bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of Chloramine-T to Control Mortality in Freshwater-Reared Salmonids Diagnosed with Bacterial Gill Disease
Authors: Bowker James D , Carty Daniel G , Telles Larry , David Bob , Oviedo David
Published: December 2007

Bacterial gill disease (BGD), caused by Flavobacterium branchiophilum and other species of yellow-pigmented, filamentous bacteria, is a common and potentially catastrophic disease of hatchery (freshwater)-reared fish. Chloramine-T (Chl-T) is a biocide proven effective for controlling mortality in freshwater-reared fish diagnosed with BGD. However, Chl-T is not approved by the U.S. Food and Drug Administration for such use. To generate data in support of a U.S. approval, we evaluated the effectiveness of Chl-T (administered at 12 mg/L of static bath water for 60 min/d on three alternate days) to control mortality caused by BGD in freshwater-reared chum salmon Oncorhynchus keta, Apache trout O. gilae apache, and rainbow trout O. mykiss. For each species, the mean percent total mortality in Chl-T-treated tanks (N = 3) was significantly less than that in control tanks (N = 3): Chum salmon = 8.9% versus 99.7%, Apache trout = 39.2% versus 97.9%, and rainbow trout = 5.7% versus 25.8%. Because the Chl-T treatment regimen was efficacious for each species, we conclude that our findings support the approval of Chl-T for use in the USA to control mortality in freshwater-reared salmonids diagnosed with BGD.
Immuno-PET: A Navigator in Monoclonal Antibody Development and Applications
Authors: van Dongen Guus A.M.S. , Visser Gerard W.M. , Lub-de Hooge Marjolijn N. , de Vries Elisabeth G. , Perk Lars R.
Published: December 2007

Learning Objectives

After completing this course, the reader will be able to: Discuss the technical advances that have led to recent rapid developments in monoclonal antibody imaging techniques.List the monoclonal antibodies that are currently available for cancer imaging and cancer therapy.Identify potential roles for immuno-PET in cancer staging and treatment selection.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Elderly Cancer Patients Receiving Chemotherapy Benefit from First-Cycle Pegfilgrastim
Authors: Balducci Lodovico , Al-Halawani Hafez , Charu Veena , Tam Jennifer , Shahin Seta , Dreiling Lyndah , Ershler William B.
Published: December 2007

Background.

There is a misconception that elderly cancer patients cannot tolerate standard doses of chemotherapy because of the frequency and severity of myelosuppressive complications. The reactive use of colony-stimulating factors (i.e., in response to severe neutropenia) commonly observed in this setting contributes to the frequency and severity of these complications. This study evaluated the incidence of febrile neutropenia and related events in elderly cancer patients receiving pegfilgrastim beginning with cycle 1 (proactive) in comparison with pegfilgrastim initiated after cycle 1 at the physician's discretion (reactive).

Methods.

Patients (≥65 years of age) with either solid tumors or non-Hodgkin's lymphoma (NHL) were randomly assigned to receive pegfilgrastim either proactively or reactively. The primary endpoint was the proportion of patients experiencing febrile neutropenia.

Results.

There were 852 patients enrolled (median age, 72 years). Proactive pegfilgrastim use resulted in a significantly lower incidence of febrile neutropenia for both solid tumor and NHL patients compared with reactive use. Proactive pegfilgrastim use also led to fewer hospitalizations resulting from neutropenia and febrile neutropenia by approximately 50%. Antibiotic use was lower for solid tumor patients receiving proactive pegfilgrastim and equivalent in the two NHL groups.

Conclusions.

This is the largest, randomized, prospective trial evaluating growth factor support in typical elderly cancer patients. Proactive pegfilgrastim use effectively produced a lower incidence of febrile neutropenia and related events in elderly patients with either solid tumors or NHL receiving an array of mild to moderately neutropenic chemotherapy regimens. Pegfilgrastim should be used proactively in elderly cancer patients to support the optimal delivery of standard chemotherapy.
Hepatocellular Carcinoma: The Role of the North American GI Steering Committee Hepatobiliary Task Force and the Advent of Effective Drug Therapy
Authors: O'Neil Bert H. , Venook Alan P.
Published: December 2007

Hepatocellular carcinoma (HCC) is a disease that requires multidisciplinary management. There has been no widely accepted standard for systemic therapy for this disease until recently. This article briefly discusses the management of earlier stage HCC, then focuses on newer agents with promise, particularly sorafenib, a drug that appears to be the new standard of care for advanced disease.
Fertility Preservation: Successful Transplantation of Cryopreserved Ovarian Tissue in a Young Patient Previously Treated for Hodgkin's Disease
Authors: Demeestere Isabelle , Simon Philippe , Emiliani Serena , Delbaere Anne , Englert Yvon
Published: December 2007

Learning Objectives

After completing this course, the reader will be able to: Discuss recent advances in the use of cryopreserved ovarian tissue to restore fertility.Explain the main aspects of the procedure for transplantation of cryopreserved ovarian tissue.Discuss the options to preserve fertility of young patients with a high risk for premature ovarian failure after cancer therapy.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Ediacaran biota on Bonavista Peninsula, Newfoundland, Canada
Authors: Hofmann H. J. , O'Brien S. J. , King A. F.
Published: December 2007

Newly found fossils in the Conception and St. John's groups of the Bonavista Peninsula considerably extend the known geographic distribution of the Ediacaran fossils in Newfoundland. They occur in deepwater sediments and are preserved as epireliefs, forming census populations underneath volcanic ash layers throughout a more than 1 km thick turbiditic sequence. the exposed fossiliferous units comprise the Mistaken Point, Trepassey, Fermeuse, and Renews Head formations. the remains are tectonically deformed, with long axes of elliptical discs aligned parallel to cleavage strike; shortening of originally circular bedding surface features is on the order of 30-50% (averaging ~35%).

