Browsing by Subject "toxicity"
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Item Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure(Oxford University Press, 2016-04) Fu, Sherleen; Jiang, Wendy; Gao, Xiang; Zeng, Andrew; Cholger, Daniel; Cannon, Jason; Chen, Jinhui; Zheng, Wei; Department of Neurological Surgery, School of MedicineAdult neurogenesis occurs in brain subventricular zone (SVZ). Our recent data reveal an elevated proliferation of BrdU(+) cells in SVZ following subchronic manganese (Mn) exposure in rats. This study was designed to distinguish Mn effect on the critical stage of adult neurogenesis, ie, proliferation, migration, survival and differentiation from the SVZ via the rostral migratory stream to the olfactory bulb (OB). Adult rats received a single ip-dose of BrdU at the end of 4-week Mn exposure to label proliferating cells. Immunostaining and cell-counting showed a 48% increase of BrdU(+) cells in Mn-exposed SVZ than in controls (P< .05). These BrdU(+) cells were identified as a mixed population of mainly GFAP(+) type-B neural stem cells, Nestin(+) type-C transit progenitor cells, DCX(+) migratory neuroblasts and Iba1(+) microglial cells. Another group of adult rats received 3 daily ip-injections of BrdU followed by subchronic Mn exposure. By 4-week post BrdU labeling, most of the surviving BrdU(+) cells in the OB were differentiated into NeuN(+) matured neurons. However, survival rates of BrdU/NeuN/DAPI triple-labeled cells in OB were 33% and 64% in Mn-exposed and control animals, respectively (P< .01). Infusion of Cu directly into the lateral ventricle significantly decreased the cell proliferation in the SVZ. Taken together, these results suggest that Mn exposure initially enhances the cell proliferation in adult SVZ. In the OB, however, Mn exposure significantly reduces the surviving adult-born cells and markedly inhibits their differentiation into mature neurons, resulting in an overall decreased adult neurogenesis in the OB.Item Aluminum Effects in Infants and Children(AAP, 2019-12) Corkins, Mark R.; Abrams, Steven A.; Fuchs, George J.; Goday, Praveen S.; Hannon, Tamara S.; Kim, Jae H.; Lindsey, C. Wesley; Rome, Ellen S.; Pediatrics, School of MedicineAluminum has no known biological function; however, it is a contaminant present in most foods and medications. Aluminum is excreted by the renal system, and patients with renal diseases should avoid aluminum-containing medications. Studies demonstrating long-term toxicity from the aluminum content in parenteral nutrition components led the US Food and Drug Administration to implement rules for these solutions. Large-volume ingredients were required to reduce the aluminum concentration, and small-volume components were required to be labeled with the aluminum concentration. Despite these rules, the total aluminum concentration from some components continues to be above the recommended final concentration. The concerns about toxicity from the aluminum present in infant formulas and antiperspirants have not been substantiated but require more research. Aluminum is one of the most effective adjuvants used in vaccines, and a large number of studies have documented minimal adverse effects from this use. Long-term, high-concentration exposure to aluminum has been linked in meta-analyses with the development of Alzheimer disease.Item Bisphenol A, Obesity, and Type 2 Diabetes Mellitus: Genuine Concern or Unnecessary Preoccupation?(Elsevier, 2014-07) Mirmira, Priyadarshini; Evans-Molina, Carmella; Department of Medicine, IU School of MedicineBisphenol A or BPA is a ubiquitious industrial chemical found in a variety of plastic containers intended for food storage and in the epoxy resin linings of metal food and beverage cans, where it is used to prevent corrosion, food contamination, and spoilage. BPA has been recently linked to a wide variety of medical disorders and is known to have estrogenic activity with genomic as well as non-genomic estrogen-receptor mediated effects. Given rapidly increasing prevalence rates of metabolic disorders like obesity and Type 2 diabetes, BPA has recently come under intense scrutiny in scientific and lay communities as a potential endocrine disrupting compound with diabetogenic effects. The purpose of this review is to critically examine available literature investigating the link between BPA and alterations in metabolic health. Here, we discuss typical levels of exposure to BPA in daily life and analyze both epidemiological human data and mechanistic preclinical studies that have tested associations between BPA and obesity and diabetes. Finally, we summarize the current policies and views of national and international regulatory agencies regarding the safety of BPA use.Item Central Airway Toxicity After High Dose Radiation: A Combined Analysis of Prospective Clinical Trials for Non-Small Cell Lung Cancer(Elsevier, 2020) Wang, Weili; Matuszak, Martha M.; Hu, Chen; Huang, Ke Colin; Chen, Eileen; Arenberg, Douglas; Curtis, Jeffrey