bluuebunny/crossref_metadata_2025 huggingface dataset:
Trisomy 18 and Trisomy 13
Authors: Merritt T. Allen , Catlin Anita , Wool Charlotte , Peverini Ricardo , Goldstein Mitchell , Oshiro Bryan
Published: December 2011

In this paper, we review the complex medical, ethical, and psychosocial decisions that confront maternal fetal medicine specialists, neonatologists, parents, nurses, and other providers in the management of infants diagnosed with two chromosomal conditions generally considered as lethal anomalies. We examine the complex decision-making processes in contemporary US neonatology, including the ethical precepts of professional paternalism and parental autonomy. Medical approaches, ethical dilemmas, and the role of perinatal palliative care are discussed. Education of parents regarding medical and developmental outcomes of affected infants, disclosure of values between physicians and parents, an understanding of the role and limitations of autonomy, transparency in the dialogue among all parties regarding the principle of “best interest” for affected infants, and the medical axiom of not doing harm are essential components in the management decisions.
Cuidado humanístico e percepções de enfermagem diante da dor do recém-nascido
Authors: Lélis Ana Luíza Paula de Aguiar , Farias Leiliane Martins , Cipriano Maria Aneuma Bastos , Cardoso Maria Vera Lúcia Moreira Leitão , Galvão Marli Teresinha Gimeniz , Caetano Joselany Afio
Published: January 2012

Este estudo objetivou apreender o significado do cuidado oferecido pelo enfermeiro ao recém-nascido em procedimentos dolorosos e conhecer as intervenções realizadas pelos enfermeiros para amenizar a dor do recém-nascido. Estudo descritivo, realizado na Unidade de Terapia Intensiva Neonatal de um hospital público de Fortaleza-CE em julho/2010. Os sujeitos foram dez enfermeiras, e a coleta de dados se realizou através de um questionário. Os dados foram organizados em três categorias: O significado de cuidado diante da dor do recém-nascido; a assistência humanizada junto ao recém-nascido; e intervenções de enfermagem diante da dor do recém-nascido. Estes foram analisados à luz da Teoria Humanística de Paterson e Zderad. Constatou-se que o cuidado ao recém-nascido deveria ser direcionado a minimizar os fatores estressores durante a situação dolorosa e que as intervenções citadas foram predominantemente não farmacológicas, envolvendo ações desenvolvidas para a recém-nascido e o ambiente da Unidade.
Redução do nível de proteína bruta em rações para frangos de corte em ambiente de termoneutralidade
Authors: Oliveira Will Pereira de , Oliveira Rita Flávia Miranda de , Donzele Juarez Lopes , Albino Luiz Fernando Teixeira , Martins Mariana dos Santos , Maia Ana Paula de Assis
Published: January 2012

O experimento foi realizado para avaliar o efeito da redução do nível de proteína bruta (PB) da ração formulada de acordo com o conceito de proteína ideal e suplementada com aminoácidos industriais, sobre o desempenho e rendimento de cortes de frangos de corte machos de 22 a 42 dias de idade mantidos em ambiente termoneutro. Foram utilizados 280 frangos de corte machos "Cobb" com peso inicial de 856 ± 6,48 g, distribuídos em delineamento experimental inteiramente casualizado, com cinco tratamentos (21,6; 20,6; 19,6; 18,6 e 17,6% de PB), oito repetições de sete aves por unidade experimental. A temperatura no interior da sala foi mantida em 21,6 ± 0,7ºC, a umidade relativa em 74 ± 4,0% e a temperatura de globo negro em 22,5 ± 0,7ºC. O índice de temperatura de globo e umidade (ITGU) calculado para o período foi de 70 ± 0,9. Não houve efeito da redução dos níveis de PB sobre o ganho de peso e o consumo de ração, entretanto, a conversão alimentar foi influenciada pela redução dos níveis de PB sendo que as aves alimentadas com a ração que continha 22,0% de PB apresentaram o melhor resultado. A redução dos níveis de PB não influenciou o peso absoluto de carcaça e os pesos absoluto e relativo de peito, coxa e sobrecoxa. A redução do nível de PB da ração, de 21,6 para 17,6%, e formulada de acordo com o conceito de proteína ideal piora a conversão alimentar dos frangos de corte mantidos em ambiente termoneutro, não influenciando as demais variáveis estudadas.
Avaliação sensorial da carne de cordeiros machos e fêmeas Texel × Corriedale terminados em diferentes sistemas
Authors: Bonacina Marlice Salete , Osório Maria Teresa Moreira , Osório José Carlos da Silveira , Corrêa Gladis Ferreira , Hashimoto Juliano Hideo , Lehmen Rosilene Inês
Published: January 2012

