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Context Fragility fractures increase risks for future fractures, morbidity, and mortality. Available pharmacotherapy for underlying osteoporosis is safe and effective but underused. Objective To improve pharmacotherapy rate representing secondary prevention of osteoporotic fractures. Methods This single-center, observational, follow-up study included patients with fragility fractures admitted to the Massachusetts General Hospital between February 2016 and December 2019. For patients admitted to the orthopedics service with fragility fracture, the Massachusetts General Hospital Fracture Liaison Service (FLS) was systematically consulted. Initial outpatient follow-up with FLS was established in conjunction with the orthopedic postoperative follow-up visit. Patients at risk for failing timely outpatient follow-up were administered zoledronic acid (ZA) during the index fracture hospitalization. The main outcome measures were percentage of patients with fragility fracture(s) started on pharmacotherapy for osteoporosis and average length of stay and 30-day readmission rate of patients treated with ZA. Results Compared with baseline (8-11%) and reference (5-20%) rates, integration of FLS to the orthopedics service, along with appropriate inpatient administration of ZA, increased the pharmacotherapy rate to 70% (412/589) among eligible patients with verified treatment status. Inpatient ZA administration neither affected the average length of stay nor 30-day readmission rate. Treatment status of 37.9% (471/1240) of the study patients remained unknown due to lack of or unknown follow-up. Conclusion Integration of a FLS and orthopedics services along with inpatient ZA administration improved the osteoporosis pharmacotherapy rate among patients with fragility fracture(s) who often had obstacles for outpatient follow-up.

Context Zoledronic acid (ZA) administered during the initial hospitalization for a fragility fracture improves the osteoporosis pharmacotherapy rate. Distinguishing the safety profile of inpatient ZA (IP-ZA) in this context is crucial if this approach is to be widely adopted. Objective To study the acute safety profile of IP-ZA. Design, Setting and Patients An observational study of patients admitted to the Massachusetts General Hospital with fragility fractures who were eligible to receive IP-ZA. Intervention Patients were treated with or without IP-ZA. Acetaminophen, either as a single pre-ZA dose or standing multiple-doses-per-day for 48 hours or longer after ZA infusion, was also administered along with protocolized vitamin D and calcium supplementation. Main outcome measures changes in body temperature, serum creatinine and serum calcium. Results 285 consecutive patients, meeting inclusion and exclusion criteria, are included in this analysis. 204 patients received IP-ZA. IP-ZA treatment was associated with a transient mean rise of body temperature of 0.31oC on the day following its administration. 15% of patients in the IP-ZA group and 4% in the non-treated group had temperatures above 38oC. Standing multiple-doses-per-day, but not a single pre-ZA dose of acetaminophen, effectively prevented this temperature increase. IP-ZA did not affect serum creatinine levels. Mean levels of serum total calcium and albumin-corrected calcium decreased by 0.54 mg/dl and 0.40 mg/dl, respectively, at their nadirs (Day 5). No patient experienced symptomatic hypocalcemia. Conclusions IP-ZA along with standing multiple-doses-per-day acetaminophen, administered to patients in the immediate post-fracture period, is not associated with significant acute adverse effects.

Context Up to 40% of patients with polycystic ovary syndrome (PCOS) have prediabetes; an optimal pharmacotherapy regimen for diabetes prevention in PCOS is yet to be established. Objective To evaluate clinical efficacy of exenatide (EX), metformin (MET), or combination (COM) for prediabetes in PCOS. Design Randomized, open-label, parallel-group controlled trial. Setting Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine. Patients PCOS with prediabetes (fasting plasma glucose 5.6-6.9 mmol/L and/or 2 hour post glucose 7.8-11.0 mmol/L on oral glucose tolerance test [OGTT]). A total of 150 out of 183 eligible enrollees completed the study. Intervention EX (10-20μg daily), MET (1500-2000 mg daily), or COM (EX plus MET) for 12 weeks. Main Outcome Measures Sustained remission rate of prediabetes (primary endpoint, a normal OGTT after 12 weeks of treatment followed by 12 weeks of washout on no drug treatment) along with anthropometric, hormonal, metabolic, and pancreatic β-cell function parameters (secondary endpoints) and potential mechanisms were assessed. Results Impaired glucose tolerance was found the dominant prediabetes phenotype. Overall sustained prediabetes remission rate was 50.7%. Remission rate of COM group (64%, 32/50) or EX group (56%, 28/50) was significantly higher than that of the MET group (32%, 16/50) (P = .003 and .027, respectively). EX was associated with superior suppression of 2-hour glucose increment in OGTT. A 2-step hyperglycemic clamp study revealed that EX had led to higher postprandial insulin secretion than MET, potentially explaining the higher remission rate. Conclusions Compared with MET monotherapy, EX or COM achieved higher rate of remission of prediabetes among PCOS patients by improving postprandial insulin secretion.