The assemblage includesAspidella, Blackbrookia, Bradgatia, Charnia, Charniodiscus, Fractofusus, Hiemalora, andIvesheadia.These occur throughout the succession, withAspidellabeing the most common genus, followed byCharniaandCharniodiscus.Four new taxa are described, with candelabra-like fossils with aHiemalora-like base referred toPrimocandelabrum hiemaloranumn. gen. and sp., bush-like fossils toParviscopa bonavistensisn. gen. and sp., ladder-like fossils toHadryniscala avalonican. gen. and sp., and string-like fossils with basal disc toHadrynichorde catalinensisn. gen. and sp. the remains also include dubiofossils. The stratigraphic ranges of some taxa on the Bonavista Peninsula are longer than previously reported from the Avalon Peninsula, withFractofususspindles present in the Trepassey Formation,Bradgatia, Charnia, Charniodiscus, andIvesheadiareaching as high as the Fermeuse Formation, andAspidellaextending into the middle of the Renews Head Formation. the spindles in the Trepassey Formation are comparable to those found mainly in the stratigraphically older Briscal Formation on the Avalon Peninsula.
Review of operating principle and performance of polarizer‐free reflective liquid‐crystal displays
Authors: Yang Deng‐Ke
Published: December 2007

Abstract—In this paper the operational principle and performance of guest‐host, liquid‐crystal/polymer‐composite scattering, and cholesteric liquid‐crystal reflective displays are reviewed. These displays do not use polarizers and have the advantage of providing high reflectance and compatibility with flexible plastic substrates.
Super‐reflective color LCD with PDLC technology
Authors: Minoura Kiyoshi , Mizushima Shigeaki , Asaoka Yasushi , Ihara Ichiro , Satoh Eiji , Fujiwara Sayuri , Itoh Yasuhisa
Published: December 2007

Abstract— A novel reflective color LCD without polarizers has been developed using a PDLC film and a retro‐reflector. Bright color images including moving images are achievable with ambient light. This novel LCD will enable the new application area of electronic paper.
Nanoparticle‐embedded polymer‐dispersed liquid crystal for paper‐like displays
Authors: Masutani Akira , Roberts Tony , Schüller Bettina , Hollfelder Nadine , Kilickiran Pinar , Sakaigawa Akira , Nelles Gabriele , Yasuda Akio
Published: December 2007

Abstract— A polymer‐dispersed liquid‐crystal (PDLC) matrix template embedded with nano/microparticles can be backfilled/infiltrated with a dye‐doped liquid crystal for a paper‐like reflective display. In this way, a desirable degree of diffusion can be realized to reduce the viewing‐angle dependency of a gain reflector and metallic glare without changing other electro‐optical properties.
A Flexible electronic‐paper display with an ultra‐thin and flexible LSI driver using quick‐response liquid‐powder technology
Authors: Sakurai Ryo , Hattori Reiji , Asakawa Michihiro , Nakashima Takuro , Tanuma Itsuo , Yokoo Akihiko , Nihei Norio , Masuda Yoshitomo
Published: December 2007

Abstract— A thin and flexible LSI driver with a thickness of less than 35 μm for a passive‐matrix‐driven Quick‐Response Liquid‐Powder Display (QR‐LPD™) was successfully mounted onto the flexible printed circuit (FPC) and the back substrates of a flexible QR‐LPD™. Amounted LSI driver on a plastic substrate shows no significant degradation in the driving performances and maintains physical flexibility without any connection failures. This technology can realize a fully flexible electronic paper in combination with a plastic‐substrate QR‐LPD™ fabricated by a roll‐to‐roll process.
A flexible full‐color AMOLED display driven by OTFTs
Authors: Yagi Iwao , Hirai Nobukazu , Miyamoto Yoshihiro , Noda Makoto , Imaoka Ayaka , Yoneya Nobuhide , Nomoto Kazumasa , Kasahara Jiro , Yumoto Akira , Urabe Tetsuo
Published: December 2007

Abstract— Organic thin‐film‐transistor (OTFT) technologies have been developed to achieve a flexible backplane for driving full‐color organic light‐emitting diodes (OLEDs) with a resolution of 80 ppi. The full‐color pixel structure can be attained by using a combination of top‐emission OLEDs and fine‐patterned OTFTs. The fine‐patterned OTFTs are integrated by utilizing an organic semiconductor (OSC) separator, which is an insulating wall structure made of an organic insulator. Organic insulators are actively used for the OTFT integration, as well as for the separator, in order to enhance the mechanical flexibility of the OTFT backplane. By using these technologies, active‐matrix OLED (AMOLED) displays can be driven by the developed OTFT backplane even when they are mechanically flexed.
High‐mobility solution‐processed organic thin‐film transistor array for active‐matrix color liquid‐crystal displays
Authors: Kawasaki Masahiro , Imazeki Shuji , Hirota Shoichi , Arai Tadashi , Shiba Takeo , Ando Masahiko , Natsume Yutaka , Minakata Takashi , Uemura Sei , Kamata Toshihide
Published: December 2007

