Coronary Microvascular Dysfunction in Acute Cholestasis-Induced Liver Injury.

BACKGROUND: Previous studies have shown cardiac abnormalities in acute liver injury, suggesting a potential role in the associated high mortality. METHODS: We designed an experimental study exploring the short-term effects of acute cholestasis-induced liver injury on cardiac function and structure in a rodent bile duct ligation (BDL) model to elucidate the potential interplay. Thirty-seven male Sprague-Dawley rats were subjected to BDL surgery (n = 28) or served as sham-operated (n = 9) controls. Transthoracic echocardiography, Doppler evaluation of the left anterior descending coronary artery, and myocardial contrast echocardiography were performed at rest and during adenosine and dobutamine stress 5 days after BDL. Immunohistochemical staining of myocardial tissue samples for hypoxia and inflammation as well as serum analysis were performed. RESULTS: BDL animals exhibited acute liver injury with elevated transaminases, bilirubin, and total circulating bile acids (TBA) 5 days after BDL (TBA control: 0.81 ± 2.54 µmol/L vs. BDL: 127.52 ± 57.03 µmol/L; p < 0.001). Concurrently, cardiac function was significantly impaired, characterized by reduced cardiac output (CO) and global longitudinal strain (GLS) in the echocardiography at rest and under pharmacological stress (CO rest control: 120.6 ± 24.3 mL/min vs. BDL 102.5 ± 16.6 mL/min, p = 0.041; GLS rest control: -24.05 ± 3.8% vs. BDL: -18.5 ± 5.1%, p = 0.01). Myocardial perfusion analysis revealed a reduced myocardial blood flow at rest and a decreased coronary flow velocity reserve (CFVR) under dobutamine stress in the BDL animals (CFVR control: 2.1 ± 0.6 vs. BDL: 1.7 ± 0.5 p = 0.047). Immunofluorescence staining indicated myocardial hypoxia and increased neutrophil infiltration. CONCLUSIONS: In summary, acute cholestasis-induced liver injury can lead to impaired cardiac function mediated by coronary microvascular dysfunction, suggesting that major adverse cardiac events may contribute to the mortality of acute liver failure. This may be due to endothelial dysfunction and direct bile acid signaling.

[Anesthesia for aortic valve stenosis : Anesthesiological management of patients with aortic valve stenosis during noncardiac surgery]. / Anästhesie bei Aortenklappenstenose : Anästhesiologisches Management von Patienten mit Aortenklappenstenose bei nichtkardiochirurgischen Eingriffen.

Aortic valve stenosis is a common condition that requires an anesthesiologist's in-depth knowledge of the pathophysiology, diagnostics and perioperative features of the disease. A newly diagnosed aortic valve stenosis is often initially identified from the anamnesis (dyspnea, syncope, angina pectoris) or a suspicious auscultation finding during the anesthesiologist's preoperative assessment. Interdisciplinary collaboration is essential to ensure the optimal management of these patients in the perioperative setting. An accurate anamnesis and examination during the preoperative assessment are crucial to select the most suitable anesthetic approach. Additionally, a precise understanding of the hemodynamic peculiarities associated with aortic valve stenosis is necessary. After a short summary of the overall pathophysiology of aortic valve stenosis, this review article focuses on the specific anesthetic considerations, risk factors for complications, and the perioperative management for noncardiac surgery in patients with aortic valve stenosis.

Sublethal necroptosis signaling promotes inflammation and liver cancer.

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner.

Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1, Fn1, and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation. In vitro and in vivo studies show that loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis after both heart and kidney injury. Moreover, we find that platelets, the most abundant source of CXCL4 in vivo, drive profibrotic Spp1 macrophage differentiation. Single nuclear RNA sequencing with ligand-receptor interaction analysis reveals that macrophages orchestrate fibroblast activation via Spp1, Fn1, and Sema3 crosstalk. Finally, we confirm that Spp1 macrophages expand in both human chronic kidney disease and heart failure.