L.; Jolly, Shruti; Jin, Jian-Yue; Machtay, Mitchell; Haken, Randall K.; Kong, Feng-Ming (Spring); Radiation Oncology, School of MedicinePurpose To study the dosimetric risk factors for radiation-induced proximal bronchial tree (PBT) toxicity in patients treated with radiation therapy for non-small cell lung cancer (NSCLC). Methods and Materials Patients with medically inoperable or unresectable NSCLC treated with conventionally fractionated 3-dimensional conformal radiation therapy (3DCRT) in prospective clinical trials were eligible for this study. Proximal bronchial tree (PBT) and PBT wall were contoured consistently per RTOG 1106 OAR-Atlas. The dose-volume histograms (DVHs) of physical prescription dose (DVHp) and biological effective dose (α/β = 2.5; DVH2.5) were generated, respectively. The primary endpoint was PBT toxicities, defined by CTCAE 4.0 under the terminology of bronchial stricture/atelectasis. Results Of 100 patients enrolled, with a median follow-up of 64 months (95% confidence interval [CI], 50-78), 73% received 70 Gy or greater and 17% developed PBT toxicity (grade 1, 8%; grade 2, 6%; grade 3, 0%; and grade 4, 3%). The median time interval between RT initiation and onset of PBT toxicity was 8.4 months (95% CI, 4.7-44.1). The combined DVHs showed that no patient with a PBT maximum physical dose <65 Gy developed any PBT toxicity. Cox proportional hazards analysis and receiver operating characteristic analysis demonstrated that V75 of PBT was the most significant dosimetric parameter for both grade 1+ (P = .035) and grade 2+ (P = .037) PBT toxicities. The dosimetric thresholds for V75 of PBT were 6.8% and 11.9% for grade 1+ and grade 2+ PBT toxicity, respectively. Conclusions V75 of PBT appeared be the most significant dosimetric parameter for PBT toxicity after conventionally fractionated thoracic 3DCRT. Constraining V75 of PBT can limit clinically significant PBT toxicity.Item Effect of oral methyl-t-butyl ether (MTBE) on the male mouse reproductive tract and oxidative stress in liver(Elsevier, 2008) de Peyster, Ann; Rodriguez, Yvonne; Shuto, Rika; Goldberg, Beck; Gonzales, Frank; Pu, Xinzhu; Klaunig, James E.; Department of Pharmacology and Toxicology, IU School of MedicineMTBE is found in water supplies used for drinking and other purposes. These experiments follow up on earlier reports of reproductive tract alterations in male mice exposed orally to MTBE and explored oxidative stress as a mode of action. CD-1 mice were gavaged with 400–2000 mg/kg MTBE on days 1, 3, and 5, injected ip with hCG (2.5 IU/g) on day 6, and necropsied on day 7. No effect was seen in testis histology or testosterone levels. Using a similar dosing protocol, others had initially reported disruption of seminiferous tubules in MTBE–gavaged mice, although later conclusions published were consistent with our findings. Another group had also reported testicular and other reproductive system abnormalities in male BALB/c mice exposed for 28 days to 80–8000 ug/ml MTBE in drinking water. We gave these MTBE concentrations to adult mice for 28 days and juvenile mice for 51 days through PND 77. Evidence of oxidative stress was examined in liver homogenates from the juvenile study using MDA, TEAC and 8OH2hG as endpoints. MTBE exposures at the levels examined indicated no significant changes in the male mouse reproductive tract and no signs of hepatic oxidative stress. This appears to be the first oral MTBE exposure of juvenile animals, and also the first to examine potential for MTBE to cause oxidative stress in vivo using a typical route of human exposure.Item Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth(Ovid Technologies Wolters Kluwer -American Heart Association, 2014-05-27) Alphonse, Rajesh S.; Vadivel, Arul; Fung, Moses; Shelley, William Chris; Critser, Paul John; Ionescu, Lavinia; O’Reilly, Megan; Ohls, Robin K.; McConaghy, Suzanne; Eaton, Farah; Zhong, Shumei; Yoder, Merv; Thébaud, Bernard; Department of Pediatrics, IU School of MedicineBACKGROUND: Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. METHODS AND RESULTS: Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth-arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood-derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. CONCLUSIONS: Impaired ECFC function may contribute to arrested alveolar growth. Cord blood-derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.Item Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup(Elsevier, 2016-02) Anseeuw, Kurt; Mowry, James B.; Burdmann, Emmanuel A.; Ghannoum, Marc; Hoffman, Robert S.; Gosselin, Sophie; Lavergne, Valery; Nolin, Thomas D.; Department of Emergency Medicine, IU School of MedicineThe Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning.Item A High Serum Level of Taurocholic Acid is Correlated with the Severity and Resolution of Drug-induced Liver Injury(Elsevier, 2020) Tian, Qiuju; Yang, Ruiyuan; Wang, Yan; Liu, Jimin; Wee, Aileen; Saxena, Romil; Wang, Lan; Li, Min; Liu, Liwei; Shan, Shan; Kong, Yuanyuan; Ma, Hong; Ou, Xiaojuan; You, Hong; Zhao, Xinyan; Jia, Jidong; Pathology