Non–small cell lung cancer with pituitary metastasis (NSCLC-PM) is a devastating disease; however, treatment is being revolutionized by a novel therapy targeting highly specific tumor signals, such as the mutation of epidermal growth factor receptors (EGFRs). Long-term management of hormonal defects in this population has become a unique neuroendocrine clinical challenge. We report the case of a 73-year-old female nonsmoker who was diagnosed with stage IV non–small cell lung cancer. The initial staging evaluation revealed a 7 × 11 × 21-mm sellar lesion abutting the optic chiasm and causing clinical hypopituitarism. The patient received three cycles of chemotherapy with carboplatin and pemetrexed, which was discontinued because of major cumulative side effects of myelosuppression and kidney disease. Eight months later, scans demonstrated evidence of disease progression. A repeated lung nodule biopsy revealed an EGFR exon 19 deletion mutation. EGFR-targeted therapy with osimertinib 80 mg daily was initiated. A complete resolution of the pituitary lesion was evident on a follow-up pituitary MRI 5 weeks later and was sustained 1 year after. However, the panhypopituitarism persisted. This is an illustrative case of NSCLC-PM with EGFR exon 19 deletion mutation, wherein osimertinib, a third-generation EGFR‒tyrosine kinase inhibitor, eradicated the sellar metastasis and prevented the need for radiotherapy. However, the neuroendocrine deficits persisted despite anatomic improvement.

Context Oxytocin (OT) and vasopressin share anatomical pathways of synthesis and secretion, and patients with central diabetes insipidus (CDI) presumably are at risk for OT deficiency. However, an OT-deficient state in hypopituitary patients has not been established. Objectives We hypothesized that men with CDI compared to patients with similar anterior pituitary deficiencies (APD) but no CDI and healthy controls (HC) of similar age and body mass index, would have lower plasma OT levels, associated with increased psychopathology. Design Cross-sectional. Setting Clinical research center. Participants Sixty-two men (20 CDI, 20 APD, 22 HC), age 18 to 60 years. Interventions Frequent sampling of blood every 5 minutes for OT over 1 hour and validated questionnaires to assess psychopathology. Main outcomes Pooled plasma OT levels; depressive, anxiety, and alexithymia symptoms; and quality of life. Results The mean 1-hour pool of fasting OT levels was lower in CDI compared with APD and HC (P = 0.02 and P = 0.009, respectively), with no differences between APD and HC (P = 0.78). Symptoms of depression, anxiety, and alexithymia were more pronounced in CDI than in HC (P = 0.001, P = 0.004, and P = 0.02, respectively). Although CDI and APD reported worse physical health compared with HC (P = 0.001 and P = 0.005) with no differences between APD and CDI, only CDI reported worse mental health compared with HC (P = 0.009). Conclusions We have demonstrated low plasma OT levels and increased psychopathology in hypopituitary men with CDI, suggestive of a possible OT-deficient state. Larger studies of both sexes are required to confirm these findings and clinically characterize hypopituitary patients with OT deficiency.

