bluuebunny/crossref_metadata_2025 huggingface dataset:
Thrombospondin 1 and Its Mimetic Peptide ABT-510 Decrease Angiogenesis and Inflammation in a Murine Model of Inflammatory Bowel Disease
Authors: Punekar Salman , Zak Samantha , Kalter Valerie G. , Dobransky Larissa , Punekar Imran , Lawler Jack W. , Gutierrez Linda S.
Published: March 2008

Objective: Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease (IBD). Thrombospondin 1 (TSP-1) is a protein well known for its antiangiogenic and anti-inflammatory properties. Using the dextran sulfate sodium (DSS) model, the role of TSP-1 in IBD has been investigated in vivo. Methods: TSP-1-deficient mice (TSP-1–/–) and WT mice were treated with DSS for 7 days. Disease activity indices, myeloperoxidase activity (MPO) and histology were analyzed. Microvascular density (MVD) was quantified using immunohistochemistry (IMH) with CD31 antibody. TGF-β1, basic FGF, VEGF, TNF-α and MMPs protein levels were evaluated by IMH and enzyme-linked immunoabsorbent assay (ELISA). Mice were treated with ABT-510 (Abbott Laboratories), an antiangiogenic TSP peptide, using miniosmotic pumps for 7 days. Results: TSP-1–/– mice had a worse clinical outcome and exhibited severe signs of rectal bleeding compared to the WT controls. The TSP-1–/– mice showed a higher level of crypt damage and deeper lesions. The grade of inflammation and the levels of MPO activity were also significantly higher in colons of TSP-1–/– mice. TSP-1–/– mice displayed higher MVD in focal areas of the colon after only 3 days of DSS treatment. Furthermore, clinical severity of the colitis and angiogenesis was significantly diminished when mice was treated with ABT-510. Conclusions: These findings directly link TSP-1 as a protective factor in IBD and suggest antiangiogenesis treatment, including compounds such as ABT-510 as an adjuvant therapy for IBD.
Serum Fetuin-A Concentration and Endothelial Dysfunction in Chronic Kidney Disease
Authors: Caglar Kayser , Yilmaz Mahmut Ilker , Saglam Mutlu , Cakir Erdinc , Kilic Selim , Sonmez Alper , Eyileten Tayfun , Yenicesu Mujdat , Oguz Yusuf , Tasar Mustafa , Vural Abdulgaffar , Ikizler T. Alp , Stenvinkel Peter , Lindholm Bengt
Published: March 2008

Background: Defective endothelial function, an initial step in the development of atherosclerotic plaque, is prevalent in moderate to advanced chronic kidney disease (CKD). In this study, the investigators hypothesized that fetuin-A, a calcification inhibitor, is a novel risk factor for the development of endothelial dysfunction in patients. Methods: 198 nondiabetic patients with a mean age of 44.0 ± 12.4 years and with different stages of CKD were studied. In addition to a detailed metabolic panel, flow-mediated dilatation assessed by high-resolution brachial ultrasonography was performed to determine endothelial dysfunction. Carotid intima-media thickness was also estimated by ultrasonography. Serum fetuin-A concentrations were determined by using a human ELISA method. Results: Endothelial dysfunction was observed in all stages (1–5) of CKD and worsened in parallel to the reduction in estimated glomerular filtration rate. Serum fetuin-A concentrations were also found to be decreased in all but stage 1 CKD. On multiple regression analysis, endothelial dysfunction was independently associated with fetuin-A (β = 0.745, p < 0.001) and intact parathyroid hormone concentrations (β = –0.216, p < 0.001). Conclusion: These data in a selected cohort of CKD patients indicate that fetuin-A may be one of the contributing factors for the development of endothelial dysfunction in CKD patients.
Ventral Intermediate Thalamic Stimulation in Complex Tremor Syndromes
Authors: Diederich N.J. , Verhagen Metman L. , Bakay R.A. , Alesch F.
Published: March 2008

Background/Aims: We report on deep brain stimulation (DBS) in the ventral intermediate part of the thalamus in 4 patients with complex tremor syndromes, 2 classified as Holmes tremor (HT) and 2 as thalamic tremor (TT). Results: Three out of 4 patients showed intraoperative improvement and underwent DBS implantation. One patient with TT without intraoperative improvement was not provided with an implant. A sustained beneficial effect was present after a follow-up ranging from 20 months to 7 years, although there was partial persistence of the intentional tremor and of proximal myoclonic-dystonic movements. The mean global clinical impression score was 2. In 1 HT patient the benefit persisted after battery failure. Conclusion: The study confirms that ventral intermediate thalamic DBS can provide long-term efficacy for HT and TT. While the patients experienced considerable and lasting functional improvement, the effect was incomplete and not all elements of their complex movement disorders were equally suppressed.
Risk Factor Profile and Management of Cerebrovascular Patients in the REACH Registry
Authors: Röther Joachim , Alberts Mark J. , Touzé Emmanuel , Mas Jean-Louis , Hill Michael D. , Michel Patrik , Bhatt Deepak L. , Aichner Franz T. , Goto Shinya , Matsumoto Masayasu , Ohman E. Magnus , Okada Yasushi , Uchiyama Shinichiro , D’Agostino Ralph , Hirsch Alan T. , Wilson Peter W.F. , Steg P. Gabriel
Published: March 2008

