bluuebunny/crossref_metadata_2025 huggingface dataset:
Prophylactic Ibuprofen for the Prevention of Intraventricular Hemorrhage Among Preterm Infants: A Multicenter, Randomized Study
Authors: Dani Carlo , Bertini Giovanna , Pezzati Marco , Poggi Chiara , Guerrini Pietro , Martano Claudio , Rubaltelli Firmino F. ,   and the IntraVentricular Ibuprofen Study Group
Published: June 2005

Objective. Ibuprofen enhances cerebral blood flow autoregulation and was shown to protect neurologic functions after oxidative stresses in an animal model. For these reasons, we hypothesized that the prophylactic use of ibuprofen would reduce the occurrence of intraventricular hemorrhage (IVH) and its worsening toward grades 2 to 4 among preterm infants. To confirm this hypothesis, we planned the present prospective study.

Methods. This was a double-blind, randomized, controlled trial in which preterm infants with gestational ages of <28 weeks received ibuprofen or placebo within the first 6 hours of life. The infants were assigned randomly, at 7 neonatal care units, to receive ibuprofen (10 mg/kg, followed by 5 mg/kg after 24 and 48 hours) or placebo. Serial echoencephalography was performed 24 and 48 hours after the initial cerebral ultrasound study, on postnatal days 7, 15, and 30, and at 40 weeks' postconceptional age. Grade 1 IVH or no IVH was considered a successful outcome, whereas grade 2 to 4 IVH represented failure. The rates of ductal closure, side effects, and complications were recorded.

Results. We studied 155 infants. Grade 2 to 4 IVH developed for 16% of the ibuprofen-treated infants and 13% of the infants in the placebo group. The occurrence of patent ductus arteriosus was less frequent only on day 3 of life in the ibuprofen group. There were no significant differences with respect to other complications or adverse effects.

Conclusions. Our study demonstrated that prophylactic ibuprofen is ineffective in preventing grade 2 to 4 IVH and that its use for this indication cannot be recommended.
Transition Planning for Youth With Special Health Care Needs: Results From the National Survey of Children With Special Health Care Needs
Authors: Lotstein Debra S. , McPherson Merle , Strickland Bonnie , Newacheck Paul W.
Published: June 2005

Objective. To describe the proportion of youth with special health care needs (YSHCN) who are receiving services for medical transitions and to describe which sociodemographic and health care-related factors are associated with receiving transition services.

Methods. We analyzed responses to questions about medical transitions from the 2001 National Survey of Children With Special Health Care Needs (NS-CSHCN). Parents or guardians of youth aged 13 to 17 years who screened positive for the survey were asked (1) whether they had discussed with health care providers how their child's health care needs might change in adulthood, (2) if they had a plan to address these changing needs, and (3) if their child's health care providers had discussed having their child eventually see a doctor who treats adults. Bivariate and multivariate associations were estimated to identify sociodemographic and health care factors related to receiving medical-transition services.

Results. Overall, 50% of respondents had discussed their child's changing health care needs with their physicians, although significantly fewer Hispanic youth compared with other youth reported these discussions. Youth who met criteria for a medical home were more likely to have discussed changing needs and to have a plan addressing these needs. Of those who had discussed changing needs, 59% had a plan to address these needs and ∼42% had reported discussing shifting care to adult-oriented providers. Younger teens and non-Hispanic black children were less likely to have discussed changing providers. Fifteen percent of YSHCN met the Maternal and Child Health Bureau's core outcome for medical transitions. A multivariate logistic-regression model found that older age and having a medical home were significantly associated with increased odds of meeting the outcome measure.

Conclusion. The proportion of YSHCN meeting the medical-transition outcome measure is quite low, particularly for youth from ethnic minorities. Higher rates are seen for older teens and those receiving care within a medical home. Significant efforts will be required to meet the proposed goal of all YSHCN receiving the services necessary to transition to adult health care.
Cardiovascular Support for Low Birth Weight Infants and Cerebral Hemodynamics: A Randomized, Blinded, Clinical Trial
Authors: Pellicer Adelina , Valverde Eva , Elorza María Dolores , Madero Rosario , Gayá Francisco , Quero José , Cabañas Fernando
Published: June 2005

Background. Maintaining adequate organ blood flow is the target of vasopressor treatment, but the impact of these measures on cerebral perfusion has not yet been evaluated systematically in a randomized, blinded, clinical trial.

Objectives. To explore the effects on brain hemodynamics of 2 different inotropic agents used to treat systemic hypotension among low birth weight (LBW) infants.

Design and Methods. Newborns of <1501 g birth weight or <32 weeks' gestational age, with a mean blood pressure (MBP) lower than gestational age in the first 24 hours of life, were assigned randomly to receive dopamine (DP) (2.5, 5, 7.5, or 10 μg/kg per minute; n = 28) or epinephrine (EP) (0.125, 0.250, 0.375, or 0.5 μg/kg per minute; n = 32), at doses that were increased in a stepwise manner every 20 minutes until the optimal MBP (MBP-OP) was attained and maintained.

Outcome Measures. Continuous monitoring of quantitative changes in cerebral concentrations of oxyhemoglobin and deoxyhemoglobin, cerebral intravascular oxygenation (HbD) (the difference between oxyhemoglobin and deoxyhemoglobin), and cerebral blood volume (CBV) were assessed with near-infrared spectroscopy. MBP, heart rate, transcutaneous Pco2 and Po2, and peripheral oxygen saturation were recorded continuously and analyzed at baseline, 20 minutes after each dose increase (T1, T2, T3, and T4) until MBP-OP was reached, and then every 20 minutes up to 1 hour of stable MBP-OP.

