bluuebunny/crossref_metadata_2025 huggingface dataset:
Constitutive NF-κB Activation in Colorectal Carcinoma Plays a Key Role in Angiogenesis, Promoting Tumor Growth
Authors: Sakamoto Kei , Maeda Shin , Hikiba Yohko , Nakagawa Hayato , Hayakawa Yoku , Shibata Wataru , Yanai Ayako , Ogura Keiji , Omata Masao
Published: March 2009

Purpose: Nuclear factor κB (NF-κB) is an important transcription factor in various biological processes. Constitutive NF-κB activation has been noted in many tumors, including colorectal cancers. However, the precise role of this activation in colorectal cancer is unclear.

Experimental Design: Constitutive NF-κB activation was evaluated in colorectal cancer tissues and cell lines. To inhibit NF-κB activation, we established cancer cells with stable knockdown of IκB kinase γ (NF-κB essential modulator), which is the regulatory subunit of the IκB kinase complex, by RNA interference. Cell growth and apoptosis were evaluated in wild-type cells (WT) and knocked-down cells (KD). Microarray and protein array analysis were also done. To determine involvement of angiogenesis, human umbilical vein endothelial cells were used. By s.c. transplantation of the cells into nude mice, tumor sizes, vascularity, and chemodrug sensitivity were analyzed.

Results: Constitutive NF-κB activation was observed in 40% of colorectal cancer tissues and 67% of cell lines. Cell proliferation was not different between WT and KD in vitro, whereas apoptosis mediated by tumor necrosis factor-α and 5-fluorouracil were increased in KD. Several angiogenic chemokines were decreased in KD. Human umbilical vein endothelial cells incubated in WT supernatant showed more branch points than in KD, suggesting that constitutive NF-κB activation was involved in angiogenesis. Subcutaneous tumor expansion was suppressed to 23% in KD, and vessels were also decreased. By 5-fluoruracil treatment, tumor expansion was suppressed to a greater extent in KD (to 6%) than in WT (to 50%).

Conclusion: NF-κB inhibition may represent a potent treatment modality in colorectal cancer, especially in cases with constitutive NF-κB activation.
Medulloblastoma Variants: Age-Dependent Occurrence and Relation to Gorlin Syndrome—A New Clinical Perspective
Authors: Garrè Maria Luisa , Cama Armando , Bagnasco Francesca , Morana Giovanni , Giangaspero Felice , Brisigotti Massimo , Gambini Claudio , Forni Marco , Rossi Andrea , Haupt Riccardo , Nozza Paolo , Barra Salvina , Piatelli Gianluca , Viglizzo GianMaria , Capra Valeria , Bruno William , Pastorino Lorenza , Massimino Maura , Tumolo Miriam , Fidani Paola , Dallorso Sandro , Schumacher Riccardo Fabian , Milanaccio Claudia , Pietsch Torsten
Published: March 2009

Purpose: We aimed to test the hypothesis that medulloblastoma (MB) variants show a different age distribution and clinical behavior reflecting their specific biology, and that MB occurring at very young age is associated with cancer predisposition syndromes such as Gorlin syndrome (GS).

Experimental Design: We investigated the frequency, age distribution, location, response to treatment, outcome, and association with familial cancer predisposition syndromes in a series of 82 cases of MB in patients ages <14 years diagnosed at the Giannina Gaslini Children's Hospital, Genoa, between 1987 and 2004.

Results: Desmoplastic MB and MB with extensive nodularity (MBEN), were present in 22 of 82 cases (27%) and were more frequent in children ages ≤3 years (13 of 25; 52%). In this age group, MBEN was significantly more frequent than desmoplastic MB and classic MB (P < 0.001) and had a good prognosis. MBEN was associated with GS in 5 of 12 cases. Overall, 8 cases occurred in the context of familial tumor predisposition syndromes (5 GS, 1 each NF1, Li-Fraumeni, and Fragile X) and 7 of these patients were ages ≤3 years at diagnosis. Desmoplastic histology and a more intensive treatment represented independent favorable prognostic factors in multivariate analysis (P = 0.003 and P = 0.0139, respectively). Metastasis was a predictor of bad outcome (P = 0.0001).

Conclusions: Our data indicate that biologically different MB entities warrant risk-adapted treatment and that MBEN is strongly associated with GS. Patients, ages ≤3 years, with MB and their families should be investigated for tumor predisposition syndromes such as GS.
Randomized Phase II Designs
Authors: Rubinstein Larry , Crowley John , Ivy Percy , LeBlanc Michael , Sargent Dan
Published: March 2009

As the use of molecularly targeted agents, which are anticipated to increase overall survival (OS)and progression-free survival (PFS) but not necessarily tumor response, has increased in oncology, there has been a corresponding increase in the recommendation and use of randomized phase II designs. Such designs reduce the potential for bias, existent in comparisons with historical controls, but also substantially increase the sample size requirements. We review the principal statistical designs for historically controlled and randomized phase II trials, along with their advantages, disadvantages, and statistical design considerations. We review the arguments for and against the use of randomization in phase II studies, the situations in which the use of historical controls is preferred, and the situations in which the use of randomized designs is preferred. We review methods used to calculate predicted OS or PFS values from historical controls, adjusted so as to be appropriate for an experimental sample with particular prognostic characteristics. We show how adjustment of the type I and type II error bounds for randomized studies can facilitate the detection of appropriate target increases in median PFS or OS with sample sizes appropriate for phase II studies. Although there continue to be differences among investigators concerning the use of randomization versus historical controls in phase II trials, there is agreement that each approach will continue to be appropriate, and the optimal approach will depend upon the circumstances of the individual trial.
LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer
Authors: Xie Han , Valera Vladimir A. , Merino Maria J. , Amato Angela M. , Signoretti Sabina , Linehan William M. , Sukhatme Vikas P. , Seth Pankaj
Published: March 2009