Background: Cerebrovascular disease (CVD) is a global public health problem. CVD patients are at high risk of recurrent stroke and other atherothrombotic events. Prevalence of risk factors, comorbidities, utilization of secondary prevention therapies and adherence to guidelines all influence the recurrent event rate. We assessed these factors in 18,992 CVD patients within a worldwide registry of stable outpatients. Methods: The Reduction of Atherothrombosis for Continued Health Registry recruited >68,000 outpatients (44 countries). The subjects were mainly recruited by general practitioners (44%) and internists (29%) if they had symptomatic CVD, coronary artery disease, peripheral arterial disease (PAD) and/or ≧3 atherothrombotic risk factors. Results: The 18,992 CVD patients suffered a stroke (53.7%), transient ischemic attack (TIA) (27.7%) or both (18.5%); 40% had symptomatic atherothrombotic disease in ≧1 additional vascular beds: 36% coronary artery disease; 10% PAD and 6% both. The prevalence of risk factors at baseline was higher in the TIA subgroup than in the stroke group: treated hypertension (83.5/82.0%; p = 0.02), body mass index ≧30 (26.7/20.8%; p < 0.0001), hypercholesterolemia (65.1/52.1%; p < 0.0001), atrial fibrillation (14.7/11.9%; p < 0.0001) and carotid artery disease (42.3/29.7%; p < 0.0001). CVD patients received antiplatelet agents (81.7%), oral anticoagulants (17.3%), lipid-lowering agents (61.2%) and antihypertensives (87.9%), but guideline treatment targets were frequently not achieved (54.5% had elevated blood pressure at baseline, while 4.5% had untreated diabetes). Conclusions: A high percentage of CVD patients have additional atherothrombotic disease manifestations. The risk profile puts CVD patients, especially the TIA subgroup, at high risk for future atherothrombotic events. Undertreatment is common worldwide and adherence to guidelines needs to be enforced.
Can Spike Coordination Be Differentiated from Rate Covariation?
Authors: Staude Benjamin , Rotter Stefan , Grün Sonja
Published: March 2008

There has been a long and lively debate on whether rate covariance and temporal coordination of spikes, regarded as potential origins for correlations in cortical spike signals, fulfill different roles in the cortical code. In this context, studies that report spike coordination have often been criticized for ignoring fast nonstationarities, which would result in wrongly assigned spike coordination. The underlying hypothesis of this critique is that spike coordination is essentially identical to rate covariation, only on a shorter timescale. This study investigates the validity of this critique. We provide a decomposition for the cross-correlation function of doubly stochastic point processes, where each of the components corresponds precisely to the concepts of dependence under investigation. This allows us to correct the correlation function for rate effects, which implies that spike coordination and rate covariation are statistically separable concepts of dependence. Furthermore, we present direct and intuitive model implementations of the discussed concepts and illustrate that their difference is not a matter of timescale. Analysis of data generated by our models and analytical description of the relevant estimators reveals, however, that spike coordination dramatically influences the accuracy of rate covariance estimation. As a consequence, extreme parameter combinations can lead to situations where the concept of dependence cannot be identified empirically. However, for a wide range of parameters, the concept of dependence underlying a given data set can be identified regardless of its timescale.
Oscillations and Spiking Pairs: Behavior of a Neuronal Model with STDP Learning
Authors: Shen Xi , Lin Xiaobin , Wilde Philippe De
Published: March 2008

In a biologically plausible but computationally simplified integrate-and-fire neuronal population, it is observed that transient synchronized spikes can occur repeatedly. However, groups with different properties exhibit different periods and different patterns of synchrony. We include learning mechanisms in these models. The effects of spike-timing-dependent plasticity have been known to play a distinct role in information processing in the central nervous system for several years. In this letter, neuronal models with dynamical synapses are constructed, and we analyze the effect of STDP on collective network behavior, such as oscillatory activity, weight distribution, and spike timing precision. We comment on how information is encoded by the neuronal signaling, when synchrony groups may appear, and what could contribute to the uncertainty in decision making.
Temporal Coding: Assembly Formation Through Constructive Interference
Authors: Burwick Thomas
Published: March 2008

Temporal coding is studied for an oscillatory neural network model with synchronization and acceleration. The latter mechanism refers to increasing (decreasing) the phase velocity of each unit for stronger (weaker) or more coherent (decoherent) input from the other units. It has been demonstrated that acceleration generates the desynchronization that is needed for self-organized segmentation of two overlapping patterns. In this letter, we continue the discussion of this remarkable feature, giving also an example with several overlapping patterns. Due to acceleration, Hebbian memory implies a frequency spectrum for pure pattern states, defined as coherent patterns with decoherent overlapping patterns. With reference to this frequency spectrum and related frequency bands, the process of pattern retrieval, corresponding to the formation of temporal coding assemblies, is described as resulting from constructive interference (with frequency differences due to acceleration) and phase locking (due to synchronization).
Syncretism Revisited: Hindus and Muslims over a Saintly Cult in Bengal
Authors: Togawa Masahiko
Published: March 2008