O objetivo neste trabalho foi avaliar o efeito do sexo e de três sistemas de terminação nas características sensoriais da carne de cordeiros Texel × Corriedale e na aceitação da carne pelo consumidor. Foram utilizados 90 animais, 45 cordeiros machos não-castrados e 45 fêmeas mantidos em pastagem até o desmame (70 dias) e terminados em três sistemas de produção: pastagem; pastagem ao pé da mãe; e pastagem com suplementação (casca de soja em nível correspondente a 1% do peso vivo dos cordeiros). Após o abate, as carcaças foram armazenadas em câmara fria, com ar forçado, a 1ºC, durante 24 horas, para retirada do músculo longissimus dorsi, que foi congelado a -18ºC para análise sensorial. A caracterização sensorial da carne foi realizada por meio da análise descritiva quantitativa: 22 termos descritivos foram desenvolvidos por uma equipe de julgadores selecionados, que geraram também a definição de cada termo e as amostras-referência. Foi realizado um teste de aceitação utilizando escala hedônica híbrida de nove pontos. A carne dos machos e dos animais terminados em pastagem ao pé da mãe caracterizou-se pelo odor e sabor residual mais suaves de carne ovina e gordura, menor maciez e maior mastigabilidade em comparação à das fêmeas e dos animais terminados nos demais sistemas. As carnes dos cordeiros terminados nos sistemas de pastagem e de pastagem com suplementação são semelhantes quanto aos aspectos sensoriais. A carne é igualmente aceita pelos consumidores, independentemente do sexo e do sistema de terminação, apresentando boa aceitação.
Current Status of Autologous Stem Cell Transplantation in Relapsed and Refractory Hodgkin's Lymphoma
Authors: Colpo Anna , Hochberg Ephraim , Chen Yi-Bin
Published: December 2011

Despite the relatively high long-term disease-free survival (DFS) rate for patients with Hodgkin lymphoma (HL) with modern combination chemotherapy or combined modality regimens, ∼20% of patients die from progressive or relapsed disease. The standard treatment for relapsed and primary refractory HL is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), which has shown a 5-year progression-free survival rate of ∼50%–60%. Recent developments in a number of diagnostic and therapeutic modalities have begun to improve these results. Functional imaging, refinement of clinical prognostic factors, and development of novel biomarkers have improved the predictive algorithms, allowing better patient selection and timing for ASCT. In addition, these algorithms have begun to identify a group of patients who are candidates for more aggressive treatment beyond standard ASCT. Novel salvage regimens may potentially improve the rate of complete remission prior to ASCT, and the use of maintenance therapy after ASCT has become a subject of current investigation. We present a summary of developments in each of these areas.
Phase II Trial of Erlotinib and Docetaxel in Advanced and Refractory Hepatocellular and Biliary Cancers: Hoosier Oncology Group GI06-101
Authors: Chiorean E. Gabriela , Ramasubbaiah Rashmi , Yu Menggang , Picus Joel , Bufill Jose A. , Tong Yan , Coleman Nicki , Johnston Erica L. , Currie Colleen , Loehrer Patrick J.
Published: December 2011

Background.

Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti-EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti-EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers.

Methods.

Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2–7, 9–14, 16–28 of each 28-day cycle. The primary endpoint was 16 weeks progression-free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E-cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two-stage initial design of the study, combined PFS was considered. A Simon optimal two-stage design tested the hypothesis that the 16-week PFS is ≤ 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study).

Results.

Twenty-five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7–56.3) for BTC, and 17.6 weeks (95% CI 8.1–49.8) for HCC. The 16-week PFS was 64% for BTC (95% CI 29.7–84.5), and 38% for HCC (95% CI 14.1–62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs 4.2 months). HCC patients with negative/low E-cadherin expression had higher median PFS (6.7 vs 2.1 months) and OS (14.5 vs 4 months).

Conclusion.

Erlotinib with docetaxel met the 16-week PFS ≥ 30% endpoint,but overall survival was comparable to that seen with single-agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E-cadherin expression (HCC) were associated with higher PFS and OS.
Is There Such a Thing as a Cancer Treatment That Isn't Worth Its Cost?
Authors: Gilligan Timothy
Published: December 2011

The point at which a cancer treatment is deemed to be too expensive is considered.
Panitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab
Authors: Wadlow Raymond C. , Hezel Aram F. , Abrams Thomas A. , Blaszkowsky Lawrence S. , Fuchs Charles S. , Kulke Matthew H. , Kwak Eunice L. , Meyerhardt Jeffrey A. , Ryan David P. , Szymonifka Jackie , Wolpin Brian M. , Zhu Andrew X. , Clark Jeffrey W.
Published: December 2011

Purpose.

Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type metastatic colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab.

Patients and Methods.

