bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategies to recruit and retain the nursing workforce in England
Authors: Gould Dinah , Fontenla Marina
Published: February 2006

Nurses have become a scarce resource nationally and globally. In the United Kingdom senior nurses are beginning to assume responsibility for strategies to improve recruitment and retention, but there appears to be a lack of research to explore their role. Telephone interviews took place with 29 senior nurses throughout the summer of 2004. The response rate was high (80.5%), representing Trusts from all major regions in England. The data were analysed by content. All respondents had been appointed during the last five years and were experienced clinical nurses who had usually been employed in the same Trust before appointment. They were selected on the basis of their local knowledge and interpersonal skills. None had received formal preparation for the role, but all reported developing invaluable new skills ‘on the job’ since appointment. Respondents worked with human resource departments but instead of overlapping with traditional human resource functions, they offered a different perspective. This was possible because of their special knowledge of professional nursing issues. They had experience of international recruitment, but reported that organised campaigns were increasingly being replaced by initiatives to attract and retain staff locally, especially newly qualified nurses. This work was undertaken in conjunction with university staff. Respondents did not implement flexible working hours and family-friendly policies for existing staff, but worked with colleagues who assumed this responsibility. All handled speculative enquiries from potential recruits and in most Trusts vacancies were reported to be now mainly for experienced nurses, especially for very specialist clinical services. Postholders considered they were making an impact on staffing levels and enjoyed high levels of job satisfaction. Further research is needed to explore whether Trusts that employ dedicated nurses to address staffing issues are able to recruit and retain more effectively than those that do not. Research should be extended to include mental health and community Trusts in the United Kingdom as well as acute Trusts. Assuming that respondents' accounts are ‘trustworthy’, this study demonstrates senior nurses' ability to undertake advanced human resource management practice which is known to contribute to the success of organisations.
Sorption of iodine on Mg-Al-layered double hydroxide
Authors: Curtius H. , Kattilparampil Z.
Published: February 2006

From leaching experiments with metallic uranium-aluminium material test reactor fuel elements in repository-relevant MgCl2-rich salt brines, a Mg-Al-layered double hydroxide with chloride as interlayer anion was identified as a crystalline secondary phase component. In the present study, this Mg-Al-Cl-layered double hydroxide (Mg-Al-Cl-LDH) was synthesized and its ability to adsorb iodine was evaluated. The adsorption of I– was rapid, and equilibrium for an initial concentration of 4.25 x 10-5 mole/l was obtained within 48 h. Further results indicated that the adsorption isotherm for I– retention could be fitted to Freundlich and Dubinin-Radushkevich equations. The values obtained indicate that iodine is adsorbed on Mg-Al-Cl-LDH by an anion- exchange process. The adsorption of I– was also studied as a function of pH. In the pH range between 3.5 and 8.5, the adsorption was independent of the pH. The effects of competiting anions were investigated using an MgCl2-solution instead of water, and indicate that chloride anions have a greater affinity towards the Mg-Al-Cl-layered double hydroxide than iodine.
Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML)
Authors: Thiede Christian , Koch Sina , Creutzig Eva , Steudel Christine , Illmer Thomas , Schaich Markus , Ehninger Gerhard ,   for the Deutsche Studieninitiative Leukämie (DSIL)
Published: February 2006

Mutations of the nucleophosmin (NPM1) gene have recently been described in patients with acute myeloid leukemia (AML). To clarify the prevalence as well as the clinical impact of this mutation, we investigated 1485 patients with AML for NPM1 exon 12 mutations using fragment analysis. A 4 bp insert was detected in 408 of 1485 patients (27.5%). Sequence analysis revealed known mutations (type A, B, and D) as well as 13 novel alterations in 229 analyzed cases. NPM1 mutations were most prevalent in patients with normal karyotype (NK) (324 of 709; 45.7%) compared with 58 of 686 with karyotype abnormalities (8.5%; P < .001) and were significantly associated with several clinical parameters (high bone marrow [BM] blasts, high white blood cell [WBC] and platelet counts, female sex). NPM1 alterations were associated with FLT3-ITD mutations, even if restricted to patients with NK (NPM1-mut/FLT3-ITD: 43.8%; versus NPM1-wt/FLT3-ITD: 19.9%; P < .001). The analysis of the clinical impact in 4 groups (NPM1 and FLT3-ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation had a significantly better overall and disease-free survival and a lower cumulative incidence of relapse. In conclusion, NPM1 mutations represent a common genetic abnormality in adult AML. If not associated with FLT3-ITD mutations, mutant NPM1 appears to identify patients with improved response toward treatment.
Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter
Authors: Helmus Yvonne , Denecke Jonas , Yakubenia Sviatlana , Robinson Peter , Lühn Kerstin , Watson Diana L. , McGrogan Paraic J. , Vestweber Dietmar , Marquardt Thorsten , Wild Martin K.
Published: February 2006