Aims To analyze mathematical relationships between timed Self-Monitored Blood Glucose (SMBG) and HbA1c, and to identify the SMBG values that correlate most strongly with HbA1c. Methods We utilized the average premeal (Pre) and 90-min postmeal (Post) SMBG results from 547 A1c-Derived Average Glucose (ADAG) study participants (285 type 1, 178 type 2 and 84 non-diabetic) to analyze the mathematical relationships with HbA1c levels. Specific times of daily SMBG that best correlate with HbA1c were identified. Results Linear regression analyses showed the following correlations for Pre and Post, Pre only and Post only, respectively: HbA1c = 2.488 + 0.018 × Premg/dl + 0.012 × Postmg/dl, R2 = 0.741, P Among patients with type 2 diabetes mellitus (DM), of the 6 individual timepoints, pre-dinner SMBG had the strongest correlation with HbA1c (R2 = 0.577). This was followed by pre-breakfast (R2 = 0.562). Examining combinations of timepoints revealed that pre-breakfast + pre-dinner (R2 = 0.666) performed similarly to the full 6-timepoints (pre-meals + post-meals, R2 = 0.712). Conclusions We have established mathematical relationships between HbA1c and timed SMBG values and identified pre-dinner and pre-breakfast as the two SMBG timepoints that best correlate with HbA1c in patients with type 2 DM.

Background: Clopidogrel (Plavix) is an antiplatelet medication that is routinely used in patients with cardiovascular disease. Cytochrome P2C19 enzymes play a major role in its metabolism, which determines its varied therapeutic level and its effectiveness. Objectives: To customize clopidogrel therapy and evaluate its efficacy by using CYP2C19 genotypic and phenotypic information to improve clinical outcomes in patients. Methods: A total of 465 patients with underlying cardiovascular disease were selected from our out-patient cardiology clinic. DNA sequences of CYP2C19 were analyzed in 465 patients. Results: Of 465 patients, 183 were wild-type homozygous (*1/*1) and 18.8% gain-of function and 19.8% loss-of-function alleles in our patient population The following changes were made: 1) Switching to prasugrel in patients whose genotype noted them to be “Slow metabolizers. This medication adjustment improved clinical outcomes in this patient group. 2) Discontinuing or lowering clopidogrel doses in patients whose genotypes noted them to be “Fast or ultra-fast metabolizes” to decrease bleeding risk. For those who were not on clopidogrel but carried abnormal allele(s), “clopidogrel caution” was documented. These individuals were followed up for 3 years and there has not been any cardiac clinical symptoms, cardiac death or excessive bleeding reported. Conclusions: Given the varied effectiveness of clopidogrel due to its metabolism by CYP2C19 enzyme, and the relatively high frequency of both gain-of-function (18.8%) and loss-of-function (19.8%) alleles in our patient population, we believe that genotyping CYP2C19 is clinically important in order to improve patient outcomes and minimize patient risk.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been found to be related with many diseases. Systemic inflammation is now considered as a major predisposition factor for diseases including diabetes mellitus (DM), coronary arterial disease (CAD), stroke, and cancer. This study aimed to investigate whether systemic inflammation is a possible underlying pathogenesis for MTHFR gene polymorphism‐related disease. METHODS: A total of 292 patients were enrolled, and single nucleotide polymorphisms for MTHFR C667T and A1298C were genotyped. Systemic inflammation markers, neutrophil‐to‐lymphocyte ratio (NLR), and platelet‐to‐lymphocyte ratio (PLR) were collected. RESULTS: In our study population, MTHFR 677 variants had significant higher NLR level than MTHFR 677 wild type (3.77 ± 0.26 vs 3.06 ± 0.18, P = .028). Logistic regression analysis showed that MTHFR 677 variants were significantly associated with increased NLR level. MTHFR 1298 variants showed the opposite effects which tended to have lower level of NLR (3.21 ± 0.16 vs 3.79 ± 0.34, P = .087) and PLR (137.0 ± 4.8 vs 157.7 ± 9.4, P = .052) than MTHFR 1298 wild type. General linear model showed that there was no statistically significant interaction between MTHFR C667T and A1298C gene polymorphism on NLR or PLR. CONCLUSIONS: This study indicates that MTHFR C677T and MTHFR A1298C gene polymorphisms have opposite effect on systemic inflammation, and systemic inflammation may contribute to the pathogenesis for diseases associated with MTHFR C667T gene polymorphism.