Results. Fifty-nine infants were considered for analysis. Patients did not differ in birth weight or gestational age (1008 ± 286 g and 28.3 ± 2.3 weeks, respectively, in the DP group and 944 ± 281 g and 27.7 ± 2.4 weeks in the EP group). Studies were performed at a mean age of 5.3 ± 3.7 hours of life (range: 2–16 hours). MBP-OP was attained for 96.3% of patients with DP and 93.7% with EP (responders). For those patients, MBP, heart rate, CBV, and HbD increased from baseline throughout the study period, with no differences between groups except for a higher heart rate with EP. Changes in MBP were correlated significantly with changes in HbD. Dose escalation of drugs produced no differences between groups in the behavior of the variables, except for a greater heart rate with EP from 20 minutes after dose 2 (T2) onward. Drug-induced changes in cerebral hemodynamics varied with gestational age; the EP-induced increase in CBV was greater among less mature patients (<28 weeks), whereas the DP-induced increase in CBV was greater among patients of ≥28 weeks.

Conclusions. Among hypotensive LBW infants, cardiovascular support with low/moderate-dose DP or low-dose EP increased cerebral perfusion, as indicated by the increase in both CBV and HbD. Low-dose EP was as effective as low/moderate-dose DP in increasing MBP among LBW infants.
The Impact of School Daily Schedule on Adolescent Sleep
Authors: Hansen Martha , Janssen Imke , Schiff Adam , Zee Phyllis C. , Dubocovich Margarita L.
Published: June 2005

Objectives. This study was initiated to examine the impact of starting school on adolescent sleep, to compare weekday and weekend sleep times, and to attempt to normalize the timing of the circadian sleep/wake cycle by administering bright light in the morning. This was a collaborative project involving high school students and their parents, as well as high school and university faculty members, for the purpose of contributing information to the scientific community while educating students about research processes and their own sleep/wake cycles and patterns.

Methods. Sixty incoming high school seniors kept sleep/wake diaries beginning in August and continuing through 2 weeks after the start of school in September. Sleep diaries were also kept for 1 month in November and 1 month in February. Early-morning light treatments were given to 19 students in the last 2 weeks of November and the last 2 weeks of February. Neuropsychologic performance was measured with computer-administered tests. Paper-and-pencil tests were used for assessment of mood and vigor. A testing period consisted of 2 consecutive days at the beginning and end of November and at the beginning and end of February. Tests were given 3 times per day, ie, in the morning before school (6:30–8:00 am), during midday lunch periods (11:30 am to 1:00 pm), and in the afternoon (3:00–4:30 pm), on each of the test days.

Results. Adolescents lost as much as 120 minutes of sleep per night during the week after the start of school, and weekend sleep time was also significantly longer (∼30 minutes) than that seen before the start of school (August). No significant differences were found between weekday sleep in the summer and weekend sleep during the school year. Early-morning light treatments did not modify total minutes of sleep per night, mood, or computer-administered vigilance test results. All students performed better in the afternoon than in the morning. Students in early morning classes reported being wearier, being less alert, and having to expend greater effort.

Conclusions. The results of this study demonstrated that current high school start times contribute to sleep deprivation among adolescents. Consistent with a delay in circadian sleep phase, students performed better later in the day than in the early morning. However, exposure to bright light in the morning did not change the sleep/wake cycle or improve daytime performance during weekdays. Both short-term and long-term strategies that address the epidemic of sleep deprivation among adolescents will be necessary to improve health and maximize school performance.
Vaccine Effectiveness During a Varicella Outbreak Among Schoolchildren: Utah, 2002–2003
Authors: Haddad Maryam B. , Hill Mary B. , Pavia Andrew T. , Green Caroline E. , Jumaan Aisha O. , De Anindya K. , Rolfs Robert T.
Published: June 2005

Objectives. In the context of a chickenpox outbreak involving 2 Utah elementary schools, we conducted an investigation to assess vaccine effectiveness, describe illness severity, and examine risk factors for breakthrough varicella (ie, varicella in those who have been vaccinated).

Methods. All parents were asked to complete a questionnaire about their child’s medical history. Parents of children with recent varicella were interviewed, and vaccination records were verified. Lesions were submitted for polymerase chain reaction testing.

Results. Questionnaires were returned for 558 (93%) of 597 students in school A and 924 (97%) of 952 students in school B. A total of 83 schoolchildren (57 unvaccinated and 26 vaccinated) had varicella during the October 2002 through February 2003 outbreak period. An additional 17 cases occurred among household contacts, including infants and adults. Polymerase chain reaction analysis recovered wild-type varicella. Vaccine effectiveness was 87%. With 1 notable exception, vaccinated children tended to have milder illness. Risk factors for breakthrough varicella included eczema, vaccination ≥5 years before the outbreak, and vaccination at ≤18 months of age. Restricting analysis to children vaccinated ≥5 years before the outbreak, those vaccinated at ≤18 months of age were more likely to develop breakthrough varicella (relative risk: 9.3; 95% confidence interval: 1.3–68.9).