Leukocyte adhesion deficiency II (LAD II) is a rare congenital disease caused by defective fucosylation leading to immuno-deficiency and psychomotor retardation. We have previously identified the genetic defect of LAD II in a patient whose Golgi GDP-fucose transporter (GFTP) bears a single amino acid exchange that renders this protein nonfunctional but correctly localized to the Golgi. We now report a novel dual defect by which a truncated GFTP causes the disease in a new LAD II patient. We show that the truncation renders this GFTP unable to localize to the Golgi, the compartment where it is required. Furthermore, the missing part of the GFTP can be dissected into 2 regions, one that is needed for Golgi localization and one that is additionally required for the function of the GFTP. We investigated the subcellular localization of all known defective GFTPs allowing us to divide all genetically analyzed LAD II patients into 2 groups, one in which single amino acid exchanges in the GFTP impair its function but not its subcellular localization, and another group with a dual defect in function and Golgi expression of the GFTP due to the absence of 2 important molecular regions.
Glycoprotein VI–dependent and –independent pathways of thrombus formation in vivo
Authors: Dubois Christophe , Panicot-Dubois Laurence , Merrill-Skoloff Glenn , Furie Bruce , Furie Barbara C.
Published: February 2006

The role of the collagen receptor glycoprotein VI (GPVI) in arteriolar thrombus formation was studied in FcRγ-null mice (FcRγ–/–) lacking platelet surface GPVI. Thrombi were induced with severe or mild FeCl3 injury. Collagen exposure was significantly delayed and diminished in mild compared with severe FeCl3 injury. Times to initial thrombus formation and vessel occlusion were delayed in FcRγ–/– compared with wild-type mice after severe injury. Platelet accumulation in wild-type mice was decreased after mild compared with severe injury. However, there was little difference between platelet accumulation after severe or mild injury in FcRγ–/–. These data indicate a significant role for GPVI in FeCl3-induced thrombus formation. Pretreatment of wild-type mice with lepirudin further impaired mild FeCl3-induced thrombus formation, demonstrating a role for thrombin. Laser-induced thrombus formation in wild-type and FcRγ–/– was comparable. Collagen exposure to circulating blood was undetectable after laser injury. Normalized for thrombus size, thrombus-associated tissue factor was 5-fold higher in laser-induced thrombi than in severe FeCl3-induced thrombi. Thus, platelet activation by thrombin appears to be more important after laser injury than platelet activation by GPVI-collagen. It may thus be important when considering targets for antithrombotic therapy to use multiple animal models with diverse pathways to thrombus formation.
STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBPα
Authors: Wierenga Albertus T. J. , Schepers Hein , Moore Malcolm A. S. , Vellenga Edo , Schuringa Jan Jacob
Published: February 2006

Previously, we demonstrated that enforced activation of signal transducer and activator of transcription 5 (STAT5A) in human cord blood (CB)–derived stem/progenitor cells results in enhanced self-renewal and impaired myelopoiesis. The present study identifies C/EBPα as a critical component that is down-regulated by STAT5. Microarray and reverse transcriptase–polymerase chain reaction (RT-PCR) analysis on STAT5A1*6-transduced CD34+ cells identified C/EBPα as the most prominently down-regulated gene. To determine the cell-biological relevance of these observations, a 4-OHT-inducible C/EBPα-ER protein was co-expressed with the STAT5A1*6 mutant in CB CD34+ cells using a retroviral approach. Re-expression of C/EBPα in STAT5A1*6 cells resulted in a marked restoration of myelopoiesis. The proliferative advantage imposed on CD34+ cells by STAT5A1*6 depended on the down-modulation of C/EBPα, as reintroduction of C/EBPα induced a quick cell-cycle arrest and the onset of myeloid differentiation. Long-term culture–initiating cell (LTC-IC) frequencies were elevated from 0.8% ± 0.6% to 7.8% ± 1.9% by STAT5A1*6 as compared with controls, but these elevated LTC-IC frequencies were strongly reduced upon re-introduction of C/EBPα in STAT5A1*6 cells, and no second cobble-stone area–forming cells (CAFCs) could be generated from double-transduced cells. Enumeration of progenitors revealed that the number of colony-forming cells (CFCs) was reduced more than 20-fold when C/EBPα was co-expressed in STAT5A1*6 cells. Our data indicate that down-modulation of C/EBPα is a prerequisite for STAT5-induced effects on self-renewal and myelopoiesis.
hnRNP L regulates differences in expression of mouse integrin α2β1
Authors: Cheli Yann , Kunicki Thomas J.
Published: February 2006

There is a 2-fold variation in platelet integrin α2β1 levels among inbred mouse strains. Decreased α2β1 in 4 strains carrying Itga2 haplotype 2 results from decreased affinity of heterogeneous ribonucleoprotein L (hnRNP L) for a 6 CA repeat sequence (CA6) within intron 1. Seven strains bearing haplotype 1 and a 21 CA repeat sequence at this position (CA21) express twice the level of platelet α2β1 and exhibit an equivalent gain of platelet function in vitro. By UV crosslinking and immunoprecipitation, hnRNP L binds more avidly to CA21, relative to CA6. By cell-free, in vitro mRNA splicing, decreased binding of hnRNP L results in decreased splicing efficiency and an increased proportion of alternatively spliced product. The splicing enhancer activity of CA21 in vivo is abolished by prior treatment with hnRNP L–specific siRNA. Thus, decreased surface α2β1 results from decreased Itga2 pre-mRNA splicing regulated by hnRNP L and depends on CA repeat length at a specific site in intron 1.
Airway inflammation in iron ore miners exposed to dust and diesel exhaust
Authors: Ädelroth E. , Hedlund U. , Blomberg A. , Helleday R. , Ledin M-C. , Levin J. O. , Pourazar J. , Sandström T. , Järvholm B.
Published: February 2006

The aim of the present study was to investigate if underground miners exposed to dust and diesel exhaust in an iron ore mine would show signs of airway inflammation as reflected in induced sputum.