This paper reconsiders the concept of “syncretism,” and identifies its range and implications when applied to the analysis of the saintly cult of the Hindus and Muslims in Bengal. The mausoleum of Manamohan Datta (1877–1909) is situated in what is currently eastern Bangladesh. Both Hindus and Muslims in the area join together in the various rituals held at the mausoleum. The article discusses the social and cultural factors that explain the sharing of rituals and beliefs by these people. In particular, word correspondences in the religious vocabulary facilitates the mutual acceptance of different cultural forms and norms. The article also examines the critical discourses on syncretistic situations related to the mausoleum in the context of contemporary Bangladesh. Finally, the article discusses the usefulness of the concept of syncretism in elucidating the social and cultural conditions which make possible religious pluralism and multiple discourses. The article opens with a literature review and a statement of the problems. This is followed by a brief history of Saint Manomohan and a description of the ritual practices at the mausoleum. The pluralistic structure of these practices is then examined, and the conditions for acceptance of pluralistic practices are discussed with reference to the critical discourses conducted by the local population. The findings are summed up in a conclusion.
A School of Christian Hebraists in Thirteenth-Century England: A Unique Hebrew-Latin-French and English Dictionary and its Sources
Authors: Olszowy-Schlanger Judith
Published: March 2008

This paper is a preliminary presentation of a unique Hebrew-Latin-Old French dictionary written by Christian scholars in 13th century England, to appear shortly in print. The authors of this exceptional work did not follow the patristic tradition of Christian Hebraism and did not focus on anti-Jewish polemics, but rather turned to Jewish Rabbinic and Medieval sources, such as commentaries of Rachi, the lexicon of Solomon ibn Parhon or Alpha Beta de-Ben Sira for their understanding of the Hebrew text of the Bible. Following the grammatical approach of the classical Spanish school of Hebrew grammar, this dictionary is a real 'philological' work. It stems from a Christian tradition of the use of the Hebrew Bible for correcting the Vulgate as represented by the bilingual Hebrew-Latin Bible manuscripts produced and studied in England in the late 12th and 13th centuries.
On the Literary Character of Abraham Ibn Da'ud's Sefer Ha-Qabbalah
Authors: Krakowski Eve
Published: March 2008

According to a currently dominant interpretation, Ibn Da'ud's Sefer ha-qabbalah presents a chronologically symmetrical schema of Jewish history that is intended to convey an esoteric messianic speculation. This paper argues that Sefer ha-qabbalah is neither esoteric nor deliberately schematic. Rather, it is a compilation of material drawn from a large number of varied sources, which is consistently organized in order to forward Ibn Da'ud's primary polemical purpose of defending a particular historical narrative from competing claims put forth by Karaites, Christians, and others. The first part of this paper argues that the textual features underlying the esoteric interpretation can be better explained as reflections of Ibn Da'ud's polemical aims and eclectic use of source material. The second part traces these characteristics through a detailed analysis of a key passage in Sefer ha-qabbalah, which deals with the chronology of the First and Second Temples; this analysis also addresses the question of chronological schematism in the work, which is examined more systematically in an Appendix. Finally, the last section applies this analysis towards a redefinition of the literary character of Sefer ha-qabbalah, and discusses Ibn Da'ud's polemical use of history in relation to twelfth-century political circumstances and developments in historiography.
The Path of Silence: An Unknown Story from a Zohar Manuscript
Authors: Meroz Ronit
Published: March 2008

This article presents a Zoharic story found in one manuscript only—ms. Vatican 206. The focal point of this story is the question whether in order to cleave to God while walking, one should make use of the homiletical discourse, which naturally involves a dialogue with one's walking partner, or whether one should focus one's heart and will on God in utter silence. Rabbi Yose represents the group consensus (widely described in the printed edition of the Zohar) as he expects Rabbi Abba to converse with him about matters of Torah; Rabbi Abba, on the other hand, represents ideas novel to that circle, probably under the influence of contemporary spiritualist trends. The story is very succinct, but its comparison to other Zoharic texts and the attention to the strong emotions alluded to between the lines reveal a rich plot. It seems that the fellows of the historical Zohar circle found themselves at a spiritual crossroads—one of them was attempting to undermine their dominant spiritual system and replace it with a more introverted one. It seems, however, that the fact that this story was excluded from the Zoharic corpus—it only appears in one manuscript—shows that the positive ending to this imaginary story, whereby Rabbi Yose silently agrees with Rabbi Abba, remains a wishful thought and that this attempt at incorporating new ways into the circle's traditions failed.
Modeling Nonignorable Missing Data in Speeded Tests
Authors: Glas Cees A. W. , Pimentel Jonald L.
Published: March 2008

