bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Variants in Two Vitamin E Transport Genes with Circulating Vitamin E Concentrations and Prostate Cancer Risk
Authors: Wright Margaret E. , Peters Ulrike , Gunter Marc J. , Moore Steven C. , Lawson Karla A. , Yeager Meredith , Weinstein Stephanie J. , Snyder Kirk , Virtamo Jarmo , Albanes Demetrius
Published: February 2009

Significant reductions in prostate cancer incidence and mortality were observed in men randomized to receive 50 mg supplemental vitamin E (α-tocopherol) per day in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We hypothesized that variation in key vitamin E transport genes might directly affect prostate cancer risk or modify the effects of vitamin E supplementation. Associations between prostate cancer risk and 13 polymorphisms in two genes, TTPA and SEC14L2, were examined in 982 incident prostate cancer cases and 851 controls drawn from the ATBC Study. There was no association between the genetic variants and prostate cancer risk. Significant interactions were observed, however, between two variants in SEC14L2 (IVS11+931A>G and IVS11−896A>T) and the trial α-tocopherol supplement such that vitamin E supplementation reduced prostate cancer risk among men who were homozygous for either common allele [odds ratios (OR) and 95% confidence intervals (95% CI), 0.52 (0.30–0.90) and 0.64 (0.46–0.88), respectively] and nonsignificantly increased risk among those who carried one or two copies of either variant allele [ORs and 95% CIs, 1.27 (0.90–1.79) and 1.21 (0.96–1.52), respectively; both P for interaction < 0.05]. Genotype-phenotype analyses revealed significant but modest differences in baseline circulating concentrations of α-tocopherol and serum responses to the vitamin E supplementation for several polymorphisms. This study shows that genetic variation in TTPA and SEC14L2 is associated with serum α-tocopherol but does not have a direct effect on prostate cancer. Our results do, however, suggest that polymorphisms in SEC14L2 may modify the effect of vitamin supplementation regimens on prostate cancer risk. [Cancer Res 2009;69(4):1429–38]
Breast Cancer Cell Lines Contain Functional Cancer Stem Cells with Metastatic Capacity and a Distinct Molecular Signature
Authors: Charafe-Jauffret Emmanuelle , Ginestier Christophe , Iovino Flora , Wicinski Julien , Cervera Nathalie , Finetti Pascal , Hur Min-Hee , Diebel Mark E. , Monville Florence , Dutcher Julie , Brown Marty , Viens Patrice , Xerri Luc , Bertucci François , Stassi Giorgio , Dontu Gabriela , Birnbaum Daniel , Wicha Max S.
Published: February 2009

Tumors may be initiated and maintained by a cellular subcomponent that displays stem cell properties. We have used the expression of aldehyde dehydrogenase as assessed by the ALDEFLUOR assay to isolate and characterize cancer stem cell (CSC) populations in 33 cell lines derived from normal and malignant mammary tissue. Twenty-three of the 33 cell lines contained an ALDEFLUOR-positive population that displayed stem cell properties in vitro and in NOD/SCID xenografts. Gene expression profiling identified a 413-gene CSC profile that included genes known to play a role in stem cell function, as well as genes such as CXCR1/IL-8RA not previously known to play such a role. Recombinant interleukin-8 (IL-8) increased mammosphere formation and the ALDEFLUOR-positive population in breast cancer cell lines. Finally, we show that ALDEFLUOR-positive cells are responsible for mediating metastasis. These studies confirm the hierarchical organization of immortalized cell lines, establish techniques that can facilitate the characterization of regulatory pathways of CSCs, and identify potential stem cell markers and therapeutic targets. [Cancer Res 2009;69(4):1302–13]
Human Renal Cancer Cells Express a Novel Membrane-Bound Interleukin-15 that Induces, in Response to the Soluble Interleukin-15 Receptor α Chain, Epithelial-to-Mesenchymal Transition
Authors: Khawam Krystel , Giron-Michel Julien , Gu Yanhong , Perier Aurélie , Giuliani Massimo , Caignard Anne , Devocelle Aurore , Ferrini Silvano , Fabbi Marina , Charpentier Bernard , Ludwig Andreas , Chouaib Salem , Azzarone Bruno , Eid Pierre
Published: February 2009

Although interleukin-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of 27 kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor α (s-IL-15Rα) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to ~induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (α-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15Rα subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Rα chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression. [Cancer Res 2009;69(4):1561–9]
Whole Genome Comparison of Allelic Imbalance between Noninvasive and Invasive Small-Sized Lung Adenocarcinomas
Authors: Nakanishi Hirofumi , Matsumoto Shingo , Iwakawa Reika , Kohno Takashi , Suzuki Kenji , Tsuta Koji , Matsuno Yoshihiro , Noguchi Masayuki , Shimizu Eiji , Yokota Jun
Published: February 2009

