stephen peterson

Objective: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardiometabolic dysfunction. NOV is manufactured and secreted from adipose tissue, with blood levels highly correlated with BMI. NOV levels are increased in obesity and a myriad of inflammatory diseases. Elevated NOV levels cause oxidative stress by increasing free radicals, decreasing antioxidants, and decreasing heme oxygenase (HO-1) levels, resulting in decreased vascular function. Silencing NOV in NOV knockout mice improved insulin sensitivity. We wanted to study how suppressing NOV expression in an obese animal model affected pathways and processes related to obesity, inflammation, and cardiometabolic function. This is the first study to investigate the interaction of adipose tissue-specific NOV/CCN3 and cardiometabolic function. Methods: We constructed a lentivirus containing the adiponectin-promoter-driven shNOV to examine the effect of NOV inhibition (shNOV) in adipose tissue on the h...

IntroductionThe accuracy of detecting myocardial infarction (MI) has greatly improved with the advent of more sensitive assays, and this has led to etiologic subtyping. Distinguishing between type 1 and type 2 non-ST-segment elevation myocardial infarction (NSTEMI) early in the clinical course allows for the most appropriate advanced diagnostic procedures and most efficacious treatments. The purpose of this study was to investigate the predictive effect of demographic and clinical variables on predicting NSTEMI subtypes in patients presenting with ischemic symptoms.Material and methodsWe performed a single institution retrospective cohort study of patients who presented to the emergency department (ED) with ischemic signs and symptoms consistent with non-ST-segment myocardial infarction, for whom results of coronary angiography were available. We analyzed demographic, laboratory, echocardiography and angiography data to determine predictors of NSTEMI sub-types.ResultsFive hundred an...

Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1α and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male mice: (1) mice fed a normal chow diet; (2) mice fed a high-fat diet (H.F.D.) for 28 weeks, and (3) mice fed a high-fat diet (H.F.D.) for 28 weeks, treated with adipose-specific overexpression of PGC-1α (transgenic-adipocyte-PGC-1α) at week 20, and continued on H.F.D. for weeks 20–28. R.N.A. arrays examined 88 genes involved in adipocyte proliferation and maturation. Blood pressure, tissue fibrosis, fasting glucose, and oxygen consumption were measured, as well as liver steatosis, and the expression levels of metabolic and mitochondrial markers. Obese mice exhibited a marked reduction of PGC1α and developed adipocyte hypertrophy, fibrosis, hepatic steatosis, and decreased mitochondrial r...

Coronaviruses are very large RNA viruses that originate in animal reservoirs and include severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS) and other inconsequential coronaviruses from human reservoirs like the common cold. SARS-CoV-2, the virus that causes COVID-19 and is believed to originate from bat, quickly spread into a global pandemic. This RNA virus has a special affinity for porphyrins. It invades the cell at the angiotensin converting enzyme-2 (ACE-2) receptor and binds to hemoproteins, resulting in a severe systemic inflammatory response, particularly in high ACE-2 organs like the lungs, heart, and kidney, resulting in systemic disease. The inflammatory response manifested by increased cytokine levels and reactive oxygen species results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. This has been seen in other viral illness like human immunodeficiency virus (HIV), Ebola, and SARS/MERS. There are...

In this review, we will evaluate how high-density lipoprotein (HDL) and the reverse cholesterol transport (RCT) pathway are critical for proper cardiovascular–renal physiology. We will begin by reviewing the basic concepts of HDL cholesterol synthesis and pathway regulation, followed by cardiorenal syndrome (CRS) pathophysiology. After explaining how the HDL and RCT pathways become dysfunctional through oxidative processes, we will elaborate on the potential role of HDL dysfunction in CRS. We will then present findings on how HDL function and the inducible antioxidant gene heme oxygenase-1 (HO-1) are interconnected and how induction of HO-1 is protective against HDL dysfunction and important for the proper functioning of the cardiovascular–renal system. This will substantiate the proposal of HO-1 as a novel therapeutic target to prevent HDL dysfunction and, consequently, cardiovascular disease, renal dysfunction, and the onset of CRS.