The genetic basis for the hereditary leiomyomatosis and renal cell cancer syndrome is germ-line inactivating mutation in the gene for the Krebs/tricarboxylic acid cycle enzyme, fumarate hydratase (FH), the enzyme that converts fumarate to malate. These individuals are predisposed to development of leiomyomas of the skin and uterus as well as highly aggressive kidney cancers. Inhibition of FH should result in significant decrease in oxidative phosphorylation necessitating that glycolysis followed by fermentation of pyruvate to lactate will be required to provide adequate ATP as well as to regenerate NAD+. Moreover, FH deficiency is known to up-regulate expression of hypoxia-inducible factor (HIF)-1α by enhancing the stability of HIF transcript. This leads to activation of various HIF-regulated genes including vascular endothelial growth factor and glucose transporter GLUT1 and increased expression of several glycolytic enzymes. Because lactate dehydrogenase-A (LDH-A), also a HIF-1α target, promotes fermentative glycolysis (conversion of pyruvate to lactate), a step essential for regenerating NAD+, we asked whether FH-deficient cells would be exquisitely sensitive to LDH-A blockade. Here, we report that hereditary leiomyomatosis and renal cell cancer tumors indeed overexpress LDH-A, that LDH-A inhibition results in increased apoptosis in a cell with FH deficiency and that this effect is reactive oxygen species mediated, and that LDH-A knockdown in the background of FH knockdown results in significant reduction in tumor growth in a xenograft mouse model. [Mol Cancer Ther 2009;8(3):626–35]
Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine
Authors: Yoon Chang-Hwan , Kim Min-Jung , Park Moon-Taek , Byun Joo-Yun , Choi Young-Hyun , Yoo Hwan-Soo , Lee Yong-Moon , Hyun Jin-Won , Lee Su-Jae
Published: March 2009

Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However, the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that sphingosine induces death receptor–independent caspase-8 activation and apoptotic cell death via p38 mitogen-activated protein kinase (MAPK) activation and that suppression of the MAPK/extracellular signal–regulated kinase (ERK) kinase/ERK pathway by protein phosphatase 2A (PP2A) is required for p38 MAPK activation. Treatment of cells with sphingosine induced suppression of ERK and activation of p38 MAPK. Inhibition of p38 MAPK led to the marked suppression of death receptor–independent caspase-8 activation and subsequent cell death induced by sphingosine. Interestingly, pretreatment with phorbol 12-myristate 13-acetate or transfection of MAPK/ERK kinase/ERK resulting in ERK activation completely attenuated sphingosine-induced p38 MAPK activation. PP2A activity was additionally elevated on sphingosine treatment. Small interfering RNA targeting of PP2A effectively attenuated sphingosine-induced p38 MAPK activation through restoration of ERK activity, suggesting PP2A-mediated opposing regulation of ERK and p38 MAPK. Our findings clearly imply that activation of p38 MAPK promotes death receptor–independent activation of caspase-8 and apoptotic cell death pathways, thus providing a novel cellular mechanism for the anticancer activity of sphingolipid metabolites. (Mol Cancer Res 2009;7(3):361–70)
Degree of Sex Differentiation of Genetic Female Chicken Treated with Different Doses of an Aromatase Inhibitor
Authors: Yang X. , Zheng J. , Na R. , Li J. , Xu G. , Qu L. , Yang N.
Published: March 2009

Injection of an aromatase inhibitor before gonadal sex differentiation can induce female-to-male sex reversal in chicken, but a higher dose could reduce hatchability. In the present study, the dosage effect of Fadrozole, a nonsteroidal aromatase inhibitor, on gonadal differentiation was analyzed in sex-reversed genetic female chicken. There was no significant difference for the hatchability among low-dose (0.1, 0.3 and 0.5 mg) Fadrozole-injected groups and control groups (p > 0.05), but in high-dose groups (1.0 mg and 1.3 mg) the hatchability was significantly reduced (p < 0.05). Complete phenotypic sex reversal was observed in both high- and low- dose groups, with more than 90% of genetic females reversed into phenotypic male chicks. The degree of gonadal differentiation in 124 chicken at 30 weeks of age was classified into 5 categories according to the visual appearance and histological structure of the gonads. Category I and V were standard ovary and testis, respectively, while category II, III, and IV represented gonads of slightly, moderately, and highly sex-reversed females, respectively. Most gonads in low-dose groups were classified into category I, II, and III, while those in high-dose groups were mainly category IV. The serum testosterone levels in the 1.3 mg group were significantly higher and the estradiol levels lower than those in low-dose groups (p < 0.05). In conclusion, the range from 0.5 to 1.0 mg Fadrozole is a key interval for survival of chicken embryos. The gonadal differentiation in sex-reversed females at 30 weeks of age is highly dependent on the dose of Fadrozole injected prior to gonadal sex differentiation.
Cytokine Changes during Warm Ischemia and Reperfusion of the Pig Liver with or without Preconditioning
Authors: Kannerup A.-S. , Grønbæk H. , Funch-Jensen P. , Tønnesen E. , Jørgensen R.L. , Mortensen F.V.
Published: March 2009