In total, 22 miners were studied, once after a holiday of at least 2 weeks and the second time after 3 months of regular work. Control subjects were 21 “white-collar” workers. All subjects completed a questionnaire regarding medical and occupational history, and underwent lung function testing and induced sputum collection. Total and differential cell counts and analyses of the fluid phase of the induced sputum were performed. Sampling of personal exposure to elemental carbon, nitrogen dioxide and inhalable dust was recorded.

The average concentrations of inhalable dust, nitrogen dioxide and elemental carbon were 3.2 mg·m−3, 0.28 mg·m−3and 27 µg·m−3, respectively. Miners had increased numbers of inflammatory cells, mainly alveolar macrophages and neutrophils, and increased concentrations of fibronectin, metalloproteinase-9 and interleukin-10 in induced sputum compared with controls.

In conclusion, miners in an underground iron ore mine demonstrated persistent airway inflammation that was as pronounced after a 4-week holiday as after a 3-month period of work underground in the mine.
C-reactive protein levels and clinically important predictive outcomes in stable COPD patients
Authors: de Torres J. P. , Cordoba-Lanus E. , López-Aguilar C. , Muros de Fuentes M. , Montejo de Garcini A. , Aguirre-Jaime A. , Celli B. R. , Casanova C.
Published: February 2006

The aim of this study was to determine the relationship between C-reactive protein (CRP) levels and factors known to predict outcome in stable chronic obstructive pulmonary disease (COPD) patients.

The following were studied in 130 stable COPD patients: spirometry, lung volume, arterial oxygen tension (Pa,O2), dyspnoea, 6-min walk distance (6MWD), body mass index, fat-free mass index, BODE (body mass index, obstruction, dyspnoea and exercise capacity), health-related quality of life, smoking status, the presence of cardiovascular risk factors or disease, corticosteroid use and number of exacerbations in the previous year. CRP levels were measured in these patients and in 65 controls. Using univariate and multivariate analyses, any possible association with the predictors of outcomes was evaluated.

CRP levels were higher in COPD patients than in controls (4.1versus1.8 mg·L−1, respectively). Correlation was found with the following variables: forced expiratory volume in one second (FEV1; −0.23), FEV1% (−0.20), forced vital capacity (FVC; −0.24), FVC % (−0.24), Global Initiative for Chronic Obstructive Lung Disease stage (0.17), BODE (0.17), inspiratory capacity/total lung capacity (−0.20),Pa,O2(−0.40) and 6MWD (−0.30). Using multivariate analysis,Pa,O2and 6MWD manifested the strongest negative association with CRP levels.

C-reactive protein levels in stable chronic obstructive pulmonary disease patients are best correlated with arterial oxygen tension and 6-min walk distance. This should be considered when C-reactive protein levels are measured in stable chronic obstructive pulmonary disease patients.
Angiotensin-converting enzyme inhibitor use and pneumonia risk in a general population
Authors: van de Garde E. M. W. , Souverein P. C. , van den Bosch J. M. M. , Deneer V. H. M. , Leufkens H. G. M.
Published: February 2006

The aim of the present study was to assess whether the use of angiotensin-converting enzyme (ACE) inhibitors is associated with a decreased risk of hospitalisation for community-acquired pneumonia (CAP) in a general, essentially white population.

Data were obtained from the Dutch PHARMO Record Linkage System. Cases were defined as patients with a first hospital admission for CAP. For each case, up to four population controls were matched by age and sex.

The study population comprised 1,108 patients with a first hospital admission for CAP and 3,817 matched controls. After adjusting for several confounders, ACE inhibitor use was not associated with a decreased incidence of pneumonia (adjusted odds ratio (OR) 1.12; 95% confidence interval (CI) 0.88–1.43). Additionally, no significant association was observed in patients with diabetes, respiratory diseases, heart failure, or patients with both of the last two conditions. Furthermore, adjustment of treatment effects on pneumonia risk using stratification on balancing score also showed no significant association between ACE inhibitor use and pneumonia risk within the different strata (overall adjusted OR 1.09; 95% CI 0.87–1.36).

In contrast with previous findings in Asian populations, the current authors were not able to confirm the beneficial effect of angiotensin-converting enzyme inhibitors on pneumonia risk in a general, essentially white population.
Effects of macrolides on pneumolysin of macrolide-resistantStreptococcus pneumoniae
Authors: Fukuda Y. , Yanagihara K. , Higashiyama Y. , Miyazaki Y. , Hirakata Y. , Mukae H. , Tomono K. , Mizuta Y. , Tsukamoto K. , Kohno S.
Published: February 2006

To clarify the discrepancy between increasing resistance and conservative clinical effects of macrolides on macrolide-resistantStreptococcus pneumoniae, the authors evaluated the effects of sub-minimum inhibitory concentrations of macrolides on pneumolysin.

In vitro,S. pneumoniaewas incubated with 1, 2 and 4 µg·mL−1of clarithromycin (CLR) and azithromycin (AZM) for 8 h. Western blot analysis and haemolytic assay were performed to examine the production and activities of pneumolysin.In vivo, mice were infected withS. pneumoniaeintra-nasally and treated with CLR (40 or 200 mg·kg−1twice daily) or AZM (40 or 200 mg·kg−1once daily) orally for 7 days. After 72 h post-infection, western blot analysis was performed to examine pneumolysin production in lungs. Survival rates were observed for 10 days.

