bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of sirolimus vs. calcineurin inhibitor‐based immunosuppressive therapies in liver transplantation
Authors: ZAGHLA H. , SELBY R. R. , CHAN L. S. , KAHN J. A. , DONOVAN J. A. , JABBOUR N. , GENYK Y. , MATEO R. , GAGANDEEP S. , SHER L. S. , RAMICONE E. , FONG T.‐L.
Published: January 2006

Background  Sirolimus is a potent immunosuppressive agent whose role in liver transplantation has not been well‐described.

Aim  To evaluate the efficacy and side‐effects of sirolimus‐based immunosuppression in liver transplant patients.

Methods  Retrospective analysis of 185 patients who underwent orthotopic liver transplantation. Patients were divided into three groups: group SA, sirolimus alone (n = 28); group SC, sirolimus with calcineurin inhibitors (n =56) and group CNI, calcineurin inhibitors without sirolimus (n = 101).

Results  One‐year patient and graft survival rates were 86.5% and 82.1% in group SA, 94.6% and 92.9% in group SC, and 83.2% and 75.2% in group CNI (P = N.S.). The rates of acute cellular rejection at 12 months were comparable among the three groups. At the time of transplantation, serum creatinine levels were significantly higher in group SA, but mean creatinine among the three groups at 1 month was similar. More patients in group SA required dialysis before orthotopic liver transplantation (group SA, 25%; group SC, 9%; group CNI, 5%; P = 0.008), but at 1 year, post‐orthotopic liver transplantation dialysis rates were similar.

Conclusions  Sirolimus given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies to evaluate the efficacy and side‐effect profile of sirolimus in liver transplant patients are warranted.
Pharmacokinetics and pharmacodynamic action of budesonide in children with Crohn's disease
Authors: DILGER K. , ALBERER M. , BUSCH A. , ENNINGER A. , BEHRENS R. , KOLETZKO S. , STERN M. , BECKMANN C. , GLEITER C. H.
Published: January 2006

Background

Budesonide is effective as initial therapy of mild to moderate Crohn's disease in adults. Superior tolerability to conventional corticosteroids might be attributed to extensive first‐pass metabolism of budesonide by cytochrome P450 3A.

Aim

To evaluate biotransformation and pharmacodynamic action of budesonide in children.

Methods

Drug disposition and effects on endogenous cortisol were evaluated in 12 children with Crohn's disease (5–15 years) after first intake of 3 mg budesonide (single dose), and again after 1 week of thrice daily dosing (steady‐state). The parent drug and cytochrome P450 3A‐dependent metabolites were analysed in blood and urine.

Results

Pharmacokinetic parameters of budesonide following single‐dose administration (e.g. AUC0−∞ 7.7 ± 5.1 h ng/mL, Cmax 1.8 ± 1.2 ng/mL) did not change upon multiple dosing. Overall systemic elimination of budesonide reflected by clearance and half‐life was not different between children and adults. After 1 week of treatment reversible adrenal suppression was observed – most pronounced in children aged below 12 years.

Conclusions

Disposition of oral budesonide appears to be similar between children and adults, but the doctor has to be aware of an increased risk for adrenal suppression in paediatric patients.
Validation of a 7‐point Global Overall Symptom scale to measure the severity of dyspepsia symptoms in clinical trials
Authors: VAN ZANTEN S. J. O. VELDHUYZEN , CHIBA N. , ARMSTRONG D. , BARKUN A. N. , THOMSON A. B. R. , MANN V. , ESCOBEDO S. , CHAKRABORTY B. , NEVIN K.
Published: January 2006

Background  Currently there is no consensus on the optimal method to measure the severity of dyspepsia symptoms in clinical trials.

Aim  To validate the 7‐point Global Overall Symptom scale.

Methods  The Global Overall Symptom scale uses a 7‐point Likert scale ranging from 1 = no problem to 7 = a very severe problem. Validation was performed in two randomized‐controlled trials (n = 1121 and 512). Construct validity: Global Overall Symptom was compared with the Quality of Life in Reflux And Dyspepsia, Gastrointestinal Symptom Rating Scale, Reflux Disease Questionnaire and 10 specific symptoms using Spearman correlation coefficients. Test–retest reliability: The Intraclass Correlation Coefficient was calculated for patients with stable dyspepsia defined by no change in Overall Treatment Effect score over two visits. Responsiveness: effect size and standardized response mean were also calculated.

Results  Construct validity: Change in Global Overall Symptom score correlated significantly with Quality of Life for Reflux And Dyspepsia, Gastrointestinal Symptom Rating Scale, Reflux Disease Questionnaire and specific symptoms (all P < 0.0002). Reliability: The Intraclass Correlation Coefficient was 0.62 (n = 205) and 0.42 (n = 270). Responsiveness: There was a positive correlation between change in Global Overall Symptom and change in symptom severity. The effect size and standardized response mean were 1.1 and 2.1, respectively.

Conclusion  The Global Overall Symptom scale is a simple, valid outcome measure for dyspepsia treatment trials.
Systematic review: complementary and alternative medicine in the irritable bowel syndrome
Authors: HUSSAIN Z. , QUIGLEY E. M. M.
Published: January 2006

Background  Complementary and alternative medical therapies and practices are widely employed in the treatment of the irritable bowel syndrome.

Aim  To review the usage of complementary and alternative medicine in the irritable bowel syndrome, and to assess critically the basis and evidence for its use.

Methods  A systematic review of complementary and alternative medical therapies and practices in the irritable bowel syndrome was performed based on literature obtained through a Medline search.