We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve patients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies.

Results.

We treated twenty patients for a median of two cycles (range 1–4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1–2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies.

Conclusions.

Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab.
Review Paper: Multi‐primary‐color displays: The latest technologies and their benefits
Authors: Teragawa Masatsugu , Yoshida Akiko , Yoshiyama Kazuyoshi , Nakagawa Shinji , Tomizawa Kazunari , Yoshida Yasuhiro
Published: January 2012

Abstract— Multi‐primary‐color (MPC) display technology is one of the fastest emerging research areas in recent years. Wide‐color‐gamut display devices have been required for visually sufficient and/or accurate color reproduction. It is well known that MPC displays can reproduce accurate colors with high efficiency. In addition, not only the image‐quality improvement but some other performance of display devices is also required for display devices. This paper reviews achievements in MPC display technologies and focuses on the benefits of MPC displays: power‐savings and high resolution.
Effects of localized warpage and stress on chip‐on‐glass packaging: Induced light‐leakage phenomenon in mid‐sized TFT‐LCD
Authors: Leu Jihperng , Chang Chin‐Cheng , Chen Alexander , Lin Mao‐Hsing , Huang Kun‐Feng
Published: January 2012

Abstract— Mura defects become visible in a 13.3‐in. TFT‐LCD using chip‐on‐glass (COG) packaging when the thickness of the glass substrate is decreased from 0.5 to 0.3 mm. Mura, the non‐uniform brightness in LCDs, is caused by COG packaging due to the mismatch of the coefficient of thermal expansion (CTE) and Young's modulus between the glass substrate and the IC‐driver Si chips. In this paper, a 3‐D finite‐element‐analysis (FEA) model, coupled with transient thermal analysis is first established to examine the warpage and stress behavior in the upper‐glass‐plate post‐COG‐package processing for identifying the root causes of the light‐leakage phenomenon. Prior to that, the simulated warpage results are validated by surface‐contour measurement. Data and modeling results show that a low bonding temperature together with a low modulus in novel ACF materials can effectively eliminate Mura. Besides, thinner silicon or a shorter length of Si chips as drivers offers enhanced reduction in the localized warpage, and thus can be a practical and low‐cost solution for eliminating mura defects.
Participant Responses to Retrospective Surveys of Child Maltreatment: Does Mode of Assessment Matter?
Authors: DiLillo David , DeGue Sarah , Kras Amanda , Di Loreto-Colgan Andrea R. , Nash Cindy
Published: December 2011

This study examines the impact that different methods of assessing child maltreatment history may have on adult participants. A total of 334 female undergraduate students were randomly assigned to complete a retrospective measure of child sexual and physical abuse in one of three conditions: paper-and-pencil questionnaire, face-to-face interview, or computer-administered survey. Disclosure rates of abuse, psychological distress and mood change, preferences for assessment format, and perceptions of confidentiality were examined across the three assessment formats. Although disclosure did not vary by condition, participants with a history of abuse reported more distress and mood change than did nonvictims, particularly in the computer condition. Nevertheless, the computer condition was rated as the most preferred format and was viewed by participants as the most confidential means of assessing maltreatment history. Participants reporting abuse through interviews were more likely than those in other conditions to state a preference for another type of assessment format. The implications of these findings for abuse history research are discussed.
Sensitive Research With Adolescents: Just How Upsetting Are Self-Report Surveys Anyway?
Authors: Langhinrichsen-Rohling Jennifer , Arata Catalina , O’Brien Natalie , Bowers David , Klibert Jeffrey
Published: December 2011

Distress related to answering personal survey questions about drug use, suicidal behavior, and physical and sexual abuse were examined in multiple convenience samples of adolescents. Samples varied in consent procedures utilized (active vs. passive parental consent), data collection setting (school vs. juvenile justice), developmental level (middle school vs. high school). Participation rates differed across consent procedures (e.g., 93% with passive vs. 62% with active parental consent). Results indicated that small percentages of adolescents in every sample reported frequently feeling upset while completing the survey (range 2.5% to 7.6%). Age, race, gender, and data collection strategy did not emerge as significant predictors of feeling upset. Instead, as hypothesized, adolescents reporting a history of suicidal ideation or attempt, illicit drug use, or experiences of physical or sexual victimization endorsed more frequent feelings of upset while completing the survey than peers without these experiences. Taken together, however, these sensitive event experiences explained only 6.6% of the variance in adolescents’ upset ratings. The scientific and ethical implications of these findings are discussed with regard to adolescent participation in survey research about sensitive topics.
Sexual Assault Survivors’ Reactions to a Thought Suppression Paradigm
Authors: Rabenhorst Mandy M.
Published: December 2011