In vitro, every concentration of macrolide inhibited pneumolysin production more than the control. CLR (2 and 4 µg·mL−1) and AZM (4 µg·mL−1) reduced the pneumolysin activities more than the control.In vivo, macrolides (200 mg·kg−1) reduced pneumolysin in murine lungs more than the control. CLR (40 and 200 mg·kg−1) and AZM (200 mg·kg−1) improved the survival rates more than the control.

The study results show that sub-minimum inhibitory concentrations of macrolides reduced pneumolysin. This might be related to the effectiveness of macrolides against pneumonia caused by high-level macrolide-resistantStreptococcus pneumoniae. Further investigations are necessary to evaluate the effects of macrolides on macrolide-resistantStreptococcus pneumoniae.
Sniff nasal inspiratory pressure: what is the optimal number of sniffs?
Authors: Lofaso F. , Nicot F. , Lejaille M. , Falaize L. , Louis A. , Clement A. , Raphael J-C. , Orlikowski D. , Fauroux B.
Published: February 2006

Sniff nasal inspiratory pressure (SNIP) measurement is a volitional noninvasive assessment of inspiratory muscle strength. A maximum of 10 sniffs is generally used. The purpose of the present study was to investigate whether the maximum SNIP improved after the tenth sniff.

In total, 20 healthy volunteers and 305 patients with various neuromuscular and lung diseases were encouraged to perform 40 and 20 sniffs, respectively.

The best SNIP among the first 10 sniffs was lower than the best SNIP among the next 10 sniffs in the healthy volunteers and patients. The SNIP improvement after the twentieth sniff was marginal.

In conclusion, a learning effect persists after the tenth sniff. The current authors suggest using 10 additional sniffs when the best result of the first 10 sniffs is slightly below normal, or when sniff nasal inspiratory pressure is used to monitor a progressive decline in inspiratory muscle strength.
Combined transbronchial needle aspiration and positron emission tomography for mediastinal staging of NSCLC
Authors: Bernasconi M. , Chhajed P. N. , Gambazzi F. , Bubendorf L. , Rasch H. , Kneifel S. , Tamm M.
Published: February 2006

There are no data available combining transbronchial needle aspiration (TBNA) of mediastinal lymph nodes and positron emission tomography (PET) in the staging of nonsmall cell lung cancer (NSCLC).

The aim of the current study was to determine if these two methods can enhance the negative predictive value of the individual modality alone, for a specific lymph node station, and if this integrated approach can reduce the number of mediastinoscopies.

A total of 113 patients with enlarged mediastinal lymph nodes (≥1 cm), who underwent both TBNA and PET scanning, were included. In 51 patients, histopathology, confirmed by surgical lymph node dissection, was compared with PET results and TBNA.

Sensitivity, specificity, positive predictive value, negative predictive value and accuracy to detect malignant lymphadenopathy was 68 (13/19), 89 (119/134), 46 (13/28), 95 (119/125) and 86% (132/152) for PET, respectively; 54% (6/11), 100 (53/53), 100 (6/6), 91 (53/58) and 92% (59/64), respectively for TBNA; and 100 (11/11), 94 (50/53), 79 (11/14), 100 (50/50) and 95 (61/64) for combined TBNA and PET, respectively.

Combination of transbronchial needle aspiration and positron emission tomography has the potential to allow adequate mediastinal staging of nonsmall cell lung cancer with enlarged lymph nodes in most patients without the need for mediastinoscopy.
Impact of initial antibiotic choice on mortality from pneumococcal pneumonia
Authors: Aspa J. , Rajas O. , Rodriguez de Castro F. , Huertas M. C. , Borderías L. , Cabello F. J. , Tábara J. , Hernández-Flix S. , Martinez-Sanchis A. , Torres A.
Published: February 2006

To determine the impact of initial antimicrobial choice on 30-day mortality rate in patients with community-acquired pneumonia due toStreptococcus pneumoniae(CAP-SP), a prospective, observational study was conducted in 35 Spanish hospitals. A total of 638 patients with CAP-SP were identified. Antimicrobials were chosen by the attending physician. Patients were grouped into the following categories: β-lactam monotherapy (n = 251), macrolide monotherapy (n = 37), β-lactam plus macrolide (n = 198), levofloxacin alone/combination (n = 48), and other combinations (n = 104). The reference category was β-lactam+macrolide.

The 30-day survival probability was 84.9%. Using multivariate survival analysis, factors related to mortality in the entire population were: bilateral disease, suspected aspiration, shock, HIV infection, renal failure and pneumonia severity index (PSI) score Class IVversusI–III and categories VversusI–III. The association of β-lactams+macrolides was not better than the use of β-lactams alone. The current authors analysed the different groups of patients with significant mortality/morbidity: intensive care unit, PSI Class >III, renal failure, chronic lung disease and bacteraemia. Only in patients with PSI Class >III, who had undergone initial antimicrobial choice classified as other combinations, were associated with higher mortality.

