bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Roles of NMDA Receptor Subtypes NR2A and NR2B in Dendritic Branch Development and Requirement of RasGRF1
Authors: Sepulveda Fernando J. , Bustos Fernando J. , Inostroza Eveling , Zúñiga Felipe A. , Neve Rachael L. , Montecino Martin , van Zundert Brigitte
Published: January 2010

N-methyl-d-aspartate receptors (NMDARs) are known to regulate axonal refinement and dendritic branching. However, because NMDARs are abundantly present as tri-heteromers (e.g., NR1/NR2A/NR2B) during development, the precise role of the individual subunits NR2A and NR2B in these processes has not been elucidated. Ventral spinal cord neurons (VSCNs) provide a unique opportunity to address this problem, because the expression of both NR2A and NR2B (but not NR1) is downregulated in culture. Exogenous NR2A or NR2B were introduced into these naturally NR2-null neurons at 4 DIV, and electrophysiological recordings at 11 DIV confirmed that synaptic NR1NR2A receptors and NR1NR2B receptors were formed, respectively. Analysis of the dendritic architecture showed that introduction of NR2B, but not NR2A, dramatically increased the number of secondary and tertiary dendritic branches of VSCNs. Whole cell patch-clamp recordings further indicated that the newly formed branches in NR2B-expressing neurons were able to establish functional synapses because the frequency of miniature AMPA-receptor synaptic currents was increased. Using previously described mutants, we also found that disruption of the interaction between NR2B and RasGRF1 dramatically impaired dendritic branch formation in VSCNs. The differential role of the NR2A and NR2B subunits and the requirement for RasGRF1 in regulating branch formation was corroborated in hippocampal cultures. We conclude that the association between NR1NR2B-receptors and RasGRF1 is needed for dendritic branch formation in VSCNs and hippocampal neurons in vitro. The dominated NR2A expression and the limited interactions of this subunit with the signaling protein RasGRF1 may contribute to the restricted dendritic arbor development in the adult CNS.
Accelerated Lyra′s Cosmology Driven by Electromagnetic Field in Inhomogeneous Universe
Authors: Pradhan Anirudh , Yadav Padmini
Published: January 2010

A new class of cylindrically symmetric inhomogeneous cosmological models for perfect fluid distribution with electromagnetic field is obtained in the context of Lyra′s geometry. We have obtained solutions by considering the time dependent displacement field. The source of the magnetic field is due to an electric current produced along the z‐axis. Only F12 is a nonvanishing component of electromagnetic field tensor. To get the deterministic solution, it has been assumed that the expansion θ in the model is proportional to the shear σ. It has been found that the solutions are consistent with the recent observations of type Ia supernovae, and the
displacement vector β(t) affects entropy. Physical and geometric aspects of the models are also discussed in presence and absence of magnetic field.
Fixed Points Approximation and Solutions of Some Equilibrium and Variational Inequalities Problems
Authors: Ali Bashir
Published: January 2010

We prove a new strong convergence theorem for an element in the intersection of the set of common fixed points of a countable family of nonexpansive mappings, the set of solutions of some variational inequality problems, and the set of solutions of some equilibrium problems using a new iterative scheme. Our theorem generalizes and improves some recent results.
Preparation and In Vitro Behavior of a Poly(lactic acid)‐Fiber/Hydroxyapatite Composite Sheet
Authors: Tanimoto Yasuhiro , Nishiyama Norihiro
Published: January 2010

This paper describes the processing and in vitro behavior of a poly(lactic acid) (PLA)‐fiber/hydroxyapatite (HA) composite sheet consisting of a knitted PLA‐fiber sheet and HA powder for bone tissue engineering. Type I collagen was used as a binding agent to combine the PLA fibers and the HA powder. Precipitate formation in Hanks′ balanced salt (HBS) solution was monitored to evaluate the in vitro apatite formation ability of the PLA‐fiber/HA composite sheet. Precipitate formation was observed on the surface of the PLA‐fiber/HA composite sheet after immersion in HBS solution for only 1 day, while no precipitate formation was observed on the PLA‐fiber sheet without HA as a control. In conclusion, a PLA‐fiber/HA composite sheet for use as a scaffold was successfully prepared. Within the limitations of this investigation, we confirmed that the PLA‐fiber/HA composite sheet has a high apatite formation activity compared with the PLA‐fiber sheet and represents a promising material for use as a scaffold.
The Importance of Saccular Function to Motor Development in Children with Hearing Impairments
Authors: Shall Mary S.
Published: January 2010

Children with hearing deficits frequently have delayed motor development. The purpose of this study was to evaluate saccular function in children with hearing impairments using the Vestibular Evoked Myogenic Potential (VEMP). The impact of the saccular hypofunction on the timely maturation of normal balance strategies was examined using the Movement Assessment Battery for Children (Movement ABC). Thirty-three children with bilateral severe/profound hearing impairment between 4 and 7 years of age were recruited from a three-state area. Approximately half of the sample had one or bilateral cochlear implants, one used bilateral hearing aids, and the rest used no amplification. Parents reported whether the hearing impairment was diagnosed within the first year or after 2 years of age. No VEMP was evoked in two thirds of the hearing impaired (HI) children in response to the bone-conducted stimulus. Children who were reportedly hearing impaired since birth had significantly poorer scores when tested with the Movement ABC.
A Flow Cytometry Method to Quantitate Internalized Immunotoxins Shows that Taxol Synergistically Increases Cellular Immunotoxins Uptake
Authors: Zhang Yujian , Hansen Johanna K. , Xiang Laiman , Kawa Seiji , Onda Masanori , Ho Mitchell , Hassan Raffit , Pastan Ira
Published: January 2010

