bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Screening for Target Regions of Histone Deacetylases in Cardiomyocytes
Authors: Kaneda Ruri , Ueno Shuichi , Yamashita Yoshihiro , Choi Young Lim , Koinuma Koji , Takada Shuji , Wada Tomoaki , Shimada Kazuyuki , Mano Hiroyuki
Published: July 2005

The acetylation status of core histones in cardiomyocytes has been linked to the development of cardiac hypertrophy and heart failure. Little is known, however, of the genes affected by abnormal histone acetylation in such pathological conditions. We recently developed a genome-wide screening method, differential chromatin scanning (DCS), to isolate genomic fragments associated with histones subject to differential acetylation. We have now applied DCS to H9C2 rat embryonic cardiomyocytes incubated with or without trichostatin A (TSA), a specific inhibitor of histone deacetylase (HDAC) activity. About 200 genomic fragments were readily isolated by DCS on the basis of the preferential acetylation of associated histones in TSA-treated cells. Quantitation of the amount of DNA in chromatin immunoprecipitates prepared with antibodies to acetylated histone H3 revealed that 37 of 38 randomly chosen DCS clones were preferentially precipitated from the TSA-treated cells, thus verifying the high fidelity of DCS. Epigenetic regulation of DCS clones was further confirmed in cells treated with sodium butyrate, another HDAC inhibitor, as well as in cardiac myocytes isolated from neonatal rats. The mRNA level of 9 (39%) of 23 genes corresponding to DCS clones changed in parallel with the level of histone acetylation in H9C2 cells. Furthermore, a physiological hypertrophic stimulus, cardiotrophin-1, affected the acetylation level of histones associated with genomic regions corresponding to certain DCS clones. Our data thus establish a genome-wide profile of HDAC targets in cardiomyocytes, which should provide a basis for further investigations into the role of epigenetic modification in cardiac disorders.
Stroke-Induced Neurogenesis in Aged Brain
Authors: Darsalia Vladimer , Heldmann Ursula , Lindvall Olle , Kokaia Zaal
Published: July 2005

Background and Purpose—

Stroke induced by middle cerebral artery occlusion (MCAO) triggers increased neurogenesis in the damaged striatum and nondamaged hippocampus of young adult rodents. We explored whether stroke influences neurogenesis similarly in the aged brain.

Methods—

Young adult (3 months) and old (15 months) rats were subjected to 1 hour of MCAO, and new cells were labeled by intraperitoneal injection of 5-bromo-2′-deoxyuridine 5′-monophosphate (BrdU), a marker for dividing cells, for 2 weeks thereafter. Animals were euthanized at 7 weeks after the insult, and neurogenesis was assessed immunocytochemically with antibodies against BrdU and neuronal markers with epifluorescence or confocal microscopy.

Results—

Young and old rats exhibited the same increased numbers of new striatal neurons after stroke, despite basal cell proliferation in the subventricular zone being reduced in the aged brain. In contrast, both the number of stroke-generated granule cells and basal neurogenesis in the dentate subgranular zone were lower in old compared with young animals. Also, the ability of newly formed cells to differentiate into neurons was impaired in the aged dentate gyrus.

Conclusions—

Basal neurogenesis is impaired in the subgranular and subventricular zones of aged animals, but both regions react to stroke with increased formation of new neurons. The magnitude of striatal neurogenesis after stroke is similar in young and old animals, indicating that this potential mechanism for self-repair also operates in the aged brain.
Taste Disorders in Acute Stroke
Authors: Heckmann Josef G. , Stössel Christina , Lang Christoph J.G. , Neundörfer Bernhard , Tomandl Bernd , Hummel Thomas
Published: July 2005

Background and Purpose—

The aim of the study was to assess whether and how frequently patients with acute first-ever stroke exhibit gustatory dysfunction.

Methods—

We performed a 1-year prospective observational study. Gustatory function was assessed using the standardized “taste strips” test. In addition, we assessed olfactory function, swallowing, stroke location, comorbidities, and the patients’ medication.

Results—

A total of 102 consecutive patients were enrolled (45 female, 57 male; mean age, 63 years); 31 of them (30%) exhibited gustatory loss and 7 (6%) had lateralized impairment of taste function. Predictors of impaired taste function were male gender (
P
=0.003), high National Institutes of Health Stroke Scale (NIHSS) score at admission (
P
=0.009), coexisting swallowing dysfunction (
P
=0.026), and a stroke of partial anterior circulation subtype (PACS) (
P
=0.008). In particular, in hypogeusic patients the lesion was most frequently localized in the frontal lobe (
P
=0.009). Follow-up examinations in 14 patients indicated improvement of taste sensitivity.

Conclusion—

Taste disorders after stroke are frequent. A significant association was found for male gender, high NIHSS score, swallowing disorder, and PACS, particularly in the frontal lobe. Generally, taste disorders after stroke seem to have a good prognosis.
Modeling the Future Burden of Stroke in the Netherlands
Authors: Struijs Jeroen N. , van Genugten Marianne L.L. , Evers Silvia M.A.A. , Ament Andre J.H.A. , Baan Caroline A. , van den Bos Geertrudis A.M.
Published: July 2005

Background and Purpose—

In the near future, the number of stroke patients and their related healthcare costs are expected to rise. The purpose of this study was to estimate this expected increase in stroke patients in the Netherlands. We sought to determine what the future developments in the number of stroke patients due to demographic changes and trends in the prevalence of smoking and hypertension in terms of the prevalence, incidence, and potential years of life lost might be.

