bluuebunny/crossref_metadata_2025 huggingface dataset:
Secreted surfactant protein A from fetal membranes induces stress fibers in cultured human myometrial cells
Authors: Breuiller-Fouché Michelle , Dubois Olivier , Sediki Mourad , Garcia-Verdugo Ignacio , Palaniyar Nades , Tanfin Zahra , Chissey Audrey , Cabrol Dominique , Charpigny Gilles , Mehats Céline
Published: March 2010

In the present study, we investigated the ability of human fetal membranes (amnion and choriodecidua) to regulate human maternal uterine cell functions through the secretion of surfactant protein (SP)-A and SP-D at the end of pregnancy. We detected the expression of both SP-A (SP-A1 and SP-A2) and SP-D by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry revealed that human fetal membranes expressed both SP-A and SP-D. By Western blot analysis, we demonstrated that SP-A protein expression was predominant in choriodecidua, whereas the amnion predominantly expressed SP-D. Only the secretion of SP-A was evidenced in the culture supernatants of amnion and choriodecidua explants by immunodot blot and confirmed by Western blot. Exogenous human purified SP-A induced stress fiber formation in cultured human myometrial cells via a pathway involving Rho-kinase. Conditioned medium from choriodecidua and amnion explants mimicked the SP-A effect. Treatment of myometrial cells with SP-A-depleted conditioned medium from choriodecidua or amnion explants failed to change the actin dynamic. These data indicate that SP-A released by human fetal membranes is able to exert a paracrine regulation of F-actin filament organization in myometrial cells.
Effects of mechanical loading on early conduction system differentiation in the chick
Authors: Sankova Barbora , Machalek Jakub , Sedmera David
Published: March 2010

The primary ring, a horseshoe-shaped structure situated between the left and right ventricle and connected superiorly to the atrioventricular canal, is the first specialized fast ventricular conduction pathway in the embryonic heart. It has been first defined immunohistochemically and is characterized as a region of slow myocyte proliferation. Recent studies have shown that it participates in spreading the ventricular electrical activation during stages preceding ventricular septation in the mouse, chick, and rat. Here we demonstrate its presence using optical mapping in chicks between embryonic days (ED) 3–5. We then tested the effects of hemodynamic unloading in the organ culture system upon its functionality. In ED3 hearts cultured without hemodynamic loading for 24 h, we observed a significant decrease in the percentage activated through the primary ring conduction pathway. A morphological examination revealed arrested growth, collapse, and elongation of the outflow tract and disorganized trabeculation. A similar reversal toward more primitive activation patterns was observed with culture between ED4 and ED5. This phenotype was completely rescued with the artificial loading of the ventricles with a droplet of silicone oil. We conclude that an appropriate loading is required during the early phases of the conduction system formation and maturation.
Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo
Authors: Riad Alexander , Westermann Dirk , Escher Felicitas , Becher Peter M. , Savvatis Konstantinos , Lettau Olga , Heimesaat Markus M. , Bereswill Stefan , Volk Hans D. , Schultheiss Heinz P. , Tschöpe Carsten
Published: March 2010

Toll-like receptor 9 (TLR9) is a member of the innate immune system and has been shown to influence myocardial function, but its role in myocarditis is hitherto unknown. We therefore investigated whether or not TLR9 plays a role in this disease in coxsackievirus B3 (CVB3)-induced myocarditis in mice. Left ventricular (LV) function, cardiac immune cell infiltration, virus mRNA, and components of the TLR9 downstream pathway were investigated in TLR9-deficient [knockout (KO)] and wild-type (WT) mice after infection with CVB3. Murine cardiac TLR9 expression was significantly increased in WT mice with acute CVB3 infection but not in WT mice with chronic myocarditis. Furthermore, in the acute phase of CVB3-induced myocarditis, CVB3-infected KO mice displayed improved LV function associated with reduced cardiac inflammation indexed by reduced amounts of immune cells compared with CVB3-infected WT mice. In contrast, in the chronic phase, LV function and inflammation were not seen to differ among the infected groups. The cardioprotective effects due to TLR9 deficiency were associated with suppression of the TLR9 downstream pathway as indexed by reduced cardiac levels of the adapter protein myeloid differentiation factor (MyD)-88 and the proinflammatory cytokine TNF-α. In addition, TLR9 deficiency led to an activation of the antiviral cytokine interferon-β in the heart as a result from viral infection. In conclusion, the MyD88/TNF-α axis due to TLR9 activation in the heart contributes the development of acute myocarditis but not of chronic myocarditis.
JNK regulates serotonin-mediated proliferation and migration of pulmonary artery smooth muscle cells
Authors: Wei Lin , Liu Yinglin , Kaneto Hideaki , Fanburg Barry L.
Published: March 2010

