bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between being African-American, serum urate levels and the risk of developing hyperuricemia: findings from the Coronary Artery Risk Development in Young Adults cohort
Authors: Gaffo Angelo L , Jacobs David R , Lewis Cora E , Mikuls Ted R , Saag Kenneth G 
Published: January 2012

Abstract
Introduction
Findings that African-American race/ethnicity is associated with higher concentrations of serum urate have not been adjusted for possible confounding factors or have not explored this question as a primary outcome. We tested this hypothesis in a bi-racial cohort of younger African-American and white men and women.

Methods
Data from 5,049 participants at the Coronary Artery Risk Development in Young Adults (CARDIA) cohort baseline (1985 to1986) and follow-up for up to 20 years of individuals without hyperuricemia (defined as a serum urate of 6.8 mg/dL or more) at baseline were utilized. We determined associations between race, serum urate and the development of hyperuricemia in sex-specific cross-sectional and longitudinal analyses. Confounding factors examined included: age at enrollment, body mass index, development of hypertension, glomerular filtration rate, medication use, diet and alcohol intake and menopausal symptoms in women.

Results
Referent to whites, African-American men and women had significantly lower concentrations of serum urate at baseline. African-American men had an essentially equal risk of developing incident hyperuricemia during follow-up compared with white men (multivariable adjusted HR = 1.12 (0.88 to1.40)). African-American women developed a significantly increased risk of hyperuricemia when compared to white women (HR = 2.31 (1.34 to 3.99)).

Conclusions
Young African-American men and women had lower concentrations of serum urate than whites. During longitudinal follow-up, African-American women had a significantly increased risk of developing hyperuricemia when compared with white women, a difference that was not observed in men. Differences in production of serum urate or a more rapid decline in fractional excretion of serum urate are potential, albeit still unproven, explanations for these findings in African-American women.
Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis
Authors: Schuelert Niklas , McDougall Jason J 
Published: January 2012

Abstract
Introduction
A subgroup of voltage gated sodium channels including Nav1.8 are exclusively expressed on small diameter primary afferent neurons and are therefore believed to be integral to the neurotransmission of nociceptive pain. The present study examined whether local application of A-803467, a selective blocker of the Nav 1.8 sodium channel, can reduce nociceptive transmission from the joint in a rodent model of osteoarthritis (OA).

Methods
OA-like changes were induced in male Wistar rats by an intra-articular injection of 3 mg sodium monoiodoacetate (MIA). Joint nociception was measured at day 14 by recording electrophysiologically from knee joint primary afferents in response to non-noxious and noxious rotation of the joint both before and following close intra-arterial injection of A-803467. The effect of Nav1.8 blockade on joint pain perception and secondary allodynia were determined in MIA treated animals by hindlimb incapacitance and von Frey hair algesiometry respectively.

Results
A-803467 significantly reduced the firing rate of joint afferents during noxious rotation of the joint but had no effect during non-noxious rotation. In the pain studies, peripheral injection of A-803467 into OA knees attenuated hindlimb incapacitance and secondary allodynia.

Conclusions
These studies show for the first time that the Nav1.8 sodium channel is part of the molecular machinery involved in mechanotransduction of joint pain. Targeting the Nav1.8 sodium channel on joint nociceptors could therefore be useful for the treatment of OA pain, avoiding the unwanted side effects of non-selective nerve blocks.
Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer
Authors: Schwab Luciana P , Peacock Danielle L , Majumdar Debeshi , Ingels Jesse F , Jensen Laura C , Smith Keisha D , Cushing Richard C , Seagroves Tiffany N 
Published: January 2012

Abstract
Introduction
Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1α is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer.

Methods
Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus β-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1α-null (KO) cells, respectively. The impact of HIF-1α deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis.

Results
Efficient deletion of HIF-1α reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1α led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF-1α also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells.

Conclusion
These results demonstrate that HIF-1α plays a key role in promoting primary mammary tumor growth and metastasis, in part through regulation of TICs. HIF-1α regulates expression of several members of the Notch pathway, CD133 and markers of the basal lineage in mammary tumors. Our results suggest that CD133, which has not been profiled extensively in breast cancer, may be a useful marker of TICs in the PyMT mouse model. These data reveal for the first time that HIF-1α directly regulates breast TIC activity in vivo.
No evidence for association of inherited variation in genes involved in mitosis and percent mammographic density
Authors: Vachon Celine M , Li Jingmei , Scott Christopher G , Hall Per , Czene Kamila , Wang Xianshu , Liu Jianjun , Fredericksen Zachary S , Rider David N , Wu Fang-Fang , Olson Janet E , Cunningham Julie M , Stevens Kristen N , Sellers Thomas A , Pankratz Shane V , Couch Fergus J 
Published: January 2012

Abstract
Introduction
Increased mammographic breast density is one of the strongest risk factors for breast cancer. While two-thirds of the variation in mammographic density appears to be genetically influenced, few variants have been identified. We examined the association of inherited variation in genes from pathways that mediate cell division with percent mammographic density (PMD) adjusted for age, body mass index (BMI) and postmenopausal hormones, in two studies of healthy postmenopausal women.