Comparative assessment of coronary physiology using transthoracic pulsed-wave Doppler and myocardial contrast echocardiography in rats.

BACKGROUND: Coronary physiology assessment in rodents by ultrasound is an excellent noninvasive and easy to perform technique, including pulsed-wave Doppler (PWD) and myocardial contrast echocardiography (MCE). Both techniques and the corresponding calculated parameters were investigated in this study at rest as well as their response to pharmacologically induced stress. METHODS: Left ventricular myocardial function was assessed in eight anaesthetised rats using transthoracic echocardiography. Coronary physiology was assessed by both PWD of the left coronary artery and MCE using a bolus method. Measurements were performed at rest and under stimulation with adenosine and dobutamine. Effects of stimulation on the calculated parameters were evaluated and rated by effect size (η2). RESULTS: Changes could be demonstrated by selected parameters of PWD and MCE. The clearest effect in PWD was found for diastolic peak velocity (η2 = 0.58). It increased from 528 ± 110 mm/s (mean ± standard deviation) at rest to 839 ± 342 mm/s (p = 0.001) with adenosine and 1093 ± 302 mm/s with dobutamine (p = 0.001). The most distinct effect from MCE was found for the normalised wash-in rate (η2 = 0.58). It increased from 1.95 ± 0.35% at rest to 3.87 ± 0.85% with adenosine (p = 0.001) and 3.72 ± 1.03% with dobutamine (p = 0.001). CONCLUSION: Induced changes in coronary physiology by adenosine and dobutamine could successfully be monitored using MCE and PWD in anaesthetised rats. Due to the low invasiveness of the measurements, this protocol could be used for longitudinal animal studies.

A neutralizing IL-11 antibody reduces vessel hyperplasia in a mouse carotid artery wire injury model.

Vascular restenosis remains a major problem in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Neointimal hyperplasia, defined by post-procedure proliferation and migration of vascular smooth muscle cells (VSMCs) is a key underlying pathology. Here we investigated the role of Interleukin 11 (IL-11) in a mouse model of injury-related plaque development. Apoe-/- mice were fed a hyperlipidaemic diet and subjected to carotid wire injury of the right carotid. Mice were injected with an anti-IL11 antibody (X203), IgG control antibody or buffer. We performed ultrasound analysis to assess vessel wall thickness and blood velocity. Using histology and immunofluorescence approaches, we determined the effects of IL-11 inhibition on VSMC and macrophages phenotypes and fibrosis. Treatment of mice with carotid wire injury using X203 significantly reduced post-endothelial injury vessel wall thickness, and injury-related plaque, when compared to control. Immunofluorescence staining of the injury-related plaque showed that X203 treatment did not reduce macrophage numbers, but reduced the number of VSMCs and lowered matrix metalloproteinase 2 (MMP2) levels and collagen content in comparison to control. X203 treatment was associated with a significant increase in smooth muscle protein 22α (SM22α) positive cells in injury-related plaque compared to control, suggesting preservation of the contractile VSMC phenotype. Interestingly, X203 also reduced the collagen content of uninjured carotid arteries as compared to IgG, showing an additional effect on hyperlipidemia-induced arterial remodeling in the absence of mechanical injury. Therapeutic inhibition of IL-11 reduced vessel wall thickness, attenuated neointimal hyperplasia, and has favorable effects on vascular remodeling following wire-induced endothelial injury. This suggests IL-11 inhibition as a potential novel therapeutic approach to reduce arterial stenosis following revascularization in CAD and PAD patients.

Investigation on the uptake of ciprofloxacin, chloramphenicol and praziquantel by button mushrooms.