Objective: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice. Method: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promot...

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1–PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. Methods: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5–33 mM). We examined the...

Hepcidin, a phase II reactant secreted by hepatocytes, regulates cellular iron levels by increasing internalization of ferroportin-a transmembrane protein facilitating egress of cellular iron. Chronic low-grade inflammatory states, such as obesity, have been shown to increase oxidative stress and enhance hepcidin secretion from hepatocytes and macrophages. Heme-heme oxygenase (HO) is a stress response system which reduces oxidative stress. We investigated the effects of HO-1 induction on hepatic hepcidin levels and on iron homeostasis in hepatic tissues from lean and obese mice. Obese mice exhibited hyperglycemia (p<0.05); increased levels of proinflammatory cytokines (MCP-1, IL-6,p<0.05); oxidative stress (p<0.05); and increased hepatic hepcidin levels (p<0.05). Enhancement of hepcidin was reflected in the reduced expression of ferroportin in obese mice (p<0.05). However, this effect is accompanied by a significant decline in ferritin expression. Additionally, there ...

Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. Method: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. Results: The PSO grou...

To investigate the etiologies of syncope and predictors of all-cause mortality, rehospitalization, and cardiac syncope in consecutive elderly patients presenting with syncope to our emergency department. Participants were 352 consecutive patients aged 65 years or older with syncope admitted to hospital from the emergency department. Observational retrospective study. Review of medical records for history, physical examination, medications, and tests to determine causes of syncope. Cox stepwise logistic regression analysis was performed to identify significant independent prognostic factors for rehospitalization with syncope, all-cause mortality, and cardiac syncope. Of 352 patients, mean age 78 years, the etiology of syncope was diagnosed in 243 patients (69%). Vasovagal syncope was diagnosed in 12%, volume depletion in 14%, orthostatic hypotension in 5%, cardiac syncope in 29%, carotid sinus hypersensitivity in 2%, and drug overdose/others in 7% of patients. During a mean follow-up of 24 months, 10 patients (3%) were readmitted to the hospital for syncope and 39 (11%) died. Stepwise logistic regression analysis identified history of congestive heart failure (OR 5.18; 95% CI 1.23-21.84, P = .0257) and acute coronary syndrome (OR 5.95; 95% CI 1.11-31.79, P = .037) as independent risk factors for rehospitalization. Significant independent prognostic factors for mortality were diabetes mellitus (OR 2.08; 95% CI 1.09-3.99, P = .0263), history of smoking (OR 2.23; 95% CI 1.10-4.49, P = .0255), and use of statins (OR 0.37; 95% CI 0.19-0.72, P = .0036). Independent risk factors for predicting a cardiac cause of syncope were an abnormal electrocardiogram (OR 2.58; 95% CI 1.46-4.57, P = .0012) and reduced ejection fraction (OR 2.92; 95% CI 1.70-5.02, P < .001). The San Francisco Syncope Rule and Osservatorio Epidemiologico sulla Sincope nel Lazio scores did not predict mortality or rehospitalization in our study population. Significant independent risk factors for rehospitalization for syncope were congestive heart failure and acute coronary syndrome. Significant independent risk factors for mortality were diabetes mellitus, history of smoking, and use of statins (inverse association).

Frailty has become more frequently recognized as an indicator of predisability. It has been shown to have an association with cardiovascular disease (CVD), just as CVD has an association with frailty, and is a predictor of hospitalization and mortality. The ability to identify this population provides a measure to more accurately assess risk and prognosis which can help the early detection of disease and dictate intervention. This has become even more critical over time with the advent of various therapeutic interventions that are geared toward patients who are poor candidates for aggressive surgical measures, such as transcatheter aortic valve replacement. The American Heart Association has called for a better understanding of frailty as it relates to CVD in the elderly.

