bluuebunny/crossref_metadata_2025 huggingface dataset:
Autologous Fixed Tumor Vaccine: A Formulation with Cytokine‐microparticles for Protective Immunity against Recurrence of Human Hepatocellular Carcinoma
Authors: Peng Bao Gang , Liu Shu Qin , Kuang Ming , He Qiang , Totsuka Saeri , Huang Lan , Huang Jiefu , Lu Ming‐De , Liang Li‐Jiang , Leong Kam W. , Ohno Tadao
Published: September 2005

We developed a tumor vaccine consisting of fixed hepatocellular carcinoma (HCC) cells/tissue fragments, biodegradable microparticles encapsulating granulocyte‐macrophage‐colony stimulating factor and interleukin‐2, and an adjuvant. The vaccine protected 33% of syngeneic mice from HCC cell challenge. The vaccine containing human autologous HCC fragments showed essentially no adverse effect in a phase I/IIa clinical trial and 8/12 patients developed a delayed‐type hyper‐sensitivity (DTH) response against the fragments. Although 2 of 4 DTH‐response‐negative patients had recurrence after curative resection, the DTH‐response‐positive patients had no recurrence. The time before the first recurrence in the vaccinated patients was significantly longer than that in 24 historical control patients operated in the same department (P<0.05). This formulation is a promising candidate to prevent recurrence of human HCC.
Expression of Macrophage Migration Inhibitory Factor in Human Breast Cancer: Association with Nodal Spread
Authors: Bando Hiroko , Matsumoto Gaku , Bando Masaki , Muta Mariko , Ogawa Taeko , Funata Nobuaki , Nishihira Jun , Koike Morio , Toi Masakazu
Published: September 2005

Macrophage migration inhibitory factor (MIF) is known to exert pleiotropic functions including inhibition of macrophage migration, anchoring, and counteraction of the anti‐inflammatory and immunosuppressive activity of glucocorticoids. Ninety‐three primary breast cancer tissues and 64 sera of primary breast cancer patients were analyzed for the expression of MIF. The clinico‐pathological significance of MIF expression was evaluated. It was found that MIF was frequently over‐expressed in primary breast cancer tissues. RT‐PCR and western blotting analysis confirmed that wild‐type MIF is expressed, and immunohistochemical analysis showed that MIF expression was localized at tumor cells as well as stromal cells, including tumor‐associated macrophages. Intra‐tumoral MIF protein concentrations detected by enzyme‐linked immunosorbent assay (ELISA) varied with a median value of 1821 ng/mg protein (range: 8–8126 ng/mg protein), and correlated inversely with nodal involvement (P=0.039). No significant correlation was observed with other clinico‐pathological factors including tumor size, menopausal status and hormone receptors. The circulating level of MIF protein ranged up to 105.7 ng/ml (median: 17.3 ng/ml), and it was also found to correlate inversely with the number of involved nodes (P=0.02). A comparative study with other soluble inflammatory mediators showed that intratumoral levels of MIF were significantly associated with those of interleukin‐1β, suggesting that interactions between tumor cells and tumor‐associated macrophages play an important role in the up‐regulation of MIF. The multifunctional inflammatory/immune mediator MIF was frequently expressed in primary breast cancer, and its expression level was inversely associated with nodal spread. Thus, MIF seems to play a role in tumor‐stroma interactions of primary breast cancers, particularly those with a phenotype of node‐negative or minimal nodal spread.
Expansion of Lung Vα14 NKT Cells by Administration of α‐Galactosylceramide‐pulsed Dendritic Cells
Authors: Akutsu Yasunori , Nakayama Toshinori , Harada Michishige , Kawano Tetsu , Motohashi Shinichiro , Shimizu Eiko , Ito Toshihiro , Kamada Noriaki , Saito Takeshi , Matsubara Hisahiro , Miyazawa Yukimasa , Ochiai Takenori , Taniguchi Masaru
Published: September 2005

NKT cells, a novel murine lymphoid lineage bearing an invariant T cell receptor encoded by Vα14 and Jα281 gene segments, recognize a specific ligand glycolipid, α‐galactosylceramide (α‐GalCer) in a CDld‐dependent manner. Recent research has revealed that activated Vα14 NKT cells have dramatic antitumor effects against a wide variety of tumor cell lines in vivo and in vitro. Here, we demonstrate strong in vivo antitumor effects brought about by treatment with α‐GalCer‐pulsed dendritic cells in comparison with in vitro‐activated Vα14 NKT cells. Furthermore, we show a significant expansion of endogenous Vα14 NKT cells in the lung following the administration of α‐GalCer‐pulsed dendritic cells. The feasibility of immunotherapy with α‐GalCer‐pulsed dendritic cells is discussed.
Betulinic Acid Inhibits Growth Factor‐induced in vitro Angiogenesis via the Modulation of Mitochondrial Function in Endothelial Cells
Authors: Kwon Ho Jeong , Shim Joong Sup , Kim Jin Hee , Cho Hyun Young , Yum Young Na , Kim Seung Hee , Yu Jaehoon
Published: September 2005

