bluuebunny/crossref_metadata_2025 huggingface dataset:
Globular adiponectin counteracts VCAM-1-mediated monocyte adhesion via AdipoR1/NF-κB/COX-2 signaling in human aortic endothelial cells
Authors: Addabbo Francesco , Nacci Carmela , Benedictis Leonarda De , Leo Valentina , Tarquinio Mariela , Quon Michael J. , Montagnani Monica
Published: September 2011

Adiponectin (Ad) is an insulin-sensitizing adipocytokine with anti-inflammatory and vasoprotective properties. Cleavage of native full-length Ad (fAd) by elastases from activated monocytes generates globular Ad (gAd). Increased gAd levels are observed in the proximity of atherosclerotic lesions, but the physiological meaning of this proteolytic Ad fragment in the cardiovascular system is controversial. We compared molecular and biological properties of fAd and gAd in human aortic endothelial cells (HAEC). In control HAEC, both fAd and gAd acutely stimulated nitric oxide (NO) production by AMPK-dependent pathways. With respect to fAd, gAd more efficiently increased activation of NF-κB signaling pathways, resulting in cyclooxygenase-2 (COX-2) overexpression and COX-2-dependent prostacyclin 2 (PGI2) release. In contrast with fAd, gAd also increased p38 MAPK phosphorylation and VCAM-1 expression, ultimately enhancing adhesion of monocytes to endothelial cells. In HAEC lacking AdipoR1 (by siRNA), both activation of NF-κB as well as COX-2 overexpression by gAd were abrogated. Conversely, gAd-mediated p38MAPK activation and VCAM-1 expression were unaffected, and monocyte adhesion was greatly enhanced. In HAEC lacking COX-2 (by siRNA), reduced levels of PGI2 further increased gAd-dependent monocyte adhesion. Our findings suggest that biological activities of fAd and gAd in endothelium do not completely overlap, with gAd possessing both AdipoR1-dependent ability to stimulate COX-2 expression and AdipoR1-independent effects related to expression of VCAM-1 and adhesion of monocytes to endothelium.
Increased maternal fat consumption during pregnancy alters body composition in neonatal mice
Authors: Krasnow Stephanie M. , Nguyen My Linh T. , Marks Daniel L.
Published: September 2011

Maternal overnutrition prior to and during gestation causes pronounced metabolic dysfunction in the adult offspring. However, less is known about metabolic adaptations in the offspring that occur independently of postnatal growth and nutrition. Therefore, we evaluated the impact of excess maternal dietary lipid intake on the in utero programming of body composition, hepatic function, and hypothalamic development in newborn (P0) offspring. Female mice were fed a low-fat (LF) or high-fat (HF) diet and were mated after 4, 12, and 23 wk. A subset of the obese HF dams was switched to the LF diet during the second (DR2) or third (DR3) pregnancies. The HF offspring accrued more fat mass than the LF pups, regardless of duration of maternal HF diet consumption or prepregnancy maternal adiposity. Increased neonatal adiposity was not observed in the DR3 pups. Liver weights were reduced in the HF offspring but not in the DR2 or DR3 pups. Offspring hepatic triglyceride content was reduced in the HF pups, but hepatic inflammation and expression of lipid metabolism genes were largely unaffected by maternal diet. Maternal diet did not alter the hypothalamic expression of orexigenic and anorexigenic neuropeptides in the offspring. Thus, the intrauterine programming of increased neonatal adiposity and reduced liver size by maternal overnutrition is evident in mice at birth and occurs prior to the development of maternal obesity. These observations demonstrate that dietary intervention during pregnancy minimizes the deleterious effects of maternal obesity on offspring body composition, potentially reducing the offsprings' risk of developing obesity and related diseases later in life.
Multisite haplotype on cattle chromosome 3 is associated with quantitative trait locus effects on lactation traits
Authors: Cohen-Zinder Miri , Donthu Ravikiran , Larkin Denis M. , Kumar Charu Gupta , Rodriguez-Zas Sandra L. , Andropolis Kalista E. , Oliveira Rosane , Lewin Harris A.
Published: September 2011

The goal of this study was to identify candidate genes and DNA polymorphisms for quantitative trait loci (QTL) affecting milk yield (MY), fat yield (FY), and protein yield (PY) previously mapped to bovine chromosome 3 (BTA3). To accomplish this, 373 half-siblings sired by three bulls previously shown to be segregating for lactation trait QTL, and 263 additional sires in the U.S. Dairy Bull DNA Repository (DBDR) were genotyped for 2,500 SNPs within a 16.3 Mbp QTL critical region on BTA3. Targeted resequencing of ∼1.8 Mbp within the QTL critical region of one of the QTL heterozygous sires identified additional polymorphisms useful for association studies. Twenty-three single nucleotide polymorphisms (SNPs) within a fine-mapped region were associated with effects on breeding values for MY, FY, or PY in DBDR sires, of which five SNPs were in strong linkage disequilibrium in the population. This multisite haplotype included SNPs located within exons or promoters of four tightly linked genes: RAP1A, ADORA3, OVGP1, and C3H1orf88. An SNP within RAP1A showed strong evidence of a recent selective sweep based on integrated haplotype score and was also associated with breeding value for PY. Because of its known function in alveolar lumen formation in the mammary gland, RAP1A is thus a strong candidate gene for QTL effects on lactation traits. Our results provide a detailed assessment of a QTL region that will be a useful guide for complex traits analysis in humans and other noninbred species.
A Comparative Study of the Inhibitory Effect of the Extracts ofOcimum sanctum,Aegle marmelos, andSolanum trilobatumon the Corrosion of Mild Steel in Hydrochloric Acid Medium
Authors: Shyamala M. , Kasthuri P. K.
Published: September 2011

