Incremental value of live/real time three-dimensional transesophageal echocardiography over the two-dimensional technique in the assessment of aortic aneurysm and dissection

We compared findings from intraoperative live/real time three-dimensional transesophageal echocardiography (3DTEE) and two-dimensional transesophageal echocardiography (2DTEE) with surgery in 67 patients having aortic aneurysm and/or aortic dissection. Of these, 20 patients had aortic aneurysm without dissection, 21 aortic aneurysm and dissection, and 26 aortic dissection without aneurysm. 3DTEE diagnosed the type and location of aneurysm correctly in all patients unlike 2DTEE, which missed an aneurysm in one case. There were four cases of aortic aneurysm rupture. Three of them were diagnosed by 3DTEE but only one by 2DTEE, and one missed by both techniques. The mouth of saccular aneurysm, site of aortic aneurysm rupture, and communication sites between perfusing and nonperfusing lumens of aortic dissection could be viewed en face only with 3DTEE, enabling comprehensive measurements of their area and dimensions as well as increasing the confidence level of their diagnosis. In all patients with aortic dissection, 3DTEE enabled a more confident diagnosis of dissection because the dissection flap when viewed en face presented as a sheet of tissue rather than a linear echo seen on 2DTEE which can be confused with an artifact. 2DTEE missed dissection in one patient. In six cases the dissection flap involved the right coronary artery orifice by 3DTEE and surgery. These were missed by 2DTEE. Aortic regurgitation severity was more comprehensively assessed by 3DTEE than 2DTEE. Aneurysm size by 3DTEE correlated well with 2DTEE and surgery/computed tomography scan. In conclusion, 3DTEE provides incremental information over 2DTEE in patients with aortic aneurysm and dissection.     

Coupled dynamics of energy budget and population growth of tilapia in response to pulsed waterborne copper

The impact of environmentally pulsed metal exposure on population dynamics of aquatic organisms remains poorly understood and highly unpredictable. The purpose of our study was to link a dynamic energy budget model to a toxicokinetic/toxicodynamic (TK/TD). We used the model to investigate tilapia population dynamics in response to pulsed waterborne copper (Cu) assessed with available empirical data. We mechanistically linked the acute and chronic bioassays of pulsed waterborne Cu at the scale of individuals to tilapia populations to capture the interaction between environment and population growth and reproduction. A three-stage matrix population model of larva-juvenile-adult was used to project offspring production through two generations. The estimated median population growth rate (λ) decreased from 1.0419 to 0.9991 under pulsed Cu activities ranging from 1.6 to 2.0?μg?L^?1. Our results revealed that the influence on λ was predominately due to changes in the adult survival and larval survival and growth functions. We found that pulsed timing has potential impacts on physiological responses and population abundance. Our study indicated that increasing time intervals between first and second pulses decreased mortality and growth inhibition of tilapia populations, indicating that during long pulsed intervals tilapia may have enough time to recover. Our study concluded that the bioenergetics-based matrix population methodology could be employed in a life-cycle toxicity assessment framework to explore the effect of stage-specific mode-of-actions in population response to pulsed contaminants.     

Assessing abalone growth inhibition risk to cadmium and silver by linking toxicokinetics/toxicodynamics and subcellular partitioning

The purpose of this study was to link toxicokinetics/toxicodynamics and subcellular partitioning for assessing the susceptibility and the growth inhibition risks of abalone Haliotis diversicolor supertexta exposed to waterborne and foodborne cadmium (Cd) and silver (Ag). We reanalyzed published data on growth inhibition and subcellular partitioning associated with the present mechanistic model to explore the correlations among elimination (k _e), detoxification (k _d), and recovery (k _r) rate constants and to assess the growth inhibition risk. We found a positive correlation among k _e, k _d, and k _r in abalone exposed to Ag. We also employed a life-stage based probabilistic assessment model to estimate the growth inhibition risk of abalone to environmentally relevant Cd (5–995 μg l⁻¹) and Ag (0.05–9.95 μg l⁻¹) concentrations in Taiwan. The results showed that abalone had a minimum 20% probability of the growth inhibition risk exposed to Cd, whereas Ag exposure was not likely to pose the risk. The maximum biomasses were estimated to be 0.0039 and 0.0038, 61.61 and 43.87, and 98.88 and 62.97 g for larvae, juveniles, and adults of abalone exposed to the same levels of Cd and Ag, respectively. Our study provides a useful tool to detect potential growth biomass of abalone populations subjected to Cd and Ag stresses and mechanistic implications for a long-term ecotoxicological risk assessment in realistic situations.     