Seventy-two small-sized (≤2 cm in diameter) lung adenocarcinomas consisting of 15 noninvasive and 57 invasive tumors were subjected to whole genome allelic imbalance (AI) scanning and mutational analysis of the EGFR, KRAS, and TP53 genes to elucidate genetic pathways of early-stage lung adenocarcinomas. The chromosome 13q13 region showed the most frequent AI (58%) and was affected at similar frequencies between noninvasive and invasive tumors (53% and 60%, respectively), as EGFR and KRAS mutations were. The number of AI regions as well as the frequency of TP53 mutations in invasive tumors was significantly higher than those in noninvasive ones [9.8 ± 5.6 versus 4.8 ± 2.8 (P = 0.00002) and 61% versus 13% (P = 0.001), respectively]. In particular, AIs at the chromosome 11p11-p12, 17p12-p13, and 18p11 regions in invasive tumors were significantly more frequent than those in noninvasive ones (P < 0.01). The results indicated that noninvasive tumors were developed by EGFR, KRAS, and 13q alterations and progressed to invasive ones by subsequent alterations of several tumor suppressor genes, including those on 11p11-p12, 17p12-p13, and 18p11 and TP53. AI at 8p21 was significantly more frequent in advanced stages (>IA) and associated with worse prognoses (P = 0.04) and, thus, would be involved in invasion and/or metastasis of adenocarcinoma cells and useful for the prediction of prognosis of patients with small-sized lung adenocarcinoma. [Cancer Res 2009;69(4):1615–23]
Functional Analysis of 11q13.5 Amplicon Identifies Rsf-1 (HBXAP) as a Gene Involved in Paclitaxel Resistance in Ovarian Cancer
Authors: Choi Jung Hye , Sheu Jim Jinn-Chyuan , Guan Bin , Jinawath Natini , Markowski Paul , Wang Tian-Li , Shih Ie-Ming
Published: February 2009

The chromosome 11q13.5 locus is frequently amplified in several types of human cancer. We have previously shown that 11q13.5 amplification was associated with significantly shorter overall survival in ovarian cancer patients, but the molecular mechanisms of how amplification of this locus contributes to disease aggressiveness remain unclear. Because ovarian cancer mortality is primarily related to resistance of chemotherapeutic agents, we screened the top six candidate genes within this amplicon for their contribution to drug resistance. Rsf-1 (also known as HBXAP) was found to be the only gene in which gene knockdown sensitized tumor cells to paclitaxel. Rsf-1 has been known to interact with hSNF2H to form an ISWI chromatin remodeling complex. We found that Rsf-1 was up-regulated in paclitaxel-resistant ovarian cancer cell lines, and Rsf-1 immunoreactivity in primary ovarian carcinoma tissues correlated with in vitro paclitaxel resistance. Ectopic expression of Rsf-1 significantly enhanced paclitaxel resistance in ovarian cancer cells. Down-regulation of hSNF2H or disruption of hSNF2H and Rsf-1 interaction enhanced paclitaxel sensitivity in tumor cells with Rsf-1 up-regulation. Rsf-1 expression altered expression in several genes and activated certain signaling pathways that may contribute to drug resistance. In conclusion, our results suggest that Rsf-1 is the major gene within the 11q13.5 amplicon that contributes to paclitaxel resistance, and the formation of the Rsf-1/hSNF2H complex is required for inducing this phenotype. [Cancer Res 2009;69(4):1407–15]
Methylation-Mediated Repression of GADD45α in Prostate Cancer and Its Role as a Potential Therapeutic Target
Authors: Ramachandran Kavitha , Gopisetty Gopal , Gordian Edna , Navarro Loida , Hader Christiane , Reis Isildinha M. , Schulz Wolfgang A. , Singal Rakesh
Published: February 2009

Defects in apoptotic pathway contribute to uncontrolled proliferation of cancer cells and confer resistance to chemotherapy. Growth arrest and DNA damage inducible, alpha (GADD45α) is up-regulated on docetaxel treatment and may contribute to docetaxel-mediated cytotoxicity. We examined the mechanism of regulation of GADD45α in prostate cancer cells and the effect of its up-regulation on sensitivity to docetaxel chemotherapy. Expression of GADD45α in PC3 cells was higher than that in Du145 and LNCaP cells (17- and 12-fold, respectively; P < 0.05). Although the proximal promoter region was unmethylated in all three cell lines, methylation of a 4 CpG region upstream of the proximal promoter correlated inversely with gene expression levels. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyltransferase inhibitors, leading to reactivation of GADD45α expression in these cells. The 5′ 4 CpG region was also frequently methylated in prostate cancer tissues. Methylation of this region correlated inversely with gene expression in prostate cancer and benign prostate tissues. The methyl binding protein MeCP2 was associated with the methylated 4 CpGs in Du145 cells, and knockdown of MeCP2 in these cells (Du145 MeCP2−) led to a significantly increased expression of GADD45α (3-fold; P = 0.035) without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by up-regulation of GADD45α in Du145 cells by recombinant expression of GADD45α or pretreatment with 5-azacytidine. Our results show that GADD45α is epigenetically repressed and is a potential target for treatment of prostate cancer. [Cancer Res 2009;69(4):1527–35]
Inhibition of eIF2α Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy
Authors: Schewe Denis M. , Aguirre-Ghiso Julio A.
Published: February 2009