Results  A wide variety of complementary and alternative medical practices and therapies are commonly employed by irritable bowel syndrome patients both in conjunction with and in lieu of conventional therapies. As many of these therapies have not been subjected to controlled clinical trials, some, at least, of their efficacy may reflect the high‐placebo response rate that is characteristic of irritable bowel syndrome.

Of those that have been subjected to clinical trials most have involved small poor quality studies. There is, however, evidence to support efficacy for hypnotherapy, some forms of herbal therapy and certain probiotics in irritable bowel syndrome.

Conclusions Doctors caring for irritable bowel syndrome patients need to recognize the near ubiquity of complementary and alternative medical use among this population and the basis for its use. All complementary and alternative medicine is not the same and some, such as hypnotherapy, forms of herbal therapy, specific diets and probiotics, may well have efficacy in irritable bowel syndrome. Above all, we need more science and more controlled studies; the absence of truly randomized placebo‐controlled trials for many of these therapies has limited meaningful progress in this area.
A prospective randomized blinded comparison of sodium phosphate and polyethylene glycol‐electrolyte solution for safe bowel cleansing
Authors: MATHUS‐VLIEGEN E. M. H. , KEMBLE U. M.
Published: January 2006

Background  Polyethylene glycol‐electrolyte solution (PEG‐ELS) is routinely prescribed for bowel cleansing. Sodium phosphate (NaP) may be an effective but potentially hazardous alternative.

Aim  To investigate the safety of prescription of either agent, without being informed of the patient's medical history.

Methods  One hundred consecutive patients were randomly allocated to PEG‐ELS or NaP. Prior to and after the bowel cleansing, blood was sampled for renal function and electrolytes. Patients answered questionnaires about complaints and ease of intake, and endoscopists rated the quality of bowel preparation.

Results  Eleven patients were identified with a theoretical contraindication for NaP, of whom nine should have been discovered by taking a detailed clinical history. Actually, six of them received NaP with a doubling of serum phosphate levels or hypokalaemia in four. In subjects without a contraindication to the use of NaP, hyperphosphataemia developed in 39% and hypocalcaemia in 5%. Patients tolerated NaP better and completed the preparation more often. Endoscopists rated the quality of bowel preparation equivalent, except for a better cleansed ascending colon with PEG‐ELS.

Conclusions  The 11% potentially hazardous allocation to NaP and the 39% incidence of hyperphosphataemia with NaP do not justify an ‘over‐the‐counter’ prescription. Taking a detailed history and, when in doubt, using PEG‐ELS will safeguard against inappropriate administration of NaP.
Identification of a novel germline MET mutation in dogs
Authors: Liao A.T. , McMahon M. , London C.A.
Published: January 2006

The MET proto‐oncogene encodes a transmembrane tyrosine kinase receptor that mediates multiple functions such as migration, cycling and survival by binding to hepatocyte growth factor (HGF). Dysregulation of MET through inappropriate expression or mutation has been shown to play an important role in human cancers. Furthermore, inherited mutations in MET are known to contribute to the development of gastric and renal cancer in humans. Lastly, mouse models of MET mutations lead to the development of a wide variety of cancers including lymphomas, sarcomas and some forms of carcinoma. In the process of cloning canine MET, a novel germline point mutation was found in the juxtamembrane domain (G966S) in two of the templates used for cloning, both of which were derived from Rottweiler dogs, a breed believed to be at high risk for the development of several cancers. Screening of germline DNA from a variety of breeds revealed that this mutation was present in approximately 70% of Rottweiler dogs and <5% of all other breeds examined, suggesting a breed‐specific heritable mutation. Stable transfection of the G966S mutant form of MET into NIH3T3 cells resulted in enhanced baseline scattering and migration of the cells, which was further increased in the presence of HGF. This study supports the notion that particular dog breeds may carry germline mutations that contribute to high rates of cancer in a manner similar to heritable, cancer‐associated mutations in humans.
The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 C3435T polymorphisms and gender on the urinary excretion of the metabolites of the H1‐receptor antihistamine ebastine: a pilot study
Authors: Gervasini Guillermo , Vizcaino Sonia , Carrillo Juan Antonio , Caballero Maria Jesus , Benitez Julio
Published: January 2006

Aims

To determine the effect of gender and the genetic polymorphisms of CYP2J2, CYP3A4, CYP3A5 and MDR1 on the urinary excretion of the H1 antihistamine ebastine in healthy subjects.

Methods

Eighty‐nine Caucasians were studied. The presence of polymorphisms in genes known to be involved in ebastine metabolism and transport (CYP2J2*2,*3,*4,*6,*7, CYP3A4*1B, CYP3A5*3, *6 and MDR1(ABCB1)C3435T) was assessed by means of PCR‐restriction fragment length polymorphism and sequencing methods. Genotype was correlated with the urinary excretion of the main ebastine metabolites (desalkylebastine and carebastine) under basal conditions and after administration of grapefruit juice.

Results

Women excreted statistically greater amounts of desalkylebastine in urine (mean ± SD (95% confidence intervals, 95% CI), 23.0 ± 19.5 (18.1, 27.9) µmol) than men (12.4 ± 11.0 (7.9, 16.9)), (mean difference: 10.6 (2.4, 18.7), P < 0.005). The CYP2J2, CYP3A4 and CYP3A5 analysed polymorphisms did not greatly affect ebastine metabolite excretion. The MDR1C3435T polymorphism was found to affect both the urinary excretion of the active metabolite carebastine (32.3 ± 18.3 (23.1, 41.4), 22.8 ± 14.7 (18.6, 27.0) and 21.5 ± 15.3 (14.7, 28.3) for CC, CT and TT carriers, respectively; P < 0.05) and the grapefruit juice‐induced inhibition of its transport/formation (mean fold‐decrease ± SD (95% CI), 1.5 ± 0.8 (1.0, 2.0), 1.1 ± 0.9 (0.7, 1.4) and 0.9 ± 0.4 (0.6, 1.2) for CC, CT and TT carriers, respectively; P = 0.01).