Abstract— A solution‐processed organic thin‐film‐transistor array to drive a 5‐in.‐diagonal liquid‐crystal display has been fabricated, where semiconductor films, a gate dielectric film, and passivation films have all been formed using solution processes. A field‐effect mobility of 1.6 cm2/V‐sec, which is among the highest for solution‐processed organic thin‐film transistors ever reported, was obtained. This result is due to semiconductor material with large‐grain‐sized pentacene crystals formed from a solution and adoption of three‐layered passivation films that minimize the performance degradation of organic thin‐film transistors.
Flexible active‐matrix OLED displays: Challenges and progress
Authors: Ma Rui‐Qing , Hewitt Richard , Rajan Kamala , Silvernail Jeff , Urbanik Ken , Hack Michael , Brown Julie J.
Published: December 2007

Abstract— Organic light‐emitting‐device (OLED) devices are very promising candidates for flexible‐display applications because of their organic thin‐film configuration and excellent optical and video performance. Recent progress of flexible‐OLED technologies for high‐performance full‐color active‐matrix OLED (AMOLED) displays will be presented and future challenges will be discussed. Specific focus is placed on technology components, including high‐efficiency phosphorescent OLED technology, substrates and backplanes for flexible displays, transparent compound cathode technology, conformal packaging, and the flexibility testing of these devices. Finally, the latest prototype in collaboration with LG. Phillips LCD, a flexible 4‐in. QVGA full‐color AMOLED built on amorphous‐silicon backplane, will be described.
Advanced impulsive‐driving technique for Super‐PVA panel
Authors: Kim Taesung , Shin Byung‐Hyuk , Nam Hyoung Sik , Berkeley Brian H. , Kim Sang Soo
Published: December 2007

Abstract— Super‐PVA (S‐PVA) technology developed by Samsung has demonstrated excellent viewing‐angle performance. However, S‐PVA panels can place extra demands on charging time due to the time‐multiplexed driving scheme required to separately address two subpixels. Specifically, a 2G‐1D pixel structure theoretically requires subpixel charging in one‐half of the time available for a conventional panel. In this paper, a new LCD driving scheme, super impulsive technology (SIT), is proposed to improve motion‐blur reduction by driving an S‐PVA LCD panel at 120 Hz. The proposed scheme allows a 120‐Hz 2G‐1D panel to be driven with an adequate charging‐time margin while providing an impulsive driving effect for motion‐blur reduction. Considering that the cost of a 2G‐1D S‐PVA panel is comparable to that of a conventional 60‐Hz panel, this method achieves good performance at a reasonable price. The detailed algorithm and implementation method are explored and the performance improvements are verified.
Assessment of display temporal response using a computational observer
Authors: Liang Hongye , Park Subok , Gallas Brandon D. , Myers Kyle J. , Badano Aldo
Published: December 2007

Abstract— Temporal response is one of the major concerns for liquid‐crystal‐display (LCD) performance. Fast response time is preferred for high‐fidelity image rendering. Several methods have been proposed to improve the LCD temporal performance. A method to assess the impact of temporal responses based on measured or modeled device temporal characteristics with a contrast‐sensitive computational observer that is intended to predict human performance is reported. A method to compare different devices and temporal blur reduction approaches has been applied. It was found that slow temporal response of the display device greatly affects signal contrast and observer performance. This methodology, after validation with human observers, could be used to compare different displays with different inter‐gray‐level transition time profiles.
A perceptually based metric to characterize the viewing‐angle range of matrix displays
Authors: Teunissen Kees , Qin Shaoling , Heynderickx Ingrid
Published: December 2007

Abstract— The current specification of a display's viewing angle as the angle within which the contrast ratio is larger than 10:1 appears not to be predictive for the acceptable viewing‐angle range obtained from perception experiments. In our search towards a perceptually relevant specification for the viewing angle, the physical characteristics of the display that are most related to the viewing‐angle‐dependent image quality were analyzed. This was done for two types of liquid‐crystal displays and one plasma TV. The results indicate that a combination of the luminance and chromaticity coordinates of the higher gray levels predicts the degradation in image quality as a function of viewing angle. As a consequence, a new definition of a display's viewing‐angle range is proposed based on these characteristics.
System design for a wide‐color‐gamut TV‐sized AMOLED display
Authors: Hamer John W. , Arnold Andrew D. , Boroson Michael L. , Itoh Masahiro , Hatwar Tukaram K. , Helber Margaret J. , Miwa Koichi , Levey Charles I. , Long Michael , Ludwicki John E. , Scheirer David C. , Spindler Jeffrey P. , van Slyke Steven A.
Published: December 2007

Abstract— By using current technology, it is possible to design and fabricate performance‐competitive TV‐sized AMOLED displays. In this paper, the system design considerations are described that lead to the selection of the device architecture (including a stacked white OLED‐emitting unit), the backplane technology [an amorphous Si (a‐Si) backplane with compensation for TFT degradation], and module design (for long life and low cost). The resulting AMOLED displays will meet performance and lifetime requirements, and will be manufacturing cost‐competitive for TV applications. A high‐performance 14‐in. AMOLED display was fabricated by using an in‐line OLED deposition machine to demonstrate some of these approaches. The chosen OLED technologies are scalable to larger glass substrate sizes compatible with existing a‐Si backplane fabs.
High‐speed driving waveform based on reset and address discharge analysis using a Vt closed curve in ACPDPs
Authors: Cho Byung‐Gwon , Tae Heung‐Sik
Published: December 2007