Trauma survivors may experience harm from participating in research on sensitive topics. The current study assessed reactions of sexual assault survivors with and without symptoms of post-traumatic stress disorder (PTSD) immediately following an experimental thought suppression task and at a 2- to 4-week follow-up period, by asking open-ended questions regarding thoughts about the experiment, feelings following the experiment, and willingness to participate in similar experiments. At both time periods, most participants reported neutral/positive thoughts (e.g., “interesting”) and feelings (e.g., “fine, good”) and indicated that they would participate in a similar study. Findings suggest that the majority of sexual assault survivors were not harmed in the short- or long-term by participation in a thought suppression paradigm in which the target of suppression/expression was their own trauma.
Effects of Method on Participants and Disclosure Rates in Research on Sensitive Topics
Authors: Reddy Madhavi K. , Fleming Matthew T. , Howells Nicolette L. , Rabenhorst Mandy M. , Casselman Robert , Rosenbaum Alan
Published: December 2011

This study replicates and extends the research of Rosenbaum, Rabenhorst, Reddy, Fleming, and Howells, which also appears in this special issue. Responses from 398 randomly assigned participants regarding differentially sensitive topics were collected via four methods of data collection: written questionnaires, face-to-face interviews, telephone interviews, and an automated telephonic data collection system (ATDC). Several significant differences in data collection methodology and topic area were found, including greater disclosure of sensitive information via the ATDC system than via face-to-face and paper-and-pencil conditions. Participants who were assigned to the ATDC condition felt significantly more comfortable answering questions compared to those in the face-to-face interview condition. Participants in the telephone interview condition reported answering significantly more carefully than participants answering via written questionnaire. Taken together, the results of this study and the previous one it replicates suggest that the ATDC produces disclosure rates that are at least equivalent to, if not greater than, those generated using traditional methods for collecting sensitive data.
Does Questionnaire Format Impact Reported Partner Violence Rates?: An Experimental Study
Authors: Hamby Sherry , Sugarman David B. , Boney-McCoy Sue
Published: December 2011

Researchers assess partner violence using numerous formats, but whether questionnaire format affects obtained rates has rarely been examined. We compared paper-and-pencil versus computer administrations, and standard Revised Conflict Tactics Scales (CTS2) categories versus dichotomous (yes/no) response categories, in a 2 × 2 experiment with 160 undergraduate students. Differential validity was also examined for gender. Results provide some support for the use of all formats, although sexual coercion rates showed more measurement variability than reports of psychological aggression, physical assault, or injury. Sexual coercion effects also differed by gender. The standard CTS2 categories resulted in more disclosures than dichotomous categories for some variables. Differences between computer and paper-and-pencil formats were generally minimal. More attention to the effects of questionnaire design on disclosures of violence is urgently needed.
How Do I Tell Thee? Voice, Pen, or Computer Key
Authors: O’Leary K. Daniel
Published: December 2011

In this issue, the previous two articles by Hamby and colleagues and Vega and O’Leary are concerned with whether the method of administration and format of the Conflict Tactics Scale influence participant responses. Because they examine different aspects of the same measure, I was asked to conclude the issue by writing a brief summary and integration of the two articles.
Effects of Low‐Dose Doxycycline and Bisphosphonate Clodronate on Alveolar Bone Loss and Gingival Levels of Matrix Metalloproteinase‐9 and Interleukin‐1β in Rats With Diabetes: A Histomorphometric and Immunohistochemical Study
Authors: Özdemir Selin P. , Kurtiş Bülent , Tüter Gülay , Bozkurt Şeyma , Gültekin Sibel Elif , Sengüven Burcu , Watanabe Keiko , Aydın Sevtap
Published: January 2012

Background: Bisphosphonates (BPs) and low‐dose doxycycline (LDD) have been shown to inhibit bone resorption and to improve the levels of proinflammatory mediators and destructive enzymes in gingival tissues, respectively. The purpose of this study is to evaluate the effect of mono and combined BP clodronate and LDD therapies in reducing gingival levels of matrix metalloproteinase‐9 (MMP‐9), interleukin‐1β (IL‐1β), and alveolar bone loss in rats with diabetes.

Methods: Fifty adult Wistar rats were divided into five study groups as follows: 1) group 1 = diabetes control; 2) group 2 = diabetes + periodontitis; 3) group 3 = diabetes + periodontitis + LDD; 4) group 4 = diabetes + periodontitis + clodronate; and 5) group 5 = diabetes + periodontitis + LDD + clodronate. LDD and clodronate were given as a single agent or as combination therapy during the 7 days of the post‐experimental periodontitis period. On day 7, the rats were sacrificed, the mobility of the tooth was recorded, and block biopsies were removed. The gingival tissues were analyzed histologically and immunohistochemically for expression of MMP‐9 and IL‐1β. Alveolar bone loss was evaluated morphometrically under a light microscope. Data analysis was performed statistically by Kruskal‐Wallis and post hoc Tukey and Spearman correlation tests.