In tests with time limits, items at the end are often not reached. Usually, the pattern of missing responses depends on the ability level of the respondents; therefore, missing data are not ignorable in statistical inference. This study models data using a combination of two item response theory (IRT) models: one for the observed response data and one for the missing data indicator. The missing data indicator is modeled using a sequential model with linear restrictions on the item parameters. The models are connected by the assumption that the respondents' latent proficiency parameters have a joint multivariate normal distribution. Model parameters are estimated by maximum marginal likelihood. Simulations show that treating missing data as ignorable can lead to considerable bias in parameter estimates. Including an IRT model for the missing data indicator removes this bias. The method is illustrated with data from an intelligence test with a time limit.
Weaving Stories: Personal Auto/Biographies in Feminist Research
Authors: Cotterill Pamela , Letherby Gayle
Published: March 2008

Feminist epistemology suggests the need for a reconceptualisation of autobiography and biography. The article is autobiographical in that it draws upon the experiences of the writers. It is specifically concerned with their personal biographies regarding their academic development and their experience of feminist qualitative research within sociology. It is concerned to show how doing feminist research involves weaving the stories of both the researcher and the researched, and also how the lives of `significant others' are part of any completed piece. Each experience of research is different. This means that the researcher's autobiography has a different place among the biographies of the researched, depending on the individuals involved and the nature of the research topic. Consideration is given to the problems of including the researcher's autobiography in the fieldwork and publication stages. The research experience prompts not only a re-evaluation of the past, but also alters the personal biographies of the future for all those involved. Attention to these issues clearly shows that autobiography and biography are relevant to a wide variety of work and should be central to a sociological approach.
Life Stories and Social Careers: Ageing and Social Life in an Ex-Mining Town
Authors: Humphrey Robin
Published: March 2008

This article puts forward the notion of a social career in order to aid analysis of the life stories of two groups of elderly men and women, one very socially involved with the surrounding community and the other socially isolated from it, both living in the `constructed community' of an ex-mining town in County Durham. It includes a comparison between the social career and the life course approach and a discussion of continuities and discontinuities in social careers, the latter being identified as the consequence of `career breaks'.
ASEAN3+India Trade Relations
Authors: Hoa Tran Van
Published: March 2008

World leaders at the First East Asia Summit in Kuala Lumpur in 2005 endorsed high-level studies and dialogues on an enlarged ASEAN free trade agreement to promote regional cooperation for mutual economic and political benefits between the ASEAN and the world's other trading blocs. The endorsement is consistent with India's contemporary reforms, with its ‘Look East’ policy and economic diplomacy. In spite of this important development, only limited research has been carried out or reported for informed discussions and policy analysis in the particular case of ASEAN3+India. This paper is a substantive evidence-based study of India's reforms, ‘Look East’ policy, economic diplomacy, and East Asia Summit trade and cooperation issues. It uses the recently developed award-winning generalised gravity theory (see Tran Van Hoa 2004) to construct an ASEAN3+India model of growth and endogenous trade. Using historical data from the Organisation for Economic Cooperation and Development (OECD), Reserve Bank of India and Japan's ICSEAD, the paper provides substantive findings on the causal impact of ASEAN3+India trade in goods, FDI and services, and post-1991 reforms on economic growth for more credible policy analysis in the sense of Kydland (2006). Implications of the findings for India's engagement with Asia are also discussed.
Uniqueness and Growth of Solutions in Two-Temperature Generalized Thermoelastic Theories
Authors: Magaña A. , Quintanilla R.
Published: March 2008

In this work we study modifications of the non-classical models of thermoelasticity, the one proposed Green and Lindsay and the one stated by Lord and Shulman, to two-temperature setting. We prove uniqueness results for the solutions of the systems of equations that model both theories for isotropic material. We also provide growth estimates for the solutions.
Health Disparities: What Can Nursing Do?
Authors: Smith Gloria R.
Published: March 2008

Health disparities result from lack of caring within the society. Central to nursing, caring makes the profession best suited for leadership in reducing disparities. Nursing is losing its capacity for caring. Nursing's progress in gaining status has alienated it from the needs of other oppressed groups. It has also been seduced by the scientific model and does not always use its best judgment of truths about human suffering. Research has identified unequal treatment, discrimination, workplace and social status, income inequality, and policy decisions to deplete resources as social and economic determinants of health. All involve relationships. Nursing is the profession for which relationships are primary. Nursing can rebuild the capacity for caring and social and relational practice through transforming nursing education on the principle of mutuality. Nursing can also promote nurse-managed primary care and focus on changing local, state, and national policies to increase access, equity, and health protection.
The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity
Authors: Finetti Francesca , Pellegrini Michela , Ulivieri Cristina , Savino Maria Teresa , Paccagnini Eugenio , Ginanneschi Chiara , Lanfrancone Luisa , Pelicci Pier Giuseppe , Baldari Cosima T.
Published: March 2008