Betulinic acid (BetA), a pentacyclic triterpene, is a selective apoptosis‐inducing agent that works directly in mitochondria. Recent study has revealed that BetA inhibits in vitro enzymatic activity of aminopeptidase N (APN, EC 3.4.11.2), which is known to play an important role in angiogenesis, but the anti‐angiogenic activity of BetA has not been reported yet. Data presented here show that BetA potently inhibited basic fibroblast growth factor (bFGF)‐induced invasion and tube formation of bovine aortic endothelial cells (BAECs) at a concentration which had no effect on the cell viability. To access whether the anti‐angiogenic nature of BetA originates from its inhibitory action against aminopeptidase N (APN) activity, the effect of BetA on APN was investigated. Surprisingly, BetA did not inhibit in vivo APN activity in endothelial cells or APN‐positive tumor cells. On the other hand, BetA significantly decreased the mitochondrial reducing potential, and treatment with mitochondrial permeability transition (MPT) inhibitors attenuated BetA‐induced inhibition of endothelial cell invasion. These results imply that anti‐angiogenic activity of BetA occurs through a modulation of mitochondrial function rather than APN activity in endothelial cells.
Cellular and Biochemical Mechanisms of the Resistance of Human Cancer Cells to a New Anticancer Ribo‐nucleoside, TAS‐106
Authors: Shimamoto Yuji , Kazuno Hiromi , Murakami Yuko , Azuma Atsushi , Koizumi Katsuhisa , Matsuda Akira , Sasaki Takuma , Fukushima Masakazu
Published: September 2005

We have established variants of DLD‐1 human colon carcinoma and HT‐1080 human fibrosarcoma cells resistant to the new anticancer ribo‐nucleosides, 1‐(3‐C‐ethynyl‐β‐D‐ribo‐pentofuranosyl)‐cytosine (ECyd, TAS‐106) and 1‐(3‐C‐ethynyl‐p‐D‐ribo‐pentofuranosyl)uracil (EUrd). Both variants were shown to have decreased (3‐ to 24‐fold decrease) uridine‐cytidine kinase (UCK) activity, and exhibited cross‐resistance to EUrd and TAS‐106. Based on the IC50 values determined by chemosensitivity testing, a 41‐ to 1102‐fold resistance to TAS‐106 was observed in the resistant cells. TAS‐106 concentration‐dependently inhibited RNA synthesis, while its effect on DNA synthesis was negligible. The degree of resistance (14‐ to 3628‐fold resistance) calculated from the inhibition of RNA synthesis tended to be close to the degree of chemoresistance of tested cells to TAS‐106. The experiments on the intracellular metabolism of TAS‐106 in the parental cells revealed a rapid phosphorylation to its nucleotides, particularly the triphosphate (ECTP), its major active metabolite. The amount of TAS‐106 transported into the resistant cells was markedly reduced and the intracellular level of ECTP was decreased from 1/19 to below the limit of detection; however, the unmetabolized TAS‐106 as a percentage of the total metabolite level was high as compared with the parental cells. The ratio of the intracellular level of ECTP between parental and resistant cells tended to approximate to the degree of resistance calculated from the inhibitory effect on RNA synthesis. These results indicate that the TAS‐106 sensitivity of cells is correlated with the intracellular accumulation of ECTP, which may be affected by both the cellular membrane transport mechanism and UCK activity.
Elevation of Serum MAGE‐4 Protein Levels and Prediction of Hepatocellular Carcinogenesis in Patients with Liver Cirrhosis
Authors: Yutani Shigeru , Tanaka Masatoshi , Mutsumoto Hajime , Imai Nobue , Sata Michio , Shichijo Shigeki , Harada Mamoru , Itoh Kyogo
Published: September 2005

Early detection of hepatocellular carcinoma (HCC) is clinically important because advanced HCC limits treatment modalities for the cancer. We have previously reported that serum levels of MAGE‐4 protein are strongly associated with the development of HCC. The present study was designed to determine whether elevated serum MAGE‐4 protein levels can predict hepatocellular carcinogenesis in patients with liver cirrhosis before clinical diagnosis. Among 62 cirrhotic patients, 28 patients were diagnosed with HCC during the follow‐up period. The levels of MAGE‐4 protein and a‐fetoprotein (AFP) were significantly elevated in cirrhotic patients with HCC. Univariate and multivariate analyses suggest that elevated serum MAGE‐4 protein is more significant than AFP. Importantly, retrospective analysis of prefrozen sera of cirrhotic patients revealed a transient or continuous elevation of serum MAGE‐4 protein levels in 14 of 28 cirrhotic patients with HCC (50%) before clinical diagnosis. In contrast, elevated serum MAGE‐4 protein levels were observed in 3 of 33 cirrhotic patients without HCC (9%), and in 2 of 34 hepatitic patients (6%). These results indicate that elevated serum MAGE‐4 protein levels can be a predictive marker of hepatocellular carcinogenesis in cirrhotic patients, thereby enabling us to treat patients at an earlier stage.
Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency
Authors: Yuen Kevin C. J. , Frystyk Jan , White Deborah K. , Twickler Th. B. , Koppeschaar Hans P. F. , Harris Philip E. , Fryklund Linda , Murgatroyd Peter R. , Dunger David B.
Published: September 2005

Objective  Untreated GH‐deficient adults are predisposed to insulin resistance and excess cardiovascular mortality. We showed previously that short‐term treatment with a very low GH dose (LGH) enhanced insulin sensitivity in young healthy adults. The present study was therefore designed to explore the hypothesis that LGH, in contrast to the standard GH dose titrated to normalize serum IGF‐I levels (SGH), may have differing effects on insulin sensitivity, body composition, and cardiovascular risk markers [lipid profile, C‐reactive protein (CRP), interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and adiponectin] in adults with severe GH deficiency.