Obstructive sleep apnea (OSA) has a strong association with cardiovascular and metabolic abnormalities, although the mechanism driving this association is not well established. NOV/CCN3, a multifunctional extracellular matrix protein, may play a mechanistic and/or prognostic role in these associations. We hypothesized that patients with OSA, which primarily affects obese individuals, will have increased levels of NOV, and that NOV can serve as a biomarker in patients to predict OSA as well as metabolic and cardiac risk. Ten morbidly obese and 10 healthy lean subjects underwent overnight polysomnography (PSG) and clinical evaluation. Blood samples were analyzed for NOV levels, adiponectin and IL-6. OSA was found in nine obese subjects and three lean subjects. NOV levels were significantly higher in the OSA vs. no OSA group (2.1 ± 0.9 vs. 1.3 ± 0.8, p < 0.03). NOV levels were significantly higher in the obese vs. lean group (2.2 ± 0.3 vs. 1.4 ± 0.2-fold change, p < 0.03). Among ...

Educational milestones are now used to assess the developmental progress of all U.S. graduate medical residents during training. Twice annually, each program's Clinical Competency Committee (CCC) makes these determinations and reports its findings to the Accreditation Council for Graduate Medical Education (ACGME). The ideal way to conduct the CCC is not known. After finding that deliberations reliant upon the new milestones were time intensive, our internal medicine residency program tested an approach designed to produce rapid but accurate assessments. For this study, we modified our usual CCC process to include pre-meeting faculty ratings of resident milestones progress with in-meeting reconciliation of their ratings. Data were considered largely via standard report and presented in a pre-arranged pattern. Participants were surveyed regarding their perceptions of data management strategies and use of milestones. Reliability of competence assessments was estimated by comparing...

Arachidonic acid (AA) is metabolized in mammals by enzymes of the CYP4A and 4F families to 20-hydroxyeicosatetraeonic acid (20-HETE) which plays an important role in the regulation of renal function, vascular tone and arterial pressure. In the vasculature, 20-HETE is a potent vasoconstrictor, the up-regulation of which contributes to inflammation, oxidative stress, endothelial dysfunction and an increase in peripheral vascular resistance in models of obesity, diabetes, ischemia/reperfusion, and vascular oxidative stress. Recent studies have established a role for 20-HETE in normal and pathological angiogenic conditions. We discuss in this review the synthesis of 20-HETE and how it and various autacoids, especially the renin-angiotensin system, interact to promote hypertension, vasoconstriction, and vascular dysfunction. In addition, we examine the molecular mechanisms through which 20-HETE induces these actions and the clinical implication of inhibiting 20-HETE production and activity.

Apolipoprotein A1 mimetic peptide (D-4F), synthesized from D-amino acid, enhances the ability of high-density lipoprotein to protect low-density lipoprotein (LDL) against oxidation in atherosclerotic disease. Using a rat model of type I diabetes, we investigated whether chronic use of D-4F would lead to up-regulation of heme oxygenase (HO)-1, endothelial cell marker (CD31(+)), and thrombomodulin (TM) expression and increase the number of endothelial progenitor cells (EPCs). Sprague-Dawley rats were rendered diabetic with streptozotocin (STZ) and either D-4F or vehicle was administered, by i.p. injection, daily for 6 weeks (100 microg/100 g b.wt.). HO activity was measured in liver, kidney, heart, and aorta. After 6 weeks of D-4F treatment, HO activity significantly increased in the heart and aorta by 29 and 31% (p < 0.05 and p < 0.49), respectively. Long-term D-4F treatment also caused a significant increase in TM and CD31(+) expression. D-4F administration increased antioxidant capacity, as reflected by the decrease in oxidized protein and oxidized LDL, and enhanced EPC function and/or repair, as evidenced by the increase in EPC endothelial nitric-oxide synthase (eNOS) and prevention of vascular TM and CD31(+) loss. In conclusion, HO-1 and eNOS are relevant targets for D-4F and may contribute to the D-4F-mediated increase in TM and CD31(+), the antioxidant and anti-inflammatory properties, and confers robust vascular protection in this animal model of type 1 diabetes.