The ShcA locus encodes 3 protein isoforms that differ in tissue specificity, subcellular localization, and function. Among these, p66Shc inhibits TCR coupling to the Ras/MAPK pathway and primes T cells to undergo apoptotic death. We have investigated the outcome of p66Shc deficiency on lymphocyte development and homeostasis. We show that p66Shc−/− mice develop an age-related lupus-like autoimmune disease characterized by spontaneous peripheral T- and B-cell activation and proliferation, autoantibody production, and immune complex deposition in kidney and skin, resulting in autoimmune glomerulonephritis and alopecia. p66Shc−/− lymphocytes display enhanced proliferation in response to antigen receptor engagement in vitro and more robust immune responses both to vaccination and to allergen sensitization in vivo. The data identify p66Shc as a negative regulator of lymphocyte activation and show that loss of this protein results in breaking of immunologic tolerance and development of systemic autoimmunity.
DNA-vaccination via tattooing induces stronger humoral and cellular immune responses than intramuscular delivery supported by molecular adjuvants
Authors: Pokorna Dana , Rubio Ivonne , Müller Martin
Published: March 2008

Tattooing is one of a number of DNA delivery methods which results in an efficient expression of an introduced gene in the epidermal and dermal layers of the skin. The tattoo procedure causes many minor mechanical injuries followed by hemorrhage, necrosis, inflammation and regeneration of the skin and thus non-specifically stimulates the immune system. DNA vaccines delivered by tattooing have been shown to induce higher specific humoral and cellular immune responses than intramuscularly injected DNA. In this study, we focused on the comparison of DNA immunization protocols using different routes of administrations of DNA (intradermal tattoo versus intramuscular injection) and molecular adjuvants (cardiotoxin pre-treatment or GM-CSF DNA co-delivery). For this comparison we used the major capsid protein L1 of human papillomavirus type 16 as a model antigen. L1-specific immune responses were detected after three and four immunizations with 50 μg plasmid DNA. Cardiotoxin pretreatment or GM-CSF DNA co-delivery substantially enhanced the efficacy of DNA vaccine delivered intramuscularly by needle injection but had virtually no effect on the intradermal tattoo vaccination. The promoting effect of both adjuvants was more pronounced after three rather than four immunizations. However, three DNA tattoo immunizations without any adjuvant induced significantly higher L1-specific humoral immune responses than three or even four intramuscular DNA injections supported by molecular adjuvants. Tattooing also elicited significantly higher L1-specific cellular immune responses than intramuscularly delivered DNA in combination with adjuvants. In addition, the lymphocytes of mice treated with the tattoo device proliferated more strongly after mitogen stimulation suggesting the presence of inflammatory responses after tattooing. The tattoo delivery of DNA is a cost-effective method that may be used in laboratory conditions when more rapid and more robust immune responses are required.
Transient T cell depletion causes regression of melanoma metastases
Authors: Rasku Mary Ann , Clem Amy L , Telang Sucheta , Taft Beverly , Gettings Kelly , Gragg Hana , Cramer Daniel , Lear Sheron C , McMasters Kelly M , Miller Donald M , Chesney Jason
Published: March 2008

Background

Cognate immunity against neoplastic cells depends on a balance between effector T cells and regulatory T (Treg) cells. Treg cells prevent immune attack against normal and neoplastic cells by directly suppressing the activation of effector CD4+and CD8+T cells. We postulated that a recombinant interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; Ontak) may serve as a useful strategy to deplete Treg cells and break tolerance against neoplastic tumors in humans.

Methods

We administered DAB/IL2 (12 μg/kg; four daily doses; 21 day cycles) to 16 patients with metastatic melanoma and measured the effects on the peripheral blood concentration of several T cell subsets and on tumor burden.

Results

We found that DAB/IL2 caused a transient depletion of Treg cells as well as total CD4+and CD8+T cells (< 21 days). T cell repopulation coincided with thede novoappearance of melanoma antigen-specific CD8+T cells in several patients as determined by flow cytometry using tetrameric MART-1, tyrosinase and gp100 peptide/MHC conjugates. Sixteen patients received at least one cycle of DAB/IL2 and five of these patients experienced regressions of melanoma metastases as measured by CT and/or PET imaging. One patient experienced a near complete response with the regression of several hepatic and pulmonary metastases coupled to thede novoappearance of MART-1-specific CD8+T cells. A single metastatic tumor remained in this patient and, after surgical resection, immunohistochemical analysis revealed MART1+melanoma cells surrounded by CD8+T cells.

Conclusion

Taken together, these data indicate that transient depletion of T cells in cancer patients may disrupt the homeostatic control of cognate immunity and allow for the expansion of effector T cells with specificity against neoplastic cells. Several T cell depleting agents are clinically available and this study provides strong rationale for an examination of their efficacy in cancer patients.

