bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Health: Data, Trends and Indicators
Authors: Wright Kath , Harden Melissa , Misso Kate 
Published: January 2010

Several websites provide information about the health of the population including health indicators at regional and district levels. These allow health services researchers to access comparable statistics for different countries. This edition of ‘What's on the web’ lists some of the websites that provide easy access to reliable population health data and statistics. If you would like to alert readers to useful web pages or suggest topics for this column, please send details to:
Differential Effects of Tau on the Integrity and Function of Neurons Essential for Learning in Drosophila
Authors: Kosmidis Stylianos , Grammenoudi Sofia , Papanikolopoulou Katerina , Skoulakis Efthimios M. C. 
Published: January 2010

Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation, or mutations of the microtubule-binding protein Tau. The heterogeneous pathology in humans and model organisms suggests differential susceptibility of neuronal types to wild-type (WT) and mutant Tau. WT and mutant human Tau-encoding transgenes expressed pan-neuronally in theDrosophilaCNS yielded specific and differential toxicity in the embryonic neuroblasts that generate the mushroom body (MB) neurons, suggesting cell type-specific effects of Tau in the CNS. Frontotemporal dementia with parkinsonism-17-linked mutant isoforms were significantly less toxic in MB development. Tau hyperphosphorylation was essential for these MB aberrations, and we identified two novel putative phosphorylation sites, Ser238and Thr245, on WT hTau essential for its toxic effects on MB integrity. Significantly, blocking putative Ser238and Thr245phosphorylation yielded animals with apparently structurally normal but profoundly dysfunctional MBs, because animals accumulating this mutant protein exhibited strongly impaired associative learning.Interestingly, the mutant protein was hyperphosphorylated at epitopes typically associated with toxicity and neurodegeneration, such as AT8, AT100, and the Par-1 targets Ser262and Ser356, suggesting that these sites in the context of adult intact MBs mediate dysfunction and occupation of these sites may precede the toxicity-associated Ser238and Thr245phosphorylation. The data support the notion that phosphorylation at particular sites rather than hyperphosphorylation per se mediates toxicity or dysfunction in a cell type-specific manner.
Die Spanische Grippe 1918/19. Verlauf, Folgen und Deutungen in Deutschland im Kontext des Ersten Weltkriegs
Authors: Michels Eckard 
Published: January 2010

Vorspann
Zwischen 25 und 39 Millionen Opfer weltweit – kein Krieg, kein Genozid, sondern eine gewöhnliche Seuche: Die spanische Grippe traf 1918 auf eine Welt, die vom Ersten Weltkrieg zutiefst gezeichnet und erschöpft war. Aber war diese Pandemie tatsächlich eine Folge des Krieges? Und vor allem: Welchen Einfluss hatte sie auf den Ausgang dieses globalen Konflikts? Eckard Michels, ein in London lehrender Historiker, räumt mit vielen falschen Vorstellungen auf und präsentiert überraschende Antworten.
Do We Have Enough Evidence to Implement Particle Therapy as Standard Treatment in Lung Cancer? A Systematic Literature Review
Authors: Pijls-Johannesma Madelon , Grutters Janneke P.C. , Verhaegen Frank , Lambin Philippe , De Ruysscher Dirk 
Published: January 2010

Abstract

Learning Objectives
After completing this course, the reader will be able to: Evaluate the published results of particle therapy in the treatment of lung cancer and discuss their implications for the treatment of stage I and stage III NSCLC.Using the available evidence to date, assess the current role of particle therapy in the treatment of lung cancer.Identify relevant outstanding issues and address these issues with an action plan for further research.
CME This article is available for continuing medical education credit at CME.TheOncologist.com

Background.
The societal burden of lung cancer is high because of its high incidence and high lethality. From a theoretical point of view, radiotherapy with beams of protons and heavier charged particles, for example, carbon ions (C-ions), should lead to superior results, compared with photon beams. In this review, we searched for clinical evidence to justify implementation of particle therapy as standard treatment in lung cancer.

Methods.
A systematic literature review based on an earlier published comprehensive review was performed and updated through November 2009.