ABSTRACT Objective: Obese leptin deficient (ob/ob) mice are a model of adiposity that displays increased levels of fat, glucose and liver lipids. Our hypothesis is that HO-1 overexpression ameliorates fatty liver development. Design and Methods: Obese mice were administered cobalt protoporphyrin (CoPP) and stannic mesoporphyrin (SnMP) for 6 weeks. Heme, HO-1, HO activity, PGC1α, FGF21, glycogen content and lipogenesis were assessed. Results: CoPP administration increased hepatic HO-1 protein levels and HO activity, decreased hepatic heme, body weight gain, glucose levels and resulted in decreased steatosis. Increased levels of HO-1 produced a decrease in lipid droplet size, FAS levels involving recruitment of FGF21, PPARα and Glut 1. These beneficial effects were reversed by inhibition of HO activity.

Heme oxygenase (HO) is important in attenuating the overall production of reactive oxygen species through its ability to degrade heme and to produce carbon monoxide, biliverdin/bilirubin, and release of free iron. Excess free heme catalyzes the formation of reactive oxygen species, which leads to endothelial cell (EC) dysfunction as seen in numerous pathologic vascular conditions including systemic hypertension and diabetes, as well as in ischemia/reperfusion injury.The up-regulation of HO-1 can be achieved through the use of pharmaceutical agents such as metalloporphyrins and statins. In addition, atrial natriuretic peptide and nitric oxide donors are important modulators of the heme-HO system, either through induction of HO-1 or the increased biologic activity of its products. Gene therapy and gene transfer, including site- and organ-specific targeted gene transfer have become powerful tools for studying the potential role of the 2 isoforms of HO, HO-1/HO-2, in the treatment of cardiovascular disease, as well as diabetes. HO-1 induction by pharmacological agents or the in vitro gene transfer of human HO-1 into ECs increases cell cycle progression and attenuates angiotensin II, tumor necrosis factor-alpha, and heme-mediated DNA damage; administration in vivo corrects blood pressure elevation after angiotensin II exposure. Delivery of human HO-1 to hyperglycemic rats significantly lowers superoxide levels and prevents EC damage and sloughing of vascular EC into the circulation. In addition, administration of human HO-1 to rats in advance of ischemia/reperfusion injury considerably reduces tissue damage.The ability to up-regulate HO-1 either through pharmacological means or through the use of gene therapy may offer therapeutic strategies for the prevention of cardiovascular disease in the future. This review discusses the implications of HO-1 delivery during the early stages of cardiovascular system injury or in early vascular pathology, and suggests that pharmacological agents that regulate HO activity or HO-1 gene delivery itself may become powerful tools for preventing the onset or progression of various cardiovascular diseases.

Background: Early mechanical revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock is associated with improved survival. The current guidelines also recommend (Class IIa) the use of intra-aortic balloon pump (IABP) in patients with cardiogenic shock. However, the evidence supporting this recommendation is controversial. Objectives: To examine the trends (2001-2010) in mechanical revascularization, IABP use and in-hospital mortality in patients with cardiogenic shock complicating AMI and to determine if IABP use is associated with improved in-hospital survival among these patients. Methods: We conducted a retrospective trend analysis of the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample (NIS) database from 2001-2010. All patients ≥ 40 years of age with AMI and cardiogenic shock were identified using ICD-9-CM diagnosis codes. Tr...