Conclusions. The vaccine, administered by >100 health care providers to 571 children during a 7-year time period, was effective. Risk factors for breakthrough varicella suggest some degree of biological interaction between age at vaccination and time since vaccination.
Randomized Trial of Liberal Versus Restrictive Guidelines for Red Blood Cell Transfusion in Preterm Infants
Authors: Bell Edward F. , Strauss Ronald G. , Widness John A. , Mahoney Larry T. , Mock Donald M. , Seward Victoria J. , Cress Gretchen A. , Johnson Karen J. , Kromer Irma J. , Zimmerman M. Bridget
Published: June 2005

Objective. Although many centers have introduced more restrictive transfusion policies for preterm infants in recent years, the benefits and adverse consequences of allowing lower hematocrit levels have not been systematically evaluated. The objective of this study was to determine if restrictive guidelines for red blood cell (RBC) transfusions for preterm infants can reduce the number of transfusions without adverse consequences.

Design, Setting, and Patients. We enrolled 100 hospitalized preterm infants with birth weights of 500 to 1300 g into a randomized clinical trial comparing 2 levels of hematocrit threshold for RBC transfusion.

Intervention. The infants were assigned randomly to either the liberal- or the restrictive-transfusion group. For each group, transfusions were given only when the hematocrit level fell below the assigned value. In each group, the transfusion threshold levels decreased with improving clinical status.

Main Outcome Measures. We recorded the number of transfusions, the number of donor exposures, and various clinical and physiologic outcomes.

Results. Infants in the liberal-transfusion group received more RBC transfusions (5.2 ± 4.5 [mean ± SD] vs 3.3 ± 2.9 in the restrictive-transfusion group). However, the number of donors to whom the infants were exposed was not significantly different (2.8 ± 2.5 vs 2.2 ± 2.0).

There was no difference between the groups in the percentage of infants who avoided transfusions altogether (12% in the liberal-transfusion group versus 10% in the restrictive-transfusion group). Infants in the restrictive-transfusion group were more likely to have intraparenchymal brain hemorrhage or periventricular leukomalacia, and they had more frequent episodes of apnea, including both mild and severe episodes.

Conclusions. Although both transfusion programs were well tolerated, our finding of more frequent major adverse neurologic events in the restrictive RBC-transfusion group suggests that the practice of restrictive transfusions may be harmful to preterm infants.
Attention-Deficit/Hyperactivity Disorder Among Adolescents: A Review of the Diagnosis, Treatment, and Clinical Implications
Authors: Wolraich Mark L. , Wibbelsman Charles J. , Brown Thomas E. , Evans Steven W. , Gotlieb Edward M. , Knight John R. , Ross E. Clarke , Shubiner Howard H. , Wender Esther H. , Wilens Timothy
Published: June 2005

Attention-deficit/hyperactivity disorder (ADHD) is the most common mental disorder in childhood, and primary care clinicians provide a major component of the care for children with ADHD. However, because of limited available evidence, the American Academy of Pediatrics guidelines did not include adolescents and young adults. Contrary to previous beliefs, it has become clear that, in most cases, ADHD does not resolve once children enter puberty. This article reviews the current evidence about the diagnosis and treatment of adolescents and young adults with ADHD and describes how the information informs practice. It describes some of the unique characteristics observed among adolescents, as well as how the core symptoms change with maturity. The diagnostic process is discussed, as well as approaches to the care of adolescents to improve adherences. Both psychosocial and pharmacologic interventions are reviewed, and there is a discussion of these patients' transition into young adulthood. The article also indicates that research is needed to identify the unique adolescent characteristics of ADHD and effective psychosocial and pharmacologic treatments.
Children's Adaptations to a Fat-Reduced Diet: The Dietary Intervention Study in Children (DISC)
Authors: Van Horn Linda , Obarzanek Eva , Friedman Lisa Aronson , Gernhofer Niki , Barton Bruce
Published: June 2005

Background. Prevention of cardiovascular disease through diet and lifestyle change is strongly advocated in adults and is initiated preferably during childhood. The Dietary Intervention Study in Children (DISC) was a multicenter, collaborative, randomized trial in 663 preadolescent children (363 boys and 301 girls) with elevated low-density lipoprotein cholesterol, designed to test the efficacy and safety of a dietary intervention to lower saturated-fat and cholesterol intake while also advocating a healthy eating pattern. DISC results have been published extensively. This ancillary study reports new data regarding changes in eating patterns among this cohort.

Objective. We set out to compare children's self-selected eating patterns and approaches to achieving adherence to the DISC fat-reduced diet intervention with children in the usual-care group.

Methods. An ancillary study was conducted to develop a detailed food-grouping system and report new analyses on dietary adherence to the recommended eating pattern. Every food in the nutrient database was ranked by its saturated-fat and cholesterol content and classified within its relevant food group as a “go” (less atherogenic) or “whoa” (more atherogenic) food.

Results. At baseline, go foods contributed ∼57% of total energy intake and 12.4% to 13.1% total fat energy intake in both groups. At 3 years, go foods contributed 67.4% and 13.7% of total and fat energy intake, respectively, in the intervention group versus 56.8% and 12.8% in the usual-care group. Differences between the 2 treatment groups were significant for changes in consumption of dairy foods, desserts, and fats/oils, with the intervention group reporting a 0.2- to 0.3-serving-per-day greater increase in go foods than the usual-care group. The intervention group also reported a 0.2- to 0.8-serving-per-day greater decrease in whoa foods than the usual-care group for breads/grains, dairy, fats/oils, meat/fish/poultry, snacks, and vegetables. Overall, snack foods, desserts, and pizza contributed approximately one third of total daily energy intake in both groups at 3 years.