Results.
Eleven fully published studies, all dealing with non-small cell lung cancer (NSCLC), mainly stage I, were identified. No phase III trials were found. For proton therapy, 2- to 5-year local tumor control rates varied in the range of 57%–87%. The 2- and 5-year overall survival (OS) and 2- and 5-year cause-specific survival (CSS) rates were 31%–74% and 23% and 58%–86% and 46%, respectively. Radiation-induced pneumonitis was observed in about 10% of patients. For C-ion therapy, the overall local tumor control rate was 77%, but it was 95% when using a hypofractionated radiation schedule. The 5-year OS and CSS rates were 42% and 60%, respectively. Slightly better results were reported when using hypofractionation, 50% and 76%, respectively.

Conclusion.
The present results with protons and heavier charged particles are promising. However, the current lack of evidence on the clinical (cost-)effectiveness of particle therapy emphasizes the need to investigate the efficiency of particle therapy in an adequate manner. Until these results are available for lung cancer, charged particle therapy should be considered experimental.
The Evolving Role of Monoclonal Antibodies in Colorectal Cancer: Early Presumptions and Impact on Clinical Trial Development
Authors: Eng Cathy 
Published: January 2010

Abstract
Targeted biologic agents have an established role in treating metastatic colorectal cancer (mCRC). Bevacizumab, a recombinant monoclonal antibody against the vascular endothelial growth factor ligand is approved by the U.S. Food and Drug Administration (FDA) for bevacizumab-naïve patients. Cetuximab, a chimeric monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) is FDA approved as a single agent, or in combination with irinotecan, in both irinotecan-naïve and refractory patients, and has additional efficacy in combination with oxaliplatin. Panitumumab, a fully human EGFR mAb, is FDA approved as a single agent in refractory patients but has additional efficacy in combination with chemotherapy. After reaching a temporary therapeutic plateau of FDA-approved agents for the treatment of mCRC, pivotal results have developed that critically affect the care for these patients. Correlative data from randomized trials of EGFR inhibitors across disease settings have demonstrated higher response rates, specifically for patients with wild-type K-RAS tumors. The interpretation of the B-RAF mutation and other molecular markers may further define the appropriateness of anti-EGFR therapy. Recent literature revealed that the first-line use of combined anti-EGFR therapy plus bevacizumab resulted in inferior outcomes and additional toxicities. Furthermore, the role of biologic agents for locally advanced colon cancer cannot be advocated at this time. With impending changes in the health care system, the economic impact of mAbs will continue to be scrutinized. Hence, as the significance of molecular markers continues to develop, their role as it pertains to the appropriate use of biologic agents in the treatment of mCRC will continue to evolve.
Functional Role of Suppressor of Cytokine Signaling 3 Upregulation in Hypothalamic Leptin Resistance and Long-Term Energy Homeostasis
Authors: Reed Alison S. , Unger Elizabeth K. , Olofsson Louise E. , Piper Merisa L. , Myers Martin G. , Xu Allison W. 
Published: January 2010

OBJECTIVE
Hypothalamic leptin resistance is found in most common forms of obesity, such as diet-induced obesity, and is associated with increased expression of suppressor of cytokine signaling 3 (Socs3) in the hypothalamus of diet-induced obese animals. This study aims to determine the functional consequence of Socs3 upregulation on leptin signaling and obesity, and to investigate whether Socs3 upregulation affects energy balance in a cell type–specific way.

RESEARCH DESIGN AND METHODS
We generated transgenic mice overexpressing Socs3 in either proopiomelanocortin (POMC) or leptin receptor–expressing neurons, at levels similar to what is observed in diet-induced obesity.

RESULTS
Upregulation of Socs3 in POMC neurons leads to impairment of STAT3 and mammalian target of rapamycin (mTOR)–S6K-S6 signaling, with subsequent leptin resistance, obesity, and glucose intolerance. Unexpectedly, Socs3 upregulation in leptin receptor neurons results in increased expression of STAT3 protein in mutant hypothalami, but does not lead to obesity.

