Liraglutide use and evaluation of pancreatic outcomes in a US commercially insured population.

AIMS: Both acute pancreatitis (AP) and pancreatic cancer (PC) have been areas of focus for studies of incretin drugs. This 5-year prospective cohort study aimed to quantify possible associations between liraglutide and risk of AP and PC as compared to other antidiabetic drugs (ADs). MATERIALS AND METHODS: Patients initiating liraglutide or other ADs who were enrolled in a US health plan (2010-2014) were included. Comparisons of AP and PC incidence rates were made between matched cohorts of liraglutide initiators and initiators of other ADs. Adjudicated AP cases and algorithm-based PC cases were identified. Propensity score-matched intention-to-treat (ITT) and time-on-drug (TOD) analyses were completed using Poisson regression. A latency analysis was performed for PC. RESULTS: Median follow-up was 405 days for AP cohorts (9995 liraglutide, 1:1 matched to all comparators) and 503 days for PC cohorts (35 163 liraglutide, 1:1 matched to all comparators). In the primary AP analysis, "current" use of liraglutide was not significantly associated with elevated risk across comparators (all comparators relative risk [RR] = 1.2; 95% confidence interval [CI], 0.6-2.3). ITT results were similar where, in the primary analysis, no RRs were significantly associated with PC (all comparators RR = 0.7; 95% CI, 0.3-1.4); latency and TOD analyses did not alter findings. There was no evidence of a dose-response effect. CONCLUSIONS: Liraglutide was not associated with an increased risk of AP or PC, although risk estimates were more variable for AP, and numbers of cases for both outcomes were limited because of the rarity of outcomes.

Characterizing idiopathic pulmonary fibrosis patients using US Medicare-advantage health plan claims data.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare life-threating interstitial lung disease (ILD). This study characterizes demographics, health care utilization, and comorbidities among elderly IPF patients and estimates prevalence and incidence rates for selected outcomes. METHODS: Cohort study using a large US health insurance database (Optum's Medicare Advantage plan). INCLUSION CRITERIA: ≥ 1 diagnosis code for IPF (2008 - 2014), age ≥65 years, no diagnosis of IPF or other ILD in prior 12 months. Demographics, health care utilization, comorbidities and incidence rates for various outcomes were estimated. Follow-up continued until the earliest of: health plan disenrollment, death, a claim for another known cause of ILD, or end of the study period. RESULTS: 4,716 patients were eligible; 53.4% had IPF diagnostic testing. Median age was 77.5 years, 50.3% were male, median follow-up time was 0.8 years. Incidence rates ranged from 1.0/1,000 person-years (lung transplantation) to 374.3/1,000 person-years (arterial hypertension). Baseline characteristics and incidence rates were similar for cohorts of patients with and without IPF diagnostic testing. CONCLUSIONS: Elderly IPF patients experience a variety of comorbidities before and after IPF diagnosis. Therapies for IPF and for the associated comorbidities may reduce morbidity and associated health care utilization of these patients.

Mitochondrial p53 Contributes to Reovirus-Induced Neuronal Apoptosis and Central Nervous System Injury in a Mouse Model of Viral Encephalitis.

UNLABELLED: The tumor suppressor p53 plays a critical part in determining cell fate both as a regulator of the transcription of several proapoptotic genes and through its binding interactions with Bcl-2 family proteins at mitochondria. We now demonstrate that p53 protein levels are increased in infected brains during reovirus encephalitis. This increase occurs in the cytoplasm of reovirus-infected neurons and is associated with the activation of caspase 3. Increased levels of p53 in reovirus-infected brains are not associated with increased expression levels of p53 mRNA, suggesting that p53 regulation occurs at the protein level. Increased levels of p53 are also not associated with the increased expression levels of p53-regulated, proapoptotic genes. In contrast, upregulated p53 accumulates in mitochondria. Previous reports demonstrated that the binding of p53 to Bak at mitochondria causes Bak activation and results in apoptosis. We now show that Bak is activated and that activated Bak is bound to p53 during reovirus encephalitis. In addition, survival is enhanced in reovirus-infected Bak(-/-) mice compared to controls, demonstrating a role for Bak in reovirus pathogenesis. Inhibition of the mitochondrial translocation of p53 with pifithrin µ prevents the formation of p53/Bak complexes following reovirus infection of ex vivo brain slice cultures and results in decreased apoptosis and tissue injury. These results suggest that the mitochondrial localization of p53 regulates reovirus-induced pathogenesis in the central nervous system (CNS) through its interactions with Bak. IMPORTANCE: There are virtually no specific treatments of proven efficacy for virus-induced neuroinvasive diseases. A better understanding of the pathogenesis of virus-induced CNS injury is crucial for the rational development of novel therapies. Our studies demonstrate that p53 is activated in the brain following reovirus infection and may provide a therapeutic target for virus-induced CNS disease.