A comparative study of the inhibitory effect of plant extracts,Ocimum sanctum, Aegle marmelos, andSolanum trilobatum, on the corrosion of mild steel in 1N HCl medium was investigated using weightloss method, electrochemical methods, and hydrogen permeation method. Polarization method indicates plant extracts behave as mixed-type inhibitor. The impedance method reveals that charge-transfer process mainly controls the corrosion of mild steel. On comparison, maximum inhibition efficiency was found inOcimum sanctumwith 99.6% inhibition efficiency at 6.0% v/v concentration of the extract. The plant extracts obey Langmuir adsorption isotherm. The SEM morphology of the adsorbed protective film on the mild steel surface has confirmed the high performance of inhibitive effect of the plant extracts. From hydrogen permeation method, all the plant extracts were able to reduce the permeation current. The reason for the reduced permeation currents in presence of the inhibitors may be attributed to the slow discharge step followed by fast electrolytic desorption step. Results obtained in all three methods were very much in good agreement in the orderOcimum sanctum>Aegle marmelos>Solanum trilobatum.
Patient-Specific Method of Generating Parametric Maps of Patlak Ki without Blood Sampling or Metabolite Correction: A Feasibility Study
Authors: Sayre George A. , Franc Benjamin L. , Seo Youngho
Published: September 2011

Currently, kinetic analyses using dynamic positron emission tomography (PET) experience very limited use despite their potential for improving quantitative accuracy in several clinical and research applications. For targeted volume applications, such as radiation treatment planning, treatment monitoring, and cerebral metabolic studies, the key to implementation of these methods is the determination of an arterial input function, which can include time-consuming analysis of blood samples for metabolite correction. Targeted kinetic applications would become practical for the clinic if blood sampling and metabolite correction could be avoided. To this end, we developed a novel method (Patlak-P) of generating parametric maps that is identical to Patlak Ki (within a global scalar multiple) but does not require the determination of the arterial input function or metabolite correction. In this initial study, we show that Patlak-P (a) mimics Patlak Ki images in terms of visual assessment and target-to-background (TB) ratios of regions of elevated uptake, (b) has higher visual contrast and (generally) better image quality than SUV, and (c) may have an important role in improving radiotherapy planning, therapy monitoring, and neurometabolism studies.
Flow Drag and Heat Transfer Reduction Characteristics of Organic Brine (Potassium Acetate) and Inorganic Brine (Calcium Chloride) Solutions with Nonionic Surfactant
Authors: Haruki Naoto , Horibe Akihiko
Published: September 2011

Flow drag and heat transfer reduction effects are useful in heat energy transportation systems and can lead to lower pumping energy requirements. The purpose of this research is to describe the flow drag and heat transfer reduction characteristics of organic (potassium acetate) and inorganic (calcium chloride) brine solutions. The nonionic surfactant oleyl dihydroxyethyl amine oxide (ODEAO) is used as a drag-reducing additive. The pipe friction coefficient and heat transfer coefficient are investigated experimentally in a straight pipe for each type of solution with ODEAO. These coefficients are found to be lower than those of water in the turbulent flow range. However, the rod-like micelles of ODEAO, which are necessary to induce the flow drag reduction effect, are not readily formed in these solutions. Hence, the flow drag and heat transfer reduction effects are measured only under limited conditions and it is difficult to apply these solutions practically as heat transfer media.
Primary Synovial Sarcoma of the Mediastinum : A Case Report
Authors: Ravikumar Gayatri , Mullick Shalini , Ananthamurthy Anuradha , Correa Marjorie
Published: September 2011

