bluuebunny/crossref_metadata_2025 huggingface dataset:
Identity Dynamics in Occupational Dirty Work: Integrating Social Identity and System Justification Perspectives
Authors: Kreiner Glen E. , Ashforth Blake E. , Sluss David M.
Published: September 2006

Ashforth and Kreiner (1999) documented how workers in so-called “dirty work” occupations were able to overcome threats to their social identities by engaging in the cognitive tactics of ideology manipulation and social weighting. This paper expands Ashforth and Kreiner’s work in three ways. First, we move beyond an exclusive focus on intense dirty work occupations by mapping the broader landscape of stigmatized work. Second, we examine how system justification theory and social identity theory—typically cast as competing mechanisms by which individuals and groups perceive their places in a social structure—can complement each other to tell a more complete story of how individuals and groups deal with stigmatized identities. Third, we consider how stigmatized workers experience identification, disidentification, and ambivalence as a result of conflicting occupational and societal influences.
Gallium‐67 scanning in patients with head and neck cancer
Authors: Kashima Haskins K. , Mckusick Kenneth A. , Malmud Leon S. , Wagner Henry N.
Published: September 2006

This study was undertaken to evaluate the use of Gallium‐67 scanning in the management of patients with malignancies in the head and neck region. The principal findings are: 1. Gallium‐67 accumulates preferentially in the lacrimal and salivary glands in a high proportion of cases and, almost invariably, in the mid‐facial zone; 2. the uptake by the lacrimal and salivary glands is permanently enhanced by prior radiation therapy; 3. tumor identification is reliable, providing that the tumor focus measures at least 2 centimeters in diameter; 4. non‐specific inflammation also accumulates this isotope; and 5. tissue analysis reveals consistently elevated Gallium‐67 concentration in tumor. These characteristics of Gallium‐67 may lead to its eventual useful role in the evaluation of patients with head and neck cancers.
Actinomycosis masquerading as depression headache: Case report — management review of sinus actinomycosis
Authors: Per‐Lee John H. , Clairmont Albert A. , Hoffman James C. , McKinney Alexander S. , Schwarzmann Stephen W.
Published: September 2006

Differentiating an organic from a functional headache can be difficult; recognizing the unusual organic cause even more so. A unique case of actinomycosis centering on the clivus and sphenoid sinus is presented. This report reviews the history, diagnosis, and treatment of actinomycosis especially as they pertain to otolaryngology.
Papillomas of the larynx and pharynx: Two case reports
Authors: Wallenborn Peter A.
Published: September 2006

Two unusual cases of papillomas are presented: the first is that of a young boy with extensive papillomas of the larynx who was treated successfully without tracheotomy using endolaryngeal surgery and steroids at the time of each procedure. This case adds to the clinical evidence that the most probable cause of juvenile papillomas is a virus, since the mother had condyloma acuminata during pregnancy and at term.

The second case is that of a young girl with rapidly recurring papillomas of the mouth and pharynx who was treated successfully with an autogenous vaccine and cryosurgery after other measures failed. This case demonstrates the effectiveness of cryosurgery in the treatment of papillomas and the possible efficacy of the autogenous vaccine suggests a viral etiology for papillomas of the pharynx and larynx.
Current adjuncts for surgery of the sphenoid sinus and pituitary gland
Authors: Calcaterra Thomas C. , Rand Robert W.
Published: September 2006

Surgical intervention in the region of the sphenoid sinus pituitary gland requires extreme precision because of enveloping vital structures. The rhinologic approach to the pituitary gland, once abandoned due to limited visibility and the risk of meningitis, has experienced a renaissance as a result of recent medical and technical advances. Antibiotics have almost eliminated the risk of meningitis, and the operating microscope and televised radiofluoroscope now provide sufficient illumination, magnification, and orientation that injury to nearby structures can be avoided. A mid‐line rhinologic approach provides ample exposure and further minimizes operative hazards.
Nasal obstruction caused by a pituitary chromophobe adenoma
Authors: Summers Gordon W.
Published: September 2006

Nasal obstruction as the only clinical manifestation of a pituitary tumor is rare. A case is reported of a 58‐year‐old white male with obstruction of the nose and nasopharynx due to a massive pituitary tumor, which recurred 21 years after primary radiation treatment. At autopsy, extensive destruction of the sphenoid and base of the skull was noted. Final pathologic diagnosis was Chromophobe Adenoma. Common clinical features of chro‐mophobe adenomas are discussed.
Dermal grafts: An alternative technique
Authors: Schaffer Robert I.
Published: September 2006

The drum dermatome technique for obtaining dermal grafts is described. Results using this technique are equivalent to conventional methods using a mechanical dermatome.
Implantation of multiple intracochlear electrodes for rehabilitation of total deafness: Preliminary report
Authors: Chouard Claude H. , Macleod Patrick
Published: September 2006

Many instances of total deafness are due to destruction of the organ of Corti but with partial or complete preservation of the function of the cochlear nerve. In such cases, it is possible to restore some hearing by electrically stimulating the fibers of the cochlear nerve with the help of implanted electrodes.

Preoperative testing with electric shocks applied to the round window have aroused sensations of noise in 45 cases of total bilateral deafness with a great variety of etiologies. The only negative results were in two cases of operated acoustic neuromas.

Our operation places up to eight intracochlear electrodes, each with a separate fenestration opening into an electrically isolated compartment of the scala tympani. Stimulation of each electrode yields a different sound sensation of a pitch that depends on its location along the cochlea. Electric filters direct different frequency bands to the appropriate electrodes, with the necessary compression of dynamic range.

In three experimental cases of unilateral deafness, pitch matches to the normal ear were made. In seven therapeutic operations on adult cases of acquired total bilateral deafness, speech recognition was usually relearned within a month or two. Improvement of voice quality was also dramatic.

