bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti‐TNF‐α Therapy in Seven Patients with Behçet's Uveitis
Authors: TOGNON S. , GRAZIANI G. , MARCOLONGO R.
Published: October 2007

Abstract:  Behcet's disease (BD) is a chronic, relapsing, multisystem disease. In some patients, ocular involvement can lead to severe vision impairment despite immunosuppressive therapy. Since high levels of circulating TNF‐α have been found both in peripheral blood and aqueous humor of patients with active BD, we evaluated the efficacy of anti‐TNF‐α therapy in seven patients with severe ocular involvement resistant to previous treatment. Seven patients with sight‐threatening relapsing uveitis refractory to immunosuppressive regimens received intravenously infliximab, at a dose of 3–5 mg/kg, on week 0–2–4 and then every 6–8 weeks, in combination with low‐dose prednisone and methotrexate or azathioprine. Efficacy was assessed in terms of number and severity of relapses of posterior uveitis, visual acuity, and reduction of corticosteroids and immunosuppressive drugs. After a mean follow‐up period of 23 months, the total number of relapses dropped to 6, compared to the 21 observed in an equivalent period of time before treatment. The visual acuity improved in 4 eyes, while it remained stable in 9. Therapy with infliximab considerably reduced the required daily dose of both corticosteroids and immunosuppressive drugs. In our experience infliximab proved to be safe and effective in controlling both the number and intensity of cases of posterior uveitis and the extraocular manifestations of BD. It also allowed a reduction of corticosteroids and immunosuppressive drugs required to control the disease. However, ocular and systemic manifestations tended to recur after drug withdrawal or when the interval between infliximab courses was longer than 8 weeks. Moreover, infliximab administration is costly and requires hospital admission.
Vascular Adhesion Protein‐1 as a Potential Therapeutic Target in Liver Disease
Authors: LALOR PATRICIA F. , TUNCER CEREN , WESTON CHRIS , MARTIN‐SANTOS AZUCENA , SMITH DAVID J. , ADAMS DAVID H.
Published: October 2007

Abstract:  Vascular adhesion protein‐1 (VAP‐1) is a homodimeric, transmembrane sialoglycoprotein, and amine‐oxidase enzyme constitutively expressed by hepatic endothelial cells, and as a soluble protein in serum (sVAP‐1). VAP‐1 mediates leukocyte adhesion and migration in an enzyme activity‐dependent manner. We wished to determine whether VAP‐1 blockade reduces leukocyte recruitment in inflammatory liver disease, and the mechanism by which this occurs. Our results show that VAP‐1 is upregulated in the liver and serum of patients with inflammatory liver disease. Expression is maintained on hepatic sinusoidal endothelial cells (HSECs) isolated from explanted livers. Blockade of VAP‐1 activity modestly decreases migration of normal lymphocytes across HSECs but has significant effects on the migration of peripheral blood lymphocytes (PBLs) and liver‐derived lymphocytes across HSECs. Engagement of VAP‐1 results in PI3‐kinase‐dependent NF‐κB activation and increased chemokine and adhesion molecule expression. Thus complex mechanisms regulate VAP‐1‐mediated recruitment of leukocytes. Direct binding to endothelial VAP‐1 protein, indirect enzyme‐dependent activation of other endothelial adhesive pathways, and activation of leukocyte by VAP‐1 ligand occupancy all contribute to adhesion. The restricted expression of VAP‐1 and increased production of sVAP‐1 in inflammatory liver disease confirm the validity of this molecule as a therapeutic target.
Intravenous Immunoglobulins in Autoimmune and Inflammatory Diseases
Authors: SIBÉRIL SOPHIE , ELLURU SRIRAMULU , GRAFF‐DUBOIS STÉPHANIE , NEGI VIR‐SINGH , DELIGNAT SANDRINE , MOUTHON LUC , LACROIX‐DESMAZES SÉBASTIEN , KAZATCHKINE MICHEL D. , BAYARY JAGADEESH , KAVERI SRINI V.
Published: October 2007

Abstract:  Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agents in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc‐dependent and/or F(ab′)2‐dependent nonexclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors, and several cell surface immunocompetent molecules. IVIg has also an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg, and we pointed out the need for new strategies to overcome the predicted increasing worldwide shortage of IVIg.
Suppression of Experimental Autoimmune Myasthenia Gravis by Intravenous Immunoglobulin and Isolation of a Disease‐Specific IgG Fraction
Authors: FUCHS SARA , FEFERMAN TALI , ZHU KAI‐YUN , MEIDLER ROBERTO , MARGALIT RAANAN , WANG NINGSHAN , LAUB ORGAD , SOUROUJON MIRIAM C.
Published: October 2007

Abstract:  Intravenous immunoglobulin (IVIG) administration has been beneficially used for the treatment of a variety of autoimmune diseases including myasthenia gravis (MG). We have demonstrated that IVIG administration in experimental autoimmune MG (EAMG) results in suppression of disease that is accompanied by decreased Th1 cell and B cell proliferation. Chromatography of pooled human immunoglobulins (IVIGs) on immobilized IgG, isolated from rats with EAMG, results in a complete depletion of the suppressive activity of the IVIG. Moreover, the eluate from this EAMG‐specific antibody column retains the immunosuppressive activity of IVIG. This study supports the notion that the therapeutic effect of IVIGs is mediated by an antigen‐specific anti‐immunoglobulin (anti‐idiotypic) activity that is essential for its suppressive activity.
A Modified Vaccination Technique for the Prevention and Treatment of an Experimental Autoimmune Kidney Disease
Authors: BARABAS ARPAD ZSIGMOND , COLE CHAD DOUGLAS , BARABAS ARPAD DAVID , LAFRENIERE RENE
Published: October 2007