Conclusions

Gender and the presence of the MDR1C3435T polymorphism both influence the excretion of ebastine metabolites in urine.
Lineage involvement in chronic myeloid leukaemia: comparison between MBCR/ABL+ and mBCR/ABL+ cases
Authors: Primo Daniel , Sanchez Maria Luz , Espinosa Ana Belén , Tabernero María Dolores , Rasillo Ana , Sayagués Jose Ma , Gonzalez Marcos , Hernandez Jose Ma , Orfao Alberto
Published: January 2006

The relationship between different Abelson/breakpoint cluster region (BCR/ABL+) gene rearrangements and the involvement of different haematopoietic cell lineages were investigated in 15 chronic myeloid leukaemia patients. Analysis of purified cell populations confirmed the involvement of the neutrophil (89%), monocytic (89%), eosinophil (88%), erythroid (100%), and CD34+ cells (100%) in virtually all patients, without differences between minor BCR/ABL+ and major BCR/ABL+ cases; BCR/ABL+ B‐ and natural killer (NK)‐cells were detected in 43% and 31% of cases, respectively, whereas BCR/ABL+ T‐cells were rare (7%). All three minor BCR/ABL+ patients showed involvement of both B‐ and NK‐cells, which was infrequent (27%, P = 0·06 and 10%, P = 0·01) among major BCR/ABL+ cases.
FQPD, a novel immunomodulatory drug, has significant in vitro activity in multiple myeloma
Authors: Kumar Shaji , Raje Noopur , Hideshima Teru , Ishitsuka Kenji , Podar Klaus , Gouille Steven Le , Chauhan Dharminder , Richardson Paul , Munshi Nikhil C. , Anderson Kenneth
Published: January 2006

Multiple myeloma (MM) is a plasma cell malignancy that claims thousands of lives each year and has considerable morbidity. The disease remains incurable despite recent advances in the understanding of the disease biology and the introduction of more effective drugs is needed. This study evaluated the anti‐MM activity of 3‐(7‐fluoro‐4H‐quinazolin‐3‐yl)‐piperidine‐2,6‐dione, hydrochloride (FQPD), a novel immunomodulatory drug. FQPD inhibited the proliferation of multiple MM cell lines, including those resistant to conventional treatments, such as dexamethasone. It induced apoptosis in MM cell lines, as well as freshly isolated patient MM cells, without cytotoxicity on normal human lymphocytes. Moreover, it induced apoptosis in MM cells adherent to bone marrow (BM) stromal cells or in the presence of cytokines, such as interleukin‐6 and vascular endothelial growth factor, confirming its ability to overcome the protective effects of the BM milieu. Apoptosis in the MM cells was mediated via poly‐ADP ribose polymerase cleavage as well as cleavage of caspase 8 and caspase 9. Our studies therefore demonstrated in vitro anti‐MM activity of FQPD and provide the rationale for its in vivo evaluation in animal models and derived clinical trials.
Optimal haemophilia care versus the reality
Authors: Bolton‐Maggs Paula H. B.
Published: January 2006

Haemophilia A and B are inherited bleeding disorders whose diagnosis and management is generally well established and best provided by specialists in a comprehensive care setting. Patients may be put at unnecessary risk if appropriate expertise is not sought for the management of accidents and surgery. The delivery of a high quality comprehensive service to patients with bleeding disorders depends upon defined standards and a network of haemophilia centres in the UK with similar models in other countries. In developing countries, despite a shortage or absence of treatment products, development of local expertise results in an improved outlook and reduction in mortality. Optimal care for severe haemophilia includes accurate diagnosis, early and adequate factor replacement for bleeding episodes and the provision of prophylaxis from an early age to prevent joint bleeding and the consequent arthropathy. Haemophilia treatment is expensive resulting in considerable inequity in provision of care across the world. Despite decades of experience, optimal treatment levels are not robustly defined. Transfusion‐transmitted infections continue to have a significant impact on patient management. The development of inhibitory antibodies seriously complicates the management both in morbidity and cost. While gene therapy has not yet produced the hoped‐for cure, new technologies will produce improved products.
Immunohistochemical analysis of the antiapoptotic Mcl‐1 and Bcl‐2 proteins in follicular lymphoma
Authors: Michels Jorg , Foria Vipul , Mead Ben , Jackson Gill , Mullee Mark , Johnson Peter W. M. , Packham Graham
Published: January 2006

In the present study, we investigated the expression of Mcl‐1 and Bcl‐2 by immunohistochemistry in 85 patients of grades 1–3 and transformed follicular lymphoma (FL). In lymphoma tissue, centroblasts uniformly expressed high levels of Mcl‐1 (Mcl‐1hi) whereas centrocytes demonstrated low Mcl‐1 expression (Mcl‐1lo). Bcl‐2 expression in centroblasts/centrocytes was reciprocal to Mcl‐1 staining in most cases. A high number of Mcl‐1hi centroblasts in tissue sections (≥200/high‐power field) correlated with poor overall survival (P < 0·001), independent of the International Prognostic Index and FL grade. This suggests that the number of centroblasts with strong Mcl‐1 staining is associated with clinical outcome in FL patients.
Model‐based design of chemotherapeutic regimens that account for heterogeneity in leucopoenia
Authors: Scholz Markus , Engel Christoph , Loeffler Markus ,   the German High Grade Non‐Hodgkin Lymphoma Study Group (DSHNHL)
Published: January 2006