Methods—

A dynamic, multistate life table was used, which combined demographic projections and existing stroke morbidity and mortality data. It projected future changes in the number of stroke patients in several scenarios for the Dutch population for the period 2000 to 2020. The model calculated the annual number of new patients by age and sex by using incidence rates, defined by age, sex, and major risk factors. The change in the annual number of stroke patients is the result of incident cases minus mortality numbers.

Results—

Demographic changes in the population suggest an increase of 27% in number of stroke patients per 1000 in 2020 compared with 2000. Extrapolating past trends in the prevalence of smoking behavior, hypertension, and stroke incidence resulted in an increase of 4%.

Conclusions—

The number of stroke patients in the Netherlands will rise continuously until the year 2020. Our study demonstrates that a large part of this increase in the number of patients is an inevitable consequence of the aging of the population.
Deriving Greenberg's Universal 20 and Its Exceptions
Authors: Cinque Guglielmo
Published: July 2005

Of the 24 mathematically possible orders of the four elements demonstrative, numeral, adjective, and noun, only 14 appear to be attested in the languages of the world. Some of these are unexpected under Greenberg's Universal 20. Here it is proposed that the actually attested orders, and none of the unattested ones, are derivable from a single, universal, order of Merge (Dem > Num > Adj > N) and from independent conditions on phrasal movement.
Potsdamer Universalgeschichte. Sanssouci und das Chinesische Haus Friedrichs II
Authors: Wilhelm Karin
Published: July 2005

In the building of the Maison de plaisir "Sanssouci" and the surrounding park with its pavilions and mythological-dynastic program of figures, Friedrich II designed an idealized image of his view of the unfolding of world history that arose from his discussions with Voltaire. At various sites in the park, personal experiences have also been impressed like ciphers, as it were. These can be read unambiguously in the Temple of Friendship built for his sister Wilhelmine, and they become visible elsewhere, too, like in the Chinese Teahouse. The grounds in Potsdam are characterised by the young Prussian king's will to represent himself, and they mirror the facets of his secret emotions.
Das (nicht-)angenommene Erbe. Zur Debatte um die deutsch-jüdische Erinnerungskultur
Authors: Schoeps Julius H.
Published: July 2005

This essay shows how Jewish identity in pre-1933 Germany defined itself and how the widely known concept of German-Jewish symbiosis came into question after the organized murder of the European Jews. The search for a German-Jewish legacy in postwar Germany as well as in the countries in which the Jewish émigrés found a new home will be explored. Moreover, the Eastern European cultural roots of Jews who migrated from Russia to Germany in the 1990s will also be discussed.
Correlation of Range of Motion and Glenohumeral Translation in Professional Baseball Pitchers
Authors: Borsa Paul A. , Wilk Kevin E. , Jacobson Jon A. , Scibek Jason S. , Dover Geoffrey C. , Reinold Michael M. , Andrews James R.
Published: July 2005

Background

Altered mobility patterns in the throwing shoulders of professional baseball pitchers have been reported. Most published reports examining glenohumeral laxity have not used an objective testing device.

Objective

Quantify and compare glenohumeral translation and rotational range of motion between the throwing and non-throwing shoulders in professional baseball pitchers.

Study Design

Descriptive laboratory study.

Methods

Force-displacement and range of motion measures were performed bilaterally on 43 asymptomatic professional baseball pitchers. Ultrasound imaging was used to measure glenohumeral translations under stressed and unstressed conditions.

Results

No significant difference in translation was found between the throwing and nonthrowing shoulders. For both shoulders, posterior translation (5.38 ± 2.7 mm) was significantly greater (P < .001) than was anterior translation (2.81 ± 1.6 mm). External rotation in the throwing shoulder was significantly greater than that in the nonthrowing shoulder (P < .001), whereas internal rotation in the throwing shoulder was significantly less than that in the nonthrowing shoulder (P < .001). The total arc of rotation for the throwing shoulder was not significantly different than that for the nonthrowing shoulder, and correlation coefficients were poor between rotational and translational range of motion in the throwing shoulder, ranging from r = 0.232 to 0.209 between variables.

Conclusion

No significant difference in glenohumeral translation exists between the throwing and nonthrowing shoulders in asymptomatic professional baseball pitchers, posterior translation is significantly greater than anterior translation in the throwing shoulders of professional baseball pitchers, and glenohumeral translation is not related to rotational range of motion in the throwing shoulders of professional baseball pitchers.