In conclusion, the current authors have not demonstrated an independent association between initial antimicrobial regimen and 30-day mortality in community-acquired pneumococcal pneumonia patients, except for those with a higher pneumonia severity index score.
Should forced expiratory volume in six seconds replace forced vital capacity to detect airway obstruction?
Authors: Hansen J. E. , Sun X-G. , Wasserman K.
Published: February 2006

It has been suggested that forced expiratory volume in six seconds (FEV6) should be substituted for forced vital capacity (FVC) to measure fractions of timed expired volume for airflow obstruction detection. The present authors hypothesised that this recommendation might be questionable because flow after 6 s of forced expiration from more diseased lung units with the longest time constants was most meaningful and should not be ignored. Furthermore, previous studies comparing FEV6and FVC included few subjects with mild or no disease.

The present study used spirometric data from the USA Third National Health and Nutrition Evaluation Survey with prior published ethnicity- and sex-specific equations for FEV1/FEV6, FEV1/FVC and FEV3/FVC, and new equations for FEV3/FEV6, all derived from ∼4,000 adult never-smokers aged 20–80 yrs.

At 95% confidence intervals, 21.3% of 3,515 smokers and 41.3% of smokers aged >51 yrs had airway obstruction; when comparing FEV1/FEV6with FEV1/FVC, 13.5% were concurrently abnormal, 1.5% were false positives and 4.1% were false negatives; and when comparing FEV3/FEV6with FEV3/FVC, 11.6% were concurrently abnormal, 3.3% were false positives and 5.7% were false negatives.

Substituting forced expiratory volume in six seconds for forced vital capacity to determine the fractional rates of exhaled volumes reduces the sensitivity of spirometry to detect airflow obstruction, especially in older individuals and those with lesser obstruction.
A controlled trial of a school-based intervention to improve asthma management
Authors: McCann D. C. , McWhirter J. , Coleman H. , Calvert M. , Warner J. O.
Published: February 2006

The present study investigated schools as an appropriate context for an intervention designed to produce clinical and psychological benefits for children with asthma.

A total of 193 out of 219 (88.1%) children with asthma (aged 7–9 yrs) from 23 out of 24 (95.8%) schools completed the study. Intervention schools received a staff asthma-training session, advice on asthma policy, an emergency β2-agonist inhaler with spacer and whole-class asthma workshops. Nonintervention schools received no asthma-related input.

Intervention children required less general practitioner-prescribed preventer medication despite no differences in symptom control compared with the nonintervention asthmatic group. Increased peer knowledge of asthma may have mediated improved active quality of life in the intervention group, together with increased self-esteem in young females. Those females not receiving the intervention, but identified as being asthmatic within the classroom, and thus possibly stigmatised, reported decreased self-esteem. Lower self-esteem in young males was associated with pet ownership. No change was found in staff knowledge, the establishment of asthma policies or school absences which were low even before intervention.

In conclusion, a whole-school intervention can improve the health of children with asthma when followed with support for all children but effects are likely to be modified by sex and the home environment.
24‐Hour Pretreatment with δ Opioid Enhances Survival from Hemorrhagic Shock
Authors: Oeltgen Peter R. , Govindaswami Meera , Witzke Donald B.
Published: February 2006

Objectives:
δ opioids have been shown to confer ischemic preconditioning and pharmacologic ischemic preconditioning to the myocardium. However, their role in providing extended pharmacologic ischemic preconditioning in hemorrhagic shock has not been explored. The authors examined the effects of 24‐hour preinfusions of a selective δ opioid receptor agonist, Deltorphin‐Dvariant (Delt‐Dvar), on hemodynamic stability and duration of survival in a rat model of severe hemorrhagic shock.

Methods:
Conscious Sprague–Dawley rats with indwelling catheters were hemorrhaged at a rate of 3.18 mL/l00 g over 20 minutes. Twenty‐four hours before hemorrhage, the control group (n= 14) was infused with 1.0 mL lactated Ringer's solution, and the Delt‐Dvar–treated group (n= 22) was infused with 5.0 mg/kg Delt‐Dvar in 1.0 mL lactated Ringer's solution. Rats were continuously monitored for heart rate (HR), mean arterial pressure, and four‐hour survival rates. Plasma lactate levels were determined at the beginning of hemorrhage and the end of hemorrhage.

Results:
At 240 minutes, only one of 14 controls (7.1%) survived, while 16 (72.7%) of the 22 experimental rats survived. No significant differences in heart rate between controls and Delt‐Dvar–treated rats were noted. Increases in mean arterial pressure of Delt‐Dvar–treated rats at the beginning of hemorrhage and at the end of hemorrhage were found to be significant (p < 0.05). At 240 minutes, heart rate and mean arterial pressure were not different between the single surviving control and the Delt‐Dvar group. At the end of hemorrhage, lactate levels in the Delt‐Dvar–treated group were 8.5 (± 0.5) mmol/L versus 10.8 (± 0.6) mmol/L (p < 0.05) in the control group.