Patients treated with multicycle chemotherapy can exhibit large interindividual heterogeneity of haematotoxicity. We describe how a biomathematical model of human granulopoiesis can be used to design risk‐adapted dose‐dense chemotherapies, leading to more similar leucopoenias in the population. Calculations were performed on a large data set for cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP)‐like chemotherapies for aggressive non‐Hodgkin lymphoma. Age, gender, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase and the degree of leucopoenia within the first therapy cycle were used to stratify patients into groups with different expected severity of leucopoenia. We estimated risk‐specific bone marrow toxicities depending on the drug doses administered. These toxicities were used to derive risk‐adapted therapy schedules. We determined different doses of cyclophosphamide and additional etoposide for patients treated with CHOP‐14. Alternatively, the model predicted that further reductions of cycle duration were feasible in groups with low toxicity. We also used the model to identify appropriate granulocyte colony‐stimulating factor (G‐CSF) schedules. In conclusion, we present a method to estimate the potential of risk‐specific dose adaptation of different cytotoxic drugs in order to design chemotherapy protocols that result in decreased diversity of leucopoenia between patients, to develop dose‐escalation strategies in cases of low leucopoenic reaction and to determine optimal G‐CSF support.
Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival
Authors: Ge Yun , Zhan Fenghuang , Barlogie Bart , Epstein Joshua , Shaughnessy John , Yaccoby Shmuel
Published: January 2006

The microenvironment plays a critical role in facilitating cancer progression and metastasis. We previously demonstrated the ability of osteoclasts to support primary myeloma plasma cell (MM PC) growth. Our study on the role of the bone marrow (BM) microenvironment in myeloma, using global gene expression profiling, has identified fibroblast activation protein (FAP) as one of 28 genes significantly overexpressed in cocultured osteoclasts. Because FAP has been previously implicated in tumorigenesis and shown to be selectively expressed by the reactive stroma of epithelial tumours, we focused our study on the role of this serine protease in myeloma. Using quantitative polymerase chain reaction amplification, we demonstrated upregulation of FAP by cocultured osteoclasts and mesenchymal stem cells, and in whole myelomatous human bone in SCID‐hu mice. Immunohistochemical analysis of myelomatous bone sections revealed FAP expression by osteoclasts, osteogenic cells, fibrotic stroma and certain adipocytes and vascular endothelial cells. FAP was not expressed in PCs by all these methods. Inhibition of FAP expression with the use of small‐interference RNA reduced MM PC survival in cocultures. Our results indicate that FAP is critical for the interaction of MM cells with the BM microenvironment – a potential therapeutic target in myeloma.
Care, control and change in child care proceedings: dilemmas for social workers, managers and lawyers
Authors: Dickens Jonathan
Published: January 2006

This paper draws on findings from an interview‐based study of the ways that local authority social workers, social services managers and lawyers work together in child care cases in England. The study shows how stressful social workers can find care proceedings, and how much they look to the lawyers for support. It also shows how the lawyers’ involvement can bring new stresses and dilemmas. The managers are especially likely to resent ‘over‐involvement’ (as they see it) from lawyers, but lawyers are quick to defend their role and responsibilities. The paper shows how the complex, multifaceted dimensions of care, control and change interweave with professional differences in care proceedings: care for children, parents and social workers; struggles for control against the court, the other parties and sometimes the other professionals on one's own side; and responsiveness to change set against wariness about ‘lawyers’ deals’ and undue risk to children. The paper concludes that the valuing of difference, rather than its avoidance or suppression, is at the heart of effective inter‐professional work. It calls for greater recognition of this in current initiatives to promote interdisciplinary working in children's services in England.
Five tumultuous years in Australian child protection: little progress
Authors: Ainsworth Frank , Hansen Patricia
Published: January 2006

In an article published in 2002, one of the authors of this paper offered an analysis of the Australian child protection data from 1999 to 2000 and raised questions about the effectiveness of mandatory reporting. Recently, child protection data for 2003–2004 has been released. This provides an opportunity to re‐examine some child protection issues and the effectiveness of mandatory reporting 5 years on. These have been tumultuous years. Each state and territory has held major inquiries into this area of practice and, as a result, significant organizational changes have taken place and new resources are being made available. Nevertheless, questions about the effectiveness of child protection services remain. There is continuing doubt about the value of comprehensive reporting systems.
The comfort of strangers: social work practice with unaccompanied asylum‐seeking children and young people in the UK
Authors: Kohli Ravi K. S.
Published: January 2006

Unaccompanied children and young people seeking sanctuary as political refugees are increasingly visible within many industrialized nations, where several studies confirm their vulnerability and needs. These studies also highlight what appears to be the poor quality of social work services and practices that these minors encounter. This paper examines some of the details contained in such reports of deficiency and seeks to place them within a more optimistic appraisal of social work practice. Based on a small research study, it suggests that resettlement for unaccompanied minors is complex and contains different types of loss as well as gain. It also asserts that practice by some social workers shows they have a grasp of this complexity as they offer practical assistance, therapeutic care and companionship to the young people to help them resettle in new environments.
Research Review: Risk and resilience in cases of emotional abuse
Authors: Iwaniec Dorota , Larkin Emma , Higgins Siobhán
Published: January 2006