Clinical Relevance

Altered mobility patterns in asymptomatic professional baseball pitchers may be due to factors other than capsular adaptive changes.
Mechanical Properties of the Posterolateral Structures of the Knee
Authors: LaPrade Robert F. , Bollom Timothy S. , Wentorf Fred A. , Wills Nicholas J. , Meister Keith
Published: July 2005

Background

The individual biomechanical strength properties of the fibular collateral ligament, popliteofibular ligament, and popliteus tendon have not been well elucidated by previous studies. To define the necessary strength requirements for a posterolateral knee reconstruction, these properties for the main individual structures of the posterolateral knee need to be defined.

Hypothesis

The biomechanical failure properties of the fibular collateral ligament, popliteofibular ligament, and popliteus tendon can be determined by cadaveric testing.

Study Design

Descriptive laboratory study.

Methods

Each structure was individually isolated in 8 fresh-frozen, nonpaired cadaveric knees and loaded to failure at more than 100%/s.

Results

The mean ultimate tensile strength of the fibular collateral ligament was 295 N, the popliteofibular ligament was 298 N, and the popliteus tendon was 700 N. The mean cross-sectional areas of these same structures at their midpoints were 11.9 mm2, 17.1 mm2, and 21.9 mm2, respectively. Although the stiffness of the fibular collateral ligament (33.5 N/m) was similar to that of the popliteofibular ligament (28.6 N/m), the popliteus tendon was significantly stiffer than both (83.7 N/m).

Conclusion

The popliteofibular ligament, fibular collateral ligament, and popliteus tendon can resist fairly large loads before failure. Knowledge of the strengths of the main native posterolateral knee stabilizers will assist with reconstructive graft choices for these structures.
Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
Authors: Schreurs Marco W. J. , Hermsen Mario A. J. A. , Geltink Ramon I. Klein , Scholten Kirsten B. J. , Brink Antoinette A. T. P. , Kueter Esther W. M. , Tijssen Marianne , Meijer Chris J. L. M. , Ylstra Bauke , Meijer Gerrit A. , Hooijberg Erik
Published: July 2005

To obtain the large amount of T cells required for adoptive immunotherapy in a clinical setting, T-cell lifespan extension by human telomerase reverse transcriptase (hTERT) transduction is of particular interest. However, constitutive expression of hTERT is associated with malignant transformation and thus warrants a detailed evaluation of the safety of hTERT-transduced T cells before clinical application. In view of this, we performed an extensive cytogenetic analysis of hTERT-transduced MART-1 (melanoma antigen recognized by T cell 1)–and human papillomavirus type 16 (HPV16) E7–specific human CD8+ cytotoxic T lymphocytes (CTLs), reactive against melanoma and cervical carcinoma, respectively. Our results, obtained by (spectral) karyotyping and array comparative genomic hybridization, showed the development of minor chromosomal aberrations in an hTERT-transduced MART-1–specific CTL clone, whereas severe clonal aberrations were detected in an hTERT-transduced HPV16 E7–specific CTL clone. Furthermore, hTERT transduction did not protect CTLs from immunosenescence, because the HPV16 E7–specific, hTERT-transduced CTL clone showed a decreased functional activity on prolonged culture. Although the general frequency of major chromosomal aberrations in hTERT-transduced CTLs and the in vivo significance of our observations remain still unclear at this point, the currently available data suggest that clinical application of hTERT-transduced CTLs should proceed with caution.
Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients
Authors: Droemann Daniel , Goldmann Torsten , Tiedje Thorsten , Zabel Peter , Dalhoff Klaus , Schaaf Bernhard
Published: July 2005

Backround

Cigarette smoke exposure including biologically active lipopolysaccharide (LPS) in the particulate phase of cigarette smoke induces activation of alveolar macrophages (AM) and alveolar epithelial cells leading to production of inflammatory mediators. This represents a crucial mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Respiratory pathogens are a major cause of exacerbations leading to recurrent cycles of injury and repair. The interaction between pathogen-associated molecular patterns and the host is mediated by pattern recognition receptors (PRR's). In the present study we characterized the expression of Toll-like receptor (TLR)- 2, TLR4 and CD14 on human AM compared to autologous monocytes obtained from patients with COPD, healthy smokers and non-smokers.

Methods

The study population consisted of 14 COPD patients without evidence for acute exacerbation, 10 healthy smokers and 17 healthy non-smokers stratified according to age. The expression of TLR2, TLR4 and CD14 surface molecules on human AM compared to autologous monocytes was assessedex vivousing FACS analysis.In situhybridization was performed on bronchoalveolar lavage (BAL) cells by application of the new developed HOPE-fixative.

Results

The expression of TLR2, TLR4 and CD14 on AM from COPD patients, smokers and non-smokers was reduced as compared to autologous monocytes. Comparing AM we detected a reduced expression of TLR2 in COPD patients and smokers. In addition TLR2 mRNA and protein expression was increased after LPS stimulation on non-smokers AM in contrast to smokers and COPD patients.