Activated Human Valvular Interstitial Cells Sustain Interleukin-17 Production To Recruit Neutrophils in Infective Endocarditis

The mechanisms that underlie valvular inflammation in streptococcus-induced infective endocarditis (IE) remain unclear. We previously demonstrated that streptococcal glucosyltransferases (GTFs) can activate human heart valvular interstitial cells (VIC) to secrete interleukin-6 (IL-6), a cytokine involved in T helper 17 (Th17) cell differentiation. Here, we tested the hypothesis that activated VIC can enhance neutrophil infiltration through sustained IL-17 production, leading to valvular damage. To monitor cytokine and chemokine production, leukocyte recruitment, and the induction or expansion of CD4⁺ CD45RA⁻ CD25⁻ CCR6⁺ Th17 cells, primary human VIC were cultured in vitro and activated by GTFs. Serum cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA), and neutrophils and Th17 cells were detected by immunohistochemistry in infected valves from patients with IE. The expression of IL-21, IL-23, IL-17, and retinoic acid receptor-related orphan receptor C (Rorc) was upregulated in GTF-activated VIC, which may enhance the proliferation of memory Th17 cells in an IL-6-dependent manner. Many chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), were upregulated in GTF-activated VIC, which might recruit neutrophils and CD4⁺ T cells. Moreover, CXCL1 production in VIC was induced in a dose-dependent manner by IL-17 to enhance neutrophil chemotaxis. CXCL1-expressing VIC and infiltrating neutrophils could be detected in infected valves, and serum concentrations of IL-17, IL-21, and IL-23 were increased in patients with IE compared to healthy donors. Furthermore, elevated serum IL-21 levels have been significantly associated with severe valvular damage, including rupture of chordae tendineae, in IE patients. Our findings suggest that VIC are activated by bacterial modulins to recruit neutrophils and that such activities might be further enhanced by the production of Th17-associated cytokines. Together, these factors can amplify the release of neutrophilic contents in situ, which might lead to severe valvular damage.     

A dose-based modeling approach for accumulation and toxicity of arsenic in tilapia Oreochromis mossambicus

We proposed an approach to relate metal toxicity to the concentrations of arsenic (As) in specific target organs of tilapia Oreochromis mossambicus. The relationships among As exposure, uptake, accumulation, and toxicity of tilapia were investigated using kinetic and dynamic modeling. The biouptake rate of waterborne As through the gills of fish was dependent on exposure concentrations, in that the relationship was well described by incorporating Michaelis-Menten type uptake kinetics. The fitted bioaffinity parameter and limiting uptake flux were 3.07 +/- 2.21 microg/mL(-1) (mean +/- SD) and 2.17 +/- 0.38 microg/mL(-1)/d(-1), respectively, suggesting that a low As binding affinity of tilapia gills, yet a relatively high binding capacity was obtained. The toxicity of As was analyzed by determining the lethal exposure concentration associated with a mortality of 50% (LC50) at different integration times. Our results demonstrate that 96-h and incipient LC50s for tilapia are 28.68 (95% CI: 15.98-47.38) and 25.55 microg/mL(-1), respectively. The organ-specific internal residue associated with 50% mortality was estimated by combining the model-predicted toxicokinetic parameters and the area-under-curve (AUC)-based time-integrated concentration toxicity model. A physiologically based toxicokinetic model was constructed to elucidate the principle mechanisms that account for the observed data and to predict the kinetics of As in tilapia under different water exposure scenarios. We employed the Hill equation model to predict the organ-specific dose-response relationships. We used the liver as a surrogate of target sites to assess the As toxicity to tilapia because of its higher sensitivity to As toxic effects. The predicted mortalities never reach 50% when the tilapia were exposed to waterborne As <2 microg/mL(-1). The predicted mortality is, however, slightly higher than the observed values before the 10th day in that the profile reached the 70% maximum mortality, which is comparable to the observed data when the tilapia were exposed to 4 microg/mL(-1). Our results show that a dose-based toxicokinetic and toxicodynamic modeling approach successfully links metal exposure to bioavailability, bioaccumulation, and toxicity, under variable exposure scenarios.     

