bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type I Membrane Klotho Expression Is Decreased and Inversely Correlated to Serum Calcium in Primary Hyperparathyroidism
Authors: Björklund Peyman , Krajisnik Tijana , Åkerström Göran , Westin Gunnar , Larsson Tobias E. 
Published: August 2008

Context: The type I membrane protein Klotho was recently shown to mediate PTH secretion in parathyroid cells in response to low extracellular calcium. In contrast, Klotho inhibits PTH secretion indirectly through the action of fibroblast growth factor-23. Abnormal Klotho expression in parathyroid disorders remains to be elucidated.
Objective: The aim of the study was to determine: 1) Klotho expression in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT) compared to normal tissue; and 2) its relation to the serum calcium and PTH levels.
Design: Surgically removed parathyroid glands (n = 40) and four normal parathyroid tissue specimens were analyzed for Klotho mRNA and protein levels by quantitative real-time PCR and immunohistochemistry. In vitro effects of calcium on Klotho mRNA expression were studied in bovine parathyroid cells.
Results: Klotho mRNA levels were significantly decreased (n = 23) or undetectable (n = 17) in parathyroid adenomas compared to normal tissues (P &lt; 0.001). Reduced Klotho protein expression was confirmed by immunohistochemistry. Klotho mRNA levels were inversely correlated to serum calcium (r = −0.97; P &lt; 0.0001), and calcium dose-dependently decreased Klotho mRNA expression in normal parathyroid cells in vitro (P &lt; 0.01). Serum calcium was the only significant marker of Klotho expression in multivariate analysis with calcium, phosphate, PTH, and adenoma weight as independent variables.
Conclusions: Parathyroid Klotho expression is decreased or undetectable in pHPT. We provide evidence that 1) serum calcium is strongly associated with parathyroid Klotho expression in pHPT; and 2) abnormal PTH secretion in hypercalcemic pHPT subjects is mediated by Klotho-independent mechanisms.
BRAFV600E Mutation and Outcome of Patients with Papillary Thyroid Carcinoma: A 15-Year Median Follow-Up Study
Authors: Elisei Rossella , Ugolini Clara , Viola David , Lupi Cristiana , Biagini Agnese , Giannini Riccardo , Romei Cristina , Miccoli Paolo , Pinchera Aldo , Basolo Fulvio 
Published: August 2008

Background: The BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAFV600E mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAFV600E mutation in PTC patients with a long-term follow-up.
Methods: We studied 102 PTC patients with a median follow-up of 15 yr. The BRAFV600E mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAFV600E mutation, clinicopathological features, and outcome of PTC patients were evaluated.
Results: The BRAFV600E mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAFV600E mutation (P &lt; 0.002). However, at multivariate analysis only the BRAFV600E mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAFV600E-mutated group (P = 0.015).
Conclusions: In this study the BRAFV600E mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAFV600E mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.
Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome
Authors: Abreu Ana Paula , Trarbach Ericka Barbosa , de Castro Margaret , Frade Costa Elaine Maria , Versiani Beatriz , Matias Baptista Maria Tereza , Garmes Heraldo Mendes , Mendonca Berenice Bilharinho , Latronico Ana Claudia 
Published: August 2008

Context: Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice.
Objective: To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities.
Design: We studied 107 Brazilian patients with HH (63 with Kallmann syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing.
Results: In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann syndrome harbored the homozygous p.G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p.I55fsX56 mutation. In PROKR2, four distinct mutations (p.R80C, p.Y140X, p.L173R, and p.R268C) were identified in five patients with Kallmann syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p.R80C, p.L173R, and p.R268C missense mutations were identified in the heterozygous state in the HH patients and in their asymptomatic first-degree relatives. In addition, no mutations of FGFR1, KAL1, GnRHR, KiSS-1, or GPR54 were identified in these patients. Notably, the new nonsense mutation (p.Y140X) was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous for this severe defect.
Conclusion: We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.
High-Circulating Leptin Levels Are Associated with Greater Risk of Hypertension in Men Independently of Body Mass and Insulin Resistance: Results of an Eight-Year Follow-Up Study
Authors: Galletti F. , D'Elia L. , Barba G. , Siani A. , Cappuccio F. P. , Farinaro E. , Iacone R. , Russo O. , De Palma D. , Ippolito R. , Strazzullo P. 
Published: August 2008