Abstract:  The main purpose of this article is to introduce a promising new vaccination technique and to outline its efficacy and safety as demonstrated in an experimental autoimmune kidney disease. We have found that antigen (AG)‐specific downregulation and/or upregulation of immune responses can be achieved by injections of immune complexes (ICs) which contain prepackaged information. This result is attained with the new vaccination method, a method developed in our laboratory which we have called “modified vaccination technique” (MVT). This MVT not only enables the prevention of pathogenic autoimmune events leading to the development of an experimental autoimmune kidney disease; it also allows, with equal effectiveness, therapeutic intervention to terminate the disease. With an injected IC containing predetermined immune response‐inducing components, the process effectuates a specific antibody information transfer conferring advantages that go beyond its prophylactic and therapeutic applicability. Its specificity can induce a precise immune response to correct mishaps, for example, in conditions where the immune system overreacts to an autologous antigen or fails to recognize unwanted self (as in autoimmune disorders, cancer, etc.) Preformed ICs are nontoxic and nonirritant, evoke a predetermined antibody response without the use of adjuvants, cause no disturbance in the overall regulatory function of the immune system, and produce no side effects. We firmly believe that proper implementation of the MVT will be able to induce and maintain specific preventive and/or curative responses in a way that is both natural and more effective in patients with chronic ailments presently treatable only with drugs.
Probiotic Supplementation with Lactobacillus casei (Actimel) Induces a Th1 Response in an Animal Model of Antiphospholipid Syndrome
Authors: AMITAL HOWARD , GILBURD B. , SHOENFELD YEHUDA
Published: October 2007

Abstract:  Probiotic fermented milk products have the capacity to modulate many immunological mechanisms. Several attempts have been made to alter the progression of various atopic and inflammatory disorders in which the immune system plays a major role. We studied this issue in an animal model of the antiphospholipid syndrome (APS) by supplementing the animals' daily intake with a probiotic mixture. We studied the effects of nutritional supplementation of a commercial product that consists of 108/ml Lactobacillus casei (Actimel) on Balb/c mice that were immunized with beta‐2‐ glycoprotein (β2GPI) in order to induce a familiar murine model of APS. As controls, we used similar animals that were fed with either yogurt or sham solution as a supplement. We analyzed the effect of Actimel on the concentrations of interleukin (IL)‐10 interferon gamma (IFNγ) as well as the extent of the primary T cell response to β2GPI, and the levels of autoantibodies to β2GPI determined by ELISA. Two weeks after priming (in the hind footpad) of Balb/c mice with β2GPI, we analyzed the cytokine profile of the animals by measuring the concentration of IL‐10 and IFNγ in the supernatants of lymphocytes that were extracted from the popliteal lymph nodes. Following stimulation with 10 μg/mL of β2GPI, we noticed significant (P < 0.05) suppression of IL‐10 production by the stimulated lymphocytes in the animals fed with Actimel and yogurt in comparison to sham solution (73.42 ± 29.4, 84.7 ± 8, 196 ± 41.62 pg/mL, respectively). Both dairy products enhanced the secretion of IFNγ from 657 ± 47.09 pg/mL to 896 ± 78.1, and 933 ± 76.7 (P < 0.01), respectively; similarly they also accelerated by a mild degree the level of the T cell primary response to β2GPI measured by [3H]thymidine incorporation. The level of autoantibodies to β2GPI was suppressed in mice fed with actimel and yogurt in a significant manner (P < 0.05). Actimel as well as yogurt confer an immunological impact on Balb/c mice immunized with β2GPI. Actimel was able not only to enhance IFNγ secretion but also to inhibit IL‐10 production.
Self‐Reactivity in the Dimeric Intravenous Immunoglobulin Fraction
Authors: SCHAUB ALEXANDER , WYMANN SANDRA , HELLER MANFRED , GHIELMETTI MARCO , BELEZNAY ZSUZSANNE , STADLER BEDA M. , BOLLI REINHARD , MIESCHER SYLVIA
Published: October 2007

Abstract:  Therapeutic intravenous immunoglobulin (IVIg) preparations contain antibodies reflecting the cumulative antigen experience of the donor population. IVIg contains variable amounts of monomeric and dimeric IgG, but there is little information available on their comparative antibody specificities. We have isolated highly purified fractions of monomeric and dimeric IgG by size‐exclusion chromatography. Following treatment of all fractions at pH4, analyses by immunodot and immunocytology on human cell lines showed a preferential recognition of autoantigens in the dimeric IgG fraction. Investigation of the HEp‐2 cytoplasmic proteome by 2D‐PAGE, Western blot, and subsequent identification of IVIg reactive spots by mass spectrometry (LC‐MS/MS) showed that IVIg recognized only a restricted set of the total proteins. Similar experiments showed that more antigens were recognized by the dimeric IgG fraction, especially when the dissociated dimer fraction was used, as compared to its monomeric counterpart. These observations are consistent with idiotype–anti‐idiotype masking of auto‐specific Abs in the dimeric fraction of IVIg.
Donor Lymphocyte Infusion in the Treatment of First Hematological Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by the EBMT Acute Leukemia Working Party
Authors: Schmid Christoph , Labopin Myriam , Nagler Arnon , Bornhäuser Martin , Finke Jürgen , Fassas Athanasios , Volin Liisa , Gürman Günham , Maertens Johan , Bordigoni Pierre , Holler Ernst , Ehninger Gerhard , Polge Emmanuelle , Gorin Norbert-Claude , Kolb Hans-Jochem , Rocha Vanderson
Published: October 2007

Purpose

To evaluate the role of donor lymphocyte infusion (DLI) in the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT).