Conclusions. Children in the intervention group reported consuming more servings per day of go grains, dairy, meats, and vegetable foods compared with children in the usual-care group, but intake of fruits and vegetables was low in both groups. Discovering that snacks, desserts, and pizza actively contribute so heavily to the diets of this age group, even among children who were part of this intervention, offers valuable insights regarding the need for more aggressive, innovative, and realistic approaches for additional dietary counseling.
Treatment of Attention-Deficit/Hyperactivity Disorder: Overview of the Evidence
Authors: Brown Ronald T. , Amler Robert W. , Freeman Wendy S. , Perrin James M. , Stein Martin T. , Feldman Heidi M. , Pierce Karen , Wolraich Mark L. ,   and the Committee on Quality Improvement, Subcommittee on Attention-Deficit/Hyperactivity Disorder
Published: June 2005

The American Academy of Pediatrics' Committee on Quality Improvement, Subcommittee on Attention-Deficit/Hyperactivity Disorder, reviewed and analyzed the current literature for the purpose of developing an evidence-based clinical practice guideline for the treatment of the school-aged child with attention-deficit/hyperactivity disorder (ADHD). This review included several key reports, including an evidence review from the McMaster Evidence-Based Practice Center (supported by the Agency for Healthcare Research and Quality), a report from the Canadian Coordinating Office for Health Technology Assessment, the Multimodal Treatment for ADHD comparative clinical trial (supported by the National Institute of Mental Health), and supplemental reviews conducted by the subcommittee. These reviews provided substantial information about different treatments for ADHD and their efficacy in improving certain characteristics or outcomes for children with ADHD as well as adverse effects and benefits of multiple modes of treatment compared with single modes (eg, medication or behavior therapies alone). The reviews also compared the effects of different medications.

Other evidence documents the long-term nature of ADHD in children and its classification as a chronic condition, meriting the application of general concepts of chronic-condition management, including an individual treatment plan with a focus on ongoing parent and child education, management, and monitoring. The evidence strongly supports the use of stimulant medications for treating the core symptoms of children with ADHD and, to a lesser degree, for improving functioning. Behavior therapy alone has only limited effect on symptoms or functioning of children with ADHD, although combining behavior therapy with medication seems to improve functioning and may decrease the amount of (stimulant) medication needed. Comparison among stimulants (mainly methylphenidate and amphetamines) did not indicate that 1 class outperformed the other.
Combined Influence of Body Mass Index and Waist Circumference on Coronary Artery Disease Risk Factors Among Children and Adolescents
Authors: Janssen Ian , Katzmarzyk Peter T. , Srinivasan Sathanur R. , Chen Wei , Malina Robert M. , Bouchard Claude , Berenson Gerald S.
Published: June 2005

Objectives. In adult populations, it is recognized widely that waist circumference (WC) predicts health risk beyond that predicted by BMI alone; current recommendations for adults are that a combination of BMI and WC be used to classify obesity-related health risk. For children and adolescents, however, little is known about the combined influence of BMI and WC on health outcomes. The objectives of this study were to determine whether BMI and WC predict coronary artery disease (CAD) risk factors independently for children and adolescents and to assess the clinical utility of using WC in combination with BMI to identify CAD risk.

Methods. Subjects included 2597 black and white, 5- to 18-year-old, male and female youths. Outcome measures included 7 CAD risk factors. In the first analysis step, BMI and WC were used as continuous variables to predict CAD risk factors. In the second analysis step, participants were placed into normal-weight, overweight, and obese BMI categories and, within each BMI category, CAD risk factors were compared for groups with low and high WC values.

Results. When BMI and WC were included in the same regression model to predict CAD risk factors, the added variance above that predicted by BMI or WC alone was minimal, which indicated that BMI and WC did not have independent effects on the risk factors. For example, for systolic blood pressure, BMI alone explained 7.3% of the variance, WC alone explained 7.7% of the variance, and the combination of BMI and WC explained 8.1% of the variance. When BMI and WC values were categorized with a threshold approach, WC provided information on CAD risk beyond that provided by BMI alone, particularly when the categories were used to predict elevated CAD risk factor levels. For instance, in the overweight BMI category, the high-WC group was ∼2 times more likely to have high triglyceride levels, high insulin levels, and the metabolic syndrome, compared with the low-WC group.

Conclusion. These findings provide some evidence that a combination of BMI and WC should be used in clinical settings to evaluate the presence of elevated health risk among children and adolescents.
Health Appraisal Guidelines for Day Camps and Resident Camps
Authors:   Committee on School Health, Section on School Health
Published: June 2005

The American Academy of Pediatrics recommends that specific guidelines be established for health appraisals of young people before participation in day and resident camps. Camp guidelines should include reference to health maintenance, storage and administration of medication, and emergency medical services. Although camps have diverse environments, there are general guidelines that apply to all situations and specific recommendations that are appropriate under special conditions. This policy statement has been reviewed and is supported by the American Camp Association.
Heady Business
Authors: Talalay Lauren E.
Published: May 2005