Tumor microenvironments present significant barriers to penetration by antibodies, immunoconjugates, and other immunotoxins. In this report, we illustrate a novel strategy to increase tumor cell uptake of immunotoxin by combination with Taxol. SS1P is an immunotoxin composed of the Fv portion of a mesothelin-specific antibody fused to a bacterial toxin that is presently undergoing phase II testing in mesothelioma. Using novel flow cytometry and gel filtration methods, we quantified SS1P uptake in individual tumor cells along with levels of shed mesothelin (sMSLN), a barrier of SS1P therapy. The validity of our flow cytometric method was confirmed by the ability to similarly quantitate tumor cell uptake of Herceptin and an immunotoxin targeting HER2/neu. SS1P uptake peaked several hours after SS1P was cleared from the blood, reflecting an intratumor distribution process of SS1P that is independent of blood supply. Using the methods developed, we demonstrated that Taxol could improve SS1P penetration into tumors in parallel with an associated reduction of sMSLN in tumor extracellular fluid. Our findings offer a mechanistic rationale to combine SS1P with Taxol or another cytotoxic drug as a strategy to increase immunotoxin uptake by tumor cells. Further, we suggest one basis to understand why chemotherapy and antibody-based therapies cooperate when combined in cancer treatment. Cancer Res; 70(3); 1082–9
Definition of a Functional Single Nucleotide Polymorphism in the Cell Migration Inhibitory Gene MIIP That Affects the Risk of Breast Cancer
Authors: Song Fangfang , Ji Ping , Zheng Hong , Song Fengju , Wang Yingmei , Hao Xishan , Wei Qingyi , Zhang Wei , Chen Kexin
Published: January 2010

The migration and invasion inhibitory protein MIIP is an inhibitor of cancer cell migration and invasion that inhibits breast tumorigenesis. In this case-control study, we evaluated the MIIP single nucleotide polymorphism (SNP) rs2295283 (codon 167, A>G, K>E) from 1,524 breast cancer patients and 1,592 age-matched controls for its association with breast cancer risk. SNP analysis included a validation set of 736 cases and 760 controls. Colony formation and cell migration assays were then conducted to functionally interrogate the genotype difference. When compared with the AA genotype, the combined AG + GG genotypes (167E) were associated with a significantly lower risk of breast cancer. In the test set, the protective effects of the AG + GG genotypes were more evident among participants with a family history of cancer. Further case series analysis revealed that the GG genotype was associated with reduced breast cancer susceptibility in cases of tumor size >2 cm and late clinical stage (II + III + IV). Colony formation assays showed that MIIP 167E (the G variant) was a more potent inhibitor of colony formation but not cell migration. These results suggest MIIP K167E as a functional genetic marker of breast cancer development and prognosis. Cancer Res; 70(3); 1024–32
Heterogeneity for Stem Cell–Related Markers According to Tumor Subtype and Histologic Stage in Breast Cancer
Authors: Park So Yeon , Lee Hee Eun , Li Hailun , Shipitsin Michail , Gelman Rebecca , Polyak Kornelia
Published: January 2010

Purpose: To evaluate the expression of stem cell–related markers at the cellular level in human breast tumors of different subtypes and histologic stage.

Experimental Design: We performed immunohistochemical analyses of 12 proteins [CD44, CD24, ALDH1, vimentin, osteonectin, EPCR, caveolin 1, connexin 43, cytokeratin 18 (CK18), MUC1, claudin 7, and GATA3] selected based on their differential expression in breast cancer cells with more differentiated and stem cell–like characteristics in 47 cases of invasive ductal carcinoma (IDC) only, 135 cases of IDC with ductal carcinoma in situ (DCIS), 35 cases of DCIS with microinvasion, and 58 cases of pure DCIS. We also analyzed 73 IDCs with adjacent DCIS to determine the differences in the expression of markers by histology within individual tumors. CD44+/CD24− and CD24−/CD24+ cells were detected using double immunohistochemistry.

Results: CD44 and EPCR expression was different among the four histologic groups and was lower in invasive compared with in situ tumors, especially in luminal A subtype. The expression of vimentin, osteonectin, connexin 43, ALDH1, CK18, GATA3, and MUC1 differed by tumor subtype in some histologic groups. ALDH1-positive cells were more frequent in basal-like and HER2+ than in luminal tumors. CD44+/CD24− cells were detected in 69% of all tumors with 100% of the basal-like and 52% of HER2+ tumors having some of these cells.

Conclusions: Our findings suggest that in breast cancer, the frequency of tumor cells positive for stem cell–like and more differentiated cell markers varies according to tumor subtype and histologic stage. Clin Cancer Res; 16(3); 876–87
18F-Fluorodeoxyglucose Positron Emission Tomography Predicts Survival of Patients with Neuroendocrine Tumors
Authors: Binderup Tina , Knigge Ulrich , Loft Annika , Federspiel Birgitte , Kjaer Andreas
Published: January 2010

Purpose: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is currently not used on a routine basis for imaging of neuroendocrine (NE) tumors. The aim of this study was to investigate the prognostic value of FDG-PET in patients with NE tumors.

