Jianjin Xu

Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns.

Background:Toll-like receptor (TLR)-mediated inflammation may contribute to neonatal sepsis, for which pentoxifylline (PTX), a phosphodiesterase inhibitor that raises intracellular cAMP, is a candidate adjunctive therapy. We characterized the anti-inflammatory effects of PTX toward TLR-mediated production of inflammatory (tumor necrosis factor (TNF) and interleukin (IL)-1β) and proresolution (IL-6 and IL-10) cytokines in human newborn and adult blood.Methods:Newborn cord and adult blood were treated with PTX (50–400 µmol/l) before, during or after stimulation with LPS (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/ATP (inflammasome activation). Cytokines were measured by multiplex assay (supernatants), intracellular cytokines and signaling molecules by flow cytometry, and mRNA by quantitative real-time PCR.Results:Whether added 2 h pre-, simultaneously to, or 2 h post-TLR stimulation, PTX inhibited TLR-mediated cytokine production in a concentration-dependent manner, with greater efficacy and potency in newborn blood, decreasing intracellular TNF and IL-1β with relative preservation of IL-10 and IL-6. PTX decreased TLR-mediated TNF mRNA while increasing IL-10 mRNA. Neonatal plasma factors contributed to the anti-inflammatory effects of PTX in newborn blood that were independent of soluble TNF receptor concentrations, p38 MAPK phosphorylation and IĸB degradation.Conclusion:PTX is a potent and efficacious inhibitor of TLR-mediated inflammatory cytokines in newborn cord blood and a promising neonatal anti-inflammatory agent.

National Trends and In-Hospital Outcomes in Pregnant Women With Heart Disease in the United States

Investigation of trends and outcomes in heart disease (HD) and pregnancy has been limited. We chose to identify the prevalence, trends, and outcomes of pregnant women with different forms of HD in the United States. Healthcare Cost and Utilization Projects National Inpatient Sample was screened for hospital admissions for delivery in pregnant women with HD from 2003 to 2012. Maternal clinical characteristics and outcomes were identified in women with and without HD, and in HD subtypes: congenital (CHD), valvular HD, cardiomyopathy, and pulmonary hypertension (PH). Primary outcomes of interest were prevalence, trends, and major adverse cardiac events (MACEs), a composite of in-hospital death, acute myocardial infarction, heart failure, arrhythmia, cerebrovascular event, embolic events, or cardiac complications of anesthesia. We studied 81,295 patients with HD and 39,894,032 without. CHD was the most frequent type (41.8%, 33,982 of 81,295 patients), followed by valvular HD (30.9%, 25,138 of 81,295 patients), cardiomyopathy (20.8%, 16,926 of 81,295 patients), and PH (6.5%, 5,250 of 81,295 patients). MACE was highest among women with cardiomyopathy and lowest among women with CHD (44.0%, 7,449 of 16,926 vs 6.2%, 2,102 of 33,982; p <0.0001). PH patients had the highest in-hospital death, followed by cardiomyopathy patients (1.0%, 51 of 5,250 and 0.7%, 124 of 16,926, respectively). Pregnant women with HD significantly increased by 24.7%, related to increases in cardiomyopathy, CHD, and PH from 2003 to 2012. MACE significantly increased by 18.8%. In conclusion, pregnancy in women with HD is increasing, particularly for high risk conditions such as cardiomyopathy and PH. There is a significant and gradual increase in MACE for women with HD.

Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro

Introduction Neonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti-inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti-inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production. Methods Whole newborn and adult blood was treated with PTX (50–200 μM), DEX (10−10–10−7 M), or AZI (2.5–20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewes additivity. Results PTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro-inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10. (PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α, while (PTX+AZI) synergistically decreased induction of TNF, IL-1β, and IL-6. Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA. Conclusions Age, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity.