Amyloidosis is a clinical disorder caused by the extracellular deposition of misfolded, insoluble aggregated protein with a characteristic ss pleated sheet configuration that produces apple-green birefringence under polarized light when stained with Congo red dye. The spectrum of organ involvement can include the kidneys, heart, blood vessels, central and peripheral nervous systems, liver, intestines, lungs, eyes, skin, and bones. Cardiovascular amyloidosis can be primary, a part of systemic amyloidosis, or the result of chronic systemic disease elsewhere in the body. The most common presentations are congestive heart failure because of restrictive cardiomyopathy and conduction abnormalities. Recent developments in imaging techniques and extracardiac tissue sampling have minimized the need for invasive endomyocardial biopsy for amyloidosis. Cardiac amyloidosis management will vary depending on the subtype but consists of supportive treatment of cardiac related symptoms and reducing ...

Heme oxygenase (HO) is important in attenuating the overall production of reactive oxygen species through its ability to degrade heme and to produce carbon monoxide, biliverdin/bilirubin, and release of free iron. Excess free heme catalyzes the formation of reactive oxygen species, which leads to endothelial cell (EC) dysfunction as seen in numerous pathologic vascular conditions including systemic hypertension and diabetes, as well as in ischemia/reperfusion injury.The up-regulation of HO-1 can be achieved through the use of pharmaceutical agents such as metalloporphyrins and statins. In addition, atrial natriuretic peptide and nitric oxide donors are important modulators of the heme-HO system, either through induction of HO-1 or the increased biologic activity of its products. Gene therapy and gene transfer, including site- and organ-specific targeted gene transfer have become powerful tools for studying the potential role of the 2 isoforms of HO, HO-1/HO-2, in the treatment of ca...

Long-term weight reduction remains the ultimate objective and challenge of obesity management. Few long-term dietary or pharmacointervention studies have been conducted and there is a critical need for long-range treatment strategies that are effective, safe, and acceptable. The authors conducted a retrospective cohort analysis of 21 euglycemic, hyperinsulinemic women with progressive, refractory, midlife weight gain (Syndrome W) who had previously lost weight (> or =10% reduction from baseline) with a comprehensive 1-year treatment program that included metformin and a hypocaloric, carbohydrate-modified (low-glycemic index) diet, as well as, other lifestyle modifications. The goal of the analysis was to determine long-term efficacy of the composite intervention using NHLBI criteria for weight stabilization, weight regain < or =3 kg (6.6 lb) in 2 years. Of a total of 26 consecutive women with Syndrome W who achieved goal weight during a 3-year period (1998-2001), 21 women (mea...

The authors conducted a retrospective analysis of a new obesity treatment protocol, metformin and hypocaloric, carbohydrate-modified diet, in high-risk, nondiabetic hyperinsulinemic women with progressive midlife weight gain (refractory to diet and exercise). Thirty consecutive nondiabetic women with glucose-mediated area-under-the-curve (AUC) insulin elevations (>or=100 microU/mL) in two body mass index (BMI) categories (group I: 25 to 32.9 kg/m(2) and group II: 33 to 41.7 kg/m(2)) participated in a 1-year treatment program of metformin (mean daily doses of 1,500 mg/day [group I] and 2,000 mg/day [group II]) and carbohydrate-modified dietary regimens. Follow-up body weight (at 3, 6, and 12 months), percentage of patients meeting goal weight attainment (10% reduction in body weight or BMI normalization), and fasting insulin levels (as available) are reported in 26 women (18/18 in group I and 8/12 in group II) who returned for one or more follow-up visits. Significant weight loss ...

Acquired methemoglobinemia usually occurs during endoscopy after exposure to a variety of drugs commonly used in critical care units and in endoscopy suites. A rapid infusion of methylene blue can result in a complete recovery of patients with a favorable prognosis. The authors describe a case of 31-year-old woman in whom methemoglobinemia developed with the use of benzocaine, and who showed complete recovery after methylene blue infusion. Hence, the availability of methylene blue in these settings is advocated.