Button mushrooms are widely produced edible basidiomycetes. Commercially, they are cultivated on substrates containing fermented horse manure and chicken feces. Since pharmacologically active substances (PAS) might be introduced into the food chain via animal treatment, their residues may be present in manure used for mushroom growth. Previous studies in plants have demonstrated an uptake of PAS from the agricultural environment. The present study was performed to investigate the presence of PAS in button mushrooms. For analysis, a multi-analyte method for the detection of 21 selected PAS using liquid chromatography tandem-mass spectrometry was developed, successfully validated and applied to commercially available button mushrooms. Traces of chloramphenicol were detected in two of 20 samples. Additionally, in a mushroom cultivation experiment an uptake of ciprofloxacin, chloramphenicol and praziquantel was conducted. Throughout the whole experiment, praziquantel was present in quantifiable amounts in mushrooms and in high quantities in soil.

Phosphatidylserine Supplementation as a Novel Strategy for Reducing Myocardial Infarct Size and Preventing Adverse Left Ventricular Remodeling.

Phosphatidylserines are known to sustain skeletal muscle activity during intense activity or hypoxic conditions, as well as preserve neurocognitive function in older patients. Our previous studies pointed out a potential cardioprotective role of phosphatidylserine in heart ischemia. Therefore, we investigated the effects of phosphatidylserine oral supplementation in a mouse model of acute myocardial infarction (AMI). We found out that phosphatidylserine increases, significantly, the cardiomyocyte survival by 50% in an acute model of myocardial ischemia-reperfusion. Similar, phosphatidylserine reduced significantly the infarcted size by 30% and improved heart function by 25% in a chronic model of AMI. The main responsible mechanism seems to be up-regulation of protein kinase C epsilon (PKC-ε), the main player of cardio-protection during pre-conditioning. Interestingly, if the phosphatidylserine supplementation is started before induction of AMI, but not after, it selectively inhibits neutrophil's activation, such as Interleukin 1 beta (IL-1ß) expression, without affecting the healing and fibrosis. Thus, phosphatidylserine supplementation may represent a simple way to activate a pre-conditioning mechanism and may be a promising novel strategy to reduce infarct size following AMI and to prevent myocardial injury during myocardial infarction or cardiac surgery. Due to the minimal adverse effects, further investigation in large animals or in human are soon possible to establish the exact role of phosphatidylserine in cardiac diseases.

Corrigendum: Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics.

[This corrects the article DOI: 10.3389/fphar.2019.00079.].

Cardiac FGF23: new insights into the role and function of FGF23 after acute myocardial infarction.

OBJECTIVE: We aimed to elucidate the local role of FGF23 after myocardial infarction in a mouse model induced by left anterior descending artery (LAD) ligation. APPROACH AND RESULTS: (C57BL/6 N) mice underwent MI via LAD ligation and were sacrificed at different time-points post MI. The expression and influence of FGF23 on fibroblast and macrophages was also analyzed using isolated murine cells. We identified enhanced cardiac FGF23 mRNA expression in a time-dependent manner with an early increase, already on the first day after MI. FGF23 protein expression was abundantly detected in the infarcted area during the inflammatory phase. While described to be primarily produced in bone or macrophages, we identified cardiac fibroblasts as the only source of local FGF23 production after MI. Inflammatory mediators, such as IL-1ß, IL-6 and TNF-α, were able to induce FGF23 expression in these cardiac fibroblasts. Interestingly, we were not able to detect FGF23 at later time points after MI in mature scar tissue or remote myocardium, most likely due to TGF-ß1, which we have shown to inhibit the expression of FGF23. We identified FGFR1c to be the most abundant receptor for FGF23 in infarcted myocardium and cardiac macrophages and fibroblasts. FGF23 increased migration of cardiac fibroblast, as well as expression of Collagen 1, Periostin, Fibronectin and MMP8. FGF23 also increased expression of TGF-ß1 in M2 polarized macrophages. CONCLUSION: In conclusion, cardiac fibroblasts in the infarcted myocardium produce and express FGF23 as well as its respective receptors in a time-dependent manner, thus potentially influencing resident cell migration. The transitory local expression of FGF23 after MI points towards a complex role of FGF23 in myocardial ischemia and warrants further exploration, considering its role in ventricular remodeling.