Conclusion

Our data suggest a smoke related change in the phenotype of AM's and the cellular response to microbial stimulation which may be associated with impairment of host defenses in the lower respiratory tract.
Cloning and functional characterization of the rabbit C-C chemokine receptor 2
Authors: Lu Deshun , Yuan Xiu-juan , Evans Robert J , Pappas Amy T , Wang He , Su Eric W , Hamdouchi Chafiq , Venkataraman Chandrasekar
Published: July 2005

Background

CC-family chemokine receptor 2 (CCR2) is implicated in the trafficking of blood-borne monocytes to sites of inflammation and is implicated in the pathogenesis of several inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. The major challenge in the development of small molecule chemokine receptor antagonists is the lack of cross-species activity to the receptor in the preclinical species. Rabbit models have been widely used to study the role of various inflammatory molecules in the development of inflammatory processes. Therefore, in this study, we report the cloning and characterization of rabbit CCR2. Data regarding the activity of the CCR2 antagonist will provide valuable tools to perform toxicology and efficacy studies in the rabbit model.

Results

Sequence alignment indicated that rabbit CCR2 shares 80 % identity to human CCR2b. Tissue distribution indicated that rabbit CCR2 is abundantly expressed in spleen and lung. Recombinant rabbit CCR2 expressed as stable transfectants in U-937 cells binds radiolabeled125I-mouse JE (murine MCP-1) with a calculatedKdof 0.1 nM. In competition binding assays, binding of radiolabeled mouse JE to rabbit CCR2 is differentially competed by human MCP-1, -2, -3 and -4, but not by RANTES, MIP-1α or MIP-1β. U-937/rabbit CCR2 stable transfectants undergo chemotaxis in response to both human MCP-1 and mouse JE with potencies comparable to those reported for human CCR2b. Finally, TAK-779, a dual CCR2/CCR5 antagonist effectively inhibits the binding of125I-mouse JE (IC50= 2.3 nM) to rabbit CCR2 and effectively blocks CCR2-mediated chemotaxis.

Conclusion

In this study, we report the cloning of rabbit CCR2 and demonstrate that this receptor is a functional chemotactic receptor for MCP-1.
Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study
Authors: Chavez-Blanco Alma , Segura-Pacheco Blanca , Perez-Cardenas Enrique , Taja-Chayeb Lucia , Cetina Lucely , Candelaria Myrna , Cantu David , Gonzalez-Fierro Aurora , Garcia-Lopez Patricia , Zambrano Pilar , Perez-Plasencia Carlos , Cabrera Gustavo , Trejo-Becerril Catalina , Angeles Enrique , Duenas-Gonzalez Alfonso
Published: July 2005

Background

The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest.

Methods

Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period.

Results

All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6–170.49 μg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid.

Conclusion

Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.
Determination of the relative amounts of Gag and Pol proteins in foamy virus particles
Authors: Cartellieri Marc , Rudolph Wolfram , Herchenröder Ottmar , Lindemann Dirk , Rethwilm Axel
Published: July 2005

We determined the relative ratios of Gag and Pol molecules in highly purified virions of spumaretroviruses or foamy viruses (FVs) using monoclonal antibodies and bacterially expressed reference proteins. We found that the cleaved p68Gag moiety dominates in infectious FVs. Furthermore, approximate mean ratios in FV are 16:1 (pr71Gag plus p68Gag:p85RT),12:1 (p68Gag:p85RT), and 10:1 (pr71Gag plus p68Gag:p40IN). Thus, the results indicate that FVs have found a way to incorporate approximately as much Pol protein into their capsids as orthoretroviruses, despite a completely different Pol expression strategy.
In vivo skin absorption and distribution of the nerve agent VX (O–ethyl–S–[2(diisopropylamino)ethyl] methylphosphonothioate) in the domestic white pig
Authors: Chilcott R P , Dalton C H , Hill I , Davison C M , Blohm K L , Clarkson E D , Hamilton M G
Published: July 2005

The purpose of this study was to characterize the skin absorption and distribution of VX (Oethyl–S–[2(diisopropylamino)ethyl] methylphosphonothioate) in the domestic pig in order to evaluate the animal as a potential model for assessing pretreatments against toxic anti–cholinesterase compounds. A liquid droplet (equivalent to a 2 LD50 dose) of radiolabelled VX was applied to the inner ear–skin of each anaesthetized animal. Blood and tissue samples (liver, lung, kidney, heart and skin exposure sites) were obtained post–mortem. The amount of radioactivity in each sample was measured by liquid scintillation counting, from which the skin absorption rate and dose distribution of VX were calculated. A substantial proportion (229±3%) of the applied dose remained within the skin at the site of application. It is conceivable that strategies to minimize or remove this reservoir may be of benefit in the early treatment of VX–exposed casualties. Image analysis of autoradiographs of exposed skin sites indicated that each milligram of radioactive VX covered an area of 1.29±0.5 cm2. The average skin absorption rate of 14C-VX was 6619±126 mg/cm2 per hour. Comparison of these data with previous studies suggests that human skin is less permeable to VX than pig skin, but VX spreads over a greater surface area when applied to human skin. Thus, paradoxically, while pig-ear skin is more permeable than human skin, the difference in skin surface spreading may lead to the absorption of an equivalent systemic dose.
Changes of acetylcholinesterase activity after long-term exposure to sarin vapors in rats
Authors: Bartosova-Sevelova L , Bajgar J
Published: July 2005