Synovial sarcomas commonly occur in the extremities of young adults. A primary occurrence in the mediastinum is very rare with only a few reported cases in the world literature. This paper is about a 42-year-old male who presented with chest pain and dyspnoea on exertion. Imaging showed an anterior mediastinal mass with adhesions to the lung. Pathological examination of the resected mass showed a biphasic neoplasm with a spindle cell component admixed with gland-like elements. The tumour showed positive staining with cytokeratin, epithelial membrane antigen, and Bcl-2 confirming the diagnosis of a biphasic synovial sarcoma. A wide range of neoplasms, both primary and metastatic, occur in the mediastinum, which pose considerable diagnostic difficulties. A synovial sarcoma should always be considered in the differential diagnosis, and immunohistochemistry is an important adjuvant tool in this situation. This paper highlights the importance of recognizing an unusual presentation of this aggressive neoplasm to aid appropriate clinical management.
Atypical Parkinsonism Revealing a Late Onset, Rigid and Akinetic Form of Huntington's Disease
Authors: Ciammola A. , Sassone J. , Poletti B. , Mencacci N. , Benti R. , Silani V.
Published: September 2011

Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized in over 90 percent of cases by chorea as the presenting motor symptom. We report a 54-year-old male who presented with Parkinsonism as the initial symptom of the disease. Genetic analysis revealed expansion of 40 CAG repeats, and brain MRI showed both severe caudate nuclei and cortical atrophy. Single-photon emission computed tomography (SPECT) imaging of the dopamine transporter showed nigrostriatal pathway degeneration. Here, we also describe his 2 years of clinical followup after ensuing dopaminergic stimulation.
Multifocal Dysembryoplastic Neuroepithelial Tumour with Intradural Spinal Cord Lipomas: Report of a Case
Authors: White Richard D. , Kanodia Avinash K. , Sammler Esther M. , Brunton John N. , Heath Craig A.
Published: September 2011

We report a case of temporal lobe epilepsy and incomplete Brown-Sequard syndrome of the thoracic cord. Computed tomography and magnetic resonance (MR) imaging showed multiple supratentorial masses with the classical radiological appearances of multifocal dysembryoplastic neuroepithelial tumour (DNET). Spinal MR imaging revealed intradural lipomas, not previously reported in association with multifocal DNET. Presentation and imaging findings are discussed along with classification and natural history of the tumour.
Secondary Ureteral Perforation by Invasive Amebiasis in a Patient with Acquired Immunodeficiency Syndrome: A Case Report
Authors: Yu Ming-Yin , Chen Chi-Cheng , Ho Cheng-Mao , Wu Hsi-Chin , Chang Chao-Hsiang , Chen Yung-Hsiang , Chen Wen-Chi
Published: September 2011

Ureteral perforation is a rare complication of abdominal infection, especially in a patient with human immunodeficiency virus (HIV) infection. We reported a case of ureteral perforation caused by a secondary amebiasis in a patient with acquired immunodeficiency syndrome (AIDS). Following bowel perforation and immunocompromised conditions, secondary right ureteral perforation was not easily to be treated well. He was treated with percutaneous drainage initially. Definite and successful treatment by a Boari flap was delayed until his underling disease was under control.
The Nurse in the University: A History of University Education for South African Nurses: A Case Study of the University of the Witwatersrand
Authors: Horwitz Simonne
Published: September 2011

This paper charts the history and debates surrounding the introduction of academic, university-based training of nurses in South Africa. This was a process that was drawn out over five decades, beginning in the late 1930s. For nurses, university training was an important part of a process of professionalization; however, for other members of the medical community, nursing was seen as being linked to women's service work. Using the case-study of the University of the Witwatersrand, one of South Africa's premier universities and the place in the country to offer a university-based nursing program, we argue that an historical understanding of the ways in which nursing education was integrated into the university system tells us a great deal about the professionalization of nursing. This paper also recognises, for the first time, the pioneers of this important process.
Laparoscopic Sacropexy: A Retrospective Analysis of the Subjective Outcome in 310 Cases
Authors: Bojahr B. , Tchartchian G. , Waldschmidt M. , Ohlinger R. , De Wilde R. L.
Published: September 2011

Background and Objective. The aim of this study was to assess the subjective outcome following laparoscopic sacropexy.Methods. We performed a retrospective cohort study among women treated for descensus with laparoscopic sacropexy between January 2000 and December 2007. 310 patients received questionnaires during followup assessing major pre- and postoperative symptoms and overall satisfaction.Results. 214 (69%) patients responded to the questionnaire. Mean followup was 24.5 months. The number of patients with back or lower abdominal pain, foreign body sensation in the vagina and prolapse-related symptoms, urinary symptoms, vaginal and bladder infections, and the need for pessary usage decreased significantly postsurgically. Bowel symptoms increased slightly but not significantly. Two years after surgery, nearly 2 thirds of the women were satisfied or very satisfied with the outcome.Conclusion. Laparoscopic sacropexy is an effective treatment of descensus, with favorable or satisfactory subjective outcomes.
Haar‐Wavelet‐Based Just Noticeable Distortion Model for Transparent Watermark
Authors: Ko Lu-Ting , Chen Jwu-E , Hsin Hsi-Chin , Shieh Yaw-Shih , Sung Tze-Yun
Published: September 2011

