The Known and Unknown: Investigating the Carcinogenic Potential of Plastic Additives.

Microplastics are routinely ingested and inhaled by humans and other organisms. Despite the frequency of plastic exposure, little is known about its health consequences. Of particular concern are plastic additives─chemical compounds that are intentionally or unintentionally added to plastics to improve functionality or as residual components of plastic production. Additives are often loosely bound to the plastic polymer and may be released during plastic exposures. To better understand the health effects of plastic additives, we performed a comprehensive literature search to compile a list of 2,712 known plastic additives. Then, we performed an integrated toxicogenomic analysis of these additives, utilizing cancer classifications and carcinogenic expression pathways as a primary focus. Screening these substances across two chemical databases revealed two key observations: (1) over 150 plastic additives have known carcinogenicity and (2) the majority (∼90%) of plastic additives lack data on carcinogenic end points. Analyses of additive usage patterns pinpointed specific polymers, functions, and products in which carcinogenic additives reside. Based on published chemical-gene interactions, both carcinogenic additives and additives with unknown carcinogenicity impacted similar biological pathways. The predominant pathways involved DNA damage, apoptosis, the immune response, viral diseases, and cancer. This study underscores the urgent need for a systematic and comprehensive carcinogenicity assessment of plastic additives and regulatory responses to mitigate the potential health risks of plastic exposure.

P076 The Role of Dual Biologic Therapy in Inflammatory Bowel Disease.

BACKGROUND: As the prevalence of complex inflammatory bowel disease and extraintestinal manifestations continue to rise, more patients are requiring complex treatment regimens. In some cases, patients may require more than one biologic agent to target different areas in the inflammatory cascade. Although a body of data is emerging, there is currently no consensus on patient and agent selection for dual therapy or adverse outcomes of therapy. METHODS: A retrospective chart review of all patients receiving dual biologic therapy for IBD at a single tertiary care center was conducted. This was exempted by the IRB. Data regarding the patient and disease course, indication for dual biologic use, other concurrent therapies, infections and any adverse events was collected from the EMR. RESULTS: Ten patients (9 Crohn's Disease, 1 Ulcerative Colitis) were identified as receiving dual biologic therapy. The most common combination therapy was ustekinumab with vedolizumab (5) or an anti-TNF (4); one patient was receiving adalimumab with vedolizumab. Nine patients were also on an immunomodulator (6 methotrexate, 2 6-mercaptopurine, 1 azathioprine) and three required steroids in addition to dual biologic therapy. The majority (8) of the patients were started on dual biologic therapy due to refractory GI symptoms, the others were due to extraintestinal manifestations (EIMs) with psoriatic arthritis and ankylosing spondylitis. Nine patients had significant symptomatic improvement on dual biologic regimen and all six patients with follow-up endoscopy demonstrated improvement. Two patients developed infectious diarrhea (C.difficile and e. coli), no other significant infections were noted. No patients were found to have malignancy or any other adverse effects of treatment during the reviewed period. CONCLUSION: Dual biologic therapy can be used with improvement in symptomatic and endoscopic findings of IBD. The combination use of two biologic agents does not appear to have additional infectious risk compared to single agent and no other adverse events were described. Longer follow-up and larger patient populations are needed to verify the combination of biologic mechanisms for therapy of refractory IBD and EIMs.

Nonalcoholic Fatty Liver Disease Among Individuals with HIV Mono-infection: A Growing Concern?

PURPOSE OF REVIEW: Liver disease is a leading cause of non-AIDS-related death in the HIV population since the introduction of highly active antiretroviral treatment (HAART). Recent studies suggest that patients with HIV are at high risk for nonalcoholic fatty liver disease (NAFLD) and progressive liver fibrosis. Evidence for the prevalence, risk factors, and diagnostic methodologies of NAFLD in patients with HIV mono-infection is summarized here. RECENT FINDINGS: Although limited, published studies suggest that the prevalence of NAFLD is higher (30-50%) and progresses at an increased rate in patients with HIV compared to the general population. Identifying those at risk for significant liver fibrosis is critical, preferably with non-invasive screening tests. While there is a paucity of evidence in this population, transient elastography (TE) appears to provide a sensitive, non-invasive screening modality. Identifying NAFLD early will allow for dietary and lifestyle interventions, as well as future drug therapies to decrease the risk of progressive liver fibrosis and cirrhosis in the high-risk HIV population. Clinicians should be aware of this risk and consider using TE for NAFLD diagnosis and surveillance.

