage option for transplant complications; however, its need is significantly influenced by the primary liver disease.

We report a case of hemimaxillofacial dysplasia followed in our clinic for 34 years. A recent literature review has brought to our attention that the subject may have a variant of hemimaxillofacial dysplasia, but with some unique features. The reconstruction procedures are detailed, and long-term follow-up findings are described.

OBJECTIVES

Involuntary weight loss affects 20% of community dwelling older adults. The underlying mechanism for this disorder is unknown. Objective is to determine if failure of older persons to regain weight is associated with elevated pro-inflammatory cytokine and leptin levels.

DESIGN

Prospective diet intervention study.

SETTING

University of Washington Medical Center from 2001-2005.

PARTICIPANTS

Twenty-one younger (18-35 years old) and nineteen older (>or= 70 years old) men and women.

INTERVENTION

Each subject was placed for two weeks on a weight-maintaining diet, followed in sequence by 2 weeks of 30% caloric restriction, then 4 weeks of ad libitum food intake.

MEASUREMENTS

Plasma leptin levels, fasting serum pro-inflammatory cytokine levels, and peripheral blood mononuclear cell cytokine levels were measured.

RESULTS

Leptin levels in the two cohorts decreased after caloric restriction and increased after ad-libitum food consumption resumed. Plasma TNF alpha levels were higher in older subjects compared to younger adults. However, there was no association between changes in TNF alpha levels and changes in AUC leptin.

CONCLUSION

Leptin levels in healthy older individuals responded appropriately in a compensatory manner to changes in body weight. These data do not support a cytokine dependent elevation in leptin levels as being responsible for the failure of older adults to regain weight.

CONTEXT

Guidelines call for documenting ischemia in patients with stable coronary artery disease prior to elective percutaneous coronary intervention (PCI).

OBJECTIVE

To determine the frequency and predictors of stress testing prior to elective PCI in a Medicare population.

DESIGN, SETTING, AND PATIENTS

Retrospective, observational cohort study using claims data from a 20% random sample of 2004 Medicare fee-for-service beneficiaries aged 65 years or older who had an elective PCI (N = 23 887).

MAIN OUTCOME MEASURES

Percentage of patients who underwent stress testing within 90 days prior to elective PCI; variation in stress testing prior to PCI across 306 hospital referral regions; patient, physician, and hospital characteristics that predicted the appropriate use of stress testing prior to elective PCI.

RESULTS

In the United States, 44.5% (n = 10 629) of patients underwent stress testing within the 90 days prior to elective PCI. There was wide regional variation among the hospital referral regions with stress test rates ranging from 22.1% to 70.6% (national mean, 44.5%; interquartile range, 39.0%-50.9%). Female sex (adjusted odds ratio [AOR], 0.91; 95% confidence interval [CI], 0.86-0.97), age of 85 years or older (AOR, 0.83; 95% CI, 0.72-0.95), a history of congestive heart failure (AOR, 0.85; 95% CI, 0.79-0.92), and prior cardiac catheterization (AOR, 0.45; 95% CI, 0.38-0.54) were associated with a decreased likelihood of prior stress testing. A history of chest pain (AOR, 1.28; 95% CI, 1.09-1.54) and black race (AOR, 1.26; 95% CI, 1.09-1.46) increased the likelihood of stress testing prior to PCI. Patients treated by physicians performing 150 or more PCIs per year were less likely to have stress testing prior to PCI (AOR, 0.84; 95% CI, 0.77-0.93). No hospital characteristics were associated with receipt of stress testing.

CONCLUSION

The majority of Medicare patients with stable coronary artery disease do not have documentation of ischemia by noninvasive testing prior to elective PCI.

Leptin is an adipocyte-derived hormone and cytokine that regulates energy balance through a wide range of functions, including several that are important to cardiovascular health. Increased circulating leptin, a marker of leptin resistance, is common in obesity and independently associated with insulin resistance and cardiovascular disease (CVD) in humans. The mechanisms of leptin resistance include genetic mutation, leptin self-regulation, limited tissue access, and cellular or circulating molecular regulation. Evidence suggests that central leptin resistance causes obesity and that obesity-induced leptin resistance injures numerous peripheral tissues, including liver, pancreas, platelets, vasculature, and myocardium. This metabolic- and inflammatory-mediated injury may result from either resistance to leptin's action in selective tissues, or excess leptin action from adiposity-associated hyperleptinemia. In this sense, the term "leptin resistance" encompasses a complex pathophysiological phenomenon. The leptin axis has functional interactions with elements of metabolism, such as insulin, and inflammation, including mediators of innate immunity, such as interleukin-6. Leptin is even purported to physically interact with C-reactive protein, resulting in leptin resistance, which is particularly intriguing, given C-reactive protein's well-studied relationship to cardiovascular disease. Given that plasma levels of leptin and inflammatory markers are correlated and also predict cardiovascular risk, it is conceivable that part of this risk may be mediated through leptin resistance-related insulin resistance, chronic inflammation, type II diabetes, hypertension, atherothrombosis, and myocardial injury. Leptin resistance and its interactions with metabolic and inflammatory factors, therefore, represent potential novel diagnostic and therapeutic targets in obesity-related cardiovascular disease.