Background: Hepatic inflow occlusion results in ischemia-reperfusion injury. The aim of the present porcine study was to investigate whether the pro- and anti-inflammatory cytokine response is involved in mediating the protective effect of ischemic preconditioning (IPC) during, and after warm liver ischemia. Methods: Fifteen randomized pigs – 7 non-IPC and 8 (IPC) – underwent laparotomy followed by 60 min of total ischemia with or without IPC continued by 3 h of reperfusion. Plasma cytokines (IL-6, IL-8, IL-10, and TNF-α) were measured during the study period as well as liver parameters (alanine-aminotransferase, alkaline phosphatase, bilirubin, and prothrombin time). Results: In the IPC group, IL-6 increased significantly during reperfusion compared to baseline and the non-IPC group. TNF-α increased nonsignificantly in the non-IPC group, while the levels remained stable in the IPC group. IL-8 and IL-10 increased in both groups after reperfusion. Only minor differences were observed in liver parameters. Conclusions: Warm liver ischemia with or without IPC activates inflammatory cytokines. IL-6 increased significantly in the IPC group compared to the non-IPC group, while the opposite was observed for TNF-α. These cytokine changes may be involved in the hepatoprotective mechanism induced by IPC.
Fractionated Plasma Separation and Adsorption Significantly Decreases Intracranial Pressure in Acute Liver Failure: Experimental Study
Authors: Ryska M. , Laszikova E. , Pantoflicek T. , Ryska O. , Prazak J. , Koblihova E.
Published: March 2009

Background: The aim of the study was to determine the influence of fractionated plasma separation and absorption (FPSA) on intracranial pressure (ICP) in acute liver failure (ALF). Methods: A surgical model of ALF in pigs (35–40 kg) was used. We compared laboratory data and haemodynamic parameters from the ALF control group to the ALF group treated by Prometheus using ANOVA with repeated measures and grouping factors, by calculating the area under the curve, and by the Mann-Whitney rank test. Results: Bilirubin levels differed significantly in favour of the FPSA treatment group: after 6 h 12.81 ± 6.54 versus 29.84 ± 9.99, after 9 h 11.94 ± 4.14 versus 29.95 ± 12.36 (p < 0.01) and after 12 h 13.88 ± 6.31 versus 26.10 ± 12.23 mmol/l (p < 0.05). ICP values differed significantly in favour of the FPSA treatment group: after 9 h 19.1 ± 4.09 versus 24.1 ± 2.85 (p < 0.01), after 10 h 21.9 ± 3.63 versus 25.1 ± 2.19, after 11 h 22.5 ± 3.98 versus 26.3 ± 3.50, and after 12 h 24.0 ± 4.66 versus 29.8 ± 5.88 mm Hg (p < 0.05). Conclusion: The authors demonstrated that a significant decrease in ICP was found in pigs with ALF following treatment by FPSA.
Analysis of Atlantic SST Variability Factoring Interbasin Links and the Secular Trend: Clarified Structure of the Atlantic Multidecadal Oscillation
Authors: Guan Bin , Nigam Sumant
Published: March 2009

Atlantic SST variability in the twentieth century is analyzed factoring the influence of natural SST variability in the Pacific basin and the secular change in global SSTs. The tropical and northern extratropical basins are analyzed together using the extended EOF technique, which permits extraction of the interannual and multidecadal modes in the pan-Atlantic basin in a single step.

The leading mode of Pacific-uninfluenced SST variability is a multidecadal oscillation focused in the extratropical basin, with a period of ∼70 yr. The mode differs from the conventional Atlantic multidecadal oscillation (AMO) in the near quiescence of the tropical–subtropical basin, highlighting the significant influence of the Pacific basin on this region in conventional analysis; as much as 45% of the regional variance resulting from the conventional AMO is due to this influence.

The second and third modes capture the growth (east-to-west development) and decay (near-simultaneous loss of amplitudes) of interannual SST variability in the eastern tropical Atlantic. A nominal 4-yr evolution cycle is identified, but phase transitions are irregular.

The fourth mode describes a north–south tripole with the mature-phase structure resembling the North Atlantic Oscillation’s (NAO’s) SST footprint in winter. The mode lags the NAO by two seasons. Modal evolution involves eastward extension of the main lobe (centered near the separation of the Gulf Stream) along with shrinkage of the oppositely signed two side lobes.
Finite Samples and Uncertainty Estimates for Skill Measures for Seasonal Prediction
Authors: Kumar Arun
Published: March 2009

The expected value for various measures of skill for seasonal climate predictions is determined by the signal-to-noise ratio. The expected value, however, is only realized for long verification time series. In practice, the verifications for specific seasons—for example, forecasts for the December–February seasonal mean—seldom exceed a sample size of 30. The estimates of skill measure based on small verification time series, because of sampling errors, can have large departures from their expected value. An analysis of spread in the estimates of skill measures with the length of verification time series and for different signal-to-noise ratios is made. The analysis is based on the Monte Carlo approach and skill measures for deterministic, categorical, and probabilistic forecasts are considered. It is shown that the behavior of spread for various skill measures can be very different and it is not always the largest for the small values of signal-to-noise ratios.
Global/Local Modeling of Ballistic Impact onto Woven Fabrics
Authors: Rao M.P. , Nilakantan G. , Keefe M. , Powers B.M. , Bogetti T.A.
Published: March 2009