The alarming increase in the prevalence of obesity in the past decade, as demonstrated by ongoing systematic population-based studies, and increased recognition of the adverse health consequences associated with excess body weight have generated widespread interest in the management of obesity. After an extensive review, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health issued a consensus statement with comprehensive clinical treatment guidelines in 1998 that is relevant to cardiologists as well as primary care physicians. A new focus on obesity research has advanced our understanding of the complexity of this disorder and provided new molecular targets for intervention, including beta(3)-adrenergic receptor agonists, leptin analogues, and uncoupling proteins (UCPs) that stimulate energy expenditure. Two newly available pharmacotherapeutic agents approved by the United States Food and Drug Administration (FDA) and increasing acceptance of bar...

: Although electronic reporting systems for near-misses and adverse events have been implemented nationwide, physician participation in such systems has typically been very limited. Previous efforts to improve such rates have met with some success but may be costly and time-consuming. To improve events reporting rates at our academic medical center, we incorporated a physician reporting module into the computer software that house officers already use for their daily sign-out routine. : During the period between January 1 and June 30, 2009, house staff were asked to report a set of 13 predefined "clinically significant events" such as cardiopulmonary arrests and unexpected transfers to the intensive care unit. Entries were maintained in an administrative data collection module and were reviewed daily by the residency program director and chief residents. : House staff reported approximately 12 incidents per month. A survey of the intern class (the heaviest users of system) showed that the principal barriers to physician reporting at our facility were related to ease of use, time pressure, and fear of disciplinary actions. Information gleaned from the reports has been useful in modifying a number of patient care processes on the medicine service. : Our experience suggests that if a training program makes it easy for the house officer to report events during routine work duties, by integrating the reporting system into the tools of daily patient care, physicians will become willing participants in the process. A handheld version of such a reporting system holds promise for even greater physician participation in the future.

Thrombotic thrombocytopenic purpura is a rare complication of ticlopidine treatment. This syndrome has been reported to occur typically within the first few weeks after the initiation of therapy. The authors describe a case of a 72-year-old woman in whom thrombotic thrombocytopenic purpura developed just 2 days after starting ticlopidine therapy for a new-onset ischemic stroke. The patient responded successfully to plasmapheresis. The authors are reporting this case to emphasize the unpredictable nature of the association between the drug and the disease, which necessitates careful hematologic monitoring.

Background The internal medicine milestones were developed to advance outcomes-based residency training and will play an important role in the next accreditation system. Innovation As an element of our program's participation in the internal medicine educational innovations project, we implemented a milestones-based evaluation process in our general medicine and pulmonary-critical care rotations on July 1, 2010. Measures Outcomes assessed included survey-rated acceptability to participating faculty, residents, and clinical competency committee members. Results Faculty and residents agreed that the milestones promoted a common understanding of what knowledge, skills, and attitudes should be displayed at particular points in residents' professional development and enhanced evaluators' ability to provide specific performance feedback. Most residents and faculty members agreed that the milestones promoted fairness and uniformity in the evaluation process. Clinical competency...

A 32-year-old white male police officer suffered blunt trauma to the anterior chest wall during a routine training session. This was accompanied by the precipitous onset of chest discomfort. There was no previous history of any cardiac risk factors. The diagnosis of an inferior wall myocardial infarction was made based on the electrocardiogram findings, at his local community hospital. The total creatine kinase, creatine kinase-MB, and troponin I were normal. The transesophageal echocardiogram performed at that time demonstrated no aortic or coronary dissection. He was transferred to our tertiary care center. Emergency cardiac catheterization demonstrated lateral wall hypokinesis with a left ventricular ejection fraction of 45% and a total occlusion of the left circumflex coronary artery in its proximal portion. This was successfully recannulized with angioplasty and stenting techniques. We believe this to be only the second reported case of circumflex coronary artery obstruction after blunt chest trauma.