JNK is a member of the MAPK family and has essential roles in inflammation and cell differentiation and apoptosis. In recent years, there have been accumulating data indicating a novel role for JNK in cell growth and migration. In this report, we demonstrate that JNK activity is necessary for serotonin (5-HT)-induced proliferation and migration of bovine pulmonary artery smooth muscle cells (PASMCs). Stimulation with 5-HT was found to lead to activation of JNK with a maximal activation at 10 min. Inhibition of JNK with its specific inhibitor, SP-600125, or its dominant-negative form, DN-JNK, significantly reduced 5-HT-stimulated [3H]thymidine incorporation and cyclin D1 expression. A similar inhibitory effect on SMC migration produced by 5-HT, as detected by a wound healing assay, was observed with inhibition of JNK. Furthermore, inhibition of 5-HT receptors 1B and 2A, but not inhibition of the 5-HT transporter, blocked 5-HT-induced JNK activation. Inhibition of phosphatidylinositol 3-kinase (PI3K) with LY-294002 and wortmannin had little or no effect on 5-HT-induced JNK phosphorylation, but JNK inhibitor SP-600125 and DN-JNK blocked 5-HT-stimulated phosphorylation of Akt and its downstream effectors, p70S6K1 and S6, indicating that Akt is a downstream effector of JNK. Activation of Akt by 5-HT was blocked only minimally, if at all, by inhibitors of ERK and p38 MAPK, indicating a uniqueness of JNK MAPK in this activation of Akt. Coimmunoprecipitation showed binding of Akt to JNK, further supporting the interaction of JNK and Akt. Thus JNK is a critical molecule in 5-HT-induced PASMC proliferation and migration and may act at an important point for cross talk of the MAPK and PI3K pathways. Its activation by 5-HT is initiated through 5-HT 1B and 2A receptors, and its stimulation of SMC proliferation and migration occurs through the Akt pathway.
Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement
Authors: Lu Qing , Harrington Elizabeth O. , Newton Julie , Casserly Brian , Radin Gregory , Warburton Rod , Zhou Yang , Blackburn Michael R. , Rounds Sharon
Published: March 2010

We have previously demonstrated that adenosine plus homocysteine enhanced endothelial basal barrier function and protected against agonist-induced barrier dysfunction in vitro through attenuation of RhoA activation by inhibition of isoprenylcysteine-O-carboxyl methyltransferase. In the current study, we tested the effect of elevated adenosine on pulmonary endothelial barrier function in vitro and in vivo. We noted that adenosine alone dose dependently enhanced endothelial barrier function. While adenosine receptor A1or A3antagonists were ineffective, an adenosine transporter inhibitor, NBTI, or a combination of DPMX and MRS1754, antagonists for adenosine receptors A2Aand A2B, respectively, partially attenuated the barrier-enhancing effect of adenosine. Similarly, inhibition of both A2Aand A2Breceptors with siRNA also blunted the effect of adenosine on barrier function. Interestingly, inhibition of both transporters and A2A/A2Breceptors completely abolished adenosine-induced endothelial barrier enhancement. The adenosine receptor A2Aand A2Bagonist, NECA, also significantly enhanced endothelial barrier function. These data suggest that both adenosine transporters and A2Aand A2Breceptors are necessary for exerting maximal effect of adenosine on barrier enhancement. We also found that adenosine enhanced Rac1 GTPase activity and overexpression of dominant negative Rac1 attenuated adenosine-induced increases in focal adhesion complexes. We further demonstrated that elevation of cellular adenosine by inhibition of adenosine deaminase with Pentostatin significantly enhanced endothelial basal barrier function, an effect that was also associated with enhanced Rac1 GTPase activity and with increased focal adhesion complexes and adherens junctions. Finally, using a non-inflammatory acute lung injury (ALI) model induced by α-naphthylthiourea, we found that administration of Pentostatin, which elevated lung adenosine level by 10-fold, not only attenuated the development of edema before ALI but also partially reversed edema after ALI. The data suggest that adenosine deaminase inhibition may be useful in treatment of pulmonary edema in settings of ALI.
Ghrelin in Chronic Kidney Disease
Authors: Cheung Wai W. , Mak Robert H.
Published: March 2010

Patients with chronic kidney disease (CKD) often exhibit symptoms of anorexia and cachexia, which are associated with decreased quality of life and increased mortality. Chronic inflammation may be an important mechanism for the development of anorexia, cachexia, renal osteodystrophy, and increased cardiovascular risk in CKD. Ghrelin is a gastric hormone. The biological effects of ghrelin are mediated through the growth hormone secretagogue receptor (GHSR). The salutary effects of ghrelin on food intake and meal appreciation suggest that ghrelin could be an effective treatment for anorexic CKD patients. In addition to its appetite-stimulating effects, ghrelin has been shown to possess anti-inflammatory properties. The known metabolic effects of ghrelin and the potential implications in CKD will be discussed in this review. The strength, shortcomings, and unanswered questions related to ghrelin treatment in CKD will be addressed.
Seamless Video Session Handoff between WLANs
Authors: Monteiro Claudio de Castro , Gondim Paulo Roberto de Lira , Rios Vinícius de Miranda
Published: March 2010