Patients and Methods

We retrospectively analyzed the data of 399 patients with AML in first hematological relapse after HSCT whose treatment did (n = 171) or did not (n = 228) include DLI. After correction for imbalances and established risk factors, the two groups were compared with respect to overall survival. Further, a detailed analysis of risk factors for survival among DLI recipients was performed.

Results

Median follow-up was 27 and 40 months, respectively. Estimated survival at 2 years (± standard deviation) was 21% ± 3% for patients receiving DLI and 9% ± 2% for patients not receiving DLI. After adjustment for differences between the groups, better outcome was associated with age younger than 37 years (P = .008), relapse occurring more than 5 months after HSCT (P < .0001), and use of DLI (P = .04). Among DLI recipients, a lower tumor burden at relapse (< 35% of bone marrow blasts; P = .006), female sex (P = .02), favorable cytogenetics (P = .004), and remission at time of DLI (P < .0001) were predictive for survival in a multivariate analysis. Two-year survival was 56% ± 10%, if DLI was performed in remission or with favorable karyotype, and 15% ± 3% if DLI was given in aplasia or with active disease.

Conclusion

Although further evidence for a graft-versus-leukemia effect by DLI is provided, our results confirm, that the clinical benefit is limited to a minority of patients. Strategies to reduce tumor burden before DLI, as well as alternative treatment options should be investigated in adults with relapsed AML after HSCT.
Skeletal Self-Repair : Stress Fracture Healing by Rapid Formation and Densification of Woven Bone
Authors: Uthgenannt Brian A , Kramer Michael H , Hwu Joyce A , Wopenka Brigitte , Silva Matthew J
Published: October 2007

Stress fractures of varying severity were created using a rat model of skeletal fatigue loading. Periosteal woven bone formed in proportion to the level of bone damage, resulting in the rapid recovery of whole bone strength independent of stress fracture severity.

Introduction: A hard periosteal callus is a hallmark of stress fracture healing. The factors that regulate the formation of this woven bone callus are poorly understood. Our objective was to produce stress fractures of varying severity and to assess the woven bone response and recovery of bone strength.

Materials and Methods: We used the forelimb compression model to create stress fractures of varying severity in 192 adult rats. Forelimbs were loaded in fatigue until the displacement reached 30%, 45%, 65%, or 85% of fracture. The osteogenic responses of loaded and contralateral control ulnas were assessed 7 and 14 days after loading using pQCT, μCT, mechanical testing, histomorphometry, and Raman spectroscopy.

Results: Loading stimulated the formation of periosteal woven bone that was maximal near the ulnar midshaft and transitioned to lamellar bone away from the midshaft. Woven bone area increased in a dose-response manner with increasing fatigue displacement. Whole bone strength was partially recovered at 7 days and fully recovered at 14 days, regardless of initial stress fracture severity. The density of the woven bone increased by 80% from 7 to 14 days, caused in part by a 30% increase in the mineral:collagen ratio of the woven bone tissue.

Conclusions: Functional healing of a stress fracture, as evidenced by recovery of whole bone strength, occurred within 2 wk, regardless of stress fracture severity. Partial recovery of strength in the first week was attributed to the rapid formation of a collar of woven bone that was localized to the site of bone damage and whose size depended on the level of initial damage. Complete recovery of strength in the second week was caused by woven bone densification. For the first time, we showed that woven bone formation occurs as a dose-dependent response after damaging mechanical loading of bone.
Youtube: Where Cultural Memory and Copyright Converge
Authors: Hilderbrand Lucas
Published: October 2007

ABSTRACT At the forefront of online streaming video, YouTube has expanded access to a rich spectrum of televisual material and suggests the potential for democratization of media memories and fl ows. Yet, the site also introduces new ways to regulate and deny access to such content under the guise of enforcing copyright.
Book Reviews
Authors: Stewart Michael
Published: October 2007

Japigia Gagi: Roma (Gypsy) Stories Directed by Giovanni Princigalli. Watertown, MA: Documentary Educational Resources, 2003.

Pretty Dyana:. Gypsy Recycling Saga Directed by Boris Mitiç. Belgrade Serbia: Dribbling Pictures, 2003.
Potential Misdiagnosis of 3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency Associated With Absent or Trace Urinary 3-Methylcrotonylglycine
Authors: Wolfe Lynne A. , Finegold David N. , Vockley Jerry , Walters Nicole , Chambaz Celine , Suormala Terttu , Koch Hans Georg , Matern Dietrich , Barshop Bruce A. , Cropcho Lorna J. , Baumgartner Matthias R. , Gibson K. Michael
Published: October 2007