This study focuses on developing a global/local three-dimensional (3D) finite element model of a Kevlar KM2® plain woven fabric applicable for examining ballistic impact from a spherical projectile. The impact event is modeled in LS-DYNA® including friction between the individual yarns as well as the projectile and fabric. When compared with the predictive capabilities of a 3D finite element model that includes the detailed undulating representation of the fabric architecture over the entire solution domain, the savings in computational effort afforded by the global/local model become especially attractive. The agreement with fully detailed 3D finite element simulations and ballistic experiments is also demonstrated.
Afghānī on Empire, Islam, and Civilization
Authors: Kohn Margaret
Published: March 2009

This essay provides an interpretation of Sayyid Jamāl ad-Dīn al-Afghānī, a controversial figure in nineteenth-century Islamic political thought. One aspect of this controversy is the tension between “Refutation of the Materialists,” Afghānī's well-known defense of religious orthodoxy, and a short newspaper article entitled “Reply to Renan” that dismisses prophetic religion as dogmatic and intellectually stifling. In this essay I argue that close attention to Afghānī's theory of civilization helps resolve this apparent contradiction. Afghānī's interest in Ibn Khaldūn and the French historian Guizot is well known, but has not been fully explored in the literature. I suggest that understanding Guizot's distinctive approach to the concept of civilization illuminates Afghānī's writings on the political utility of religion. Afghānī was an ardent anti-imperialist and his goal was to encourage reform in Islamic countries while resisting Western hegemony. He concluded that the tension between prophetic religion and critical thought could help Islamic civilization to flourish.
The Minute Hand Phenomenon in the Clock Test of Patients With Early Alzheimer Disease
Authors: Leyhe Thomas , Milian Monika , Müller Stephan , Eschweiler Gerhard W. , Saur Ralf
Published: March 2009

Common scoring systems for the Clock Test do not sufficiently emphasize the correct time representation by the clock hands. We compared Clock Drawing, Clock Setting, and Clock Reading in healthy control persons, patients with mild cognitive impairment, early Alzheimer disease and progressed Alzheimer disease particularly analyzing clock time representation. We found that healthy control persons and participants with mild cognitive impairment did not show any impairment in Clock Test performance. Patients with early Alzheimer disease could be discriminated from healthy control persons and participants with mild cognitive impairment solely by misplacement of the minute hand in Clock Drawing and Clock Setting. The progressed Alzheimer disease group showed significantly more impairments in all Clock Test variants. It is assumed that early stage Alzheimer disease patient deficits in Clock Tests are mainly determined by a reduced access to semantic memory about the appearance and functionality of a clock.
`9/11 changed everything': an intertextual analysis of the Bush Doctrine
Authors: Dunmire Patricia L.
Published: March 2009

This article presents an intra- and inter-textual analysis of the `Bush Doctrine,' the security strategy response to 9/11 which sanctions a policy of preventive war. Using Thibault's (1991) framework of `critical, intertextual analysis,' I examine the Doctrine synchronically as it is articulated in the 2002 `National Security Strategy.' This analysis demonstrates the disjuncture created in NSS02 and the key discursive formations that underlie the Doctrine and link it to its earlier articulation in post-Cold War documents. I then examine the Doctrine diachronically by situating it within the context of these earlier texts and demonstrate the paradigmatic choices and linguistic transformations that occur across each document's security strategy. I argue that post-Cold War and post-9/11 security discourses comprise an intertextual system that has been suppressed by articulations of post-9/11 discourses. Within this system, 9/11 serves as the legitimating device that enabled the Bush Administration to sanction a security policy designed to maintain US global supremacy.
Entrepreneurial identities and the problematic of subjectivity in media-mediated discourses
Authors: Iyer Radha
Published: March 2009

This article examines discourses of patriarchy and femininity in representations of Indian women entrepreneurs in the popular Indian print media. Through critical discourse analysis of data consisting of 46 articles, the article examines the subtle positioning of Indian women entrepreneurs in language that is at once restraining and indicative of empowerment and independence. The analysis illustrates media stance as ambivalent and ambiguous with Indian women portrayed as traditional and modern, passive and proactive, dependent and independent. The resistive stance of women entrepreneurs provides the oppositional discourse of difference termed the discourses of `being' and `becoming'1 based on Deleuze and Guattari's (1987) notion of `becoming'. I conclude the article by accentuating that a critical reading practice is required to identify stereotypes and tease out discourses that illustrate transformative practices.
Statistical Versus Clinical Significance for Infants With Brain Injury
Authors: Lina Kurdahi Badr
Published: March 2009

By adopting more appropriate statistical methods to appraise data from a previously published randomized controlled trial, the statistical and clinical significance of an intervention on the 18-month neurodevelopmental outcome of infants with suspected brain injury is evaluated. The intervention group ( n = 32) receives extensive, individualized cognitive/sensorimotor stimulation by public health nurses while the control group ( n = 30) receives standard follow-up care. At 18 months, 43 infants remain in the study (22 intervention and 21 control). The results indicate that there is a significant statistical change within groups and a clinical significance whereby more infants in the intervention group improve in mental, motor, and neurological functioning at 18 months compared to the control group. The benefits of looking at clinical significance from a meaningful aspect for practitioners are emphasized.
Examining the safety and efficacy of a chemotherapy dosing method in Allogeneic Stem Cell Transplant patients of extreme body size
Authors: Sriharsha Lakshmi , Lipton Jeffrey H , Pond Greg , Ma Clement , Raybardhan Sumit , Messner Hans A , Seki Jack T
Published: March 2009