Handoff in a distributed IEEE 802.11 Wireless LAN network is a source of significant amount of problems on the video transmission environment. The visual quality of video streaming applications is lowered when stations are in handoff status. In this paper, we introduce an architecture of a session proxy (SP), which tries to preserve the quality of the streaming video upon each handoff between access points. We have evaluated thresholds of RSSI and Loss Frame Rate (LFR) for deciding the moment when the handoff process shall begin. Our solution performance was evaluated in a testbed implementation for MPEG-4 video on demand with one video server (VLS) and two FreeBSD-based access points supporting Mobile IP, DHCP Server and IAPP approach.
Colitis-Associated Cancer Is Dependent on the Interplay between the Hemostatic and Inflammatory Systems and Supported by Integrin αMβ2 Engagement of Fibrinogen
Authors: Steinbrecher Kris A. , Horowitz Netanel A. , Blevins Elizabeth A. , Barney Kelley A. , Shaw Maureen A. , Harmel-Laws Eleana , Finkelman Fred D. , Flick Matthew J. , Pinkerton Malinda D. , Talmage Kathryn E. , Kombrinck Keith W. , Witte David P. , Palumbo Joseph S.
Published: March 2010

A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we used gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor αMβ2 binding motif (Fibγ390-396A), revealed that αMβ2-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., interleukin-6 elaboration) and epithelial alterations that contribute to adenoma formation. Consistent with these findings, the majority of Fibγ390-396A mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibγ390-396A mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies show, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-αMβ2 interactions may be useful in preventing and/or treating this important subset of malignancies. Cancer Res; 70(7); 2634–43
Phase I Evaluation of Telatinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Combination with Irinotecan and Capecitabine in Patients with Advanced Solid Tumors
Authors: Langenberg Marlies H.G. , Witteveen Petronella O. , Roodhart Jeanine M. , Verheul Henk M.W. , Mergui-Roelvink Marja , van der Sar Jana , Brendel Erich , Laferriere Nicole , Schellens Jan H.M. , Voest Emile E.
Published: March 2010

Purpose: We studied the safety and tolerability of telatinib, an orally available, small-molecule tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR-2/VEGFR-3), platelet-derived growth factor receptor β, and c-Kit in combination with capecitabine and irinotecan.

Experimental Design: Telatinib twice daily continuously, irinotecan once every 3 weeks, and capecitabine oral twice daily on day 1 to 14 were administered in cycles of 21 days in escalating doses in successive cohorts. Toxicity was evaluated to conform to the Common Terminology Criteria for Adverse Events version 3.0. Pharmacokinetic and (circulating) endothelial (progenitor) cell measurements were done. Tumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors.

Results: Twenty-three patients were included in this phase I trial. Most frequently (>25%) reported adverse events of any grade were vomiting, nausea, fatigue, diarrhea, alopecia, and hand-foot syndrome. A silent myocardial infarction and two cases of decreased left ventricular ejection fraction were reported; both were reversible. Cardiac monitoring of the subsequent patients did not reveal other abnormalities. The study was terminated when the recommended single agent phase II doses of telatinib (900 mg twice daily) and capecitabine/irinotecan was reached. Pharmacokinetic profiles showed no clinically relevant changes upon coadministration of the three drugs. (Circulating) endothelial (progenitor) cell levels stabilized during treatment. Five of 23 patients had partial remission and 9 of 23 patients showed stable disease.

Conclusions: Continuous administration of 900 mg telatinib twice daily can be safely combined with irinotecan (180 mg/m2) and capecitabine (1,000 mg/m2 twice daily, day 1-14) and is the recommended schedule for further phase II studies. Tumor shrinkage and disease stabilization was observed. Cardiac toxicity needs further investigation in following studies. Clin Cancer Res; 16(7); 2187–97. ©2010 AACR.
In vitro and In vivo Selective Antitumor Activity of Edelfosine against Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Involving Lipid Rafts
Authors: Mollinedo Faustino , de la Iglesia-Vicente Janis , Gajate Consuelo , de Mendoza Ander Estella-Hermoso , Villa-Pulgarin Janny A. , de Frias Mercè , Roué Gaël , Gil Joan , Colomer Dolors , Campanero Miguel A. , Blanco-Prieto Maria J.
Published: March 2010

Purpose: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL.

Experimental Design: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice.

Results: Here, we have found that the phospholipid ether edelfosine was the most potent alkyl-lysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine > perifosine ≫ erucylphosphocholine ≥ miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor.