The proteasome inhibitor bortezomib (Velcade) effectively eradicates multiple myeloma (MM) cells, partly by activating endoplasmic reticulum (ER) stress apoptotic signaling. However, MM recurrences in bortezomib-treated patients are invariable. We have shown that ER stress signaling can also induce growth arrest and survival in cancer cells. Thus, we hypothesized that bortezomib therapy could induce quiescence and survival of residual MM cells, contributing to disease recurrence. Here, we report that in MM cells, proteasome inhibition with MG-132 or bortezomib results in a surviving cell fraction that enters a prolonged quiescent state (G0-G1 arrest). Mechanism analysis revealed that bortezomib-surviving quiescent cells attenuate eIF2α phosphorylation and induction of the ER stress proapoptotic gene GADD153. This occurs independently of the eIF2α upstream kinases PERK, GCN2, and PKR. In contrast, the prosurvival ER-chaperone BiP/Grp78 was persistently induced. The bortezomib-surviving quiescent fraction could be eradicated by a simultaneous or sequential combination therapy with salubrinal, an inhibitor of GADD34-PP1C phosphatase complex, and, in consequence, eIF2α dephosphorylation. This effect was mimicked by expression of a phosphorylated mimetic eIF2α-S51D mutant. Our data indicate that bortezomib can induce growth arrest in therapy-surviving MM cells and that attenuation of eIF2α phosphorylation contributes to this survival. Most importantly, this survival mechanism can be blocked by inhibiting eIF2α dephosphorylation. Thus, strategies that maintain eIF2α in a hyperphosphorylated state may be a novel therapeutic approach to maximize bortezomib-induced apoptosis and reduce residual disease and recurrences in this type of cancer. [Cancer Res 2009;69(4):1545–52]
Local Delivery of Poly Lactic-co-glycolic Acid Microspheres Containing Imatinib Mesylate Inhibits Intracranial Xenograft Glioma Growth
Authors: Benny Ofra , Menon Lata G. , Ariel Gilert , Goren Effrat , Kim Seung-Ki , Stewman Chaney , Black Peter M. , Carroll Rona S. , Machluf Marcelle
Published: February 2009

Purpose: In an effort to develop new therapeutic strategies to treat malignant gliomas, we have designed poly (lactic-co-glycolic) acid (PLGA) microparticles that deliver imatinib mesylate, a small molecule tyrosine kinase inhibitor. The local continuous release of imatinib mesylate at the tumor site overcomes many obstacles associated with systemic delivery.

Experimental Design: Polymeric microspheres were prepared from various compositions of PLGA and loaded with imatinib mesylate. Imatinib release profiles, biological activity, and effect on PDGFR-B phosphorylation were confirmed in vitro. The therapeutic efficacy of imatinib microspheres was examined in two s.c. and orthotopic human glioblastoma xenograft models.

Results: A single local injection of PLGA microspheres loaded with a low concentration of imatinib mesylate led to 88% and 79% reduction in s.c. human (U87-MG) and murine (GL261) glioma tumors, respectively. PLGA-imatinib mesylate administered intracranially led to a 79% reduction in U87MG tumor volume. Immunohistochemical analysis showed a marked decrease in proliferation indices and tumor vessel density in the s.c. model and induction of apoptosis in an intracranial model.

Conclusion: This is the first study to show the therapeutic efficacy of the local delivery of imatinib mesylate using a polymeric delivery system.
Small-Molecule Drugs Mimicking DNA Damage: A New Strategy for Sensitizing Tumors to Radiotherapy
Authors: Quanz Maria , Berthault Nathalie , Roulin Christophe , Roy Maryline , Herbette Aurélie , Agrario Céline , Alberti Christophe , Josserand Véronique , Coll Jean-Luc , Sastre-Garau Xavier , Cosset Jean-Marc , Larue Lionel , Sun Jian-Sheng , Dutreix Marie
Published: February 2009

Purpose: Enhanced DNA repair activity is often associated with tumor resistance to radiotherapy. We hypothesized that inhibiting DNA damage repair would sensitize tumors to radiation-induced DNA damage.

Experimental Design: A novel strategy for inhibiting DNA repair was tested. We designed small DNA molecules that mimic DNA double-strand breaks (called Dbait) and act by disorganizing damage signaling and DNA repair. We analyzed the effects of Dbait in cultured cells and on xenografted tumors growth and performed preliminary studies of their mechanism(s) of action.

Results: The selected Dbait molecules activate H2AX phosphorylation in cell culture and in xenografted tumors. In vitro, this activation correlates with the reduction of Nijmegen breakage syndrome 1 and p53-binding protein 1 repair foci formation after irradiation. Cells are sensitized to irradiation and do not efficiently repair DNA damage. In vivo, Dbait induces regression of radioresistant head and neck squamous cell carcinoma (Hep2) and melanoma (SK28 and LU1205) tumors. The combination of Dbait32Hc treatment and fractionated radiotherapy significantly enhanced the therapeutic effect. Tumor growth control by Dbait molecules depended directly on the dose and was observed with various irradiation protocols. The induction of H2AX phosphorylation in tumors treated with Dbait suggests that it acts in vivo through the induction of “false” DNA damage signaling and repair inhibition.