Patients and methods  In this 12‐month open, prospective study, 25 GH‐deficient adults were randomized to receive either a fixed LGH (0·10 mg/day, n = 13) or SGH (mean dose 0·48 mg/day, n = 12), and eight age‐ and body mass index (BMI)‐matched GH‐deficient adults acted as untreated controls. Fasting blood samples were collected at baseline and at months 1, 3, 6, 9 and 12. Assessments of insulin sensitivity, using the hyperinsulinaemic euglycaemic clamp technique, and body composition, using dual‐energy X‐ray absorptiometry, were performed at baseline and at month 12.

Results  The LGH decreased fasting glucose levels (P < 0·01) and enhanced insulin sensitivity (P < 0·02), but body composition, nonesterified fatty acid (NEFA) levels and cardiovascular risk markers were unchanged. The SGH did not modify insulin sensitivity, decreased truncal fat mass (P < 0·05), CRP (P < 0·05) and IL‐6 (P < 0·05) levels, and increased NEFA levels (P < 0·05). No changes were observed with the untreated controls.

Conclusion  Our data indicate that, in contrast to the SGH, fixed administration of the LGH enhances insulin sensitivity with no apparent effects on body composition, lipolysis and other surrogate cardiovascular risk markers in adults with severe GH deficiency. Thus, the LGH may potentially be a beneficial replacement dose in reducing type 2 diabetes risk in adults with severe GH deficiency.
Ghrelin in human medullary thyroid carcinomas
Authors: Morpurgo P. S. , Cappiello V. , Verga U. , Vicentini L. , Vaghi I. , Lauri E. , Nebuloni M. , Beck‐Peccoz P. , Spada A.
Published: September 2005

Objective  Ghrelin is a novel gastrointestinal hormone involved in several metabolic functions. It has been identified previously in several normal and tumoral neuroendocrine tissues, including human medullary thyroid carcinomas (MTCs). The aim of the study was to evaluate ghrelin levels in patients with MTC and nontoxic goitre (NTG) with elevated calcitonin (CT) levels, as an additional marker of the disease.

Patients and design  The study included 22 patients with MTC (four before and 18 after thyroidectomy), 12 patients with NTG with basal CT levels exceeding 10 ng/l and 15 healthy subjects matched for age, sex and body mass index (BMI). After thyroidectomy, MTC patients were considered cured when basal and pentagastrin‐stimulated CT levels were < 0·2 and < 10 ng/l, respectively. A pentagastrin‐induced CT peak over 50 ng/l was considered as an abnormal response while 100 ng/l was the cut‐off accepted for the diagnosis of C‐cell hyperplasia or tumour. Circulating ghrelin and CT levels were evaluated at baseline in patients and controls and at −10, 0, 1, 2, 5 and 15 min after pentagastrin injection (0·5 µg/kg body weight) in 12 patients with MTC and nine with NTG. Four surgically removed MTCs were tested for ghrelin expression.

Measurements  Total plasma ghrelin and CT levels were measured with a commercially available radioimmunoassay (RIA) and two‐site chemiluminescence immunometric assays, respectively. In paraffin‐embedded MTC samples ghrelin immunostaining was performed with a polyclonal antibody (1 : 1000) and the reaction visualized by an indirect immunoperoxidase system.

Results  Plasma ghrelin levels found in cured or not cured MTC and in NTG patients were similar to those of BMI‐matched healthy controls. No correlation between ghrelin and CT levels, thyroid disease or previous thyroidectomy was observed. The administration of pentagastrin caused a 17% increase in ghrelin levels (basal ghrelin vs. peak: 162 ± 62 pmol/l vs. 189 ± 58 pmol/l, P < 0·05) that was particularly evident (33% increase) in patients with an abnormal CT response to the test (CT > 50 ng/l). Immunohistochemistry showed positivity for ghrelin in a small proportion of CT positive cells from the four MTCs removed.

Conclusions  Patients with MTC, NTG and controls showed similar ghrelin levels, ruling out this parameter as a marker of MTC. The increase in ghrelin levels in patients with a positive CT response to pentagastrin, together with the immunopositivity for ghrelin in some MTC cells, suggests C cells as minor source of ghrelin production.
In vivo activity of 11β‐hydroxysteroid dehydrogenase type 1 and free fatty acid‐induced insulin resistance
Authors: Mai K. , Kullmann V. , Bobbert T. , Maser‐Gluth C. , Möhlig M. , Bähr V. , Pfeiffer A. F. H. , Spranger J. , Diederich S.
Published: September 2005

Introduction  Free fatty acids (FFAs) induce hepatic insulin resistance and enhance hepatic gluconeogenesis. Glucocorticoids (GCs) also stimulate hepatic gluconeogenesis. The aim of this study was to investigate whether the FFA‐induced hepatic insulin resistance is mediated by increased activity of hepatic 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), accompanied by elevated hepatic cortisol levels.