The intracochlear electrodes have been well tolerated for months, but the method of connection to the external equipment still presents difficulties.
Histiocytic medullary reticulosis with involvement of the nose
Authors: Mogi Goro , Maeda Shoichi , Yoshida Toyoharu
Published: September 2006

A case of histiocytic medullary reticulosis in which nasal involvement was predominant is reported. The patient was a 33‐year‐old woman with a 14‐month history of unilateral nasal stuffiness. The diagnosis was established by antemortem examination of films of bone marrow aspirates and by clinical features including fever, wasting, hepatosplenomegaly, anemia, and leukopenia. The histologic examination of autopsy specimens disclosed proliferation of histiocytes, which ingested nuclear debris and erythrocytes, in the necrotic lesion of the nose, sternal bone marrow, liver, spleen, thymus, uterus, ovali, and ileum. On reviewing literature on this subject, such a case of histiocytic medullary reticulosis which predominantly involves the nose is very rare.
Neue Methoden für die dynamische Identifikation mit Neuro-Fuzzy Netzen (New Methods for Dynamic Identification with Neuro-Fuzzy Networks)
Authors: Jakubek Stefan , Hametner Christoph , Keuth Nikolaus , Voigt Andreas
Published: September 2006

Dieser Artikel behandelt die Identifikation nichtlinearer dynamischer Prozesse mit lokalen Neuro-Fuzzy Netzen. Diese bieten den Vorteil, dass aufgrund ihrer Architektur die Möglichkeit besteht, Prozesswissen bei der Modellbildung mit einzubinden. Es werden Lösungsansätze für zwei wesentliche Problemstellungen der dynamischen Identifikation präsentiert: Einerseits wird die Problematik verrauschter Ein- und Ausgangsdaten behandelt, die bei der Parameterbestimmung mit herkömmlichen Regressionsmethoden zu biasbehafteten Resultaten führt. Als Lösungsweg wird die Total Least Squares Methode vorgestellt, und für die Anwendung in lokalen Neuro-Fuzzy Netzen adaptiert. Andererseits wird eine Methode vorgestellt, mit der die Einhaltung von Stationärpunkten erzwungen werden kann, was wesentlich zur Verbesserung der stationären Genauigkeit des Modells beiträgt. Resultate aus einem Praxisbeispiel illustrieren die Anwendbarkeit beider Konzepte.
Fehlerkompensation in dynamisch verteilten Systemen (Error Compensation in Dynamically Distributed Systems)
Authors: Kiencke Uwe , Brummund Stephan
Published: September 2006

In diesem Beitrag wird die Fehlerkompensation in dynamisch verteilten Systemen behandelt. Diese Systeme besitzen den Vorteil der räumlichen und funktionalen Trennung von Informationsgewinnung, -verarbeitung und -speicherung. Dabei bestehen die Systeme aus einzelnen Einheiten, welche zwar unabhängig voneinander arbeiten, aber über ihren Informationsaustausch dennoch gemeinsame Aufgaben ausführen. In derzeitigen Kraftfahrzeugen befinden sich bereits bis zu 70 ECUs (Electronic Control Units), die sowohl für Aufgaben der Fahrdynamikregelung als auch der Navigation eingesetzt werden. In Zukunft werden Systeme wie X-by-wire nicht nur die Anzahl dieser ECUs erhöhen, sondern auch die Forderung nach Zuverlässigkeit und Sicherheit. Ein Lösungsansatz ist die dynamische Funktionsverlagerung während des Echtzeitbetriebs. In diesem Beitrag wird diese Methode der Fehlerkompensation mit Hilfe der Max-Plus-Algebra in Echtzeit realisiert. Um allerdings die verlagerte Softwarefunktion auf den jeweiligen Steuergeräten ausführen zu können, basiert dieser Ansatz auf der Annahme zusätzlicher Kapazität (Speicher, Rechenzeit) in den einzelnen Steuergeräten. Dieser zusätzliche Aufwand ist jedoch geringer als im Falle klassischer Redundanzkonzepte.
Neue Anwendungen der Nanomessmaschine (NPM-Maschine) durch die Entwicklung nanoskaliger optischer und taktiler Tastsensoren (New Applications of the Nanomeasuring Machine (NPM-Machine) by Novel Optical and Tactile Probes with Subnanometer Repeatability)
Authors: Jäger Gerd , Manske Eberhard , Hausotte Tino
Published: September 2006

Der vorliegende Beitrag beschreibt neue Anwendungen der Nanomessmaschine des Institutes für Prozessmess- und Sensortechnik der TU Ilmenau. Die neuen Anwendungen in der Mikro- und Nanotechnik resultieren aus der Entwicklung von nanoskaligen Tastsensoren, die in der Nanomessmaschine nur als Nullindikatoren eingesetzt werden. Entwickelt und erprobt wurden: Fokussensor mit 10 mm Arbeitsabstand, Weißlichtinterferenzsensor, taktiler Tastschnittsensor und Rastersondenmikroskop mit Fokussensor. Gegenwärtig wird ein taktiler 3D-Taster der Fa. IBS Precision Engineering in die Nanomessmaschine eingebunden.
Messunsicherheitsanalyse von Nanopositionier- und Nanomessmaschinen mit Hilfe eines neuen vektoriellen Modellansatzes (Analysis of the Measurement Uncertainties of Nanopositioning and Nanomeasuring Machines (NPM-Machines) by Means of a New Vectorial Model Approach)
Authors: Füßl Roland , Grünwald Rainer , Schmidt Ingomar
Published: September 2006