We report 2 patients with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency whose urine was devoid of, or contained only trace, 3-methylcrotonylglycine, the pathognomonic marker for this disorder. The first patient, a girl with trisomy 21, was detected through newborn screening with an elevated 5 carbon hydroxycarnitine species level, and the second patient came to clinical attention at the age of 5 months because of failure to thrive and developmental delay. Investigation of urinary organic acids revealed an elevated 3-hydroxyisovaleric acid level but no demonstrable 3-methylcrotonylglycine in both patients. Enzyme studies in cultured fibroblasts confirmed isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency with residual activities of 5% to 7% and 12% of the median control value, respectively. Incorporation of 14C-isovaleric acid into intact fibroblasts was essentially normal, showing that the overall pathway was at least partially functional and potentially explaining the absence of 3-methylcrotonylglycine in urine. Mutation analysis of the MCCA and MCCB genes revealed that both patients were compound heterozygous for a missense mutation, MCCB-c.1015G→A (p.V339M), and a second mutation that leads to undetectable MCCB messenger (poly A+) RNA. Absent or trace 3-methylcrotonylglycine levels in urine raises the potential for misdiagnosis in the clinical biochemical genetics laboratory based solely on urine organic acid analysis using combined gas chromatography-mass spectrometry.
Discussing Shiloh: A Conversation Beyond the Book
Authors: Clarke Lane W.
Published: October 2007

An analysis of what appears initially to be a typical literature circle discussion about the book Shiloh illuminates larger issues of the influence of class and gendered discursive practices. Drawing on critical discourse analysis, the author suggests that the ways these fifth‐grade students enact class and gender roles actually positions them outside of desired literacy behaviors.

By understanding how students' language practices are shaped and influenced beyond the text, teachers can help students engage in more productive discussions and can create a more positive classroom environment for learning.
Think‐Aloud Strategy: Metacognitive Development and Monitoring Comprehension in the Middle School Second‐Language Classroom
Authors: McKeown Regina G. , Gentilucci James L.
Published: October 2007

Twenty‐seven middle school English learners participated in a study to determine the efficacy of the Think‐Aloud Strategy, one of several metacognitive strategies created to help students strategically negotiate appropriate meaning from text. Students were grouped by level of English‐language proficiency and were administered a reading comprehension pretest. They were then taught how to use the Think‐Aloud Strategy and were administered a posttest to assess the strategy's effect on their reading comprehension.

Use of the Think‐Aloud Strategy was expected to improve comprehension of expository text among all three groups. However, each group presented different results, with only the intermediate group exhibiting benefits from using the strategy.

The findings suggest English learners with varying levels of native‐language proficiency have unique instructional needs in reading. No single reading strategy may exist that will improve comprehension in all English learners.
A Case Study of a High School English‐Language Learner and His Reading
Authors: Cohen James
Published: October 2007

Mario, an adolescent English‐language learner and struggling reader, participated in a university‐sponsored summer literacy program. After the program, a follow‐up literacy assessment was conducted, and Mario was interviewed about his perceptions of and practices with literacy.

The findings of this case study demonstrate the possibility that one‐on‐one tutoring, performing specific activities such as think‐alouds when reading, engaging in sustained silent reading for extended periods each day, writing in dialogue journals, and conducting inquiry projects can all influence the motivation and the reading effectiveness of an adolescent English‐language learner who struggles to read. Although it is not possible to make conclusive assertions that any of these activities are effective for all students, it is clear by that they had a positive influence on Mario as a reader.
Race, Region, Rule: Genre and the Case of Charlie Chan
Authors: Rzepka Charles J.
Published: October 2007

This essay analyzes genre's impact on racial representation in a body of popular fiction that has shaped European Americans' definition of Asian American identity for more than three-quarters of a century: the Charlie Chan novels of Earl Derr Biggers. To advance his stated goal of overturning Chinese stereotypes, Biggers experimented with genres of locale and criminality. The Hawaiian setting of his first Chan story,The House without a Key,challenged the generic topography of Chinatown regionalism by invoking a counterintuitive regionalist prototype, while the book's plot followed the conventions of classical detective fiction, a highly formulaic subgenre of crime literature that perpetuated racist stereotypes while dominating best-seller lists throughout the 1920s and 1930s. Exploiting a unique feature of the detective formula known as rule subversion, however, Biggers enlisted the genre's very tendencies toward racism to undermine racist stereotypes.
Pioneers of Inner Space: Drug Autobiography and Manifest Destiny
Authors: Zieger Susan
Published: October 2007

The drug autobiography emerged as a genre in the United States primarily through imitations of Thomas De Quincey'sConfessions of an English Opium-Eater(1821). For De Quincey, the intoxicating consumption of opium and print was linked to imperial mastery. Texts such as Fitz Hugh Ludlow'sHasheesh Eater(1857) adapted this association to suit the westward expansion of the United States and its accompanying ideology of manifest destiny. Under the influence of hashish, Ludlow explored his inner psychic space as if it were the United States frontier. As nineteenth-century Romantic models of intoxicated dreaming gave way to early-twentieth-century theories of addiction, drug autobiographies such as D. F. MacMartin'sThirty Years in Hell(1921) readapted the genre, representing the disappointments of manifest destiny as addicted exile. While drug autobiographies accrued countercultural authority, appearing to signify the irrational underside of Enlightenment modernity, their fantasies of esoteric exploration derived from broader cultural ideals of imperial power and knowledge.
Afterword
Authors: ROBBINS BRUCE
Published: October 2007

Why should we care about genre?

