bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet-Activating Factor Inhibits the Secretion of Platelet-Activating Factor Acetylhydrolase by Human Decidual Macrophages
Authors: Narahara Hisashi , Kawano Yasushi , Nasu Kaei , Yoshimatsu Jun , Johnston John M. , Miyakawa Isao 
Published: December 2003

AbstractTo clarify the role of platelet-activating factor (PAF) in parturition, the effects of PAF on the secretion of PAF-acetylhydrolase (PAF-AH), a PAF-inactivating enzyme, by decidual macrophage populations were examined. The cells were isolated from human decidual tissue by enzymatic digestion, Ficoll-Paque centrifugation, or flow cytometric sorting. The nonhydrolyzable agonist of PAF, carbamyl-PAF (C-PAF), inhibited the secretion of PAF-AH by either decidual cells or flow cytometrically purified decidual macrophages. A specific PAF receptor antagonist, WEB 2086, blocked the C-PAF-induced inhibition. Lyso-PAF, a metabolite of PAF, had no effect on the enzyme secretion. An intracellular calcium channel blocker, bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid, tetra(acetoxymethyl)-ester, partially blocked the inhibition by C-PAF, whereas extracellular calcium channel blockers, nifedipine and verapamil, were without effect. The inhibitory effect of C-PAF was also partially blocked by protein kinase C (PKC) inhibitors, sphingosine and H-7. A PKC activator, 12-O-tetradecanoylphobol 13-acetate, decreased the secretion of PAF-AH. The decrease was abolished by the addition of sphingosine and H-7. It is suggested that PAF inhibits the PAF-AH secretion by decidual macrophages and that the inhibitory action is mediated by a signal transduction mechanism involving intracellular calcium and PKC.
Effects of Chemotherapeutic Agents on the Function of Primary Human Osteoblast-Like Cells Derived from Children
Authors: Davies J. H. , Evans B. A. J. , Jenney M. E. M. , Gregory J. W. 
Published: December 2003

Abstract
Studies in children treated with chemotherapy suggest that chemotherapeutic agents have deleterious effects on bone metabolism. We therefore evaluated the in vitro effects of clinically relevant concentrations of chemotherapeutic agents on the synthesis of type I collagen, alkaline phosphatase (AP) activity, and mineralization by primary human osteoblast-like (HOB) cells derived from children. Because serum 1,25-dihydroxyvitamin D3 concentrations may be reduced during treatment with chemotherapy, the effect of chemotherapeutic agents on HOB cells cultured in the presence or absence of 1,25-dihydroxyvitamin D3 was also evaluated.
Type I collagen synthesis was reduced by all agents (P &lt; 0.01) other than methotrexate, whereas the relative AP activity was increased (P &lt; 0.01) by all agents. The relative number of cells staining intensely for AP after culture with agents increased (P &lt; 0.05), and AP mRNA expression was increased (P &lt; 0.01) with vincristine. 1,25-Dihydroxyvitamin D3 ameliorated (P &lt; 0.01) the depletion of HOB cell numbers by chemotherapeutic agents. Furthermore, vincristine and daunorubicin inhibited 1,25-dihydroxyvitamin D3-mediated AP activity (P &lt; 0.01).
We conclude that chemotherapeutic agents can adversely affect HOB cell function, and we speculate that this observation may account, in part, for the osteopenia observed during and after treatment of children with chemotherapy.
Pegvisomant-Induced Serum Insulin-Like Growth Factor-I Normalization in Patients with Acromegaly Returns Elevated Markers of Bone Turnover to Normal
Authors: Parkinson C. , Kassem M. , Heickendorff L. , Flyvbjerg A. , Trainer P. J. 
Published: December 2003

Abstract
Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28–78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)2 vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 ± 76 to 242 ± 28 μg/liter, P &lt; 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)2 vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P &lt; 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)2 vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.
A Novel Semiquantitative Polymerase Chain Reaction/Enzyme Digestion-Based Method for Detection of Large Scale Deletions/Conversions of the CYP21 Gene and Mutation Screening in Turkish Families with 21-Hydroxylase Deficiency
Authors: Tukel T. , Uyguner O. , Wei J. Q. , Yuksel-Apak M. , Saka N. , Song D. X. , Kayserili H. , Bas F. , Gunoz H. , Wilson R. C. , New M. I. , Wollnik B. 
Published: December 2003