Experimental Design: Ninety-eight prospectively enrolled patients with NE tumors underwent FDG-PET imaging. FDG uptake was quantified by maximal standardized uptake value (SUVmax). The prognostic value of FDG uptake, proliferation index, chromogranin A, and liver metastases were assessed.

Results: During the 1-year follow-up, 14 patients died. The diagnostic sensitivity of FDG-PET was 58% (n = 57) and a positive FDG-PET result was associated with a significantly higher risk of death with a hazard ratio (HR) of 10.3 [95% confidence interval (CI), 1.3-78.9]. Thirteen of the 57 (23%) FDG-PET–positive patients died compared with 1 of 41 (2%) FDG-PET–negative patients. By univariate analysis, a SUVmax of >9 and a high Ki67 index were significant predictors of overall survival with a HR of 8.8 (95% CI, 2.7-28.7) and a HR of 2.6 (95% CI, 1.3-5.1), respectively. In a multivariate analysis including a SUVmax of >3, Ki67, and chromogranin A, SUVmax of >3 was the only predictor of progression-free survival (HR, 8.4; P < 0.001).

Conclusions: This study shows a strong prognostic value of FDG-PET for NE tumors, which exceeds the prognostic value of traditional markers such as Ki67, chromogranin A, and liver metastases. FDG-PET may obtain an important role for NE tumors. Clin Cancer Res; 16(3); 978–85
Efficacy of Combining GMX1777 with Radiation Therapy for Human Head and Neck Carcinoma
Authors: Kato Hisayuki , Ito Emma , Shi Wei , Alajez Nehad M. , Yue Shijun , Lee Carolina , Chan Norman , Bhogal Nirmal , Coackley Carla L. , Vines Doug , Green David , Waldron John , Gullane Patrick , Bristow Rob , Liu Fei-Fei
Published: January 2010

Purpose: Rapidly metabolizing tumor cells have elevated levels of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD+ biosynthesis, which serves as an important substrate for proteins involved in DNA repair. GMX1777, which inhibits nicotinamide phosphoribosyltransferase, was evaluated in two human head and neck cancer models in combination with radiotherapy.

Experimental Design: Effects of GMX1777-mediated radiosensitization were examined via metabolic and cytotoxicity assays in vitro; mechanism of action, in vivo antitumor efficacy, and radiosensitization were also investigated.

Results: IC50 values of GMX1777 for FaDu and C666-1 cells were 10 and 5 nmol/L, respectively, which interacted synergistically with radiotherapy. GMX1777 induced a rapid decline in intracellular NAD+ followed by ATP reduction associated with significant cytotoxicity. These metabolic changes were slightly increased with the addition of radiotherapy, although poly(ADP-ribose) polymerase activity was significantly reduced when GMX1777 was combined with radiotherapy, thereby accounting for the synergistic cytotoxicity of these two modalities. Systemic GMX1777 administration with local tumor radiotherapy caused complete disappearance of FaDu and C666-1 tumors for 50 and 20 days, respectively. There was also significant reduction in tumor vascularity, particularly for the more sensitive FaDu model. [18F]FDG-positron emission tomography/computed tomography images showed reduction in [18F]FDG uptake after GMX1777 administration, showing decreased glucose metabolism in vivo.

Conclusions: Our data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Therefore, GMX1777 combined with radiotherapy definitely warrants clinical evaluation in human head and neck cancer patients. Clin Cancer Res; 16(3); 898–911
Associations between Radiocurability and Interstitial Fluid Pressure in Human Tumor Xenografts without Hypoxic Tissue
Authors: Rofstad Einar K. , Ruud Else-Beate M. , Mathiesen Berit , Galappathi Kanthi
Published: January 2010

Purpose: The interstitial fluid pressure (IFP) of the primary tumor is an independent prognostic parameter for cervical cancer patients treated with radiation therapy. The aim of this preclinical study was to investigate whether tumor radiocurability may be associated with IFP through hypoxia-independent mechanisms.

Experimental Design: Small A-07 and R-18 melanoma xenografts without hypoxic tissue were used as preclinical tumor models. IFP was measured by using the wick-in-needle method. Radiation dose resulting in 50% local tumor control (TCD50), cell density, cell tumorigenicity, plating efficiency in vitro, mitotic index, fraction of Ki67-positive cells, vascular endothelial growth factor-A (VEGF-A) concentration, and radiation-induced endothelial cell apoptosis were assessed in tumors with low and high IFP.

Results: TCD50 was found to be higher for tumors with high IFP than for tumors with low IFP by factors of 1.13 ± 0.03 (A-07; P < 0.0001) and 1.10 ± 0.03 (R-18; P < 0.0001). In the A-07 line, tumors with high IFP showed a larger number of clonogenic cells and a higher rate of cell proliferation than tumors with low IFP. In the R-18 line, tumors with high IFP showed a higher concentration of VEGF-A and a lower endothelial cell apoptotic index after irradiation than tumors with low IFP.