Watermark transparency is required mainly for copyright protection. Based on the characteristics of human visual system, the just noticeable distortion (JND) can be used to verify the transparency requirement. More specifically, any watermarks whose intensities are less than the JND values of an image can be added without degrading the visual quality. It takes extensive experimentations for an appropriate JND model. Motivated by the texture masking effect and the spatial masking effect, which are key factors of JND, Chou and Li (1995) proposed the well‐known full‐band JND model for the transparent watermark applications. In this paper, we propose a novel JND model based on discrete wavelet transform. Experimental results show that the performance of the proposed JND model is comparable to that of the full‐band JND model. However, it has the advantage of saving a lot of computation time; the speed is about 6 times faster than that of the full‐band JND model.
Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung Cancer
Authors: Aftab Blake T. , Dobromilskaya Irina , Liu Jun O. , Rudin Charles M.
Published: September 2011

The antiangiogenic agent bevacizumab has been approved for the treatment of non–small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor–mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxia-inducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic NSCLC. Cancer Res; 71(21); 6764–72. ©2011 AACR.
Circulating Tumor Cell Isolation and Diagnostics: Toward Routine Clinical Use
Authors: van de Stolpe Anja , Pantel Klaus , Sleijfer Stefan , Terstappen Leon W. , den Toonder Jaap M.J.
Published: September 2011

From February 7–11, 2011, the multidisciplinary Lorentz Workshop Circulating Tumor Cell (CTC) Isolation and Diagnostics: Toward Routine Clinical Use was held in Leiden (The Netherlands) to discuss progress and define challenges and potential solutions for development of clinically useful circulating tumor cell (CTC) diagnostics. CTCs, captured as “liquid biopsy” from blood, for counting and characterization using pathology and molecular assays, are expected to replace metastatic tissue biopsies to be used to predict drug response and resistance and to monitor therapy response and cancer recurrence. CTCs are highly heterogeneous; therefore, cancer type–specific isolation technologies, as well as complex clinical interpretation software, are required. Cancer Res; 71(18); 5955–60. ©2011 AACR.
Systems Biology: Confronting the Complexity of Cancer
Authors: Gentles Andrew J. , Gallahan Daniel
Published: September 2011

The AACR-NCI Conference “Systems Biology: Confronting the Complexity of Cancer” took place from February 27 to March 2, 2011, in San Diego, CA. Several themes resonated during the meeting, notably (i) the need for better methods to distill insights from large-scale networks, (ii) the importance of integrating multiple data types in constructing more realistic models, (iii) challenges in translating insights about tumorigenic mechanisms into therapeutic interventions, and (iv) the role of the tumor microenvironment, at the physical, cellular, and molecular levels. The meeting highlighted concrete applications of systems biology to cancer, and the value of collaboration between interdisciplinary researchers in attacking formidable problems. Cancer Res; 71(18); 5961–4. ©2011 AACR.
Inverse Association of Eosinophil Count with Colorectal Cancer Incidence: Atherosclerosis Risk in Communities Study
Authors: Prizment Anna E. , Anderson Kristin E. , Visvanathan Kala , Folsom Aaron R.
Published: September 2011

Background: Allergic conditions are associated with reduced risk of several malignancies. We hypothesized that blood eosinophil count, a marker for allergic disorders, is inversely associated with the risk of colorectal cancer (CRC) in the Atherosclerosis Risk in Communities prospective cohort. To our knowledge, the association between blood eosinophil count and cancer risk has not been investigated before.

Methods: Relative eosinophil and total leukocyte counts were measured in blood at baseline. Absolute eosinophil counts were calculated by multiplying relative count by the total leukocyte count. Proportional hazards regression provided HRs and 95% CIs of CRC in relation to eosinophil count.

Results: From 1987–2006, 242 incident CRC cases (187 colon and 56 rectal) occurred in 10,675 initially cancer-free participants. In a multivariate-adjusted model, HRs were 1.0, 0.70 (95% CI: 0.50–0.98) and 0.58 (95% CI: 0.40–0.83) across tertiles of absolute eosinophil count (Ptrend = 0.003). A similar inverse association was observed for relative eosinophil count. Age, sex, race, or smoking status did not modify associations.

Conclusions and Impact: We observed an inverse association between blood eosinophil count and CRC risk. This novel finding supports the hypothesis that allergies are protective for CRC, as an increased eosinophil count correlates with allergy in the developed world. Cancer Epidemiol Biomarkers Prev; 20(9); 1861–4. ©2011 AACR.
Mitochondrial DNA Copy Number and Risk of Gastric Cancer: a Report from the Shanghai Women's Health Study
Authors: Liao Linda M. , Baccarelli Andrea , Shu Xiao-Ou , Gao Yu-Tang , Ji Bu-Tian , Yang Gong , Li Hong-Lan , Hoxha Mirjam , Dioni Laura , Rothman Nathaniel , Zheng Wei , Chow Wong-Ho
Published: September 2011

Background: Mitochondrial DNA (mtDNA) is an approximately 16,000-bp circular double-stranded DNA molecule that is a prime target of oxidative damage. Several somatic mutations in mtDNA have been observed in gastric tumors, suggesting an involvement in gastric cancer risk and progression. mtDNA copy number in leukocyte DNA has also been linked to several other cancers, although the temporal relationship between mtDNA and cancer has not been adequately explored.

