bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin II Dilates Bovine Adrenal Cortical Arterioles: Role of Endothelial Nitric Oxide
Authors: Gauthier Kathryn M. , Zhang David X. , Edwards Erik M. , Holmes Blythe , Campbell William B. 
Published: May 2005

Abstract
Adrenal steroidogenesis is modulated by humoral and neuronal factors and blood flow. Angiotensin II (AII) stimulates adrenal cortical aldosterone and cortisol production and medullary catecholamine release. However, AII regulation of adrenal vascular tone has not been characterized. We examined the effect of AII on diameters of cannulated bovine adrenal cortical arteries. Cortical arteries (average internal diameter = 230 μm) were constricted with U46619 and concentration-diameter responses to AII (10−13 to 10−8 mol/liter) were measured. In endothelium-intact arteries, AII induced dilations at low concentrations (maximum dilation = 25 ± 6% at 10−10 mol/liter) and constrictions at high concentrations (maximum constriction = 25 ± 18% at 10−8 mol/liter). AII constrictions were blocked by the angiotensin type 1 (AT1) receptor antagonist, losartan (10−6 mol/liter). AII dilations were enhanced by losartan (maximal dilation = 48 ± 8%), abolished by endothelial cell removal or N-nitro-l-arginine (L-NA, 3 × 10−5 mol/liter) and inhibited by the angiotensin type 2 (AT2) receptor antagonist, PD123319 (10−6 mol/liter, maximal dilation = 18 ± 4%). In a 4,5-diaminofluorescein diacetate nitric oxide (NO) assay of isolated cortical arteries, AII stimulated NO production, which was abolished by PD123319, L-NA, or endothelial cell removal. Western immunoblot of arterial homogenates and endothelial and zona glomerulosa cell lysates revealed 48-kD and 50-kD bands corresponding to AT1 and AT2 receptors, respectively, in all three and a 140-kD band corresponding to endothelial NO synthase in endothelial cells and arteries. Our results demonstrate that AII stimulates adrenal cortical arterial dilation through endothelial cell AT2 receptor activation and NO release and AT1 receptor-dependent constriction.
The Spot 14 Protein Is Required for de Novo Lipid Synthesis in the Lactating Mammary Gland
Authors: Zhu Qihong , Anderson Grant W. , Mucha Gregory T. , Parks Elizabeth J. , Metkowski Jennifer K. , Mariash Cary N. 
Published: May 2005

Abstract
We generated a Spot 14 null mouse to assess the role of Spot 14 in de novo lipid synthesis and report the Spot 14 null mouse exhibits a phenotype in the lactating mammary gland. Spot 14 null pups nursed by Spot 14 null dams gain significantly less weight than wild-type pups nursed by wild-type dams. In contrast, Spot 14 null pups nursed by heterozygous dams show similar weight gain to wild-type littermates. We found the triglyceride content in Spot 14 null milk is significantly reduced. We demonstrate this reduction is the direct result of decreased de novo lipid synthesis in lactating mammary glands, corroborated by a marked reduction of medium-chain fatty acids in the triglyceride pool. Importantly, the reduced lipogenic rate is not associated with significant changes in the activities or mRNA of key lipogenic enzymes. Finally, we report the expression of a Spot 14-related gene in liver and adipose tissue, which is absent in the lactating mammary gland. We suggest that expression of both the Spot 14 and Spot 14-related proteins is required for maximum efficiency of de novo lipid synthesis in vivo and that these proteins impart a novel mechanism regulating de novo lipogenesis.
Transactivation of the Parathyroid Hormone Promoter by Specificity Proteins and the Nuclear Factor Y Complex
Authors: Alimov Alexander P. , Park-Sarge Ok-Kyong , Sarge Kevin D. , Malluche Hartmut H. , Koszewski Nicholas J. 
Published: May 2005