Nanopositionier- und Nanomessmaschinen (NPM-Maschinen) sind technologische Ausrüstungen, die die Positionierung, Antastung und Messung von zentimetergroßen Objekten mit Nanometerpräzision ermöglichen. Die Ausgabe von Messergebnissen erfordert die Angabe von Messunsicherheiten. Der vorliegende Artikel beschreibt ein neuartiges modulares Konzept zur Erstellung von Mess-unsicherheitsbudgets für NPM-Maschinen auf der Basis eines vektoriellen metrologischen Modells.
Materials, Bearings, and Lubricants for Nanopositioning (Materialien, Lager und Schmiermittel für Nanopositionierung)
Authors: Liu Yonghe , Schaefer Juergen A. , Jäger Gerd
Published: September 2006

Most friction models for automatic control are targeted for the macro world, and are of questionable value for the motion control of the nanopositioning and nanomeasuring machine (NPM) system. We present the frictional behaviour of some selected materials, coatings, lubricants, and bearings tested under running conditions similar to a NPM system. Continuous change of surface properties results in various friction characteristics, which substantiate the further development of tribological coatings, particularly for vacuum applications. We emphasize the system engineering approach in developing friction models, which combines fundamental knowledge of surface science, materials science, and its applications in design, construction and automatic control.
Nanometrologie in zweieinhalb Dimensionen: Entwicklung einer Nanometer-Koordinaten-Messmaschine mit rasterkraftmikroskopischer Antastung (Nanometrology in Two and a Half Dimensions: Development of a Nanometer Coordinate Measuring Machine with Atomic Force Scanning)
Authors: Rothe Hendrik , Gruhlke Martin , Petersen Ralph
Published: September 2006

Dieser Artikel beschreibt die Entwicklung einer Nanometer-Koordinaten-Messmaschine (NCMM) mit rasterkraftmikroskopischer Antastung für großflächige Messungen in zweieinhalb Dimensionen. Es wird der Systemaufbau aus einem Positioniersystem und einem Rasterkraftmikroskop vorgestellt und es werden Maßnahmen bezüglich Reduzierung von Messunsicherheiten, Verkürzung der Messdauer und Verbesserung der Bedienbarkeit aufgezeigt.
Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern
Authors: Pérez-Palacios Gregorio , Santillán René , García-Becerra Rocío , Borja-Cacho Elizabeth , Larrea Fernando , Damián-Matsumura Pablo , González Leticia , Lemus Ana E
Published: September 2006

Breast cancer is a sex steroid hormone-dependent malignant neoplasia. The role of oestradiol in this malignancy has been well documented; however, the involvement of androgens has remained controversial. To determine the role of non-phenolic androgen metabolites in human breast cancer, we studied the metabolism of [14C] testosterone and [14C] androstenedione in oestrogen-dependent MCF-7 cells and non-oestrogen-dependent MDA-MB 231 cells, at different substrate concentrations (1–10 μM) and time periods (30 min–48 h). Cultured non-oestrogen-dependent HeLa and yeast cells served as controls. Metabolites were identified and quantified by reverse isotope dilution. A distinctive pattern of androgen metabolism was identified in MCF-7 cells, being the 5α-androstane-3α,17β-diol (3α,5α-diol) and its 3β epimer (3β,5α-diol), the major conversion products of testosterone (48.3%), with 5α-dihydrotestosterone as intermediary. The formation of 3α,5α-diol and 3β,5α-diol (diols) was substrate concentration- and time-dependent, and abolished by finasteride. In contrast, very little of any diol formation was observed in MDA-MB 231, HeLa and yeast cell incubations. Additional enzyme gene expression studies revealed an overexpression of 5α-steroid reductase type-1 in MCF-7 cells, as compared with MDA-MB 231 cells. The oestrogen-like activities of diols were assessed in HeLa cells co-transfected with expression vectors for α or β subtypes of the human oestrogen receptor (hER) genes and for an oestrogen-responsive reporter gene. The results show that 3β, 5α-diol and to a lesser extent 3α,5α-diol bind with high relative affinity to hERα and hERβ.

Both diols induced hER-mediated reporter gene transactivation in a dose–response manner, similar to that induced by oestradiol, though with lower potency, an effect that was abolished by ICI-182 780. Furthermore, 3β,5α-diol and to lesser extent 3α,5α-diol induced MCF-7 cell proliferation. The overall results demonstrated that MCF-7 cells exhibit enhanced expression and activity of androgen-metabolising enzymes, leading to rapid and large diol formation, and provide evidence that these androgen metabolites exert a potent oestrogen-agonistic effect, at genomic level, in oestrogen-dependent breast cancer cells. The data suggest that diols may act as in situ intracrine factors in breast cancer and that its formation can be pharmacologically inhibited.
Oral administration of glucose promotes intracellular partitioning of fatty acid toward storage in white but not in red muscle
Authors: Fosgerau Keld , Fledelius Christian , Pedersen Kent E , Kristensen Jesper B , Daugaard Jens R , Iglesias Miguel A , Kraegen Edward W , Furler Stuart M
Published: September 2006

Lipid accumulation in non-adipose tissues is strongly associated with the metabolic syndrome, possibly due to aberrant partitioning of intracellular fatty acids between storage and oxidation. In the present study, we administered the non-metabolizable fatty acid analog [9,10-3H]-(R)-2-bromopalmitate, and authentic 14C-palmitate to conscious rats, in order to directly examine the initial intracellular fate of fatty acids in a range of insulin-sensitive tissues, including white and red muscles, liver, white adipose tissue, and heart. Rats were studied after administration of an oral glucose load to examine the effect of physiological elevation of glucose and insulin. The tracer results showed that glucose administration partitioned fatty acid toward storage in white muscle (storage:uptake ratios, vehicle vs glucose; 0.64 ± 0.02 vs 0.92 ± 0.09, P < 0.05), and in liver (0.66 ± 0.07 vs 0.98 ± 0.04, P < 0.05), but not in red muscle (1.18 ± 0.07 vs 1.36 ± 0.11, P = not significant). These results demonstrate the physiological relevance of the so-called ‘reverse’ Randle cycle, but surprisingly show that it may be more important in white rather than oxidative red muscle.
Insulin resistance and increased pancreatic β-cell proliferation in mice expressing a mutant insulin receptor (P1195L)
Authors: Ogino J , Sakurai K , Yoshiwara K , Suzuki Yoichi , Ishizuka N , Seki N , Suzuki Yoshifumi , Koseki H , Shirasawa T , Hashimoto N , Yagui K , Saito Y
Published: September 2006