Conclusions: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine. Clin Cancer Res; 16(7); 2046–54. ©2010 AACR.
The Core Circadian GeneCryptochrome 2Influences Breast Cancer Risk, Possibly by Mediating Hormone Signaling
Authors: Hoffman Aaron E. , Zheng Tongzhang , Yi Chun-Hui , Stevens Richard G. , Ba Yue , Zhang Yawei , Leaderer Derek , Holford Theodore , Hansen Johnni , Zhu Yong
Published: March 2010

As transcriptional regulators, circadian genes have the potential to influence a variety of biological pathways, including many cancer-related processes. Cryptochrome 2 (CRY2) is essential for proper circadian timing and is a key component of the circadian regulatory feedback loop. Here, we report findings from genetic, epigenetic, loss-of-function, and transcriptional profiling analyses of CRY2 in breast cancer. Six single-nucleotide polymorphisms in CRY2 were identified for genotyping in a case-control population (n = 441 cases and n = 479 controls), and three single-nucleotide polymorphisms (rs11038689, rs7123390, and rs1401417) were significantly associated with postmenopausal breast cancer risk, with significant effect modification by menopausal status [dominant model for rs11038689: odds ratio (OR), 0.71; 95% confidence interval (95% CI), 0.51-0.99; P for trend = 0.028; homozygous variants for rs7123390: OR, 0.44; 95% CI, 0.22-0.86; P for trend = 0.028; and rs1401417: OR, 0.44; 95% CI, 0.21-0.92; P for trend = 0.017]. Interestingly, this association was only evident in women with estrogen and progesterone receptor (ER/PR)–negative breast tumors but not with ER/PR-positive tumors. Breast cancer patients also had significantly higher levels of CRY2 promoter methylation relative to controls, which is consistent with tissue array data showing lower levels of CRY2 expression in tumor tissue relative to adjacent normal tissue. Furthermore, in vitro analyses identified several breast cancer–relevant genes that displayed altered expression following CRY2 knockdown. These findings suggest a role for CRY2 in breast tumorigenesis and provide further evidence that the circadian system may be an important modulator of hormone-related cancer susceptibility. Cancer Prev Res; 3(4); 539–48. ©2010 AACR.
5-Deoxykaempferol Plays a Potential Therapeutic Role by Targeting Multiple Signaling Pathways in Skin Cancer
Authors: Lee Kyung Mi , Lee Ki Won , Byun Sanguine , Jung Sung Keun , Seo Sang Kwon , Heo Yong-Seok , Bode Ann M. , Lee Hyong Joo , Dong Zigang
Published: March 2010

Nontoxic small molecules with multitargeting effects are believed to have potential in cancer prevention. Dietary phytochemicals were shown to exhibit cancer-preventive effects attributed to their antioxidant capacities. In this report, we show that the natural compound 5-deoxykaempferol (5-DK) exerts a chemopreventive effect on UVB-induced skin carcinogenesis by targeting multiple signaling molecules. 5-DK suppressed the UVB-induced expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor in mouse skin epidermal JB6 P+ cells. Moreover, 5-DK inhibited phosphorylation of MKK3/6, MKK4, and Akt, but had no effect on phosphorylation of Src, extracellular signal–regulated kinases, or ribosomal S6 kinase (RSK). However, 5-DK affected multiple targets by reducing Src, phosphoinositide 3-kinase (PI3K), and RSK2 activities. In particular, pull-down assays revealed that 5-DK specifically bound to and competed with ATP for binding with Src, PI3K, and RSK2. Exposure to 5-DK significantly suppressed UVB-induced tumorigenesis in mouse skin in a dose-dependent manner, and it inhibited the UVB-induced expression of COX-2, proliferating cell nuclear antigen, vascular endothelial growth factor, and matrix metalloproteinase-9. Our data suggest that 5-DK docks at the ATP-binding site of Src, PI3K, and RSK2. For RSK2, the ATP-binding site is located between the N- and C-lobes of the kinase domain. Taken together, our results indicate that 5-DK holds promise for the treatment of UVB-induced skin cancer by targeting Src, PI3K, and RSK2 signaling. Cancer Prev Res; 3(4); 454–65. ©2010 AACR.
Gonadal mRNA Expression Levels of TGFβ Superfamily Signaling Factors Correspond with Post-Hatching Morphological Development in American Alligators
Authors: Moore B.C. , Hamlin H.J. , Botteri N.L. , Guillette, Jr. L.J.
Published: March 2010

Paracrine factor signaling regulates many aspects of vertebrate gonadal development. We investigated key ovarian and testicular morphological markers of the American alligator (Alligator mississippiensis) during the first 5 months post-hatching and correlated gonadal development with mRNA expression levels of a suite of regulatory factors. In both sexes, we observed significant morphology changes, including ovarian follicle assembly and meiotic progression of testicular germ cells. Concomitant with these changes were sexually dimorphic and ontogenetically variable mRNA expressions. In ovaries, FOXL2, aromatase, and follistatin mRNA expression was greater than in testes at all ages. At one week after hatching, we observed ovarian medullary remodeling in association with elevated activin/inhibin βA subunit, follistatin, and aromatase mRNA expressions. Three and 5 months following hatching and concomitant with follicle assembly, ovaries showed increased mRNA expression levels of GDF9 and the mitotic factor PCNA. In testes, the activin/inhibin α and βB subunit transcript levels were greater than in ovaries at all ages. Elevated testicular expression of GDF9 mRNA levels at 5 months after hatching aligned with increased spermatogenic activity. We propose that the mRNA expression levels and concomitant morphological changes observed here affect the establishment of alligator reproductive health and later fertility.
Investigations into the Binding Affinities of Different Human 5-HT4 Receptor Splice Variants
Authors: Irving Helen R. , Tochon-Danguy Nathalie , Chinkwo Kenneth A. , Li Jian G. , Grabbe Carmen , Shapiro Marina , Pouton Colin W. , Coupar Ian M.
Published: March 2010