Abstract— Driving waveforms having both high‐speed address and low background were developed using Vt closed curve analysis. To prevent a misfired discharge during a sustain period, the voltage difference at the end of the ramp setup between the X‐Y electrodes remains constant. Because background luminance becomes higher (although the address discharge time lag becomes shorter) as the voltage difference between the A‐Y electrodes becomes larger, a low reset voltage and an address bias voltage were adopted during the ramp‐up period.
Towards faster liquid crystals at lower driving voltages
Authors: Kilickiran Pinar , Masutani Akira , Roberts Tony , Hollfelder Nadine , Schüller Bettina , Nelles Gabriele , Yasuda Akio
Published: December 2007

Abstract— Response times and switching voltages of positive‐ and negative‐type nematic liquid‐crystal mixtures are improved by the addition of small amounts of diaryl‐ether derivatives. The effect of such doping is directly seen as a reduction in the rotational viscosities of the mixtures. Despite their non‐planar nature, the dopant molecules do not cause any detrimental changes to the black levels and the contrast ratios of the displays filled with the doped LC mixtures.
New electrical test method for LCD cell‐manufacturing process
Authors: Miyake Yasuhiro , Chikamatsu Kiyoshi , Mizoguchi Junichi
Published: December 2007

Abstract— A new electrical test method resulting in repeatable and unambiguous test results, which solves the drawback of the current lighting test used for the LCD cell‐manufacturing process, is proposed. This paper shows the basic scheme and the wide test coverage of this test method to detect defects in the cell process and gives an example of the actual measurement result.
A Polymorphism in the Zinc Transporter GeneSLC30A8Confers Resistance Against Posttransplantation Diabetes Mellitus in Renal Allograft Recipients
Authors: Kang Eun Seok , Kim Myoung Soo , Kim Yu Seun , Kim Chul Hoon , Han Seung Jin , Chun Sung Wan , Hur Kyu Yeon , Nam Chung Mo , Ahn Chul Woo , Cha Bong Soo , Kim Soon Il , Lee Hyun Chul
Published: December 2007

OBJECTIVE—Posttransplantation diabetes mellitus (PTDM) is a major metabolic complication in renal transplant recipients, and insulin secretory defects play an important role in the pathogenesis of PTDM. The R325W (rs13266634) nonsynonymous polymorphism in the islet-specific zinc transporter protein gene, SLC30A8, has been reported to be associated with type 2 diabetes and possibly with a defect in insulin secretion. This study investigated the association between genetic variations in the SLC30A8 gene and PTDM in renal allograft recipients.

RESEARCH DESIGN AND METHODS—A total of 624 unrelated renal allograft recipients without previously diagnosed diabetes were enrolled. Rs13266634 was genotyped in the cohort, which consisted of 174 posttransplantation diabetic patients and 450 non-posttransplantation diabetic subjects. The genotyping of the SLC30A8 polymorphism was performed using real-time PCR.

RESULTS—The prevalence of PTDM was 33.8% in patients carrying the R/R genotype, 26.8% in patients with the R/W genotype, and 19.8% in patients with the W/W genotype. There was a strong association between the number of W-alleles and PTDM risk reduction (P for trend = 0.007). Patients with at least one T-allele showed a decreased risk of PTDM compared with those with the R/R genotype (R/W, risk ratio [RR] 0.78, P = 0.126; W/W, RR 0.52, P = 0.007). The effect of the SLC30A8 genotype remained significant after adjustments for age, sex, body weight gain, and type of immunosuppressant (R/W, hazard ratio [HR] 0.77, P = 0.114; W/W, HR 0.58, P = 0.026).

CONCLUSIONS—These data provide evidence that the SLC30A8 rs13266634 gene variation is associated with protection from the development of PTDM in renal allograft recipients.
Evidence of Interaction Between PPARG2 and HNF4A Contributing to Variation in Insulin Sensitivity in Mexican Americans
Authors: Black Mary Helen , Fingerlin Tasha E. , Allayee Hooman , Zhang Weiming , Xiang Anny H. , Trigo Enrique , Hartiala Jaana , Lehtinen Allison B. , Haffner Steven M. , Bergman Richard N. , McEachin Richard C. , Kjos Siri L. , Lawrence Jean M. , Buchanan Thomas A. , Watanabe Richard M.
Published: December 2007

OBJECTIVE—We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes–related quantitative traits in Mexican-American families of a proband with previous gestational diabetes.

RESEARCH DESIGN AND METHODS—The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests.

RESULTS—Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes–related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (SI) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher SI compared with individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for SI was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher SI compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401).

CONCLUSIONS—Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes.
Identification and Replication of a Novel Obesity Locus on Chromosome 1q24 in Isolated Populations of Cilento
Authors: Ciullo Marina , Nutile Teresa , Dalmasso Cyril , Sorice Rossella , Bellenguez Céline , Colonna Vincenza , Persico Maria Graziella , Bourgain Catherine
Published: December 2007

OBJECTIVE—Obesity is a complex trait with a variety of genetic susceptibility variants. Several loci linked to obesity and/or obesity-related traits have been identified, and relatively few regions have been replicated. Studying isolated populations can be a useful approach to identify rare variants that will not be detected with whole-genome association studies in large populations.

RESEARCH DESIGN AND METHODS—Random individuals were sampled from Campora, an isolated village of the Cilento area in South Italy, phenotyped for BMI, and genotyped using a dense microsatellite marker map. An efficient pedigree-breaking strategy was applied to perform genome-wide linkage analyses of both BMI and obesity. Significance was assessed with ad hoc simulations for the two traits and with an original local false discovery rate approach to quantitative trait linkage analysis for BMI. A genealogy-corrected association test was performed for a single nucleotide polymorphism located in one of the linkage regions. A replication study was conducted in the neighboring village of Gioi.