Abstract
21-Hydroxylase deficiency is a recessively inherited disorder resulting from mutations in the CYP21 gene. The CYP21 gene is located along with the CYP21P pseudogene in the human leukocyte antigen major histocompatibility complex region on chromosome 6. Molecular diagnosis is difficult due to the 98% similarity of CYP21 and CYP21P genes and the fact that almost all frequently reported mutations reside on the pseudogene. Allele-specific PCR for the 8 most frequently reported point mutations was performed in 31 Turkish families with at least a single 21-hydroxylase-deficient individual. The allele frequencies of the point mutations were as follows: P30L, 0%; IVS2 (AS,A/C-G,-13), 22.5%; G110Δ8nt, 3.2%; I172N, 11.4%; exon 6 cluster (I236N, V237E, M239K), 3.2%; V281L, 0%; Q318X, 8%; and R356W, 9.6%. Large deletions and gene conversions were detected by Southern blot analysis, and the allele frequencies were 9.6% and 22.5%, respectively. Sequence analysis of the gene, performed on patients with only 1 mutated allele, revealed 2 missense mutations (R339H and P435S). A novel semiquantitative PCR/enzyme digestion-based method for the detection of large scale deletions/conversions of the gene was developed for routine diagnostic purposes, and its accuracy was shown by comparison with the results of Southern blot analysis.
Molecular Changes Underlying Reduced Pineal Melatonin Levels in Alzheimer Disease: Alterations in Preclinical and Clinical Stages
Authors: Wu Ying-Hui , Feenstra Matthijs G. P. , Zhou Jiang-Ning , Liu Rong-Yu , Toranõ Javier Sastre , Van Kan Hendrikus J. M. , Fischer David F. , Ravid Rivka , Swaab Dick F. 
Published: December 2003

AbstractA disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak stages), already in cognitively intact subjects with the earliest AD neuropathology (Braak stages I-II) (preclinical AD). To investigate the molecular mechanisms behind the decreased melatonin levels, we measured monoamines and mRNA levels of enzymes of the melatonin synthesis and its noradrenergic regulation in pineal glands from 18 controls, 33 preclinical AD subjects, and 25 definite AD patients. Pineal melatonin levels were highly correlated with cerebrospinal fluid melatonin levels. The circadian melatonin rhythm disappeared because of decreased nocturnal melatonin levels in both the preclinical AD and AD patients. Also the circadian rhythm of β1-adrenergic receptor mRNA disappeared in both patient groups. The precursor of melatonin, serotonin was stepwise depleted during the course of AD, as indicated by the up-regulated monoamine oxidase A mRNA and activity (5-hydroxyindoleacetic acid:serotonin ratio). We conclude that a dysfunction of noradrenergic regulation and the depletion of serotonin by increased monoamine oxidase A result in the loss of melatonin rhythm already in preclinical AD.
The Role of the Orphan Nuclear Receptor, Liver Receptor Homologue-1, in the Regulation of Human Corpus Luteum 3β-Hydroxysteroid Dehydrogenase Type II
Authors: Peng Noel , Kim Joung W. , Rainey William E. , Carr Bruce R. , Attia George R. 
Published: December 2003

AbstractAfter ovulation, ovarian 3β-hydroxysteroid dehydrogenase type II (HSD3B2) expression increases to enhance the shift of steroidogenesis toward progesterone biosynthesis. Steroidogenic factor-1 (SF-1) is a transcription factor for several genes encoding steroidogenic enzymes. However, the level of SF-1 expression decreases in the human corpus luteum (CL) after ovulation. Liver receptor homolog-1 (LRH-1) is another member of the orphan nuclear receptor family. We hypothesize that LRH-1, rather than SF-1, plays an essential role in the regulation of corpus luteum steroidogenesis. Semiquantitative RT-PCR and real-time PCR were performed to quantify the level of LRH-1 expression and correlate with HSD3B2 level. Cell transfection, mutation analysis, and EMSA were performed to examine the role of LRH-1 in the regulation of HSD3B2. LRH-1 expression was higher in CL, compared with mature ovarian follicles. Cotransfection of granulosa cells with HSD3B2 and LRH-1 resulted in a 10-fold increase of transcription. DAX-1 inhibited LRH-1-stimulated HSD3B2, which was maintained in the presence of dibutyryl cAMP. Mutation of the either of the two putative LRH-1 binding sites, which were confirmed by EMSA, in the HSD3B2 promoter decreased LRH-1 stimulation. Our findings suggest that LRH-1 is highly expressed in CL, and it plays an essential role in the regulation of HSD3B2.
Is the Thyrotropin-Releasing Hormone Test Necessary in the Diagnosis of Central Hypothyroidism in Children
Authors: Mehta Ameeta , Hindmarsh Peter C. , Stanhope Richard G. , Brain Caroline E. , Preece Michael A. , Dattani Mehul T. 
Published: December 2003