This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT4 receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pKi: 7.38–7.91) ≧ Y-36912 (pKi: 7.03–7.85) = BIMU 1 (pKi: 6.92–7.78) ≧ DAU 6236 (pKi: 6.79–7.99) ≧ 5-HT (pKi: 5.82–7.29) ≧ 5-MeOT (pKi: 5.64–6.83) ≧ renzapride (pKi: 4.85–5.56). We obtained affinity values for the 5-HT4(b), (d) and (g) variants for RS67333 (pKi: 7:48–8.29), prucalopride (pKi: 6.86–7.37) and zacopride (pKi: 5.88–7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically.
Temperature-Dependent Sex Determination and Contemporary Climate Change
Authors: Mitchell N.J. , Janzen F.J.
Published: March 2010

Whether species that have persisted throughout historic climatic upheavals will survive contemporary climate change will depend on their ecological and physiological traits, their evolutionary potential, and potentially upon the resources that humans commit to prevent their extinction. For those species where temperatures influence sex determination, rapid global warming poses a unique risk of skewed sex ratios and demographic collapse. Here we review the specific mechanisms by which reptiles with temperature-dependent sex determination (TSD) may be imperilled at current rates of warming, and discuss the evidence for and against adaptation via behavioural or physiological means. We propose a scheme for ranking reptiles with TSD according to their vulnerability to rapid global warming, but note that critical data on the lability of the sex determining mechanism and on the heritability of behavioural and threshold traits are unavailable for most species. Nevertheless, we recommend a precautionary approach to management of reptiles identified as being at relatively high risk. In such cases, management should aim to neutralise directional sex ratio biases (e.g. by manipulating incubation temperatures or assisted migration) and promote adaptive processes, possibly by genetic supplementation of populations. These practices should aid species’ persistence and buy time for research directed at more accurate prediction of species’ vulnerability.
Molecular Mechanisms of Sex Determination in Reptiles
Authors: Rhen T. , Schroeder A.
Published: March 2010

Charles Darwin first provided a lucid explanation of how gender differences evolve nearly 140 years ago. Yet, a disconnect remains between his theory of sexual selection and the mechanisms that underlie the development of males and females. In particular, comparisons between representatives of different phyla (i.e., flies and mice) reveal distinct genetic mechanisms for sexual differentiation. Such differences are hard to comprehend unless we study organisms that bridge the phylogenetic gap. Analysis of variation within monophyletic groups (i.e., amniotes) is just as important if we hope to elucidate the evolution of mechanisms underlying sexual differentiation. Here we review the molecular, cellular, morphological, and physiological changes associated with sex determination in reptiles. Most research on the molecular biology of sex determination in reptiles describes expression patterns for orthologs of mammalian sex-determining genes. Many of these genes have evolutionarily conserved expression profiles (i.e., DMRT1 and SOX9 are expressed at a higher level in developing testes vs. developing ovaries in all species), which suggests functional conservation. However, expression profiling alone does not test gene function and will not identify novel sex-determining genes or gene interactions. For that reason, we provide a prospectus on various techniques that promise to reveal new sex-determining genes and regulatory interactions among these genes. We offer specific examples of novel candidate genes and a new signaling pathway in support of these techniques.
Influence of Family History of Cardiovascular Disease on Clinicians’ Preventive Recommendations and Subsequent Adherence of Patients without Cardiovascular Disease
Authors: Zlot A.I. , Valdez R. , Han Y. , Silvey K. , Leman R.F.
Published: March 2010

Background: Family history of cardiovascular disease (CVD) is an independent risk factor for CVD. Therefore, efforts to prevent CVD among asymptomatic persons with a family history are warranted. Little is known about preventive recommendations clinicians offer their patients with a family history of CVD, and adherence to preventive recommendations by patients at risk for CVD has not been well described. Methods: We used the 2007 Oregon Behavioral Risk Factor Surveillance System to evaluate among 2,566 adults without CVD associations between family history of CVD and (a) clinician recommendations; (b) perceived risk of developing CVD; (c) adoption of preventive and screening behaviors; and (d) risk factors of CVD. Results: Compared with adults with no family history of CVD, those with a family history reported that their clinician was more likely to ask about their family history information (OR = 2.6; 95% CI, 1.9–3.4), discuss the risk of developing CVD (OR = 2.0; 95% CI, 1.6–2.5), and make recommendations to prevent CVD (OR = 2.1; 95% CI, 1.7–2.7). Family history and clinician recommendations were associated with a higher likelihood of reported changes in diet or physical activity to prevent CVD (OR = 2.7; 95% CI, 2.3–3.2). Persons with a family history of CVD were more likely to report having high cholesterol, having high blood pressure, taking aspirin, and having had their cholesterol checked. Conclusion: The presence of a family history of CVD appears to prompt clinicians to recommend preventive changes and may motivate patients without CVD to adopt these recommendations.
Natural Killer T Cells and Atherosclerosis: Form and Function Meet Pathogenesis
Authors: Braun Nicole A. , Covarrubias Roman , Major Amy S.
Published: March 2010