Methods: Using a nested case–control study design, we examined the association between mtDNA copy number in 162 gastric cancer cases and 299 matched controls within the Shanghai Women's Health Study, a large population-based prospective cohort. Relative mtDNA copy number was measured in triplicate by a quantitative real-time PCR assay in peripheral leukocytes.

Results: mtDNA copy number levels were comparable among cases and controls, with a median of 1.04 [interquartile range (IQR), 0.87–1.25] and 1.06 (IQR, 0.88–1.29), respectively. Overall, mtDNA was not associated with gastric cancer risk. However, the association differed when stratified by the time between sample collection and cancer diagnosis. An association between low levels of mtDNA copy number (<median) and gastric cancer risk was apparent among earlier diagnosed cases, in particular, those diagnosed within 2 years of sample collection (OR = 5.32; 95% CI = 1.03–27.60). This association was not present as the time between sample collection and cancer diagnosis increased.

Conclusions and Impact: Our findings suggest that there is no association between leukocyte mtDNA copy number and risk of developing gastric cancer; however, we observed a possible early disease effect on mtDNA copy number levels. Cancer Epidemiol Biomarkers Prev; 20(9); 1944–9. ©2011 AACR.
Sucrose, High-Sugar Foods, and Risk of Endometrial Cancer—a Population-Based Cohort Study
Authors: Friberg Emilie , Wallin Alice , Wolk Alicja
Published: September 2011

Background: Consumption of high-sugar foods stimulates insulin production, which has been associated with endometrial cancer. Although a relationship between sucrose, high-sugar food consumption, and endometrial cancer risk is biologically plausible, this hypothesis has previously been explored in very few studies.

Methods: We used data from the Swedish Mammography Cohort, including 61,226 women aged 40 to 74 years. We examined the association between consumption of total sucrose, high-sugar foods (at baseline 1987–1990 and 1997) and endometrial cancer risk by using Cox proportional hazards models to estimate incidence rate ratios (RR) with 95% CI.

Results: During 18.4 years of follow-up, 729 participants were diagnosed with incident endometrial cancer. Total sucrose intake and consumption of sweet buns and cookies was associated with increased risk of endometrial cancer. RRs (with 95% CIs) for consuming more than 35 grams of sucrose per day and consuming sweet buns and cookies more than 3 times per week were 1.36 (1.04–1.77) and 1.42 (1.15–1.75) as compared with less than 15 grams of sucrose per day and consuming sweet buns and cookies less than 0.5 times per week, respectively. RRs for consuming more than 15 grams of sucrose per day as compared with 15 grams or less were 1.97 (1.27–3.04) among obese women and 1.56 (1.20–2.04) among women with low fat intake.

Conclusions: These data indicate that sucrose intake and consumption of sweet buns and cookies may be associated with increased risk of endometrial cancer.

Impact: Given the high intake of sweetened foods, these results have public health implications in terms of prevention of endometrial cancer. Cancer Epidemiol Biomarkers Prev; 20(9); 1831–7. ©2011 AACR.
Functional Polymorphisms in UDP-Glucuronosyl Transferases and Recurrence in Tamoxifen-Treated Breast Cancer Survivors
Authors: Ahern Thomas P. , Christensen Mariann , Cronin-Fenton Deirdre P. , Lunetta Kathryn L. , Søiland Håvard , Gjerde Jennifer , Garne Jens Peter , Rosenberg Carol L. , Silliman Rebecca A. , Sørensen Henrik Toft , Lash Timothy L. , Hamilton-Dutoit Stephen
Published: September 2011

Background: Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyl transferases (UGT). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors.

Methods: We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least 1 year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched one control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence OR for the UGT polymorphisms by using logistic regression models, with and without stratification on CYP2D6*4 genotype.

Results: No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER−/TAM− groups [in the ER+/TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI, 0.70–1.5); adjusted OR for two UGT2B7*2 variant alleles = 0.96 (95% CI, 0.65–1.4); adjusted OR for one or two UGT1A8*3 variant alleles = 0.95 (0.49–1.9)]. Associations were similar within strata of CYP2D6*4 genotype.

Conclusions: Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk.

Impact: Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy. Cancer Epidemiol Biomarkers Prev; 20(9); 1937–43. ©2011 AACR.
Replication of Breast Cancer GWAS Susceptibility Loci in the Women's Health Initiative African American SHARe Study
Authors: Hutter Carolyn M. , Young Alicia M. , Ochs-Balcom Heather M. , Carty Cara L. , Wang Tao , Chen Christina T.L. , Rohan Thomas E. , Kooperberg Charles , Peters Ulrike
Published: September 2011

Background: Genome-wide association studies (GWAS) have identified loci associated with risk of breast cancer. These studies have primarily been conducted in populations of European descent. To fully understand the impact of these loci, it is important to study groups with other genetic ancestries, including African American women.