AbstractWe previously identified a highly conserved specificity protein 1 (Sp1) DNA element in mammalian PTH promoters that acted as an enhancer of gene transcription and bound Sp1 and Sp3 proteins present in parathyroid gland nuclear extracts. More recently, a nuclear factor (NF)-Y element (NF-Yprox) was also described by our group, which was located approximately 30 bp downstream from the Sp1 site in the human PTH (hPTH) promoter and by itself acted as a weak enhancer of gene transcription. We now report that Sp proteins and NF-Y can synergistically enhance transcription of a minimal hPTH promoter construct. Positioning of the Sp1 DNA element appears to be critical for this synergism because deviations of one half of a helical turn caused an approximate 60% decrease in transactivation. Finally, examination of the bovine PTH (bPTH) promoter also revealed Sp1/NF-Y synergism, in conjunction with the identification of an analogous NF-Y binding site similarly positioned downstream from the bPTH Sp1 element. In summary, synergistic transactivation of the hPTH and bPTH promoters is observed by Sp proteins and the NF-Y complex. The conservation of this transactivation in the human and bovine promoters suggests that this may be a principle means of enhancing PTH gene transcription.
Heterodimeric Fly Glycoprotein Hormone-α2 (GPA2) and Glycoprotein Hormone-β5 (GPB5) Activate Fly Leucine-Rich Repeat-Containing G Protein-Coupled Receptor-1 (DLGR1) and Stimulation of Human Thyrotropin Receptors by Chimeric Fly GPA2 and Human GPB5
Authors: Sudo Satoko , Kuwabara Yoshimitsu , Park Jae-Il , Hsu Sheau Yu , Hsueh Aaron J. W. 
Published: May 2005

AbstractGlycoprotein hormones play important roles in thyroid and gonadal function in vertebrates. The glycoprotein hormone α-subunit forms heterodimers with different β-subunits to activate TSH or gonadotropin (LH and FSH) receptors. Recent genomic analyses allowed the identification of another α-subunit, GPA2, and another β-subunit, GPB5, in human, capable of forming heterodimers to activate TSH receptors. Based on comparative genomic searches, we isolated the fly orthologs for human GPA2 and GPB5, each consisting of 10 cysteine residues likely involved in cystine-knot formation. RT-PCR analyses in Drosophila melanogaster demonstrated the expression of GPA2 and GPB5 at different developmental stages. Immunoblot analyses further showed that fly GPA2 and GPB5 subunit proteins are of approximately 16 kDa, and coexpression of these subunits yielded heterodimers. Purified recombinant fly GPA2/GPB5 heterodimers were found to be glycoproteins with N-linked glycosylated α-subunits and nonglycosylated β-subunits, capable of stimulating cAMP production mediated by fly orphan receptor DLGR1 but not DLGR2. Although the fly GPA2/GPB5 heterodimers did not activate human TSH or gonadotropin receptors, chimeric fly GPA2/human GPB5 heterodimers stimulated human TSH receptors. These findings indicated that fly GPA2/GPB5 is a ligand for DLGR1, thus showing the ancient origin of this glycoprotein hormone-seven transmembrane receptor-G protein signaling system. The fly GPA2 also could form heterodimers with human GPB5 to activate human TSH receptors, indicating the evolutionary conservation of these genes and suggesting that the GPA2 subunit may serve as a scaffold for the β-subunit to activate downstream G protein-mediated signaling.
Haploinsufficiency of Chicken Ovalbumin Upstream Promoter Transcription Factor II in Female Reproduction
Authors: Takamoto Norio , Kurihara Isao , Lee Kevin , DeMayo Francesco J. , Tsai Ming-Jer , Tsai Sophia Y. 
Published: May 2005

AbstractThe chicken ovalbumin upstream promoter transcription factor II, COUP-TFII, is a member of the orphan nuclear receptor transcription factor family. Genetic ablation of COUP-TFII results in early embryonic lethality and demonstrates that this gene is required for cardiac and vascular development. Expression of COUP-TFII persists throughout postnatal life in various tissues including the female reproductive tract. However, the physiological function of COUP-TFII in female reproduction has not been extensively analyzed. Here, we provide phenotypic evidences that haploinsufficiency of COUP-TFII in mice demonstrates an important role of COUP-TFII for normal female reproduction. COUP-TFII +/− females show significantly reduced fecundity, irregular estrus cycles, delayed puberty, and retarded postnatal growth. Analysis of the reduced fertility revealed that although ovarian function was normal with respect to ovulation, the ovaries have reduced ability to synthesize progesterone in response to exogenous gonadotropins. This reduction is due to the reduction of the expression of steroidogenic enzymes important for progesterone synthesis and the reduction of vascularization in COUP-TFII heterozygotes. Analysis of uterine function demonstrated a reduced response to an experimentally induced decidual cell reaction indicating that the ability of the uterus to support embryo implantation was reduced. Taken together, our data show global impact of gene dosage effects of COUP-TFII on female postnatal life and indicates requirement of COUP-TFII in normal female reproduction, in particular for uterine endometrial functions during the periimplantation period.
Association of Human Follitropin (FSH) Receptor with Splicing Variant of Human Lutropin/Choriogonadotropin Receptor Negatively Controls the Expression of Human FSH Receptor
Authors: Yamashita Soichi , Nakamura Kazuto , Omori Yuki , Tsunekawa Katsuhiko , Murakami Masami , Minegishi Takashi 
Published: May 2005