Bodily dismemberment—particularly decapitation—appears in the iconography and mortuary practices of many ancient societies. A powerful and complex cultural statement, decapitation has been explored in some depth by archaeologists working in the prehistoric Levant and contiguous regions of the Near East. Very little research, however, has focused on the notion of headlessness and decapitation throughout the rest of the prehistoric Mediterranean. Some limited examples appear in the artistic traditions and burial practices of Anatolia and Greece; Anatolian wall paintings depict headless individuals, Neolithic burials in both regions produce skulls placed in specially designated locations, and select figurines appear to be designed with detachable heads. This paper gathers together some of the disparate information on headless bodies and bodiless heads from Anatolia and Greece, and offers preliminary conclusions on the range of their possible functions and meanings.
Caring about Sediments
Authors: Walsh Kevin
Published: May 2005

Geoarchaeology and, in particular, the way in which it is exploited in the Mediterranean, emphasises the study of human and climate impact on the geomorphic system. This paper assesses some of the problems with this approach, as well as some of the more recent uses of Mediterranean geoarchaeology, where authors tend to underplay the importance of geoarchaeological processes in the past. Case studies from two different environment types in Provence (south of France) are presented. These are used to demonstrate how we might employ geoarchaeological information in discourses that emphasise human appreciation and perception of natural processes and geomorphological features in the past.
Direct activation of telomerase by GH via phosphatidylinositol 3′-kinase
Authors: Gómez-García L , Sánchez F M , Vallejo-Cremades M T , de Segura I A Gómez , De Miguel del Campo E
Published: June 2005

Telomerase is a ribonucleoprotein DNA polymerase that has been associated with cell proliferation, cell survival and apoptosis inhibition. Telomerase is regulated by specific growth factors, cytokines and hormones. The present study examines the effect of GH on telomerase activity and identifies the signal transduction pathway involved in this process in Chinese hamster ovary (CHO)4 cells, which express rat GH receptor cDNA. Telomeric repeat amplification protocol assays demonstrated that treating CHO4 cells with increasingly high doses of GH up-regulated telomerase activity with the maximum activation at 24 h. Similarly, GH activated telomerase in another cell system, primary cultures of rat hepatocytes. The telomerase activation in CHO4 cells was produced with an increase in hamster telomerase catalytic subunit (hamTERT) mRNA expression. The telomerase activity induced by GH was specifically blocked by the phosphatidylinositol 3′-kinase (PI3-K) inhibitor, LY294002, but not by the MAP kinase kinase inhibitor, PD98059. These findings suggest that GH could activate telomerase through the direct activation of TERT transcription, as well as through the PI3-K signalling pathway.
Regulation of vitamin D receptor expression via estrogen-induced activation of the ERK 1/2 signaling pathway in colon and breast cancer cells
Authors: Gilad Liat Abovich , Bresler Tali , Gnainsky Julia , Smirnoff Patricia , Schwartz Betty
Published: June 2005

We previously demonstrated that 17β-estradiol (E2) regulates the transcription and expression of the vitamin D receptor (VDR) in rat colonocytes and duodenocytes in vivo. The aim of the present study was to assess whether the extracellular signal-regulated kinase (ERK) induced by E2 is involved in regulating VDR expression. We compared E2-associated signaling activity in HT29 colon cancer cells, a non-classical E2-target, with that in MCF-7 breast cancer cells, the natural targets of the hormone. E2 did not affect proliferation of HT29 cells, but enhanced proliferation of MCF-7 cells. Vitamin D inhibited proliferation of both cell lines and the combined treatment induced potentiation of vitamin D activity. E2 upregulated VDR transcription and protein expression concomitantly with ERK 1/2 phosphorylation in both cell lines. PD98059, a specific mitogen-activated protein kinase (MAPK) inhibitor, prevented E2-mediated activation of ERK 1/2, with concomitant inhibition of VDR expression. ICI182780 inhibited VDR expression in HT29 and MCF-7 cell lines. A conjugate of E2 and bovine serum albumin upregulated phosphorylation of ERK 1/2 and concomitantly enhanced VDR expression in a similar fashion as the nonconjugated hormone. Expression of ERα and ERβ was detected in MCF-7 and HT29 cell lines respectively, which localized to the nuclei, cytosol and caveolar membrane rather than non-caveolar membrane. Disruption of lipid rafts/caveolae by depleting cellular cholesterol with the cholesterol-binding reagent β-methylcyclodextrin blocked ERK 1/2 phosphorylation concomitantly with VDR upregulation. The tyrosine phosphorylation inhibitor suramin and src kinase inhibitor PP2 inhibited both ERK 1/2 phosphorylation and VDR expression. E2 induced phosphorylation of Raf and Jun in a time-dependent manner. The Ras/Raf dependent inhibitor of transactivation sulindac sulfide also blocked E2 effects. The specific c-Jun phosphorylation inhibitor SP600125 dose dependently inhibited c-Jun phosphorylation and VDR expression. The MAPK/ERK kinase inhibitor PD 98059 downregulated both c-Jun phosphorylation and VDR expression indicating that upstream and downstream events in the signaling cascade are all related to the control of VDR expression. Taken together, our data suggest that E2 binds to receptors compartmentalized to membranal caveolar domains in HT29 and MCF-7 cells, inducing ERK 1/2 activation and transcriptional activity, which finally results in upregulation of expression of the VDR gene.
Resistin expression and plasma concentration peak at different times during pregnancy in rats
Authors: Caja Sergio , Martínez Izaskun , Abelenda María , Puerta Marisa
Published: June 2005