Pulmonary Hypertension and Pregnancy Outcomes: Insights From the National Inpatient Sample

Background Pregnant women with pulmonary hypertension (PH) are at risk for adverse cardiac outcomes, particularly at the time of labor and delivery. The purpose of this study is to define the impact of PH on pregnancy outcomes and the risk of major adverse cardiac events (MACE). Methods and Results The National Inpatient Sample was screened for hospital admissions of women delivering during the years 2003 to 2012. The primary outcome was MACE, a composite of death, cardiac arrest, cardiogenic shock, myocardial infarction, respiratory failure, arrhythmia, stroke, and embolic event. Data on 1519 patients with PH and 6 757 582 without heart disease or PH were available. There were 59.6% with isolated PH; 10.7% with PH and congenital heart disease; 18.1% with PH and valvular heart disease; 3% with PH and valvular heart disease and congenital heart disease; 6.6% PH and cardiomyopathy; and 1.9% with PH and cardiomyopathy and valvular heart disease. Compared with women without heart disease or PH, women with PH experienced significantly higher MACE (24.8 versus 0.4%, P<0.0001). Among the subsets of women with PH, the highest MACE was noted in women with the combination of PH and cardiomyopathy and valvular heart disease, and PH and cardiomyopathy, primarily because of heart failure and arrhythmia. Women with PH were significantly more likely to experience eclampsia syndromes, preterm delivery, and intrauterine fetal demise (P<0.0001 for all). PH subtype was significantly associated with MACE in multivariable analysis (P<0.001). Conclusions In a contemporary data set of pregnant women in the United States, PH was associated with an increase in MACE during the hospitalization for delivery, with an exceptionally elevated risk among women with associated cardiomyopathy.

Impact of chronic kidney disease in patients undergoing percutaneous or surgical carotid artery revascularization: Insights of the healthcare cost and utilization Project's National Inpatient Sample

BACKGROUND/PURPOSE Carotid artery stenting (CAS) and carotid artery endarterectomy (CEA) are complementary techniques for management of patients with carotid artery stenosis. This study investigates the impact of chronic kidney disease (CKD) and age on outcomes after carotid artery revascularization. METHODS/MATERIALS National Inpatient Sample was surveyed for CAS and CEA among stage 3 and 4 CKD and stage 5/end stage renal disease (ESRD) patients from 2004 to 2012. Primary endpoint was in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) stratified by kidney function and age. Regression analysis and propensity score matching were utilized. RESULTS There were 3299 patients that underwent CEA and 652 underwent CAS with stage 3 and 4 CKD. Whereas, 1630 patients underwent CEA and 511 patients underwent CAS with stage 5 CKD/ESRD. Patients undergoing CAS had more in-hospital MACCE. Coronary artery disease (OR1.35, 95%CI:1.07-1.70) and CAS (OR1.35, 95%CI:1.02-1.77) were independently associated with MACCE for stage 3 and 4 CKD patients. For the stage 5 CKD/ESRD cohort, CAS (OR1.75, 95%CI:1.29-2.37) was independently associated with MACCE. Stratifying by age, showed no difference in event rates except for higher MACCE among patients <60years old with stage 5 CKD/ESRD undergoing CAS (p<0.001). Propensity score matching showed that treatment type had no significant effect on MACCE rates. CONCLUSIONS Among CKD cohorts studied nationally, in-hospital MACCE were higher for patients that underwent CAS. Overall, age group analyses showed that there was no difference in MACCE rates between CAS and CEA. Although CAS was independently associated with MACCE, propensity score matching showed no risk difference of MACCE between CAS and CEA for either CKD cohort.

Abstract 33: The Risk-Adjusted Impact of Patient Insurance Status on Perioperative Outcomes Following Ventral Hernia Repair in New York State

METHODS: We analyzed data from our institution’s prospectively collected National Cancer Institute-Designated Comprehensive Cancer Center Tumor Registry. We used the Chi-squared test and multivariable logistic regression to estimate associations between race/ethnicity, insurance type, age, and breast reconstruction rate. Likelihood-ratio tests assessed the interaction between these associations and period of surgery.