Several mutations of the tyrosine kinase domain of insulin receptor (IR) have been clinically reported to lead insulin resistance and insulin hypersecretion in humans. However, it has not been completely clarified how insulin resistance and pancreatic β-cell function affect each other under the expression of mutant IR. We investigated the response of pancreatic β-cells in mice carrying a mutation (P1195L) in the tyrosine kinase domain of IR β-subunit. Homozygous (IrP1195L/P1195L) mice showed severe ketoacidosis and died within 2 days after birth, and heterozygous (IrP1195L/wt) mice showed normal levels of plasma glucose, but high levels of plasma insulin in the fasted state and after glucose loading, and a reduced response of plasma glucose lowering effect to exogenously administered insulin compared with wild type (Irwt/wt) mice. There were no differences in the insulin receptor substrate (IRS)-2 expression and its phosphorylation levels in the liver between IrP1195L/wt and Irwt/wt mice, both before and after insulin injection. This result may indicate that IRS-2 signaling is not changed in IrP1195L/wt mice. The β-cell mass increased due to the increased numbers of β-cells in IrP1195L/wt mice. More proliferative β-cells were observed in IrP1195L/wt mice, but the number of apoptotic β-cells was almost the same as that in Irwt/wt mice, even after streptozotocin treatment. These data suggest that, in IrP1195L/wt mice, normal levels of plasma glucose were maintained due to high levels of plasma insulin resulting from increased numbers of β-cells, which in turn was due to increased β-cell proliferation rather than decreased β-cell apoptosis.
A complex containing α6β1-integrin and phosphorylated focal adhesion kinase between Sertoli cells and elongated spermatids during spermatid release from the seminiferous epithelium
Authors: Beardsley Amanda , Robertson David M , O’Donnell Liza
Published: September 2006

Spermiation is the final step of spermatogenesis and culminates in the disengagement (release) of elongated spermatids from Sertoli cells into the seminiferous tubule lumen. Spermiation failure, wherein spermatids are retained by Sertoli cells instead of releasing, occurs after hormone suppression. The mechanisms involved in spermatid disengagement and retention are not well understood. We previously showed that β1-integrin is associated with spermatids until the point of disengagement, but the ectoplasmic specialisation junction (ES) is not. The aims of this paper are to further characterise the complex that is present immediately prior to spermatid disengagement by identifying the α-integrin form dimerised with β1-integrin, localising focal adhesion kinase (FAK) and determining if microtubules are involved. Adult Sprague–Dawley rats received testosterone and oestradiol implants and an FSH antibody for 7 days to suppress testicular testosterone and FSH and induce spermiation failure. Control rats were treated with saline. Immunohistochemical analysis showed that α6-integrin and a phosphorylated form of FAK (FAK-Tyr397) are present between late spermatids and Sertoli cells after ES removal, until the point of disengagement, and both proteins remain associated with retained spermatids after spermiation failure induced by hormone suppression. Using dual-label immunofluorescence, tubulins (and thus microtubules) were observed to co-localise with ES, but were neither associated with elongated spermatids just prior to release nor with retained spermatids following hormone suppression. These results suggest that microtubules are not involved in the final release of spermatids from Sertoli cells. We conclude that spermatid release during spermiation is mediated by a ‘disengagement complex’ containing α6β1-integrin and phospho-FAK, the function of which can be affected by gonadotrophin suppression.
Glutamine regulates expression of key transcription factor, signal transduction, metabolic gene, and protein expression in a clonal pancreatic β-cell line
Authors: Corless Mary , Kiely Aoife , McClenaghan Neville H , Flatt Peter R , Newsholme Philip
Published: September 2006

We have investigated the effects of prolonged exposure (24 h) to the amino acid l-glutamine, on gene and protein expression using clonal BRIN-BD11 β-cells. Expression profiling of BRIN-BD11 cells was performed using oligonucleotide microarray analysis. Culture for 24 h with 10 mM l-glutamine compared with 1 mM resulted in substantial changes in gene expression with 148 genes upregulated more than 1.8-fold, and 18 downregulated more than 1.8-fold, including many genes involved in cellular signaling, metabolism, gene regulation, and the insulin-secretory response. Subsequent functional experiments confirmed that l-glutamine increased the activity of the Ca2+ regulated phosphatase calcineurin and the transcription factor Pdx1. Additionally, we demonstrated that β-cell-derived l-glutamate was released into the extracellular medium at high rates. As calcineurin is a regulator of the glutamate N-methyl-d-aspartate (NMDA) receptor activity, we investigated the action of NMDA on nutrient-induced insulin secretion, and demonstrated suppressed insulin release. These observations indicate important long-term effects of l-glutamine in regulating β-cell gene expression, signaling, and secretory function.
Developmental and hormonal regulation of progesterone receptor A-form expression in female mouse lung in vivo: interaction with glucocorticoid receptors
Authors: Shao Ruijin , Egecioglu Emil , Weijdegård Birgitta , Ljungström Karin , Ling Charlotte , Fernandez-Rodriguez Julia , Billig Håkan
Published: September 2006