Resistin has been proposed as both an anti-adipogenic factor and an inducer of insulin resistance. During late pregnancy, white adipose tissue mass increases and insulin sensitivity decreases. To check for the involvement of resistin in these processes, we measured plasma resistin in pregnant and non-pregnant rats and in lactating dams. Plasma resistin increased by day 15 of pregnancy and remained high 5 days post partum. The simultaneous increase in plasma resistin concentration and the decrease in insulin sensitivity is compatible with resistin depressing maternal insulin sensitivity. Resistin expression increased 5–15 times in visceral white adipose tissue depots by day 8 of pregnancy but was similar to pre-pregnancy values by day 19. Resistin expression in the placenta and mammary gland was similar to that in the parametrial adipose depot by day 8 but was almost null by day 19. There was therefore a time-lag between the peaks in expression and in plasma concentration. White adipose tissue mass increased without changes in adipocyte size once peaks in resistin expression had passed, which is compatible with an anti-adipogenic role for enhanced resistin expression. A bolus injection of chorionic gonadotrophin – which peaks in early pregnancy – to non-pregnant rats increased resistin expression in white adipose tissue, indicating that this hormone is involved in controlling resistin expression. Resistin was not detected in cerebrospinal fluid. Our results have suggested a role for resistin in pregnancy.
Corticosterone-induced negative feedback mechanisms within the hypothalamo–pituitary–adrenal axis of the chicken
Authors: Vandenborne Kristien , De Groef Bert , Geelissen Sofie M E , Kühn Eduard R , Darras Veerle M , Van der Geyten Serge
Published: June 2005

This paper reports the results of in vivo and in vitro experiments on the feedback effects of corticosterone on the hypothalamo–pituitary–adrenal axis in embryos at day 18 of incubation and in 9-day-old chickens. In vivo, a significant negative feedback was detected on the levels of corticotropin-releasing factor (CRF) precursor (proCRF) mRNA and on the plasma concentration of corticosterone, two hours after a single intravenous injection with 40 μg corticosterone. In contrast, the levels of CRF peptide in the hypothalamic area, the CRF receptor type 1 (CRF-R1) mRNA and pro-opiomelanocortin (POMC) mRNA levels in the pituitary were not affected by the in vivo administration of corticosterone. In vitro, incubation with 1 μM corticosterone did not affect the CRF-R1 mRNA levels in the pituitary, but significant feedback inhibition was observed on the POMC mRNA levels. These in vitro effects were the same at the two ages studied. The in vitro feedback effect on the proCRF gene expression, however, differed with age. In 9-day-old animals a decrease in gene expression was observed which was not detectable in embryonic tissue at day 18 of the ontogeny.
α-Lipoic acid suppresses osteoclastogenesis despite increasing the receptor activator of nuclear factor κB ligand/osteoprotegerin ratio in human bone marrow stromal cells
Authors: Koh Jung-Min , Lee Young-Sun , Byun Chang-Hyun , Chang Eun-Ju , Kim Hyunsoo , Kim Yong Hee , Kim Hong-Hee , Kim Ghi Su
Published: June 2005

Growing evidence has shown a biochemical link between increased oxidative stress and reduced bone density. Although α-lipoic acid (α-LA) has been shown to act as a thiol antioxidant, its effect on bone cells has not been determined. Using proteomic analysis, we identified six differentially expressed proteins in the conditioned media of α-LA-treated human bone marrow stromal cell line (HS-5). One of these proteins, receptor activator of nuclear factor κB ligand (RANKL), was significantly up-regulated, as confirmed by immunoblotting with anti-RANKL antibody. ELISA showed that α-LA stimulated RANKL production in cellular extracts (membranous RANKL) about 5-fold and in conditioned medium (soluble RANKL) about 23-fold, but had no effect on osteoprotegerin (OPG) secretion. Despite increasing the RANKL/OPG ratio, α-LA showed a dose-dependent suppression of osteoclastogenesis, both in a coculture system of mouse bone marrow cells and osteoblasts and in a mouse bone marrow cell culture system, and reduced bone resorption in a dose-dependent manner. In addition, α-LA-induced soluble RANKL was not inhibited by matrix metalloprotease inhibitors, indicating that soluble RANKL is produced by α-LA without any posttranslational processing. In contrast, α-LA had no significant effect on the proliferation and differentiation of HS-5 cells. These results suggest that α-LA suppresses osteoclastogenesis by directly inhibiting RANKL–RANK mediated signals, not by mediating cellular RANKL production. In addition, our findings indicate that α-LA-induced soluble RANKL is not produced by shedding of membranous RANKL.
Gene therapy of pituitary diseases
Authors: Lee Eun Jig , Jameson J Larry
Published: June 2005

Despite a stuttering course, gene therapy continues to provide a potential treatment avenue for many human diseases, including cancer and various inherited disorders. Gene therapy is also attractive for the treatment of local, benign disorders, such as pituitary adenomas. Advances in technology have focused on modifying existing viral vectors and developing targeted expression of therapeutic genes in an effort to achieve efficacy with minimal toxicity. Gene therapy also offers innovative strategies for treating hypopituitarism by replacing hormones such as growth hormone (GH) and vasopressin.
Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells
Authors: Lai K P , Wong M H , Wong C K C
Published: June 2005