Performance of claims-based algorithms for identifying incident thyroid cancer in commercial health plan enrollees receiving antidiabetic drug therapies.

BACKGROUND: Thyroid cancer incidence is increasing in the United States (US) and many other countries. The objective of this study was to develop and evaluate algorithms using administrative medical claims data for identification of incident thyroid cancer. METHODS: This effort was part of a prospective cohort study of adults initiating therapy on antidiabetic drugs and used administrative data from a large commercial health insurer in the US. Patients had at least 6 months of continuous enrollment prior to initiation during 2009-2013, with follow-up through March, 2014 or until disenrollment. Potential incident thyroid cancers were identified using International Classification of Diseases, 9th Revision (ICD-9) diagnosis code 193 (malignant neoplasm of the thyroid gland). Medical records were adjudicated by a thyroid cancer specialist. Several clinical variables (e.g., hospitalization, treatments) were considered as predictors of case status. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated to evaluate the performance of two primary algorithms. RESULTS: Charts were requested for 170 patients, 150 (88%) were received and 141 (80%) had sufficient information to adjudicate. Of the 141 potential cases identified using ≥1 ICD-9 diagnosis code 193, 72 were confirmed as incident thyroid cancer (PPV of 51% (95% CI 43-60%)). Adding the requirement for thyroid surgery increased the PPV to 68% (95% CI 58-77%); including the presence of other therapies (chemotherapy, radio-iodine therapy) had no impact. When cases were required to have thyroid surgery during follow-up and ≥2 ICD-9 193 codes within 90 days of this surgery, the PPV was 91% (95% CI 81-96%); 62 (82%) of the true cases were identified and 63 (91%) of the non-cases were removed from consideration by the algorithm as potential cases. CONCLUSIONS: These findings suggest a significant degree of misclassification results from relying only on ICD-9 diagnosis codes to detect thyroid cancer. An administrative claims-based algorithm was developed that performed well to identify true incident thyroid cancer cases.

Interaction of thrombospondin1 and CD36 contributes to obesity-associated podocytopathy.

Obesity is associated with podocyte injury and the development of proteinuria. Elevated plasma free fatty acid is one of the characteristics of obesity and has been linked to podocyte dysfunction. However, the mechanisms remain unclear. In the current study, we examined the effect of saturated free fatty acid (FFA) on human podocyte apoptosis and function in vitro. The mechanism and its in vivo relevance were also determined. We found that FFA treatment induced human podocyte apoptosis and dysfunction, which was associated with increased expression of a matricellular protein-thrombospondin1 (TSP1). FFA stimulated TSP1 expression in podocytes at the transcriptional levels through activation of MAPK pathway. Addition of purified TSP1 to cell culture media induced podocyte apoptosis and dysfunction. Tis effect is though a TGF-ß independent mechanism. Moreover, peptide treatment to block TSP1 binding to its receptor-CD36 attenuated FFA induced podocyte apoptosis, suggesting that TSP1/CD36 interaction mediates FFA-induced podocyte apoptosis. Importantly, using a diet-induced obese mouse model, in vivo data demonstrated that obesity-associated podocyte apoptosis and dysfunction were attenuated in TSP1 deficient mice as well as in CD36 deficient mice. Taken together, these studies provide novel evidence that the interaction of TSP1 with its receptor CD36 contributes to obesity--associated podocytopathy.