Conclusions:
Twenty‐four–hour pretreatment with Delt‐Dvar decreases plasma lactate levels and improves hemodynamic stability and survival during hemorrhagic shock. The use of δ‐specific opioids may improve survival from hemorrhagic shock and have clinical utility in providing ischemic protection in scenarios of planned ischemia.
Regulation of Hepatic Insulin-Like Growth Factor-Binding Protein-1 Gene Expression by Insulin: Central Role for Mammalian Target of Rapamycin Independent of Forkhead Box O Proteins
Authors: Mounier Catherine , Dumas Victor , Posner Barry I.
Published: February 2006

The expression of IGF-binding protein-1 (IGFBP-1) is induced in rat liver by dexamethasone and glucagon and is completely inhibited by 100 nm insulin. Various studies have implicated phosphatidylinositol 3-kinase, protein kinase B (Akt), phosphorylation of the transcription factors forkhead in rhabdomyosarcoma 1 (Foxo1)/Foxo3, and the mammalian target of rapamycin (mTOR) in insulin’s effect. In this study we examined insulin regulation of IGFBP-1 in both subconfluent and confluent hepatocytes. In subconfluent hepatocytes, insulin inhibition of IGFBP-1 mRNA levels was blocked by inhibiting PI3 kinase activation, and there was a corresponding inhibition of Foxo1/Foxo3 phosphorylation. In these same cells, inhibition of the insulin effect by rapamycin occurred in the presence of insulin-induced Foxo1/Foxo3 phosphorylation. In confluent hepatocytes, insulin could not activate the phosphatidylinositol 3-kinase (PI3 kinase)-Akt-Foxo1/Foxo3 pathway, but still inhibited IGFBP-1 gene expression in an mTOR-dependent manner. In subconfluent hepatocytes, the serine/threonine phosphatase inhibitor okadaic acid (100 nm) partially inhibited IGFBP-1 gene expression by 40%, but did not produce phosphorylation of either Akt or Foxo proteins. In contrast, 1 nm insulin inhibited the IGFBP-1 mRNA level by 40% and correspondingly activated Akt and Foxo1/Foxo3 phosphorylation to a level comparable to that observed with 100 nm insulin. These results suggest a potential role for a serine/threonine phosphatase(s) in the regulation of IGFBP-1 gene transcription, which is not downstream of mTOR and is independent of Akt. In conclusion, we have found that in rat liver, insulin inhibition of IGFBP-1 mRNA levels can occur in the absence of the phosphorylation of Foxo1/Foxo3, whereas activation of the mTOR pathway is both necessary and sufficient.
Runx2 Is a Target of Mechanical Unloading to Alter Osteoblastic Activity and Bone Formation in Vivo
Authors: Salingcarnboriboon Ruchanee , Tsuji Kunikazu , Komori Toshihisa , Nakashima Kazuhisa , Ezura Yoichi , Noda Masaki
Published: February 2006

Molecular mechanisms underlying unloading-induced reduction of bone formation have not yet been fully understood. In vitro, Runx2 has been suggested to be involved in mechanical signaling in osteoblasts. However, the roles of Runx2 in vivo during the bone response to mechanical stimuli have not yet been known. The purpose of this paper was to examine the roles of Runx2 in unloading-induced bone loss in vivo. Tail suspension was conducted for 2 wk using 9- to 11-wk-old Runx2 heterozygous knockout mice (Runx2+/−) and wild-type (Wt) littermates. Bones were subjected to two-dimensional micro-x-ray computed tomography, bone histomorphometry and RT-PCR analyses. Loss of half Runx2 gene dosage-exacerbated unloading-induced bone loss in trabecular and cortical envelopes. Unloading-induced reduction in mineral apposition rate and bone formation rate in cortical bone as well as trabecular bone was exacerbated in Runx2+/− mice, compared with Wt mice. Bone resorption parameters were not significantly affected by unloading or Runx2+/− genotype. Basal Runx2 and osterix mRNA levels in bone were reduced by 50% in Wt, whereas unloading in Runx2+/− mice did not further alter Runx2 and osterix mRNA levels. In contrast, osteocalcin mRNA levels were reduced by unloading, regardless of Runx2 gene dosage. These data demonstrated that full Runx2 gene dosage is required for maintaining normal function of osteoblasts in mechanical unloading or nonphysiological condition. Finally, we propose Runx2 as a critical target gene in unloading to alter osteoblastic activity and bone formation in vivo.
Ribonucleic Acid Polymerase II Binding Subunit 3 (Rpb3), a Potential Nuclear Target of Insulin-Like Growth Factor Binding Protein-3
Authors: Oufattole Mohammed , Lin Sally Wan-Jung , Liu Bingrong , Mascarenhas Desmond , Cohen Pinchas , Rodgers Buel D.
Published: February 2006

IGF-binding protein (IGFBP)-3 has intrinsic antiproliferative and proapoptotic functions that are independent of IGF binding and may involve nuclear localization. We determined that exogenous IGFBP-3 rapidly translocates to myoblast nuclei and that a 22-residue peptide containing the metal binding domain (MBD) and nuclear localization sequence (NLS) can similarly direct chimeric GFP into myoblast nuclei. Furthermore, a non-IGF-binding IGFBP-3 mutant inhibited myoblast proliferation without stimulating apoptosis. These results suggest that IGFBP-3 inhibits muscle cell growth in an IGF-independent manner that may be influenced by its rapid nuclear localization. We therefore identified IGFBP-3 interacting proteins by screening a rat L6 myoblast cDNA library using the yeast two-hybrid assay and two N-terminal deletion mutants as bait: BP3/231 (231 residues, L61 to K291) and BP3/111 (K181-K291). Proteins previously known to interact with IGFBP-3 as well as several novel proteins were identified, including RNA polymerase II binding subunit 3 (Rpb3). The domain necessary for Rpb3 binding was subsequently identified using different IGFBP-3 deletion mutants and was localized to the MBD/NLS epitope. Rpb3/IGFBP-3 binding was confirmed by coimmunoprecipitation assays with specific antisera, whereas a NLS mutant IGFBP-3 did not associate with Rpb3, suggesting that a functional NLS is required. Rpb3 facilitates recruitment of the polymerase complex to specific transcription factors and is necessary for the transactivation of many genes. Its association with IGFBP-3 provides a functional role for IGFBP-3 in the direct modulation of gene transcription.
Comparative Analysis of the Effects of Ghrelin and Unacylated Ghrelin on Luteinizing Hormone Secretion in Male Rats
Authors: Martini A. C. , Fernández-Fernández R. , Tovar S. , Navarro V. M. , Vigo E. , Vazquez M. J. , Davies J. S. , Thompson N. M. , Aguilar E. , Pinilla L. , Wells T. , Dieguez C. , Tena-Sempere M.
Published: February 2006