Following a hint from Wai Chee Dimock, let us perform a conceptual experiment. Imagine that literature departments were to begin hiring faculty members primarily by their expertise in particular genres instead of (as is usually the case in the larger departments) primarily by their expertise in particular historical periods. Literary study, I hope you will agree, would very soon cease to exist in its present form. This prospect exposes something about literary study in its present form that might after all prove unworthy of being mourned, which is to say of being preserved.
Oligonucleotide microarray analysis of estrogen receptor α-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen
Authors: Tozlu-Kara S , Roux V , Andrieu C , Vendrell J , Vacher S , Lazar V , Spyratos F , Tubiana-Hulin M , Cohen P , Dessen P , Lidereau R , Bièche I
Published: October 2007

The estrogen receptor α (ERα) status of breast tumors is used to identify patients who may respond to endocrine agents such as tamoxifen. However, ERα status alone is not perfectly predictive, and there is a pressing need for more reliable markers of endocrine responsiveness. In this aim, we used a two-step strategy. We first screened genes of interest by a pangenomic 44 K oligonucleotide microarray in a series of ten ERα-positive tumors from five tamoxifen-treated postmenopausal patients who relapsed (distant metastasis) and five tamoxifen-treated postmenopausal patients who did not relapse, matched with respect to age, Scarff–Bloom–Richardson grade, lymph node status, and macroscopic tumor size. Genes of interest (n=24) were then investigated in an independent well-characterized series of ERα-positive unilateral invasive primary breast tumors from postmenopausal women who received tamoxifen alone as adjuvant hormone therapy after primary surgery. We identified four genes (HRPAP20, TIMELESS, PTPLB, and MGC29814) for which high mRNA levels were significantly associated with shorter relapse-free survival (log-rank test). We also showed that hormone-regulated proliferation-associated 20 kDa protein (HRPAP20) and TIMELESS are 17β-estradiol-regulated in vitro and are ectopically expressed in OH-Tam-resistant cell lines. In conclusion, these findings point to HRPAP20 and TIMELESS as promising markers of tamoxifen resistance in women with ERα-positive breast tumors.
Identification of regulatory elements in the Cyp19 proximal promoter in rat luteal cells
Authors: Stocco Carlos , Kwintkiewicz Jakub , Cai Zailong
Published: October 2007

The cytochrome P450 aromatase (Cyp19) gene encodes an enzyme of crucial importance in the synthesis of estradiol. Estradiol is luteotropic in the rat. In this species, luteal Cyp19 expression increases progressively during pregnancy and falls before parturition. The mechanisms that control these changes are unknown. Using gel shift assays, we sought to identify the promoter regions that control Cyp19 expression in the rat corpus luteum (CL). The Cyp19 promoter contains a cAMP response element-like sequence (CLS), two nuclear receptor elements half sites (NREs), a GATA binding site, a Yin Yang-1 (YY1) response element, and an activation protein 3 (AP3) binding site. Nuclear extracts were obtained from CL of rats on days 4, 15, and 23 of pregnancy and from the ovaries of immature rats treated with vehicle or a hormone that induces Cyp19 expression in the follicles. CLS was active in immature ovaries but inactive in the CL of pregnant rats, whereas binding to NREs and GATA was observed in both tissues. YY1 was inactive in all samples tested. In the CL, AP3 binding was higher on day 15 of pregnancy when compared with day 4 and day 23 but it was absent in ovaries of immature rats, whereas luteinization increased AP3 binding activity. Mutation of the AP3 site blunted the stimulation of Cyp19 promoter activity in granulosa cells. Our results indicate that CLS is active only in follicles; whereas in the CL, binding to the GATA, NRE, and AP3 sites associates with changes in Cyp19 expression, suggesting that they control Cyp19 promoter activity in luteal cells.
Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells
Authors: Ichikawa T , Horie-Inoue K , Ikeda K , Blumberg B , Inoue S
Published: October 2007

Vitamin K is known as a critical nutrient required for bone homeostasis and blood coagulation, and it is clinically used as a therapeutic agent for osteoporosis in Japan. Besides its enzymatic action as a cofactor of vitamin K-dependent γ-glutamyl carboxylase (GGCX), we have previously shown that vitamin K2 is a transcriptional regulator of bone marker genes and extracellular matrix-related genes, by activating the steroid and xenobiotic receptor (SXR). To explore a novel action of vitamin K in osteoblastic cells, we identified genes up-regulated by a vitamin K2 isoform menaquinone-4 (MK-4) using oligonucleotide microarray analysis. Among these up-regulated genes by MK-4, growth differentiation factor 15 (GDF15) and stanniocalcin 2 (STC2) were identified as novel MK-4 target genes independent of GGCX and SXR pathways in human and mouse osteoblastic cells. The induction of GDF15 and STC2 is likely specific to MK-4, as it was not exerted by another vitamin K2 isoform MK-7, vitamin K1, or the MK-4 side chain structure geranylgeraniol. Investigation of the involved signaling pathways revealed that MK-4 enhanced the phosphorylation of protein kinase A (PKA), and the MK-4-dependent induction of both GDF15 and STC2 genes was reduced by the treatment with a PKA inhibitor H89 or siRNA against PKA. These results suggest that vitamin K2 modulates its target gene expression in osteoblastic cells through the PKA-dependent mechanism, which may be distinct from the previously known vitamin K signaling pathways.
Recurrence of the p.R277X/p.R1511X compound heterozygous mutation in the thyroglobulin gene in unrelated families with congenital goiter and hypothyroidism: haplotype analysis using intragenic thyroglobulin polymorphisms
Authors: Caputo Mariela , Rivolta Carina M , Gutnisky Viviana J , Gruñeiro-Papendieck Laura , Chiesa Ana , Medeiros-Neto Geraldo , González-Sarmiento Rogelio , Targovnik Héctor M
Published: October 2007