RESULTS—A new locus on chr1q24 significantly linked to BMI was identified in Campora. Linkage at the same locus is suggested with obesity. Three additional loci linked to BMI were also detected, including the locus including the INSIG2 gene region. No evidence of association between the rs7566605 variant and BMI or obesity was found. In Gioi, the linkage on chr1q24 was replicated with both BMI and obesity.

CONCLUSIONS—Overall, our results confirm that successful linkage studies can be accomplished in these populations both to replicate known linkages and to identify novel quantitative trait linkages.
Association ofCDKAL1, IGF2BP2, CDKN2A/B, HHEX,SLC30A8,andKCNJ11With Susceptibility to Type 2 Diabetes in a Japanese Population
Authors: Omori Shintaro , Tanaka Yasushi , Takahashi Atsushi , Hirose Hiroshi , Kashiwagi Atsunori , Kaku Kohei , Kawamori Ryuzo , Nakamura Yusuke , Maeda Shiro
Published: December 2007

OBJECTIVE—Recently, several genes have been shown to be associated with an increased risk of type 2 diabetes by genome-wide association studies in white populations. To further investigate the involvement of these polymorphisms in conferring susceptibility to type 2 diabetes, we examined the association of 14 single nucleotide polymorphisms (SNPs) within 11 candidate loci with type 2 diabetes in a Japanese population.

RESEARCH DESIGN AND METHODS—We analyzed 14 SNPs (rs4402960 in IGF2BP2, rs10811661 in CDKN2A/B, rs1111875 and rs7923837 in HHEX, rs13266634 in SLC30A8, rs1113132 and rs11037909 in EXT2, rs9939609 and rs8050136 in FTO, rs7756992 in CDKAL1, rs1801282 in PPARG Pro12Ara, rs5219 in KCNJ11 Glu23Lys, rs7480010 in LOC387761, and rs9300039 in Ch11) in 1,630 Japanese subjects with type 2 diabetes and in 1,064 control subjects by using an invader assay or a TaqMan assay.

RESULTS—Among the 11 loci examined, 6 were significantly associated with type 2 diabetes in our population by a logistic regression analysis, similar to previously reported results (rs4402960, P = 0.00009; rs10811661, P = 0.0024; rs5219, P = 0.0034; rs1111875, P = 0.0064; rs13266634, P = 0.0073; rs7756992, P = 0.0363). In this population, the remaining five loci were not significantly associated with type 2 diabetes. In addition, we identified significant association of the SNPs in FTO gene with BMI in the control subjects.

CONCLUSIONS—We have identified 6 of the 11 loci that were identified by genome-wide association studies in white populations, and these loci are considered strong candidates for type 2 diabetes susceptibility across different ethnicities.
Obestatin Promotes Survival of Pancreatic β-Cells and Human Islets and Induces Expression of Genes Involved in the Regulation of β-Cell Mass and Function
Authors: Granata Riccarda , Settanni Fabio , Gallo Davide , Trovato Letizia , Biancone Luigi , Cantaluppi Vincenzo , Nano Rita , Annunziata Marta , Campiglia Pietro , Arnoletti Elisa , Ghè Corrado , Volante Marco , Papotti Mauro , Muccioli Giampiero , Ghigo Ezio
Published: December 2007

OBJECTIVE—Obestatin is a newly discovered peptide encoded by the ghrelin gene whose biological functions are poorly understood. We investigated obestatin effect on survival of β-cells and human pancreatic islets and the underlying signaling pathways.

RESEARCH DESIGN AND METHODS—β-Cells and human islets were used to assess obestatin effect on cell proliferation, survival, apoptosis, intracellular signaling, and gene expression.

RESULTS—Obestatin showed specific binding on HIT-T15 and INS-1E β-cells, bound to glucagon-like peptide-1 receptor (GLP-1R), and recognized ghrelin binding sites. Obestatin exerted proliferative, survival, and antiapoptotic effects under serum-deprived conditions and interferon-γ/tumor necrosis factor-α/interleukin-1β treatment, particularly at pharmacological concentrations. Ghrelin receptor antagonist [D-Lys3]-growth hormone releasing peptide-6 and anti-ghrelin antibody prevented obestatin-induced survival in β-cells and human islets. β-Cells and islet cells released obestatin, and addition of anti-obestatin antibody reduced their viability. Obestatin increased β-cell cAMP and activated extracellular signal–related kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt; its antiapoptotic effect was blocked by inhibition of adenylyl cyclase/cAMP/protein kinase A (PKA), PI 3-kinase/Akt, and ERK1/2 signaling. Moreover, obestatin upregulated GLP-1R mRNA and insulin receptor substrate-2 (IRS-2) expression and phosphorylation. The GLP-1R antagonist exendin-(9-39) reduced obestatin effect on β-cell survival. In human islets, obestatin, whose immunoreactivity colocalized with that of ghrelin, promoted cell survival and blocked cytokine-induced apoptosis through cAMP increase and involvement of adenylyl cyclase/cAMP/PKA signaling. Moreover, obestatin 1) induced PI 3-kinase/Akt, ERK1/2, and also cAMP response element–binding protein phosphorylation; 2) stimulated insulin secretion and gene expression; and 3) upregulated GLP-1R, IRS-2, pancreatic and duodenal homeobox-1, and glucokinase mRNA.