Abstract
To determine the value of the TRH test, we analyzed the unstimulated serum T4 and TSH concentrations in 54 children with central hypothyroidism. A TRH test was performed in 30 patients. Midline brain defects (septo-optic dysplasia, 28; holoprosencephaly, 2) and combined pituitary hormone deficiencies were present in 30 and 52 patients, respectively. The mean serum free T4, total T4, and basal TSH concentrations were 0.6 ng/dl, 4.0 μg/dl, and 2.8 μU/ml, respectively. Five patients demonstrated elevated basal serum TSH concentrations. A normal TRH test [increase (Δ) in TSH, 4.5–17.8], based on data from 30 controls, was documented in 23.3% of patients. Brisk (ΔTSH, &gt;17.8), absent/blunted (ΔTSH, &lt;4.5), and delayed responses were documented in 16.7%, 30%, and 30% of patients, respectively. The mean age at diagnosis was 2.8 yr, with 8 patients evolving into TSH deficiency. It was not possible to differentiate patients as having pituitary or hypothalamic disease based solely on the TRH test results. Patients with septo-optic dysplasia were diagnosed earlier and had elevated basal serum TSH and PRL concentrations, diabetes insipidus, and evolving disease. Although full pituitary function assessment is mandatory to identify combined pituitary hormone deficiencies, a TRH test is not essential, and the diagnosis should be made by serial T4 measurements.
In Vivo Phosphorylation of the Somatostatin 2A Receptor in Human Tumors
Authors: Liu Qisheng , Reubi Jean-Claude , Wang Yining , Knoll Brian J. , Schonbrunn Agnes 
Published: December 2003

AbstractHormone-stimulated receptor internalization and desensitization occur widely in the G protein-coupled receptor (GPCR) family. A critical first step in both these processes is thought to be receptor phosphorylation, a reaction which has been extensively characterized in cell culture. However, little is known about GPCR phosphorylation in vivo. The somatostatin (SS) receptor subtype (sst)2A is widely distributed in human neuroendocrine tumors, and SS analogs are commonly used to target this receptor for both therapy and diagnosis. In cultured pituitary cells sst2A is rapidly phosphorylated and internalized after hormone binding. The aim of the present study was to go one crucial step further and characterize the phosphorylation state of this receptor in human neuroendocrine tumors using a newly developed gel-shift assay. The receptor from a somatostatinoma was completely phosphorylated. In contrast, only unphosphorylated sst2A was present in human tumors that were not exposed to autocrine stimulation. Both in vivo and in cultured cells, the phosphorylation state of the sst2A receptor was correlated with its subcellular localization: phosphorylated receptor was mostly intracellular, whereas unphosphorylated receptor was localized at the cell surface. These results are the first to demonstrate ligand-stimulated GPCR phosphorylation in human tissue in situ, providing a crucial step toward a better understanding of receptor regulation in vivo. Analysis of sst2A phosphorylation promises to provide a sensitive indicator of the effectiveness of SS analogs in diagnostic and therapeutic situations in tumor patients.
P450c17 Deficiency in Brazilian Patients: Biochemical Diagnosis through Progesterone Levels Confirmed by CYP17 Genotyping
Authors: Martin Regina M. , Lin Chin J. , Costa Elaine M. F. , de Oliveira Maria Leocadia , Carrilho Alexandre , Villar Heloisa , Longui Carlos A. , Mendonca Berenice B. 
Published: December 2003