Results: Alveolar bone loss was significantly greater in groups 2 through 5 than group 1 (P <0.05) but was not significantly different among groups 2 through 5 (P >0.05). Animals with periodontitis (group 2) expressed significantly higher levels of MMP‐9 and IL‐1β compared with those without periodontitis (group 1) (P <0.05). MMP‐9 expression was significantly lower in group 3 than groups 1, 2, and 5 (P <0.05). IL‐1β expression was significantly lower in the groups 1, 3, 4, and 5 than 2 (P <0.01) but was not significantly different among groups 1, 3, 4, and 5. Positive correlations were found between alveolar bone loss and density of inflammation (ρ = 0.319, P = 0.021) and between MMP‐9 and IL‐1β (ρ = 0.418, P = 0.002), respectively.

Conclusion: Our findings suggest that ligature‐induced periodontitis in animals with diabetes results in significantly higher levels of MMP‐9 and IL‐1β expression in gingiva. The use of mono and combined clodronate and LDD administrations may significantly reduce levels of MMP‐9 and IL‐1β expression. However, drug administration did not affect alveolar bone levels during the study period.
The Impact of Household Investments on Early Child Neurodevelopment and on Racial and Socioeconomic Developmental Gaps: Evidence from South America
Authors: Wehby George L. , McCarthy Ann Marie , Castilla Eduardo , Murray Jeffrey C.
Published: December 2011

This paper assesses the effects of household investments through child educating activities on child neurodevelopment between the ages of 3 and 24 months, and evaluates whether investments explain racial and socioeconomic developmental gaps in South America. Quantile regression is used to evaluate the heterogeneity in investment effects by unobserved developmental endowments. The study finds large positive investment effects on early child neurodevelopment, with generally larger effects among children with low developmental endowments (children at the left margin of the development distribution). Investments explain part of the observed racial gaps and the whole socioeconomic developmental gap. Investments may compensate for low endowments and policy interventions to increase investments may reduce early development gaps and result in high social and economic returns.
The Economics of the Long Tail
Authors: Kendall Todd D. , Tsui Kevin
Published: December 2011

Anderson (2006) argues that e-commerce and other new technologies improve efficiency by encouraging the entry of new producers and innovations, creating a “long tail” of niche products while reducing the market share of previously popular products. We study the strategic interaction between hits and niches in their pricing, entry, and innovation decisions using a model of competition under product differentiation and generalized cost structure. In contrast to the popular view, we show that improvements in information and communication technology can lead to either the long tail effect or an opposite “superstar” effect (Rosen, 1981), depending on (a) how the structure (not simply the level) of producer costs changes, and (b) how disparate are consumer preferences. These two factors also determine whether there is excessive or insufficient product diversity. Post-entry product and technology innovation incentives may be inefficient in the long tail market structure because producers can soften price competition by engaging in excessive product differentiation and adopting technologies with high variable costs. These results have implications for various competition-related policies.
“Incorporating” American Colonialism: Accounting and the Alaska Native Claims Settlement Act
Authors: Thornburg Steven W. , Roberts Robin W.
Published: January 2012

The history of Alaska is a colonial history (Pomeroy 1947; Haycox 2002). The purpose of this paper is to examine how the corporate form of organization and corporate accounting were used by the United States (U.S.) government to rationalize decisions, exercise control, and exploit Alaskan resources to benefit corporate America and the existing U.S. states. The Alaska Native Claims Settlement Act of 1971 (ANCSA) established Alaska Native Corporations (ANCs), whose stock was distributed to qualifying Alaska Natives in exchange for their agreement to extinguish all aboriginal land claims. Guided by prior work in accounting and postmodern colonialism, our analysis uncovers ways in which ANCSA, though lauded by the U.S. government as an innovative and generous settlement, perpetuated a historical pattern of indigenous exploitation by western economic interests, and employed corporate accounting policies and techniques to further the interests of the U.S. government and large corporations at the expense of Native Alaskans.
Apelin Treatment Increases Complete Fatty Acid Oxidation, Mitochondrial Oxidative Capacity, and Biogenesis in Muscle of Insulin-Resistant Mice
Authors: Attané Camille , Foussal Camille , Le Gonidec Sophie , Benani Alexandre , Daviaud Danièle , Wanecq Estelle , Guzmán-Ruiz Rocío , Dray Cédric , Bezaire Veronic , Rancoule Chloé , Kuba Keiji , Ruiz-Gayo Mariano , Levade Thierry , Penninger Josef , Burcelin Rémy , Pénicaud Luc , Valet Philippe , Castan-Laurell Isabelle
Published: December 2011

