Atrazine-Induced Aromatase Expression Is SF-1 Dependent: Implications for Endocrine Disruption in Wildlife and Reproductive Cancers in Humans

BACKGROUND: Atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. The mechanism involves the inhibition of phosphodiesterase and subsequent elevation of cAMP. METHODS: We compared steroidogenic factor 1 (SF-1) expression in atrazine responsive and non-responsive cell lines and transfected SF-1 into nonresponsive cell lines to assess SF-1’s role in atrazine-induced aromatase. We used a luciferase reporter driven by the SF-1–dependent aromatase promoter (ArPII) to examine activation of this promoter by atrazine and the related simazine. We mutated the SF-1 binding site to confirm the role of SF-1. We also examined effects of 55 other chemicals. Finally, we examined the ability of atrazine and simazine to bind to SF-1 and enhance SF-1 binding to ArPII. RESULTS: Atrazine-responsive adrenal carcinoma cells (H295R) expressed 54 times more SF-1 than nonresponsive ovarian granulosa KGN cells. Exogenous SF-1 conveyed atrazine-responsiveness to otherwise nonresponsive KGN and NIH/3T3 cells. Atrazine induced binding of SF-1 to chromatin and mutation of the SF-1 binding site in ArPII eliminated SF-1 binding and atrazine-responsiveness in H295R cells. Out of 55 chemicals examined, only atrazine, simazine, and benzopyrene induced luciferase via ArPII. Atrazine bound directly to SF-1, showing that atrazine is a ligand for this “orphan” receptor. CONCLUSION: The current findings are consistent with atrazine’s endocrine-disrupting effects in fish, amphibians, and reptiles; the induction of mammary and prostate cancer in laboratory rodents; and correlations between atrazine and similar reproductive cancers in humans. This study highlights the importance of atrazine as a risk factor in endocrine disruption in wildlife and reproductive cancers in laboratory rodents and humans

Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages

PPARγ plays a key role in adipocyte biology, and Rosiglitazone (Rosi), a thiazolidinedione (TZD)/PPARγ agonist, is a potent insulin-sensitizing agent. Recent evidences demonstrate that adipose tissue inflammation links obesity with insulin resistance and that the insulin-sensitizing effects of TZDs result, in part, from their anti-inflammatory properties. However the underlying mechanisms are unclear.In this study, we establish a link between free fatty acids (FFAs) and PPARγ in the context of obesity-associated inflammation. We show that treatment of adipocytes with FFAs, in particular Arachidonic Acid (ARA), downregulates PPARγ protein and mRNA levels. Furthermore, we demonstrate that the downregulation of PPARγ by ARA requires the activation the of Endoplamsic Reticulum (ER) stress by the TLR4 pathway. Knockdown of adipocyte PPARγ resulted in upregulation of MCP1 gene expression and secretion, leading to enhanced macrophage chemotaxis. Rosi inhibited these effects. In a high fat feeding mouse model, we show that Rosi treatment decreases recruitment of proinflammatory macrophages to epididymal fat. This correlates with decreased chemokine and decreased chemokine receptor expression in adipocytes and macrophages, respectively.In summary, we describe a novel link between FAs, the TLR4/ER stress pathway and PPARγ, and adipocyte-driven recruitment of macrophages. We thus both describe an additional potential mechanism for the anti-inflammatory and insulin-sensitizing actions of TZDs and an additional detrimental property associated with the activation of the TLR4 pathway by FA