Conclusions: The radiation resistance of normoxic tumor tissue with highly elevated IFP may be an indirect consequence of increased tumor cell clonogenicity as well as increased VEGF-A expression, possibly caused by hypertension-induced modifications of signaling pathways regulating cell proliferation, cell survival, and/or angiogenesis. Clin Cancer Res; 16(3); 936–45
Monitoring Drug-Induced γH2AX as a Pharmacodynamic Biomarker in Individual Circulating Tumor Cells
Authors: Wang Lihua H. , Pfister Thomas D. , Parchment Ralph E. , Kummar Shivaani , Rubinstein Larry , Evrard Yvonne A. , Gutierrez Martin E. , Murgo Anthony J. , Tomaszewski Joseph E. , Doroshow James H. , Kinders Robert J.
Published: January 2010

Purpose: Circulating tumor cells (CTC) in peripheral blood of patients potentially represent a fraction of solid tumor cells available for more frequent pharmacodynamic assessment of drug action than is possible using tumor biopsy. However, currently available CTC assays are limited to cell membrane antigens. Here, we describe an assay that directly examines changes in levels of the nuclear DNA damage marker γH2AX in individual CTCs of patients treated with chemotherapeutic agents.

Experimental Design: An Alexa Fluor 488–conjugated monoclonal γH2AX antibody and epithelial cancer cell lines treated with topotecan and spiked into whole blood were used to measure DNA damage–dependent nuclear γH2AX signals in individual CTCs. Time-course changes in both CTC number and γH2AX levels in CTCs were also evaluated in blood samples from patients undergoing treatment.

Results: The percentage of γH2AX-positive CTCs increased in a concentration-dependent manner in cells treated with therapeutically relevant concentrations of topotecan ex vivo. In samples from five patients, percent γH2AX-positive cells increased post-treatment from a mean of 2% at baseline (range, 0-6%) to a mean of 38% (range, 22-64%) after a single day of drug administration; this increase was irrespective of increases or decreases in the total CTC count.

Conclusions: These data show promise for monitoring dynamic changes in nuclear biomarkers in CTCs (in addition to CTC count) for rapidly assessing drug activity in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research. Clin Cancer Res; 16(3); 1073–84
Short Note The Jubilee: Its Reckoning and Inception Day
Authors: Kim Young Hye
Published: January 2010

New solutions are proposed to the puzzles of how the Jubilee Year is reckoned and why the Jubilee begins on the Day of Atonement. The Jubilee cycle begins not in the first year of the Sabbath-year cycle, but the seventh, fallow year. The Jubilee begins on the Day of Atonement because of its Sabbath associations.
Short Note On in 2 Kings 9:37
Authors: Walsh Jerome T.
Published: January 2010

Reading whyt in 2 Kgs 9:37 as “destruction” avoids emendation and resolves the problem of the absence in 1 Kgs 21:23 of anything corresponding to 2 Kgs 9:37.
“A Young Goat in Its Mother’s Milk”? Understanding an Ancient Prohibition
Authors: Schorch Stefan
Published: January 2010

The passage should be understood as “you shall not cook (for eating purposes) a sucking kid”. This is not only the meaning of the passage in the Covenant Code (Exod 23:19) and in the so-called “Privilegrecht” (Exod 34:26), but it was the way as well in which this passage was understood by the authors of Deuteronomy (Deut 14:21). Amos 6:4 seems to contain an early reference to the prohibition of the sucking kid.
'Fortress Europe' and FRONTEX: Within or Without International Law?
Authors: Papastavridis Efthymios
Published: January 2010

It is true that the problem of interception of human beings on the high seas is more acute than ever, not only in terms of the number of vessels intercepted but also in terms of the variety of legal issues that it raises. The most worrisome observation, however, is that while interception of human beings has been practiced for centuries, currently the pendulum has swung from interception to free and save lives, for example, in the context of chattel slavery, to interception to prevent people from entering developed States and claiming a better future. This is particularly reflected in the practice of EU Member States, which have taken many initiatives in the maritime domain to strengthen the external borders of 'fortress' Europe. Lately, this practice is coordinated by a European Agency, commonly referred to as FRONTEX, which was established in 2004 in order to "coordinate the operational cooperation between Member States in the field of external borders management". To this end, FRONTEX has launched a number of maritime interdiction operations carried out on the high seas and even further, i.e. in the territorial seas of States of departure or transit, such as Mauritania, Senegal, Cape Verde. The purpose of this article is to address the most important questions that these maritime operations of FRONTEX raise, analysing them through the lens of the law of the sea and other rules of corpus juris gentium. Accordingly, in the first part there will be a thorough discussion of the pertinent legal bases of the interception operations on the high seas and in the territorial waters, while in the second the analysis will focus more on the relevance of other international rules like the use of force or the principle of non-refoulement to the present context. The application of the latter principle appears to be especially problematic in the majority of these operations since it is very likely that the persons onboard the intercepted vessels would be forced to return to their countries of origin, where they may be subjected to torture or inhuman or degrading treatment.
The Competency of Children to Testify: Psychological Research Informing Canadian Law Reform
Authors: Lee Kang ,   Lindsay, Talwar Victoria , Bala Nicholas
Published: January 2010

The competency inquiry has traditionally been a critical initial challenge for child witnesses, most of who are called to testify about their own victimization or as witnesses of family violence. In most common law countries children can only testify if they can correctly answer questions about such abstract concepts as the “oath,” the “promise” and “truth.” These inquiries can be confusing to children, and may prevent children who are capable of giving important evidence from testifying. Recent psychological research establishes that the ability of children to answer questions about the meaning of such concepts as “truth” and “promise” is not related to whether they will actually tell the truth, but the act of “promising to tell the truth” increases the likelihood that children will tell the truth. Informed by this research, in 2006 Canada significantly reformed its laws governing the process for determining the competence of child witnesses. The last section of the paper briefly surveys laws that govern the competency of child witnesses in a number of other jurisdictions and offers proposals for reform.
Effect of a Speech Aid Prosthesis on Reducing Muscle Fatigue
Authors: Nohara K. , Kotani Y. , Sasao Y. , Ojima M. , Tachimura T. , Sakai T.
Published: January 2010