Contemporary imaging following atrial redirection surgery for transposition of the great arteries.

CLINICAL INTRODUCTION: A young man attended the adult congenital heart disease clinic for routine follow-up. He had a diagnosis of transposition of the great arteries (TGA) and underwent a Senning procedure at 10 months of age. He had remained well over the intervening years, was fully saturated, with a normal exercise tolerance, no cardiovascular symptoms and no history of arrhythmia or symptoms suggesting thromboembolic events. Transthoracic echocardiogram is shown in figure 1A and cardiac MRI image in figure 1B. QUESTION: Which of the following is the most likely diagnosis? Intact atrial pathwaysSecundum atrial septal defectBaffle leakPrimum atrial septal defectBaffle obstruction.

Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats.

Combining effective treatments with diverse mechanisms of action for smoking cessation may provide better therapy by targeting multiple points of control in the neural circuits underlying addiction. Previous research in a rat model has shown that dextromethorphan, which has α3ß4 nicotinic and NMDA glutamatergic antagonist actions, significantly decreases nicotine self-administration. We have found in the rat model that the H1 histamine antagonist pyrilamine and the serotonin 5HT2C agonist lorcaserin also significantly reduce nicotine self-administration. The current studies were conducted to determine the interactive effects of dextromethorphan with pyrilamine and lorcaserin on nicotine self-administration in rats. Young adult female rats were fitted with jugular IV catheters and trained to self-administer a nicotine infusion dose of 0.03-mg/kg/infusion. In an initial dose-effect function study of dextromethorphan, we found a monotonic decrease in nicotine self-administration over a dose range of 1 to 30-mg/kg with the lowest effective dose of 3-mg/kg. Then, with two separate cohorts of rats, dextromethorphan (0, 3.3, and 10-mg/kg) interactions with pyrilamine (0, 4.43, and 13.3-mg/kg) were investigated as well as interactions with lorcaserin (0, 0.3125 and 0.625-mg/kg). In the pyrilamine-dextromethorphan interaction study, an acute dose of pyrilamine (13.3-mg/kg) as well as an acute dose of dextromethorphan caused a significant decrease in nicotine self-administration. There were mutually augmenting effects of these two drugs. The combination of dextromethorphan (10-mg/kg) and pyrilamine (13.3-mg/kg) significantly lowered nicotine self-administration relative to either 10-mg/kg of dextromethorphan alone (p<0.05) or 13.3-mg/kg of pyrilamine alone (p<0.0005). In the lorcaserin-dextromethorphan study, an acute dose of lorcaserin (0.312-mg/kg) as well as an acute dose of dextromethorphan (10-mg/kg) caused a significant decrease in nicotine self-administration replicating previous findings. Augmenting interactions were observed with dextromethorphan and pyrilamine as well as lorcaserin. These findings suggest that combination therapy may be more effective smoking cessation treatments than monotherapy.

Postoperative pulmonary calcification in a child with truncus arteriosus.

Pulmonary calcification is uncommon in children. It is rarely described following cardiac surgery. Here, the authors describe the case of an infant who developed extensive pulmonary calcification following the repair of truncus arteriosus.

Aberrant production of extracellular matrix proteins and dysfunction in kidney endothelial cells with a short duration of diabetes.