Conclusions: These data validate the concept of introducing small DNA molecules, which mimic DNA damage, to trigger “false” signaling of DNA damage and impair DNA repair of damaged chromosomes. This new strategy could provide a new method for enhancing radiotherapy efficiency in radioresistant tumors.
Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma
Authors: Milano Vanessa , Piao Yuji , LaFortune Tiffany , de Groot John
Published: February 2009

Glioblastoma is defined by its aggressive invasion, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and epidermal growth factor receptor by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phospho-SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. Reduction of invasive potential was observed in vitro at concentrations well below the IC50 of dasatinib, which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in focal adhesion kinase autophosphorylation. Cell cycle analysis revealed minimal G1 arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in light chain 3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death. Dasatinib in combination with temozolomide more effectively increased the therapeutic efficacy of temozolomide than when dasatinib was combined with carboplatin or irinotecan. These results strongly support the clinical use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide. [Mol Cancer Ther 2009;8(2):394–406]
MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib
Authors: Houben Roland , Voigt Heike , Noelke Christiane , Hofmeister Valeska , Becker Juergen C. , Schrama David
Published: February 2009

Sorafenib, originally developed as CRAF inhibitor but soon recognized as a multikinase inhibitor, is currently widely tested for the treatment of different cancers either alone or in combination therapy. However, the clinical success, particularly in immunogenic tumors such as melanoma, was less than anticipated. Because T-cell activation is tightly regulated by a multitude of kinases, we scrutinized effects of sorafenib on immune responses. To this end, comprehensive in vitro studies revealed that the presence of sorafenib concentrations comparable with observed plasma levels in patients strongly impairs the activation of T cells. Notably, even established tumor-specific immune responses are influenced by sorafenib. Indeed, ELISPOT data of peripheral blood lymphocytes obtained from melanoma patients vaccinated against survivin show markedly diminished survivin-specific immune responses in the presence of sorafenib. Surprisingly, inhibition of T-cell activation was not associated with reduced extracellular signal-regulated kinase phosphorylation. In fact, on T-cell receptor stimulation phospho-extracellular signal-regulated kinase and phospho-mitogen-activated protein kinase kinase levels were found to be elevated in the presence of sorafenib, showing the complexity of signal transduction events following T-cell receptor stimulation. In conclusion, our data show that T-cell function is sensitive toward the multikinase inhibitor sorafenib in a mitogen-activated protein kinase-independent fashion. This observation has important implications for the use of sorafenib as therapy for immunogenic cancers. [Mol Cancer Ther 2009;8(2):433–40]
Skin Substitutes and Wound Healing
Authors: Auger F.A. , Lacroix D. , Germain L.
Published: February 2009

Medical science has vastly improved on the means and methods available for the treatment of wounds in the clinic. The production and use of various types of skin substitutes has led to dramatic improvements in the odds of survival for severely burned patients, but they have also shown promise for many other applications, including cases involving chronic wounds that are not life threatening. Nowadays, more than 20 products are commercially available, more are undergoing clinical trials and a large number of new models are being investigated in various research laboratories worldwide. Many of the current products do not contain any living cells and vary in their capacity to harness the innate capacity of the body to heal itself. Others include living cells, of allogeneic or autologous origin, and are often referred to as ‘cellular therapy’ or ‘tissue-engineered’ products. Modifications and improvements are currently investigated that aim at improving the healing potential of those products through the use of recombinant growth factors and additional features such as microvascularization. Fundamental research into wound healing and scar-free regeneration raises the hope that we will eventually be able to restore almost completely the appearance and function of skin after the healing of wounds.
Reference Values for CD4+ and CD8+ T Lymphocytes with Naïve or Memory Phenotype and Their Association with Mortality in the Elderly
Authors: Provinciali Mauro , Moresi Raffaella , Donnini Alessia , Lisa Rosa Maria
Published: February 2009

Background: Well-established reference values which take into account the influence of age on immune cell phenotype, and the impact of naïve or memory T cells on mortality have not been well defined in the elderly. Objective: The aim of this study was to evaluate the reference values for the peripheral number of total and naïve or memory CD4 and CD8 T cells in a healthy population in Italy, and to analyze whether the immune phenotype was associated with an increased risk of death among older adults. Methods: The number of total or naïve and memory CD4+ or CD8+ T cells was evaluated in the peripheral blood of 288 healthy people ranging in age from 20 to 107 years. Furthermore, to correlate peripheral immune phenotype with mortality rate after a 3-years follow-up, a retrospective analysis was performed on the results from those individuals aged >65 years at the time of the enrolment in the study. Results: The absolute number of total and naïve T cells was progressively reduced with increasing age in both the CD4+ and CD8+ T cell populations. The decrease was particularly evident for cells with naïve phenotype, since CD4-naïve and CD8-naïve T cells respectively showed a 4- and a 2- to 3-fold reduction in 70- to >90-year-old subjects in comparison with young adults. The number of CD4 memory T cells significantly increased with age. No significant age-related change was observed in the number of CD8+ memory T cells. Of the 194 subjects included in the study of association of immune phenotype with mortality, 121 were alive and 73 deceased during the 3-year follow-up. The impact of immune parameters on survival demonstrated that only the absolute number of CD8 memory T cells, after adjustment for age, correlated with increased mortality (OR 1.007, 95% CI 1.002–1.012, p = 0.01). The correlation was significant in female but not in male subjects. Conclusion: We provide reference values for total and naïve or memory CD4 and CD8 T cell populations, and demonstrate that the absolute number of CD8 memory T cells, after adjustment for age, correlates with increased mortality.
Gender-Related Differences in the Relationship between Plasma Homocysteine, Anthropometric and Conventional Biochemical Coronary Heart Disease Risk Factors in Middle-Aged Indians
Authors: Pitla Sujatha , Nagalla Balakrishna
Published: February 2009