In our study, rats were exposed to sarin vapors for 240 min at four different concentrations (0.30, 0.43, 0.58 and 0.82 mg/L) in a whole-body inhalation chamber. The acetylcholinesterase activity (AChE, EC 3.1.1.7) was measured in the whole blood, frontal cortex (FC), pontomedullar area (PM) and basal ganglia (BG). Convulsions and hypersalivation were observed in only one animal of the group exposed to the highest sarin concentration. The decrease in blood AChE activity was significant in all animals exposed to sarin vapors. The highest inhibition of AChE activity (61%) was determined in animals exposed to sarin vapors at a concentration of 0.82 μg/L. In the PM, AChE activity was decreased in all experimental groups, significantly only in the group exposed to sarin vapors at a concentration of 0.58 μg/L. Our results show that in long-term exposure to low concentrations of sarin, the significant decrease in AChE activity in the blood is followed by significant changes of AChE activity in the PM only. This part of the brain seems to be more sensitive than the FC or BG.
Efficacy of an adenosine A1 receptor agonist compared with atropine and pralidoxime in a rat model of organophosphate poisoning
Authors: Kalkan S , Ergur B U , Akgun A , Kaplan Y C , Kinay A O , Tuncok Y
Published: July 2005

The objective of this study was to evaluate the effects of an adenosine A1 agonist, phenylisopropyl adenosine (PIA), on metamidophos poisoning compared to specific antidotes. Rats were poisoned with metamidophos (30 mg/kg, oral) and observed for 24 hours. One group received sodium chloride (1 mL/kg) and four experimental groups received atropine (5 mg/kg), pralidoxime (PAM, 20 mg/kg), atropine/PAM (5/20 mg/kg) or PIA (1 mg/kg) intraperitoneally. Atropine reduced salivation and prevented respiratory distress when compared to sodium chloride-treated rats. Treatment with PAM did not cause any suppression of cholinergic signs. Atropine and PAM combination prevented salivation, convulsion and respiratory distress. PIA delayed initial time of the salivation, convulsion and time to death. However, PIA was found ineffective against the metamidophos-induced cholinergic symptoms and mortality. All treatments, except PIA, lead to survival of these animals. Acetylcholinesterase (AChE) activity was not normalized by PIA or PAM. PIA prevented metamidophos-induced diaphragmatic muscle necrosis as much as PAM. In conclusion, a single dose of PIA was unable to protect the rats from metamidophos toxicity. Further studies are needed involving a combination of PAM and/or atropine with repeated doses of PIA to clarify the efficacy of adenosine agonists in OP poisoning.
AKT Activation Promotes Metastasis in a Mouse Model of Follicular Thyroid Carcinoma
Authors: Kim Caroline S. , Vasko Vasily V. , Kato Yasuhito , Kruhlak Michael , Saji Motoyasu , Cheng Sheue-Yann , Ringel Matthew D.
Published: July 2005

The phosphatidylinositol 3-kinase/AKT pathway is crucial to many cell functions, and its dysregulation in tumors is a common finding. The molecular basis of follicular thyroid cancer metastasis is not well understood but may also be influenced by AKT activation. We previously created a knockin mutant mouse that expresses a mutant thyroid hormone receptor-β gene (TRβPV mouse) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. In this study, we investigated whether our mouse model exhibits similar AKT activation as human follicular thyroid cancer. Western blot analysis on thyroids from both wild-type and TRβPV/PV mice revealed elevation of activated AKT in TRβPV/PV mice. Immunohistochemistry and confocal microscopy reveal activated AKT in both the thyroid and metastatic lesions of TRβPV/PV mice. Whereas all three AKT isoforms were overexpressed in primary tumors from TRβPV/PV mice in the cytoplasm of thyroid cancer cells, only AKT1 was also found in the nucleus, matching the localization of activated AKT in a pattern similar to human follicular thyroid cancer. In the metastases, all AKT isoforms correlated with phosphorylated AKT nuclear localization. We created primary thyroid cell lines derived from TRβPV/PV mice and found reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility. Activated AKT is common to both human and mouse follicular thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo. Thus, TRβPV/PV mice could be used to further dissect the detailed pathways underlying the progression and metastasis of follicular thyroid carcinoma.
Cyclooxygenase-2 Regulation of the Age-Related Decline in Testosterone Biosynthesis
Authors: Wang XingJia , Shen Chwan-Li , Dyson Matthew T. , Eimerl Sarah , Orly Joseph , Hutson James C. , Stocco Douglas M.
Published: July 2005