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. Keywords: Modified Early Warning System; mortality; rapid response system; patient safety (Published: 1 April 2015) Citation: Journal of Community Hospital Internal Medicine Perspectives 2015, 5 : 26716 - http://dx.doi.org/10.3402/jchimp.v5.26716

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. Keywords: implantable cardioverter–defibrillator; cardiac resynchronization treatment; sudden cardiac death; criteria; electrophysiology (Published: 14 April 2014) Citation: Journal of Community Hospital Internal Medicine Perspectives 2014, 4 : 23909 - http://dx.doi.org/10.3402/jchimp.v4.23909

Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped. CYP2C9*1 allele is in complete linkage disequilibrium with CYP2C19*2 and CYP2C19*17 (D' = 1) in our study population. Patient with VKORC1-1639 G > A, CYP2C9*2 and CYP2C9*3 genetic variants need significant lower warfarin dose than patient with wild type allele of VKORC1 1639 G or CYP2C9*1. There is no significant differences between CYP2C19 allele variants for warfarin stable dose and INR > 5 event. Because of the complete linkage disequilibrium between CYP2C19*2,*17 and CYP2C9*1, patient with CYP2C19 *2/*2, *2/*17 and *17/*17 genotypes tend to have higher warfarin dose than patient with CYP2C19*1/*1 genotype. Stepwise regression analysis showed that VKORC1, CYP2C9, body mass index (BMI), age and gender were included as a factor significantly contributing to warfarin dose, whereas CYP2C19 did not contribute to warfarin dose. No statistically significant interaction between CYP2C9 and VKORC1 on warfarin dose and INR > 5 event was detected in univariate general linear model analysis. Our study suggests that polymorphic variants of VKORC1 and CYP2C9 affect warfarin dose independently, whereas CYP2C19 did not contribute to warfarin therapy.

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. Keywords: takotsubo cardiomyopathy; left ventricular outflow tract obstruction; mitral regurgitation; systolic anterior motion of the mitral valve (Published: 11 December 2015) Citation: Journal of Community Hospital Internal Medicine Perspectives 2015, 5 : 29419 - http://dx.doi.org/10.3402/jchimp.v5.29419

Insulin resistance, tissue inflammation and adipose tissue dysfunction are features of obesity/Type 2 diabetes. Accordingly, we generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knock-out (AKO) mice to investigate the function of NCoR in adipocyte biology and glucose/insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and euglycemic clamp studies demonstrated enhanced insulin sensitivity in liver, muscle and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies a novel function of NCoR as an adaptor protein which enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD treated state.

In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is a determinant of insulin sensitivity and this receptor mediates the insulin-sensitizing effects of thiazolidinediones (TZDs). As PPAR-γ is also expressed in neurons, we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-γ signaling contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to Pparg(f/f) mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Pparg(f/f) mice. When treated with the TZD rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone-induced hyperphagia and weight gain and, relative to rosiglitazone-treated Pparg(f/f) mice, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPAR-γ signaling to limit thermogenesis and increase food intake. Neuronal PPAR-γ signaling is also required for the hepatic insulin sensitizing effects of TZDs.

ObjectiveAdiponectin, an abundant adipokine with insulin-sensitizing properties, exists in different multimeric forms, including low-molecular weight, medium-molecular weight, and high-molecular weight (HMW) species. Alterations in the distribution of adiponectin multimers and the relationship between adiponectin multimers and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) remain unclear. The objective of this study was to compare adiponectin multimerization status and estimate insulin sensitivity in Chinese women with PCOS compared with age- and body mass index (BMI)-matched controls.MethodsCross-sectional study involving 64 Chinese women with PCOS and 59 normal women. Circulating total adiponectin and its multimeric forms were determined by ELISA, and IR was estimated using the homeostasis model assessment IR index (HOMA-IR).ResultsAfter controlling for BMI status, levels of both total and HMW adiponectin were significantly lower in women with PCOS compared with normal women (PConclusionLevels of both total and HMW adiponectin were decreased in Chinese women with PCOS compared with normal control women, and the differences in HMW adiponectin persisted after controlling for BMI. Furthermore, HMW adiponectin is a stronger predictor of IR than total adiponectin in both women with PCOS and normal women.

Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.