Background. There is no consensus on a universal dosing method for calculating high-dose chemotherapy in allogeneic Stem Cell Transplant (SCT) patients. The Metropolitan Life (Met-Life) Insurance Company’s weight—height tables have been used to determine body weight for chemotherapy dosing for SCT, however no formal study has been done to determine if the Met-Life weight— height tables can be used for chemotherapy dosing in SCT. We retrospectively studied the use of Met-Life weight—height tables for chemotherapy dosing in SCT. Our goal is to determine if patients with extremes of body size who had undergone an SCT and were dosed according to the Met-Life weight— height tables had an increase of Treatment Related Morbidity (TRM) or mortality or relapse.

Patients and Methods. Patients were grouped into three different treatment regimens, cyclophosphamide/TBI, busulphan/cyclophosphamide, and AraC/cyclophosphamide/TBI. Patients in each treatment regimen were further divided into five equal groups based on weight. Treatment related morbidity and mortality was evaluated by comparing the lowest and highest quintiles to the middle quintiles within each treatment regimen.

Result. Data from 262 patients was evaluated in this study. Overall, there was not an increase in TRM or mortality or in relapse in patients with extremes of body size.

Conclusion. The Met-Life weight—height tables could be used to dose patients undergoing allogeneic SCTs. Additional prospective studies would need to be done comparing other chemotherapy dosing methods with the Met-Life weight—height tables to further validate this conclusion.
Using evidence-based guidelines to reduce catheter related urinary tract infections in England
Authors: Pellowe Carol
Published: March 2009

Acquiring a healthcare associated infection (HCAI) in hospital remains a significant threat to patient safety, and catheter associated urinary tract infections (CAUTI) account for the majority of these infections. This review focuses on the complementary and continuing influence of central policy, evidence for practice, and educational support on strategies to reduce the incidence of CAUTI in the National Health Service (NHS). The development of the Department of Health's (DH) national guidelines for preventing HCAI (the `epic' guidelines) (Pratt et al, 2001, 2007) became the evidence base for the development of the DH Saving Lives strategy (DH, 2007). This initiative provides the tools and resources for NHS trusts to embed clinically effective HCAI prevention and control measures into everyday practice that are applied consistently to everyone. The national guidelines are also providing the evidence base for various educational initiatives designed to support guideline implementation, including the NHS Core Learning Unit's (CLU) Infection Control Programme.
Topological and organizational properties of the products of house-keeping and tissue-specific genes in protein-protein interaction networks
Authors: Lin Wen-hsien , Liu Wei-chung , Hwang Ming-jing
Published: March 2009

Background

Human cells of various tissue types differ greatly in morphology despite having the same set of genetic information. Some genes are expressed in all cell types to perform house-keeping functions, while some are selectively expressed to perform tissue-specific functions. In this study, we wished to elucidate how proteins encoded by human house-keeping genes and tissue-specific genes are organized in human protein-protein interaction networks. We constructed protein-protein interaction networks for different tissue types using two gene expression datasets and one protein-protein interaction database. We then calculated three network indices of topological importance, the degree, closeness, and betweenness centralities, to measure the network position of proteins encoded by house-keeping and tissue-specific genes, and quantified their local connectivity structure.

Results

Compared to a random selection of proteins, house-keeping gene-encoded proteins tended to have a greater number of directly interacting neighbors and occupy network positions in several shortest paths of interaction between protein pairs, whereas tissue-specific gene-encoded proteins did not. In addition, house-keeping gene-encoded proteins tended to connect with other house-keeping gene-encoded proteins in all tissue types, whereas tissue-specific gene-encoded proteins also tended to connect with other tissue-specific gene-encoded proteins, but only in approximately half of the tissue types examined.

Conclusion

Our analysis showed that house-keeping gene-encoded proteins tend to occupy important network positions, while those encoded by tissue-specific genes do not. The biological implications of our findings were discussed and we proposed a hypothesis regarding how cells organize their protein tools in protein-protein interaction networks. Our results led us to speculate that house-keeping gene-encoded proteins might form a core in human protein-protein interaction networks, while clusters of tissue-specific gene-encoded proteins are attached to the core at more peripheral positions of the networks.
Human Papillomavirus Quadrivalent Vaccine: A Look Behind The Numbers
Authors: Flaherty Dennis K , Alkhateeb Fadi M
Published: March 2009

The human papillomavirus (HPV) quadrivalent vaocine was licensed in 2006 for prevention of cervical, vulvar, and vaginal cancers caused by HPV-16 and −18 and genital warts caused by HPV-6 and −11. It is also indicated for prevention of precancerous and dysplastic lesions caused by HPV-6, −11, −16, and −18. Questions exist about the number of women and girls infected with the HPV strains covered by the vaccine, as well as about the vaccine's cost-effectiveness. There are also concerns about the efficacy of the vaccine in girls and young women, the population impact of the vaccine, the duration of protection, and the usefulness of the vaccine in developing countries. Careful consideration should be given to these issues by pharmacy and pharmacy professional organizations. To formulate reasonable healthcare guidelines, pharmacists and other healthcare professionals will need to engage policymakers in conversations concerning the vaccine's merits or limitations and the economic impact.
Gemifloxacin-Associated Neurotoxicity Presenting as Encephalopathy
Authors: Barrett Matthew J , Login Ivan S
Published: March 2009

Objective:

To report a case of acute encephalopathy associated with ingestion of gemifloxacin, a fluoroquinolone.