Abstract
A splice variant of human lutropin (LH)/choriogonadotropin (CG)-receptor [hLHR(exon 9)] that lacks exon 9 was previously cloned in the corpus luteum of a woman with a normal menstrual cycle. Supported by a detergent-soluble binding assay and a receptor biotinylation experiment, the receptor binding assay shows hLHR(exon 9) is neither expressed at the cell surface nor has the capability of binding to hCG. In addition, hLHR(exon 9) was confirmed in the endoplasmic reticulum (ER) by endoglycosidase H treatment. A coimmunoprecipitation experiment clearly showed that hLHR(exon 9) and constitutively inactivate mutant-LHRs, which stay in the ER, form an association with the human follitropin (FSH)-receptor (hFSHR). This suggests that in the presence of mutant-LHR, hFSHR, which is trapped in the ER and associated with hLHR(exon 9), is unable to come up to the plasma membrane. This phenomenon is specific among gonadotropin receptors because human TSH receptor failed to be coimmunoprecipitated. Furthermore, this receptor complex attenuated the hFSHR receptor protein level within the cells, which impaired cAMP production. To elucidate the mechanism underlying the decrease in hFSHR protein by this receptor complex, we performed a Percoll fractionation experiment, which indicated that the receptor complex drove hFSHR to the lysosome instead of the plasma membrane. These results reveal a novel mechanism of FSHR expression regulation.
The 1,25(OH)2D3-Regulated Transcription Factor MN1 Stimulates Vitamin D Receptor-Mediated Transcription and Inhibits Osteoblastic Cell Proliferation
Authors: Sutton Amelia L. M. , Zhang Xiaoxue , Ellison Tara I. , MacDonald Paul N. 
Published: May 2005

AbstractThe vitamin D endocrine system is essential for maintaining mineral ion homeostasis and preserving bone density. The most bioactive form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] elicits its effects by binding to the vitamin D receptor (VDR) and regulating the transcription of target genes. In osteoblasts, the bone-forming cells of the skeleton, 1,25-(OH)2D3 regulates cell proliferation, differentiation, and mineralization of the extracellular matrix. Despite these well-characterized biological functions, relatively few 1,25-(OH)2D3 target genes have been described in osteoblasts. In this study, we characterize the regulation and function of MN1, a novel 1,25-(OH)2D3-induced gene in osteoblastic cells. MN1 is a nuclear protein first identified as a gene disrupted in some meningiomas and leukemias. Our studies demonstrate that MN1 preferentially stimulates VDR-mediated transcription through its ligand-binding domain and synergizes with the steroid receptor coactivator family of coactivators. Furthermore, forced expression of MN1 in osteoblastic cells results in a profound decrease in cell proliferation by slowing S-phase entry, suggesting that MN1 is an antiproliferative factor that may mediate 1,25-(OH)2D3-dependent inhibition of cell growth. Collectively, these data indicate that MN1 is a 1,25-(OH)2D3-induced VDR coactivator that also may have critical roles in modulating osteoblast proliferation.
Gonadotropin-Releasing Hormone Induction of Extracellular-Signal Regulated Kinase Is Blocked by Inhibition of Calmodulin
Authors: Roberson Mark S. , Bliss Stuart P. , Xie Jianjun , Navratil Amy M. , Farmerie Todd A. , Wolfe Michael W. , Clay Colin M. 
Published: May 2005