Methods
We investigated 2,058 single nucleotide polymorphisms (SNPs) in 378 genes involved in regulation of mitosis for associations with adjusted PMD among 484 unaffected postmenopausal controls (without breast cancer) from the Mayo Clinic Breast Cancer Study (MCBCS) and replicated the findings in postmenopausal controls (n = 726) from the Singapore and Sweden Breast Cancer Study (SASBAC) study. PMD was assessed in both studies by a computer-thresholding method (Cumulus) and linear regression approaches were used to assess the association of SNPs and PMD, adjusted for age, BMI and postmenopausal hormones. A P-value threshold of 4.2 × 10-5 based on a Bonferroni correction of effective number of independent tests was used for statistical significance. Further, a pathway-level analysis was conducted of all 378 genes using the self-contained gene-set analysis method GLOSSI.

Results
A variant in PRPF4, rs10733604, was significantly associated with adjusted PMD in the MCBCS (P = 2.7 × 10-7), otherwise, no single SNP was associated with PMD. Additionally, the pathway analysis provided no evidence of enrichment in the number of associations observed between SNPs in the mitotic genes and PMD (P = 0.60). We evaluated rs10733604 (PRPF4), and 73 other SNPs at P < 0.05 from 51 genes in the SASBAC study. There was no evidence of an association of rs10733604 (PRPF4) with adjusted PMD in SASBAC (P = 0.23). There were, however, consistent associations (P < 0.05) of variants at the putative locus, LOC375190, Aurora B kinase (AURKB), and Mini-chromosome maintenance complex component 3 (MCM3) with adjusted PMD, although these were not statistically significant.

Conclusions
Our findings do not support a role of inherited variation in genes involved in regulation of cell division and adjusted percent mammographic density in postmenopausal women.
Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure
Authors: Breidthardt Tobias , Socrates Thenral , Drexler Beatrice , Noveanu Markus , Heinisch Corinna , Arenja Nisha , Klima Theresia , Züsli Christina , Reichlin Tobias , Potocki Mihael , Twerenbold Raphael , Steiger Jürg , Mueller Christian 
Published: January 2012

Abstract
Introduction
The accurate prediction of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel sensitive and specific marker of AKI.

Methods
A total of 207 consecutive patients presenting to the emergency department with AHF were enrolled. Plasma NGAL was measured in a blinded fashion at presentation and serially thereafter. The potential of plasma NGAL levels to predict AKI was assessed as the primary endpoint. We defined AKI according to the AKI Network classification.

Results
Overall 60 patients (29%) experienced AKI. These patients were more likely to suffer from pre-existing chronic cardiac or kidney disease. At presentation, creatinine (median 140 (interquartile range (IQR), 91 to 203) umol/L versus 97 (76 to 132) umol/L, P < 0.01) and NGAL (114.5 (IQR, 67.1 to 201.5) ng/ml versus 74.5 (60 to 113.9) ng/ml, P < 0.01) levels were significantly higher in AKI compared to non-AKI patients. The prognostic accuracy for measurements obtained at presentation, as quantified by the area under the receiver operating characteristic curve was mediocre and comparable for the two markers (creatinine 0.69; 95%CI 0.59 to 0.79 versus NGAL 0.67; 95%CI 0.57 to 0.77). Serial measurements of NGAL did not further increase the prognostic accuracy for AKI. Creatinine, but not NGAL, remained an independent predictor of AKI (hazard ratio (HR) 1.12; 95%CI 1.00 to 1.25; P = 0.04) in multivariable regression analysis.

Conclusions
Plasma NGAL levels do not adequately predict AKI in patients with AHF.
Tissue stroma as a regulator of leukocyte recruitment in inflammation
Authors: McGettrick Helen M , Butler Lynn M , Buckley Chris D , Ed Rainger G , Nash Gerard B 
Published: January 2012