Hepatic outcomes among adults taking duloxetine: a retrospective cohort study in a US health care claims database.

BACKGROUND: Hepatic injury has been reported following duloxetine use. This study further examines the hepatic safety of duloxetine in a large US health insurance database. METHODS: In this propensity score-matched cohort analysis in a US commercially insured population (01 August 2004 to 31 December 2010), we compared individuals with depression and without liver disease who initiated duloxetine to comparators (venlafaxine or selective serotonin reuptake inhibitors [SSRIs], and individuals with pharmacologically untreated depression). We estimated incidence rates (IR) and 95 % confidence intervals (CI) for medical record-confirmed hepatic-related death, liver failure, and other clinically significant hepatic injury. RESULTS: Among 30,844 duloxetine initiators, 21,000 were matched to venlafaxine initiators, 28,479 to SSRI initiators, and 22,714 to untreated patients. There were no cases of hepatic-related death or liver failure. IRs of other clinically significant hepatic injury without documented alternate etiologies were higher but not statistically significant among duloxetine initiators compared to initiators of venlafaxine (0.7/1000 person-years [PY] [95 % CI: 0.2 - 1.5] vs. 0.0/1000 PY [95 % CI: 0.0 - 0.3]) and SSRIs (0.4/1000 PY [95 % CI: 0.1 - 1.0] vs. 0.0/1000 PY [95 % CI: 0.0 - 0.3]). IRs were similar among duloxetine and untreated patients (0.5/1000 PY [95 % CI: 0.1 - 1.3] vs. 0.5/1000 PY [95 % CI: 0.1 - 1.5]). When hepatic outcomes were considered irrespective of alternate etiologies, similar results were observed. CONCLUSIONS: Our findings, while not statistically significant, may suggest a higher incidence of hepatic injury other than hepatic-related death or liver failure among duloxetine initiators compared to venlafaxine and possibly SSRIs, but not untreated patients. These differences remain consistent with chance, and an elevated risk cannot be ruled in or out.

Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis.

Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-ß signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-ß levels. The interaction between macrophages and tubular cells contributes to TGF-ß-induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-ß-induced fibrosis.

A cross-sectional study of the identification of prevalent asthma and chronic obstructive pulmonary disease among initiators of long-acting ß-agonists in health insurance claims data.

BACKGROUND: Claims data are potentially useful for identifying long-acting ß-agonist (LABA) use by patients with asthma, a practice that is associated with increased mortality. We evaluated the accuracy of claims data for classifying prevalent asthma and chronic obstructive pulmonary disease (COPD) among initiators of LABAs. METHODS: This study included adult LABA initiators during 2005-2008 in a US commercial health plan. Diagnosis codes from the 6 months before LABA initiation identified potential asthma or COPD and a physician adjudicated case status using abstracted medical records. We estimated the positive predictive value (PPV) and 95% confidence intervals (CI) of covariate patterns for identifying asthma and COPD. RESULTS: We sought 520 medical records at random from 225,079 LABA initiators and received 370 (71%). The PPV for at least one asthma claim was 74% (CI 63-82), and decreased as age increased. Having at least one COPD claim resulted in a PPV of 82% (CI 72-89), and of over 90% among older patients, men, and recipients of inhaled anticholinergic drugs. Only 2% (CI 0.2-7.6) of patients with a claim for COPD alone were found to have both COPD and asthma, while 9% (CI 4-16) had asthma only. Twenty-one percent (CI 14-30) of patients with claims for both diagnoses had both conditions. Among patients with no asthma or COPD claims, 62% (CI 50-72) had no confirmed diagnosis and 29% (CI 19-39) had confirmed asthma. CONCLUSIONS: Subsets of patients with asthma, COPD, and both conditions can be identified and differentiated using claims data, although categorization of the remaining patients is infeasible. Safety surveillance for off-label use of LABAs must account for this limitation.

Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity.

Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly upregulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild-type mice. Obese wild-type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated transforming growth factor (TGF)-ß signaling and renal fibrosis. In contrast, obese TSP1-deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-ß1, fibronectin, and collagen type IV in mesangial cells isolated from wild-type mice. These leptin-stimulated effects were abolished in TSP1-deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity- or hyperleptinemia-induced kidney dysfunction.

Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function.

Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear, and the renoprotective agents during cisplatin treatment are still lacking. Here, we demonstrated that the expression and activity of cGMP-dependent protein kinase-I (PKG-I) were reduced in cisplatin-treated renal tubular cells in vitro as well as in the kidney tissues from cisplatin-treated mice in vivo. Increasing PKG activity by both pharmacological and genetic approaches attenuated cisplatin-induced kidney cell apoptosis in vitro. This was accompanied by decreased Bax/Bcl2 ratio, caspase 3 activity, and cytochrome c release. Cisplatin-induced mitochondria membrane potential loss in the tubular cells was also prevented by increased PKG activity. All of these data suggest a protective effect of PKG on mitochondria function in renal tubular cells. Importantly, increasing PKG activity pharmacologically or genetically diminished cisplatin-induced tubular damage and preserved renal function during cisplatin treatment in vivo. Mitochondria structural and functional damage in the kidney from cisplatin-treated mice was inhibited by increased PKG activity. In addition, increasing PKG activity enhanced ciaplatin-induced cell death in several cancer cell lines. Taken together, these results suggest that increasing PKG activity may be a novel option for renoprotection during cisplatin-based chemotherapy.

Linkage of routinely collected oncology clinical data with health insurance claims data--an example with aromatase inhibitors, tamoxifen, and all-cause mortality.

PURPOSE: Studies of cancer based solely on health insurance claims data typically lack information on cancer clinical characteristics that are strong predictors of treatment and prognosis. Our objective was to evaluate routinely collected cancer clinical data for adjustment of confounding using an example evaluation of mortality associated with aromatase inhibitors and tamoxifen. METHODS: This cohort study identified women with breast cancer from 2008 through 2010 using health insurance claims data linked to clinical information on stage at diagnosis, current clinical status, histology, and other clinical markers. Estimated mortality rates (MRs) and 95% confidence intervals (CI) were compared between users of aromatase inhibitors or tamoxifen, adjusted for claims-identified covariates and additionally for the clinical variables using propensity scores and proportional hazards regression models. RESULTS: The overall (n = 7974) estimated MR was 69/1000 person-years (95%CI = 62-76 person-years), 308/1000 person-years (95% CI = 273-345 person-years) for women with metastasis, and 12/1000 person-years (95%CI = 8-16 person-years) for women without active cancer. Propensity score matching of aromatase inhibitor users (n = 777) with tamoxifen users (n = 535) removed many, but not all, covariate imbalances. The hazard ratios (HRs) of all-cause mortality comparing users of aromatase inhibitors with tamoxifen users ranged from 1.0 to 1.6, with the HR most similar to previous clinical trials (0.87) coming from the claims-only analysis. CONCLUSIONS: We were able to address potential unmeasured confounders by linking clinical information to the claims data; however, there was no apparent improvement in confounding control in the chosen example. Conditioning eligibility on the clinical data restricted the sample size substantially.

Adherence to recommended dosing and monitoring for mitoxantrone in patients with multiple sclerosis: a healthcare claims database study supplemented with medical records--the RETRO study.