Background/Objective: Gender-related differences in anthropometric measures [body mass index (BMI) and waist circumference (WC)] and other coronary heart disease (CHD) risk factors have been reported in other ethnics. However, information available on middle aged healthy Indians are scanty. The aim of our present study is to determine plasma total homocysteine (tHcy), anthropometric measures (BMI and WC) and conventional biochemical CHD risk factors, and to examine their relationship in healthy middle-aged men and women. Methods: Fifty-two middle aged (40–59 years) apparently healthy volunteers (29 men and 23 women) were recruited from the staff of the National Institute of Nutrition at Hyderabad. Subjects were screened for plasma tHcy concentrations, lipid profile and blood pressure. Anthropometric Indices (BMI, WC) were measured as per standard protocols. Data on education, income, diet (vegetarians vs. omnivores) and lifestyle factors such as smoking, alcohol consumption and exercise were recorded. Results: At similar age and BMI, men had higher WCs (mean ± SD, 91.2 ± 5.44 vs. 78.9 ± 7.62 cm, p < 0.001) than women. Plasma tHcy concentrations (17.9 ± 9.88 vs. 8.2 ± 1.90 μmol/l, p < 0.001) were also higher in men than in women. Among men, vegetarian men had significantly higher plasma tHcy than omnivorous men (median 22.80 vs. 9.85 μmol/l, p < 0.05). Plasma tHcy concentrations were comparable between vege- tarian and omnivorous women. Of known conventional CHD risk factors, blood pressure, total cholesterol and triglycerides were also significantly (p < 0.05) higher in men than in women. A significant positive correlation was found between plasma tHcy and WC in men only (r = 0.484, p < 0.01). In women, in turn, plasma tHcy was positively correlated with low-density-lipoprotein cholesterol (r = 0.567, p < 0.01). Conclusions: This study on apparently healthy Indians confirms the known associations between gender and conventional CHD risk factors, while diet (vegetarian vs. omnivorous) had no influence on CHD risk factors with the exception of tHcy in men.
Intake of Chlorella vulgaris Improves Antioxidative Capacity in Rats Oxidatively Stressed with Dietary Cadmium
Authors: Son Young Ae , Shim Jee Ae , Hong Soyoung , Kim Mi Kyung
Published: February 2009

Background/Aims: This study was designed to examine the antioxidative capacity of chlorella in rats oxidatively stressed with dietary cadmium (Cd). Method: Sixty male Sprague-Dawley rats (14 weeks old) were fed diets containing 0, 3 or 5% chlorella, and 0 or 160 ppm Cd for 10 weeks. Activities of antioxidant enzymes and xanthine oxidase (XO), lipid peroxide concentration and superoxide radical generation were examined in blood and liver. Results: Erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase activities were not different among the groups. Cd treatment significantly lowered liver SOD and GPx activities; however, there were no differences induced by the chlorella content. Dietary Cd markedly increased XO activities in plasma and liver. Five percent chlorella-containing diets significantly lowered plasma XO activity, 3% chlorella-containing diets significantly lowered liver XO activity. Plasma malondialdehyde (MDA) concentration of the Cd-3% chlorella group was significantly lower than that of the Cd-0% chlorella group. Liver MDA concentration of the Cd-5% chlorella group was significantly lower than that of the Cd-0% chlorella group. Increased serum and liver superoxide radical generation by Cd was significantly attenuated by chlorella intake. Conclusion: Chlorella could be applied as potential substance for reducing oxidative stress, since XO activity, MDA concentration and superoxide radical generation were decreased by chlorella intake.
Prevalence of Vitamin D Insufficiency in Brazilian Adolescents
Authors: Peters Barbara Santarosa Emo , dos Santos Luana Caroline , Fisberg Mauro , Wood Richard James , Martini Lígia Araújo
Published: February 2009