ABSTRACT
The stromal milieu (cellular and matrix components) helps establish tissue “address-codes” that direct leukocyte behavior in inflamed tissue. Coordinated interactions among the stroma, leukocytes, and ECs dictate which leukocytes are recruited, whether they are retained within the inflamed site, and how long they survive. Herein, we discuss how the stromal milieu influences the leukocyte recruitment cascade. Moreover, we explore how corruption of the stromal phenotype in chronic inflammatory diseases contributes to undesired, continuous recruitment of leukocytes. Emerging complex, multicellular, multilayered (co-)culture models are now addressing the molecular circuitry involved in regulating stromal organization during inflammation. Understanding context-specific changes in pro- or anti-inflammatory agents derived from the stroma, such as IL-6 (and its cofactors), is important for the generation of therapeutic strategies that restore the balance between recruitment and clearance of the inflammatory infiltrate in chronic disease.
Unusual timing of CD127 expression by mouse uterine natural killer cells
Authors: Zhang Jianhong , Chen Zhilin , Fritz Jörg H , Rochman Yrina , Leonard Warren J , Gommerman Jennifer L , Plumb Adam W , Abraham Ninan , Croy B Anne 
Published: January 2012

ABSTRACT
Decidualization, a progesterone-dependent process that alters endometrial stromal cells at implantation sites in humans and rodents, is accompanied by a highly regulated, NK cell-dominated leukocyte influx into decidual basalis (DB). Whether uNK cells differentiate from uterine progenitor cells is unknown, as are the mechanisms restricting leukocytes to DB. We asked if cells expressing the early NK lineage marker CD127 (IL-7Rα) occurred in mouse decidua. CD127 was absent from gd6.5 decidual lymphoid cells but became expressed by a mature uNK cell subset in gd10.5 DB. DB and transient myometrial structures (MLAp) that ring maternal blood vessels supplying placentae expressed IL-7 and TSLP, the CD127 ligands, but with differing temporal and spatial patterns. UNK cells expressed TSLPR, and study of gd10.5 implantation sites from mice deleted for IL-7, CD127, or TSLPR suggested that IL-7 and its receptor have physiological roles in limiting expansion of immature uNK cells within MLAp, while the TSLP signaling pathway is used in DB to sustain IFN-γ production from a subset of mature uNK cells. Regionalized, dynamic expression of the additional lymphoid organ stromal markers gp38/podoplanin and ER-TR7, but not CD157, were seen by immunohistochemistry in implantation sites, and DB and MLAp contained transcripts for Aire, a tolerance-promoting factor. These observations suggest that CD127+ NK lineage progenitors are not present in the early postimplantation period of mouse uterus and that decidualized endometrial stroma has key immunoregulatory properties.
Sall1 regulates cortical neurogenesis and laminar fate specification, implications for neural abnormalities in Townes Brocks Syndrome
Authors: Harrison Susan J. , Nishinakamura Ryuichi , Jones Kevin R. , Monaghan A. Paula 
Published: January 2012

SummaryProgenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder, Townes Brocks syndrome is associated with mutations of the SALL1 gene. Townes Brocks syndrome is characterized by renal, anal, limb, and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ~10% of patients exhibit neural or behavioral abnormalities. We demonstrate that Sall1 is robustly expressed in progenitor cells of the central nervous system, in addition to peripheral organs. Both classical and condition knockout studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1 both the surface area and depth of the cerebral cortex were decreased at E18.5. These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells Sall1 promotes proliferative over neurogenic division whereas at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing cortex and provide avenues for future research into potential neural deficits in Townes Brocks patients.
Absence of the Cdk5 activator p35 causes adult-onset neurodegeneration in the central brain of Drosophila
Authors: Trunova Svetlana , Giniger Edward 
Published: January 2012

SUMMARY
Altered function of Cdk5 kinase is associated with many forms of neurodegenerative disease in humans. We show here that inactivating the Drosophila Cdk5 ortholog, by mutation of its activating subunit, p35, causes adult-onset neurodegeneration in the fly. In the mutants, a vacuolar neuropathology is observed in a specific structure of the central brain, the ‘mushroom body’, which is the seat of olfactory learning and memory. Analysis of cellular phenotypes in the mutant brains reveals some phenotypes that resemble natural aging in control flies, including an increase in apoptotic and necrotic cell death, axonal fragmentation, and accumulation of autophagosomes packed with crystalline-like depositions. Other phenotypes are unique to the mutants, notably age-dependent swellings of the proximal axon of mushroom body neurons. Many of these phenotypes are also characteristic of mammalian neurodegenerative disease, suggesting a close relationship between the mechanisms of Cdk5-associated neurodegeneration in fly and human. Together, these results identify the cellular processes that are unleashed in the absence of Cdk5 to initiate the neurodegenerative program, and they provide a model that can be used to determine what part each process plays in the progression to ultimate degeneration.
A FRT-flankedp53mouse to generate primary tumors with Flp recombinase
Authors: Lee Chang-Lung , Moding Everett J. , Huang Xiaofang , Li Yifan , Woodlief Loretta Z. , Rodrigues Rafaela C. , Ma Yan , Kirsch David G. 
Published: January 2012