There is a widespread epidemic of obesity in the United States, which has been associated with an increased risk of diabetes mellitus, cancer, and cardiovascular diseases. Although lifestyle modifications and long-term dietary vigilance remain cornerstones of weight reduction treatment, the continued availability of U.S. Food and Drug Administration-approved pharmacotherapies has expanded the options available for the management of obesity. These agents include anorexiants, thermogenic drugs, and lipid-partitioning drugs. As knowledge regarding the possible causes of obesity increases, there are new drugs under investigation, which include beta3-adrenergic receptor agonists, modifiers of leptin, and cannabinoid receptor-1 antagonists (rimonabant). Also under investigation are antidiabetic agents (metformin, exenatide), anticonvulsant drugs (topiramate, zonisamide), antidepressants (bupropion, fluoxetine), and growth hormones. New targets for pharmacotherapy include uncoupling proteins, fatty acid synthase, neuropeptide Y, melanocortin, ghrelin, various regulatory gut peptides, and ciliary neurotropic factor. Pharmacologic agents are in clinical development that target these substances.

Since the discovery of sildenafil in 1989 as a highly selective inhibitor of the phosphodiesterase type-5 (PDE-5) receptor, 2 additional PDE-5 inhibitors, tadalafil and vardenafil, have emerged as safe and effective treatments of erectile dysfunction (ED). Enzymes in the PDE family catalyze the hydrolysis of the intracellular signaling molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which is the second messenger of nitric oxide (NO) and a principal mediator of smooth muscle relaxation and vasodilation. Sildenafil was initially introduced for clinical use as the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Erection is largely a hemodynamic event, which is regulated by vascular tone and blood flow balance in the penis. Endothelial dysfunction, an early component of atherosclerosis, may inhibit a vascular event such as erection and is rarely confined to the arteries supplying blood to the penis, but more likely occurs throughout the vascular bed. In addition to the effects of the NO-cGMP signaling pathway on cavernosal smooth muscle, clinical findings have suggested that vascular tone in the pulmonary, coronary, and other vascular tissues expressed by PDE-5 is also influenced by this signal transduction mechanism. This has led to the emergence of novel therapeutic indications for sildenafil over a range of cardiovascular conditions that are either well-established risk factors or comorbidities with ED. Recently, the U.S. Food and Drug Administration approved sildenafil as an orally active therapy for the treatment of primary pulmonary hypertension. The drug will be marketed under the trade name of Revatio, not Viagra, the name used for the ED indication. The approved dose for primary pulmonary hypertension is 20 mg 3 times daily.

To characterize a new insulin resistance syndrome in euglycemic midlife women and the relationship of its features (including hypertension and dyslipidemia), with hyperinsulinemia (AUC insulin > or = 100 microU/mL), retrospective cohort analysis was conducted in 278 consecutive women who presented to a Menopausal Health Program. Of 67 women with midlife weight gain "greater than 20 pounds since their twenties" and body mass indices (BMIs) between 25 and 32 kg/m(2), none of the subjects met criteria for Type 2 diabetes, 5 women had impaired glucose tolerance, and 36 women were hyperinsulinemic. Hyperinsulinemia was a highly statistically significant determinant of hypertension, dyslipidemia, and truncal obesity (Odds Ratios 10.6, 4.0, and 13.7; P values < or = 0.0001, < or = 0.007, and < or = 0.0001) in cross-tabulations. AUC insulin was the best predictor variable of hypertension and dyslipidemia in univariate and multivariate logistic regression models (univariate P values 0.0004 and 0.0088). After adjustment for BMI, age, and estrogen use, the final models, correctly classified, respectively, 74% and 69% of all cases in the dataset (model P values: < or = 0.0001 and < or = 0.0067) and AUC insulin had a log-linear (i.e., dose-dependent) relationship with hypertension and dyslipidemia, which suggests causality. We propose that the constellation of symptoms that includes midlife weight gain, "waist-gain," hypertension, dyslipidemia, and appetite dysregulation in euglycemic women with hyperinsulinemia be titled Syndrome W and suggest that the highly statistically significant relationship of hyperinsulinemia with the characteristic features are evidence of a causal role for insulin in its etiology. The identification of Syndrome W before the onset of overt impaired glucose tolerance, diabetes, or manifestations of coronary artery disease could have important clinical and public health implications for midlife women.