The link between intra-abdominal adiposity and type II diabetes has been known for decades, and adipose tissue macrophage (ATM)-associated inflammation has recently been linked to insulin resistance. However, the mechanisms associated with ATM recruitment remain ill defined. Herein, we describe in vitro chemotaxis studies, in which adipocyte conditioned medium was used to stimulate macrophage migration. We demonstrate that tumor necrosis factor alpha and free fatty acids, key inflammatory stimuli involved in obesity-associated autocrine/paracrine inflammatory signaling, stimulate adipocyte expression and secretion of macrophage chemoattractants. Pharmacological studies showed that peroxisome proliferator-activated receptor gamma agonists and glucocorticoids potently inhibit adipocyte- induced recruitment of macrophages. This latter effect was mediated by the glucocorticoid receptor, which led to decreased chemokine secretion and expression. In vivo results were quite comparable; treatment of high fat diet-fed mice with dexamethasone prevented ATM accumulation in epididymal fat. This decrease in ATM was most pronounced for the proinflammatory F4/80(+), CD11b(+), CD11c(+) M-1-like ATM subset. Overall, our results elucidate a beneficial function of peroxisome proliferator-activated receptor gamma activation and glucocorticoid receptor/glucocorticoids in adipose tissue and indicate that pharmacologic prevention of ATM accumulation could be beneficial.

Testosterone (T) is an important factor for determining body composition in males. Abdominal obesity is inversely correlated with serum T levels in men, leading to greater mortality. Pathologically hypogonadal men also have a significantly higher fat mass, which is reversed by T administration. However, the mechanism for such anti-obesity effect of androgen has not been well clarified. Androgen receptor (AR) null male mice revealed late-onset obesity. Male ARKO mice were euphagic compared to the wild-type male controls, but also less dynamic and less oxygen consuming. Transcript profiling indicated that male ARKO mice had lower transcripts for the thermogenetic uncoupling protein 1 (UCP1). We also found enhanced secretion of adiponectin, which is insulin-sensitizing, from adipose tissue in comparison to wild type, which might partly explain why the overall insulin sensitivity of male ARKO mice remained almost intact despite their apparent obesity. In addition, decreased lipolysis rather than increased lipid synthesis was observed, which might also account for the increased adiposity in male ARKO mice. The results revealed that AR plays important roles in male metabolism by affecting the energy balance, and is negative to both adiposity and insulin sensitivity.

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. Keywords: Brugada syndrome; sodium channelopathy; sudden cardiac arrest; implantable cardioverter defibrillator (Published: 15 June 2015) Citation: Journal of Community Hospital Internal Medicine Perspectives 2015, 5 : 27241 - http://dx.doi.org/10.3402/jchimp.v5.27241

Aims While steroidogenic factor 1 (SF-1) is traditionally an essential nuclear receptor for steroidogenic tissues, current emerging studies revealed that the receptor is also closely implicated in metabolism. Mutations of SF-1 gene cause metabolic disorders like obesity in both human and mice. The aim of the present study is to examine whether the Gly146Ala variation in the gene for SF-1, that is known to impair SF-1 function and related to adrenal disorders, affects susceptibility to type 2 diabetes. Methods Hundred and fifty-one type 2 diabetic subjects and 141 non-diabetic control subjects of Han Chinese were recruited and the SF-1 genotype were analyzed by PCR-RFLP method. Results The Gly146Ala variation occurs frequently in the Han Chinese. Allele Ala frequency in the control subjects (27.3%) was significantly lower than that in type 2 diabetic subjects (37.1%, χ2 = 6.37, p = 0.01). The Gly/Ala and Ala/Ala genotypes frequencies were also higher in diabetic subjects. In both the diabetic and control populations, subjects carrying allele Ala, as compared to those not, had higher fasting insulin levels and higher HOMA values. Conclusions The SF-1 Gly146Ala variation may constitute a susceptible factor for development of type 2 diabetes and impairment of insulin actions.