Application of ICD guidelines and indications in a community-based academic hospital: a case series-based discussion.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) are indeed beneficial in selected patients as evidenced by multiple large randomized controlled trials (RCTs) since 1980. A systematic method for stratification of patients and hospital-wide criteria/guidelines to ascertain appropriate device implantation became necessary. METHODS: Major ICD/CRT (cardiac resynchronization therapy) clinical studies and relevant guidelines were reviewed, and an institution-wide inclusion and exclusion criteria for ICD/CRT was formulated. A retrospective analysis of selected cases was performed to discuss the criteria and special clinical situations. RESULTS: We have translated the evolving ICD/CRT studies into a standard of care at our hospital by formulating a standard, practical, and update-to-date ICD inclusion and exclusion criteria. Thirteen cases were selected to represent major indications and contraindications of ICDs in our practice. These cases cover indications of ICD for secondary prevention of sudden cardiac death (SCD), primary prevention of SCD in patients with CHF resulted from either ischemic or non-ischemic cardiomyopathy, as well as for infiltrative cardiomyopathy and inherited conditions. We discussed the application of CRT in patients with CHF associated with prolonged QRS duration. We then covered the potential benefits of ICD with/without CRT in certain special populations of patients that have not been adequately evaluated by currently available RCTs; these include alcoholic, elderly, female, and ESRD/HD patients. Finally, we addressed risks, complications and contraindications of ICD, as well as application of an external wearable defibrillator in AMI, or status post-CABG patient during the mandatory waiting period for an ICD. CONCLUSIONS: Establishment of the ICD/CRT criteria represents a practical translation of emerging CRTs and helps to standardize patient care in our hospital. It also improves cost-effectiveness as well as appropriate utilization of institute and device resources

Key clinical features a general internist needs to know about Brugada syndrome: a case-based discussion

Introduction: Brugada syndrome (BrS) is an autosomal dominant genetic disorder involving the abnormal function of cardiac voltage-gated sodium ion channels. Sodium channel loss of function can lead to early repolarization and loss of the Phase 2 action potential dome in cardiomyocytes. In BrS, this sodium channelopathy occurs in some, but not all, epicardial cells thus creating 1) juxtaposition of depolarized and repolarized cells in the epicardium and 2) a transmural voltage gradient. Together, these conditions can set up a Phase 2 reentry and resultant malignant cardiac arrhythmia. Of the three types of electrocardiogram (EKG) changes seen in BrS, only the Type 1 EKG is considered diagnostic. In a controlled setting, sodium channel blockers and Brugada EKG leads may be used to unmask this diagnostic EKG finding. Fever and certain medications that interfere with the sodium channel can also trigger these changes, which can be catastrophic. Case report: A 26-year-old white male presented with febrile upper respiratory infection symptoms and had an EKG change, which was initially misinterpreted as an ST elevated myocardial infarction due to ST-T segment elevation in leads V1 and V2. The patient reported past recurrent syncopal episodes leading to a recent suspected diagnosis of BrS. A later episode of febrile illness, triggering a Type 1 EKG pattern, led to a subsequent hospital admission for continuous cardiac monitoring. On that occasion, he was placed on a wearable external defibrillator pending placement of implantable cardioverter defibrillator (ICD) device. Conclusion: Due to the gravity of symptoms that can manifest in the BrS patient, it is important to recognize and treat this condition promptly and effectively. BrS patients require admission for continuous cardiac monitoring when febrile and certain medications interfering with the sodium channel should be avoided in this population. Although medications may be used as one treatment modality, definitive therapy is placement of an ICD device

Thyroid storm presenting as psychosis: masked by diabetic ketoacidosis

Introduction: While extremely uncommon, diabetic ketoacidosis (DKA) and thyroid storm (TS) are endocrine emergencies that can coexist. We describe a case with a confounding clinical presentation that identifies these two emergencies within the setting of sepsis and influenza. Case: A 69-year-old diabetic female was found by the paramedic staff to be disoriented. She demonstrated tachycardia and had a foul-smelling abdominal wound. Laboratory evaluation revealed DKA, leukocytosis, influenza B, and urinary tract infection. After appropriate management in the intensive care unit, the DKA resolved the following morning. However, the patient developed a fever, and her psychosis became more pronounced. Extensive analysis was performed but did not explain her mental status. The patient was found to have thyroid stimulating hormone of 0.06 mIU/mL, free T4 (thyroxine) of 2.38 ng/dL, and total T3 (triiodothyronine) of 72 ng/dL. Based on the Burch and Wartofsky criteria (score of 65), TS was diagnosed. Based on more recent diagnostic criteria suggested by Akamizu et al., the patient met criteria for TS grade 1. Within several hours of initiating treatment, the patient's mental state and tachycardia improved, and her psychosis resolved by the third day. Conclusion: This case highlights the importance of recognizing the clinical diagnosis of TS, as the magnitude of thyroid hormone derangements may not correlate with clinical severity. While rare, DKA and TS can simultaneously occur and are associated with increased morbidity and mortality if not promptly recognized and treated