This paper examines risk and resilience in relation to emotional abuse. Research has identified numerous child and family factors that may increase the risk of emotional abuse occurring and has also identified numerous ways in which an experience of emotional abuse can enhance vulnerability to negative outcomes. However, relatively little is known about the factors that determine the extent to which an experience of emotional abuse predicts later psychosocial functioning. Factors that may determine risk and resilience in children who experience emotional abuse are discussed. These include predisposing factors such as early caregiving experiences; precipitating factors such as the frequency, intensity and duration of the abuse; factors intrinsic to the child such as working models of the self and others, internal or external attributions, behavioural and coping strategies, self‐esteem, and disposition; and external factors such as school and availability of supportive relationships. The need to pay attention to the particular vulnerabilities and protective factors pertaining to each emotionally abused child in order to most effectively enhance resilience is highlighted.
Influence of mattress characteristics on house dust mite allergen concentration
Authors: van den Bemt L. , de Vries M. P. , van Knapen L. , Jansen M. , Goossens M. , Muris J. W. M. , van Schayck C. P.
Published: January 2006

Background
Exposure to a high level of house dust mite allergens (HDMAs) is considered as a risk factor for HDM sensitization and development of asthma in genetically disposed people. Mattresses are one of the most important sources of HDMA in people's living environment.

Objective
The aim of this study was to evaluate the association between mattress characteristics and HDMA concentrations on mattresses.

Methods
Dust samples of mattress surfaces were taken to evaluate the level of Der p 1 allergen. All participants filled in a questionnaire about the type of mattress, the type of covering (upper layer) of the mattress, dwelling characteristics and cleaning habits. Humidity and temperature of the bedroom were measured at the time of dust sampling.

Results
One hundred and sixty‐eight questionnaires were filled in. Synthetic upper layer of the mattress was associated with a higher level of Der p 1 compared with cotton upper layer (2.6 vs. 0.8 μg/g Der p 1). Moreover, higher relative humidity (RH) was associated with significant higher concentrations and density of Der p 1.

Conclusions
Two factors were associated with lower levels of Der p 1 found on mattresses, namely: a cotton upper layer of the mattress compared with a layer of synthetic material and lower RH at the time of sampling. As far as we know, the association between type of upper layer and concentration of Der p 1 has not been described before and could lead to the formulation of practical advices in order to reduce HDMA concentrations on mattresses.
Biochemical evaluation of disease activity after pituitary surgery in acromegaly: a critical analysis of patients who spontaneously change disease status
Authors: Espinosa‐de‐los‐Monteros Ana Laura , Sosa Ernesto , Cheng Sonia , Ochoa Raquel , Sandoval Carolina , Guinto Gerardo , Mendoza Victoria , Hernández Irma , Molina Mario , Mercado Moisés
Published: January 2006

Background  The definition of biochemical cure in acromegaly involves both the normalization of IGF‐1 and a glucose‐suppressed GH level of < 1 ng/ml. These criteria were reached by several consensus meetings, although no evidence‐based recommendations as to the optimal time to perform biochemical evaluations were made, nor was the fact that several patients may change biochemically upon long‐term follow‐up taken into consideration.

Objectives  To identify and characterize biochemical changes in the follow‐up of acromegaly.

Patients and methods  One hundred and twenty‐six acromegalic patients seen at a referral centre were followed prospectively (6–108 months) with regard to glucose‐suppressed GH levels and IGF‐1 concentrations.

Results  Eighty‐nine patients did not change biochemical status, whereas in 37 (29·3%), one or more changes were identified, mostly during the first year. When glucose‐suppressed GH values were discordant with the IGF‐1 results, the likelihood of biochemical status modification was significantly greater than when such results were concordant [concordant 19·4%, discordant 57·6%, odds ratio (OR) = 5·6, 95% confidence interval (CI) = 2·3–13·3, P = 0·0001]. Among the changing patients, four out of the nine subjects initially considered as cured remained so at the last follow‐up, whereas five became discordant; of the nine initially categorized as active, only three kept such a status at the last evaluation, whereas five became GH discordant and one achieved full biochemical criteria of cure; of 17 initially GH‐discordant patients, seven remained so upon the last evaluation, whereas six became concordantly active and four concordantly cured.

Conclusion  A significant proportion of acromegalic patients change biochemical status upon long‐term follow‐up after surgery. Most of these changes occur within the first postoperative year and are more likely to take place if the initial GH postglucose and IGF‐1 levels are discordant.
Endoscopic ultrasound‐guided fine needle aspiration of the pancreas: cytomorphological evaluation with emphasis on adequacy assessment, diagnostic criteria and contamination from the gastrointestinal tract1
Authors: Mitsuhashi T. , Ghafari S. , Chang C. Y. , Gu M.
Published: January 2006

Objective:  Endoscopic ultrasound (EUS)‐guided fine needle aspiration (FNA) has been proved to be safe, efficient and reliable in the diagnosis of pancreatic lesions. This study evaluated specimen adequacy, diagnostic criteria of various pancreatic neoplasms and contamination from the gastrointestinal (GI) tract.

Methods:  EUS‐guided FNA of the pancreas and subsequent surgical resections performed at the University of California Irvine Medical Center during February 1996–October 2000 were retrospectively selected. Modified Papanicolaou staining method was used for immediate evaluation and cell block prepared.