Progesterone (P4) regulates many aspects of physiological functions via two nuclear P4 receptors (PR), PRA and PRB, which are members of a structurally related nuclear hormone receptor superfamily that includes glucocorticoid receptors (GR). The regulation and cellular distribution of PR protein isoforms have been extensively studied in reproductive tissues, but this is not the case in the lung. In the present study, reverse transcriptase (RT)-PCR, Western blotting, and immunolocalization supported the presence of PRA in the lung of female mice, with PRA protein levels significantly increased between postnatal day 7 and 12, declined at postnatal day 26, and minimal in adults when compared to postnatal day 2. The peak was temporally related to postnatal lung maturation in rodents. Immunoreactivity for PR was detected in the alveolar and bronchial epithelia. We then extended this study to examine, for the first time, the regulation of PRA protein expression in female mouse lung in vivo. Neither the increase in endogenous P4 nor treatment with exogenous P4 regulated PRA protein expression in female mouse lung. However, treatment of mice with the GR/PR antagonist RU 486, but not Org 31710 (a specific PR antagonist), significantly increased PRA protein expression in parallel to a decrease in GR protein expression. In addition, treatment with the synthetic glucocorticoid dexamethasone led to a decrease in PRA protein expression independent of endogenous P4 levels. Furthermore, immunoprecipitation followed by Western blot analysis revealed that, under in vivo conditions, PRA physically interacted with GR in mouse lung. Confocal laser microscopy revealed that PRA and GR co-localized in the nuclei of alveolar epithelia cells, whereas nuclear PR and cytoplasmic GR were detected in bronchial epithelium. Taken together, our observations suggest that PRA may be an important physiological factor involved in postnatal lung development and that the regulation of PRA protein expression is not dependent on P4, but rather on functional glucocorticoid/GR signaling mediated by protein–protein interaction in the mouse lung.
Differential expression and regulation of progesterone receptor isoforms in rat and mouse pituitary cells and LβT2 gonadotropes
Authors: Turgeon Judith L , Waring Dennis W
Published: September 2006

Manipulation of endogenous progesterone receptor (PR) does not produce equivalent physiological effects in mouse and rat pituitary cells. To test whether this may be due in part to difference in PR isoform expression, we examined hormonally regulated pituitary PR-A and PR-B mRNA levels using quantitative real-time PCR. The LβT2 mouse gonadotrope line or pituitary cells from adult, ovariectomized rats or mice were cultured with or without 0.2 nM 17β-estradiol (E2) for 3 days. PR-A was the predominant form expressed for all groups. For mouse cells, E2 led to an increase in both isoforms without a change in the A:B ratio; for rat cells, the PR-B response to E2 was more robust resulting in a decrease in the A:B ratio. Exposure of E2-treated pituitary cells to 200 nM progesterone for 6 h decreased both PR-A and PR-B levels in rat cells, but had no effect on PR isoform expression in mouse cells even when exposure was extended to 12 h. The low level of PR expression found in LβT2 gonadotropes was unaffected by E2, alone or with progesterone. The weak PR expression and lack of responsiveness of LβT2 cells cannot be explained by a male phenotype as was shown by the more than tenfold higher PR mRNA level in primary cultures of male mouse pituitary cells, which responded to E2 stimulation with a proportional increase in PR isoforms similar to female cells. Functionally, E2-stimulated changes in PR mRNA isoform ratios in rat, mouse or LβT2 cells correlated with the degree of progesterone augmentation of GnRH-stimulated LH secretion in these models. These results are consistent with the hypothesis that robust GnRH priming and progesterone augmentation of LH secretion in the rat compared to these events in the mouse are a consequence, in part, of differences in the E2-modulated ratio of PR isoforms.
C16:0 Sulfatide Inhibits Insulin Secretion in Rat β-Cells by Reducing the Sensitivity of KATP Channels to ATP Inhibition
Authors: Buschard Karsten , Blomqvist Maria , Månsson Jan-Eric , Fredman Pam , Juhl Kirstine , Gromada Jesper
Published: September 2006

Sulfatide (3′-sulfo-β-galactosyl ceramide) is a glycosphingolipid present in mammalians in various fatty acid isoforms of which the saturated 16 carbon-atom length (C16:0) is more abundant in pancreatic islets than in neural tissue, where long-chain sulfatide isoforms dominate. We previously reported that sulfatide isolated from pig brain inhibits glucose-induced insulin secretion by activation of ATP-sensitive K+ channels (KATP channels). Here, we show that C16:0 sulfatide is the active isoform. It inhibits glucose-stimulated insulin secretion by reducing the sensitivity of the KATP channels to ATP. (The half-maximal inhibitory concentration is 10.3 and 36.7 μmol/l in the absence and presence of C16:0 sulfatide, respectively.) C16:0 sulfatide increased whole-cell KATP currents at intermediate glucose levels and reduced the ability of glucose to induce membrane depolarization, reduced electrical activity, and increased the cytoplasmic free Ca2+ concentration. Recordings of cell capacitance revealed that C16:0 sulfatide increased Ca2+-induced exocytosis by 215%. This correlated with a stimulation of insulin secretion by C16:0 sulfatide in intact rat islets exposed to diazoxide and high K+. C24:0 sulfatide or the sulfatide precursor, β-galactosyl ceramide, did not affect any of the measured parameters. C16:0 sulfatide did not modulate glucagon secretion from intact rat islets. In βTC3 cells, sulfatide was expressed (mean [±SD] 0.30 ± 0.04 pmol/μg protein), and C16:0 sulfatide was found to be the dominant isoform. No expression of sulfatide was detected in αTC1-9 cells. We conclude that a major mechanism by which the predominant sulfatide isoform in β-cells, C16:0 sulfatide, inhibits glucose-induced insulin secretion is by reducing the KATP channel sensitivity to the ATP block.
Low Concentration of Interleukin-1β Induces FLICE-Inhibitory Protein–Mediated β-Cell Proliferation in Human Pancreatic Islets
Authors: Maedler Kathrin , Schumann Desiree M. , Sauter Nadine , Ellingsgaard Helga , Bosco Domenico , Baertschiger Reto , Iwakura Yoichiro , Oberholzer José , Wollheim Claes B. , Gauthier Benoit R. , Donath Marc Y.
Published: September 2006