Methods  Following a 10‐h overnight fast, six healthy male volunteers were investigated. A euglycaemic hyperinsulinaemic clamp was performed during lipid or saline infusion. To assess hepatic 11β‐HSD1 activity, plasma cortisol levels were measured after oral administration of cortisone acetate during lipid or saline infusion. In addition, 11β‐HSD activities were determined in vivo by calculating the urinary ratios of GC metabolites.

Results  Lipid infusion increased FFAs (5·41 ± 1·00 vs. 0·48 ± 0·20 mmol/l; P < 0·005) and significantly increased insulin resistance [glucose infusion rate (GIR) 6·02 ± 2·60 vs. 4·08 ± 2·15 mg/kg/min; P < 0·005]. After lipid and saline infusions no changes in 11β‐HSD1 activity were found, neither by changes in cortisone acetate to cortisol conversion nor by differences in urinary free cortisol (UFF) or cortisone (UFE), 5β‐tetrahydrocortisol (THF), 5α‐THF, cortisone (THE), UFF/UFE and (5α‐THF + THF)/THE ratios.

Conclusions  We found no change in hepatic and whole‐body 11β‐HSD1 activity during acute FFA‐induced insulin resistance. Further studies are necessary to clarify whether 11β‐HSD1 in muscle and adipose tissue is influenced by FFAs and whether 11β‐HSD1 is involved in other conditions of insulin resistance.
Hypertension in acromegaly and in the normal population: prevalence and determinants
Authors: Vitale Giovanni , Pivonello Rosario , Auriemma Renata S. , Guerra Ermelinda , Milone Francesco , Savastano Silvia , Lombardi Gaetano , Colao Annamaria
Published: September 2005

Background  The GH/IGF‐I axis has a relevant role to play in the cardiovascular system but its implication in the pathogenesis of hypertension in the normal population and in acromegaly is not yet clear.

Patients and measurements  The aim of this retrospective and controlled study was to evaluate the prevalence and determinants of hypertension in 200 patients with acromegaly and 200 nonacromegalic subjects, matched for sex, age, body mass index (BMI) and smoking habits.

Results  Hypertension was found in 46% of patients and in 25% of controls (P < 0·0001), without any difference between men and women. Family history of hypertension occurred in 30% of hypertensive acromegalic patients and in 62% of hypertensive controls (P < 0·0001). In both groups, hypertensive subjects were older than normotensive subjects. Systolic (SBP) and diastolic blood pressures (DBP) in hypertensive acromegalic patients were lower and higher, respectively, than in hypertensive controls. The risk of hypertension increased with age and was higher in the patients than in the controls [hazard ratio (HR) 1·9; P = 0·0002]. Independent predictors of SBP were age and glucose in the acromegalic population, and BMI, age and glucose levels in the controls. Independent predictors of DBP were age and glucose in the patients, and BMI, age and IGF‐I in the controls.

Conclusions  In acromegaly, hypertension is more frequent than in the general population, involves predominantly DBP, and occurs earlier, is not related to gender, and is less frequently related to family history of hypertension and IGF‐I levels. IGF‐I may have a protective role for DBP in the general population.
Indoleamine 2,3 dioxygenase and human leucocyte antigen‐G inhibit the T‐cell alloproliferative response through two independent pathways
Authors: Le Rond Solène , Gonzalez Alvaro , Gonzalez Ana S. L. , Carosella Edgardo D. , Rouas‐Freiss Nathalie
Published: September 2005

Both human leucocyte antigen (HLA)‐G and indoleamine 2,3 dioxygenase (IDO) are key molecules involved in immune tolerance. HLA‐G is a non‐classical HLA class I molecule that can be expressed in both membrane‐bound (HLA‐G1) and soluble (HLA‐G5) forms, both of which exhibit tolerogenic properties via interaction with inhibitory receptors present on natural killer (NK) cells, T cells and antigen‐presenting cells (APC). IDO is an enzyme that acts by depleting the surrounding microenvironment of the essential amino acid, tryptophan, thereby inhibiting T‐cell proliferation. Our present study was aimed at analysing the potential link that may exist between IDO and HLA‐G. Our results showed that during allogeneic reactions, soluble HLA‐G expression was not regulated by the addition of IDO substrate (i.e. tryptophan), metabolite (i.e. kynurenine) or inhibitor (i.e. 1‐methyl‐tryptophan), that IDO activity was not altered by HLA‐G5 treatment, and that HLA‐G5‐mediated inhibition of the T‐cell alloproliferative response was neither affected by the presence of tryptophan and kynurenine nor reversed after IDO activity blockage, demonstrating that HLA‐G5 can exert its function in the absence of functional IDO. Similarly, inhibition of the T‐cell alloresponse, induced by HLA‐G1‐expressing antigen‐presenting cells, was not altered by IDO metabolites or inhibitor. Taken together, these findings show that the function and expression of IDO and HLA‐G5 are not mutually influenced, but rather inhibit the T‐cell alloproliferative response through two independent pathways. IDO and HLA‐G are thus complementary for inducing and maintaining immune tolerance in physiological (pregnancy) and pathological (tumour and allograft) situations.
Gambol and Tc1 are two distinct families of DD34E transposons: analysis of the Anopheles gambiae genome expands the diversity of the IS630‐Tc1‐mariner superfamily
Authors: Coy M. R. , Tu Z.
Published: September 2005