PURPOSE: Mitoxantrone was approved for treatment of multiple sclerosis (MS) in October 2000. Monitoring and dosing guidelines in the product labeling accompanying this indication include blood counts, liver function, and pregnancy tests at each administration. Due to potential cardiotoxicity, left ventricular ejection fraction (LVEF) testing prior to initial infusion and all infusions at a cumulative dose >or=100 mg/m(2) was recommended until April 2005 when LVEF testing before all infusions was recommended in the approved labeling. We sought to estimate provider adherence to dosing and monitoring guidelines and the effect of changes in LVEF monitoring guidelines. METHODS: MS patients who received mitoxantrone between October 2000 and June 2006 were selected from the claims of a large US health insurer. Claims for infusions and for specified tests prior to an infusion determined adherence to guidelines, with medical records providing additional information for a subset. RESULTS: There were 1827 mitoxantrone infusions to 548 eligible patients; medical records were obtained for 261 patients (1096 infusions). Most mitoxantrone recipients were 30-59 years of age and 73% were female. Adherence to recommended dosing was higher than for recommended monitoring. Blood counts were conducted for most infusions (78-83%), while liver function tests (LFT) were performed less often (47-54% of infusions). Pregnancy tests were performed for 10% or fewer of the infusions administered to reproductive age women. Adherence with LVEF testing guidelines improved following labeling changes. CONCLUSIONS: Adherence to recommended monitoring was incomplete, but amenable to change. Automated assessment through insurance claims supplemented with medical record data provides a balanced means for studying adherence to recommendations.

Is there an association between liraglutide use and female breast cancer in a real-world setting?

BACKGROUND: Liraglutide is a human glucagon-like peptide-1 receptor agonist approved for treatment of adults with type 2 diabetes mellitus at a maximum dose of 1.8 mg/day (Victoza®) and more recently at 3.0 mg/day for weight management (Saxenda®). During the evaluation of liraglutide for approval in weight management, a minor imbalance in the numbers of reported breast neoplasms was observed, motivating the present study. Our objective was to quantify the association between liraglutide and incidence of breast cancer (BC) among women in a real-world setting. PATIENTS AND METHODS: Women initiating liraglutide or other antidiabetic therapies and who were enrolled in a large US health plan (2010-2014) were included. Comparisons of BC incidence rates were made between matched cohorts of initiators of liraglutide and cohorts of initiators of exenatide, metformin, pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors separately and as two "all comparators" groupings: with or without exenatide. Women with two or more claims with BC diagnosis codes within 61days of each other were identified as possible cases, with additional confirmation by clinician review of comprehensive claims listings. Propensity score matched intention-to-treat (ITT) and time-on-drug (TOD) analyses were completed via Poisson regression. A latency analysis was performed. RESULTS: Relative risks for BC for liraglutide vs comparators from the ITT analyses ranged from 0.90 (95% CI: 0.67-1.22) for both the "all comparator" and "all comparator except exenatide" cohorts to 1.46 (95% CI: 0.96-2.22) relative to exenatide. Latency analyses excluding the first year of follow-up yielded slightly attenuated point estimates. The TOD analyses of cumulative use of liraglutide suggested no increased risk of BC. CONCLUSION: Neither the ITT (overall or latency analysis) nor cumulative TOD analyses suggested an elevated risk of BC among liraglutide initiators. Short length of follow-up and the potential for confounding by unmeasured factors limit the full assessment of long-term risk.

Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users.

OBJECTIVE: To estimate the incidence of venous thromboembolism, acute myocardial infarction, and ischemic stroke among transdermal contraceptive system users compared with users of norgestimate-containing oral contraceptives with 35 mcg ethinyl estradiol. METHODS: We began with insurance claims data from UnitedHealthcare. We identified women exposed to the transdermal contraceptive system or norgestimate-containing oral contraceptives from April 2002 through December 2004. Outcomes were confirmed from medical records. We calculated incidence rates and age-adjusted incidence rate ratios. In a nested case-control analysis, we investigated and controlled for confounding. RESULTS: There were 49,048 woman-years of transdermal contraceptive system exposure and 202,344 woman-years of norgestimate-containing oral contraceptives exposure. There was a more than two-fold increase in the venous thromboembolism rate (incidence rate ratio 2.2, 95% confidence interval [CI] 1.3-3.8) among transdermal contraceptive system users (20 cases, 40.8 per 100,000 woman-years) compared with norgestimate-containing oral contraceptives users (37 cases, 18.3 per 100,000 woman-years). Acute myocardial infarction occurred in three transdermal contraceptive system users compared with seven among norgestimate-containing oral contraceptives users (incidence rate ratio 1.8, 95% CI 0.5-6.8). No strokes occurred among transdermal contraceptive system users, whereas 10 occurred among norgestimate-containing oral contraceptives users. In the nested case-control analysis, after exclusions for high-risk factors, the odds ratio for venous thromboembolism was 2.4 (95% CI 1.1-5.5). CONCLUSION: There was a more than two-fold increase in the risk of venous thromboembolism associated with use of the transdermal contraceptive system. Acute myocardial infarction and stroke occurred too rarely to ascertain precise risk estimates. LEVEL OF EVIDENCE: II.