The age-related decline in testosterone biosynthesis in testicular Leydig cells has been well documented, but the mechanisms involved in the decline are not clear. Recent studies have described a cyclooxygenase-2 (COX2)-dependent tonic inhibition of Leydig cell steroidogenesis and expression of the steroidogenic acute regulatory protein (StAR). The present study was conducted to determine whether COX2 protein increases with age in rat Leydig cells and whether COX2 plays a role in the age-related decline in testosterone biosynthesis. Our results indicate that from 3 months of age to 30 months, COX2 protein in aged rat Leydig cells increased by 346% over that of young Leydig cells, StAR protein decreased to 33%, and blood testosterone concentration and testosterone biosynthesis in Leydig cells decreased to 41 and 33%, respectively. Further experiments demonstrated that overexpressing COX2 in MA-10 mouse Leydig cells inhibited StAR gene expression and steroidogenesis and that the inhibitory effects of COX2 could be reversed by blocking COX2 activity. Notably, incubation of aged Leydig cells with the COX2 inhibitor NS398 enhanced their testosterone biosynthesis. Blood testosterone concentrations in aged rats fed the COX2 inhibitor DFU, at doses of 5, 10, 15, and 20 mg/kg body weight per day were increased by 15, 23, 56, and 120%, respectively, over the levels in the rats receiving no DFU. The present study suggests a novel mechanism in male aging involving COX2 and a potential application of the mechanism to delay the age-related decline in testosterone biosynthesis.
Tungstate Decreases Weight Gain and Adiposity in Obese Rats through Increased Thermogenesis and Lipid Oxidation
Authors: Claret Marc , Corominola Helena , Canals Ignasi , Saura Josep , Barcelo-Batllori Silvia , Guinovart Joan J. , Gomis Ramon
Published: July 2005

The increasing worldwide incidence of obesity and the limitations of current treatments raise the need for finding novel therapeutic approaches to treat this disease. The purpose of the current study was first to investigate the effects of tungstate on body weight and insulin sensitivity in a rat model of diet-induced obesity. Second, we aimed to gain insight into the molecular mechanisms underlying its action. Oral administration of tungstate significantly decreased body weight gain and adiposity without modifying caloric intake, intestinal fat absorption, or growth rate in obese rats. Moreover, the treatment ameliorated dislipemia and insulin resistance of obese rats. These effects were mediated by an increase in whole-body energy dissipation and by changes in the expression of genes involved in the oxidation of fatty acids and mitochondrial uncoupling in adipose tissue. Furthermore, treatment increased the number of small adipocytes with a concomitant induction of apoptosis. Our results indicate that tungstate treatment may provide the basis for a promising novel therapy for obesity.
Intermedin Functions as a Pituitary Paracrine Factor Regulating Prolactin Release
Authors: Lin Chang Chia , Roh Jaesook , Park Jae-Il , Klein Cynthia , Cushman Nicole , Haberberger Rainer V. , Hsu Sheau Yu Teddy
Published: July 2005

Calcitonin, α- and β-calcitonin gene-related peptides, amylin, and adrenomedullin belong to a unique group of peptide hormones important for homeostasis maintenance. We recently identified intermedin (IMD) as a novel member of the calcitonin/calcitonin gene-related peptide family expressed in the pituitary, digestive tract, and other organs of vertebrates. Real-time PCR and immunohistochemical analysis of pituitaries from rats at different stages of development showed that IMD is expressed in the intermediate lobe and select adrenocorticotrophs in the anterior lobe, suggesting that IMD could function as a paracrine factor regulating anterior pituitary hormone secretion. In support of a paracrine role for IMD in the pituitary, quantitative and in situ hybridization analyses showed the expression of IMD receptor transcripts including the calcitonin receptor-like receptor and receptor activity-modifying proteins in the pituitary. Treatment with IMD leads to a dose-dependent increase of prolactin release in cultured rat pituitary cells. In contrast, IMD treatment has negligible effects on the release of GH, FSH, or ACTH. Likewise, in vivo treatment with IMD leads to an elevation of plasma prolactin levels in conscious rats. Based on these functional characteristics, we hypothesized that IMD could represent one of the intermediate lobe-derived prolactin-releasing factors important for prolactin regulation during reproduction. In support of this hypothesis, studies of IMD expression in lactating and ovariectomized rats showed that pituitary IMD transcripts in lactating animals increased to more than 2-fold over nonlactating controls whereas ovariectomy leads to a 90% reduction of IMD expression in the pituitary. Of importance, subsequent treatment with 17β-estradiol or diethylstilbestrol increased pituitary IMD expression in ovariectomized rats. In addition, analysis of the proximate region of the IMD gene promoter showed that the IMD gene promoter contains consensus estrogen response element sequences, and estrogen treatments up-regulate the promoter reporter activity in transfected pituitary cells. Collectively, the present study indicates that IMD represents a novel estrogen-dependent intermediate lobe-derived prolactin-releasing factor and could play important roles in the regulation of prolactin release during reproduction in females.
A simplified thermohydrodynamic stability analysis of journal bearings
Authors: Singhal S , Khonsari M. M.
Published: July 2005

This work investigates the stability of a journal bearing system, including the effects of inlet viscosity. Simplified thermohydrodynamic design charts for the rapid prediction of stiffness coefficients, damping coefficients, and threshold speed have been developed. This investigation reveals that the inlet viscosity has a pronounced influence on the bearing dynamic coefficients of the lubricating oil film. This investigation also reveals that it is possible to stabilize a journal bearing either by heating the oil or by cooling the oil depending on the operating region.
On the two points of views of plastically deformed asperity contacts with friction loading
Authors: Chang L , Zhang H
Published: July 2005