Case Summary:

A 67-year-old woman presented to the emergency department with an acute alteration in mental status. Twenty-four hours earlier she had taken one 320-mg tablet of her husband's gemifloxacirt prescription to treat symptoms of a mild upper respiratory infection. During her initial evaluation at our institution, the woman was dysphasia, unable to follow commands, and agitated, suggesting encephalopathy. A thorough diagnostic investigation did not reveal any structural, metabolic, or infectious etiology. Her mental status returned to normal within 2 days without any definitive treatment.

Discussion:

Fluoroquinolone-associated neurotoxicity may manifest as encephalopathy, seizures, confusion, or toxic psychosis. To date, none of these adverse effects, specifically encephalopathy, has been reported with gemifloxacin. An objective causality assessment revealed that encephalopathy was probably associated with gemifloxacin use. Seizures, either convulsive or nonconvulsive, may have contributed to our patient's presentation, but she denied seizures prior to this event and did not suffer a seizure in the 18 months following her discharge, However, her second electroencephalograph revealed an underlying predisposition to seizures, which gemifioxacin may have unmasked.

Conclusions:

This report illustrates that severe central nervous system adverse effects associated with some fluoroquinolones may also occur with gemifloxacin. Gemifloxacin and other fluoroquinolones should be considered in the etiologic evaluation of patients with acute encephalopathy.
Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Expression in Canine and Feline Meningioma
Authors: Mandara M. T. , Pavone S. , Mandrioli L. , Bettini G. , Falzone C. , Baroni M.
Published: March 2009

Fifty-one meningiomas obtained from 28 dogs and 23 cats were selected for this study to investigate the immunohistochemical expression of matrix metalloproteinase (MMP)-2 and MMP-9 and to compare it to the reverse transcriptase subunit of human-telomerase, progesterone receptor expression, and the proliferative index of the tumors, expressed by Ki67 and proliferating cellular nuclear antigen. Paraffin-embedded tumor tissue was obtained from biopsy samples (28 cases) and at necropsy (23 cases). The most common histotype was malignant in dogs (12/28) and transitional in cats (12/23). Slides immunolabelled for MMPs showed a diffuse cytoplasmic pattern. Twenty-one cases (19 dogs and 2 cats) did not express MMP-2, while only 2 cases were completely negative for MMP-9. The highest values of MMP-2 and MMP-9 were observed in a psammomatous and meningothelial tumor, respectively. On statistical analysis, MMP-2 expression did not show a significant correlation with MMP-9. Moreover, both MMP expressions failed to show significant variance among histologic patterns of the tumor and correlation with the proliferative index. MMP immunolabeling showed an inconstant correlation with progesterone receptor expression. No significant correlation was found between MMP and reverse transcriptase subunit of human-telomerase expression. In feline meningiomas, the MMP-2 value was significantly higher than in canine tumors and the MMP-9 value tended to be low for meningiomas with a follow-up duration from the 23rd month to the 44th month. In cats, the longer the time from surgery, the lower the proliferative index seemed to be. In dogs, we failed to find a correlation between MMP expression and the follow-up duration.
Tumor Morphology and Immunohistochemical Expression of Estrogen Receptor, Progesterone Receptor, p53, and Ki67 in Urogenital Carcinomas of California Sea Lions (Zalophus californianus)
Authors: Colegrove K. M. , Gullanda F. M. D. , Naydan D. K. , Lowenstine L. J.
Published: March 2009

Metastatic carcinoma of urogenital origin is a common cause of mortality in free-ranging California sea lions (Zalophus californianus). The etiology of this cancer is likely multifactorial, with viral infection, genetic factors, and exposure to environmental organochlorine contaminants possible contributing factors. In this study, expression of estrogen receptor α (ER α), progesterone receptor (PR), p53, and Ki67 were evaluated by immunohistochemistry in 12 sea lions with metastatic carcinoma, genital epithelial dysplasia, and intraepithelial neoplasia; 4 with genital epithelial dysplasia and intraepithelial neoplasia without metastases; and 6 control animals. Dysplastic and neoplastic lesions were identified in multiple areas of the cervix, vagina, penis, prepuce, and urethra in affected animals, suggesting multicentric development. Lesions were graded according to degree of epithelial dysplasia and infiltration and lesions of different grades were evaluated separately. Estrogen receptor expression was lower in intraepithelial lesions compared with normal genital epithelium, and expression in metastatic lesions was completely absent. There was progesterone receptor expression in neoplastic cells in intraepithelial lesions of all grades and in metastases, with no significant difference between lesion grades or between control and affected epithelium. Ki67 index and p53 expression increased with lesion grade and were higher in lesions than normal epithelium. Metastatic tumors exhibited highly variable morphology; however, proliferation index, ER α, PR, and p53 expression were similar in tumors with different patterns of growth. These results suggest that endogenous hormones, environmental contaminants that interact with steroid hormone receptors, and alterations in p53 may play a role in urogenital carcinogenesis in California sea lions.
Review Paper: Cancer Chemopreventive Compounds and Canine Cancer
Authors: Baek S. J. , Mcentee M. F. , Legendre A. M.
Published: March 2009