Methods: We examined 22 single-nucleotide polymorphisms (SNP), previously identified in GWAS of breast cancer risk in European and Asian descent women (index SNPs), and SNPs in the surrounding regions in a study of 7,800 African American women (including 316 women with incident invasive breast cancer) from the Women's Health Initiative SNP Health Association Resource.

Results: Two index SNPs were associated with breast cancer: rs3803662 at 16q12.2/TOX3 (Hazard ratio [HR] for the T allele = 0.79, 95% CI: 0.67–0.92, P = 0.003) and rs10941679 at 5p12 (HR for the G allele = 1.31, 95% CI: 1.06–1.63, P = 0.014). When we expanded to regions, the 3p24.1 region showed an association with breast cancer risk (permutation based P = 0.027) and three regions (10p15.1, 10q26.13/FGFR2, and 16q12.2/TOX3) showed a trend toward association.

Conclusion: Our findings provide evidence that some breast cancer GWAS regions may be associated with breast cancer in African American women. Larger, more comprehensive studies are needed to fully assess generalizability of published GWAS findings and to identify potential novel associations in African American populations.

Impact: Both replication and lack of replication of published GWAS findings in other ancestral groups provides important information of the genetic etiology of this disease and may impact translation of GWAS findings to clinical and public health settings. Cancer Epidemiol Biomarkers Prev; 20(9); 1950–9. ©2011 AACR.
Diagnostic Workup of the Short Child
Authors: Hokken-Koelega Anita C.S.
Published: September 2011

Documents detailing the diagnostic approach to identification of short stature in children have been generated following several consensus meetings. Besides assessment of medical history and a physical examination, specific tests are proposed based on clinical suspicion. In the absence of abnormal findings, patients are typically screened using laboratory tests and radiographs of the hand. However, there is limited evidence as to the choice of screening components; these decisions are based on clinical experience. To improve the diagnostic approach in children with short stature, diagnostic tools should be improved to allow better characterization of patient subpopulations and better measures of certain parameters.
Genetics of Human Stature: Insight from Single Gene Disorders
Authors: Kiess W. , Kratzsch J. , Kruis T. , Müller E. , Wallborn T. , Odeh R. , Schlicke M. , Klammt J. , Pfäffle R.
Published: September 2011

Mutations of numerous genes encoding proteins that affect multiple pathways responsible for regulation of cell proliferation can cause growth disturbances in humans. Genes such as HESX1, PROP1, PIT1/POU1F1 and GLI2 have been shown to cause pituitary hormone deficiency. In addition, heterozygous mutations or gene deletions in the growth hormone-insulin-like growth factor (GH-IGF) axis such as the GH, GH-releasing hormone receptor, GH receptor, STAT5b, IGF-I, IGF-I receptor and the acid labile subunit have also been observed in children with growth failure and short stature. More recently, mutations of genes encoding regulators of cell proliferation and division, i.e., the pericentrin gene, have also resulted in severe growth disturbances.
Auxological Criteria for Treating Children with Idiopathic Short Stature
Authors: Loche Sandro
Published: September 2011

Children with idiopathic short stature (ISS) may not reach an adult height within their genetic target. In 2003, the United States Food and Drug Administration approved biosynthetic growth hormone (GH) for the treatment of children with ISS whose heights exceeded 2.25 standard deviation scores below the mean and who were considered unlikely to reach a normal adult height. Results of controlled studies have shown that, although GH treatment leads to a substantial increase in adult height, the individual response to therapy is difficult to predict. A number of auxological variables (i.e., age and height at start of treatment, bone age delay, mean predicted height, height velocity and first-year responsiveness) are used in multivariate analyses to predict outcomes. Estimation of target height, predicted adult height and pattern of growth should guide the decision to treat a child with ISS.
Criteria for Treating Children with Idiopathic Short Stature: Laboratory (Biochemical)
Authors: Chernausek Steven D.
Published: September 2011

Idiopathic short stature (ISS) is a diagnosis of exclusion. No specific laboratory test can identify it. Rather, a series of tests that examine a person’s genetic, nutritional and hormonal makeup are used to exclude specific diagnoses. However, abnormalities of the growth hormone-insulin-like growth factor (GH-IGF) axis appear to be common in children with ISS. As the only growth-promoting treatments available to children with ISS are either human GH or recombinant human IGF-I, it is plausible that measures of the GH-IGF axis or of growth factor response might be useful in predicting response to therapy or choosing the optimal medical regimen.
Treatment of Idiopathic Short Stature: Effects of Gonadotropin-Releasing Hormone Analogs, Aromatase Inhibitors and Anabolic Steroids
Authors: Dunkel Leo
Published: September 2011