Background: We previously reported a significant association between plasma leptin (LPT) concentration and blood pressure (BP), which was partly independent of serum insulin levels and insulin resistance. The aims of this study were to detect whether serum LPT levels predict the development of hypertension (HPT) in the 8-yr follow-up investigation of a sample of an adult male population (the Olivetti Heart Study), and to evaluate the role of body mass index (BMI) and insulin resistance in this putative association.Patients and Methods: The study population was made up of 489 untreated normotensive subjects examined in 1994–1995 (age: 50.1 ± 6.7 yr; BMI: 26.3 ± 2.8 kg/m2; BP: 120 ± 10/78 ± 6 mm Hg; and homeostatic model assessment index: 2.1 ± 1.6).Results: The HPT incidence over 8 yr was 35%. The participants with incident HPT had similar age but higher BMI (P &lt; 0.001), serum LPT (P &lt; 0.001), and BP (P &lt; 0.01) at baseline. One sd positive difference in baseline serum LPT log was associated at univariate analysis with a 49% higher rate of HPT [95% confidence interval (CI) 22–83; P &lt; 0.001]). In three different models of multivariable logistical regression analysis, LPT was respectively associated with a 41% greater risk to develop HPT (95% CI 15–74; P &lt; 0.001) upon adjustment for age and baseline BP, with a 48% (95% CI 20–81) greater risk when adding the homeostatic assessment model index to the model, and with 33% greater risk (95% CI 6–67; P &lt; 0.02) upon adjustment for BMI.Conclusions: In this sample of originally normotensive men, circulating LPT level was a significant predictor of the risk to develop HPT over 8 yr, independently of BMI and insulin resistance.
Genetic Testing for Warfarin Therapy Initiation
Authors: Hynicka Lauren M , Cahoon William D , Bukaveckas Bonny L 
Published: August 2008

Objective To review the literature regarding the efficacy of genetic testing for determining the appropriate initial dose of warfarin and the effect that this testing has on the safety and efficacy of therapy. Data Sources: Searches of MEDLINE (1966–May 2008) and Cochrane Database (1993–May 2008) were conducted using the search terms warfarin, anticoagulation, pharmacogenomics, pharmacogenetics, CYP2C9, VKORC1, and interindividual variability. Limits included articles written in English with human subjects. Additional data were identified through bibliographic reviews. Study Selection And Data Extraction: All English-language articles identified from the data sources were evaluated. Studies were eligible for inclusion if they evaluated the efficacy of pharmacogenomic testing to improve outcomes with initiation of warfarin therapy. Data Synthesis: The use of warfarin presents numerous challenges in clinical practice. Four studies (N = 38, 48, 200, 297) evaluating the efficacy of genetic testing for determining the initial dose of warfarin therapy have been published. Results show that time to therapeutic international normalized ratio (INR) and time to stable warfarin dose are similar regardless of genotype. When conventional warfarin dosing was compared with pharmacogenomic-based dosing, no significant difference was seen between groups in terms of time spent within the target INR range (41.5% vs 41.7%; no p value reported). Similar results were found in a subsequent study in which patients receiving conventional dosing were outside their target INR range 33.1% of the time compared with 30.7% of the lime for patients whose dose was guided by pharmacogenomics (p = 0.47). Conclusions: There is growing evidence that variant alleles for CYP2C9 and VKORC1 genotypes account for a proportion of the variability seen in warfarin dosing. The currently available literature related to the use of pharmacogenomic testing in the initiation of warfarin therapy does not show improved outcomes in either safety or efficacy with warfarin therapy and therefore does not support the routine use of pharmacogenomic testing when initiating warfarin therapy.
Prediction of Incident Hip Fracture Risk by Femur Geometry Variables Measured by Hip Structural Analysis in the Study of Osteoporotic Fractures
Authors: Kaptoge Stephen , Beck Thomas J , Reeve Jonathan , Stone Katie L , Hillier Teresa A , Cauley Jane A , Cummings Steven R 
Published: August 2008