Atherosclerosis is a chronic inflammatory disease characterized by dyslipidemia and accumulation of lipids in the arterial intima, with activation of both innate and adaptive immunity. Reciprocally, dyslipidemia associated with atherosclerosis can perturb normal immune function. Natural killer T (NKT) cells are a specialized group of immune cells that share characteristics with both conventional T cells and natural killer cells. However, unlike these cells, NKT cells recognize glycolipid antigens and produce both pro- and anti-inflammatory cytokines upon activation. Because of these unique characteristics, NKT cells have recently been ascribed a role in the regulation of immunity and inflammation, including cardiovascular disease. In addition, NKT cells represent a bridge between dyslipidemia and immune regulation. This review summarizes the current knowledge of NKT cells and discusses the interplay between dyslipidemia and the normal functions of NKT cells and how this might modulate inflammation and atherosclerosis.
Inducible Nitric Oxide Synthase-Activated Mitochondrial Apoptotic Pathway in Hypoxic and Aged Rat Hearts
Authors: Zara S. , Rapino M. , Centurione L. , di Giacomo V. , Petruccelli G. , Cataldi A.
Published: March 2010

Background: Hypoxia and aging determine on mammalian cells a stress response which implies modified production of oxidants, reactive oxygen species or reactive nitrogen species at the mitochondrial level, interfering with cell-signaling proteins and inducing mitochondrial damage, apoptosis occurrence and functional consequences. Objective: Here we report the effects of hypoxia on the in vivo morphological and biochemical response of young and aged Wistar rat hearts. Methods: Left ventricles were excised from each experimental point and processed. Investigations of vascular endothelial growth factor (VEGF) expression and apoptotic events, mitochondrial damage, were performed by light and electron microscopy, respectively; endothelial, inducible and neuronal NOS, PKCα, pPKCα, caspase-3 expression and Apaf-1/cytochrome c complex formation were assessed by Western blotting and co-immunoprecipitation analyses, respectively. Results: Besides morphological modifications, which confirm mitochondrial suffering upon hypoxia exposure in both young and aged hearts, the role played by PKCα in controlling nitric oxide synthase (NOS) protein level was investigated. Downstream PKCα activation, a dramatic iNOS expression increase, concomitant to enhanced apoptotic cell percentage and Apaf-1/cytochrome c co-immunoprecipitation, is evident in the hypoxic young, suggesting iNOS-mediated activation of the mitochondrial apoptotic pathway. Conclusions: Moreover, overexpression of iNOS and VEGF in the hypoxic young rat hearts suggests that an increased VEGF level may allow coordinated development of the lymphatic and blood vasculature, necessary for fluid homeostasis and to counteract oxidative stress. Thus the inhibition of such growth factor proposes new therapeutic possibilities for diseases associated to vascular function and for solid tumors which show pathological angiogenesis and lymphoangiogenesis.
From Instrumental to Expressive: The Changing Goals of the U.S. Cold War Strategic Embargo
Authors: Dobson Alan P.
Published: March 2010

The U.S. strategic embargo against the Soviet bloc, adopted in 1947–1948, had been designed to restrict the supply of weapons technology to the Soviet Union and to retard Soviet economic growth. When these objectives failed to materialize by 1957, a lengthy reevaluation of the purpose, benefits, and costs of the embargo ensued. The Kennedy administration eventually concluded that the strategic embargo was an integral part of U.S. Cold War strategy and, as such, could not be abandoned without suffering important diplomatic costs. The embargo became a means of bargaining with the Soviet Union and a medium through which to convey messages. Like any other tool of statecraft, the embargo proved to be as flexible as officials wanted to make it. Even if it failed in its original purpose, it could be used in other ways.
Learning Spike-Based Population Codes by Reward and Population Feedback
Authors: Friedrich Johannes , Urbanczik Robert , Senn Walter
Published: March 2010

We investigate a recently proposed model for decision learning in a population of spiking neurons where synaptic plasticity is modulated by a population signal in addition to reward feedback. For the basic model, binary population decision making based on spike/no-spike coding, a detailed computational analysis is given about how learning performance depends on population size and task complexity. Next, we extend the basic model to [Formula: see text]-ary decision making and show that it can also be used in conjunction with other population codes such as rate or even latency coding.
Statistical Computer Model Analysis of the Reciprocal and Recurrent Inhibitory Postsynaptic Potentials in α-Motoneurons
Authors: Gradwohl G. , Grossman Y.
Published: March 2010