Modulation of sex steroid action on the growth plate can, at least theoretically, increase adult height in children and adolescents with idiopathic short stature. Gonadotropin-releasing hormone (GnRH) analog therapy during adolescence has been shown effective in a placebo-controlled study, but to obtain clinically significant increases in adult height, the treatment duration must be lengthy (several years). Furthermore, such treatment seems to compromise bone health and, because of the resulting delay in pubertal development, likely has psychosocial consequences. Therefore, GnRH analogs are no longer recommended to augment height in adolescents with short stature and normally timed puberty. Aromatase inhibitors are probably more effective than GnRH analogs in promoting increased adult height in children with short stature and, unlike GnRH analogs, do not delay pubertal development in males. However, due to a dearth of safety data with aromatase inhibitors for the treatment of short stature, their use outside a research setting is currently not recommended. Positive effects of anabolic steroids on adult height have not been documented
Psychosocial Aspects of Short Stature and Its Management: Good Deeds Require Good Science
Authors: Sandberg David E.
Published: September 2011

Beliefs and assumptions regarding the presumed negative influence of height on psychological adaptation and quality of life contribute to the growth hormone (GH) therapy decision-making process. Although bioethics considers more than empirical evidence when providing guidance, recommendations based on poor-quality science will certainly diminish their ultimate value. This brief and selective overview identifies pitfalls and deficiencies in the existing literature on the psychosocial aspects of short stature and its management with GH. It concludes with a call for methodologically robust psychosocial research together with a careful risk/benefit analysis for the individual child.
Safety of Growth Hormone Treatment of Children with Idiopathic Short Stature: The US Experience
Authors: Allen David B.
Published: September 2011

Recombinant human growth hormone (rhGH) is approved in the United States for treatment of idiopathic short stature (ISS). The occurrence of adverse events (AEs) and the long-term safety of rhGH treatment in this patient population are reviewed. Data were analyzed from postmarketing surveillance studies that included ISS patients, prospective ISS treatment trials and studies of specific AEs in smaller groups of rhGH-treated children. Frequency rates of targeted AEs (i.e., scoliosis, slipped capital femoral epiphysis, intracranial hypertension, pancreatitis) in patients with ISS are similar to or lower than the rates observed in other rhGH-treated conditions. At dosages of 0.24–0.37 mg/kg/week, rhGH treatment in children with ISS does not adversely affect blood glucose levels. At dosages ≧0.3 mg/kg/week, a dose-dependent increase in mean fasting and stimulated insulin levels is observed. Current evidence derived from ‘on-treatment’ surveillance studies suggests that rhGH does not increase the risk for new malignancies in children with ISS.The safety profile of rhGH at doses ≤0.37 mg/kg/week for the treatment of children with ISS is similar to or better than the profile seen in other rhGH-treated conditions and is not associated with any predictable AEs. Due to a continuing trend toward dose escalation to achieve greater height-promoting effects and the possibility of delayed post-treatment effects of hyperinsulinemia and/or heightened GH and insulin-like growth factor I exposure on cancer risk, caution and ongoing scrutiny of risks versus benefits are warranted.
Psychological Functioning in Idiopathic Short Stature
Authors: Noeker Meinolf
Published: September 2011

Living with idiopathic short stature (ISS) may entail significant risks to psychological functioning and quality of life. Apparent inconsistency among study findings can be resolved if methodological differences among study designs are taken into account (i.e., definition of particular endpoints, sample selection from clinic or population, source of report, specific or generic assessment instruments, statistical control of confounders). Some individuals fail and others succeed in mastering the challenges of ISS. The principles of multifinality and equifinality may explain the emergence of a broad variation of individuals with ISS as a result of an interaction of the individual medical and auxological features on the one side, and psychosocial risk and protective factors on the other. As a result, patients may show heterogeneous developmental outcomes ranging from clinical psychopathology to development of resilience. A taxonomy of four distinct pathways of adaptation to ISS is delineated as a basis for case formulation and treatment planning. Psychological intervention in ISS includes counseling, cognitive-behavioral therapy and assertiveness training to improve psychological functioning via enhancement of target coping behaviors for critical situations.
Full-Body Skin Mapping for Six Biophysical Parameters: Baseline Values at 16 Anatomical Sites in 125 Human Subjects
Authors: Kleesz P. , Darlenski R. , Fluhr J.W.
Published: September 2011