Drug copayment and adherence in chronic heart failure: effect on cost and outcomes.

STUDY OBJECTIVE: To measure the association among prescription copayment, drug adherence, and subsequent health outcomes among patients with chronic heart failure (CHF). DESIGN: Retrospective cohort study. DATA SOURCE: Database of a large, national health insurance plan. PATIENTS: Patients with CHF receiving commercial and Medicare supplemental benefits. MEASUREMENTS AND MAIN RESULTS: We estimated adherence to therapy with beta-blockers or angiotensin-converting enzyme (ACE) inhibitors in 2002 by using the medication possession ratio, an estimate of the proportion of days a patient was exposed to a drug while taking a drug regimen. For 2003, we measured the annualized total cost of health care and identified hospitalizations with a diagnostic code for CHF. We used a two-stage regression approach to model the association among copayment, adherence, and patient outcomes. For patients taking ACE inhibitors, a $10 increase in copayment was associated with a 2.6% decrease in the medication possession ratio (95% confidence interval [CI] 2.0-3.1%). This change in adherence was associated with a predicted 0.8% decrease in medical costs (95% CI -4.2-2.5%) but a predicted 6.1% increase in the risk of hospitalization for CHF (95% CI 0.5-12.0%). Among patients taking beta-blockers, a $10 increase in copayment was associated with a 1.8% decrease in the medication possession ratio (95% CI 1.4-2.2%). This change in adherence was associated with a predicted 2.8% decrease in medical costs (95% CI -5.9-0.1%) and a predicted 8.7% increase in the risk of hospitalization for CHF (95% CI 3.8-13.8%). CONCLUSION: Among patients with CHF, higher drug copayments were associated with poorer adherence. The change was relatively small and did not affect predicted total health care costs, but it was sufficient to increase the predicted risk of hospitalization for CHF.

CD47 deficiency protects mice from diet-induced obesity and improves whole body glucose tolerance and insulin sensitivity.

CD47 is a transmembrane protein with several functions including self-recognition, immune cell communication, and cell signaling. Although it has been extensively studied in cancer and ischemia, CD47 function in obesity has never been explored. In this study, we utilized CD47 deficient mice in a high-fat diet induced obesity model to study for the first time whether CD47 plays a role in the development of obesity and metabolic complications. Male CD47 deficient and wild type (WT) control mice were fed with either low fat (LF) or high fat (HF) diets for 16 weeks. Interestingly, we found that CD47 deficient mice were protected from HF diet-induced obesity displaying decreased weight gain and reduced adiposity. This led to decreased MCP1/CCR2 dependent macrophage infiltration into adipose tissue and reduced inflammation, resulting in improved glucose tolerance and insulin sensitivity. In addition, CD47 deficiency stimulated the expression of UCP1 and carnitine palmitoyltransferase 1b (CPT1b) levels in brown adipose tissue, leading to increased lipid utilization and heat production. This contributes to the increased energy utilization and reduced adiposity observed in these mice. Taken together, these data revealed a novel role for CD47 in the development of obesity and its related metabolic complications.

Thrombospondin1 deficiency attenuates obesity-associated microvascular complications in ApoE-/- mice.