Both acute and chronic apelin treatment have been shown to improve insulin sensitivity in mice. However, the effects of apelin on fatty acid oxidation (FAO) during obesity-related insulin resistance have not yet been addressed. Thus, the aim of the current study was to determine the impact of chronic treatment on lipid use, especially in skeletal muscles. High-fat diet (HFD)-induced obese and insulin-resistant mice treated by an apelin injection (0.1 μmol/kg/day i.p.) during 4 weeks had decreased fat mass, glycemia, and plasma levels of triglycerides and were protected from hyperinsulinemia compared with HFD PBS-treated mice. Indirect calorimetry experiments showed that apelin-treated mice had a better use of lipids. The complete FAO, the oxidative capacity, and mitochondrial biogenesis were increased in soleus of apelin-treated mice. The action of apelin was AMP-activated protein kinase (AMPK) dependent since all the effects studied were abrogated in HFD apelin-treated mice with muscle-specific inactive AMPK. Finally, the apelin-stimulated improvement of oxidative capacity led to decreased levels of acylcarnitines and enhanced insulin-stimulated glucose uptake in soleus. Thus, by promoting complete lipid use in muscle of insulin-resistant mice through mitochondrial biogenesis and tighter matching between FAO and the tricarboxylic acid cycle, apelin treatment could contribute to insulin sensitivity improvement.
Heterozygous Mutations Causing Partial Prohormone Convertase 1 Deficiency Contribute to Human Obesity
Authors: Creemers John W.M. , Choquet Hélène , Stijnen Pieter , Vatin Vincent , Pigeyre Marie , Beckers Sigri , Meulemans Sandra , Than Manuel E. , Yengo Loïc , Tauber Maithé , Balkau Beverley , Elliott Paul , Jarvelin Marjo-Riitta , Van Hul Wim , Van Gaal Luc , Horber Fritz , Pattou François , Froguel Philippe , Meyre David
Published: December 2011

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.
Potential Role of Tumor Necrosis Factor-α in Downregulating Sex Hormone–Binding Globulin
Authors: Simó Rafael , Barbosa-Desongles Anna , Lecube Albert , Hernandez Cristina , Selva David M.
Published: December 2011

Low plasma sex hormone–binding globulin (SHBG) levels are associated with obesity and predict the development of type 2 diabetes. The reason why obese individuals have low circulating SHBG has been attributed to hyperinsulinemia, but no mechanistic evidence has been described. The aim of the current study is to explore whether tumor necrosis factor-α (TNF-α) rather than insulin could be the main factor accounting for low SHBG levels in obesity. We performed in vitro and in vivo studies using human HepG2 cells and human SHBG transgenic mice. In addition, a cross-sectional study to explore the relationship between TNF-α and SHBG in obese patients and an interventional study to examine the effect of insulin administration on circulating SHBG in type 2 diabetic patients were performed. We provide evidence that TNF-α, but not insulin, is the main factor by which SHBG is reduced in obesity. Plasma SHBG was significantly increased rather than decreased after insulin treatment in diabetic patients. TNF-α–induced reduction of SHBG expression was mediated by downregulating HNF4A. Finally, a negative and independent correlation was found between plasma TNF-α receptor 1 and SHBG levels in obese patients. Our results suggest that TNF-α plays an important role downregulating SHBG in chronic low-grade inflammatory diseases such as obesity and type 2 diabetes.
Low-Frequency Variants in HMGA1 Are Not Associated With Type 2 Diabetes Risk
Authors: Marquez Marcel , Huyvaert Marlène , Perry John R.B. , Pearson Richard D. , Falchi Mario , Morris Andrew P. , Vivequin Sidonie , Lobbens Stéphane , Yengo Loïc , Gaget Stefan , Pattou Francois , Poulain-Godefroy Odile , Charpentier Guillaume , Carlsson Lena M.S. , Jacobson Peter , Sjöström Lars , Lantieri Olivier , Heude Barbara , Walley Andrew , Balkau Beverley , Marre Michel ,   the DIAGRAM Consortium, Froguel Philippe , Cauchi Stéphane
Published: December 2011

It has recently been suggested that the low-frequency c.136–14_136–13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136–14_136–13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136–14_136–13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.
FGF21 Analogs of Sustained Action Enabled by Orthogonal Biosynthesis Demonstrate Enhanced Antidiabetic Pharmacology in Rodents
Authors: Mu James , Pinkstaff Jason , Li Zhihua , Skidmore Lillian , Li Nina , Myler Heather , Dallas-Yang Qing , Putnam Anna-Maria , Yao Jun , Bussell Stuart , Wu Margaret , Norman Thea C. , Rodriguez Carlos G. , Kimmel Bruce , Metzger Joseph M. , Manibusan Anthony , Lee Darin , Zaller Dennis M. , Zhang Bei B. , DiMarchi Richard D. , Berger Joel P. , Axelrod Douglas W.
Published: December 2011