CONCLUSIONS—These results indicate that obestatin promotes β-cell and human islet cell survival and stimulates the expression of main regulatory β-cell genes, identifying a new role for this peptide within the endocrine pancreas.
PPARGC1A Variation Associated With DNA Damage, Diabetes, and Cardiovascular Diseases
Authors: Lai Chao-Qiang , Tucker Katherine L. , Parnell Laurence D. , Adiconis Xian , García-Bailo Bibiana , Griffith John , Meydani Mohsen , Ordovás José M.
Published: December 2007

OBJECTIVE—Individuals with type 2 diabetes exhibit higher DNA damage and increased risk of cardiovascular disease (CVD). However, mechanisms underlying the association between DNA damage and development of type 2 diabetes and CVD are not understood. We sought to link peroxisome proliferator–activated receptor-γ coactivator-1 α (PPARGC1A), a master transcriptional regulator of mitochondrial oxidative phosphorylation and cellular energy metabolism, with DNA damage, type 2 diabetes, and CVD.

RESEARCH DESIGN AND METHODS—We measured DNA damage as urinary 8-hydroxydeoxyguanosine (8-OHdG) concentration and examined the relationship between nine PPARGC1A genetic variants, DNA damage, type 2 diabetes, and self-reported CVD in 959 participants of the Boston Puerto Rican Health Study.

RESULTS—With respect to urinary 8-OHdG, PPARGC1A variants showed significant association, and PPARGC1A haplotypes exhibited significant association after correction for multiple testing. Two independent PPARGC1A variants associated significantly with type 2 diabetes (odds ratios [ORs] 1.35 and 2.46; P = 0.045 and <0.001). Carriers of minor alleles of two other PPARGC1A variants, both in strong linkage disequilibrium and associated with lower DNA damage, showed lower prevalence of CVD (ORs 0.53 and 0.65; P = 0.030 and 0.175). Moreover, we found that physical activity correlated negatively with DNA damage.

CONCLUSIONS—It is plausible that low physical activity combined with risk haplotyes contribute to the high prevalence of type 2 diabetes in this population. We propose that PPARGC1A influences development of type 2 diabetes and CVD via DNA damage. Increasing physical activity, which induces PPARGC1A expression, is a potential strategy to slow DNA damage, thereby decreasing the risk of CVD for individuals with type 2 diabetes.
Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients
Authors: Muscelli Elza , Mari Andrea , Casolaro Arturo , Camastra Stefania , Seghieri Giuseppe , Gastaldelli Amalia , Holst Jens J. , Ferrannini Ele
Published: December 2007

OBJECTIVE—To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose).

RESEARCH DESIGN AND METHODS—Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20–61 kg/m2). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique.

RESULTS—The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P ≤ 0.05). The results were similar when subjects were stratified by BMI tertile (P ≤ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27–0.59, P ≤ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients.

CONCLUSIONS—Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.
Insulin Resistance and Progression to Type 1 Diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT)
Authors: Bingley Polly J. , Mahon Jeffrey L , Gale Edwin A.M. ,   for the European Nicotinamide Diabetes Intervention Trial (ENDIT) Group
Published: December 2007

OBJECTIVE—Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers.

RESEARCH DESIGN AND METHODS—The retrospective cohort analysis included 213 family members participating in the European Nicotinamide Diabetes Intervention Trial. All were aged <25 years, with at least one islet antibody in addition to ICA ≥20 Juvenile Diabetes Foundation units. Median length of follow-up was 4.21 years, and 105 individuals developed diabetes. Oral and intravenous glucose tolerance tests were performed at baseline; antibodies to GAD, IA-2, and insulin were determined by radioimmunoassay; and insulin resistance was estimated by homeostasis model assessment. Risk was assessed by Cox regression analysis

RESULTS—The overall cumulative risk of diabetes within 5 years was 54.1% (95% CI 46.0–62.3). Multivariate analysis confirmed that baseline first-phase insulin response (FPIR) quartile (P < 0.0001), number of additional antibody markers (P < 0.0001), and 120-min glucose in the oral glucose tolerance test (P < 0.0001) were independent determinants of risk of progression, whereas addition of homeostasis model assessment of insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0.025) but not in those with preserved FPIR (P = 0.3).

CONCLUSIONS—These data suggest that insulin resistance accelerates progression to type 1 diabetes in antibody-positive relatives in whom insulin secretion is markedly reduced but does not affect progression when insulin secretion is relatively well preserved.
Relationship of Polyunsaturated Fatty Acid Intake to Peripheral Neuropathy Among Adults With Diabetes in the National Health and Nutrition Examination Survey (NHANES) 1999–2004
Authors: Tao Min , McDowell Margaret A. , Saydah Sharon H. , Eberhardt Mark S.
Published: December 2007

OBJECTIVE—This study investigated the association between dietary intake of polyunsaturated fatty acids (PUFAs) and peripheral neuropathy in the U.S. population.

RESEARCH DESIGN AND METHODS—We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 for adults ≥40 years of age with diagnosed diabetes, an assessment of peripheral neuropathy, and reliable 24-h dietary recall. The dietary intake of PUFAs was analyzed by peripheral neuropathy status. Multivariate logistic regression models were used to estimate the odds of having peripheral neuropathy in higher quintiles of PUFA intake compared with the lowest quintile.

RESULTS—The mean dietary intake of linolenic acid was 1.25 ± 0.07 g among adults with peripheral neuropathy, significantly lower than the 1.45 ± 0.05 g intake among those without peripheral neuropathy. After controlling for potential confounding variables, adults whose linolenic acid intake was in the highest quintile had lower odds of peripheral neuropathy than adults in the lowest quintile (adjusted odds ratio 0.40 [95% CI 0.21–0.77]).