and Laboratory Medicine, School of MedicineBackground & Aims Alterations in the serum levels of bile acids are associated with drug-induced liver injury (DILI). We investigated the association between serum levels of bile acids and the severity and outcome of DILI, along with the potential role of variants in the ATP binding cassette subfamily B member 11 ( ABCB11) gene and expression of its product, ABCB11 (also called BSEP). Methods We performed this prospective study of 95 patients (median age, 53 years; 73.7% female) with DILI from August 2018 through August 2019. Patients were matched for age, gender, and body mass index with healthy individuals (n=100; healthy controls) and patients with chronic hepatitis B (n=105; CHB controls). We collected demographic and biochemical data at baseline and 1 week, 1 month, 3 months, and 6 months after DILI onset and at the time of biochemical recovery, liver failure or liver transplantation. Serum levels of bile acids were measured using high-performance liquid-chromatography tandem mass-spectrometry. All 27 exons of ABCB11 were sequenced and expression of BSEP were analyzed by immunohistochemistry in liver biopsy specimens. Results Levels of 30 of the 37 bile acids analyzed differed significantly between patients with DILI and healthy controls. Changes in levels of taurocholic acid (TCA), glycocholic acid, taurochenodeoxycholate, and glycochenodeoxycholate associated with the increased levels of bilirubin and greater severity of DILI, and were also associated with CHB. Cox regression analysis showed that only change in the levels of TCA independently associated with biochemical resolution of DILI. Combination of TCA level (≥ 1955.41 nmol/L), patient age, and DILI severity was associated with abnormal blood biochemistry at 6 months after DILI onset (area under the curve, 0.81; 95% confidence interval, 0.71–0.88; sensitivity, 0.69; specificity, 0.81). ABCB11 missense variants were not associated with differences in the serum bile acid profiles, DILI severity, or clinical resolution. However, lower levels of BSEP in bile canaliculi in liver biopsies were associated with altered serum levels of bile acids. Conclusions In this prospective study performed in Chinese patients, we found that the serum levels of TCA were associated with the severity and clinical resolution of DILI. Reduced protein expression of BSEP in liver tissue, rather than variants of the ABCB11 gene were associated with altered serum levels of bile acids.Item Local Anesthetic Systemic Toxicity Simulation Survey: A Resident Experience(2020-09-12) Schell, Zachary J.; Mitchell, Sally A.; Boyer, Tanna J.Item The p75NTR SIGNALING CASCADE MEDIATES MECHANICAL HYPERALGESIA INDUCED BY NERVE GROWTH FACTOR INJECTED INTO THE RAT HIND PAW(Elsevier, 2013-12-19) Khodorova, Alla; Nicol, Grant D.; Strichartz, Gary; Department of Pharmacology and Toxicology, IU School of MedicineNerve Growth Factor (NGF) augments excitability of isolated rat sensory neurons through activation of the p75 neurotrophin receptor (p75NTR) and its downstream sphingomyelin signaling cascade, wherein neutral sphingomyelinase(s) (nSMase), ceramide, and the atypical PKC (aPKC), PKMζ, are key mediators. Here we examined these same receptor-pathways in vivo for their role in mechanical hyperalgesia from exogenous NGF. Mechanical sensitivity was tested by the number of paw withdrawals in response to 10 stimuli (PWF = n/10) by a 4g von Frey hair (VFH, testing “allodynia”) and by 10g and 15g VFHs (testing “hyperalgesia”). NGF (500 ng/10 µl) injected into the male rat’s plantar hind paw induced long lasting ipsilateral mechanical hypersensitivity. Mechano-hypersensitivity, relative to baseline responses and to those of the contralateral paw, developed by 0.5–1.5h and remained elevated at least for 21–24h, Acute intraplantar pre-treatment with nSMase inhibitors, GSH or GW4869, prevented the acute hyperalgesia from NGF (at 1.5h) but not that at 24h. A single injection of N-acetyl sphingosine (C2-ceramide), simulating the ceramide produced by nSMase activity, induced ipsilateral allodynia that persisted for 24h, and transient hyperalgesia that resolved by 2h. Intraplantar injection of hydrolysis-resistant mPro-NGF, selective for the p75NTR over the TrkA receptor, gave very similar results to NGF and was susceptible to the same inhibitors. Hyperalgesia from both NGF and mPro-NGF was prevented by paw pre-injection with blocking antibodies to rat p75NTR receptor. Finally, intraplantar (1 day before NGF) injection of mPSI, the myristolated pseudosubstrate inhibitor of PKCζ/PKMζ, decreased the hyperalgesia resulting from NGF or C2-ceramide, although scrambled mPSI was ineffective. The findings indicate that mechano-hypersensitivity from peripheral NGF involves the sphingomyelin signaling cascade activated via p75NTR, and that a peripheral aPKC is essential for this sensitization.