Abstract
The role of bone tissue's geometric distribution in hip fracture risk requires full evaluation in large population-based datasets. We tested whether section modulus, a geometric index of bending strength, predicted hip fracture better than BMD. Among 7474 women from the Study of Osteoporotic Fractures (SOF) with hip DXA scans at baseline, there were 635 incident hip fractures recorded over 13 yr. Hip structural analysis software was used to derive variables from the DXA scans at the narrow neck (NN), intertrochanter (IT), and shaft (S) regions. Associations of derived structural variables with hip fracture were assessed using Cox proportional hazard modeling. Hip fracture prediction was assessed using the C-index concordance statistic. Incident hip fracture cases had larger neck-shaft angles, larger subperiosteal and estimated endosteal diameters, greater distances from lateral cortical margin to center of mass (lateral distance), and higher estimated buckling ratios (p &lt; 0.0001 for each). Areal BMD, cross-sectional area, cross-sectional moment of inertia, section modulus, estimated cortical thickness, and centroid position were all lower in hip fracture cases (p &lt; 0.044). In hip fracture prediction using NN region parameters, estimated cortical thickness, areal BMD, and estimated buckling ratio were equivalent (C-index = 0.72; 95% CI, 0.70, 0.74), but section modulus performed less well (C-index = 0.61; 95% CI, 0.58, 0.63; p &lt; 0.0001 for difference). In multivariable models combining hip structural analysis variables and age, effects of bone dimensions (i.e., lateral distance, subperiosteal diameter, and estimated endosteal width) were interchangeable, whereas age and neck-shaft angle were independent predictors. Several parsimonious multivariable models that were prognostically equivalent for the NN region were obtained combining a measure of width, a measure of mass, age, and neck-shaft angle (BMD is a ratio of mass to width in the NN region; C-index = 0.77; 95% CI, 0.75, 0.79). Trochanteric fractures were best predicted by analysis of the IT region. Because section modulus failed to predict hip fracture risk as well as areal BMD, the thinner cortices and wider bones among those who fractured may imply that simple failure in bending is not the usual event in fracture. Fracture might require initiation (e.g., by localized crushing or buckling of the lateral cortex).
A Haplotype-Based Analysis of the LRP5 Gene in Relation to Osteoporosis Phenotypes in Spanish Postmenopausal Women
Authors: Agueda Lídia , Bustamante Mariona , Jurado Susana , Garcia-Giralt Natalia , Ciria Manel , Saló Guillem , Carreras Ramon , Nogués Xavier , Mellibovsky Leonardo , Díez-Pérez Adolfo , Grinberg Daniel , Balcells Susana 
Published: August 2008

Abstract
LRP5 encodes the low-density lipoprotein receptor-related protein 5, a transmembrane protein involved in Wnt signaling. LRP5 is an important regulator of osteoblast growth and differentiation, affecting bone mass in vertebrates. Whether common variations in LRP5 are associated with normal BMD variation or osteoporotic phenotypes is of great relevance. We used a haplotype-based approach to search for common disease-associated variants in LRP5 in a cohort of 964 Spanish postmenopausal women. Twenty-four SNPs were selected, covering the LRP5 region, including the missense changes p.V667M and p.A1330V. The SNPs were genotyped and evaluated for association with BMD at the lumbar spine (LS) or femoral neck (FN) and with osteoporotic fracture, at single SNP and haplotype levels, by regression methods. Association with LS BMD was found for SNP 1, rs312009, located in the 5′-flanking region (p = 0.011, recessive model). SNP 6, rs2508836, in intron 1, was also associated with BMD, both at LS (p = 0.025, additive model) and FN (p = 0.031, recessive model). Two polymorphisms were associated with fracture: SNP 11, rs729635, in intron 1, and SNP 15, rs643892, in intron 5 (p = 0.007 additive model and p = 0.019 recessive model, respectively). Haplotype analyses did not provide additional information, except for haplotype “GC” of the block located at the 3′end of the gene. This haplotype spans intron 22 and the 3′ untranslated region and was associated with FN BMD (p = 0.029, one copy of the haplotype versus none). In silico analyses showed that SNP 1 (rs312009) lies in a putative RUNX2 binding site. Electro-mobility shift assays confirmed RUNX2 binding to this site.
Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1
Authors: Podkrajšek Katarina Trebušak , Milenković Tatjana , Odink Roelof J , Claasen-van der Grinten Hedi L , Bratanič Nina , Hovnik Tinka , Battelino Tadej 
Published: August 2008

ObjectiveAutoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis.DesignAIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation.MethodsSequencing and TaqMan genotyping were used to identify AIRE mutations. Complete AIRE deletion was confirmed and framed by real-time PCR, long-range amplification and analysis of the microsatellite markers.ResultsSeven different mutations were detected, three were novel: c.892G>A in exon 8, silent mutation c.462A>T in exon 3 most likely affecting splicing, and a complete deletion of a single AIRE allele ((?_68)_(1567-14_?)del). Novel (chronic otitis) and rare (systemic juvenile rheumatoid arthritis, autoimmune bronchiolitis, epilepsy) clinical presentations were observed.ConclusionsAIRE mutation detection was valuable in the diagnostics of APS-1 in patients with atypical presentation. Chronic otitis media possibly broadened the cluster of APS-1 manifestations.
Partitioning of current-use and legacy pesticides in salmon habitat in British Columbia, Canada
Authors: Harris Kate A , Dangerfield Neil , Woudneh Million , Brown Tom , Verrin Stacey , Ross Peter S 
Published: August 2008