AbstractOur previous studies demonstrate that GnRH-induced ERK activation required influx of extracellular Ca2+ in αT3-1 and rat pituitary cells. In the present studies, we examined the hypothesis that calmodulin (Cam) plays a fundamental role in mediating the effects of Ca2+ on ERK activation. Cam inhibition using W7 was sufficient to block GnRH-induced reporter gene activity for the c-Fos, murine glycoprotein hormone α-subunit, and MAPK phosphatase (MKP)-2 promoters, all shown to require ERK activation. Inhibition of Cam (using a dominant negative) was sufficient to block GnRH-induced ERK but not c-Jun N-terminal kinase activity activation. The Cam-dependent protein kinase (CamK) II inhibitor KN62 did not recapitulate these findings. GnRH-induced phosphorylation of MAPK/ERK kinase 1 and c-Raf kinase was blocked by Cam inhibition, whereas activity of phospholipase C was unaffected, suggesting that Ca2+/Cam modulation of the ERK cascade potentially at the level of c-Raf kinase. Enrichment of Cam-interacting proteins using a Cam agarose column revealed that c-Raf kinase forms a complex with Cam. Reconstitution studies reveal that recombinant c-Raf kinase can associate directly with Cam in a Ca2+-dependent manner and this interaction is reduced in vitro by addition of W7. Cam was localized in lipid rafts consistent with the formation of a Ca2+-sensitive signaling platform including the GnRH receptor and c-Raf kinase. These data support the conclusion that Cam may have a critical role as a Ca2+ sensor in specifically linking Ca2+ flux with ERK activation within the GnRH signaling pathway.
A case-control study to estimate the impact on breast cancer death of the breast screening programme in Wales
Authors: Fielder HM , Warwick J , Brook D , Gower-Thomas K , Cuzick J , Monypenny I , Duffy SW 
Published: May 2005

Objectives: The aim of this study was to estimate the effect of service screening, as provided by the NHS breast screening programme, on breast cancer mortality in Wales. Furthermore, we wished to ascertain whether a reduction in breast cancer mortality consistent with that observed in the randomised screening trials was being achieved. Setting: The NHS Breast Screening Programme in Wales, managed by Breast Test Wales, with headquarters in Cardiff. Methods: A case-control study design with 1:2 matching. The cases were deaths from breast cancer in women aged 50–75 years at diagnosis who were diagnosed after the instigation of screening in 1991 and who died after 1998. The controls were women who had not died of breast cancer or any other condition during the study period. One was from the same GP practice and the other from a different GP practice within the same district, matched by year of birth. Results: Based on 419 cases, the odds ratio for risk of death from breast cancer for women who have attended at least one routine screen compared to those never screened was 0.62 (95% confidence interval [CI] 0.47–0.82, p=0.001). After excluding cases diagnosed prior to 1995 and adjusting for self-selection bias, the estimated mortality reduction was 25% (odds ratio=0.75, 95% CI 0.49–1.14, p=0.09). Conclusion: The Breast Test Wales screening programme is achieving a reduction in breast cancer mortality of 25% in women attending for screening, which is consistent with the results of the randomized controlled trials of mammographic screening.
Identifying homozygous sickle cell disease when neonatal screening is not available: a clinic-based observational study
Authors: Hambleton IR , Wierenga KJJ 
Published: May 2005

Objectives: Life-threatening clinical complications can occur in the first years of life in people with homozygous sickle cell disease. There is consensus that a clinical care programme comanaged by a specialist clinic should follow early-life disease identification. In a setting without widespread neonatal screening for this disease, we predict the percentage of affected births that enrol in specialist clinics during childhood, and the percentage that enrol early enough to benefit from penicillin prophylaxis (which is offered until five years of age). Setting: A retrospective study of enrolment between 1973 and 1999 at three clinics in Jamaica, the country's only referral centres for sickle cell disease. Results: Among enrolees not screened at birth, observed enrolment by age five was 10.1% (95% confidence interval [CI] 5.7–16.7%) among 1974 births, which is predicted to rise to 35.7% (95% CI 35.0–36.4%) among 1999 births. Observed enrolment by 18 years of age was 45.9% (95% CI 35.7–58.2%) among 1974 births, which is predicted to peak at 61.9% (95% CI 60.5–63.2%) among 1984 births, and fall to 48.9% (95% CI 40.9–56.9%) among 1999 births. Median age at enrolment was 10.5 years (95% CI 10.0–11.3). Conclusions: Based on 1999 estimates, almost 65% of children affected by homozygous sickle cell disease not identified at birth will not benefit from important early-life clinical intervention, and half will not enrol for specialised care by their 18th birthday. Among patients that enrol, half do so in adolescence when management is less focused on preventive care.
The reference range and within-person variability of thyroid stimulating hormone during the first and second trimesters of pregnancy
Authors: Haddow JE , Knight GJ , Palomaki GE , McClain MR , Pulkkinen AJ 
Published: May 2005