High glucose concentrations have a dual effect on β-cell turnover, inducing proliferation in the short-term and apoptosis in the long-term. Hyperglycemia leads to β-cell production of interleuking (IL)-1β in human pancreatic islets. Fas, a death receptor regulated by IL-1β, is involved in glucose-induced β-cell apoptosis. Fas engagement can be switched from death signal to induction of proliferation when the caspase 8 inhibitor, FLICE-inhibitory protein (FLIP), is active. Here, we show that IL-1β at low concentrations may participate in the mitogenic actions of glucose through the Fas-FLIP pathway. Thus, exposure of human islets to low IL-1β concentrations (0.01–0.02 ng/ml) stimulated proliferation and decreased apoptosis, whereas increasing amounts of IL-1β (2–5 ng/ml) had the reverse effects. A similarly bimodal induction of FLIP, pancreatic duodenal homeobox (PDX)-1, and Pax4 mRNA expression, as well as glucose-stimulated insulin secretion, was observed. In contrast, Fas induction by IL-1β was monophasic. Low IL-1β also induced the IL-1 receptor antagonist (IL-1Ra), suppression of which by RNA interference abrogated the beneficial effects of low IL-1β. The Fas antagonistic antibody ZB4 and small interfering RNA to FLIP prevented low IL-1β–stimulated β-cell proliferation. Consistent with our in vitro results, IL-1β knockout mice displayed glucose intolerance along with a decrease in islet Fas, FLIP, Pax4, and PDX-1 transcripts. These findings indicate that low IL-1β levels positively influence β-cell function and turnover through the Fas-FLIP pathway and that IL-1Ra production prevents harmful effects of high IL-1β concentrations.
Suppressed Insulin Signaling and Increased Apoptosis inCd38-Null Islets
Authors: Johnson James D. , Ford Eric L. , Bernal-Mizrachi Ernesto , Kusser Kim L. , Luciani Dan S. , Han Zhiqiang , Tran Hung , Randall Troy D. , Lund Frances E. , Polonsky Kenneth S.
Published: September 2006

CD38 is a multifunctional enzyme capable of generating metabolites that release Ca2+ from intracellular stores, including nicotinic acid adenine dinucleotide phosphate (NAADP). A number of studies have led to the controversial proposal that CD38 mediates an alternate pathway for glucose-stimulated insulin release and contributes to the pathogenesis of diabetes. It has recently been shown that NAADP mediates Ca2+ mobilization by insulin in human pancreatic β-cells. In the present study, we report altered Ca2+ homeostasis and reduced responsiveness to insulin, but not glucose, in Cd38−/− β-cells. In keeping with the antiapoptotic role of insulin signaling, Cd38−/− islets were significantly more susceptible to apoptosis compared with islets isolated from littermate controls. This finding correlated with disrupted islet architecture and reduced β-cell mass in Cd38−/− mice, both in the context of a normal lab diet and a high-fat diet. Nevertheless, we did not find robust differences in glucose homeostasis in vivo or glucose signaling in vitro in Cd38−/− mice on the C57BL/6 genetic background, in contrast to previous studies by others of Cd38 knockout mice on the ICR background. Thus, our results suggest that CD38 plays a role in novel antiapoptotic signaling pathways but does not directly control glucose signaling in pancreatic β-cells.
Imaging Docking and Fusion of Insulin Granules Induced by Antidiabetes Agents
Authors: Nagamatsu Shinya , Ohara-Imaizumi Mica , Nakamichi Yoko , Kikuta Toshiteru , Nishiwaki Chiyono
Published: September 2006

Sulfonylurea and glinide drugs, commonly used for antidiabetes therapies, are known to stimulate insulin release from pancreatic β-cells by closing ATP-sensitive K+ channels. However, the specific actions of these drugs on insulin granule motion are largely unknown. Here, we used total internal reflection fluorescence (TIRF) microscopy to analyze the docking and fusion of single insulin granules in live β-cells exposed to either the sulfonylurea drug glibenclamide or the glinide drug mitiglinide. TIRF images showed that both agents caused rapid fusion of newcomer insulin granules with the cell membrane in both control and diabetic Goto-Kakizaki (GK) rat pancreatic β-cells. However, in the context of β-cells from sulfonylurea receptor 1 (SUR1) knockout mice, TIRF images showed that only mitiglinide, but not glibenclamide, caused fusion of newcomer insulin granules. Compositely, our data indicate that 1) the mechanism by which both sulfonylurea and glinide drugs promote insulin release entails the preferential fusion of newcomer, rather than previously docked, insulin granules, and that 2) mitiglinide can induce insulin release by a mechanism independent of mitiglinide binding to SUR1.
Immunoneutralization of Endogenous Glucagon Reduces Hepatic Glucose Output and Improves Long-Term Glycemic Control in Diabetic ob/ob Mice
Authors: Sørensen Heidi , Brand Christian L. , Neschen Susanne , Holst Jens Juul , Fosgerau Keld , Nishimura Erica , Shulman Gerald I.
Published: September 2006