Fibroblast growth factor 21 (FGF21) mitigates many of the pathogenic features of type 2 diabetes, despite a short circulating half-life. PEGylation is a proven approach to prolonging the duration of action while enhancing biophysical solubility and stability. However, in the absence of a specific protein PEGylation site, chemical conjugation is inherently heterogeneous and commonly leads to dramatic loss in bioactivity. This work illustrates a novel means of specific PEGylation, producing FGF21 analogs with high specific activity and salutary biological activities. Using homology modeling and structure-based design, specific sites were chosen in human FGF21 for site-specific PEGylation to ensure that receptor binding regions were preserved. The in vitro activity of the PEGylated FGF21 ana-logs corresponded with the site of PEG placement within the binding model. Site-specific PEGylated analogs demonstrated dramatically increased circulating half-life and enhanced efficacy in db/db mice. Twice-weekly dosing of an optimal FGF21 analog reduced blood glucose, plasma lipids, liver triglycerides, and plasma glucagon and enhanced pancreatic insulin content, islet number, and glucose-dependent insulin secretion. Restoration of insulin sensitivity was demonstrated by the enhanced ability of insulin to induce Akt/protein kinase B phosphorylation in liver, muscle, and adipose tissues. PEGylation of human FGF21 at a specific and preferred site confers superior metabolic pharmacology.
Expression and Regulation of Chemokines in Murine and Human Type 1 Diabetes
Authors: Sarkar Suparna A. , Lee Catherine E. , Victorino Francisco , Nguyen Tom T. , Walters Jay A. , Burrack Adam , Eberlein Jens , Hildemann Steven K. , Homann Dirk
Published: December 2011

More than one-half of the ~50 human chemokines have been associated with or implicated in the pathogenesis of type 1 diabetes, yet their actual expression patterns in the islet environment of type 1 diabetic patients remain, at present, poorly defined. Here, we have integrated a human islet culture system, murine models of virus-induced and spontaneous type 1 diabetes, and the histopathological examination of pancreata from diabetic organ donors with the goal of providing a foundation for the informed selection of potential therapeutic targets within the chemokine/receptor family. Chemokine (C-C motif) ligand (CCL) 5 (CCL5), CCL8, CCL22, chemokine (C-X-C motif) ligand (CXCL) 9 (CXCL9), CXCL10, and chemokine (C-X3-C motif) ligand (CX3CL) 1 (CX3CL1) were the major chemokines transcribed (in an inducible nitric oxide synthase–dependent but not nuclear factor-κB–dependent fashion) and translated by human islet cells in response to in vitro inflammatory stimuli. CXCL10 was identified as the dominant chemokine expressed in vivo in the islet environment of prediabetic animals and type 1 diabetic patients, whereas CCL5, CCL8, CXCL9, and CX3CL1 proteins were present at lower levels in the islets of both species. Of importance, additional expression of the same chemokines in human acinar tissues emphasizes an underappreciated involvement of the exocrine pancreas in the natural course of type 1 diabetes that will require consideration for additional type 1 diabetes pathogenesis and immune intervention studies.
Global DNA Methylation Is Associated With Insulin Resistance
Authors: Zhao Jinying , Goldberg Jack , Bremner James D. , Vaccarino Viola
Published: December 2011

Insulin resistance (IR), the hallmark of type 2 diabetes, may be under epigenetic control. This study examines the association between global DNA methylation and IR using 84 monozygotic twin pairs. IR was estimated using homeostasis model assessment (HOMA). Global DNA methylation of Alu repeats in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between global DNA methylation and IR was examined using generalized estimating equation (GEE) and within–twin pair analyses, adjusting for potential confounders. Results show that methylation levels at all four CpG sites were individually associated with IR by GEE (all false discovery rate–adjusted P values ≤0.026). A 10% increase in mean Alu methylation was associated with an increase of 4.55 units (95% CI 2.38–6.73) in HOMA. Intrapair difference in IR was significantly associated with intrapair difference in global methylation level. A 10% increase in the difference in mean Alu methylation was associated with an increase of 4.54 units (0.34–8.71; P = 0.036) in the difference in HOMA. Confirmation of the results by intrapair analyses suggests that genetic factors do not confound the association between global DNA methylation and IR. Exclusion of twins taking diabetes medication (n = 17) did not change our results.
Brain Glucose Sensors Play a Significant Role in the Regulation of Pancreatic Glucose-Stimulated Insulin Secretion
Authors: Osundiji Mayowa A. , Lam Daniel D. , Shaw Jill , Yueh Chen-Yu , Markkula S. Pauliina , Hurst Paul , Colliva Carolina , Roda Aldo , Heisler Lora K. , Evans Mark L.
Published: December 2011