Tc1 is a family of DNA transposons found in diverse organisms including vertebrates, invertebrates and fungi. Tc1 belongs to the IS630‐Tc1‐mariner superfamily, which is characterized by common ‘TA’ target site and conserved D(Asp)DE(Glu) or DDD catalytic triad. All functional Tc1‐like transposons contain a transposase with a DD34E catalytic triad. We conducted a systematic analysis of DD34E transposons in the African malaria mosquito, Anopheles gambiae, using a reiterative and exhaustive search program. In addition to previously described Tc1‐like elements, we uncovered 26 new DD34E transposons including a novel family that we named gambol. Designation of family status to gambol is based on phylogenetic analyses of transposase sequences that showed gambol and Tc1 transposons as distinct clades that were separated by mariner and other families of the IS630‐Tc1‐mariner superfamily. The distinction between Tc1 and gambol is also consistent with the unique TIRs in gambol elements and the presence of a ‘W[I/L/V]DEDC’ signature near their N‐termini. This signature is predicted as part of the ‘RED’ domain, a component of the ‘PAI’ and ‘RED’ DNA binding domains in Tc1 and possibly mariner. Although gambol appears to be related to a few DD34E transposons from cyanobacteria and fungi, no gambol has been reported in any other insects or animals thus far. Several gambol and Tc1 elements have intact ORFs and different genomic copies with high sequence identity, which suggests that they may have been recently active.
Nurses’ assessment of pain in surgical patients
Authors: Sloman Rod , Rosen Gila , Rom Miriam , Shir Yoram
Published: September 2005

Aim.  This paper reports a study to compare nurses’ ratings of pain intensity and suffering (affect) in adult surgical patients with patients’ own ratings of these variables, and to investigate whether pain ratings were influenced by cultural and ethnic differences.

Background.  Studies show that postoperative pain continues to be under‐treated in a large proportion of cases. The problem may be partly due to inaccurate pain assessment by nurses.

Method.  A convenience sample of 95 patients and 95 nurses in adult surgical units was selected from four hospitals in Jerusalem, Israel in 2003–2004. A questionnaire was administered to each patient by the researcher. The questionnaire included: (a) a Hebrew translation of the Short‐Form McGill Pain Questionnaire for pain sensation, pain affect, and present pain intensity at rest and on movement; (b) visual analogue scales for overall pain intensity, suffering, and satisfaction with treatment; and (c) demographic and cultural data. Within a few minutes of the patient completing the questionnaire, a nurse who had been allocated to care for that patient made an independent assessment of the patient's pain. The nurse then left the patient's room and filled in the same questionnaire.

Findings.  Nurses significantly underestimated all dimensions of pain on the above scales, but accurately assessed patient treatment satisfaction. There were no statistically significant effects for cultural and ethnic differences in pain assessment. Both types of clinical area where nurses worked and nurses’ level of nursing education were found not to influence their assessment.

Conclusion.  The findings have implications for the management of postoperative pain by highlighting the need for more accurate pain assessment. Further research is required to elucidate the way in which nurses and patients conceptualize pain and to understand better the process of pain assessment in clinical nursing practice.
Midwives’ visual interpretation of intrapartum cardiotocographs: intra‐ and inter‐observer agreement
Authors: Devane Declan , Lalor Joan
Published: September 2005

Aim.  This paper reports an examination of intra‐ and inter‐observer agreement in midwives’ visual interpretation of intrapartum cardiotocographs (CTGs).

Background.  The issue of intra‐ and inter‐observer agreement in the interpretation of CTG interpretation has serious implications for the validity of electronic fetal heart rate monitoring and subsequent decisions on intrapartum management. However, no studies were found that assessed intra‐ and inter‐observer agreement in midwives’ interpretations of CTG tracings.

Methods.  Twenty‐eight midwives independently interpreted three intrapartum CTG tracings on two separate occasions using a self‐administered Cardiotocograph Interpretation Skills Test. Inter‐rater agreement in interpretation was assessed by cross‐tabulating the two sets of raw data obtained at time 1 and time 2 and computing Cohen's Kappa (κ). Intra‐rater agreement was assessed by computing κ for each rater with the two sets of raw data (time 1 and time 2) obtained from each individual. The data were collected in 2000.

Results.  Overall intra‐rater agreement ranged from ‘fair to good’ (κ = 0·48) to ‘excellent’ (κ = 0·92). Raters’ classifications altered in 18% (n = 5) of cases for the normal tracing, in 29% (n = 8) for the suspicious tracing and in 11% (n = 3) for the pathological tracing. Inter‐rater agreement was fair to good, with κ statistics ranging from 0·65 to 0·74, respectively. Agreement was highest in the classification of decelerations (κ = 0·79) and lowest in the assessment of baseline variability (κ = 0·50). Overall inter‐rater agreement was highest in the suspicious tracing (κ = 0·77, excellent) and lowest in the normal tracing (κ = 0·54, fair to good).

Conclusion.  Inter‐ and intra‐observer variability are intrinsic characteristics of the interpretation of intrapartum CTGs. Levels of agreement revealed degrees of variation that expose room for improvement. Efforts are needed to reduce inter‐ and intra‐observer variation in interpretation of intrapartum CTG tracings. In addition, research should focus on the development and evaluation of non‐invasive, low observer variability methods of intrapartum assessment of fetal well‐being. The subjectivity of CTG interpretation and inconsistencies in interpretation should also be considered in intrapartum management, clinical audit and in medico‐legal settings.
Simulating biological impairment to evaluate the accuracy of ecological indicators
Authors: CAO YONG , HAWKINS CHARLES P.
Published: September 2005

Biological indicators are used to measure the biological health of ecosystems. Resource managers may uncritically assume that such indicators give unbiased estimates of true biological condition, but this assumption is largely untested. Use of biased indicators could lead to ineffective and potentially damaging management.