This article discusses two very different points of views of the behaviour of plastically deformed asperity contacts with friction loading. A fundamental mechanics study is carried out using the concept of contact hydrostatic pressure. The study reveals various features of the two view-points. Some literature results are subsequently analysed. The analysis suggests that the friction force may significantly reduce the contact hydrostatic pressure thereby reducing asperity load capacity along with other consequences in the tribo-systems. This article may increase the understanding of the behaviour of asperity microcontacts and may be useful for future modelling of frictional contact of rough surfaces.
Finite element analysis of the geometric stiffening effect. Part 1: A correction in the floating frame of reference formulation
Authors: García-Vallejo D , Sugiyama H , Shabana A A
Published: July 2005

The fact that incorrect unstable solutions are obtained for linearly elastic models motivates the analytical study presented in this paper. The increase in the number of finite elements only leads to an increase in the critical speed. Crucial in the analysis presented in this paper is the fact that the mass matrix and the form of the elastic forces obtained using the absolute nodal coordinate formulation remain the same under orthogonal coordinate transformation. The absolute nodal coordinate formulation, in contrast to conventional finite element formulations, does account for the effect of the coupling between bending and extension. Based on the analytical results obtained using the absolute nodal coordinate formulation, a new correction is proposed for the finite element floating frame of reference formulation in order to introduce coupling between the axial and bending displacements. In this two-part paper, two- and three-dimensional finite element models are used to study the problem of rotating beams. The models are developed using the absolute nodal coordinate formulation that allows for accurate representation of the axial strain, thereby avoiding the ill-conditioning problem that arises when classical displacement-based finite element formulations are used. In the first part of the paper, the case of linear elasticity is considered and assumptions used in the finite element floating frame of reference formulation are investigated. In the second part of the paper, non-linear elasticity is considered. A rotating helicopter blade is simulated, and the complexity of the motion suggests the inclusion of rotary inertia, shear deformation, and non-linear elastic forces in order to obtain an accurate solution that does not suffer from the instability problem regardless of the number of finite elements used.
Finite element analysis of the geometric stiffening effect. Part 2: Non-linear elasticity
Authors: García-Vallejo D , Sugiyama H , Shabana A A
Published: July 2005

In the first part of this paper, the relationship between the number of finite elements used to model the dynamics of rotating beams and the critical speed at which an incorrect solution is obtained when using linear elasticity theory is discussed. The increase in the number of finite elements leads to an increase in the critical speed when linear elasticity is used and no measures are taken, as recommended in the literature, to account for the effect of the coupling between the bending and axial displacements. In this part of the paper, a non-linear finite element model based on the absolute nodal coordinate formulation is used to study the dynamics of rotating beams. It is shown that, when the non-linear elasticity theory is used, a stable solution is always obtained regardless of the number of finite elements used. Numerical results of various simulations are presented in order to compare the solution of a three-dimensional rotating beam that is obtained using the absolute nodal coordinate formulation with the results previously reported in the literature. A finite element numerical study of the dynamics of a helicopter rotor blade is also presented in this investigation. It is shown that, when the finite element absolute nodal coordinate formulation is used in the analysis of helicopter blades, the problem of ill-conditioning that characterizes many of the existing formulations is not encountered.
Special relativity: Interpretation and implications for space-time geometry
Authors: Rahnejat H
Published: July 2005

The paper commemorates the centenary of the special theory of relativity, which effectively sets the limit for the structure of space-time to that of the stationary system. The long lasting debate for definition of concepts of instantaneity and simultaneity was thus resolved by the declaration of constancy of speed of light in vacuo as a law of physics. All motions were thus bounded by the light cone and described by the properties of differential geometry, firmly anchored in the calculus of variations. The key contribution underpinning the theory was the resolution of the contradiction imposed by the Galilean transformation through physical explanation and the adoption of the Lorentzian transformation. This highlighted the relative nature of both space and time and the linkage of these to preserve the sanctity of the light cone. The resulting space-time geometry was then founded on the traditional calculus of variation with the addition of this transformation. This retains the time as an independent coordinate and its linkage to space in an explicit form. One implication of this approach has been the retention of the concept of infinitum for some physical quantities as a drawback for use of the Lorentzian transformation. The paper shows that this singular behaviour need not arise if the explicit linkage in space-time is abandoned in favour of the implicit inclusion of time as a link between the curved structure of space and the speed of light, thus restating the calculus of variation in line with special relativity. This points to a closed loop space-matter field, which may belie the fabric of the continuum. One implication of this interpretation is that a small variation in speed of light within the field would be required to dispense with the aforementioned singular nature of the Lorentzian boost, while still remaining within the spirit of special relativity.
Progressive Immunopathological Changes during Early Stages of Experimental Infection of Goats with Mycobacterium avium subspecies paratuberculosis
Authors: Munjal S. K. , Tripathi B. N. , Paliwal O. P.
Published: July 2005