Trial registration

NCT00299689 (ClinicalTrials.gov Identifier).
Atherogenic diet-induced hepatitis is partially dependent on murine TLR4
Authors: Desai Moreshwar S , Mariscalco M Michele , Tawil Ahmad , Vallejo J G , Smith C W
Published: March 2008

Diets high in cholesterol and cholate such as the Paigen diet have been used to study atherogenesis, lithogenesis, and proinflammatory microvascular changes induced by nutritional hypercholesterolemia. Although these diets lead to chronic hepatic inflammation and fibrosis, the early inflammatory changes have been poorly characterized. TLR4, a known receptor for LPS, is also a receptor for a variety of endogenous ligands and has been implicated in atheroma formation. Here, we specifically examined the early inflammatory response of the liver to the atherogenic (ATH) diet and the possible contribution of TLR4. Animals fed the high-cholesterol/cholate diet for 3 weeks developed a significant, predominantly mononuclear leukocyte infiltration in the liver, hepatic steatosis, elevated hepatic expression of MCP-1, RANTES, and MIP-2, and increased serum levels of liver enzymes. In TLR4-deleted animals, there was a 30% attenuation in the serum alanine transaminase levels and a 50% reduction in the leukocyte infiltration with a fourfold reduction in chemokine expression. In contrast, hepatic steatosis did not differ from wild-type controls. TLR2 deletion had no effect on diet-induced hepatitis but increased the amount of steatosis. We conclude that the early inflammatory liver injury but not hepatic lipid loading induced by the ATH diet in mice is mediated in part by TLR4.
Evidence for Acyl-Ghrelin Modulation of Growth Hormone Release in the Fed State
Authors: Nass Ralf , Farhy Leon S. , Liu Jianhua , Prudom Catherine E. , Johnson Michael L. , Veldhuis Paula , Pezzoli Suzan S. , Oliveri Mary Clancy , Gaylinn Bruce D. , Geysen H. Mario , Thorner Michael O.
Published: March 2008

Context: The timing and frequency of GH secretory episodes is regulated by GHRH and somatostatin. This study provides evidence for amplification of these GH pulses by endogenous acyl-ghrelin.

Design: Blood was sampled every 10 min for 26.5 h during a fed admission with standardized meals and also during the final 24 h of a 61.5-h fast. GH secretion profiles were derived from deconvolution of 10-min sampling data, and full-length acyl-ghrelin levels were measured using a newly developed two-site sandwich assay.

Setting: The study was conducted at a university hospital general clinical research center.

Participants: Participants included eight men with mean (± sd) age 24.5 ± 3.7 yr (body mass index 24 ± 2.1 kg/m2).

Results: Correlations were computed between amplitudes of individual GH secretory events and the average acyl-ghrelin concentration in the 60-min interval preceding each GH burst. In the fed state, the peak correlations were positive for all subjects and significantly higher than in the fasting state when acyl-ghrelin levels declined [mean (± sem): 0.7 (0.04) vs. 0.29 (0.08), P = 0.017]. In addition, long-term fasting was associated with an increase in the GH secretory pulse mass and amplitude but not frequency [fed vs. fasting pulse mass: 0.22 (0.05) vs. 0.44 (0.06) μg/liter, P = 0.002; amplitude: 5.2 (1.3) vs. 11.8 (1.9) μg/liter/min, P = 0.034; pulses per 24 h: 19.4 (0.5) vs. 22.0 (1.4), P = 0.1].

Conclusion: Our data support the hypothesis that under normal conditions in subjects given regular meals endogenous acyl-ghrelin acts to increase the amplitude of GH pulses.
Dictyostelium MEGAPs: F-BAR domain proteins that regulate motility and membrane tubulation in contractile vacuoles
Authors: Heath Robert J. W. , Insall Robert H.
Published: March 2008

PCH family proteins are fundamentally important proteins, linking membrane curvature events with cytoskeletal reorganisation. One group, the MEGAPs (also called srGAPs and WRPs) contain RhoGAP domains in addition to the F-BAR domain. We disrupted MEGAP1 and MEGAP2 in Dictyostelium both singly and in combination. We found a strong cytoskeletal phenotype in MEGAP1– cells and a subtle phototaxis defect in MEGAP2– slugs. MEGAP1–/2– cells have an overabundance of filopodia and slug motility and function are affected. The most dramatic changes, however, are on contractile vacuoles. MEGAP1–/2– cells empty their contractile vacuoles less efficiently than normal and consequently have three times the usual number. GFP-tagged MEGAP1 localises to tubules of the contractile vacuole network and when vacuoles start to empty they recruit cytosolic GFP-MEGAP1. Mutants in the Saccharomyces homologues RGD1 and RGD2 also show abnormal vacuoles, implying that this role is conserved. Thus, MEGAP is an important regulator of the contractile vacuole network, and we propose that tubulation of the contractile vacuole by MEGAP1 represents a novel mechanism for driving vacuole emptying.
Targeted transgenic expression of the mutation causing Hutchinson-Gilford progeria syndrome leads to proliferative and degenerative epidermal disease
Authors: Sagelius Hanna , Rosengardten Ylva , Hanif Mubashir , Erdos Michael R. , Rozell Björn , Collins Francis S. , Eriksson Maria
Published: March 2008

Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disorder characterized by striking progeroid features. Clinical findings in the skin include scleroderma, alopecia and loss of subcutaneous fat. HGPS is usually caused by a dominant-negative mutation in LMNA, a gene that encodes two major proteins of the inner nuclear lamina: lamin A and lamin C. We have generated tetracycline-inducible transgenic lines that carry a minigene of human LMNA under the control of a tet-operon. Two mouse lines were created: one carrying the wild-type sequence of LMNA and the other carrying the most common HGPS mutation. Targeted expression of the HGPS mutation in keratin-5-expressing tissues led to abnormalities in the skin and teeth, including fibrosis, loss of hypodermal adipocytes, structural defects in the hair follicles and sebaceous glands, and abnormal incisors. The severity of the defects was related to the level of expression of the transgene in different mouse lines. These transgenic mice appear to be good models for studies of the molecular mechanisms of skin abnormalities in HGPS and other related disorders.
Lymph drainage in patients with joint immobility due to chronic ulcerated lesions
Authors: Pereira de Godoy J M , Braile D M , de Fátima Guerreiro Godoy M
Published: March 2008