Evaluation of Riboflavin Transporters as Targets for Drug Delivery and Theranostics.

The retention and cellular internalization of drug delivery systems and theranostics for cancer therapy can be improved by targeting molecules. Since an increased uptake of riboflavin was reported for various cancers, riboflavin and its derivatives may be promising binding moieties to trigger internalization via the riboflavin transporters (RFVT) 1, 2, and 3. Riboflavin is a vitamin with pivotal role in energy metabolism and indispensable for cellular growth. In previous preclinical studies on mice, we showed the target-specific accumulation of riboflavin-functionalized nanocarriers in cancer cells. Although the uptake mechanism of riboflavin has been studied for over a decade, little is known about the riboflavin transporters and their expression on cancer cells, tumor stroma, and healthy tissues. Furthermore, evidence is lacking concerning the representativeness of the preclinical findings to the situation in humans. In this study, we investigated the expression pattern of riboflavin transporters in human squamous cell carcinoma (SCC), melanoma and luminal A breast cancer samples, as well as in healthy skin, breast, aorta, and kidney tissues. Low constitutive expression levels of RFVT1-3 were found on all healthy tissues, while RFVT2 and 3 were significantly overexpressed in melanoma, RFVT1 and 3 in luminal A breast cancer and RFVT1-3 in SCC. Correspondingly, the SCC cell line A431 was highly positive for all RFVTs, thus qualifying as suitable in vitro model. In contrast, activated endothelial cells (HUVEC) only presented with a strong expression of RFVT2, and HK2 kidney cells only with a low constitutive expression of RFVT1-3. Functional in vitro studies on A431 and HK2 cells using confocal microscopy showed that riboflavin uptake is mostly ATP dependent and primarily driven by endocytosis. Furthermore, riboflavin is partially trafficked to the mitochondria. Riboflavin uptake and trafficking was significantly higher in A431 than in healthy kidney cells. Thus, this manuscript supports the hypothesis that addressing the riboflavin internalization pathway may be highly valuable for tumor targeted drug delivery.

Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin.

UVB wavelengths of light induce the formation of photoproducts in genomic DNA that are potentially mutagenic and detrimental to epidermal cell function. The mineralocorticoid and androgen receptor antagonist spironolactone (SP) was recently identified as an inhibitor of UV photoproduct removal in human cancer cells in vitro via its ability to promote the rapid proteolytic degradation of the DNA repair protein XPB. Using normal human keratinocytes in vitro and skin explants ex vivo, we found that SP rapidly depleted XPB protein in both systems and abrogated two major responses to UVB-induced DNA damage, including the removal of UV photoproducts from genomic DNA and the activation of ATR/ATM DNA damage kinase signaling. These effects were also correlated with both mutagenesis and a predisposition to UVB-induced cell death but were unique to SP, because neither the SP metabolites canrenone and 7α-thiomethylspironolactone nor the more specific mineralocorticoid receptor antagonist eplerenone affected XPB protein levels or the UVB response. Our findings provide an approach for studying XPB and its roles in the UVB DNA damage response in human skin ex vivo and indicate that SP may increase UVB mutagenesis and skin cancer risk in certain individuals.

Effect of Helicobacter pylori on marginal ulcer and stomal stenosis after Roux-en-Y gastric bypass.