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.
Androgen Activation of the Sterol Regulatory Element-Binding Protein Pathway: Current Insights
Authors: Heemers Hannelore V. , Verhoeven Guido , Swinnen Johannes V.
Published: February 2006

The cellular effects of androgens are mediated by a cognate receptor, the androgen receptor. Typically, the androgen receptor is viewed to exert its activity by binding to androgen response elements located in or near the promoter region of target genes, thereby directly affecting the expression of these genes. However, increasing evidence indicates that androgens may also indirectly influence the expression of genes that do not contain androgen response elements by modulating the activity of secondary transcription factors, mediating the expression of growth factors acting in a paracrine or autocrine fashion, or by inducing changes in the production of other hormones. These indirect effects of androgens can induce cascade-like actions and may play an important role in more complex processes involving coordinated responses of genes, cells, and organs. Previously, our laboratory has identified and characterized a novel indirect mechanism of androgen action involving proteolytical activation of the key lipogenic transcription factor sterol regulatory element-binding protein (SREBP), resulting in the coordinate up-regulation of entire cellular lipogenic pathways. Interestingly, activation of SREBPs by androgens occurs not only under normal physiological conditions but has also been observed in a growing number of pathologies, and more in particular in the setting of steroid-regulated cancers, where increased lipogenesis has been shown to have remarkable diagnostic and prognostic potential and is considered a prime target for novel therapeutic approaches. This review aims to analyze current insights into the molecular mechanism(s) underlying androgen activation of the SREBP pathway and to ascertain the extent to which this phenomenon can be generalized to androgen-responsive cell systems.
Inactivation ofTbx1in the pharyngeal endoderm results in 22q11DS malformations
Authors: Arnold Jelena S. , Werling Uwe , Braunstein Evan M. , Liao Jun , Nowotschin Sonja , Edelmann Winfried , Hebert Jean M. , Morrow Bernice E.
Published: February 2006

The 22q11 deletion (22q11DS; velo-cardio-facial syndrome/DiGeorge syndrome)is characterized by defects in the derivatives of the pharyngeal apparatus. Mouse genetic studies have identified Tbx1, a member of the T-box family of transcription factors, as being responsible for the physical malformations of the syndrome. Mice heterozygous for a null mutation in Tbx1 have mild anomalies, whereas homozygous Tbx1 mutants die at birth with severe defects in the derivatives of the pharyngeal apparatus, including cleft palate, thymus gland aplasia and cardiac outflow tract malformations. Tbx1 is expressed in the splanchnic mesenchyme,the pharyngeal endoderm (PE) and in the core mesoderm of the pharyngeal apparatus. Tissue interactions between the epithelia and mesenchyme of the arches are required for development of the pharyngeal apparatus; the precise role of Tbx1 in each tissue is not known. To assess the role of Tbx1 in the PE, a conditional allele of Tbx1 was generated using the Cre/loxP system. Foxg1-Cre was used to drive PE-specific ablation of Tbx1. Conditional null mutants survived embryogenesis, but died in the neonatal period with malformations identical to the defects observed in Tbx1 homozygous null mutants. The abnormalities appear to be secondary to failed outgrowth of the pharyngeal pouches. These results show that Tbx1 in the PE is required for the patterning and development of the pharyngeal apparatus, thereby disrupting the formation of its derivative structures.
Decade-long use of continuous combined hormone replacement therapy is associated with better health-related quality of life in postmenopausal women, as measured by the generic 15D instrument
Authors: Ylikangas Stiina , Sintonen Harri , Heikkinen Jorma
Published: February 2006

Objective: To examine quality of life after a decade of continuous combined hormone replacement therapy.

Study design: The 15D, a generic health-related quality-of-life (HRQoL) instrument, was used to evaluate trends in HRQoL in women who used continuous combined hormone replacement therapy (ccHRT; Indivina®, Orion Pharma, Finland) for up to nine years. These women had a mean age of 56 years of age at the start of therapy. Control data on HRQoL were obtained from age-matched women participating in Finnish population health surveys.