The fibrous process of chronic ulcerated lesions of lower limbs can impair the mobility of the affected limb. The aim of this work was to assess the benefits of lymph drainage in patients who suffer from this disease. Twenty female and five male patients with ages ranging from 53 to 69 years (mean age 60.6 years) were evaluated. All had a history of at least 10 years of varicose veins and/or ulcerated lesions of the lower limbs with initial dermatofibrosis, with the positive Godet sign during the physical examination of the limb. Patients with intermittent claudication, diabetes and trauma were excluded from the study, as well as patients with chronic dermatofibrosis, and in whom positive Godet sign was not seen. Patients with immobility or very limited movement of the ankle and with some limitation in the toe joints were selected. The patients were randomly divided into group A comprising 15 individuals, and group B 10. All the individual treatments were established before the start of the evaluation period. Lymph drainage was performed on the patients of group A four or five times per week. Group B was subjected to a type of massage for the same period and at the same frequency. The mobility of the ankle joints was evaluated using goniometry before the start and after 30 days of treatment. In all the patients who underwent lymph drainage, an improvement of the joint mobility was seen, whereas in the control, group B, there was no obvious change. In conclusion, lymph drainage gave an improvement in the mobility of the ankle joint after impairment due to initial dermatofibrosis in patients with chronic ulcerated lesions.
Mental Accounting and Consumer Choice
Authors: Thaler Richard H.
Published: March 2008

Anew model of consumer behavior is developed using a hybrid of cognitive psychology and microeconomics. The development of the model starts with the mental coding of combinations of gains and losses using the prospect theory value function. Then the evaluation of purchases is modeled using the new concept of “transaction utility.” The household budgeting process is also incorporated to complete the characterization of mental accounting. Several implications to marketing, particularly in the area of pricing, are developed.

This article was originally published in Marketing Science, Volume 4, Issue 3, pages 199–214, in 1985.
Defensive Marketing Strategies
Authors: Hauser John R. , Shugan Steven M.
Published: March 2008

This paper analyzes how a firm should adjust its marketing expenditures and its price to defend its position in an existing market from attack by a competitive new product. Our focus is to provide usable managerial recommendations on the strategy of response. In particular we show that if products can be represented by their position in a multiattribute space, consumers are heterogeneous and maximize utility, and awareness advertising and distribution can be summarized by response functions, then for the profit maximizing firm: it is optimal to decrease awareness advertising, it is optimal to decrease the distribution budget unless the new product can be kept out of the market, a price increase may be optimal, and even under the optimal strategy, profits decrease as a result of the competitive new product.

Furthermore, if the consumer tastes are uniformly distributed across the spectrum a price decrease increases defensive profits, it is optimal (at the margin) to improve product quality in the direction of the defending product's strength and it is optimal (at the margin) to reposition by advertising in the same direction.

In addition we provide practical procedures to estimate (1) the distribution of consumer tastes and (2) the position of the new product in perceptual space from sales data and knowledge of the percent of consumers who are aware of the new product and find it available. Competitive diagnostics, such as the angle of attack, are introduced to help the defending manager.

This article was originally published in Marketing Science, Volume 2, Issue 4, pages 319–360, in 1983.
An Industry Equilibrium Analysis of Downstream Vertical Integration
Authors: McGuire Timothy W. , Staelin Richard
Published: March 2008

This paper investigates the effect of product substitutability on Nash equilibrium distribution structures in a duopoly where each manufacturer distributes its goods through a single exclusive retailer, which may be either a franchised outlet or a factory store. Static linear demand and cost functions are assumed, and a number of rules about players' expectations of competitors' behavior are examined. It is found that for most specifications product substitutability does influence the equilibrium distribution structure. For low degrees of substitutability, each manufacturer will distribute its product through a company store; for more highly competitive goods, manufacturers will be more likely to use a decentralized distribution system.