Objective/Background : To discuss a unique clinical entity where inappropriate activity of inhibitory and stimulatory thyroid antibodies resulted in alternating hypothyroidism and hyperthyroidism. Methods : We report the clinical history, laboratory data, and results of imaging studies, along with the pathophysiological mechanism and the subsequent treatment in a patient with fluctuating thyroid functional status. Results : A 52-year-old female was treated for hypothyroidism for more than two decades. She started having symptoms of hyperthyroidism along with a suppressed thyroid-stimulating hormone (TSH). She continued to have persistent symptoms despite stopping her levothyroxine. Her free T3 and T4 were elevated along with an increased radioactive uptake scan. She was diagnosed with Graves’ disease and started on methimazole, which relieved her symptoms for a few months. Subsequently, her TSH began to rise beyond expected level, her hypothyroid symptoms reappeared, and methimazole was discontinued. Following this, she again developed symptoms of hyperthyroidism and thyroid values revealed an undetectable TSH. She had at least two such documented cycles of hyperthyroidism alternating with hypothyroidism. She was eventually treated with radioactive iodine ablation followed by levothyroxine replacement. Swinging dominance of TSH-blocking autoantibodies (TBAb) and thyroid-stimulating autoantibodies (TSAb) triggered by methimazole and levothyroxine, respectively, is likely the underlying mechanism. Conclusions : Physicians should be vigilant to the phenomenon of spontaneous conversion of hypothyroidism to hyperthyroidism, or vice versa, in a subset of patients with autoimmune thyroid disease. Repeated assessment of thyroid function along with measurement of TBAb and TSAb are invaluable in identifying this rare clinical entity. Keywords: hypothyroidism; hyperthyroidism; TBAb; TSAb; oscillating (Published: 25 November 2014) Citation: Journal of Community Hospital Internal Medicine Perspectives 2014, 4 : 25734 - http://dx.doi.org/10.3402/jchimp.v4.25734

The mechanism through which protein kinase A (PKA) potentiates the transactivation ability of adrenal 4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) is currently unclear. In the present study, we investigated the mechanism by applying laser confocal microscopy and fluorescence recovery after photobleaching technique. In KGN cells, forskolin (a PKA stimulator) could reorganize wild-type Ad4BP/SF-1, but not mutant Ad4BP/SF-1 (G35E), from a diffuse distribution pattern to foci formation in the nucleus. The subcellular distributions of GCN5 (general control nonderepressed) and TRRAP (transformation/transcription domain-associated protein), both of which were recently proved to be working in the same complex as the third class of nuclear receptor coactivators, were unexpectedly diffuse inside and outside the nucleus, respectively, when they were separately transfected. However TRRAP was translocated into the nucleus in the presence of GCN5, and together with GCN5 colocalized with Ad4BP/SF-1 in the same foci when PKA was activated. A luciferase assay also indicated that these two cofactors enhanced Ad4BP/SF-1 transactivation.Dosage-sensitive sex reversal (DAX-1) interacts with and thus inhibits Ad4BP/SF-1 transactivation. The coexistence of the two proteins dramatically altered their respective subnuclear distributions. They colocalized extensively, suggestive of binding, and Ad4BP/SF-1 was sharply immobilized when DAX-1 was coexpressed, whereas PKA could maintain mobility, as evidenced by Fluorescence Recovery After Photobleaching showing that Ad4BP/SF-1 mobility recovered after forskolin treatment.Therefore, the PKA signal pathway may modify the interaction between Ad4BP/SF-1 and its activators and repressor (GCN5 and TRRAP are integrated, whereas DAX-1 is disassociated), and thus stimulate the Ad4BP/SF-1 transactivation.

The baroreceptors in the neck and aortic arch are important regulators of sudden blood pressure changes. They are innervated by CN IX and X and synapse in the brainstem. Baroreceptor failure is an underrecognized cause of recurrent syncope, orthostatic hypotension, and volatile hypertension, which is refractory to and may in fact worsen with conventional treatments. Baroreflex failure can be the result of neck and chest radiation, head and neck surgery, and cerebrovascular accidents involving the brainstem nuclei. The management of baroreflex failure is a challenge since patient education, lifestyle changes, and family support are extremely important in managing blood pressure. Leg exercises and Thrombo-Embolic Deterrent Stockings (TED) stockings are important in treating orthostatic hypotension. Clonidine is the antihypertensive of choice for supine hypertension. Low-dose benzodiazepines are helpful in suppressing sympathetic surges. We have encountered two patients with baroreflex failure after chemotherapy and radiation to the neck or upper chest. Temporal relationship between symptoms onset and the history of head, neck, and upper chest radiation or trauma is important in reaching a diagnosis. Keywords: baroreflex failure; baroreceptors; carotid sinus; orthostatic hypotension (Published: 5 July 2013) Citation: Journal of Community Hospital Internal Medicine Perspectives 2013, 3 : 20741 - http://dx.doi.org/10.3402/jchimp.v3i2.20741