BACKGROUND: Conflicting data have been published regarding whether Helicobacter pylori (HP) positivity is associated with increased complication rates in patients undergoing Roux-en-Y gastric bypass (RYGB). METHODS: We retrospectively examined the rate of complications in patients undergoing RYGB according to preoperative HP positivity and persistent post-treatment positivity to determine whether a correlation exists. RESULTS: A total of 228 patients underwent RYGB during a 2-year period (2009-2011). No patient had evidence of active ulcer disease on preoperative endoscopy. Of the 228 patients, 68 tested positive for HP on serum antigen screening and were treated with omeprazole, clarithromycin, and amoxillin. After treatment, 24 patients were persistently positive on repeat endoscopic biopsy. Of the 228 patients, 12 experienced a total of 13 complications (stomal stenosis in 8, marginal ulcer in 5, and none with anastomotic leak or gastrointestinal bleeding). Of the 68 patients with HP positivity preoperatively, 1 complication (2.3%) developed in the 44 patients who had responded to triple therapy, and no complications occurred in the 24 patients who had remained positive after treatment (P = 1.00), showing no difference. Also, no significant difference was found in the rate of complications (P = .11) between patients who were HP negative preoperatively (11 of 160, 6.9%) and those who were positive preoperatively (1 of 68, 1.5%). CONCLUSION: HP status, whether positive preoperatively or persistently positive after treatment, had no effect on the marginal ulcer or stomal stenosis rates in patients undergoing RYGB in the present study.

Effect of elevated hemoglobin A1c in diabetic patients on complication rates after Roux-en-Y gastric bypass.

BACKGROUND: Little is known regarding the effect of chronic hyperglycemia, expressed by glycated hemoglobin, on the healing-related complication rates in Roux-en-Y gastric bypass (RYGB). METHODS: We retrospectively examined the rate of complications in patients with type 2 diabetes mellitus undergoing RYGB according to the preoperative glycated hemoglobin (HbA1c) level, focusing specifically on the complications related to wound healing (i.e., anastomotic leak, stomal stenosis, and wound infection). Two groups were formed separating those with HbA1c values >7 and <7 g/dL. All patients were taking oral antiglycemic medications or insulin to control their blood glucose levels. RESULTS: A total of 342 patients with type 2 diabetes mellitus underwent laparoscopic RYGB during a 3-year period (2008-2011). Of the 342 patients, 170 had elevated HbA1c values >7 g/dL (average 9.0) preoperatively, of which there were 4 superficial surgical site infections and 1 stomal stenosis, but no anastomotic leaks. Of the remaining 172 diabetic patients whose HbA1c level was <7 g/dL preoperatively (average 6.0 g/dL), 2 superficial surgical site infections, 2 stomal stenoses, and, again, no anastomotic leaks. No difference was seen in the combined complication rates between the 2 groups (2.9% versus 2.3%, P = .50). CONCLUSION: In the present study, an elevated HbA1c >7 g/dL in patients with type 2 diabetes mellitus did not convey increased complication rates after RYGB.

Sleeve gastrectomy: 5-year outcomes of a single institution.

BACKGROUND: Laparoscopic sleeve gastrectomy (SG) is the most recent bariatric surgical procedure to gain universal acceptance by providers and payers. Long-term clinical data on outcomes is limited at this time. METHODS: We retrospectively examined 5-year outcomes (weight loss, complications, and resolution of co-morbid conditions) of patients undergoing SG at our institution. RESULTS: Our initial SG was performed in 2005, and we operated on 55 consecutive patients who are 5 years out from surgery. Six patients were excluded from the long-term results. Four patients underwent conversion to a duodenal switch, and 2 patients died in the first year outside the perioperative period. Average starting body mass index was 65 kg/m(2). Five-year average percent excess weight loss was 86% (range 50%-103%). Percentage of co-morbidities resolved: hypertension (95%), type 2 diabetes mellitus (100%), hyperlipidemia (100%), and obstructive sleep apnea (100%). Gastroesophageal reflux disease (GERD) was resolved in 53%, and new GERD symptoms developed in 11% of patients. There was 1 staple line leak (1.9%), no strictures, no gastrointestinal bleeding, and no perioperative deaths. CONCLUSION: In this study, SG is a well-tolerated and effective bariatric surgical procedure with good long-term weight loss and resolution of co-morbid medical conditions.

The prevalence of self-harm behaviors among a sample of gastric surgery candidates.