Results: Relative to controls, ccHRT was associated with significantly better HRQoL after six and nine years of treatment. Dose minimization at 8.5 years was not associated with a decline in HRQoL in the ensuing six months. One year after discontinuation of ccHRT there was evidence of a decline in HRQoL in women who discontinued ccHRT as planned, whereas HRQoL was maintained in women who had continued or resumed ccHRT during the one-year post-study follow-up. The benefits of ccHRT were apparent in multiple dimensions of the 15D, being largest and most robustly reproduced in the dimension 'discomfort and symptoms'. It is conjectured that the effectiveness of ccHRT in relieving symptoms of menopause may have contributed to the improved HRQoL scores registered in other dimensions, in addition to any direct effects of ccHRT on specific aspects of those other dimensions.

Conclusions: These data indicate that up to 10 years of low-dose ccHRT has sustained value in the enhancement of HRQoL when used by women for whom relief of symptoms of menopause and control of bleeding are primary objectives of treatment.
Pharmacotherapy of female urinary incontinence
Authors: Naumann Gert , Koelbl Heinz
Published: February 2006

Urinary incontinence is a major clinical problem and a significant cause of disability and dependency in older adults. Overall, the prevalence of urinary incontinence approaches 55% among women aged over 55 years. The past few years have seen significant advances in the pharmacotherapy of overactive bladder and stress incontinence. The review examines the evidence regarding their benefits and side-effects.
Advances in the management of cervical cancer
Authors: Sundar Sudha S , Gornall Robert J , Kehoe Sean T
Published: February 2006

This review presents key advances in the management of cervical cancer. Traditionally, cervical cancer is staged clinically and has been treated either by radical hysterectomy or by radiotherapy. Improvements in imaging have led to more accurate therapeutic decision making and treatment planning. The evidence on fertility-preserving surgery for cervical cancer and chemoradiotherapy for locally advanced cancer is summarized here. An improved understanding of the viral aetiology of cervical cancer has led to the development of therapeutic vaccination, with limited success. There is increasing recognition of the psychosexual needs of women who have survived cervical cancer.
The menopause transition: endocrine changes and clinical symptoms
Authors: Buckler Helen
Published: February 2006

Several biological changes take place during the menopause transition. The number of oocytes declines progressively from before birth but reaches a critically low level by the time of the menopause. The regular pattern of the menstrual cycle becomes disrupted and the frequency of normal ovulatory cycles declines. Rising gonadotrophin levels, particularly of follicle stimulating hormones (FSH), and declining estrogen levels are thought to characterize the menopausal transition. It now appears that declining levels of inhibin may play an important role in maintaining estrogen levels until just before the menopause, while causing increased levels of gonadotrophins. Wide variations in hormonal profiles between and within individuals occur. The clinical responses to this endocrine instability include vasomotor symptoms, psychological symptoms, sexual dysfunction and irregular menstrual bleeding. Estradiol deficiency induces a rapid phase of increased bone turnover in the early postmenopausal period, which can contribute to osteoporosis later in life. Similarly, changes in lipid profiles, particularly high-density lipoprotein (HDL) and triglycerides, can also occur.
Domestic Violence Recent Research (2004–2005) Part III: Risk Assessment, Diagnosis and Treatment
Authors: Lowenstein L. F.
Published: February 2006

The causes of and reasons for spousal abuse are many. There is the need to abuse in order to control and hence to assert power by preventing the victim from seeking a greater say in the relationship. Abusers are often jealous and possessive, preventing their partners from having contacts outside their relationship. Abusers often belittle and isolate their partner and make them feel inept, worthless and dependent. Sometimes abusers have alcohol or substance abuse problems. The reaction of the victims is to become dependent, fearful and to develop low self-esteem. Numerous psychological problems also develop in victims.

The following important individualised goals must be achieved to protect victims. First, and most importantly, is to safeguard victims from abuse, providing treatment for the victim and children as well as for the abuser. This must be done individually rather than as a couple. Perpetrators must not only accept that what they do is wrong, and that there must be zero tolerance in relation to this, but they must also learn to develop the capacity to change both attitudes and behaviour. They need to learn to deal with their anger and to attend treatment on the basis of this. Legal action is also vital.
Multiplex Tetra-Primer Amplification Refractory Mutation System PCR to Detect 6 Common Germline Mutations of the MUTYH Gene Associated with Polyposis and Colorectal Cancer
Authors: Piccioli Patrizia , Serra Martina , Gismondi Viviana , Pedemonte Simona , Loiacono Fabrizio , Lastraioli Sonia , Bertario Lucio , De Angioletti Maria , Varesco Liliana , Notaro Rosario
Published: February 2006

Background: We describe a simple tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) for detecting MUTYH mutations, which are associated with colorectal adenomas and colorectal cancer.

Methods: We designed specific T-ARMS-PCR assays for 6 mutations (Y165C, G382D, 1395_7delGGA, Y90X, 1103delC, and R231H) selected on the basis of the frequency of their occurrence. We also designed a set of 3 multiplex T-ARMS PCR assays, each for detection of 2 mutations. We tested DNA samples from patients with attenuated or classic adenomatous polyposis coli and no detectable APC germline mutations.

Results: All mutations were easily detected with both the specific and multiplex T-ARMS-PCR assays. Results were confirmed by DNA HPLC analysis in all 54 patients, and each mutation was confirmed by direct DNA sequencing.

Conclusions: T-ARMS-PCR does not require any special equipment, and it provides rapid, reproducible, and cost-effective detection of common MUTYH mutations. Multiplex T-ARMS-PCR allows the detection of 6 common MUTYH mutations with use of as few as 3 single tube PCR reactions. It could be useful to carry out large population-based epidemiologic studies.