Female obesity is associated with insulin resistance, hyperandrogenemia, and reproductive dysfunction. We hypothesized that elevated free fatty acids (FFAs) might directly modulate pituitary gonadotropin production. FFAs caused a time- and dose-dependent increase in phosphorylation of the MAPKs p38MAPK, c-Jun N-terminal kinase (JNK)-1/2, and ERK1/2 in LβT2 gonadotrope cells. Furthermore, FFAs up-regulated Lhb mRNA expression acutely, an effect that was blocked by JNK inhibition, but suppressed Fshb mRNA expression, an effect that was independent of MAPK signaling. FFAs enhanced the activation of the MAPKs in the presence of GnRH, although the cotreatment did not alter Lhb induction but did eliminate the GnRH induction of Fshb. FFAs also suppressed activin-induced Fshb expression. Knockdown experiments showed that the FFA effect on the inflammatory kinases p38MAPK and JNK and on Lhb, but not Fshb, mRNA expression is mediated via toll-like receptor-2 and toll-like receptor-4 and was mimicked by lipopolysaccharide stimulation. In vivo, male C57BL/6 mice on a high-fat diet showed reduced FSH levels consistent with the suppression of Fshb seen in vitro. Histological analysis of the testes showed an increased number of abnormal seminiferous tubules. Female mice on a high-fat diet lacked the expected proestrus LH and FSH surge and exhibited an increase in the number of days at estrus and a reduced number of days at proestrus, and ovaries had significantly fewer corpora lutea. Taken together, our findings suggest that lipid excess can lead to reproductive defects in both male and female mice.

The macrophage-mediated inflammatory response is a key etiologic component of obesity-related tissue inflammation and insulin resistance. The transcriptional factor FoxO1 is a key regulator of cell metabolism, cell cycle and cell death. Its activity is tightly regulated by the phosphoinositide-3-kinase-AKT (PI3K-Akt) pathway, which leads to phosphorylation, cytoplasmic retention and inactivation of FoxO1. Here, we show that FoxO1 promotes inflammation by enhancing Tlr4-mediated signalling in mature macrophages. By means of chromatin immunoprecipitation (ChIP) combined with massively parallel sequencing (ChIP-Seq), we show that FoxO1 binds to multiple enhancer-like elements within the Tlr4 gene itself, as well as to sites in a number of Tlr4 signalling pathway genes. While FoxO1 potentiates Tlr4 signalling, activation of the latter induces AKT and subsequently inactivates FoxO1, establishing a self-limiting mechanism of inflammation. Given the central role of macrophage Tlr4 in transducing extrinsic proinflammatory signals, the novel functions for FoxO1 in macrophages as a transcriptional regulator of the Tlr4 gene and its inflammatory pathway, highlights FoxO1 as a key molecular adaptor integrating inflammatory responses in the context of obesity and insulin resistance.

Recent findings denote an important contribution of macrophage inflammatory pathways in causing obesity-related insulin resistance. Inducible nitric oxide synthase (iNOS) is activated in proinflammatory macrophages and modestly elevated in insulin-responsive tissues. Although the benefits of systemic iNOS inhibition in insulin-resistant models have been demonstrated, the role of macrophage iNOS in metabolic disorders is not clear. In the current work, we used bone marrow transplantation (BMT) to generate mice with myeloid iNOS deficiency [iNOS BMT knockout (KO)]. Interestingly, disruption of iNOS in myeloid cells did not protect mice from high-fat diet-induced obesity and insulin resistance. When mice were treated with the iNOS inhibitor, N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), we observed a significant and comparable improvement of glucose homeostasis and insulin sensitivity in both wild-type and iNOS BMT KO mice. We further demonstrated that absence of iNOS in primary macrophages did not affect acute TLR4 signaling pathways and had only a modest and mixed effect on inflammatory gene expression. With respect to TNFα treatment, iNOS KO macrophages showed, if anything, a greater inflammatory response. In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance.