The power of anecdotes on resident HVCCC curriculum

A formal high value, cost-conscious care (HVCCC) curriculum was implemented at a community hospital-based university-affiliated residency program starting January 1, 2014, based on the recommendations of the American Board of Internal Medicine's (ABIM) Choosing Wisely campaign. The program included a competition requiring each resident to write a HVCCC case based on an actual patient experience. Residents completed a questionnaire assessing their understanding of HVCCC near the end of the program. Residents subsequently reviewed two actual cases that had vividly described unexpected adverse outcomes (‘anecdotal’ cases). Postexposure data were collected and the results were analyzed

Key clinical features a general internist needs to know about Brugada syndrome: a case-based discussion.

INTRODUCTION: Brugada syndrome (BrS) is an autosomal dominant genetic disorder involving the abnormal function of cardiac voltage-gated sodium ion channels. Sodium channel loss of function can lead to early repolarization and loss of the Phase 2 action potential dome in cardiomyocytes. In BrS, this sodium channelopathy occurs in some, but not all, epicardial cells thus creating 1) juxtaposition of depolarized and repolarized cells in the epicardium and 2) a transmural voltage gradient. Together, these conditions can set up a Phase 2 reentry and resultant malignant cardiac arrhythmia. Of the three types of electrocardiogram (EKG) changes seen in BrS, only the Type 1 EKG is considered diagnostic. In a controlled setting, sodium channel blockers and Brugada EKG leads may be used to unmask this diagnostic EKG finding. Fever and certain medications that interfere with the sodium channel can also trigger these changes, which can be catastrophic. CASE REPORT: A 26-year-old white male presented with febrile upper respiratory infection symptoms and had an EKG change, which was initially misinterpreted as an ST elevated myocardial infarction due to ST-T segment elevation in leads V1 and V2. The patient reported past recurrent syncopal episodes leading to a recent suspected diagnosis of BrS. A later episode of febrile illness, triggering a Type 1 EKG pattern, led to a subsequent hospital admission for continuous cardiac monitoring. On that occasion, he was placed on a wearable external defibrillator pending placement of implantable cardioverter defibrillator (ICD) device. CONCLUSION: Due to the gravity of symptoms that can manifest in the BrS patient, it is important to recognize and treat this condition promptly and effectively. BrS patients require admission for continuous cardiac monitoring when febrile and certain medications interfering with the sodium channel should be avoided in this population. Although medications may be used as one treatment modality, definitive therapy is placement of an ICD device

Modified Early Warning System improves patient safety and clinical outcomes in an academic community hospital

Background and objective: Severe adverse events such as cardiac arrest and death are often heralded by abnormal vital signs hours before the event. This necessitates an organized track and trigger approach of early recognition and response to subtle changes in a patient's condition. The Modified Early Warning System (MEWS) is one of such systems that use temperature, blood pressure, pulse, respiratory rate, and level of consciousness with each progressive higher score triggering an action. Root cause analysis for mortalities in our institute has led to the implementation of MEWS in an effort to improve patient outcomes. Here we discuss our experience and the impact of MEWS implementation on patient care at our community academic hospital. Methods: MEWS was implemented in a protocolized manner in June 2013. The following data were collected from non-ICU wards on a monthly basis from January 2010 to June 2014: 1) number of rapid response teams (RRTs) per 100 patient-days (100PD); 2) number of cardiopulmonary arrests ‘Code Blue’ per 100PD; and 3) result of each RRT and Code Blue (RRT progressed to Code Blue, higher level of care, ICU transfer, etc.). Overall inpatient mortality data were also analyzed. Results: Since the implementation of MEWS, the number of RRT has increased from 0.24 per 100PD in 2011 to 0.38 per 100PD in 2013, and 0.48 per 100PD in 2014. The percentage of RRTs that progressed to Code Blue, an indicator of poor outcome of RRT, has been decreasing. In contrast, the numbers of Code Blue in non-ICU floors has been progressively decreasing from 0.05 per 100PD in 2011 to 0.02 per 100PD in 2013 and 2014. These improved clinical outcomes are associated with a decline of overall inpatient mortality rate from 2.3% in 2011 to 1.5% in 2013 and 1.2% in 2014. Conclusions: Implementation of MEWS in our institute has led to higher rapid response system utilization but lower cardiopulmonary arrest events; this is associated with a lower mortality rate, and improved patient safety and clinical outcomes. We recommend the widespread use of MEWS to improve patient outcomes

Modified Early Warning System improves patient safety and clinical outcomes in an academic community hospital.