Results:  A total of 267 cases were available for review, including 147 (55.1%) positive/suspicious, 10 (3.7%) atypical, 96 (36.0%) negative and 14 (5.2%) unsatisfactory cases. Eighty‐six (58.5%) positive/suspicious cases had histological confirmation and 12 (8.3%) had lymph node or distant metastases by cytology. Three atypical, two negative, and two unsatisfactory cases proved to have adenocarcinoma. Contamination from duodenum, stomach or pancreas was found in 77 positive/suspicious, three atypical and 90 negative cases. The sensitivity, specificity, diagnostic accuracy, positive and negative predictive values were 94.6%, 100%, 95.6%, 100%, 82% respectively.

Conclusions:  EUS FNA is efficient and accurate in the diagnosis of pancreatic neoplasms in adequate samples. Contamination from the GI tract should be well recognized to avoid misinterpretation.
Endoscopic ultrasound‐guided fine needle aspiration cytology of pancreatic neuroendocrine tumours: cytomorphological and immunocytochemical evaluation
Authors: Chang F. , Vu C. , Chandra A. , Meenan J. , Herbert A.
Published: January 2006

Objectives:  Endoscopic ultrasound (EUS)‐guided fine needle aspiration (FNA) is increasingly used in preoperative localization and diagnosis of pancreatic neoplasms including neuroendocrine tumours (NETs). The objective of the present study was to identify the cytological features of pancreatic NETs obtained by EUS‐FNA.

Methods:  The study group consisted of nine cases of pancreatic tumours correctly diagnosed or strongly suggestive of NETs based on EUS‐FNA. Cytological smears were retrospectively reviewed. The clinical data and immunocytochemical stains applied to the cell block preparations were also reviewed and examined.

Results:  All cases except one showed characteristic cytomorphological features sufficient for their recognition and separation from pancreatic adenocarcinoma and other lesions. The most helpful cytological features that facilitated the cytological diagnosis of NET were a richly cellular aspirate with a monotonous, poorly cohesive population of small cells with a speckled or dusty chromatin pattern and plasmacytoid morphology. The neuroendocrine differentiation of these tumours was further confirmed by immunocytochemistry.

Conclusion:  EUS‐FNA is a valuable method in the recognition of pancreatic NETs. By adherence to the characteristic cytomorphological criteria of pancreatic NET together with collection of suitable material for ancillary immunocytochemical stains, cytopathologists could reach a correct diagnosis in most instances.
Endoscopic ultrasound‐guided FNA biopsy of bile duct and gallbladder: analysis of 53 cases
Authors: Meara R. S. , Jhala D. , Eloubeidi M. A. , Eltoum I. , Chhieng D. C. , Crowe D. R. , Varadarajulu S. , Jhala N.
Published: January 2006

Objective:  Endoscopic retrograde cholangiopancreaticography (ERCP)‐guided brushing has been the standard of practice for surveillance and detection of carcinoma in the biliary tree. Few studies have evaluated the role of endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) in diagnosing clinically suspected cholangiocarcinoma. The role of this method in diagnosing clinically suspected gallbladder malignancies has not been extensively evaluated in the USA. This study investigates the role of EUS‐FNA in the diagnosis of clinically suspected biliary tree and gallbladder malignancies in a large patient series.

Methods:  EUS‐FNAs were obtained from 46 bile duct and seven gallbladder lesions. On‐site rapid interpretation was provided using air‐dried Diff Quik stained smears. In addition, alcohol fixed Papanicoloau stained smears and Thin Prep preparations (Cytye Corp., Marlborough, MA, USA) were evaluated before providing a final cytological diagnosis. Tissue biopsies and/or clinical follow‐up were used as the standards to determine operating characteristics for EUS‐FNA.

Results:  The mean ages for bile duct and gallbladder lesions were 66 years (range: 37–84 years), and 69 years (range 49–86 years), respectively. All cases diagnosed as suspicious/malignant on preliminary evaluation were confirmed on final cytological interpretation (27/27). The operating characteristics show that EUS‐FNA is highly specific (100%) with sensitivity rates of 87% and 80% from clinically suspected malignancies of biliary tract and gallbladder, respectively. Sampling error in three cases and associated acute inflammation in two cases resulted in false‐negative diagnoses.

Conclusions:  EUS‐FNA of biliary tree and gallbladder carcinoma is highly specific and should be considered for evaluation of clinically suspicious lesions. Marked inflammation may result in false‐negative diagnoses.
Lipoprotein profiles in plasma and interstitial fluid analyzed with an automated gel‐filtration system
Authors: Parini P. , Johansson L. , Bröijersén A. , Angelin B. , Rudling M.
Published: January 2006

Background  High‐quality methods for lipoprotein characterization are warranted in studies on various metabolic diseases.

Materials and methods  An automated system for size‐exclusion chromatography (SEC) of lipoproteins using commercially available components is described. Cholesterol or triglyceride content in separated lipoproteins from plasma and interstitial fluid (IF) was continuously determined on‐line using microlitre sample volumes.

Results  The lipoprotein assay showed a good concordance with the classic ultra‐centrifugation/precipitation technique using fresh or frozen samples. Determination of lipoproteins in IF obtained from vacuum‐induced skin blisters from 18 healthy subjects revealed that very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels were 18%, 19% and 25%, respectively, of concomitant plasma concentrations. The size‐exclusion chromatography (SEC) system also allows for triglyceride determination on‐line and it could be shown that the system is advantageous for an accurate determination of triglycerides in conditions when there are high levels of glycerol, e.g. in mice and in patients with hyperglycerolaemia (pseudo‐hypertriglyceridaemia).