The androgen-androgen receptor (AR) system plays important roles in a variety of biological processes, including prostate cancer (PC) development and progression. Insulin and Insulin-like growth factor-1 (IGF-1) signaling negatively regulate a member of the forkhead box-containing protein O subfamily (FoxO), Foxo-1, and associated biological functions. IGF-1 can potentiate androgen signaling through AR activation. Foxo-1, phosphorylated and inactivated by phosphatidylinositol-3-kinase (PI3K)/Akt kinase induced by IGF-1 or insulin, suppresses ligand-mediated AR transactivation. Foxo-1 reduces expression of androgen-induced AR target genes and suppresses in vitro growth of PC cells. These inhibitory effects of Foxo-1 are attenuated by IGF-1, but enhanced when it was rendered Akt-non-phosphorylatable. Foxo-1 directly interacts with the C-terminus of AR in a ligand-dependent manner, and disrupts ligand-induced AR subnuclear compartmentalization. Foxo-1 is recruited by liganded AR to the chromatin of the AR target gene promoter, while IGF-1 or insulin abolishes the Foxo-1 occupancy on the promoter. Liganded AR stimulates IGF-1 receptor expression, suggesting the presence of local positive feedback between IGF-1 and AR signaling in PC cells, presumably resulting in higher IGF-1 signaling tension and further enhancing the functions of the receptor itself. Thus, Foxo-1 is a novel corepressor for AR and IGF-1/insulin signaling may confer stimulatory effects on AR by attenuating Foxo-1 inhibition. Positive feedback between the growth factor and androgen in the local cellular environment may play important roles in AR transactivation regulation in several clinical situations including refractory PC.

The androgen-androgen receptor (AR) system plays important roles in a variety of biological processes, including prostate cancer (PC) development and progression. Insulin and Insulin-like growth factor-1 (IGF-1) signaling negatively regulate a member of the forkhead box-containing protein O subfamily (FoxO), Foxo-1, and associated biological functions. IGF-1 can potentiate androgen signaling through AR activation. Foxo-1, phosphorylated and inactivated by phosphatidylinositol-3-kinase (PI3K)/Akt kinase induced by IGF-1 or insulin, suppresses ligand-mediated AR transactivation. Foxo-1 reduces expression of androgen-induced AR target genes and suppresses in vitro growth of PC cells. These inhibitory effects of Foxo-1 are attenuated by IGF-1, but enhanced when it was rendered Akt-non-phosphorylatable. Foxo-1 directly interacts with the C-terminus of AR in a ligand-dependent manner, and disrupts ligand-induced AR subnuclear compartmentalization. Foxo-1 is recruited by liganded AR to the chromatin of the AR target gene promoter, while IGF-1 or insulin abolishes the Foxo-1 occupancy on the promoter. Liganded AR stimulates IGF-1 receptor expression, suggesting the presence of local positive feedback between IGF-1 and AR signaling in PC cells, presumably resulting in higher IGF-1 signaling tension and further enhancing the functions of the receptor itself. Thus, Foxo-1 is a novel corepressor for AR and IGF-1/insulin signaling may confer stimulatory effects on AR by attenuating Foxo-1 inhibition. Positive feedback between the growth factor and androgen in the local cellular environment may play important roles in AR transactivation regulation in several clinical situations including refractory PC.

In animal experiments, adrenal cortical tissue has been successfully regenerated through xenotransplantation of cloned adrenocortical cells, suggesting that the intraadrenal stem cells required for such tissue formation may be present in the adrenal cortex. Stable expression of Ad4BP/SF-1, a key factor for adrenal and gonadal development and steroidogenesis, has been shown to direct embryonic stem cells toward the steroidogenic lineage. However, this steroidogenic capacity was very limited since progesterone was only produced in the presence of an exogenous substrate. Bone marrow mesenchymal cells are thought to contain pluripotent progenitor cells, which differentiate into multiple lineages. We have demonstrated that adenovirus-mediated forced expression of SF-1 in long-term cultured bone marrow cells can produce steroidogenic cells with the capacity for de novo synthesis of various steroid hormones in response to ACTH. This discovery may represent the first step in autologous cell transplantation therapy for patients with steroid hormone deficiency.

The Foxo1 forkhead transcription factor is a critical negative regulator of insulin action. In this issue of The EMBO Journal , Nakae and colleagues (Nakae et al , 2012) describe a novel Foxo1 Co‐Repressor (FCoR) protein in adipocytes, showing that FCoR enhances the acetylation of Foxo1 to inhibit Foxo1 activity, promote adipocyte differentiation, and improve insulin sensitivity.

Background 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. Methodology and Principal Findings 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. Conclusions and Significance 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.