Objective: To further explore first and second trimester reference ranges for thyroid stimulating hormone (TSH) and examine within-person variability of TSH and thyroid peroxidase (TPO) antibody. Setting: Women coming for routine prenatal care in early pregnancy agreed to participate in a trial of integrated serum screening for Down's syndrome. Two serum samples were obtained from each woman, one each in the first and second trimesters. These samples were also available for TSH and TPO measurements in the present study. Methods: TSH and TPO antibody measurements were performed in 1126 women with ultrasound-dated pregnancies who provided serum samples in both trimesters. TSH reference ranges were established for the entire cohort and for the antibody-negative subgroup. Within-person variability of TSH measurements between trimesters was examined. Results: Median TSH values are lower in the first trimester than in the second (1.00 versus 1.29 mIU/l), but 98th centile values are higher (5.20 versus 4.18 mIU/l). High correlation exists between individual women's first and second trimester TSH measurements (r=0.75, r2=0.56, p<0.001). Among 23 women with TSH values above the 98th centile in the second trimester, 17 (74%) were over the 95th centile in the first trimester. TPO antibody measurements are also highly correlated between trimesters (r=0.97, r2=0.94). Conclusion: Proper interpretation of TSH measurements during pregnancy requires that laboratories establish and monitor appropriate reference ranges. TSH levels show high within-person consistency between trimesters.
Will men attribute fault to their GP for adverse effects arising from controversial screening tests? An Australian study using scenarios about PSA screening
Authors: Gattellari Melina , Ward Jeanette E 
Published: May 2005

Objective: To determine men's attribution of fault for adverse consequences of prostate-specific antigen (PSA) screening. Setting: Representative, population-based sample recruited from Sydney, Australia (n=405). Methods: Telephone interview to assess reactions to two scenarios: Scenario 1, depicting a GP who dismisses an opportunity to order a PSA test (missed diagnosis); and Scenario 2, depicting a GP who recommends PSA screening to a patient who then experiences adverse outcomes from treatment of his prostate cancer (iatrogenic consequences). Results: Two-thirds of participants (66.9%) ascribed fault to the GP in Scenario 1. Men in fair or poor health (adjusted odds ratio [AOR] 1.81; 95% confidence interval [CI] 1.04–3.12; p=0.03) and those with better knowledge about PSA screening (AOR 0.98; 95% CI 0.97–0.99; p=0.002) were significantly and independently more likely to ascribe fault in Scenario 1. By contrast, only 15.8% of participants ascribed responsibility to the GP in Scenario 2. Older men (AOR 1.05; 95% CI 1.00–1.10; p=0.04) and those with higher levels of decisional conflict (AOR 1.19; 95% CI 1.04–1.37; p=0.01) were significantly and independently more likely to ascribe responsibility. Conclusion: Public education could better target men's tendency to ascribe fault to GPs when they miss an opportunity to diagnose prostate cancer early through PSA screening, even though the corollary of potential iatrogenic consequences is perceived as less blameworthy. As decisional conflict and knowledge were found to predict attribution of fault, evidence-based information may reduce the medicolegal volatility of this controversy.
An audit of assessment procedures in women who develop breast cancer after a negative result
Authors: Warren R , Allgood P , Hunnam G , Godward S , Duffy S ,   The East Anglian Breast Screening Programme
Published: May 2005

Objectives: A case audit was undertaken to determine the extent to which the early diagnosis of cancer could be improved by better adherence to screening guidelines, and to estimate the effect that this might have on breast cancer survival. Although affecting only a small proportion of the cancers of the screening programme, this exercise had an educational function for screening radiologists. Setting: The East Anglian breast screening programme, a group of seven centres offering screening to a total population of 2.2 million inhabitants. Women were screened every three years between the ages of 50 and 64. Methods: Adherence to the guidelines of the UK National Breast Screening Programme (as published in 2001) was tested in women assessed between the start of screening on 1 April 1989 and 31 December 1999, in cases where the screen was negative but who were subsequently diagnosed with breast cancer. Results: In this period the programme screened 503,493 women, recalled 25,346 and diagnosed 3689 with cancer. 194 cancers in 193 women were reviewed, comprising those cancers that arose at the site of the lesion previously assessed. 96 women (49.5%) had calcifications, 48 (24.7%) had opacities. 139 of 194 cases were judged to have been inadequately assessed. A recurring theme showed that biopsies not undertaken or with false negative findings led to failure to diagnose lesions which were subsequently shown to be cancer. Microcalcifications and opacities were more likely to have been inadequately assessed than spiculate masses, parenchymal deformities, or asymmetric densities. In the earliest time period (1989–1993), there were a larger proportion of inadequately assessed cases than in the period 1994–1999. Conclusion: Scrupulous adherence to good guidelines will result in a greater proportion of cancers being diagnosed. Failure to perform effective percutaneous biopsy was the usual cause of missed diagnoses. Although an infrequent occurrence this may have an effect on subsequent survival from breast cancer.