BACKGROUND AND OBJECTIVE: Severe adverse events such as cardiac arrest and death are often heralded by abnormal vital signs hours before the event. This necessitates an organized track and trigger approach of early recognition and response to subtle changes in a patient\u27s condition. The Modified Early Warning System (MEWS) is one of such systems that use temperature, blood pressure, pulse, respiratory rate, and level of consciousness with each progressive higher score triggering an action. Root cause analysis for mortalities in our institute has led to the implementation of MEWS in an effort to improve patient outcomes. Here we discuss our experience and the impact of MEWS implementation on patient care at our community academic hospital. METHODS: MEWS was implemented in a protocolized manner in June 2013. The following data were collected from non-ICU wards on a monthly basis from January 2010 to June 2014: 1) number of rapid response teams (RRTs) per 100 patient-days (100PD); 2) number of cardiopulmonary arrests \u27Code Blue\u27 per 100PD; and 3) result of each RRT and Code Blue (RRT progressed to Code Blue, higher level of care, ICU transfer, etc.). Overall inpatient mortality data were also analyzed. RESULTS: Since the implementation of MEWS, the number of RRT has increased from 0.24 per 100PD in 2011 to 0.38 per 100PD in 2013, and 0.48 per 100PD in 2014. The percentage of RRTs that progressed to Code Blue, an indicator of poor outcome of RRT, has been decreasing. In contrast, the numbers of Code Blue in non-ICU floors has been progressively decreasing from 0.05 per 100PD in 2011 to 0.02 per 100PD in 2013 and 2014. These improved clinical outcomes are associated with a decline of overall inpatient mortality rate from 2.3% in 2011 to 1.5% in 2013 and 1.2% in 2014. CONCLUSIONS: Implementation of MEWS in our institute has led to higher rapid response system utilization but lower cardiopulmonary arrest events; this is associated with a lower mortality rate, and improved patient safety and clinical outcomes. We recommend the widespread use of MEWS to improve patient outcomes

Left ventricular outflow track obstruction and mitral valve regurgitation in a patient with takotsubo cardiomyopathy

Introduction: Takotsubo cardiomyopathy (TCM) can be complicated by left ventricular outflow tract (LVOT) obstruction and severe acute mitral regurgitation (MR), leading to hemodynamic instability in an otherwise benign disorder. Despite the severity of these complications, there is a paucity of literature on the matter. Because up to 20–25% of TCM patients develop LVOT obstruction and/or MR, it is important to recognize the clinical manifestations of these complications and to adhere to specific management in order to reduce patient morbidity and mortality. We report the clinical history, imaging, treatment strategy, and clinical outcome of a patient with TCM that was complicated with severe MR and LVOT obstruction. We then discuss the pathophysiology, characteristic imaging, key clinical features, and current treatment strategy for this unique patient population. Case report: A postmenopausal woman with no clear risk factor for coronary artery disease (CAD) presented to the emergency department with chest pain after an episode of mental/physical stress. Physical examination revealed MR, mild hypotension, and pulmonary vascular congestion. Her troponins were mildly elevated. Cardiac catheterization excluded obstructive CAD, but revealed severe apical hypokinesia and ballooning. Notably, multiple diagnostic tests revealed the presence of severe acute MR and LVOT obstruction. The patient was diagnosed with TCM complicated by underlying MR and LVOT obstruction, and mild hemodynamic instability. The mechanism of her LVOT and MR was attributed to systolic anterior motion of the mitral valve (SAM), which the transesophageal echocardiogram clearly showed during workup. She was treated with beta-blocker, aspirin, and ACE-I with good outcome. Nitroglycerin and inotropes were discontinued and further avoided. Conclusions: Our case illustrated LVOT obstruction and MR associated with underlying SAM in a patient with TCM. LVOT obstruction and MR are severe complications of TCM and may result in heart failure and/or pulmonary edema. Timely and accurate identification of these complications is critical to achieve optimal clinical outcomes in patients with TCM