As patients decline from health to type 2 diabetes, glucose-stimulated insulin secretion (GSIS) typically becomes impaired. Although GSIS is driven predominantly by direct sensing of a rise in blood glucose by pancreatic β-cells, there is growing evidence that hypothalamic neurons control other aspects of peripheral glucose metabolism. Here we investigated the role of the brain in the modulation of GSIS. To examine the effects of increasing or decreasing hypothalamic glucose sensing on glucose tolerance and insulin secretion, glucose or inhibitors of glucokinase, respectively, were infused into the third ventricle during intravenous glucose tolerance tests (IVGTTs). Glucose-infused rats displayed improved glucose handling, particularly within the first few minutes of the IVGTT, with a significantly lower area under the excursion curve within the first 10 min (AUC0-10). This was explained by increased insulin secretion. In contrast, infusion of the glucokinase inhibitors glucosamine or mannoheptulose worsened glucose tolerance and decreased GSIS in the first few minutes of IVGTT. Our data suggest a role for brain glucose sensors in the regulation of GSIS, particularly during the early phase. We propose that pharmacological agents targeting hypothalamic glucose-sensing pathways may represent novel therapeutic strategies for enhancing early phase insulin secretion in type 2 diabetes.
Glucocorticoid Signaling in the Arcuate Nucleus Modulates Hepatic Insulin Sensitivity
Authors: Yi Chun-Xia , Foppen Ewout , Abplanalp William , Gao Yuanqing , Alkemade Anneke , la Fleur Susanne E. , Serlie Mireille J. , Fliers Eric , Buijs Ruud M. , Tschöp Matthias H. , Kalsbeek Andries
Published: December 2011

Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic–euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic–euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC–induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism.
Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4)
Authors: Russell-Jones David , Cuddihy Robert M. , Hanefeld Markolf , Kumar Ajay , González Jose G. , Chan Melanie , Wolka Anne M. , Boardman Marilyn K. ,   on behalf of the DURATION-4 Study Group
Published: December 2011

OBJECTIVE

To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily.

RESULTS

Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were −1.53 vs. −1.48 (P = 0.620), −1.63 (P = 0.328), and −1.15 (P < 0.001), respectively. Weight changes (kg) were −2.0 vs. −2.0 (P = 0.892), +1.5 (P < 0.001), and −0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred.

CONCLUSIONS

EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.
Insulin Secretion and Its Determinants in the Progression of Impaired Glucose Tolerance to Type 2 Diabetes in Impaired Glucose-Tolerant Individuals
Authors: de Mello Vanessa D.F. , Lindström Jaana , Eriksson Johan , Ilanne-Parikka Pirjo , Keinänen-Kiukaanniemi Sirkka , Sundvall Jouko , Laakso Markku , Tuomilehto Jaakko , Uusitupa Matti
Published: December 2011

OBJECTIVE

We investigated the effect of early-phase insulin secretion on the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). We examined how a lifestyle intervention affected early-phase insulin secretion (ratio of total insulin area under the curve [AUC] and total glucose AUC [AIGR] from 0 to 30 min) during a 4-year follow-up intervention trial and whether AIGR0–30 response was modified by insulin sensitivity (IS) and obesity.

RESEARCH DESIGN AND METHODS

A total of 443 participants with IGT originally randomized to a lifestyle intervention or control group were studied. IS and AIGR0–30 were estimated from an oral tolerance glucose test administered annually during the 4-year follow-up trial and were related to the risk of diabetes onset over a 6-year follow-up.

RESULTS

Lifestyle intervention resulted in higher IS (P = 0.02) and lower unadjusted AIGR0–30 (P = 0.08) during the 4-year follow-up. A higher IS and a lower BMI during the follow-up were associated with a lower unadjusted AIGR0–30 during the follow-up, independently of study group (P < 0.001). A greater increase in IS on the median cutoff point of a 0.69 increase was associated with higher IS-adjusted AIGR0–30 during the follow-up (P = 0.002). In multivariate models, IS and IS-adjusted AIGR0–30 were both inversely associated with diabetes incidence (P < 0.001). Participants who progressed to type 2 diabetes were more obese and had lower IS and Matsuda IS index-AIGR0–30 than nonprogressors.

CONCLUSIONS

Our results indicate that the reduction in the risk of developing type 2 diabetes after lifestyle intervention is related to the improvement of IS along with weight loss. Improved IS may also have beneficial effects on preservation of β-cell function.