Conclusions  The described system should be of value in studies where detailed lipoprotein analysis is warranted and particularly when significant sample series with small volumes are available. Our data also suggest that there is a 4–5·5‐fold concentration gradient between plasma and IF for the three major plasma lipoproteins.
Potential role of soluble angiopoietin‐2 and Tie‐2 in patients with inflammatory bowel disease
Authors: Koutroubakis I. E. , Xidakis C. , Karmiris K. , Sfiridaki A. , Kandidaki E. , Kouroumalis E. A.
Published: January 2006

Background  Angiogenesis has been suggested to play an important role in inflammatory bowel disease (IBD). The aim of the study was to evaluate the serum markers of angiogenesis angiopoietin‐2 (Ang‐2) and soluble angiopoietin receptor Tie‐2 in patients with ulcerative colitis (UC) and Crohn's disease (CD).

Materials and methods  Serum Ang‐2 and Tie‐2 serum levels were measured in 160 IBD patients (79 UC and 81 CD) and in 80 matched healthy controls using commercially available enzyme‐linked immunosorbent assays. Serum Ang‐2 and Tie‐2 levels were correlated with the disease activity, as well as the type, localization and treatment of the disease.

Results  Median serum Ang‐2 and Tie‐2 levels were significantly higher in both the UC patients and the CD patients compared with the healthy controls (P < 0·05 and P < 0·001, respectively). The IBD patients with early disease (diagnosis < 2 years) had significantly higher (P = 0·04) median serum Ang‐2 levels but significantly lower (P = 0·02) median serum Tie‐2 levels as compared with IBD patients with late disease (diagnosis > 2 years). The CD patients with active disease had significantly higher levels of Ang‐2 compared with non‐active disease (P = 0·02). Serum levels of both Ang‐2 and Tie‐2 were not correlated with laboratory markers such as ESR, CRP, white blood cell count, platelet count and albumin.

Conclusions  Serum Ang‐2 and Tie‐2 levels are elevated in patients with IBD. These markers may mediate angiogenesis and vascular permeability in the mucosa of patients with IBD.
Activation of p38 mitogen‐activated protein kinase and partial reactivation of the cell cycle bycis‐4‐methylsphingosine direct postmitotic neurons towards apoptosis
Authors: Naetzker Sven , Hagen Nadine , van Echten‐Deckert Gerhild
Published: January 2006

As shown before in three different cell types,cis‐4‐methylsphingosine is a synthetic, membrane permeable, pro‐drug, that is taken up by cells and phosphorylated to a metabolically stablecis‐4‐methylsphingosine‐phosphate. The synthetic compound mimicked the mitogenic effect of sphingosine‐1‐phosphate (S1P) in Swiss 3T3 fibroblasts, but induced apoptosis in B104 neuroblastoma cells. We now investigated its effect in differentiated primary cultured neurons. In contrast to S1P, which had no effect on growth of these postmitotic cells,cis‐4‐methylsphingosine‐phosphate induced apoptosis. Interestingly, both compounds stimulated extracellular regulated kinase (ERK) and also p38 mitogen‐activated protein kinase (MAPK). Additionally, both compounds induced an increased expression of cyclin D1 but not of cyclin E. Our results document that the different physiological effects, apoptosis in the case of the accumulating metabolically stable synthetic compound vs. no apoptosis in the case of the short‐living S1P, rely only on nuances of impact. In other words both sphingoid phosphates affect similar pathways albeit in a sustained and more pronounced manner in case of the metabolically stable synthetic compound. Experiments with several pharmacological inhibitors indicate thatcis‐4‐methylsphingosine‐phosphate‐induced neuronal apoptosis is mediated on the one hand by a caspase dependent and p38 MAPK forwarded pathway and on the other hand by an abortive reactivation of the cell cycle, a caspase independent process.
Onset of spring starting earlier across the Northern Hemisphere
Authors: SCHWARTZ MARK D. , AHAS REIN , AASA ANTO
Published: January 2006

Recent warming of Northern Hemisphere (NH) land is well documented and typically greater in winter/spring than other seasons. Physical environment responses to warming have been reported, but not details of large‐area temperate growing season impacts, or consequences for ecosystems and agriculture. To date, hemispheric‐scale measurements of biospheric changes have been confined to remote sensing. However, these studies did not provide detailed data needed for many investigations. Here, we show that a suite of modeled and derived measures (produced from daily maximum–minimum temperatures) linking plant development (phenology) with its basic climatic drivers provide a reliable and spatially extensive method for monitoring general impacts of global warming on the start of the growing season. Results are consistent with prior smaller area studies, confirming a nearly universal quicker onset of early spring warmth (spring indices (SI) first leaf date, −1.2 days decade−1), late spring warmth (SI first bloom date, −1.0 days decade−1; last spring day below 5°C, −1.4 days decade−1), and last spring freeze date (−1.5 days decade−1) across most temperate NH land regions over the 1955–2002 period.