SummaryThe site-specific recombinases Cre and Flp can mutate genes in a spatially and temporally restricted manner in mice. Conditional recombination of the tumor suppressor p53 using the Cre-loxP system has led to the development of multiple genetically engineered mouse models of human cancer. However, initiation of tumors with Cre recombinase limits the utilization of Cre to genetically modify other genes in stromal cells. To overcome this limitation, we inserted FRT sites flanking exons 2 through 6 of the endogenous p53 gene in mice to generate a p53FRT allele that can be deleted by Flp recombinase. We show that FlpO-mediated deletion of p53 in mouse embryonic fibroblasts impairs the p53-dependent response to genotoxic stress in vitro. In addition, using FSF-KrasG12D/+; p53FRT/FRT mice, we demonstrate an adenovirus expressing FlpO recombinase can initiate primary lung cancers and sarcomas in mice. p53FRT mice will enable dual recombinase technology to study cancer biology because Cre is available to modify genes specifically in stromal cells to investigate their role in tumor development, progression, and response to therapy.
Effect of α-Lipoic Acid on Platelet Reactivity in Type 1 Diabetic Patients
Authors: Mollo Roberto , Zaccardi Francesco , Scalone Giancarla , Scavone Giuseppe , Rizzo Paola , Navarese Eliano Pio , Manto Andrea , Pitocco Dario , Lanza Gaetano Antonio , Ghirlanda Giovanni , Crea Filippo 
Published: January 2012

OBJECTIVE
Type 1 diabetes is associated with increased platelet reactivity. We investigated whether α-lipoic acid (ALA) has any effect on platelet reactivity in these patients.

RESEARCH DESIGN AND METHODS
We randomly assigned 51 type 1 diabetic patients to ALA (600 mg once daily) or placebo for 5 weeks. Platelet reactivity was evaluated by the PFA-100 method and by measuring CD41 and CD62 platelet expression. C-reactive protein (CRP) and 8-iso-prostaglandin F2α serum levels also were measured.

RESULTS
Baseline variables were similar in the two groups. After treatment, closure time was longer (P = 0.006) and CD62P platelet expression was lower, both before (P = 0.002) and after (P = 0.009) ADP stimulation in the ALA group compared with the placebo group. CRP and 8-iso-prostaglandin F2α levels showed no differences between the two groups.

CONCLUSIONS
Our data show that ALA reduces measures of platelet reactivity ex vivo in type 1 diabetic patients, independently of antioxidant or anti-inflammatory effects.
Attitudes Toward Diabetes Affect Maintenance of Drug-Free Remission in Patients With Newly Diagnosed Type 2 Diabetes After Short-Term Continuous Subcutaneous Insulin Infusion Treatment
Authors: Chen Ailing , Huang Zhimin , Wan Xuesi , Deng Wanping , Wu Jiyan , Li Licheng , Cai Qiuling , Xiao Haipeng , Li Yanbing 
Published: January 2012

OBJECTIVE
Short-term intensive insulin treatment in patients with newly diagnosed type 2 diabetes can improve β-cell function and insulin sensitivity, which results in long-term remission without need for further antidiabetes medication. Patient attitudes toward their disease were assessed using the Diabetes Care Profile (DCP) tool to evaluate the potential impact on maintaining long-term remission.

RESEARCH DESIGN AND METHODS
Newly diagnosed patients with type 2 diabetes were recruited and treated with continuous subcutaneous insulin infusion (CSII) for 2–3 weeks. They were also invited to participate in diabetes self-management intervention during hospitalization and complete a DCP questionnaire on attitudes toward diabetes at baseline and 3, 6, and 12 months after suspension of CSII.

RESULTS
Near normoglycemia was achieved by 118 patients after short-term CSII, with 65 remaining in drug-free remission for &gt;1 year. They had significantly better glycemic control and greater restoration of acute insulin response after CSII as well as higher educational attainment compared with patients experiencing relapse. They also achieved higher scores in positive attitude, (belief in) importance of care, care ability, self-care adherence, and less negative attitude. Differences between the two groups became greater over time. Cox proportional hazards model analysis indicated that greater self-care adherence (hazard ratio 0.184, P &lt; 0.001) and homeostasis model assessment of insulin resistance before treatment (0.854, P = 0.053) were independent predictors for long-term remission, whereas elevated 2-h postprandial plasma glucose after CSII (1.156, P = 0.015) was a risk factor for relapse.

CONCLUSIONS
Attitudes toward diabetes affect long-term drug-free remission in newly diagnosed patients with type 2 diabetes after short-term CSII.