A dose of 1010 Mycobacterium avium subspecies paratuberculosis was administered orally on seven occasions to produce experimental paratuberculosis infection in 10 5-8-week-old goat kids. Bacteriological, immunological, and histopathological changes, their relationships, and the efficacy of the commonly used diagnostic methods were studied during the progressive disease up to 270 days postinfection (DPI). Significant lymphocyte proliferative responses in the peripheral blood of five goats were detected as early as 60 DPI. A lymphoproliferative test was also performed on lymphocytes purified from different compartments of the guts of five infected and five control goats. Significant proliferative responses were observed in lymphocytes of jejunal compartments of all five goats, of which four had also significant lymphocyte proliferation in the blood. The ileal lymphocytes from two goats, one each at 120 and 270 DPI, had significant proliferation. The histological lesions were mainly observed in the gut-associated lymphoid tissues of the ileocecal valve, the ileum, and the terminal jejunum. Acid-fast bacilli were demonstrated in the lesions of two goats at 60 and 210 DPI. Bacterial culture showed poor sensitivity, detecting positive results for only one goat in the fecal and tissue samples at 210 DPI, whereas polymerase chain reaction (PCR) detected one goat in fecal sample at 210 DPI and two goats in tissue samples at 60 and 210 DPIs, respectively. Enzyme-linked immunosorbent assay and agar gel immunodiffusion test were found to be 100% sensitive from 180 and 210 DPI onwards, respectively.
Immunohistochemical and Histochemical Stains for Differentiating Canine Cutaneous Round Cell Tumors
Authors: Fernandez N. J. , West K. H. , Jackson M. L. , Kidney B. A.
Published: July 2005

Immunohistochemical and histochemical stains are useful adjunct techniques in the diagnosis of canine cutaneous round cell tumors, which can appear histologically similar We applied a panel of monoclonal antibodies (recognizing tryptase, chymase, serotonin for mast cells; CD1a, CD18, MHC class II for histiocytes; CD3 for T lymphocytes; CD79a for B lymphocytes and plasma cells) and one histochemical stain (naphthol AS-D chloroacetate for chymase activity) to formalin-fixed, paraffin-embedded sections of canine cutaneous mast cell tumors, histiocytomas, lymphosarcomas, plasmacytomas, and unidentified round cell tumors. Of 21 tumors with a histologic diagnosis of mast cell tumor, 7/7 (100%) grade I, 6/7 (85.7%) grade II, and 3/7 (42.9%) grade III tumors were diagnosed as mast cell tumors based on positive staining for tryptase antigen and chymase activity. Mast cells were positive for both tryptase antigen and chymase activity, indicating equal efficacy of tryptase immunohistochemistry and chymase histochemistry. Chymase was detected immunohistochemically in both tumor and nontumor cells, while serotonin was not detected in most mast cell tumors, and thus, neither was useful in the diagnosis of mast cell tumors. Immunohistochemistry to detect CD18 and MHC class II was equally effective in staining histiocytomas, although lymphosarcoma must be ruled out through the use of CD3 and CD79a immunohistochemistry. Immunohistochemistry using three different monoclonal antibodies to human CD1a showed no cross-reactivity in canine histiocytomas and was not useful. A final diagnosis was obtained for 4/5 (80%) of the unidentified tumors, indicating the usefulness of multiple stains in poorly differentiated round cell tumors.
“Gas and Fat Embolic Syndrome” Involving a Mass Stranding of Beaked Whales (Family Ziphiidae) Exposed to Anthropogenic Sonar Signals
Authors: Fernández A. , Edwards J. F. , Rodríguez F. , de los Monteros A. Espinosa , Herráez P. , Castro P. , Jaber J. R. , Martín V. , Arbelo M.
Published: July 2005

A study of the lesions of beaked whales (BWs) in a recent mass stranding in the Canary Islands following naval exercises provides a possible explanation of the relationship between anthropogenic, acoustic (sonar) activities and the stranding and death of marine mammals. Fourteen BWs were stranded in the Canary Islands close to the site of an international naval exercise (Neo-Tapon 2002) held on 24 September 2002. Strandings began about 4 hours after the onset of midfrequency sonar activity. Eight Cuvier's BWs (Ziphius cavirostris), one Blainville's BW (Mesoplodon densirostris), and one Gervais' BW (Mesoplodon europaeus) were examined postmortem and studied histopathologically. No inflammatory or neoplastic processes were noted, and no pathogens were identified. Macroscopically, whales had severe, diffuse congestion and hemorrhage, especially around the acoustic jaw fat, ears, brain, and kidneys. Gas bubble-associated lesions and fat embolism were observed in the vessels and parenchyma of vital organs. In vivo bubble formation associated with sonar exposure that may have been exacerbated by modified diving behavior caused nitrogen supersaturation above a threshold value normally tolerated by the tissues (as occurs in decompression sickness). Alternatively, the effect that sonar has on tissues that have been supersaturated with nitrogen gas could be such that it lowers the threshold for the expansion of in vivo bubble precursors (gas nuclei). Exclusively or in combination, these mechanisms may enhance and maintain bubble growth or initiate embolism. Severely injured whales died or became stranded and died due to cardiovascular collapse during beaching. The present study demonstrates a new pathologic entity in cetaceans. The syndrome is apparently induced by exposure to mid-frequency sonar signals and particularly affects deep, long-duration, repetitive-diving species like BWs.