We simulate reconstructed α-motoneurons (MNs) under physiological and morphological realistic parameters and compare the modeled reciprocal (REC) and recurrent (REN) inhibitory postsynaptic potentials (IPSPs) containing voltage-dependent channels on the dendrites with the IPSPs of a passive MN model. Three distribution functions of the voltage-dependent channels on the dendrites are applied: a step function (ST) with uniform spatial dispersion; an exponential decay (ED) function, with channels with high density located proximal to the soma; and an exponential rise (ER) with a higher density of channels located distally. The excitatory and REN inhibitory inputs are located as a gaussian function on the dendrites, while the REC inhibitory synapses are located proximal to the soma. Our simulations generate four key results. (1) The distribution pattern of the voltage-dependent channels does not affect the IPSP peak, its time integral (TI), or its rate of rise (RR). However, the IPSP peak decreased in the presence of the active dendrites, while the EPSP peak increased. (2) Proximally located IPSP conductance produces greater IPSP peak, RR, and TI. (3) Increased duration of the IPSP produces greater RR and moderately increased TI and has a small effect on the peak amplitude. (4) The IPSP of both REC and REN models is specific to each MN: its amplitude is proportional to the MNs' input resistance, RN; the increase of IPSP at the proximal location of the IPSP synapses is inversely related to RN; and the effect of the IPSP conductance duration is insensitive to RN.
Hebbian Plasticity and Homeostasis in a Model of Hypercolumn of the Visual Cortex
Authors: Pool R. Rossi , Mato G.
Published: March 2010

Neurons in the nervous system display a wide variety of plasticity processes. Among them are covariance-based rules and homeostatic plasticity. By themselves, the first ones tend to generate instabilities because of the unbounded potentiation of synapses. The second ones tend to stabilize the system by setting a target for the postsynaptic firing rate. In this work, we analyze the combined effect of these two mechanisms in a simple model of hypercolumn of the visual cortex. We find that the presence of homeostatic plasticity together with nonplastic uniform inhibition stabilizes the effect of Hebbian plasticity. The system can reach nontrivial solutions, where the recurrent intracortical connections are strongly modulated. The modulation is strong enough to generate contrast invariance. Moreover, this state can be reached even beginning from a weakly modulated initial condition.
On the Noise-Enhancing Ability of Stochastic Hodgkin-Huxley Neuron Systems
Authors: Chen Bor-Sen , Li Cheng-Wei
Published: March 2010

Recently noise has been shown to be useful in enhancing neuron sensitivity by stochastic resonance. In this study, in order to measure the noise-enhancing factor (NEF), a nonlinear stochastic model is introduced for the Hodgkin-Huxley (HH) neuron system with synaptic noise input stimulation and channel noises in the sodium and potassium channels. The enhancing factor of the HH neuron system is measured from the point of view of the noise-exploiting level of nonlinear stochastic H∞ signal processing. Since the nonlinear stochastic-enhancing measure problem of HH neuron systems requires a solution for the difficulty presented by the Hamilton Jacobi inequality (HJI), a fuzzy interpolation of locally linearized systems is employed to simplify the nonlinear noise-enhancing problems by solving only a set of linear matrix inequalities. The NEF of the HH neuron system is found to be related to the locations of eigenvalues of linearized HH neuron systems and can be estimated through the H∞ signal processing method. Based on a stochastic fuzzy linearized HH neuron system, we found that channel noises are enhanced by the active eigenvalues of ionic channels while synaptic noises are attenuated by the passive eigenvalues of synaptic process.
In Search of Stakeholder Salience
Authors: Weber James , Marley Kathryn A.
Published: March 2010

This research draws on the stakeholder salience framework to explore more deeply the web of business–stakeholder relationships that characterize the Fortune Global 100’s corporate social responsibility and sustainability reports. By better understanding stakeholder salience, defined as the power, legitimacy, and urgency attributed to stakeholders in these corporate reports, this research enables business leaders and scholars to further their recognition and comprehension of the characteristics of the critical stakeholder relationships that link business’s social and sustainability performance with its economic performance—the triple bottom line. Despite the predictions of this research, nationality was not found to be a differentiating factor of stakeholder salience, whereas industry membership, in one of two instances, was found to differentiate stakeholder salience in the corporate reports. Implications of these findings are discussed.
Illuminating User Experience of a Website for the Relatives of Persons With Depression
Authors: Stjernswärd Sigrid , Östman Margareta
Published: March 2010

Background: The aim of the study was to illuminate users’ experiences of a website aimed at helping relatives of persons with depression.

Material: Data was collected through forum posts, a usability scale and focus groups, and was analyzed using content analysis.

Discussion: The diary and forum seemed to fill different and valuable functions (i.e. think tank, exchange of stories), allowing communication with the self and others.