Background/Aims: Cutaneous sun exposure and dietary vitamin D intake are important determinants of vitamin D status. The objective of the present study was to evaluate the vitamin D status of a group of healthy adolescent students living in Brazil. Methods: One hundred and thirty-six adolescents, 64 boys and 72 girls, aged 16–20 years old, living in a rural town in the state of São Paulo, Brazil, participated in this study. Results: The mean dietary vitamin D intake was 140 (120–156) IU/day [3.5 (3.0–3.9) μg/day]. Only 14.9% of the students met the daily adequate intake recommendation of vitamin D. Only 27.9% practice physical activity outdoors and 17.6% of the adolescents apply sunscreen daily. The mean 25(OH)D concentration was 73.0 (22.0) nmol/l [29.2 (8.8) ng/ml]. Vitamin D insufficiency was observed in 60% of adolescents. Conclusions: The present study suggests that even in a sunny climate like Brazil the prevalence of vitamin D insufficiency in adolescents is high. Most likely this is due to low intakes of vitamin D in this group. Due to the limited extent of natural dietary sources of vitamin D, a policy of vitamin D food fortification should be considered in the future, and in the meantime greater use of vitamin D supplements in this population group should be encouraged to provide the increased amounts of this essential nutrient for optimal health.
A Circulating β2-Microglobulin Intermediate in Hemodialysis Patients
Authors: Uji Yoshinori , Motomiya Yoshihiro , Ando Yukio
Published: February 2009

Background/Aims: A misfolded β2-microglobulin (β2m) is a principle component in dialysis-related amyloidosis. However, no such conformational variant of β2m has yet been reported in a clinical setting. Capillary electrophoresis is a tool that can identify the conformational variant of β2m. Methods: Capillary electrophoresis was used to measure a transitional intermediate from native β2m (N-β2m) to the amyloid β2m. This technique was utilized to assay for intermediate β2m (I-β2m) in serum from 31 hemodialysis (HD) patients before and after HD, 5 patients with non-dialysis chronic renal failure (CRF), and 5 healthy persons. Results:The predialysis values of serum I-β2m and N-β2m were 2.7 ± 1.4 and 29.4 ± 6.8 mg/l, respectively, in the HD patients. The presence of serum I-β2m correlated weakly with the total serum β2m concentration in all HD patients. The serum N-β2m concentration decreased significantly during two types of dialysis treatment: by 32.8% on HD using a polymethylmethacrylate (PMMA) membrane and by 71.2% on online hemodiafiltration (HDF) with a polysulfone (PS) membrane. On the other hand, a dialysis-associated change in serum I-β2m varied from –36.4 to +203.5% in HD patients using PMMA and from –70.8 to +62.5% in online HDF patients using PS. Moreover, a rebound β2m profile suggested that I-β2m might be immobilized in the extracellular space. Conclusion: This study demonstrated that two or three conformational isomers of β2m were probably ubiquitously recognized in human serum. Though no progressive increase in serum I-β2m concentration could be found along with HD, this study shows a significantly poor removal of I-β2m in comparison to N-β2m in patients receiving ongoing dialysis treatment, even with online HDF.
Aminoterminal B-Type Natriuretic Peptide (NT-proBNP) in End-Stage Renal Failure Patients on Regular Hemodialysis: Does It Have Diagnostic and Prognostic Implications?
Authors: Pimenta Joana , Sampaio Francisco , Martins Patrícia , Carvalho Berta , Rocha-Gonçalves Francisco , Ferreira António , Bettencourt Paulo
Published: February 2009

Background: Amino-terminal B-type natriuretic peptide (NT-proBNP) quantification is a useful cardiovascular diagnostic and prognostic test. In renal failure its use may have constraints, as it depends on renal clearance. We aimed to evaluate the clinical usefulness of NT-proBNP in hemodialysis (HD) patients. Methods: We measured NT-proBNP levels in 44 patients before and after a regular high-flux HD. Cardiac parameters were evaluated by echocardiography. Patients were followed up for 656.5 ± 476.4 days for the occurrence of hospital admission or death. Results: NT-proBNP levels decreased after HD (p < 0.0001) without correlation with ultrafiltration volume, Kt/V index, weight decrease or pulse pressure decrease. Pre- and post-HD NT-proBNP were similar in patients with and without left ventricular hypertrophy. Pre-HD levels were not significantly associated with prognosis, probably due to a type 2 error; post-HD NT- proBNP and NT-proBNP reduction ratio (RR) were predictive of the outcome by Kaplan-Meier analysis, but only RR remained associated with prognosis on multivariate regression analysis (hazard ratio 0.96; 95% confidence interval 0.93–0.99). Conclusion: Our results do not support the use of NT-proBNP in the diagnosis of left ventricular hypertrophy or volume status in HD patients, but suggest its utility in prognostic stratification. HD-related variation in NT-proBNP was associated with prognosis.
Including Atmospheric Layers in Vegetation and Urban Offline Surface Schemes
Authors: Masson Valéry , Seity Yann
Published: February 2009