It has been reported that the levator veli palatini muscles of speakers with velopharyngeal incompetence tend to demonstrate muscle fatigue during speech. This study examined whether a speech aid prosthesis might reduce levator muscle fatigue in such speakers. Eight individuals with post-surgical cleft palates, and who wore a speech aid prosthesis, were studied. Each person was asked to pronounce the syllable [pu] more than 50 times. Mean power frequency (MPF) of one syllable was obtained from electromyographic data from the levator muscle. The MPF regression line was calculated during the course of syllable repetition. The absolute values of the slopes of the regression lines with the prosthesis were significantly smaller than those without the prosthesis. It was shown that the prosthesis reduced the decrease in MPF during speech. These results suggested that speech aid prostheses reduce levator muscle fatigue during speech in persons with velopharyngeal incompetence.
Sensemaking, rhetoric and the socially competent entrepreneur
Authors: Holt Robin , Macpherson Allan
Published: January 2010

A significant barrier to creating and sustaining firms are the difficulties experienced in continually legitimating their institutional structures. This is especially the case for small firms; entrepreneurs struggle to create and sustain often novel ideas and nascent firm structures set within, or against, well-established market environments. To better understand connections between organization formation and legitimacy of small firms we use accounts from three entrepreneurs. We break down their accounts using Aristotle’s concept of rhetoric. By attending to what Aristotle identified as the three areas of concern for rhetorical method ( logos, ethos and pathos) to analyse the entrepreneurs’ sensemaking, we show their awareness of the negotiated, situated and social nature of their enterprises. Our findings expand on existing concepts such as Lounsbury and Glynn’s (2001) ‘cultural entrepreneurship’, by demonstrating how collaborative sensemaking might be practised and how social competence and an awareness of others’ needs, wishes, ambitions and objectives are central to the foundation and potential success of small firms.
Leveraging tenant-incubator social capital for organizational learning and performance in incubation programme
Authors: Fang Shieh-Chieh , Tsai Fu-Sheng , Lin Julia L.
Published: January 2010

This article seeks to construct and examine a model of entrepreneurial learning in incubation programmes by investigating focal tenants’ proactive leveraging of incubator-tenant social capital. Few have examined the interrelationships between social capital, interorganizational learning and incubation from a perspective treating tenant firms as focal actors. Surveys were collected from incubation programmes in Taiwan, where innovation and knowledge-based entrepreneurship is a critical success factor for both social and economic progress. Data were analysed by multiple regression and structural equation modelling. Results indicate that tenants’ proactive utilization of tenant-incubator social capital positively influences interorganizational learning mechanisms (OLM), which in turn transforms the benefit of social relationships into tenants’ performance, in terms of technological capability, managerial competence and satisfaction with (the) incubation programme. Theoretically, this article complements interorganizational network and interorganizational relation perspectives of social capital to understand the complex entrepreneurial learning, value creation and appropriation for entrepreneurial firms in incubation programmes. We argue that strong relationship and network contents with the hub organization can complement weakness in structural status. Practically, design for strategic networking practices, interorganizational learning management for capability building and innovation and policy considerations are discussed.
The Pathogenesis of Primary and Secondary Infection with Fasciola hepatica in Mice
Authors: Masake R. A. , Wescott R. B. , Spencer G. R. , Lang B. Z.
Published: January 2010

Primary and secondary infections of F. hepatica in mice were compared to determine how prior exposure to the parasite affected host response. Mice with primary parenchymal Fasciola infections initially had hemorrhagic tunnels filled with inflammatory cells and connective tissue. These lesions were progressive and became most severe 30 days after exposure as the parasites entered the bile ducts. At this time there was much hyperplasia and thickening of all layers of the duct system near the parasites and occasionally severe periportal fibrosis. By 2 months after exposure regeneration of the damaged liver cells was complete although hyperplasia persisted in bile ducts containing flukes. In mice with secondary infections (mice exposed 40 to 50 days after first infection), the inflammatory response was faster and shorter. Most lesions were resolved by 30 days after the second exposure. There was little difference in histology of primary and secondary infections during the chronic phase of the disease.
Early Colonic Lesions in Experimental Shigella Infection in Rhesus Monkeys: Revisited
Authors: Takeuchi A.
Published: January 2010

Rhesus monkeys (Macaca mulatta), given 3 × 108 to 5 × 1010Shigella flexneri 2a orally, developed signs of acute shigellosis within 24 hours. A diffuse acute colitis was well established at 48 hours. The inflammatory reaction was confined to the mucosa. The submucosa showed only edema. The shigellae were found predominantly in the columnar cells of the surface epithelium, less frequently in those of the crypt, and least frequently in the lamina propria. Shigella bacilli invaded the columnar cells from the intestinal lumen. The bacilli multiplied within epithelial cells and spread laterally to adjacent epithelial cells and penetrated the lamina propria. The bacterial invasion affected epithelial cells unevenly and resulted in the disappearance of goblet cells and pyknotic shrinkage of the surface epithelial cells. Epithelial cells had abnormal and accelerated exfoliation which resulted in multifocal epithelial defects. There was a distinct correlation between the quantity of bacilli present in tissues and the intensity of the inflammatory response. The small intestines were spared.
Gastrointestinal Neoplasms in Nonhuman Primates: A Review and Report of Eleven New Cases
Authors: DePaoli A. , McClure H. M.
Published: January 2010