Canine cancer has become more prevalent in recent years because of increased life expectancy and greater attention to the health of pets. The range of cancers seen in dogs is as diverse as that in human patients, and despite more intensive therapeutic interventions, fatality rates remain unacceptably high in both species. Chemoprevention is therefore an important means of confronting this disease. Because domestic pets share our environment, greater cross-application and study of the protumorigenic and antitumorigenic factors in our shared environment will benefit all species, leading to the development of new families of less toxic antitumorigenic compounds based on novel and established molecular targets. Currently, the most interesting cancer preventive agents are nonsteroidal anti-inflammatory drugs, peroxisome proliferator-activated receptor-γ ligands, and dietary compounds. This article provides an overview of what is known about how these agents affect molecular signaling in neoplastic disease, with reference to reported application and/or study in dogs where available.
The Pathologic Features of Neurocutaneous Melanosis in a Cynomolgus Macaque
Authors: Chen Y. , Deng W. , Zhu H. , Li J. , Xu Y. , Dai X. , Jia C. , Kong Q. , Huang L. , Liu Y. , Ma C. , Xiao C. , Liu Y. , Li Q. , Bezard E. , Qin C.
Published: March 2009

Neurocutaneous melanosis (NCM) is a rare phakomatosis characterized by proliferation of melanin-producing cells in both the skin and the brain. In this study, we describe the clinical and pathologic features of NCM in a 4.5-year-old female cynomolgus macaque. Histopathologically, skin lesions showed foci of nests and cords of pigmented cells in the dermis similar to blue nevi in humans. In the brain, focal pigmented cell infiltration was observed in the connective tissue under the leptomeninges and in the brain parenchyma. The pigmented cell was moderately reactive with a pan-melanoma antibody (melanoma(pan)) in the skin. In the brain, the pigmented cell was moderately to strongly positive for melanoma(pan) in subleptomeningeal areas and in the cerebral cortex. Melanosomes were observed in pigmented cells in the brain by electron microscopic examination. Based on the histologic, immunohistochemical, and electron microscopic results, the diagnosis of NCM was made. This case is possibly the first report of the condition in animals.
Anal Sac Gland Carcinoma in 64 Cats in the United Kingdom (1995-2007)
Authors: Shoieb A. M. , Hanshaw D. M.
Published: March 2009

A retrospective study was performed to characterize 64 cases of anal sac gland carcinoma (ASGC) in cats. All ASGCs diagnosed between 1995 and 2007 at a private diagnostic laboratory in the UK were reviewed. Apocrine gland origin was confirmed in a subset of these tumors by immunohistochemistry and the use of the glandular cytokeratin antibody (CAM 5.2). Associated clinical, gross, and histologic features were compared with those of canine ASGC. Anal sac gland carcinoma accounted for 0.5% of all feline skin neoplasms. Thirty-nine of the cats with ASGC were female, with a female: male ratio of 1.56. Fifty-two (81.1%) of the 64 tumors were in Domestic Shorthair cats, 5 (7.8%) in Siamese, 3 (4.8%) in Domestic Longhair, 2 (3.1%) in Burmese, and 1 (1.6%) each in a Birman and a Persian cat. Significant differences in prevalence of ASGC among breeds were not detected. Cats ranged in age from 6 to 17 years (median and mean age, 12 years). More than three quarters of the affected cats for which postsurgical outcome was known were euthanatized or died as a direct consequence of the neoplasm, with a median survival of 3 months. Survival rates at 1 and 2 years were 19 and 0%, respectively.
Collagenofibrotic Glomerulonephropathy with Fibronectin Deposition in a Dog
Authors: Kamiie J. , Yasuno K. , Ogihara K. , Nakamura A. , Tamahara S. , Fujino Y. , Ono K. , Shirota K.
Published: March 2009

We report herein a case of collagenofibrotic glomerulonephropathy in a 3-year-old Shiba Inu with severe proteinuria. Histologically, renal glomeruli were enlarged with massive deposition of a homogeneous eosinophilic substance within the mesangium and capillary walls. The deposits reacted weakly with periodic acid-Schiff, stained deep blue with Masson's trichrome, and were positive by immunofluorescence for type III collagen and fibronectin. Ultrastructurally, the deposits consisted of fibrils and amorphous material in the mesangial matrix and beneath the glomerular capillary endothelium. The fibrils had transverse bands analogous to those of collagen fibrils. Electron microscopy also revealed focal detachment of podocytes and foot process effacement in glomerular tufts, which suggested that podocyte injury had contributed to the development of proteinuria in this dog. The current case resembles collagenofibrotic glomerulonephropathy (CFGN) in humans in histopathologic, immunofluorescence, and electron microscopic findings. This is the first report of CFGN in a nonhuman species with glomerular deposition of fibronectin and type III collagen.
Pheochromocytoma in Six New World Primates
Authors: Juan-Sallés C. , Ramos-Vara J. A. , Garner M. M.
Published: March 2009