Conclusions: The website www.sommarregn.se has the potential to work as an empowering self-help instrument online, representing a viable medium to help relatives cope. Its usability can be enhanced through further development.
Burden Sharing in the Funding of the UNHCR: Refugee Protection as an Impure Public Good
Authors: Roper Steven D. , Barria Lilian A.
Published: March 2010

The authors apply the theory of collective action and alliance behavior first developed by Olson and Zeckhauser and later extended by Sandler in a series of studies to test whether the nature of refugee protection influences state motivations to provide contributions. The authors investigate whether refugee protection can be viewed as a pure public good with the concomitant problem of free riding leading to suboptimal outcomes or whether contributions provide states private benefits that transform the nature of the good. Using a Heckman selection model, they test for the determinants of state contributions to the United Nations High Commissioner for Refugees and find that refugee protection offers several private benefits, indicating that it is best understood as an impure public good. They conclude, however, that even when states are able to secure these private benefits, it does not necessarily lead to the optimal provision of refugee protection.
Quantifying the effects of climate change and risk level on peak load design in buildings
Authors: Watkins R. , Levermore GJ
Published: March 2010

Good building design aims to balance providing a comfortable internal environment for as much of the time as possible within a variety of constraints. An important factor is the expected weather, but in a changing climate this poses additional challenges to engineers and architects. This paper examines the effects of increased external temperature on the size of the central air conditioning and heating plant for an example building. It is found that for each 1°C rise in external temperatures, the peak cooling load increases approximately by 10%, the chiller power by 14% and fan power for distribution by 30-50%. These are relatively large increases in power needed to counteract rising external temperature and the paper considers the choice of risk level for sizing building plant. From HadRM3 data, the future frequency distribution of higher external temperatures is examined to evaluate the effects on plant size of designing to a fixed percentile of risk. Projected changes in absolute humidity are also discussed.

Practical applications: Climate change is an important topic for building services engineers, resulting in the UK in the new, performance-based Building Regulations Part L. New, future weather data will also become available with different climate change scenarios. This paper examines the implications of both climate change and the risk level on the peak load for natural ventilation or air conditioning and heating that is used in the design of systems.
Palliative care discharge from paediatric intensive care units in Great Britain
Authors: Fraser Lorna K , Fleming Thomas , Miller Michael , Draper Elizabeth S , McKinney Patricia A , Parslow Roger C ,   On behalf of the Paediatric Intensive Care Audit Network
Published: March 2010

We aim to describe the demographics and clinical characteristics of children discharged to palliative care from 31 paediatric intensive care units in Great Britain, using a cohort of admissions and discharges from the database of paediatric intensive care units (Paediatric Intensive Care Audit Network (PICANet)). The patients included in this study were children discharged alive from paediatric intensive care units ( n = 68882) between 1 January 2004 and 31 December 2008. The main outcome measure was Odds Ratios for discharge of children from paediatric intensive care units to palliative care and their referral destination. We found that palliative care status was recorded for 68,090 live discharges from paediatric intensive care units, with 492 (0.7%) discharges to palliative care, a proportion that varied by Strategic Health Authority (range 0 to 1.1). The odds of discharge to palliative care were increased by expected probability of death (log odds of mortality) associated with an oncology, neurology or respiratory diagnosis. South Asian children referred to palliative care were less likely to receive this care in a hospice (OR 0.18, 95% CI 0.04,0.83) and more likely to receive it in a hospital setting (OR 2.57, 95% CI 1.16,5.71). We conclude that children admitted to paediatric intensive care units have a very low rate of discharge to palliative care. Specific demographic and clinical variables are associated with referral to palliative care.
A Time Tradeoff Method for Eliciting Partner’s Quality of Life due to Patient’s Health States in Prostate Cancer
Authors: Basu Anirban , Dale William , Elstein Arthur , Meltzer David
Published: March 2010

Background. Cost-effectiveness analyses may better reflect the full costs and benefits of medical interventions if they incorporate the effects of patients’ health on their family members. Objective. To develop and apply a time tradeoff (TTO) technique to measure the impact of potential prostate cancer—related health states of the patients on the quality of life (QOL) of their partners. Methods. We developed modified TTO questions and applied them in a pilot study in which we asked the partner of the patient to tradeoff his or her own life in order to reduce the burden that he himself or she herself expects to experience if the patient developed one of the prostate cancer—related health states. We reviewed the theoretical justification for this question and carefully framed the question so as to reduce measurement error and also to avoid possible double counting with the effect on the partner’s health. Results. We collected data from 26 partners about their preferences for their own health, which is influenced by the patient’s health condition. The mean QOL weights for the partners when the patients are the following states are healthy, 0.81; impotent, 0.66; incontinent, 0.68; have metastatic disease, 0.50; and dead, 0.28. Partners’ responses varied by how close they felt to the patients. Low correlations between partners’ and patients’ QOL ratings (n = 15) suggest that the partners were not responding as proxies for the patient. Conclusions. A new TTO method is proposed to measure a partner’s QOL due to a patient’s health. Preliminary test results of validity were promising.