Polychlorinated dibenzo-p-dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been recognized as highly potent developmental and reproductive toxins. We have previously demonstrated effects of TCDD in modulating the expression of rat Sertoli cell secretory products and markers for cell–cell interaction. In this study, we examined the direct biological effects of TCDD in rat Leydig cell primary cultures. Mature rat Leydig cells were purified by Percoll gradient centrifugation and the cell purity was determined by 3β-hydroxysteroid dehydrogenase (3β-HSD) staining and a testosterone induction assay. To examine TCDD-induced biological consequences, we measured the changes in the secretion of progesterone and testosterone, as well as transcript levels of some selected steroidogenic enzymes (i.e. StAR, P450scc, 3β-HSD and CYP17α), in TCDD/human chorionic gonadotropin (hCG) co-treated cells. Our results indicated that TCDD (0.2 or 2 ng/ml) treatment significantly suppressed hCG (5 or 10 ng/ml)-induced testosterone secretion. The suppressive effect aligned with a reduction of progesterone secretion (P<0.05), as well as a decrease of P450scc mRNA and protein expression (P<0.05). The mechanistic action of TCDD was found to be via the reduction of cellular cAMP levels in the hCG-treated cells. This observation was further confirmed, as the TCDD-mediated suppressive effect could be reversed by dibutyryl cAMP co-treatment. The data indicate that TCDD can modulate cAMP signaling in rat Leydig cells to affect the process of steroidogenesis.
Differential actions of acute and chronic citalopram on the rodent hypothalamic–pituitary–adrenal axis response to acute restraint stress
Authors: Hesketh S , Jessop D S , Hogg S , Harbuz M S
Published: June 2005

Serotonin re-uptake inhibitors (SSRIs) can affect the basal activity of the hypothalamic–pituitary–adrenal (HPA) axis in rats. A single injection of citalopram has been shown to stimulate the HPA axis while repeated administration leads to attenuation of the corticosterone response to the SSRI. The purpose of this work was to investigate the rodent HPA axis response to restraint stress, following acute and chronic treatment with the SSRI citalopram. We have demonstrated that a single injection of citalopram is able to prolong acute restraint-induced increases in plasma levels of corticosterone and adrenocorticotrophin (ACTH). This is possibly mediated by arginine vasopressin (AVP) in the parvocellular cells of the paraventricular nucleus (pPVN), as treatment with citalopram or restraint alone did not increase AVP mRNA in pPVN while the combination of treatments resulted in a significant increase in AVP mRNA in the pPVN. In contrast, the increase in corticotrophin-releasing factor (CRF) mRNA in the pPVN in response to acute restraint stress was not altered by citalopram. Oxytocin (OT) mRNA was also increased in the magnocellular PVN (mPVN) by the solo treatments of citalopram and restraint, and was not further enhanced by the dual treatment of restraint and citalopram. Chronic treatment with citalopram did not alter basal plasma levels of corticosterone or ACTH. However, the ACTH response to acute restraint was attenuated following chronic citalopram treatment. AVP mRNA in the pPVN was significantly elevated in response to chronic citalopram compared with saline controls suggesting an effect mediated through the AVP subset of pPVN neurones. The CRF mRNA response to acute restraint was not altered in rats treated chronically with citalopram. OT mRNA was not enhanced in the mPVN following chronic infusion of citalopram but was increased by acute restraint stress. We conclude from these data that both acute and chronic citalopram treatment has the potential to alter the rodent response to acute restraint stress. These effects appear to be regulated by the AVP-containing subset of CRF neurons in the pPVN and thus suggest that parvocellular AVP may have an important role in mediating the actions of SSRIs.
Blocking BRE expression in Leydig cells inhibits steroidogenesis by down-regulating 3β-hydroxysteroid dehydrogenase
Authors: Miao J , Chan K-W , Chen G G , Chun S-Y , Xia N-S , Chan J Y H , Panesar N S
Published: June 2005

Conversion of cholesterol to biologically active steroids is a multi-step enzymatic process. Along with some important enzymes, like cholesterol side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD), several proteins play key role in steroidogenesis. The role of steroidogenic acute regulatory (StAR) protein is well established. A novel protein, BRE, found mainly in brain, adrenals and gonads, was highly expressed in hyperplastic rat adrenals with impaired steroidogenesis, suggesting its regulation by pituitary hormones. To further elucidate its role in steroidogenic tissues, mouse Leydig tumor cells (mLTC-1) were transfected with BRE antisense probes. Morphologically the BRE antisense cells exhibited large cytoplasmic lipid droplets and failed to shrink in response to human chorionic gonadotropin. Although cAMP production, along with StAR and P450scc mRNA expression, was unaffected in BRE antisense clones, progesterone and testosterone yields were significantly decreased, while pregnenolone was increased in response to human chorionic gonadotropin stimulation or in the presence of 22(R)OH-cholesterol. Furthermore, whereas exogenous progesterone was readily converted to testosterone, pregnenolone was not, suggesting impairment of pregnenolone-to-progesterone conversion, a step metabolized by 3β-HSD. That steroidogenesis was compromised at the 3β-HSD step was further confirmed by the reduced expression of 3β-HSD type I (3ß-HSDI) mRNA in BRE antisense cells compared with controls. Our results suggest that BRE influences steroidogenesis through its effects on 3β-HSD action, probably affecting its transcription.
Involvement of endogenous glucagon-like peptide-1(7–36) amide on glycaemia-lowering effect of oligofructose in streptozotocin-treated rats
Authors: Cani Patrice D , Daubioul Catherine A , Reusens Brigitte , Remacle Claude , Catillon Grégory , Delzenne Nathalie M
Published: June 2005

We have evaluated the influence of oligofructose (OFS), a fermentable dietary fibre, on glucose homeostasis, insulin production and intestinal glucagon-like peptide-1 (GLP-1) in streptozotocin-treated diabetic rats.