Prediction of heat-induced collagen shrinkage by use of second harmonic generation microscopy

Collagen shrinkage associated with denaturation from thermal treatment has a number of important clinical applications. However, individualized treatment is hindered by the lack of reliable noninvasive methods to monitor the process of collagen denaturation. We investigate the serial changes of collagen denaturation from thermal treatment of rat tail tendons at 58 degrees C by use of second harmonic generation (SHG) microscopy. We find that rat tail tendon shrinks progressively from 0 to 9 min of thermal treatment, and remains unchanged in length upon further thermal treatment. The SHG intensity also decreases from 0 to 9 min of thermal treatment and becomes barely detectable from further thermal treatment. Collagen shrinkage and the SHG intensity are well correlated in a linear model. In addition, SHG imaging reveals a tiger-tail-like pattern of collagen denaturation. The bands of denatured collagen progressively widen from increased thermal treatment and completely replace the adjacent bands of normal collagen after 9 min of thermal treatment. Our results show that collagen denaturation in rat tail tendon from thermal treatment is inhomogeneous, and that SHG intensity can be used to predict the degree of thermally induced collagen shrinkage. With additional development, this approach has the potential to be used in biomedical applications.     

Zebrafish as a disease model for studying human hepatocellular carcinoma

Liver cancer is one of the world's most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma(HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel smallmolecule inhibitors. This review will focus on illustrativeexamples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts,drug discovery, and drug-induced toxic liver injury.     

1,2-Ethanedithiol-induced erythema multiforme-like contact dermatitis

Contact dermatitis simulating erythema multiforme can be caused by many allergens. The chemical agent 1,2-ethanedithiol, which serves as a protective group in chemical synthesis, has hitherto only been implicated as an irritant. We report on a 22-year-old female chemistry student who developed widespread erythema multiforme-like lesions after local contact with 1,2-ethanedithiol. Many target lesions were observed bilaterally on her hands, forearms, arms, and on her forehead. One such lesion was histologically compatible with erythema multiforme. The patient had a positive patch test to 1,2-ethanedithiol, whereas none of 30 healthy subjects showed a positive reaction. However, eight of the 30 controls (26.7%) developed irritant reactions to 1,2-ethanedithiol. Cautious handling of the compound is a prudent precaution.     

Overexpression of Thy1/CD90 in human hepatocellular carcinoma is associated with HBV infection and poor prognosis

Thy1/CD90 is an important marker of many types of stem cells. It functions as a tumor suppressor in ovarian cancer and in nasopharyngeal carcinoma. In this study, the expression status of Thy1 in clinical hepatocellular carcinoma (HCC) tissue samples was investigated. Relationships of Thy1 expression with clinical parameters and patient survival rate were analyzed. The quantities of Thy1 mRNA were statistically higher in tumor tissues than those in the adjacent non-tumor tissues (p < 0.001). Immunohistochemical data confirmed that Thy1 protein was increased in 73% of HCC samples. Thy1 expression was not influenced by chronic alcohol exposure or cirrhosis. Overexpression in Thy1 was correlated with age (p = 0.006), hepatitis B virus (HBV) infection (p = 0.044), and histological grade (p = 0.014). Patients with the highest level of Thy1 expression showed the poorest prognosis (p = 0.040). In conclusion, overexpression of Thy1 may not suppress the development of HCC. Thy1 could provide a clinical prognostic marker for HCC.     

Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction

Tumor-associated macrophages (TAMs) and cyclooxygenase-2 (COX-2) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human basal cell carcinoma (BCC) remains elusive. We found that the number of TAMs infiltrating the tumor is correlated with the depth of invasion, microvessel density, and COX-2 expression in human BCC cells. TAMs also aggregate near COX-2 expressing BCC tumor nests. We hypothesize that TAMs might activate COX-2 in BCC cells and subsequently increase their invasion and angiogenesis. TAMs are a kind of M2 macrophage derived from macrophages exposed to Th2 cytokines. M2-polarized macrophages derived from peripheral blood monocytes were cocultured with BCC cells without direct contact. Coculture with the M2 macrophages induced COX-2-dependent invasion and angiogenesis of BCC cells. Human THP-1 cell line cells, after treated with phorbol myristate acetate (PMA), differentiated to macrophages with M2 functional profiles. Coculture with PMA-treated THP-1 macrophages induced COX-2-dependent release of matrix metalloproteinase-9 and subsequent increased invasion of BCC cells. Macrophages also induced COX-2-dependent secretion of basic fibroblast growth factor and vascular endothelial growth factor-A, and increased angiogenesis in BCC cells.