CONCLUSIONS
Our study establishes that Socs3 upregulation alone in POMC neurons is sufficient to cause leptin resistance and obesity. Socs3 upregulation impairs both STAT3 and mTOR signaling before the onset of obesity. The lack of obesity in mice with upregulated Socs3 in leptin receptor neurons suggests that Socs3's effect on energy balance could be cell type specific. Our study indicates that POMC neurons are important mediators of Socs3's effect on leptin resistance and obesity, but that other cell types or alteration of other signaling regulators could contribute to the development of obesity.
High Glucose–Induced Oxidative Stress Increases Transient Receptor Potential Channel Expression in Human Monocytes
Authors: Wuensch Tilo , Thilo Florian , Krueger Katharina , Scholze Alexandra , Ristow Michael , Tepel Martin 
Published: January 2010

OBJECTIVE
Transient receptor potential (TRP) channel–induced cation influx activates human monocytes, which play an important role in the pathogenesis of atherosclerosis. In the present study, we investigated the effects of high glucose–induced oxidative stress on TRP channel expression in human monocytes.

RESEARCH DESIGN AND METHODS
Human monocytes were exposed to control conditions (5.6 mmol/l d-glucose), high glucose (30 mmol/l d-glucose or l-glucose), 100 μmol/l peroxynitrite, or high glucose in the presence of the superoxide dismutase mimetic tempol (100 μmol/l). TRP mRNA and TRP protein expression was measured using quantitative real-time RT-PCR and quantitative in-cell Western assay, respectively. Calcium influx and intracellular reactive oxygen species were measured using fluorescent dyes.

RESULTS
Administration of high d-glucose significantly increased reactive oxygen species. High d-glucose or peroxynitrite significantly increased the expression of TRP canonical type 1 (TRPC1), TRPC3, TRPC5, TRPC6, TRP melastatin type 6 (TRPM6), and TRPM7 mRNA and TRPC3 and TRPC6 proteins. High d-glucose plus tempol or high l-glucose did not affect TRP expression. Increased oxidative stress by lipopolysaccharide or tumor necrosis factor-α increased TRP mRNA expression, whereas the reduction of superoxide radicals using diphenylene iodonium significantly reduced TRP mRNA expression. Increased TRPC3 and TRPC6 protein expression was accompanied by increased 1-oleoyl-2-acetyl-sn-glycerol–induced calcium influx, which was blocked by the TRPC inhibitor 2-aminoethoxydiphenylborane. TRPC6 mRNA was significantly higher in monocytes from 18 patients with type 2 diabetes compared with 28 control subjects (P &lt; 0.05).

CONCLUSIONS
High d-glucose–induced oxidative stress increases TRP expression and calcium influx in human monocytes, pointing to a novel pathway for increased activation of monocytes and hence atherosclerosis in patients with diabetes.
Deficiency of Phosphoinositide 3-Kinase Enhancer Protects Mice From Diet-Induced Obesity and Insulin Resistance
Authors: Chan Chi Bun , Liu Xia , Jung Dae Young , Jun John Y. , Luo Hongbo R. , Kim Jason K. , Ye Keqiang 
Published: January 2010

OBJECTIVE
Phosphoinositide 3-kinase enhancer A (PIKE-A) is a proto-oncogene that promotes tumor growth and transformation by enhancing Akt activity. However, the physiological functions of PIKE-A in peripheral tissues are unknown. Here, we describe the effect of PIKE deletion in mice and explore the role of PIKE-A in obesity development.

RESEARCH DESIGN AND METHODS
Whole-body PIKE knockout mice were generated and subjected to high-fat–diet feeding for 20 weeks. The glucose tolerance, tissue-specific insulin sensitivity, adipocyte differentiation, and lipid oxidation status were determined. The molecular mechanism of PIKE in the insulin signaling pathway was also studied.

RESULTS
We show that PIKE-A regulates obesity development by modulating AMP-activated protein kinase (AMPK) phosphorylation. PIKE-A is important for insulin to suppress AMPK phosphorylation. The expression of PIKE-A is markedly increased in adipose tissue of obese mice, whereas depletion of PIKE-A inhibits adipocyte differentiation. PIKE knockout mice exhibit a prominent phenotype of lipoatrophy and are resistant to high-fat diet–induced obesity, liver steatosis, and diabetes. PIKE knockout mice also have augmented lipid oxidation, which is accompanied by enhanced AMPK phosphorylation in both muscle and adipose tissue. Moreover, insulin sensitivity is improved in PIKE-A–deficient muscle and fat, thus protecting the animals from diet-induced diabetes.