We used a simulation model to compare estimated indicator values objectively with true impairment. We used the model to progressively alter the densities of 155 stream invertebrate taxa as functions of stress and taxon‐specific sensitivities to stress. We applied the model to large samples collected from five reference‐quality sites. After each stress event, we randomly collected 100, 300 and 600 fixed‐count subsamples from the remaining assemblages and recorded the densities of all taxa in both the large sample and the fixed‐count subsamples. We then examined how well two indicators, non‐metric multidimensional scaling (NMDS) and sample taxa richness, detected the simulated impairment when derived from fixed‐count subsamples.

NMDS ordinations of artificially impaired samples, and samples from reference and impaired sites, showed that the simulated impairments were realistic. NMDS further showed that impairment trajectories were evident for subsamples of 100, 300 and 600 individuals. However, the discrimination of stress levels within ordination space greatly improved with increasing sampling effort. The ordination also showed that increasing stress could cause assemblages at some sites to resemble unstressed assemblages at other sites.

Taxa‐richness indicators were much more problematic. Estimates of taxa richness from 100‐ and 300‐count samples often substantially underestimated true taxa loss and frequently indicated taxa gain. Apparent gains in taxa richness occurred because stress caused changes in evenness that compensated for, or even overrode, the effect of true taxa loss. Estimates of taxa loss derived from 600‐count subsamples also underestimated true taxa loss, but these estimates were strongly correlated with true taxa loss.

Synthesis and applications. Bioassessements that rely on richness‐based indicators derived from small fixed‐count subsamples may substantially underestimate true biological impairment. Simulation models provide an objective means to evaluate how well different types of biotic indicators measure true biological impairment in aquatic and other types of ecosystems.
Elevational gradients of species diversity, breeding system and floral traits of orchid species on Réunion Island
Authors: Jacquemyn Hans , Micheneau Claire , Roberts David L. , Pailler Thierry
Published: September 2005

Aim  This research investigates changes in orchid species composition and diversity, plant breeding system and floral traits along an elevational gradient spanning 2300 m (200–2500 m).

Location  The study was conducted on Réunion Island (Mascarene Islands, Indian Ocean).

Methods  Data on the distribution of 135 orchid species from 35 genera were gathered from 121 localities situated between 200 and 2500 m a.s.l. For each locality, 500‐m transects were walked and each orchid species was recorded. Measures of species diversity (species richness, a modified Shannon diversity index and the modified Shannon equitability index) were related to altitude using ordinary least‐squares regression. Species turnover and elevational gradients in species composition were determined by: (1) relating scores of detrended correspondence analysis to altitude using ordinary least‐squares regression, and (2) relating Sørensen similarity indices to differences in altitude using Mantel tests. Finally, the average proportion of species displaying similar floral traits or showing the same breeding system were compared among altitudinal zones.

Results  Species richness per transect ranged from 1 to 36 species (mean 14.3) and decreased significantly with increasing altitude. Similarly, species evenness decreased significantly with increasing altitude. Around 50% of all orchid species were rare (occurred in fewer than 5% of all localities), and only a few occurred in more than 50% of all localities. Orchid species composition changed continuously with altitude, indicating turnover of species with increasing altitude. Analogously, orchid breeding systems and floral traits also changed with altitude. Relatively more auto‐pollinating species were found at high altitudes compared with mid‐ and low‐altitude sites where animal‐pollinated species were most abundant. Species characterized by a cleistogamous pollination system were found almost exclusively in high‐altitude sites, whereas the proportion of species displaying floral traits related to pollination by long‐tongued moths (sphinx) and flies sharply decreased with increasing altitude.

Main conclusions  Environmental conditions associated with altitude exert a large influence on orchid species composition and the distribution of orchid breeding systems. Our results revealed a high proportion of auto‐pollinating species, and confirm earlier findings that auto‐pollinating species are more frequent in high‐altitude sites.
Body size evolution in insular vertebrates: generality of the island rule
Authors: Lomolino Mark V.
Published: September 2005

Aim  My goals here are to (1) assess the generality of the island rule – the graded trend from gigantism in small species to dwarfism in larger species – for mammals and other terrestrial vertebrates on islands and island‐like ecosystems; (2) explore some related patterns of body size variation in insular vertebrates, in particular variation in body size as a function of island area and isolation; (3) offer causal explanations for these patterns; and (4) identify promising areas for future studies on body size evolution in insular vertebrates.

Location  Oceanic and near‐shore archipelagos, and island‐like ecosystems world‐wide.

Methods  Body size measurements of insular vertebrates (non‐volant mammals, bats, birds, snakes and turtles) were obtained from the literature, and then regression analyses were conducted to test whether body size of insular populations varies as a function of body size of the species on the mainland (the island rule) and with characteristics of the islands (i.e. island isolation and area).