Abstract
Current regulatory paradigms have favored a shift from persistent pesticides that amplify in aquatic food webs to pesticides with reduced persistence and bioaccumulative potential (low log KOW). Although these new generation pesticides preferentially partition away from food web–associated lipids, aquatic biota may nonetheless be exposed to them via other environmental compartments. To characterize pesticide patterns in coho salmon (Oncorhynchus kisutch) habitat, we studied two salmon-bearing watersheds (agricultural and urban) in British Columbia, Canada's Fraser River valley and one in a remote area of the province's central coast. The agricultural and remote sites exhibited pesticide patterns dominated by current-use pesticides, whereas the urban site was largely dominated by legacy organochlorine pesticides. When adjusted to trans-chlordane concentrations across environmental matrices, correlations were observed between water to sediment ratios for the pesticides and their octanol:water partitioning coefficients (log KOW; r2 = 0.48, p &lt; 0.0001); between air to water ratios and Henry's Law coefficients (r2 = 0.55, p &lt; 0.0001); and between fish to water ratios and log KOW (r2 = 0.74, p &lt; 0.0001). These relationships underscore the importance of physicochemical properties in determining the fate of pesticides in freshwater salmon habitat, and highlight the need for research on the nature of health risks associated with exposure where little or no accumulation occurs.
Histological and Immunological Observations of Bacterial and Allergic Chronic Rhinosinusitis in the Mouse
Authors: Wang Heng , Lu Xiang , Cao Ping-Ping , Chu Yan , Long Xiao-Bo , Zhang Xin-Hao , You Xue-Jun , Cui Yong-Hua , Liu Zheng 
Published: August 2008

Background The purpose of this study was to elucidate histological and immunologic features of mouse models of bacterial chronic rhinosinusitis (BCRS) and allergic chronic rhinosinusitis (ACRS). Methods A BCRS mouse model was established using Streptococcus pneumoniae inoculation plus Merocel (Medtronic, Jacksonville, FL) ostiomeatal obstruction for 12 weeks. An ACRS mouse model was developed by means of ovalbumin (OVA) i.p. injection and subsequent repeated OVA intranasal challenge for 12 weeks. Histological changes of sinonasal mucosa of both models were examined by means of hematoxylin and eosin staining for general morphology and inflammatory cell, periodic acid-Schiff staining for goblet cell, and Masson-trichrome staining for collagen. Enzyme-linked immunosorbent assay was used to detect the concentrations of various cytokines in nasal lavage fluid. Results Polymorphonuclear neutrophil infiltration in lamina propria was more obvious in the BCRS model, whereas eosinophil infiltration was more apparent in the ACRS model. Significant goblet cell and subepithelial gland hyperplasia, subepithelial fibrosis, epithelial thickening, and mononuclear cell infiltration were shown in both models with more severe extent found in the ACRS model. Interleukin (IL)-6 and tumor necrosis factor alpha levels in NLF from both models were increased and peaked at 1 week. Interferon gamma levels were also up-regulated in both models but reached maximum at 1 week in the BCRS model and 4 weeks in the ACRS model. IL-8 (CXCL8) levels were only increased in BCRS mice and peaked at 1 week, whereas IL-5, IL-13, and eotaxin (CCL11) levels were only enhanced in ACRS mice and peaked at 1 week. The Th1/Th2 ratio in BCRS mice was significantly higher than that in ACRS mice (6.68 ± 2.33 versus 1.37 ± 0.86; p < 0.01). Conclusion Histological and immunologic features of BCRS and ACRS mouse models were similar to those of human noneosinophilic and eosinophilic CRS, respectively. BCRS and ACRS mouse models have distinct immunologic characteristics and are applicable for CRS research.
Occupational Risk Factors for Rhinitis in Greenhouse Flower and Ornamental Plant Growers
Authors: Riu Elena , Monsó Eduard , Marin Alicia , Magarolas Ramón , Radon Katja , Morera J. , Andreo F. , Nowak Dennis 
Published: August 2008

Background The purpose of this study was to assess the relationships between rhinitis, exposure to workplace air contaminants, and occupational characteristics in greenhouse flower and ornamental plant (OP) growers. Methods A random sample of growers cultivating such crops and participating in the European Farmers’ Study was selected for a cross-sectional assessment of (1) rhinitis in the last year, (2) sensitization to workplace allergens, and (3) occupation characteristics. Associations between variables were assessed through univariate and multivariate analyses. Results Thirty-nine greenhouse flower and OP growers participated in the study (mean, 48.6; SD, 10.2 years; 35 men). Rhinitis was reported by 12 (31%) of them and was significantly related to sensitization to workplace allergens (odds ratio [OR], 13.20; 95% confidence interval [CI], 2.59–67.23) and pesticide application by hand pump (OR, 12.50; 95% CI, 2.00–78.05). After adjustment for these variables rhinitis emerged as significantly related to number of hours worked inside the greenhouse per day (OR, 1.85; 95% CI, 1.05–3.23). Conclusion Rhinitis is often reported by greenhouse flower and OP growers and is related to sensitization to workplace allergens and pesticide application by hand pump. The disease shows a dose–response relationship with the number of hours spent inside the greenhouse per day, a finding supporting a causal link with greenhouse exposure.