AbstractP450c17 deficiency is an autosomal recessive disorder and a rare cause of congenital adrenal hyperplasia characterized by hypertension, hypokalemia, and impaired production of sex hormones. We performed a clinical, hormonal, and molecular study of 11 patients from 6 Brazilian families with the combined 17α-hydroxylase/17,20-lyase deficiency phenotype. All patients had elevated basal serum levels of progesterone (1.8–38 ng/ml; 0.57–12 pmol/liter) and suppressed plasma renin activity. CYP17 genotyping identified 5 missense mutations. The compound heterozygous mutation R362C/W406R was found in 1 family, whereas the homozygous mutations R96W, Y329D, and P428L were seen in the other 5 families. The R96W mutation has been described as the cause of P450c17 deficiency in Caucasian patients. The other mutations were not found in 50 normal subjects screened by allele-specific oligonucleotide hybridization (Y329D, R362C, and W406R) or digestion with HphI (P428L) and were recently found in other Brazilian patients. Therefore, we elucidated the genotype of 11 individuals with P450c17 deficiency and concluded that basal progesterone measurement is a useful marker of P450c17 deficiency and that its use should reduce the misdiagnosis of this deficiency in patients presenting with male pseudohermaphroditism, primary or secondary amenorrhea, and mineralocorticoid excess syndrome.
Treatment of Recurrent Thyroid Cysts with Ethanol: A Randomized Double-Blind Controlled Trial
Authors: Bennedbæk Finn Noe , Hegedüs Laszlo 
Published: December 2003

Abstract
Thyroid nodules are prevalent; when evaluated by ultrasonography (US), 15–25% of solitary thyroid nodules are cystic or predominantly cystic, and most are benign. Simple aspiration is the treatment of choice, but the recurrence rate is 10–80% depending on the number of aspirations and the cyst volume. The aim of this study was to evaluate the effect on recurrence rate of benign recurrent thyroid cysts in a double-blind randomized study comparing ethanol instillation with instillation of isotonic saline and subsequent complete emptying. Sixty-six consecutive patients with recurrent and benign (based on US-guided biopsy) thyroid cysts (≥2 ml) were randomly assigned to either subtotal cyst aspiration, flushing with 99% ethanol, and subsequent complete fluid aspiration (n = 33), or to subtotal cyst aspiration, flushing with isotonic saline, and subsequent complete fluid aspiration (n = 33). In case of recurrence (defined as cyst volume &gt;1 ml) at the monthly evaluations, the treatment was repeated but limited to a maximum of three treatments. Procedures were US-guided, and patients were followed for 6 months. Age, sex, number of previous aspirations, pretreatment cyst volume, and serum TSH did not differ in the two groups. Cure (defined as a cyst volume ≤1 ml at the end of follow-up) was obtained in 27 of 33 [82%; confidence interval (CI), 65–93] patients treated with ethanol and in 16 of 33 (48%; CI, 31–66) patients treated with saline (P = 0.006). In the ethanol group, 21 of 33 (64%) patients were cured after one session only, compared with six of 33 (18%) in the saline group (P = 0.002). The number of previous aspirations (P = 0.005) and baseline cyst volume (P = 0.005) had influence on outcome, i.e. the chance of success decreased with the number of previous aspirations and with increasing cyst volume. Seven patients (21%) treated with ethanol had moderate to severe pain (median duration, 5 min; CI, 2–10), and one had transient dysphonia. Indirect laryngoscopy was performed before and after the last session and was normal in all patients.
We concluded that treatment of recurrent thyroid cysts with ethanol is superior to simple aspiration and flushing with saline and devoid of serious side effects. Our study demonstrates that flushing with ethanol is a clinically significant nonsurgical alternative for thyroid cysts that recur despite repeat aspirations.
Intramyocellular Lipid Changes in Men and Women during Aerobic Exercise: A 1H-Magnetic Resonance Spectroscopy Study
Authors: White Lesley J. , Ferguson Michael A. , McCoy Sean C. , Kim HeeWon 
Published: December 2003