CONCLUSIONS—Among adults with diagnosed diabetes, dietary intake of linolenic acid is positively associated with lower odds of peripheral neuropathy.
Bloodletting Ameliorates Insulin Sensitivity and Secretion in Parallel to Reducing Liver Iron in Carriers of HFE Gene Mutations
Authors: Equitani Francesco , Fernandez-Real Josè Manuel , Menichella Giacomo , Koch Maurizio , Calvani Menotti , Nobili Valerio , Mingrone Geltrude , Manco Melania
Published: December 2007

OBJECTIVE—To clarify the pathogenesis of diabetes associated with mutations of the hemochromatosis (HFE) gene, 17 carriers, 9 normal glucose tolerant (NGT) and 8 diabetic, were evaluated in an interventional trial.

RESEARCH DESIGN AND METHODS—At enrollment and after a 2-year bloodletting period, euglycemic-hyperinsulinemic clamp, oral glucose tolerance test (OGTT), liver histology (nonalcoholic fatty liver disease activity score [NAS]), and liver iron content (LIC) were assessed.

RESULTS—NGT subjects had significantly higher baseline insulin sensitivity (P ≤ 0.001), secretion, and insulinogenic index (calculated from the OGTT) (P ≤ 0.0001 for both) and lower LIC (P = 0.004) and NAS (P = 0.02) than diabetic patients. Baseline LIC correlated negatively with insulin secretion (NGT r0 = −0.676, P ≤ 0.0001; diabetes r0 = −0.589, P = 0.02) and insulin sensitivity (M value) (NGT r0 = −0.597, P = 0.009; diabetes r0 = −0.535, P = 0.03) and positively with NAS (diabetes r0 = 0.649, P = 0.007) and triglycerides (NGT r0 = 0.563, P = 0.015). At month 24, circulating iron was reduced by 179 ± 26% in NGT and 284 ± 54% in diabetic subjects. Insulin secretion (NGT 20 ± 4%; diabetes 33 ± 7%) and insulin sensitivity (NGT 25 ± 5%; diabetes 18 ± 3%) increased. LIC decreased in both groups (NGT 126 ± 42%; diabetes 61 ± 13%), and NAS ameliorated (NGT 65.1 ± 6.5 vs. 38.1 ± 6.83; P ≤ 0.0001; diabetes 2.1 ± 10.7 vs. 69.9 ± 10; P ≤ 0.0001).

CONCLUSIONS—Iron depletion ameliorates insulin secretion and sensitivity in NGT and diabetic carriers of HFE gene mutations. This amelioration occurs in parallel with decreased LIC and improved NAS. These results justify glucose tolerance testing and prophylactic iron depletion in asymptomatic carriers as well.
A Variant of the Transcription Factor 7-Like 2 (TCF7L2) Gene and the Risk of Posttransplantation Diabetes Mellitus in Renal Allograft Recipients
Authors: Kang Eun Seok , Kim Myoung Soo , Kim Yu Seun , Hur Kyu Yeon , Han Seung Jin , Nam Chung Mo , Ahn Chul Woo , Cha Bong Soo , Kim Soon Il , Lee Hyun Chul
Published: December 2007

OBJECTIVE—Posttransplantation diabetes mellitus (PTDM) is a major complication associated with kidney transplantation. Defects in insulin secretion play a pivotal role in the pathogenesis of PTDM. A polymorphism in the transcription factor 7-like 2 (TCF7L2) gene was reported to be associated with type 2 diabetes and possibly associated with an insulin secretion defect. The aim of this study was to investigate the association between genetic variations in TCF7L2 and PTDM in renal allograft recipients.

RESEARCH DESIGN AND METHODS—A total of 511 unrelated renal allograft recipients without previously known diabetes were enrolled. Six single nucleotide polymorphisms (rs11196205, rs4506565, rs12243326, rs7903146, rs12255372, and rs7901695) were genotyped in the cohort, which consisted of 119 PTDM patients and 392 non-PTDM subjects. The genotyping of TCF7L2 polymorphisms was performed using real-time PCR.

RESULTS—rs4506565, rs7901695, and rs7903146 were found to be in complete linkage disequilibrium. The rs7903146 genotype distribution was CC 94.3% and CT 5.7%. The incidence of PTDM was significantly higher in patients with the CT genotype than in patients with the CC genotype (41.4 vs. 22.2%) (odds ratio 2.474 [95% CI 1.146–5.341]; P = 0.024). The effect of this genotype remains significant after adjustment for age, sex, amount of body weight gain, and type of immunosuppressant (2.655 [1.168–6.038]; P = 0.020).

CONCLUSIONS—These data suggest that the TCF7L2 rs7903146 genetic variation is associated with an increased risk of PTDM in renal allograft recipients.
Hypoglycemia in Pregnant Women With Type 1 Diabetes
Authors: Nielsen Lene Ringholm , Pedersen-Bjergaard Ulrik , Thorsteinsson Birger , Johansen Marianne , Damm Peter , Mathiesen Elisabeth R.
Published: December 2007

OBJECTIVE—In pregnancy with type 1 diabetes, we evaluated occurrence of mild and severe hypoglycemia and analyzed the influence of strict metabolic control, nausea, vomiting, and other potential predictors of occurrence of severe hypoglycemia.