In type 2 diabetes, glucagon levels are elevated in relation to the prevailing insulin and glucose levels. The relative hyperglucagonemia is linked to increased hepatic glucose output (HGO) and hyperglycemia. Antagonizing the effects of glucagon is therefore considered an attractive target for treatment of type 2 diabetes. In the current study, effects of eliminating glucagon signaling with a glucagon monoclonal antibody (mAb) were investigated in the diabetic ob/ob mouse. Acute effects of inhibiting glucagon action were studied by an oral glucose tolerance test (OGTT) and by measurement of HGO. In addition, the effects of subchronic (5 and 14 days) glucagon mAb treatment on plasma glucose, insulin, triglycerides, and HbA1c (A1C) levels were investigated. Glucagon mAb treatment reduced the area under the curve for glucose after an OGTT, reduced HGO, and increased the rate of hepatic glycogen synthesis. Glucagon mAb treatment for 5 days lowered plasma glucose and triglyceride levels, whereas 14 days of glucagon mAb treatment reduced A1C. In conclusion, acute and subchronic neutralization of endogenous glucagon improves glycemic control, thus supporting the contention that glucagon antagonism may represent a beneficial treatment of diabetes.
The α-Adducin Gene Is Associated With Macrovascular Complications and Mortality in Patients With Type 2 Diabetes
Authors: Yazdanpanah Mojgan , Sayed-Tabatabaei Fakhredin A. , Hofman Albert , Aulchenko Yurii S. , Oostra Ben A. , Stricker Bruno H.C. , Pols Huibert A.P. , Lamberts Steven W.J. , Witteman Jacqueline C.M. , Janssen Joop A.M.J.L. , van Duijn Cornelia M.
Published: September 2006

We examined the association between α-adducin 1 (ADD1) gene polymorphism (Gly460Trp) with macrovascular complications and mortality in type 2 diabetes in a Caucasian population aged ≥55 years. The study was part of the Rotterdam Study, a prospective population-based cohort study. ADD1 polymorphism was determined in 6,471 participants, including 599 patients with type 2 diabetes at baseline. The prevalence of hypertension in type 2 diabetic patients was 2.57 times higher in ADD1 TT carriers compared with GG carriers (95% CI 1.05–6.32, P = 0.03). Homozygous T carriers also had a higher mean common carotid intima media thickness (IMT) compared with GG carriers (mean difference 0.05 mm, P for trend = 0.03). In diabetic patients with hypertension, the risk of mortality was 1.83 times higher in homozygous T carriers compared with the GG genotype group (95% CI 1.07–3.16, P = 0.03). The increased risk was only present among TT carriers who did not use antidiabetes medication (hazard ratio 2.18 [95% CI 1.12–4.24], P = 0.02). The results of this population-based cohort study suggest that the ADD1 gene contributes to the risk of hypertension and increases mean common carotid IMT in patients with type 2 diabetes. Furthermore, the study indicates that the ADD1 polymorphism could be useful in identifying hypertensive type 2 diabetic patients with a high risk of mortality.
Vitamin E and Risk of Type 2 Diabetes in the Women’s Health Study Randomized Controlled Trial
Authors: Liu Simin , Lee I-Min , Song Yiqing , Van Denburgh Martin , Cook Nancy R. , Manson JoAnn E. , Buring Julie E.
Published: September 2006

We directly assessed the efficacy of vitamin E supplements for primary prevention of type 2 diabetes among apparently healthy women in the Women’s Health Study randomized trial. Between 1992 and 2004, 38,716 apparently healthy U.S. women aged ≥45 years and free of diabetes, cancer, and cardiovascular disease were in two randomly assigned intervention groups and received 600 IU of vitamin E (α-tocopherol, n = 19,347) or placebo (n = 19,369) on alternate days. During a median 10-year follow-up, there were 827 cases of incident type 2 diabetes in the vitamin E group and 869 in the placebo group, a nonsignificant 5% risk reduction (relative risk [RR] 0.95 [95% CI 0.87–1.05], P = 0.31). There was no evidence that diabetes risk factors including age, BMI, postmenopausal hormone use, multivitamin use, physical activity, alcohol intake, and smoking status modified the effect of vitamin E on the risk of type 2 diabetes. In a sensitivity analysis taking compliance into account, women in the vitamin E group had an RR of 0.93 (95% CI 0.83–1.04) (P = 0.21) compared with those randomized to placebo. In this large trial with 10-year follow-up, alternate-day doses of 600 IU vitamin E provided no significant benefit for type 2 diabetes in initially healthy women.
Mechanisms of the Depot Specificity of Peroxisome Proliferator–Activated Receptor γ Action on Adipose Tissue Metabolism
Authors: Laplante Mathieu , Festuccia William T. , Soucy Geneviève , Gélinas Yves , Lalonde Josée , Berger Joel P. , Deshaies Yves
Published: September 2006

In this study, we aimed to establish the mechanisms whereby peroxisome proliferator–activated receptor γ (PPARγ) agonism brings about redistribution of fat toward subcutaneous depots and away from visceral fat. In rats treated with the full PPARγ agonist COOH (30 mg · kg−1 · day−1) for 3 weeks, subcutaneous fat mass was doubled and that of visceral fat was reduced by 30% relative to untreated rats. Uptake of triglyceride-derived nonesterified fatty acids was greatly increased in subcutaneous fat (14-fold) and less so in visceral fat (4-fold), with a concomitant increase, restricted to subcutaneous fat only, in mRNA levels of the uptake-, retention-, and esterification-promoting enzymes lipoprotein lipase, aP2, and diacylglycerol acyltransferase 1. Basal lipolysis and fatty acid recycling were stimulated by COOH in both subcutaneous fat and visceral fat, with no frank quantitative depot specificity. The agonist increased mRNA levels of enzymes of fatty acid oxidation and thermogenesis much more strongly in visceral fat than in subcutaneous fat, concomitantly with a stronger elevation in O2 consumption in the former than in the latter. Mitochondrial biogenesis was stimulated equally in both depots. These findings demonstrate that PPARγ agonism redistributes fat by stimulating the lipid uptake and esterification potential in subcutaneous fat, which more than compensates for increased O2 consumption; conversely, lipid uptake is minimally altered and energy expenditure is greatly increased in visceral fat, with consequent reduction in fat accumulation.
Common Haplotypes at the Adiponectin Receptor 1 (ADIPOR1) Locus Are Associated With Increased Risk of Coronary Artery Disease in Type 2 Diabetes
Authors: Soccio Teresa , Zhang Yuan-Yuan , Bacci Simonetta , Mlynarski Wojciech , Placha Grzegorz , Raggio Greer , Di Paola Rosa , Marucci Antonella , Johnstone Michael T. , Gervino Ernest V. , Abumrad Nada A. , Klein Samuel , Trischitta Vincenzo , Doria Alessandro
Published: September 2006

Adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common polymorphisms in the adiponectin receptor 1 (ADIPOR1) gene mediating these effects influence the risk of coronary artery disease (CAD) in type 2 diabetes. Linkage disequilibrium analysis of 28 single nucleotide polymorphisms (SNPs) spanning the entire ADIPOR1 locus revealed two haplotype blocks that could be tagged by six SNPs. These six markers were typed in two populations of CAD-positive and -negative subjects with type 2 diabetes, one from Boston (n = 411) and the other from Italy (n = 533). In the Boston population, the three tags of the more 3′ block were all significantly associated with CAD (P = 0.001–0.01). A similar trend, although not significant, was found in Italian subjects. Haplotype analysis of the combined populations revealed different haplotype distributions in case and control subjects (P = 0.0002), with one common haplotype being associated in homozygotes with a greater than threefold increase in cardiovascular risk (odds ratio 3.6 [95% CI 1.8–7.2]). Some of the genotypes associated with increased cardiovascular risk were associated with 30–40% lower ADIPOR1 mRNA levels in blood mononuclear cells (n = 60) and adipose tissue biopsies (n = 28) (P = 0.001–0.014). Our findings point to genetic variability at the ADIPOR1 locus as a strong determinant of CAD susceptibility in type 2 diabetes.
Cholesterol Absorption and Synthesis in Children With Type 1 Diabetes
Authors: Järvisalo Mikko , Raitakari Olli , Gylling Helena , Miettinen Tatu A.
Published: September 2006

OBJECTIVE—The levels of the surrogate markers of cholesterol absorption (cholestanol and plant sterols) and synthesis (cholesterol precursors) in serum have suggested that in adult type 1 diabetes, cholesterol absorption is high and synthesis is low compared with type 2 diabetic or control subjects. Accordingly, these findings were further studied in children with type 1 diabetes.

RESEARCH DESIGN AND METHODS—Forty-eight children with diabetes were compared with 79 age- and sex-matched control subjects. The serum ratios of cholesterol absorption and synthesis markers were measured with gas-liquid chromatography. The study population was divided into triads (combining the two lowest triads) by serum cholestanol ratios of the control subjects indicating low to high cholesterol absorption efficiency.

RESULTS—The ratios of the absorption and synthesis markers were similar in case and control subjects, and they were negatively related to each other in control subjects, being less consistent in diabetic patients. Thus, high cholesterol absorption was associated with low synthesis. Plant sterol ratios increased significantly with increasing cholestanol triads in both groups, but the values in the lowest triads were higher in case versus control subjects.

CONCLUSIONS—Homeostasis between cholesterol absorption and synthesis is maintained in control children and somewhat less consistently in those with diabetes. The higher plant sterol ratios in diabetic versus control subjects in the lowest cholestanol triads suggest that cholesterol absorption is higher in children with diabetes versus control subjects but only within the range of low cholesterol absorption.
A Double-Blind, Placebo-Controlled Trial Assessing Pramlintide Treatment in the Setting of Intensive Insulin Therapy in Type 1 Diabetes
Authors: Edelman Steve , Garg Satish , Frias Juan , Maggs David , Wang Yan , Zhang Bei , Strobel Susan , Lutz Karen , Kolterman Orville
Published: September 2006

OBJECTIVE—To assess safety, efficacy, and tolerability of pramlintide dose escalation with proactive mealtime insulin reduction, followed by insulin optimization, in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—This 29-week, double-blind, placebo-controlled study randomized 296 patients to pramlintide or placebo as an adjunct to insulin. During initiation, pramlintide was escalated from 15 to 60 μg/meal (15-μg increments) with recommended reductions (30–50%) in mealtime insulin. Insulin was subsequently adjusted to optimize glycemic control. End points included safety and change in HbA1c (A1C), postprandial glucose, insulin, weight, and tolerability.

RESULTS—Baseline A1C was 8.1% for both groups and at week 29 had decreased comparably (pramlintide −0.5% [95% CI −0.61 to −0.33]; placebo −0.5% [−0.63 to −0.35]). Pramlintide treatment significantly reduced postprandial glucose excursions (incremental area under the curve [AUC]0–3h: pramlintide −175 ± 40, placebo −64 ± 38 mg · h−1 · dl−1; P < 0.0005) and weight (pramlintide −1.3 ± 0.30, placebo +1.2 ± 0.30 kg; P < 0.0001). At week 29, insulin dose decreased by 28 and 4% in pramlintide- and placebo-treated groups, respectively. Nausea, reported by 63 and 36% of patients in pramlintide and placebo groups (P < 0.01), respectively, was predominately mild to moderate in intensity. Severe hypoglycemia rates were low in both groups (pramlintide 0.57 ± 0.09, placebo 0.30 ± 0.06 event rate/patient-year; P < 0.05), with increased rates observed in patients remaining at 30 μg pramlintide.

CONCLUSIONS—Pramlintide dose escalation with reduced mealtime insulin was effective during therapy initiation in patients with type 1 diabetes. While both groups experienced equivalent A1C reductions relative to placebo, pramlintide-treated patients experienced reductions in postprandial glucose excursions and weight, not achievable with insulin therapy alone.