Thyroglobulin (TG) functions as the matrix for thyroid hormone synthesis. Thirty-five different loss-of-function mutations in the TG gene have been reported. These mutations are transmitted in an autosomal recessive mode. The objective of this study is to analyze the recurrence of the p.R277X/p.R1511X compound heterozygous mutation in the TG gene in two unrelated families (one Argentinian and another Brazilian) with congenital hypothyroidism, goiter and impairment of TG synthesis. The first and last exon of the TG gene, the exons where previously mutations and single nucleotide polymorphisms (SNPs) were detected, as well as the TG promoter, were analyzed by automatic sequencing in one affected member of the each family. Four microsatellite markers localized in introns 10, 27, 29 and 30 of the TG gene, one insertion/deletion intragenic polymorphism and 15 exonic SNPs were used for haplotype analysis. A p.R277X/p.R1511 compound heterozygous mutation in the TG gene was found in two members of an Argentinian family. The same mutations had been also reported previously in two members of a Brazilian family. We constructed mutation-associated haplotypes by genotyping members of the two families. Our results suggest that the cosegregating haplotype is different in each one of these families. Different haplotypes segregated with the p.R277X and p.R1511 mutations demonstrating the absence of a founder effect for these mutations between Argentinian and Brazilian populations. However, haplotyping of Argentinian patients showed the possibility that the p.R277X alleles might be derived from a common ancestral chromosome.
Antibody-induced modulation of TSH receptor post-translational processing
Authors: Ando Takao , Latif Rauf , Davies Terry F
Published: October 2007

The post-translational processing of the TSH receptor (TSHR) includes intra-molecular cleavage with the loss of a 50 amino acid ectodomain region and the formation of two subunits (α and β), followed by likely α subunit shedding. TSHR antibodies (TSHR-Abs), which are directed at the ectodomain, may influence thyroid function by stimulating or inhibiting TSHR signaling or may bind without any such influence (the neutral group of antibodies). When we examined the characteristics of a series of monoclonal TSHR-Abs, we found that many were able to inhibit receptor cleavage and enhance TSHR expression. This was especially apparent with the neutral type of TSHR-Abs directed to the cleaved region of the ectodomain (aa 316–366). Indeed, such inhibition appeared to be epitope dependent with TSHR-Abs directed to regions after residues 335–354 showing no such activity. We propose that this aberrant process, whereby TSHR-Abs influence antigen processing, is a novel mechanism for the maintenance and exacerbation of autoimmune thyroid disease.
Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes
Authors: Crescioli C , Cosmi L , Borgogni E , Santarlasci V , Gelmini S , Sottili M , Sarchielli E , Mazzinghi B , Francalanci M , Pezzatini A , Perigli G , Vannelli G B , Annunziato F , Serio M
Published: October 2007

CXC chemokine ligand 10 (CXCL10) plays a pivotal role in the self-perpetuation of the inflammatory processes in patients with autoimmune thyroid disease. Treatment with methimazole (MMI) reduces serum CXCL10 in patients with Graves’ disease. In isolated human thyrocytes, tumor necrosis factor (TNF)α demonstrates a potent synergistic effect on interferon (IFN)γ-induced CXCL10 secretion. We investigated the mechanism underlying the synergism between IFNγ and TNFα and the effect of MMI on CXCL10 secretion in human thyrocytes. A peroxisome proliferator-activated receptor γ agonist, rosiglitazone (RGZ), a known inhibitor of T helper 1 (Th1)-mediated responses, was also studied for comparison. Experiments were carried out in human thyrocytes isolated from internodular parenchyma of thyroid tissues derived from patients who had undergone surgery for multinodular goiter. ELISA was used to measure CXCL10 levels in culture supernatant. Flow cytometry was used to assess IFNγ membrane receptor expression. Specific mRNA analysis was performed by Taqman real-time PCR. Immunofluorescence was performed to detect nuclear translocation of nuclear factor-κB (NF-κB). In human thyrocytes, the synergistic effect of TNFα with IFNγ on CXCL10 secretion is due to the upregulation of IFNγ receptor expression. MMI decreased cytokine-induced CXCL10 secretion by reducing TNFα-induced upregulation of the IFNγ receptor. RGZ decreased the cytokine-induced CXCL10 secretion by impairing NF-κB translocation, without affecting IFNγ receptor. MMI and RGZ targeted thyrocytes with the same pharmacological potency, likely acting throughout different mechanisms. Targeting T helper 1-mediated autoimmune thyroid disease with drugs that impair different intracellular pathways could be a novel pharmacological tool.
Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor
Authors: Renlund Nina , O’Neill Francis H , Zhang LiHua , Sidis Yisrael , Teixeira Jose
Published: October 2007