RESEARCH DESIGN AND METHODS—A prospective observational study of 108 consecutive pregnant women with type 1 diabetes was conducted. At 8, 14, 21, 27, and 33 weeks of gestation, patients performed self-monitored plasma glucose (SMPG) (eight/day) for 3 days and completed a questionnaire on nausea, vomiting, hypoglycemia awareness, and history of mild (managed by the patient) and severe (requiring assistance from others) hypoglycemia.

RESULTS—Forty-nine (45%) women experienced 178 severe hypoglycemic events, corresponding to 5.3, 2.4, and 0.5 events/patient-year in the first, second, and third trimesters, respectively. The incidence of mild hypoglycemia was 5.5 events/patient-week in early pregnancy and decreased throughout pregnancy (P < 0.0001), regardless of presence of severe hypoglycemia. Prevalence of nausea and vomiting, mild hypoglycemia, and fraction of SMPG readings ≤3.9 mmol/l did not differ between women with and without severe hypoglycemia. A1C, median SMPG, and fluctuations in SMPG decreased during pregnancy, with no differences between women with and without severe hypoglycemia. Logistic regression analysis identified history of severe hypoglycemia the year preceding pregnancy (odds ratio 3.3 [95% CI 1.2–9.2]) and impaired awareness or unawareness (3.2 [1.2–8.2]) as independent predictors for severe hypoglycemia.

CONCLUSIONS—In pregnancy with type 1 diabetes, the incidence of mild and severe hypoglycemia was highest in early pregnancy, although metabolic control was tighter in the last part of pregnancy. Predictors for severe hypoglycemia were history of severe hypoglycemia and impaired awareness.
Increased Risks of Hip Fracture in Diabetic Patients of Taiwan
Authors: Chen Hua-Fen , Ho Ching-An , Li Chung-Yi
Published: December 2007

OBJECTIVE—Using Taiwan's National Health Insurance claim data, we evaluated the age-, sex-, and urbanization-specific incidence density and relative risks of hip fracture in the diabetic population.

RESEARCH DESIGN AND METHODS—Diabetic patients (n = 500,868) and an age- and sex-matched control group (n = 500,248) were linked to inpatient claims (1997–2002) to identify hospitalizations for nontransport accident hip fracture. The person-year approach with Poisson assumption and Kaplan-Meier analysis were used to estimate the incidence and the cumulative event rates. We also assessed the age-, sex-, and urbanization-specific relative risks of hip fracture in relation to diabetes with the Cox proportional hazard regression model.

RESULTS—The overall incidences of hip fracture for diabetic men and women, respectively, were 3.01 and 6.75/1,000 person-years, which were higher than those for control men and women. There were significant interactions of diabetes and age and diabetes and urbanization statuses. Hazard ratios (HRs) of diabetic patients aged 35–44 years (men 2.45 [95% CI 1.65–3.64]; women 3.19 [1.39–7.33]) were higher than those of diabetic patients aged 55–64 years (men 1.90; women 2.81), but in diabetic men aged >74 years and diabetic women aged >84 years, the HRs were compared with null statistically (HRs 0.98 and 0.91, respectively). Diabetic patients living in rural areas tended to have higher HRs of hip fracture.

CONCLUSIONS—In Taiwan, diabetes increased the risk of hip fracture in both sexes in all age-groups except in diabetic men aged >74 years and diabetic women aged >84 years. Higher HRs of hip fracture were disproportionately observed in younger diabetic patients and in those living in rural areas.
Advancing Insulin Therapy in Type 2 Diabetes Previously Treated With Glargine Plus Oral Agents
Authors: Rosenstock Julio , Ahmann Andrew J. , Colon Gildred , Scism-Bacon Jamie , Jiang Honghua , Martin Sherry
Published: December 2007

OBJECTIVE—The purpose of this study was to compare two analog insulin therapies (prandial premixed therapy [PPT] versus basal/bolus therapy [BBT]) in type 2 diabetic patients previously treated with insulin glargine (≥30 units/day) plus oral agents, with the aim of demonstrating noninferiority of PPT to BBT.

RESEARCH DESIGN AND METHODS—Patients were randomly assigned to PPT (lispro mix 50/50: 50% insulin lispro protamine suspension and 50% lispro; n = 187) t.i.d. with meals or BBT (glargine at bedtime plus mealtime lispro; n = 187) in a 24-week, multicenter, open-label, noninferiority trial. Investigators could replace lispro mix 50/50 with lispro mix 75/25 at the evening meal if the fasting plasma glucose target was unachievable.

RESULTS—Baseline A1C was similar (PPT 8.8%; BBT 8.9%; P = 0.598). At week 24, A1C was lower with BBT (6.78 vs. 6.95%, P = 0.021). A1C was reduced significantly from baseline for both therapies (P < 0.0001). The difference in A1C change from baseline to the end point (BBT minus PPT) was −0.22% (90% CI −0.38 to −0.07). Noninferiority of PPT to BBT was not demonstrated based on the prespecified noninferiority margin of 0.3%. The percentages of patients achieving target A1C <7.0% (PPT versus BBT, respectively) were 54 vs. 69% (P = 0.009) and for target ≤6.5% were 35 vs. 50% (P = 0.01) but did not differ for target ≤6.0% or <7.5%. Rates of hypoglycemia were similar for both groups.

CONCLUSIONS—Although noninferiority of PPT to BBT was not demonstrated, findings for A1C reduction, percentage of patients achieving A1C targets, hypoglycemia, and number of required injections should be considered in the individual decision-making process of advancing insulin replacement to PPT versus BBT in type 2 diabetes.