Results  The island rule appears to be a general phenomenon both with mammalian orders (and to some degree within families and particular subfamilies) as well as across the species groups studied, including non‐volant mammals, bats, passerine birds, snakes and turtles. In addition, body size of numerous species in these classes of vertebrates varies significantly with island isolation and island area.

Main conclusions  The patterns observed here – the island rule and the tendency for body size among populations of particular species to vary with characteristics of the islands – are actually distinct and scale‐dependent phenomena. Patterns within archipelagos reflect the influence of island isolation and area on selective pressures (immigration filters, resource limitation, and intra‐ and interspecific interactions) within particular species. These patterns contribute to variation about the general trend referred to as the island rule, not the signal for that more general, large‐scale pattern. The island rule itself is an emergent pattern resulting from a combination of selective forces whose importance and influence on insular populations vary in a predictable manner along a gradient from relatively small to large species. As a result, body size of insular species tends to converge on a size that is optimal, or fundamental, for a particular bau plan and ecological strategy.
Species richness, environmental heterogeneity and area: a case study based on land snails in Skyros archipelago (Aegean Sea, Greece)
Authors: Triantis K. A. , Mylonas M. , Weiser M. D. , Lika K. , Vardinoyannis K.
Published: September 2005

Aim  To test the performance of the choros model in an archipelago using two measures of environmental heterogeneity. The choros model is a simple, easy‐to‐use mathematical relationship which approaches species richness as a combined function of area and environmental heterogeneity.

Location  The archipelago of Skyros in the central Aegean Sea (Greece).

Methods  We surveyed land snails on 12 islands of the archipelago. We informed the choros model with habitat data based on natural history information from the land snail species assemblage. We contrast this with habitat information taken from traditional vegetation classification to study the behaviour of choros with different measures of environmental heterogeneity. R2 values and Akaike's information criterion (AIC) were used to compare the choros model and the Arrhenius species–area model. Path analysis was used to evaluate the variance in species richness explained by area and habitat diversity.

Results  Forty‐two land snail species were recorded, living in 33 different habitat types. The choros model with habitat types had more explanatory power than the classic species–area model and the choros model using vegetation types. This was true for all islands of the archipelago, as well as for the small islands alone. Combined effects of area and habitat diversity primarily explain species richness in the archipelago, but there is a decline when only small islands are considered. The effects of area are very low both for all the islands of the archipelago, and for the small islands alone. The variance explained by habitat diversity is low for the island group as a whole, but significantly increases for the small islands.

Main conclusions  The choros model is effective in describing species‐richness patterns of land snails in the Skyros Archipelago, incorporating ecologically relevant information on habitat occupancy and area. The choros model is more effective in explaining richness patterns on small islands. When using traditional vegetation types, the choros model performs worse than the classic species–area relationship, indicating that use of proxies for habitat diversity may be problematic. The slopes for choros and Arrhenius models both assert that, for land snails, the Skyros Archipelago is a portion of a larger biogeographical province. The choros model, informed by ecologically relevant habitat measures, in conjunction with path analysis points to the importance of habitat diversity in island species richness.
Diagnosis: contemporary medical hubris; Rx: a tincture of humility
Authors: Genuis Stephen J.
Published: September 2005

Despite increasing attention to evidence‐based medicine, unprecedented advances in medical technology, and rapid diffusion of innovative information, there continues to be disturbing disclosures of widespread iatrogenic illness resulting from harmful medical interventions. The medical community at times displays a lethargic and lackluster response to important scientific and epidemiological data that challenges prevailing conventional wisdom or that elucidates existing medical miscalculations. To ensure that long‐term health and well‐being for patients and the community remains the primary goal of medicine, it is necessary to revisit the important issues of scientific integrity, health care objectives, and medical professionalism. Furthermore, to be trustworthy advisors for individual patients and credible advocates for the health of populations, the medical community needs to critically evaluate the profound influence of commercial interests on medical research, medical education and clinical practice.
Oxygen therapy in hospitalized patients: the impact of local guidelines
Authors: Kbar Fazal A , Campbell Ian Allen
Published: September 2005

Objective  To study the influence of local guidelines on the behaviour of nursing  and  medical  staff  to  optimize  the  oxygen  use  in  patients  admitted to hospital.

Methods  Study was performed in a district teaching hospital. Guidelines produced suggested indications, monitoring, use of arterial blood gases (ABGs) and advice on when to stop oxygen therapy. The guidelines were implemented both verbally and in writing to all the nursing and medical staff before and after an audit studying the oxygen use by patients on medical and surgical wards.

Results  Ninety patients were included in pre‐intervention audit and 59 in post‐intervention study. Oxygen prescription did not change with guidelines 30% (27/90) vs. 32% (19/59). Nurses administered oxygen better 95% (18/19) vs. 70% (19/27) (P = 0.043) and monitored more frequently using oximetry 91% (54/59) vs. 69% (62/90) (P = 0.001) after the guidelines. Patients with airway disease had their ABGs checked more frequently 87% (14/16) vs. 65% (15/23) on admission and after they started oxygen inhalation 68% (11/16) vs. 34% (8/23).