Background/Aim: The skin, as the outermost organ, protects against exogenous hazards (outside-in barrier) and prevents the loss of essential parts of the body (inside-out barrier). The epidermal barrier exerts several functions with specific morphological elements. Regional differences in skin functions are well known. The aim of the present study was to assess and compare skin physiological parameters in vivo at 16 anatomical sites: Barrier function in terms of transepidermal water loss (TEWL), stratum corneum (SC) hydration (assessed by capacitance), skin surface pH, skin surface temperature, erythema index and skin pigmentation were quantified at 16 anatomical sites under basal conditions. In addition, casual skin lipid level as a function of sebaceous lipids was measured on the forehead. Material and Methods: The 6 functions at the 16 anatomical sites were assessed in a cohort of 125 volunteers working in the food processing industry. These functions were quantified with noninvasive instruments, namely a Tewameter (barrier function), a Corneometer (SC hydration), a pH-meter, a Mexameter (erythema index and pigmentation), a skin surface thermometer and a Sebumeter (casual sebum level). Results: We identified ranges for the 16 anatomical locations for each instrument and some parameters could be classified into distinctive groups. Furthermore, a left-right comparison was performed at 3 sites (dorsal hand, ventral hand and ventral forearm). Certain side differences could be shown for SC hydration, surface pH, erythema index, melanin index and skin surface temperature in the 3 assessed areas. A left-to-right, statistically nonsignificant difference was also established for TEWL. Conclusion: The detected site-specific characteristics could be attributed to factors such as occlusion, different degrees of UV exposure, microcirculation and distribution of afferent and efferent nerve endings as well as fat distribution. External factors, such as life style, UV exposure and working conditions need to be taken into account. The present data are intended for an adequate selection of parameters and anatomical locations when assessing working conditions and designing clinical dermatological and pharmaceutical studies.
Innate Immune Activation in Intestinal Homeostasis
Authors: Harrison Oliver J. , Maloy Kevin J.
Published: September 2011

Loss of intestinal immune regulation leading to aberrant immune responses to the commensal microbiota are believed to precipitate the chronic inflammation observed in the gastrointestinal tract of patients with inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis. Innate immune receptors that recognize conserved components derived from the microbiota are widely expressed by both epithelial cells and leucocytes of the gastrointestinal tract and play a key role in host protection from infectious pathogens; yet precisely how pathogenic and commensal microbes are distinguished is not understood. Furthermore, aberrant innate immune activation may also drive intestinal pathology, as patients with IBD exhibit extensive infiltration of innate immune cells to the inflamed intestine, and polymorphisms in many innate immunity genes influence susceptibility to IBD. Thus, a balanced interaction between the microbiota and innate immune activation is required to maintain a healthy mutualistic relationship between the microbiota and the host, which when disturbed can result in intestinal inflammation.
Role of Cardiovascular Magnetic Resonance as a Gatekeeper to Invasive Coronary Angiography in Patients Presenting With Heart Failure of Unknown Etiology
Authors: Assomull Ravi G. , Shakespeare Carl , Kalra Paul R. , Lloyd Guy , Gulati Ankur , Strange Julian , Bradlow William M. , Lyne Jonathan , Keegan Jennifer , Poole-Wilson Philip , Cowie Martin R. , Pennell Dudley J. , Prasad Sanjay K.
Published: September 2011

Background—

In patients presenting with new-onset heart failure of uncertain etiology, the role of coronary angiography (CA) is unclear. Although conventionally performed to differentiate underlying coronary artery disease from dilated cardiomyopathy, CA is associated with a risk of complications and may not detect an ischemic cause resulting from arterial recanalization or an embolic episode. In this study, we assessed the diagnostic accuracy of a cardiovascular magnetic resonance (CMR) protocol incorporating late gadolinium enhancement (LGE) and magnetic resonance CA as a noninvasive gatekeeper to CA in determining the etiology of heart failure in this subset of patients.

Methods and Results—

One hundred twenty consecutive patients underwent CMR and CA. The etiology was ascribed by a consensus panel that used the results of the CMR scans. Similarly, a separate consensus group ascribed an underlying cause by using the results of CA. The diagnostic accuracy of both strategies was compared against a gold-standard panel that made a definitive judgment by reviewing all clinical data. The study was powered to show noninferiority between the 2 techniques. The sensitivity of 100%, specificity of 96%, and diagnostic accuracy of 97% for LGE-CMR were equivalent to CA (sensitivity, 93%; specificity, 96%; and diagnostic accuracy, 95%). As a gatekeeper to CA, LGE-CMR was also found to be a cheaper diagnostic strategy in a decision tree model when United Kingdom–based costs were assumed. The economic merits of this model would change, depending on the relative costs of LGE-CMR and CA in any specific healthcare system.

Conclusion—

This study showed that LGE-CMR is a safe, clinically effective, and potentially economical gatekeeper to CA in patients presenting with heart failure of uncertain etiology.
Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate
Authors: Eerenberg Elise S. , Kamphuisen Pieter W. , Sijpkens Meertien K. , Meijers Joost C. , Buller Harry R. , Levi Marcel
Published: September 2011

Background—

Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs.

Methods and Results—

In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline;
P
<0.001) that was immediately and completely reversed by PCC (12.8±1.0;
P
<0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%;
P
=0.002) and normalized with PCC (114±26%;
P
<0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests.

Conclusion—

Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study.

Clinical Trial Registration—

URL:
http://www.trialregister.nl
. Unique identifier: NTR2272.