Reported gastrointestinal neoplasms in nonhuman primates are reviewed, and the clinical and pathologic features of 11 new cases are described. The 11 monkeys had a total of 12 malignant gastrointestinal neoplasms; one had two primary carcinomas, one in the colon and one in the duodenum. Ten of the 12 tumors were adenocarcinomas: two in the duodenum, one in the jejunum, four in the distal ileum or region of the ileocecal valve and three in the large intestine. The remaining two lesions were a histiocytic lymphosarcoma of the stomach and a poorly differentiated sarcoma of the cecum. The 11 animals included nine Macaca mulatta, one Saguinus oedipus oedipus and one Galago crassicaudatus. All were adults and most were aged. There were six females and five males. Clinical signs included progressive weight loss, a palpable abdominal mass and intermittent diarrhea.

Grossly, five of the adenocarcinomas were annular, and constricted the intestinal lumen. Microscopically, the carcinomas generally were well differentiated, and two produced mucin in quantities warranting the modifier “mucinous” adenocarcinoma. All tumors were locally invasive and six of nine monkeys with carcinomas had metastases, with the regional lymph nodes the principal site of involvement.
Clinicopathological Studies of Gastrointestinal Disease in Macaques
Authors: Holmberg C. A. , Leininger R. , Wheeldon E. , Slater D. , Henrickson R. , Anderson J.
Published: January 2010

Evaluation of mortality during a two-year period at a primate colony indicated that 34% of nonexperimental deaths in macaques one year of age and older were due to gastrointestinal disease. Of deaths related to gastrointestinal disease, 12% had acute gastric dilatation, 18% had shigellosis, 12% had nontuberculous mycobacterial disease, and 58% were of undetermined cause. Histologic evaluation of the alimentary tract indicated that the large intestine was the most common site of anatomical change in monkeys that had diarrhea at the time of death. Monkeys that had a single terminal episode of diarrhea had less gastric inflammatory lesions than those that had multiple episodes of diarrhea in the last year of life.
Cutaneous Plasmacytomas in Dogs: A Morphologic and Immunohistochemical Study
Authors: Baer K. E. , Patnaik A. K. , Gilbertson S. R. , Hurvitz A. I.
Published: January 2010

Forty-nine cutaneous plasmacytomas in 46 dogs were studied. Tumors occurred at solitary sites in middle-aged to old dogs (mean age, 9.7 years) and most commonly involved the skin of the digits, lips, and ears. Initial diagnosis was made on the basis of light microscopic morphologic findings. Tumors were graded according to the extent of cellular differentiation and immunoreactivity to a panel of immunohistochemical markers (cytokeratins, canine IgG F[ab]2, neurofilament, neuron-specific enolase, S-100 protein, and vimentin). Immunoreactivity was limited to antibodies directed at canine IgG F(ab)2, and vimentin. Vimentin immunoreactivity was usually greater than that of canine IgG F(ab)2, but there was no correlation between immunoreactivity and histologic grade of the tumors. Thirty-six of 39 dogs (92.3%) followed (mean follow-up, 13 months) were cured by surgical excision. The results of this study indicate that canine cutaneous plasmacytomas are benign neoplasms that should be included in the differential diagnosis of cutaneous round cell tumors in dogs.
Toxicity of Microcystin LR, a Cyclic Heptapeptide Hepatotoxin fromMicrocystis aeruginosa,to Rats and Mice
Authors: Hooser S. B. , Beasley V. R. , Lovell R. A. , Carmichael W. W. , Haschek W. M.
Published: January 2010

Abstract. Rats (Sprague-Dawley) and mice (Balb/c) were given microcystin LR intraperitoneally and were killed at intervals up to 24 hr (rats) or 90 min (mice) and necropsied. The lowest consistently lethal dose was 160 μg/kg in rats and 100 μg/kg in mice. Rats that were clinically unaffected had no lesion. All clinically affected rats in all dose groups died (from 20 to 32 hr after toxin) and had similar hepatic lesions. Livers were enlarged and dark red beginning 40 to 60 min after toxin. Mild disassociation and rounding of centrilobular hepatocytes developed within 20 min. By 60 min after toxin, degeneration and necrosis of hepatocytes involved most of the lobules except for small per portal zones. Weights of livers and kidneys were significantly increased. Eosinophilic fibrillar material filled renal glomerular capillaries as early as 9 hr after toxin. At 18 to 24 hr there was moderate vacuolation of proximal tubular epithelium with mild tubular dilatation. Beginning at 1 hr, intact hepatocytes and hepatic debris were present in pulmonary vessels. Analysis of serum revealed an increase in alanine aminotransferase 40 min after toxin; at 6 to 12 hr there were significant increases in alkaline phosphatase, total bilirubin, blood urea nitrogen, and creatinine. Mice survived only 60 to 90 min after toxin. Hepatic lesions were similar to those in rats, but renal and pulmonary lesions were not seen.
Clinical Pathology and Hemostatic Abnormalities in Experimental African Horsesickness
Authors: Skowronek A. J. , LaFranco L. , Stone-Marschat M. A. , Burrage T. G. , Rebar A. H. , Laegreid W. W.
Published: January 2010