AbstractThis study was designed to compare intramyocellular lipid (IMCL) changes during 60 min of submaximal exercise in men and women. Eighteen moderately active (18–38 yr) men (n = 9) and women (n = 9) were recruited. Maximum oxygen consumption (V̇O2max) and body composition were used to match subjects for aerobic fitness and body composition. Subjects performed cycle ergometry for 1 h at 65% of V̇O2max. Expired gases were collected throughout exercise to determine caloric expenditure and substrate use. Blood samples were collected before and after exercise to evaluate markers of lipid metabolism. Pre- and postexercise proton spectra were acquired from the vastus lateralis using a 3-T whole-body imaging system. Spectra were acquired from an 18-mm3 region of interest (echo time = 45 msec; repetition time = 2000 msec) for IMCL evaluation. IMCL decreased significantly with exercise (11.5–28.5% for men and 17.1–21.7% for women) (P &lt; 0.05); however, there were no significant differences between men and women. Although changes were found for many plasma variables [free fatty acids, glycerol, and norepinephrine (P &lt; 0.05)], group differences were only evident for norepinephrine. In conclusion, a significant decrease in IMCL was observed during 60 min of cycling in matched men and women.
Mutational Analysis of the FOXP3 Gene and Evidence for Genetic Heterogeneity in the Immunodysregulation, Polyendocrinopathy, Enteropathy Syndrome
Authors: Owen Catherine J. , Jennings Claire E. , Imrie Helen , Lachaux Alain , Bridges Nicola A. , Cheetham Tim D. , Pearce Simon H. S. 
Published: December 2003

Abstract
The immunodysregulation, polyendocrinopathy, enteropathy syndrome (IPEX), is a rare disorder of immune regulation resulting in multiple autoimmune disorders, which demonstrates X-linked recessive inheritance. The disease gene, FOXP3, was identified in 2001, and several mutations within this gene have since been described in patients with IPEX. We used linkage analysis, mutational screening of the FOXP3 gene, human leukocyte antigen typing, and analysis of X-chromosome inactivation to investigate 2 kindreds (21 subjects in total) with 4 male infants (3 now deceased) and 1 girl affected by IPEX. In 1 family a novel FOXP3 mutation was identified in the proband, with a single base deletion at codon 76 of exon 2, leading to a frameshift, which predicted a truncated protein product (108 residues vs. 431 in wild type). In the second family, the FOXP3 locus was excluded by recombination, and mutational analysis of the gene was negative. The affected girl from this family was shown to have human leukocyte antigen DR2 and DR6 alleles and random X-chromosome inactivation in peripheral blood mononuclear cells. Our analysis has elucidated the molecular basis of IPEX in one family and has, for the first time, provided evidence for an autosomal locus, suggesting genetic heterogeneity in this syndrome.
Pharmacokinetics and Dose Finding of a Potent Aromatase Inhibitor, Aromasin (Exemestane), in Young Males
Authors: Mauras Nelly , Lima John , Patel Deval , Rini Annie , di Salle Enrico , Kwok Ambrose , Lippe Barbara 
Published: December 2003

Abstract
Suppression of estrogen, via estrogen receptor or aromatase blockade, is being investigated in the treatment of different conditions. Exemestane (Aromasin) is a potent and selective irreversible aromatase inhibitor. To characterize its suppression of estrogen and its pharmacokinetic (PK) properties in males, healthy eugonadal subjects (14–26 yr of age) were recruited. In a cross-over study, 12 were randomly assigned to 25 and 50 mg exemestane daily, orally, for 10 d with a 14-d washout period. Blood was withdrawn before and 24 h after the last dose of each treatment period. A PK study was performed (n = 10) using a 25-mg dose. Exemestane suppressed plasma estradiol comparably with either dose [25 mg, 38% (P ≤ 0.002); 50 mg, 32% (P ≤ 0.008)], with a reciprocal increase in testosterone concentrations (60% and 56%; P ≤ 0.003 for both). Plasma lipids and IGF-I concentrations were unaffected by treatment. The PK properties of the 25-mg dose showed the highest exemestane concentrations 1 h after administration, indicating rapid absorption. The terminal half-life was 8.9 h. Maximal estradiol suppression of 62 ± 14% was observed at 12 h. The drug was well tolerated. In conclusion, exemestane is a potent aromatase inhibitor in men and an alternative to the choice of available inhibitors. Long-term efficacy and safety will need further study.
Polymer Nanocomposites for Aerospace Applications: Properties
Authors: Njuguna J. , Pielichowski K. 
Published: December 2003

AbstractPolymer nanocomposites may provide significantly increased modulus, gas barrier, thermal performance, atomic oxygen resistance, resistance to small molecule permeation and improved ablative performance when compared to typical traditional carbon‐fiber‐reinforced polymeric composites. This presentation gives a review on both theoretical and experimental investigations extracting valuable fundamental elements including field emission, thermal stability, and electrical, optical and mechanical properties of polymer nanocomposites for aerospace applicability.