Male Wistar rats received either i.v. streptozotocin (STZ; 40 mg/kg) or vehicle (CT); one week later, they were fed for 6 weeks with either the standard diet (STZ-CT), or with a diet containing 10% oligofructose (STZ-OFS); both diets were available ad libitum. In a second set of experiments (duration 4 weeks), a supplemental group of food-restricted rats (STZ-Res) receiving a similar intake as CT rats, was added.

OFS improved glucose tolerance and reduced food intake as compared with STZ-CT rats in both the post-prandial state and after an oral glucose tolerance test. After 6 weeks, portal and pancreatic insulin concentrations were doubled in STZ-OFS rats. Food restriction improved these parameters when compared with STZ-CT rats, but to a lesser extent than in the STZ-OFS group. We have shown that OFS treatment increased portal and colonic GLP-1(7–36) amide levels and doubled colonic proglucagon and prohormone convertase 1 mRNA levels; both OFS and food restriction lowered ileal GLP-1(7–36) amide levels as compared with levels in STZ-CT rats.

We propose that OFS, through its fermentation in the colon, promotes the expression and secretion of colonic peptides, namely GLP-1(7–36) amide, with beneficial consequences on glycaemia, insulin secretion and hyperphagia in diabetic rats.
Dexamethasone administration attenuates the inhibitory effect of lipopolysaccharide on IGF-I and IGF-binding protein-3 in adult rats
Authors: Priego Teresa , Granado Miriam , Martín Ana Isabel , López-Calderón Asunción , Villanúa María Angeles
Published: June 2005

The aim of this study was to investigate whether glucocorticoid administration had a beneficial effect on serum concentrations of insulin-like growth factor I (IGF-I) and on IGF-binding protein 3 (IGFBP-3) in rats injected with lipopolysaccharide (LPS). Adult male rats were injected with LPS or saline and pretreated with dexamethasone or saline. Dexamethasone administration decreased growth hormone (GH) receptor and IGF-I mRNA levels in the liver of control rats. LPS decreased GH receptor and IGF-I gene expression in the liver of saline-treated rats but not in the liver of dexamethasone-pretreated rats. In the kidney, GH receptor mRNA levels were not modified by dexamethasone or LPS treatment. However, LPS decreased renal IGF-I gene expression and dexamethasone pretreatment prevented this decrease. Serum concentrations of IGF-I were decreased by LPS, and dexamethasone pretreatment attenuated this effect. The gene expression of IGFBP-3 in the liver and kidney and its circulating levels were decreased by LPS. In control rats dexamethasone increased circulating IGFBP-3 and its gene expression in the liver, and decreased the proteolysis of this protein. Dexamethasone pretreatment attenuated the LPS-induced decrease in IGFBP-3 gene expression in the liver and prevented the LPS-induced decrease in IGFBP-3 gene expression in the kidney. Moreover, dexamethasone pretreatment attenuated the LPS-induced decrease in serum concentrations of IGFBP-3 and decreased the LPS-induced IGFBP-3 proteolysis in serum. In conclusion, dexamethasone pretreatment partially attenuates the inhibitory effect of LPS on serum IGF-I by blocking the decrease of its gene expression in the kidney as well as by attenuating the decrease in serum concentrations of IGFBP-3.
Chromosomal mapping and quantitative analysis of estrogen-related receptor alpha-1, estrogen receptors alpha and beta and progesterone receptor in the bovine mammary gland
Authors: Connor E E , Wood D L , Sonstegard T S , da Mota A F , Bennett G L , Williams J L , Capuco A V
Published: June 2005

Steroid receptors are key transcriptional regulators of mammary growth, development and lactation. Expression of estrogen receptors alpha (ERα) and beta (ERβ), progesterone receptor (PR), and estrogen-related receptor alpha-1 (ERRβ) have been evaluated in bovine mammary gland. The ERRα is an orphan receptor that, in other species and tissues, appears to function in the regulation of estrogen-response genes including lactoferrin and medium chain acyl-CoA dehydrogenase and in mitochondrial biogenesis. Expression of ERα, ERβ, PR and ERRα was characterized in mammary tissue obtained from multiple stages of bovine mammary gland development using quantitative real-time RT-PCR. Expression was evaluated in prepubertal heifers, primigravid cows, lactating non-pregnant cows, lactating pregnant cows and non-lactating pregnant cows (n=4 to 9 animals/stage). In addition, ERα, ERβ, PR and ERRα were mapped to chromosomes 9, 10, 15 and 29 respectively, by linkage and radiation hybrid mapping. Results indicated that expression of ERα, PR and ERRα was largely coordinately regulated and they were present in significant quantity during all physiological stages evaluated. In contrast, ERβ transcripts were present at a very low concentration during all stages. Furthermore, no ERβ protein could be detected in bovine mammary tissue by immunohistochemistry. The ERα and PR proteins were detected during all physiological states, including lactation. Our results demonstrate the presence of ERα, PR and ERRα during all physiological stages, and suggest a functional role for ERRα and a relative lack of a role for ERβ in bovine mammary gland development and lactation.