Infection of naive North American horses with 104cell culture infectious doses (CCID50) of virulence variants of African horsesickness virus (AHSV), designated AHSV/4SP, AHSV/9PI, and AHSV/4PI, reproduced three classical forms of African horsesickness: acute (pulmonary), subacute (cardiac), and febrile, respectively. Distinct clinicopathologic and hemostatic abnormalities were associated with each form of disease. Hemostatic abnormalities included increased concentration of fibrin degradation products and prolongation of prothrombin, activated partial thromboplastin, and thrombin clotting times. Hemostatic findings indicated activation of the coagulation and fibrinolytic systems with clotting factor consumption in acute and subacute cases of African horsesickness. Hematologic abnormalities in acute and subacute cases of African horsesickness included leukopenia, decreased platelet counts, elevated hematocrit, and increased erythrocyte counts and hemoglobin concentration. Leukopenia was characterized by lymphopenia, neutropenia, and a left shift. Increased levels of serum creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase, hypocalcemia, hypoalbuminemia, hypoproteinemia, and elevated creatinine, phosphorus, and total bilirubin levels were present in some but not all horses. Metabolic acidosis, indicated by decreased total bicarbonate and increased lactate and anion gap, was present in horses with the acute form of disease. Mild thrombocytopenia and leukopenia were occasionally associated with the febrile form of disease. These results suggest a role for intravascular coagulation in the pathogenesis of African horsesickness.
Murine Cytomegalovirus-associated Arteritis
Authors: Dangler C. A. , Baker S. E. , Njenga M. Kariuki , Chia S. H.
Published: January 2010

Unique inflammatory lesions affecting the ascending aorta and pulmonary artery of BALB/c and C57BL/6 mice infected with murine cytomegalovirus (MCMV) were identified in a pilot and two subsequent experiments to characterize the potential effect of MCMV infection on diet-induced atherosclerotic lesions. Suckling BALB/c and C57BL/6 mice were inoculated with MCMV and subsequently fed either a commercial mouse diet or a synthetic atherogenic diet from weaning. The three experiments varied with respect to the age of the mice at the time of MCMV inoculation and the dose of virus given. The conditions of MCMV exposure were progressively modified in the three experiments to increase the prevalence of MCMV-associated inflammatory lesions in the pulmonary artery and aorta. In the final experiment, in which suckling mice were inoculated at 9 days of age, MCMV-associated arteritic lesions had an observed prevalence at 8 weeks post-inoculation of 87.5% (7/8) in BALB/c mice on the normal diet and 100% (8/8) in C57BL/6 mice on the normal diet and in both strains on the atherogenic diet. The inflammatory lesions in both vessels were characterized by mononuclear cell infiltrates containing CD3+, CD4+, and CD8+ lymphocytes. The cellular infiltrates were often more intense on the adventitial surface and infiltrated into the overlying tunica media. The intima was infiltrated by mononuclear cell infiltrates that appeared to contain more macrophages and fewer lymphocytes than did the adventitial infiltrates. Although the prevalence of inflammatory lesions in the pulmonary artery and ascending aorta was independent of the atherogenic diet, lipid accumulation with formation of foam cells within the inflammatory foci was clearly dependent on exposure to the atherogenic diet in both strains. Total arterial lipid accretion in MCMV-inoculated mice of both strains was greater than that in their noninoculated counterparts because of the occurrence of inflammation-associated lipid accretion in addition to the lipid accumulation induced by the atherogenic diet alone. MCMV-associated arteritis can serve as a useful model to examine more fully the possible role of human cytomegalovirus infections in enhancing the pathogenesis of human atherosclerosis.
Immunoreactivity of Canine Epithelial and Nonepithelial Neoplasms with Monoclonal Antibody B72.3
Authors: Clemo F. A. S. , DeNicola D. B. , Morrison W. B. , Carlton W. W.
Published: January 2010

Monoclonal antibody (MAb) B72.3, which binds to a human tumor-associated glycoprotein termed TAG-72, was applied to a wide range of epithelial and nonepithelial neoplasms from dogs. Immunoreactivity was detected by the use of an avidin-biotin complex (ABC) immunoperoxidase method. A variety of epithelial neoplasms, but none of the nonepithelial neoplasms, were positive (≥ 5% staining) for MAb B72.3. MAb B72.3 stained 100% (4/4) of gastric, 100% (6/6) of intestinal, 50% (2/4) of pancreatic, and 80% (4/5) of rectal adenocarcinomas but only 20% (1/5) of squamous cell carcinomas and 20% (1/5) of complex tubular mammary gland adenocarcinomas. None of the hepatocellular carcinomas and perianal and sebaceous gland adenocarcinomas stained. Most types of benign epithelial neoplasms did not stain, except for 75% (6/8) of rectal adenomas and 25% (1/4) of squamous cell papillomas. Normal gastrointestinal mucosa adjacent to and entrapped in neoplasms did stain with MAb B72.3. None of the benign and malignant nonepithelial neoplasms of mesenchymal, neuroendocrine, or lymphohematopoietic tissue origin stained. The results of this study demonstrate that MAb B72.3 has selective immunoreactivity for adenocarcinomas, especially those arising from the digestive tract; however, limited immunoreactivity was observed for other types of carcinomas and benign epithelial neoplasms and for normal gastrointestinal mucosa in the dog.
Intracranial Gangliocytoma in a Dog
Authors: Nyska A. , Shamir M. H. , Harmelin A. , Sandbank J. , Waner T.
Published: January 2010