However, dynamics differ among major continental areas with North American first leaf and last freeze date changes displaying a complex spatial relationship. Europe presents a spatial pattern of change, with western continental areas showing last freeze dates getting earlier faster, some central areas having last freeze and first leaf dates progressing at about the same pace, while in portions of Northern and Eastern Europe first leaf dates are getting earlier faster than last freeze dates. Across East Asia last freeze dates are getting earlier faster than first leaf dates.
Mice overexpressing p40 in lungs have reduced leucocyte influx and slightly impaired resistance during tuberculosis
Authors: Leemans Jaklien C. , Wieland Catharina W. , Florquin Sandrine , van der Poll Tom , Vervoordeldonk Margriet J. B. M.
Published: January 2006

Interleukin (IL)‐12 (p70) is a heterodimeric cytokine composed of p40 and p35, that plays a major role in the protective immune response to Mycobacterium tuberculosis. To define the role of p40 in lungs during pulmonary M. tuberculosis infection we generated transgenic (Tg) mice overexpressing p40 under control of the surfactant protein C promoter. Tg mice expressed the transgene in their lungs, yet demonstrated elevated pulmonary p40 protein levels. After infection, Tg mice displayed higher pulmonary p40 and p70 levels than wild type mice. Interferon‐γ concentrations were similar in uninfected and infected Tg and wild type mice, arguing against agonistic effects of p40. Tg mice demonstrated reduced recruitment of macrophages, lymphocytes and neutrophils to the lungs early after infection. This was accompanied by reduced pulmonary tumour necrosis factor‐α, macrophage inflammatory protein (MIP)‐2 and MIP‐1α levels. This suggests that elevated p40 concentrations inhibited the chemotactic effects of p70 on leucocytes. Furthermore, Tg mice displayed slightly higher pulmonary mycobacterial outgrowth late in the infection than wild type mice. Taken together, we demonstrate that constitutive overexpression of p40 in lungs negatively influences IL‐12‐mediated leucocyte migration and protection against lung tuberculosis. This suggests a novel antagonistic role for p40 homodimers in regulating the chemotactic bioactivity of IL‐12 after pulmonary mycobacterial infection.
Immunohistochemical analysis of cytokines and apoptosis in tuberculous lymphadenitis
Authors: Mustafa Tehmina , Mogga Stanley J. , Mfinanga Sayoki G. M. , Mørkve Odd , Sviland Lisbet
Published: January 2006

Relatively little is known about the effector mechanisms whereby the human immune system controls Mycobacterium tuberculosis infection. In this study we elaborate on the immune response and mechanisms of persistence of mycobacteria in lesions by analysing, using immunohistochemistry, the expression of cytokines [tumour necrosis factor‐α (TNF‐α), interleukin‐10 (IL‐10), transforming growth factor‐β (TGF‐β) and interferon‐γ (IFN‐γ)], apoptotic cells and apoptosis‐related proteins [Bcl2, Bax, Fas ligand (FasL) and Fas] in the human tuberculous lymphadenitis lesions. The expression of apoptosis‐related proteins has been shown to be exploited by mycobacteria to evade the immune response and persist in the host. Foreign body (FB) granulomas were used as controls. In tuberculosis (TB) granulomas, epithelioid cells and multinucleated giant cells expressed cytokines differently. In epithelioid cells, the numbers of TNF‐α‐, IL‐10‐ and TGF‐β‐stained cells were higher than IFN‐γ‐stained cells (P < 0·01). TGF‐β and FasL were strongly expressed in the necrotic centres as compared with other cytokines. More giant cells expressed IL‐10 and TGF‐β than expressed TNF‐α and IFN‐γ (P < 0·01). Staining of consecutive sections revealed that some giant cells expressed IL‐10 but not TNF‐α. Apoptotic TB giant cells correlated positively with the expression of TNF‐α, IFN‐γ and TGF‐β, but not with the expression of IL‐10. The percentage of giant cells expressing Bax was lower than those expressing Fas, unlike the epithelioid cells, suggesting that TB giant cells are less susceptible to apoptosis. Compared with FB giant cells, there were fewer TB giant cells showing TNF‐α, IFN‐γ, FasL, Fas expression or undergoing apoptosis (P < 0·05). Taken together, these observations show that the cellular microenvironment of TB granulomas down‐regulates microbicidal functions, favouring bacillary survival and persistence. TGF‐β and FasL may be responsible for tissue destruction. The giant cells, being less susceptible to apoptosis, may remain a continuous source of pro‐inflammatory cytokines, causing immune pathology.
Nurses’ perceptions of quality end‐of‐life care on an acute medical ward
Authors: Thompson Genevieve , McClement Susan , Daeninck Paul
Published: January 2006

Aim.  This paper reports the findings of a study that generated a conceptual model of the nursing behaviours and social processes inherent in the provision of quality end‐of‐life care from the perspective of nurses working in an acute care setting.

Background.  The majority of research examining the issue of quality end‐of‐life care has focused on the perspectives of patients, family members and physicians. The perspective of nurses has generally received minimal research attention, with the exception of those working within palliative or critical care. The vast majority of hospitalized patients, however, continue to be cared for and die on medical units. To date, little research has been conducted examining definitions and determinants of quality end‐of‐life care from the perspective of nurses working in acute adult medical settings.

Method.  Grounded theory method was used in this study of 10 nurses working on acute medical units at two tertiary university‐affiliated hospitals in central Canada. Data were collected during 2002 by interview and participant observation.

Findings.  The basic social problem uncovered in the data was that of nurses striving to provide high quality end‐of‐life care on an acute medical unit while being pulled in all directions. The unifying theme of ‘Creating a haven for safe passage’ integrated the major sub‐processes into the key analytic model in this study. ‘Creating a haven for safe passage’ represents a continuum of behaviours and strategies, and includes the sub‐processes of ‘facilitating and maintain a lane change’; ‘getting what's needed’; ‘being there’; and ‘manipulating the care environment’.

Conclusion.  The ability of nurses to provide quality end‐of‐life care on an acute medical unit is a complex process involving many factors related to the patient, family, healthcare providers and the context in which the provision of end‐of‐life care takes place.