Obesity is associated with insulin resistance and the increased development of vascular complications. Previously, we have demonstrated that thrombospondin1 (TSP1) regulates macrophage function and contributes to obesity associated inflammation and insulin resistance. However, the role of TSP1 in the development of obesity associated vascular complications is not clear. Therefore, in the current study, we investigated whether TSP1 deficiency protects mice from obesity associated micro as well as macro-vascular complications in ApoE-/- mice. In this study, male ApoE-/- mice and ApoE-/-TSP1-/- mice were fed with a low-fat (LF) or a high-fat (HF) diet for 16 weeks. We found that body weight and fat mass increased similarly between the ApoE-/-TSP1-/- mice and ApoE-/- mice under HF feeding conditions. However, as compared to obese ApoE-/- mice, obese ApoE-/-TSP1-/- mice had improved glucose tolerance, increased insulin sensitivity, and reduced systemic inflammation. Aortic atherosclerotic lesion formation was similar in these two groups of mice. In contrast, albuminuria was attenuated and kidney fibrosis was reduced in obese ApoE-/-TSP1-/- mice compared to obese ApoE-/- mice. The improved kidney function in obese ApoE-/-TSP1-/- mice was associated with decreased renal lipid accumulation. Together, these data suggest that TSP1 deficiency did not affect the development of obesity associated macro-vascular complication, but attenuated obesity associated micro-vascular complications.

Biliary dyskinesia: how effective is cholecystectomy?

INTRODUCTION: Studies on biliary dyskinesia have been based on short-term surgical follow-up and do not take into consideration that most patients are discharged from surgical follow-up after the first postoperative visit and that for persistent or recurrent symptoms they are frequently seen by primary care providers and subsequently referred to gastroenterologists. We aimed to study this pattern and assess which factors predict patients that will benefit from cholecystectomy. METHOD: This is a retrospective analysis of medical records of patients who underwent cholecystectomy for biliary dyskinesia from February 2001 to January 2010 with a minimum postoperative follow-up of 6 months. RESULTS: At initial surgical follow-up, 19 of 141 (13.4%) patients said they had persistent symptoms. However, when subsequent visits were analyzed, 61 of 141 (43.3%) patients with persistent or recurrent symptoms saw their primary care provider. These symptoms were epigastric or right upper quadrant pain in 43 patients or 30% of those undergoing cholecystectomy. The only factor that distinguished patients with and without resolution of symptoms after cholecystectomy was the pathologic finding of inflammation (p = 0.02). CONCLUSION: Cholecystectomy does not appear to be as effective for biliary dyskinesia when long-term follow-up is evaluated.

Risk of mortality, fatal infection, and fatal malignancy related to use of anti-tumor necrosis factor-α biologics by rheumatoid arthritis patients.

OBJECTIVE: To estimate rates of all-cause mortality, fatal infection, and fatal malignancy in rheumatoid arthritis (RA) patients treated with anti-tumor necrosis factor-α (anti-TNF) biologics. METHODS: A retrospective cohort study of RA patients initiating therapy with adalimumab, etanercept, or infliximab from January 2000 to December 2008 was conducted using an administrative database of a large health care insurer. Patients were followed for the occurrence of fatal events, which were identified using the National Death Index database. Overall and anti-TNF biologic-stratified incidence rates per 1000 person-years were calculated. Primary analyses were time-on-drug based on current anti-TNF biologic exposure on the outcome date for fatal infection and intent-to-treat based on the anti-TNF biologic initiated at cohort entry for fatal malignancy. RESULTS: Seven thousand seven hundred thirty-four patients initiated an anti-TNF biologic with 13,296 person-years of observation. Seventy-one deaths were identified, including 12 fatal infections and 21 fatal malignancies. The all-cause mortality rate was 5.34 per 1000 person-years. Incidence rates for fatal infection were similar among anti-TNF biologic current exposure groups (0.78 to 0.88 per 1000 person-years). Incidence rates for fatal malignancy were similar among anti-TNF biologic initiator groups (1.24 to 1.84 per 1000 person-years). CONCLUSIONS: The all-cause mortality rate in RA patients treated with anti-TNF biologics was lower than in previous studies in similar non-US populations, but comparable to mortality rates in the US general population. Fatal infection and fatal malignancy rates were similar across anti-TNF biologic groups. Further studies, designed to detect risk differences associated with anti-TNF biologic use and baseline risk factors, would provide additional information.