OBJECTIVE: The surgical treatment of obesity is becoming increasingly popular; yet, little is known about the self-harm characteristics and adjunctive self-regulation difficulties of those seeking such surgery. In the literature, one study has explored presurgery suicide attempts and several studies have explored the prevalence of postsurgical completed suicides. However, beyond suicide attempts and completions, little is known about the broader self-harm/self-regulation profiles of these patients. In this study, we examined the prevalence of 22 such behaviors among a sample of gastric surgery candidates. METHOD: Using a cross-sectional approach, we examined 121 surgical candidates for 22 self-reported self-harm and self-regulatory behaviors. RESULTS: The studied behaviors with the highest prevalence rates in this cohort were sexual promiscuity (22.3%), torturing oneself with self-defeating thoughts (20.7%), alcohol abuse (19.0%), and engaging in emotionally abusive relationships (16.5%). With regard to suicide attempts, 9.1% of participants acknowledged a history and 9.1% reported past overdoses. CONCLUSIONS: These data suggest that (a) adjunctive self-regulatory difficulties may affect a substantial minority of individuals who are seeking gastric surgery for obesity (e.g., promiscuity and alcohol abuse), and (b) the anticipated prevalence rate for past suicide attempts in this population appears to be approximately 10%.

The prevalence of binge eating disorder and borderline personality symptomatology among gastric surgery patients.

In this study, we examined the prevalence of binge eating disorder (BED) and borderline personality disorder (BPD) in a sample of 121 candidates seeking surgery for obesity. In this predominantly female sample (85.9%), according to the Questionnaire on Eating and Weight Patterns-Revised (QEWP-R), the prevalence of BED was 6.5%. As for the prevalence of BPD, 14.0% exceeded the clinical cut-off score on the Self-Harm Inventory (SHI), 14.0% exceeded the clinical cut-off score on the borderline personality scale of the Personality Diagnostic Questionnaire-4 (PDQ-4), and 7.4% exceeded the clinical cut-off score on the McLean Screening Inventory for Borderline Personality Disorder (MSI-BPD). Overall, 24.8% of the sample exceeded the clinical cut-off on at least one measure of BPD whereas only 3.3% exceeded the clinical cut-off on all three measures. In addition, there was a significant inverse relationship between the discrepancy between highest and lowest adult body mass index, and scores on the PDQ-4 and the MSI-BPD. The authors discuss the implications of these findings.

The prevalence of childhood trauma and parental caretaking quality among gastric surgery candidates.

In this study, we examined the prevalence of traumatic childhood experiences as well as the quality of parental caretaking among 121 individuals (85.9% of which were women) seeking surgical treatment for obesity (mean body mass index of 47.2). Among this sample, 43.0% reported emotional abuse, 39.0% the witnessing of violence, 19.0% sexual abuse, 17.4% physical abuse, and 9.1% physical neglect. While the overall quality of parental caretaking was skewed toward a positive rating, those respondents who indicated each form of childhood trauma rated the quality of parental caretaking lower than did those without that specific form of abuse. The authors discuss the implications of these findings.

Mutagenicity of the mycotoxin alternariol in cultured mammalian cells.

The mycotoxin alternariol (AOH) is an important contaminant of fruit and cereal products. Concern about exposure to low levels of AOH was raised after the disclosure that contamination of food with the AOH-producing species Alternaria alternata is associated with oesophagal cancer. Previously we have reported that AOH induces kinetochore-negative micronuclei in cultured Chinese hamster V79 cells. The present study investigates the mutagenicity of AOH at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene locus in V79 cells and at the thymidine kinase (TK) gene locus in mouse lymphoma L5178Y tk(+/-) cells (MLC). Concentrations of 10 microM AOH and more gave rise to a significant and concentration-dependent induction of HPRT and TK mutations in V79 cells and in MLC, respectively. The mutagenic potency of AOH was about 50-fold lower than that of the established mutagen 4-nitroquinoline-N-oxide in both cell lines. Discrimination between small and large colonies in the TK assay revealed the predominant induction of small colonies, which are indicative for extensive chromosomal deletions and which correlated with the induction of micronuclei in MLC. The mutagenicity of AOH may have a bearing on the carcinogenicity of this mycotoxin.