A formulation to include prognostic atmospheric layers in offline surface schemes is derived from atmospheric equations. Whereas multilayer schemes developed previously need a complex coupling between atmospheric-model levels and surface-scheme levels, the coupling proposed here remains simple. This is possible because the atmospheric layers interacting with the surface scheme are independent of the atmospheric model that could be coupled above. The surface boundary layer (SBL; both inside and just above the canopy) is resolved prognostically, taking into account large-scale forcing, turbulence, and, if any, drag and canopy forces and surface fluxes. This formulation allows one to retrieve the logarithmic law in neutral conditions, and it has been validated when coupled to a 3D atmospheric model. Systematic comparisons with 2-m observations and 10-m wind have been made for 2 months. The SBL scheme is able to model the 2-m temperature accurately, as well as the 10-m wind, without any use of analytical interpolation. The largest improvement takes place during stable conditions (i.e., by night), during which analytical laws and interpolation methods are known to be less accurate, and in mountainous areas, in which nocturnal low-level flow is strongly influenced by surface cooling. The prognostic SBL scheme is shown to solve the nighttime physical disconnection problem between surface and atmosphere models. The inclusion of the SBL into the urban Town Energy Balance scheme is presented in a paper by Hamdi and Masson in which the ability of the method to simulate the profiles of both mean and turbulent quantities from above the building down to the road surface is shown using data from the Basel Urban Boundary Layer Experiment (BUBBLE). The proposed method will allow the inclusion of the detailed physics of the multilayer schemes (e.g., the interactions of the SBL flow with forest or urban canopy) into a single-layer scheme that is easily coupled with atmospheric models.
Parameterization of Cloud Drop Activation Based on Analytical Asymptotic Solutions to the Supersaturation Equation
Authors: Khvorostyanov Vitaly I. , Curry Judith A.
Published: February 2009

Toward improving parameterization of cloud droplet activation in cloud and climate models, the integro–differential equation for supersaturation is solved analytically for the algebraic size spectrum of the cloud condensation nuclei (CCN) that is equivalent to the lognormal spectrum. The analytical solutions are obtained for four limiting cases that are combinations of two different values of the updraft vertical velocity (small and large) and two different values of the condensation coefficient that correspond to pure and polluted cloud drops. The characteristics of the CCN can vary within each limit. Thus, these four limits and interpolation among them cover the vast majority of cloudy conditions. Analytical expressions are obtained for the time of CCN activation, maximum supersaturation, and the concentration of activated droplets.

For small updraft vertical velocities, these quantities are the products of the power laws by six variables: CCN concentration, mean radius, soluble fraction, vertical velocities, surface tension, and condensation coefficient. At large updraft vertical velocities, the activation time and maximum supersaturation are the products of the power laws of only two variables—CCN concentration and vertical velocity—and are independent of the CCN physicochemical properties. The first limit is a generalization of the Twomey power laws, with Twomey’s coefficient CT and index k expressed via CCN physicochemical properties; the other three limits are new. The accuracy and regions of validity of these limits are determined by comparison with the exact numerical solution to the supersaturation equation. These solutions can be used for parameterization of drop activation in cloud and climate models and for control of numerical solutions. An advantage of this method is that it does not require running parcel models, and the drop concentrations can be obtained from lookup tables or as simple interpolation among the limiting solutions for the instantaneous model parameters.
Numerical Simulations of Conditionally Unstable Flows over a Mountain Ridge
Authors: Miglietta Mario Marcello , Rotunno Richard
Published: February 2009

Numerical simulations of conditionally unstable flows impinging on a mesoscale mountain ridge have been performed with an explicitly resolving cloud model to investigate the statistically stationary features of the solution precipitation characteristics. The simulations are performed on a three-dimensional domain and at high resolution (grid spacing: 250 m) to properly resolve cellular-scale features. Although the environmental conditions are specified by a simplified idealized conditionally unstable sounding, there are still quite a few external parameters, so only a limited portion of the parameter space was explored. Numerical solutions were first carried out for different uniform-wind profiles impinging on a bell-shaped ridge 2000 m high. In the experiments with weaker environmental wind speeds (2.5 m s−1), the cold-air outflow, caused by the evaporative cooling of rain from precipitating convective cells, is the main mechanism for cell redevelopment and movement; this outflow produces new convective cells near the head of the up- and downstream density currents, which rapidly propagate far from the ridge so that no rainfall is produced close to the ridge at later times. For larger wind speeds (10 and 20 m s−1), there is less time for upwind, evaporation-induced cold-pool formation before air parcels reach the ridge top and descend downwind. For the intermediate wind speed (10 m s−1), evaporation is effective in generating a cold pool only on the downstream side of the ridge, in a region where the air is unsaturated and slow moving. Further experiments with different ridge heights and half-widths were carried out in order to analyze their effect on the distribution and intensity of precipitation. Dimensional analysis reveals that the maximum (nondimensional) rainfall rate mainly depends on the ratio of mountain height to the level of free convection, the ridge aspect ratio, and a parameter that measures the ratio of advective to convective time scales.
A High-Resolution Record of Atmospheric Dust Composition and Variability since a.d. 1650 from a Mount Everest Ice Core
Authors: Kaspari S. , Mayewski P. A. , Handley M. , Kang S. , Hou S. , Sneed S. , Maasch K. , Qin D.
Published: February 2009