Six New World primates, including 2 golden lion tamarins (Leontopithecus rosalia), 2 cotton-top tamarins (Saguinus o. oedipus), 1 black howler monkey (Alouatta caraya), and 1 black-handed spider monkey (Ateles g. geoffroyi), were diagnosed with unilateral (4/6) or bilateral (1/6) adrenal or extra-adrenal (1/6) pheochromocytoma by light microscopy and immunohistochemical staining for chromogranin A. Overt invasive behavior or metastases were not observed in any primate, and thus these neoplasms were considered benign. All primates either died spontaneously (4/6) or were euthanatized (2/6) as a result of concurrent malignant neoplasia, infection, renal disease, or a combination of several disease processes. Although we did not determine whether these pheochromocytomas were functional, all 6 primates had myocardial fibrosis, and some had arteriosclerosis.
A Backward Glance O'er the (Dis)United States: William Blake, Ralph Waldo Emerson and the Authentic American Religion
Authors: Elliott Clare
Published: March 2009

This article begins with a brief consideration of the resurgence of religious rhetoric as currently used by George W. Bush. It discusses this alongside what Harold Bloom terms an authentic American religion in his article, Reflections in the Evening Land (December 17, 2005). Bloom looks
retrospectively at Emersonian self-reliance as the authentic American religion and he urges contemporary American readers to remember this as a truly American religion. An exploration of this apparent correlation between self-reliance and an authentic American religion uncovers the somewhat
unnoticed influence of William Blake's poetry on Ralph Waldo Emerson's essays. A close analysis of Emerson's early reading of Blake beside a consideration of Blake's London (1794), The Clod and the Pebble (1794) and Emerson's Self-Reliance (1841) and Society and Solitude (1870) documents the
development of Emersonian self-reliance into a more assured term. This is accounted for by Emerson's growing interest and immersion in the poetry of this English poet, William Blake. The article concludes, contentiously, with the declaration that it is only through this transatlantic study
of Blake's and Emerson's writing that Bloom's authentic American religion can really be understood.
The Septate Junction Protein Caspr Is Required for Structural Support and Retention of KCNQ4 at Calyceal Synapses of Vestibular Hair Cells
Authors: Sousa Aurea D. , Andrade Leonardo R. , Salles Felipe T. , Pillai Anilkumar M. , Buttermore Elizabeth D. , Bhat Manzoor A. , Kachar Bechara
Published: March 2009

The afferent innervation contacting the type I hair cells of the vestibular sensory epithelia form distinct calyceal synapses. The apposed presynaptic and postsynaptic membranes at this large area of synaptic contact are kept at a remarkably regular distance. Here, we show by freeze-fracture electron microscopy that a patterned alignment of proteins at the calyceal membrane resembles a type of intercellular junction that is rare in vertebrates, the septate junction (SJ). We found that a core molecular component of SJs, Caspr, colocalizes with the K+channel KCNQ4 at the postsynaptic membranes of these calyceal synapses. Immunolabeling and ultrastructural analyses ofCasprknock-out mice reveal that, in the absence of Caspr, the separation between the membranes of the hair cells and the afferent neurons is conspicuously irregular and often increased by an order of magnitude. In these mutants, KCNQ4 fails to cluster at the postsynaptic membrane and appears diffused along the entire calyceal membrane. Our results indicate that a septate-like junction provides structural support to calyceal synaptic contact with the vestibular hair cell and that Caspr is required for the recruitment or retention of KCNQ4 at these synapses.
Musical Training Shapes Structural Brain Development
Authors: Hyde Krista L. , Lerch Jason , Norton Andrea , Forgeard Marie , Winner Ellen , Evans Alan C. , Schlaug Gottfried
Published: March 2009

The human brain has the remarkable capacity to alter in response to environmental demands. Training-induced structural brain changes have been demonstrated in the healthy adult human brain. However, no study has yet directly related structural brain changes to behavioral changes in the developing brain, addressing the question of whether structural brain differences seen in adults (comparing experts with matched controls) are a product of “nature” (via biological brain predispositions) or “nurture” (via early training). Long-term instrumental music training is an intense, multisensory, and motor experience and offers an ideal opportunity to study structural brain plasticity in the developing brain in correlation with behavioral changes induced by training. Here we demonstrate structural brain changes after only 15 months of musical training in early childhood, which were correlated with improvements in musically relevant motor and auditory skills. These findings shed light on brain plasticity and suggest that structural brain differences in adult experts (whether musicians or experts in other areas) are likely due to training-induced brain plasticity.
Synaptic Depolarization Is More Effective than Back-Propagating Action Potentials during Induction of Associative Long-Term Potentiation in Hippocampal Pyramidal Neurons
Authors: Hardie Jason , Spruston Nelson
Published: March 2009

Long-term potentiation (LTP) requires postsynaptic depolarization that can result from EPSPs paired with action potentials or larger EPSPs that trigger dendritic spikes. We explored the relative contribution of these sources of depolarization to LTP induction during synaptically driven action potential firing in hippocampal CA1 pyramidal neurons. Pairing of a weak test input with a strong input resulted in large LTP (∼75% increase) when the weak and strong inputs were both located in the apical dendrites. This form of LTP did not require somatic action potentials. When the strong input was located in the basal dendrites, the resulting LTP was smaller (≤25% increase). Pairing the test input with somatically evoked action potentials mimicked this form of LTP. Thus, back-propagating action potentials may contribute to modest LTP, but local synaptic depolarization and/or dendritic spikes mediate a stronger form of LTP that requires spatial proximity of the associated synaptic inputs.