CONCLUSIONS
Our results suggest that PIKE-A is implicated in obesity and associated diabetes development by negatively regulating AMPK activity.
The Prostacyclin Analog Beraprost Sodium Ameliorates Characteristics of Metabolic Syndrome in Obese Zucker (Fatty) Rats
Authors: Sato Nahoko , Kaneko Masayuki , Tamura Mitsutaka , Kurumatani Hajimu 
Published: January 2010

OBJECTIVE
The prostacyclin analog, beraprost sodium (BPS), was examined for its potential to improve the symptoms of obesity-type diabetes (i.e., hyperglycemia, hyperinsulinemia, dyslipidemia, histopathologic changes, and diabetic complications).

RESEARCH DESIGN AND METHODS
Obese Zucker rats, an experimental model of genetic obesity-induced type 2 diabetes, were repeatedly administered BPS at oral doses of 0.2 or 0.6 mg · kg−1 · day−1 b.i.d. for 12 weeks, and serum chemistry, urinalysis, and histopathologic examination were performed.

RESULTS
BPS dose-dependently suppressed serum glucose, insulin, triglyceride, and cholesterol levels in obese animals. In oral glucose tolerance test, BPS suppressed the post–glucose-loading elevation of serum glucose in a dose-dependent manner. Urinary N-acetyl-β-D-glucosaminidase was significantly lower in BPS-treated obese animals compared with control animals, although no significant differences were observed in urinary protein levels between the BPS-treated groups and the control group. In addition, histopathologic examination revealed significant protective effects of BPS against renal disorder in obese animals. Histopathologically, BPS also inhibited the progression of hepatic steatosis, hypertrophy of adipose tissue, and pancreatic fibrosis. Furthermore, thermographic analysis of the hind limb sole skin surface indicated a significant increase in temperature in BPS-treated animals, compared with control animals, which was likely due to improved blood circulation by administration of BPS.

CONCLUSIONS
BPS suppressed the pathogenesis and development of diabetes and its complication, nephropathy, which was presumably accompanied by improving glucose intolerance and insulin resistance in obese Zucker rats.
Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated With Aging and Obesity
Authors: Law Ivy K.M. , Xu Aimin , Lam Karen S.L. , Berger Thorsten , Mak Tak W. , Vanhoutte Paul M. , Liu Jacky T.C. , Sweeney Gary , Zhou Mingyan , Yang Bo , Wang Yu 
Published: January 2010

OBJECTIVEThe proinflammatory cytokines/adipokines produced from adipose tissue act in an autocrine and/or endocrine manner to perpetuate local inflammation and to induce peripheral insulin resistance. The present study investigates whether lipocalin-2 deficiency or replenishment with this adipokine has any impact on systemic insulin sensitivity and the underlying mechanisms.METHODS AND RESULTSUnder conditions of aging or dietary-/genetic-induced obesity, lipocalin-2 knockout (Lcn2-KO) mice show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity compared with their wild-type littermates. Despite enlarged fat mass, inflammation and the accumulation of lipid peroxidation products are significantly attenuated in the adipose tissues of Lcn2-KO mice. Adipose fatty acid composition of these mice varies significantly from that in wild-type animals. The amounts of arachidonic acid (C20:4 n6) are elevated by aging and obesity and are paradoxically further increased in adipose tissue, but not skeletal muscle and liver of Lcn2-KO mice. On the other hand, the expression and activity of 12-lipoxygenase, an enzyme responsible for metabolizing arachidonic acid, and the production of tumor necrosis factor-α (TNF-α), a critical insulin resistance–inducing factor, are largely inhibited by lipocalin-2 deficiency. Lipocalin-2 stimulates the expression and activity of 12-lipoxygenase and TNF-α production in fat tissues. Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-α expression induced by lipocalin-2. Moreover, treatment with TNF-α neutralization antibody or CDC significantly attenuated the differences of insulin sensitivity between wild-type and Lcn2-KO mice.CONCLUSIONSLipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-α levels in adipose tissue.
Association Between Iron Deficiency and A1C Levels Among Adults Without Diabetes in the National Health and Nutrition Examination Survey, 1999–2006
Authors: Kim Catherine , Bullard Kai McKeever , Herman William H. , Beckles Gloria L. 
Published: January 2010