The clinical, pathologic, immunohistochemical, and electron microscopic characteristics of a pure intracranial gangliocytoma in a 6-year-old spayed female dog are presented. The tumor is very rare in humans, and has not been previously reported in the dog. The most remarkable feature of this tumor was that it was composed of a single neuronal cell type without the presence of glial elements, as demonstrated by the negative immunohistochemical reaction to glial fibrillary acidic protein.
Assignment of Islet Amyloid Polypeptide (IAPP) Gene to Feline Chromosome B4 Using the Polymerase Chain Reaction Technique on Feline-Rodent Hybrid Cell Lines
Authors: Jordan K. , O'Brien S. J. , Johnson K. H. , O'Brien T. D.
Published: January 2010

The most characteristic morphologic features of the pancreatic islets of human non-insulin-dependent diabetes mellitus (NIDDM, or type 2 diabetes mellitus) and of similar forms of diabetes in cats and macaques are the deposition of amyloid (islet amyloid) and the loss of beta cells. Islet amyloid is derived from islet amyloid polypeptide (IAPP), which is a normal secretory product of the beta cells. Therefore, knowledge of the IAPP gene is of potential importance in defining the pathogenesis of NIDDM. To identify the feline chromosome(s) on which the IAPP gene is located, we screened genomic DNA obtained from 38 feline-rodent hybrid cell lines that have a known feline chromosome content. Feline IAPP DNA was amplified and detected using the polymerase chain reaction technique. Discordancy analysis for each feline chromosome showed that chromosome B4 had the lowest discordancy ( P < 0.0001). Feline chromosome B4 shows an extensive conserved syntenic relationship with human chromosome 12, on which the human IAPP gene is located. This study therefore extends and confirms the homology between human chromosome 12 and feline chromosome B4 and provides an additional genetic marker for feline chromosome B4.
Immunohistochemical Identification of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Antigen in the Heart and Lymphoid System of Three-week-old Colostrum-deprived Pigs
Authors: Halbur P. G. , Miller L. D. , Paul P. S. , Meng X.-J. , Huffman E. L. , Andrews J. J.
Published: January 2010

Porcine reproductive and respiratory syndrome virus (PRRSV) antigens were detected by a streptavidin-biotin complex technique in tissues of 3-week-old colostrum-deprived pigs that had been inoculated intranasally with PRRSV and had developed moderate respiratory disease. Moderate, multifocal, tan-colored consolidation of the lungs and severe enlargement of the lymph nodes were noted at necropsy. Severe interstitial pneumonia characterized by type 2 pneumocyte proliferation, septal infiltration with mononuclear cells, and accumulation of macrophages and necrotic cells in alveolar spaces was observed at 4 and 9 days postinoculation. Moderate multifocal perivascular lymphohistiocytic myocarditis was observed at 9 days postinoculation. Marked lymphoid follicular hyperplasia and follicular necrosis in the tonsil, spleen, and lymph nodes was observed. A monoclonal antibody that recognizes a conserved epitope of PRRSV nucleocapsid protein was used as primary antibody for immunohistochemistry. Antigen was readily detected in alveolar macrophages in the lung and in endothelial cells and macrophages in the heart. Macrophages and cells resembling dendritic cells in tonsil, lymph nodes, thymus, and spleen also stained intensely positive for viral antigen. PRRSV appears to replicate primarily within macrophages in the respiratory and lymphoid systems of the pig.
Blood and Serous Cysts in the Atrioventricular Valves of the Bovine Heart
Authors: Marcato P. S. , Benazzi C. , Bettini G. , Masi M. , Della Salda L. , Sarli G. , Vecchi G. , Poli A.
Published: January 2010

A survey of 30,907 slaughterhouse cattle (5,984 calves, 15,937 young adult, 8,986 cows) was carried out to determine the incidence of blood and serous cysts on atrioventricular valves. The cysts were classified by their content (blood/serous fluid), location (mitral/tricuspid valve), and size. Cyst wall samples were processed for histology, immunohistochemistry for factor VIII-related antigen, and transmission electron microscopy. The content of some cysts was studied by electrophoresis and biochemical and microbiologic methods. Older cows had a higher incidence (16.2%) than younger animals (11.5% in calves, 7.9% in steers, 6.4% in heifers), suggesting that the lesions may be acquired. Blood cysts were often present on both atrioventricular valves; serous cysts prevailed on the mitral valve. Cysts of both types were larger in older animals; serous cysts were larger than the blood cysts. Histologically, blood cysts contained fresh blood, and serous cysts were filled with a hyaline fluid devoid of cells, sterile, and biochemically similar to lymph. All the cysts were lined with endothelium, but a positive immunostaining for the factor VIII-related antigen was appreciable only in blood cysts. Ultrastructurally, the endothelium was composed of flat endothelial cells holding several cytoplasmic filaments, lying in blood cysts on a continuous and often laminated basal lamina with many cytoplasmic projections. The results support the hypothesis that cysts of the atrioventricular valves derive from the dilation of blood and lymphatic valvular vessels, do not regress with age, and are mainly the result of mechanical effects.