Diabetic nephropathy is the most common cause of end-stage renal disease and is a major risk factor for cardiovascular disease. In the United States, microvascular complications during diabetic nephropathy contribute to high morbidity and mortality rates. However, the cell-autonomous impact of diabetes on kidney endothelial cell function requires further investigation. Male Akita/+ [autosomal dominant mutation in the insulin II gene (Ins2)] mice reproducibly develop diabetes by 4 wk of age. Here, we examined the impact a short duration of diabetes had on kidney endothelial cell function. Kidney endothelial cells were prepared from nondiabetic and diabetic mice (4 wk of diabetes) to delineate the early changes in endothelial cell function. Kidney endothelial cells from Akita/+ mice following 4 wk of diabetes demonstrated aberrant expression of extracellular matrix proteins including decreased osteopontin and increased fibronectin expression which correlated with increased α5-integrin expression. These changes were associated with the attenuation of migration and capillary morphogenesis. Kidney endothelial cells from Akita/+ mice had decreased VEGF levels but increased levels of endothelial nitric oxide synthase(eNOS) and NO, suggesting uncoupling of VEGF-mediated NO production. Knocking down eNOS expression in Akita/+ kidney endothelial cells increased VEGF expression, endothelial cell migration, and capillary morphogenesis. Furthermore, attenuation of sprouting angiogenesis of aortas from Akita/+ mice with 8 wk of diabetes was restored in the presence of the antioxidant N-acetylcysteine. These studies demonstrate that aberrant endothelial cell function with a short duration of diabetes may set the stage for vascular dysfunction and rarefaction at later stages of diabetes.

BIM deficiency differentially impacts the function of kidney endothelial and epithelial cells through modulation of their local microenvironment.

The extracellular matrix (ECM) acts as a scaffold for kidney cellular organization. Local secretion of the ECM allows kidney cells to readily adapt to changes occurring within the kidney. In addition to providing structural support for cells, the ECM also modulates cell survival, migration, proliferation, and differentiation. Although aberrant regulation of ECM proteins can play a causative role in many diseases, it is not known whether ECM production, cell adhesion, and migration are regulated in a similar manner in kidney epithelial and endothelial cells. Here, we demonstrate that lack of BIM expression differentially impacts kidney endothelial and epithelial cell ECM production, migration, and adhesion, further emphasizing the specialized role of these cell types in kidney function. Bim -/- kidney epithelial cells demonstrated decreased migration, increased adhesion, and sustained expression of osteopontin and thrombospondin-1 (TSP1). In contrast, bim -/- kidney endothelial cells demonstrated increased cell migration, and decreased expression of osteopontin and TSP1. We also observed a fivefold increase in VEGF expression in bim -/- kidney endothelial cells consistent with their increased migration and capillary morphogenesis. These cells also had decreased endothelial nitric oxide synthase activity and nitric oxide bioavailability. Thus kidney endothelial and epithelial cells make unique contributions to the regulation of their ECM composition, with specific impact on adhesive and migratory properties that are essential for their proper function.

Under the radar: smokeless tobacco advertising in magazines with substantial youth readership.

OBJECTIVES: In light of the Smokeless Tobacco Master Settlement Agreement (STMSA) and the fact that smokeless tobacco advertising has received little attention, we examined industry data to assess smokeless tobacco advertising in popular magazines. Of particular interest was the level of advertising in magazines with high youth readership and the amount of reach and frequency that was generated among readers aged 12 to 17 years. METHODS: We used readership data from Mediamark Research Inc, advertising expenditure data from TNS Media Intelligence, and Adplus, a media planning program from Telmar to document the composition of adult and youth readership of magazines in which smokeless tobacco products were advertised, industry expenditures on advertising, and adolescents' exposure to smokeless tobacco advertising. RESULTS: The STMSA appears to have had a limited effect on the advertising of smokeless tobacco products to youth; both before and after the agreement, smokeless tobacco companies advertised in magazines with high adolescent readership. CONCLUSIONS: Popular magazines with smokeless tobacco advertising reach a large number of adolescents through a combination of both youth-oriented and adult magazines. These exposure levels have generally increased since the STMSA.

Understanding the role of cigarette promotion and youth smoking in a changing marketing environment.

In 2001, $11.21 billion was spent on domestic cigarette advertising and promotion, an increase of 16.9% over 2000. This article explains how cigarette industry efforts stimulate demand and encourage smoking within the context of recent changes, including the 1998 Master Settlement Agreement (MSA) and resulting litigation, and variations in tobacco marketing policies. Communication concepts are combined with adolescent development concepts to explain how youth are impacted. Industry documents and current syndicated research data are used to reveal and explain key concepts.