Activin receptor-like kinase-2 (Alk2) has been shown to be a promiscuous type I receptor for the transforming growth factor β (TGFβ) family of growth and differentiation factors, such as activin, bone morphogenetic proteins, and Müllerian inhibiting substance (MIS). We have studied the putative role of Alk2 in activin signaling using MA-10 cells, a mouse transformed Leydig cell line, in which endogenous expression of cytochrome P450 c17 hydroxylase/C17–20 lyase mRNA is inhibited by both MIS and activin A. Overexpression of Alk2 in MA-10 cells inhibited the activation of the activin-responsive CAGA-luciferase reporter and, conversely, transfection of siRNA for Alk2 increased the response. In contrast, overexpression of the MIS type II receptor in MA-10 cells increased the activin-mediated induction of CAGA-luciferase approximately fivefold, which we hypothesized occurs by MIS type II receptor sequestering endogenous Alk2. Binding experiments with 125I-labeled activin show that the underlying mechanism of Alk2-mediated inhibition of activin signaling involves Alk2 blocking the access of activin to its type II receptor, which we show can bind Alk2 in the absence of ligand. These results show that the complement of other type I receptors in addition to the ligand-specific type I receptor can provide an important mechanism for modulating cell-specific responses to members of the TGFβ family.
Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic β-cell line
Authors: Kiely Aoife , McClenaghan Neville H , Flatt Peter R , Newsholme Philip
Published: October 2007

We have investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines on β-cell metabolism and insulin secretion using clonal BRIN-BD11 β cells. Addition of IL-1β, tumour necrosis factor-α and IFN-γ (at concentrations that did not induce apoptosis) inhibited chronic (24 h) and acute stimulated levels of insulin release (by 59 and 93% respectively), increased cellular glucose and alanine consumption, and also elevated lactate and glutamate release. However, ATP levels and cellular triacylglycerol were decreased while glutathione was increased. We conclude that sub-lethal concentrations of pro-inflammatory cytokines appear to shift β-cell metabolism away from a key role in energy generation and stimulus–secretion coupling and towards a catabolic state which may be related to cell defence.
Diamonds are forever: the cortisone legacy
Authors: Hillier Stephen G
Published: October 2007

The year 1946 was not only the year that the Society for Endocrinology was founded, but also the year that Edward Kendall’s compound E (cortisone) was first synthesised by Louis Sarett. By 1948, sufficient quantities of compound E were available for the rheumatologist Philip Hench to test it successfully for the first time in a patient with rheumatoid arthritis. It was immediately hailed as a ‘wonder drug’ and was shown to be effective in a number of inflammation-associated conditions, most notably rheumatoid arthritis. The subsequent development of endocrinology as a discipline is inextricably linked to the chemistry, biology and medicine of antiinflammatory glucocorticoids. Sixty years after the first chemical synthesis of cortisone, corticosteroids remain among the top ten most commonly used prescription and over the counter drugs. Basic and clinical studies of glucocorticoid biosynthesis, metabolism and action have trail-blazed developments in endocrinology ever since. This article surveys the extraordinary cortisone timeline, from first synthesis until now. The concluding scientific message is that intracrine metabolism of cortisone to cortisol via 11βhydroxysteroid dehydrogenase type 1 likely sustains local amplification of glucocorticoid action at sites of inflammation throughout the body. The broader message is that the discovery of compound E by Kendall (basic scientist), its large-scale synthesis by Sarett (industrial chemist) and its therapeutic application by Hench (rheumatologist) serves as a paradigm for modern translational medicine. It is concluded that endocrinology will remain a force in health and disease if it continues to evolve sans frontières at the basic/applied/clinical science interface. A challenge for the Society for Endocrinology is to ensure this happens.
UNDERAPPRECIATED SPECIES IN ECOLOGY: “UGLY FISH” IN THE NORTHWEST ATLANTIC OCEAN
Authors: Link Jason S.
Published: October 2007

Species shifts and replacements are common in ecological studies. Observations thereof serve as the impetus for many ecological endeavors. Many of the species now known to dominate ecosystem functioning were largely ignored until studies of those underappreciated species elucidated their critical roles. Recognizing the potential importance of underappreciated species has implications for functional redundancies in ecosystems and should alter our approach to long‐term monitoring. One example of an applied ecological system containing species shifts, underappreciated species, and potential changes in functional redundancies is the topic of fisheries. The demersal component of many fish communities usually consists of high‐profile and commercially valuable species that are targets of fisheries, plus a diverse group of lesser known species that have minimal commercial value and focus. Yet ecologically these traditionally nontargeted species are often a major biomass sink in marine ecosystems and can also be critical in the functioning of bentho‐demersal food webs. I examined the biomass trajectories of several species of skates, cottids, lophiids, anarhichadids, zooarcids, and similar species in the northeast U.S. Atlantic ecosystem to determine whether their relative abundance has changed across the past four decades. Distribution and stomach contents of these species were also evaluated over time to further elucidate the relative importance of these species. Landings of these underappreciated bentho‐demersal fish were also examined in comparison to those species that historically have been commercially targeted. Of particular emphasis was the evaluation of evidence for sequential stock depletion and the ramifications for functional redundancy for this ecosystem. Results indicate that some of these fish species are now the dominant piscivores, benthivores, and scavengers in this ecosystem. These formerly under‐studied species generally have either maintained a consistent population size or have increased in abundance (and expanded in distribution) over the past several decades. Nontraditionally targeted fish species are an often overlooked but important component of bentho‐demersal fish communities. Implications for the energy flow and resilience specifically for future fisheries and generally for harvesting biological resources are significant, remaining critical issues for the world's ecosystems.
FLOW REGULATION AND FRAGMENTATION IMPERIL PELAGIC‐SPAWNING RIVERINE FISHES
Authors: Dudley Robert K. , Platania Steven P.
Published: October 2007