OBJECTIVEIron deficiency has been reported to elevate A1C levels apart from glycemia. We examined the influence of iron deficiency on A1C distribution among adults without diabetes.RESEARCH DESIGN AND METHODSParticipants included adults without self-reported diabetes or chronic kidney disease in the National Health and Nutrition Examination Survey 1999–2006 who were aged ≥18 years of age and had complete blood counts, iron studies, and A1C levels. Iron deficiency was defined as at least two abnormalities including free erythrocyte protoporphyrin &gt;70 μg/dl erythrocytes, transferrin saturation &lt;16%, or serum ferritin ≤15 μg/l. Anemia was defined as hemoglobin &lt;13.5 g/dl in men and &lt;12.0 g/dl in women.RESULTSAmong women (n = 6,666), 13.7% had iron deficiency and 4.0% had iron deficiency anemia. Whereas 316 women with iron deficiency had A1C ≥5.5%, only 32 women with iron deficiency had A1C ≥6.5%. Among men (n = 3,869), only 13 had iron deficiency and A1C ≥5.5%, and only 1 had iron deficiency and A1C ≥6.5%. Among women, iron deficiency was associated with a greater odds of A1C ≥5.5% (odds ratio 1.39 [95% CI 1.11–1.73]) after adjustment for age, race/ethnicity, and waist circumference but not with a greater odds of A1C ≥6.5% (0.79 [0.33–1.85]).CONCLUSIONSIron deficiency is common among women and is associated with shifts in A1C distribution from &lt;5.5 to ≥5.5%. Further research is needed to examine whether iron deficiency is associated with shifts at higher A1C levels.
Type 2 Diabetes, Medication-Induced Diabetes, and Monogenic Diabetes in Canadian Children
Authors: Amed Shazhan , Dean Heather J. , Panagiotopoulos Constadina , Sellers Elizabeth A.C. , Hadjiyannakis Stasia , Laubscher Tessa A. , Dannenbaum David , Shah Baiju R. , Booth Gillian L. , Hamilton Jill K. 
Published: January 2010

OBJECTIVE
To determine in Canadian children aged &lt;18 years the 1) incidence of type 2 diabetes, medication-induced diabetes, and monogenic diabetes; 2) clinical features of type 2 diabetes; and 3) coexisting morbidity associated with type 2 diabetes at diagnosis.

RESEARCH DESIGN AND METHODS
This Canadian prospective national surveillance study involved a network of pediatricians, pediatric endocrinologists, family physicians, and adult endocrinologists. Incidence rates were calculated using Canadian Census population data. Descriptive statistics were used to illustrate demographic and clinical features.

RESULTS
From a population of 7.3 million children, 345 cases of non–type 1 diabetes were reported. The observed minimum incidence rates of type 2, medication-induced, and monogenic diabetes were 1.54, 0.4, and 0.2 cases per 100,000 children aged &lt;18 years per year, respectively. On average, children with type 2 diabetes were aged 13.7 years and 8% (19 of 227) presented before 10 years. Ethnic minorities were overrepresented, but 25% (57 of 227) of children with type 2 diabetes were Caucasian. Of children with type 2 diabetes, 95% (206 of 216) were obese and 37% (43 of 115) had at least one comorbidity at diagnosis.

CONCLUSIONS
This is the first prospective national surveillance study in Canada to report the incidence of type 2 diabetes in children and also the first in the world to report the incidence of medication-induced and monogenic diabetes. Rates of type 2 diabetes were higher than expected with important regional variation. These results support recommendations that screening for comorbidity should occur at diagnosis of type 2 diabetes.
Failure to Preserve β-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes
Authors: Gottlieb Peter A. , Quinlan Scott , Krause-Steinrauf Heidi , Greenbaum Carla J. , Wilson Darrell M. , Rodriguez Henry , Schatz Desmond A. , Moran Antoinette M. , Lachin John M. , Skyler Jay S. ,   for the Type 1 Diabetes TrialNet MMF/DZB Study Group
Published: January 2010

OBJECTIVE
This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes.

RESEARCH DESIGN AND METHODS
A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test.

RESULTS
One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly.

CONCLUSIONS
Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process.