A Mount Everest ice core analyzed at high resolution for major and trace elements (Sr, Cs, Ba, La, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb, Lu, Bi, U, Tl, Al, S, Ca, Ti, V, Cr, Mn, Fe, Co) and spanning the period a.d. 1650–2002 is used to investigate the sources of and variations in atmospheric dust through time. The chemical composition of dust varies seasonally, and peak dust concentrations occur during the winter–spring months. Significant correlations between the Everest dust record and dust observations at stations suggest that the Everest record is representative of regional variations in atmospheric dust loading. Back-trajectory analysis in addition to a significant correlation of Everest dust concentrations and the Total Ozone Mapping Spectrometer (TOMS) aerosol index indicates that the dominant winter sources of dust are the Arabian Peninsula, Thar Desert, and northern Sahara. Factors that contribute to dust generation at the surface include soil moisture and temperature, and the long-range transport of dust aerosols appears to be sensitive to the strength of 500-mb zonal winds. There are periods of high dust concentration throughout the 350-yr Mount Everest dust record; however, there is an increase in these periods since the early 1800s. The record was examined for recent increases in dust emissions associated with anthropogenic activities, but no recent dust variations can be conclusively attributed to anthropogenic inputs of dust.
The 1997/98 Summer Rainfall Season in Southern Africa. Part II: Model Simulations and Coupled Model Forecasts
Authors: Lyon Bradfield , Mason Simon J.
Published: February 2009

This is the second of a two-part investigation of rainfall in southern Africa during the strong El Niño of 1997/98. In Part I it was shown that widespread drought in southern Africa, typical of past El Niño events occurring between 1950 and 2000, generally failed to materialize during the 1997/98 El Niño, most notably during January–March (JFM) 1998. Here output from three atmospheric general circulation models (AGCMs) forced with observed sea surface temperatures (SSTs) and seasonal forecasts from three coupled models are examined to see to what extent conditions in JFM 1998 could have potentially been anticipated.

All three AGCMs generated widespread drought conditions across southern Africa, similar to those during past El Niño events, and did a generally poor job in generating the observed rainfall and atmospheric circulation anomaly patterns, particularly over the eastern and southern Indian Ocean. In contrast, two of the three coupled models showed a higher probability of wetter conditions in JFM 1998 than for past El Niño events, with an enhanced moisture flux from the Indian Ocean, as was observed. However, neither the AGCMs nor the coupled models generated anomalous stationary wave patterns consistent with observations over the South Atlantic and Pacific. The failure of any of the models to reproduce an enhanced Angola low (favoring rainfall) associated with an anomalous wave train in this region suggests that the coupled models that did indicate wetter conditions in JFM 1998 compared to previous El Niño episodes may have done so, at least partially, for the wrong reasons. The general inability of the climate models used in this study to generate key features of the seasonal climate over southern Africa in JFM 1998 suggests that internal atmospheric variability contributed to the observed rainfall and circulation patterns that year. With the caveat that current climate models may not properly respond to SST boundary forcing important to simulating southern Africa climate, this study finds that the JFM 1998 rainfall in southern Africa may have been largely unpredictable on seasonal time scales.
Implication of the Madden–Julian Oscillation in the 40-Day Variability of the West African Monsoon
Authors: Pohl Benjamin , Janicot Serge , Fontaine Bernard , Marteau Romain
Published: February 2009

Madden–Julian oscillations (MJOs) are extracted over the Indo-Pacific basin using a local mode analysis. The convective perturbations are then projected over a larger domain to evaluate their remote consequences over the West African monsoon (WAM) intraseasonal variability. Rather weak (4–6 W m−2) convective fluctuations occurring in phase with those over the southern Indian basin are found over Africa, confirming the results of Matthews. In reverse, 40-day fluctuations in the WAM, similarly detected and projected over a widened area, demonstrate that a large majority of these events are embedded in the larger-scale patterns of the MJO. The regional amplitude of intraseasonal perturbations of the West African convection is not statistically associated with the amplitude of the MJO over the Indian basin but is instead closely related to background vertical velocity anomalies over Africa, possibly embedded in changes in the regional Walker-type circulation. Subsiding motion over Africa is recorded during the most energetic convective perturbations in the WAM.

Composites analyses over the MJO life cycle, as depicted by the real-time daily indices developed by Wheeler and Hendon, show that positive outgoing longwave radiation (OLR) anomalies during the dry phase are of larger amplitude and spatially more coherent than negative anomalies during the wet phase, especially over the Sahel region. Over West Africa, the phase of suppressed convection is thus of greater importance for the region than the phase of enhanced convection. Rain gauge records fully confirm these results. The MJO appears to be significantly involved in the occurrences of dry spells during the monsoon over the Sahel, whereas large-scale convective clusters are only restricted to the equatorial latitudes and thus affect the Guinean belt, which experiences its short dry season at this time of the year.
Tidal Conversion by Supercritical Topography
Authors: Balmforth Neil J. , Peacock Thomas
Published: February 2009

Calculations are presented of the rate of energy conversion of the barotropic tide into internal gravity waves above topography on the ocean floor. The ocean is treated as infinitely deep, and the topography consists of periodic obstructions; a Green function method is used to construct the scattered wavefield. The calculations extend the previous results of Balmforth et al. for subcritical topography (wherein waves propagate along rays whose slopes exceed that of the topography everywhere), by allowing the obstacles to be arbitrarily steep or supercritical (so waves propagate at shallower angles than the topographic slopes and are scattered both up and down). A complicated pattern is found for the dependence of energy conversion on ε, the ratio of maximum topographic slope to wave slope, and the ratio of obstacle amplitude and separation. This results from a sequence of constructive and destructive interferences between scattered waves that has implications for computing tidal conversion rates for the global ocean.