This article was originally published in Marketing Science, Volume 2, Issue 2, pages 161–191, in 1983.
Commentary—An Industry Equilibrium Analysis of Downstream Vertical Integration: Twenty-Five Years Later
Authors: Staelin Richard
Published: March 2008

The goal of this brief note is to provide the reader with an appreciation of how this paper was initially conceived, to state what I think are the paper's key insights, and to outline a few of the many challenges and opportunities that still exist in studying channel management issues.
Commentary—Defensive Marketing Strategies
Authors: Hauser John R. , Shugan Steven M.
Published: March 2008

For every new product and service entrant, there are usually many incumbents who must defend their positions in the market. Hence, defensive strategy is as least as critical as new-product strategy. Our 1983 article argued that defensive strategy critically depends on the distribution of buyer preferences and the position of the new entrant relative to the position of the incumbent in a multidimensional attribute space. Since the appearance of our 1983 article in Marketing Science, research in defensive strategy has progressed in both prescriptive and descriptive directions. Subsequent research on defensive strategy has also addressed empirical, methodological, theoretical, and substantive issues. Today, defensive strategy is more important than ever, with shorter new-product life cycles, persistent service innovation, remarkable technological change, global competition, and the invention of new channels of distributions.
Toward a Theory of Behavioral Operations
Authors: Gino Francesca , Pisano Gary
Published: March 2008

Human beings are critical to the functioning of the vast majority of operating systems, influencing both the way these systems work and how they perform. Yet most formal analytical models of operations assume that the people who participate in operating systems are fully rational or at least can be induced to behave rationally. Many other disciplines, including economics, finance, and marketing, have successfully incorporated departures from this rationality assumption into their models and theories. In this paper, we argue that operations management scholars should do the same. We explore the theoretical and practical implications of incorporating behavioral and cognitive factors into models of operations management and suggest fruitful avenues for research in behavioral operations.
Finding Supply Function Equilibria with Asymmetric Firms
Authors: Anderson Edward J. , Hu Xinmin
Published: March 2008

Firms compete in supply functions when they offer a schedule of prices and quantities into a market; for example, this occurs in many wholesale electricity markets. We study the equilibrium behaviour when firms differ, both with regard to their costs and their capacities. We characterize strong equilibrium solutions in which, given the other players' supply functions, optimal profits are achieved for every demand realisation. If the demand can be low enough for it to be met economically with supply from just one firm, then the supply function equilibria are ordered in a natural way. We consider equilibria in which, for the highest levels of demand, all but one of the firms have reached their capacity limit. We show that there can be at most one supply function equilibrium with this property. We also propose a new numerical method to find asymmetric supply function equilibria, using piecewise-linear approximations and a discretization of the demand distribution. We show that this approach has good theoretical convergence behaviour. Finally, we present numerical results from an implementation using GAMS to demonstrate that the approach is effective in practice.
N-Terminal Mutant Huntingtin Associates with Mitochondria and Impairs Mitochondrial Trafficking
Authors: Orr Adam L. , Li Shihua , Wang Chuan-En , Li He , Wang Jianjun , Rong Juan , Xu Xingshun , Mastroberardino Pier Giorgio , Greenamyre J. Timothy , Li Xiao-Jiang
Published: March 2008

Huntington's disease (HD) is caused by polyglutamine (polyQ) expansion in huntingtin (htt), a large (350 kDa) protein that localizes predominantly to the cytoplasm. Proteolytic cleavage of mutant htt yields polyQ-containing N-terminal fragments that are prone to misfolding and aggregation. Disease progression in HD transgenic models correlates with age-related accumulation of soluble and aggregated forms of N-terminal mutant htt fragments, suggesting that multiple forms of mutant htt are involved in the selective neurodegeneration in HD. Although mitochondrial dysfunction is implicated in the pathogenesis of HD, it remains unclear which forms of cytoplasmic mutant htt associate with mitochondria to affect their function. Here we demonstrate that specific N-terminal mutant htt fragments associate with mitochondria inHdh(CAG)150 knock-in mouse brain and that this association increases with age. The interaction between soluble N-terminal mutant htt and mitochondria interferes with thein vitroassociation of microtubule-based transport proteins with mitochondria. Mutant htt reduces the distribution and transport rate of mitochondria in the processes of cultured neuronal cells. Reduced ATP level was also found in the synaptosomal fraction isolated fromHdh(CAG)150 knock-in mouse brain. These findings suggest that specific N-terminal mutant htt fragments, before the formation of aggregates, can impair mitochondrial function directly and that this interaction may be a novel target for therapeutic strategies in HD.
Rapid Loss of Dendritic Spines after Stress Involves Derangement of Spine Dynamics by Corticotropin-Releasing Hormone
Authors: Chen Yuncai , Dubé Céline M. , Rice Courtney J. , Baram Tallie Z.
Published: March 2008

Chronic stress causes dendritic regression and loss of dendritic spines in hippocampal neurons that is accompanied by deficits in synaptic plasticity and memory. However, the responsible mechanisms remain unresolved. Here, we found that within hours of the onset of stress, the density of dendritic spines declined in vulnerable dendritic domains. This rapid, stress-induced spine loss was abolished by blocking the receptor (CRFR1) of corticotropin-releasing hormone (CRH), a hippocampal neuropeptide released during stress. Exposure to CRH provoked spine loss and dendritic regression in hippocampal organotypic cultures, and selective blockade of the CRFR1receptor had the opposite effect. Live, time-lapse imaging revealed that CRH reduced spine density by altering dendritic spine dynamics: the peptide selectively and reversibly accelerated spine retraction, and this mechanism involved destabilization of spine F-actin. In addition, mice lacking the CRFR1receptor had augmented spine density. These findings support a mechanistic role for CRH–CRFR1signaling in stress-evoked spine loss and dendritic remodeling.