Flow regulation and fragmentation of the world's rivers threaten the integrity of freshwater ecosystems and have resulted in the loss or decline of numerous fish species. Pelagic‐spawning fishes (pelagophils) are thought to be particularly susceptible to river regulation because their early life stages (ichthyoplankton) drift until becoming free‐swimming, although the extent of transport is largely unknown. Transport velocity and distance were determined for passively drifting particles, which mimicked physical properties of ichthyoplankton, in two large, regulated rivers (Rio Grande and Pecos River) of the arid Southwest United States. Particle drift data were incorporated into celerity–discharge equations (r2 > 0.90; P < 0.001), and reach‐specific transport velocity was modeled as a function of discharge. Transport velocities of particles exceeded 0.7 m/s in all river reaches during typical spawning flows (i.e., reservoir releases or rainstorms) and were greatest in highly incised and narrow channel reaches. Mean transport distance of particles released in the Pecos River during sustained reservoir flows (141.1 km; 95% CI = 117.0–177.5 km) was significantly longer than during declining reservoir flows that mimicked a natural rainstorm (52.4 km; 95% CI = 48.8–56.5 km). Mean transport distance of particles in the Rio Grande during sustained reservoir flows was 138.7 km (95% CI = 131.0–147.2 km). There are 68 dams and 13 reservoirs that fragment habitats and regulate flow in the Rio Grande Basin (Rio Grande and Pecos River) in areas historically occupied by pelagophils. While the basin historically provided 4029 km of free‐flowing riverine habitat, reservoir habitat now represents >10% of the longitudinal distance. Only five unfragmented nonreservoir reaches >100 km remain in the Rio Grande, and two remain in the Pecos River. Pelagophils were extirpated from all reservoirs and from nearly all short, fragmented reaches (<100 km) of the Rio Grande Basin, but at least some fraction persisted in all longer reaches (>100 km). The recovery and long‐term persistence of pelagophils in regulated rivers, including those in this study, will likely depend on reestablishment and protection of long unfragmented reaches coupled with mimicry of the natural flow regime.
AMMONIA MODELING FOR ASSESSING POTENTIAL TOXICITY TO FISH SPECIES IN THE RIO GRANDE, 1989–2002
Authors: Passell Howard D. , Dahm Clifford N. , Bedrick Edward J.
Published: October 2007

Increasing volumes of treated and untreated human sewage discharged into rivers around the world are likely to be leading to high aquatic concentrations of toxic, un‐ionized ammonia (NH3), with negative impacts on species and ecosystems. Tools and approaches are needed for assessing the dynamics of NH3. This paper describes a modeling approach for first‐order assessment of potential NH3 toxicity in urban rivers. In this study daily dissolved NH3 concentrations in the Rio Grande of central New Mexico, USA, at the city of Albuquerque's treated sewage outfall were modeled for 1989–2002. Data for ammonium (NH4+) concentrations in the sewage and data for discharge, temperature, and pH for both sewage effluent and the river were used. We used State of New Mexico acute and chronic NH3‐N concentration values (0.30 and 0.05 mg/L NH3‐N, respectively) and other reported standards as benchmarks for determining NH3 toxicity in the river and for assessing potential impact on population dynamics for fish species. A critical species of concern is the Rio Grande silvery minnow (Hybognathus amarus), an endangered species in the river near Albuquerque. Results show that NH3 concentrations matched or exceeded acute levels 13%, 3%, and 4% of the time in 1989, 1991, and 1992, respectively. Modeled NH3 concentrations matched or exceeded chronic values 97%, 74%, 78%, and 11% of the time in 1989, 1991, 1992, and 1997, respectively. Exceedences ranged from 0% to 1% in later years after enhancements to the wastewater treatment plant. Modeled NH3 concentrations may differ from actual concentrations because of NH3 and NH4+ loss terms and additive terms such as mixing processes, volatilization, nitrification, sorbtion, and NH4+ uptake. We conclude that NH3 toxicity must be considered seriously for its potential ecological impacts on the Rio Grande and as a mechanism contributing to the decline of the Rio Grande fish community in general and the Rio Grande silvery minnow specifically. Conclusions drawn for the Rio Grande suggest that NH3 concentrations may be high in rivers around the world where alkaline pH values are prevalent and sewage treatment capabilities are poorly developed or absent.
QUANTITATIVE THREAT ANALYSIS FOR MANAGEMENT OF AN IMPERILED SPECIES: CHINOOK SALMON (ONCORHYNCHUS TSHAWYTSCHA)
Authors: Hoekstra Jonathan M. , Bartz Krista K. , Ruckelshaus Mary H. , Moslemi Jennifer M. , Harms Tamara K.
Published: October 2007

Chinook salmon (Oncorhynchus tshawytscha) have declined dramatically across the Pacific Northwest because of multiple human impacts colloquially characterized as the four “H's”: habitat degradation, harvest, hydroelectric and other dams, and hatchery production. We use this conceptual framework to quantify the relative importance of major threats to the current status of 201 Chinook populations. Current status is characterized by two demographic indices: population density and trend. We employ path analytic models and information theoretic methods for multi‐model inference. Our results indicate that dams most strongly affect variation in population density, while harvest and hatchery production most strongly affect variation in population trend. Comparable results arise when the sample size of the analysis is reduced to 22 Chinook populations within a smaller region typical of the scale at which salmon recovery planning is conducted. Results from these threat analyses suggest that recovery strategies targeting specific demographic indices, and those considering natural and human‐mediated interdependencies of major threats, are most likely to succeed.