Conclusion  The guidelines disseminated verbally and in writing had no influence on oxygen prescription but improved the practice of close monitoring of patients with airway disease. Nurses improved their performance of both administration of oxygen according to the prescribed dose and monitoring with oximetry.
Amyloid beta peptide causes chronic glial cell activation and neuro‐degeneration after intravitreal injection
Authors: Walsh D. T. , Bresciani L. , Saunders D. , Manca M. F. , Jen A. , Gentleman S. M. , Jen L. S.
Published: September 2005

We have previously demonstrated that amyloid beta (Aβ) peptide is acutely toxic to retinal neurones in vivo and that this toxicity is mediated by an indirect mechanism. We have now extended these studies to look at the chronic effect of intravitreal injection of Aβ peptides on retinal ganglion cells (RGC), the projection neurones of the retina and the glial cell response. 5 months after injection of Aβ1−42 or Aβ42−1 there was no significant reduction in RGC densities but there was a significant reduction in the retinal surface area after both peptides. Phosphate‐buffered saline (PBS) injection had no effect on retinal size or RGC density. There was a pronounced reduction in the number of large RGCs with a concomitant significant increase in medium and small RGCs. There was no change in cell sizes 5 months after injection with PBS. At 5 months after injection of both peptides, there was marked activation of Muller glial cells and microglia. There was also expression of the major histocompatibility complex (MHC) class II molecule on some of the microglial cells but we saw no evidence of T‐cell infiltration into the injected retinas. In order to elucidate potential toxic mechanisms, we have looked at levels of glutamine synthetase and nitric oxide synthase. As early as 2 days after injection we noted that activation of Muller glia was associated with a decrease in glutamine synthetase immuno‐reactivity but there was no detectable expression of inducible nitric oxide synthase in any retinal cells. These results suggest that chronic activation of glial cells induced by Aβ peptides may result in chronic atrophy of projection neurones in the rat retina.
Expression of allograft inflammatory factor‐1 and haeme oxygenase‐1 in brains of rats infected with the neurotropic Borna disease virus
Authors: Herden C. , Schluesener H. J. , Richt J. A.
Published: September 2005

Experimental infection of Lewis rats with Borna disease virus (BDV) causes an immune‐mediated nonpurulent meningoencephalitis. Viral persistence in the central nervous system is accompanied by mononuclear infiltrates, activated monocytic/microglial cells and reactive astrocytes. The immune‐mediated process was further characterized by expression analysis of allograft inflammatory factor‐1 (AIF‐1), a novel marker of monocyte/microglial activation and of glial fibrillary acid protein (GFAP) between day 3 and day 50 post infection (p.i.). Potential neuroprotective effects of these cells were studied by the induction of haeme oxygenase‐1 (HO‐1), a defensive molecule against oxidative stress in various brain insults. In BDV‐infected rat brains, mononuclear infiltrates and AIF‐1 expression increased up to day 28 p.i. During early time points p.i., AIF‐1 expression was mainly found in inflammatory lesions and adjacent brain parenchyma. Already 24 days p.i., a widespread upregulation of AIF‐1 was observed which declined only moderately beyond day 28 p.i. HO‐1 induction was maximal between days 18 and 28 p.i. Increased amounts of GFAP‐positive astrocytes were present beyond 24 days p.i. Viral antigen expression increased simultaneously to the inflammatory reaction and persisted up to 50 days p.i. Widespread upregulation of AIF‐1 indicates an early, long‐lasting microglial activation, which might be involved in the immunesurveillance of the immune‐mediated inflammatory events. The early peak of HO‐1 most likely represents a neuroprotective, anti‐inflammatory response by invading monocytes, microglial cells and astrocytes during the formation of encephalitic lesions and acute viral replication.
Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux–Lamy) disease
Authors: Walkley S. U. , Thrall M. A. , Haskins M. E. , Mitchell T. W. , Wenger D. A. , Brown D. E. , Dial S. , Seim H.
Published: September 2005

Mucopolysaccharidosis (MPS) type VI, also known as Maroteaux–Lamy disease, is an inherited disorder of glycosaminoglycan  catabolism  caused  by  deficient  activity of the lysosomal hydrolase, N‐acetylgalactosamine 4‐sulphatase (4S). A variety of prominent visceral and skeletal defects are characteristic, but primary neurological involvement has generally been considered absent. We report here that the feline model of MPS VI exhibits abnormal lysosomal storage in occasional neurones and glia distributed throughout the cerebral cortex. Abnormal lysosomal inclusions were pleiomorphic with some resembling zebra bodies and dense core inclusions typical of other MPS diseases or the membranous storage bodies characteristic of the gangliosidoses. Pyramidal neurones were shown to contain abnormal amounts of GM2 and GM3 gangliosides by immunocytochemical staining and unesterified cholesterol by histochemical (filipin) staining. Further, Golgi staining of pyramidal neurones revealed that some possessed ectopic axon hillock neurites and meganeurites similar to those described in Tay–Sachs and other neuronal storage diseases with ganglioside storage. Some animals evaluated in this study also received allogeneic bone marrow transplants, but no significant differences in neuronal storage were noted between treated and untreated individuals. These studies demonstrate that deficiency of 4S activity can lead to metabolic abnormalities in the neurones of central nervous system in cats, and that these changes may not be readily amenable to correction by bone marrow transplantation. Given the close pathological and biochemical similarities between feline and human MPS VI, it is conceivable that children with this disease have similar neuronal involvement.
Comparative study of three diagnostic approaches (FISH, STRs and MLPA) in 30 patients with 22q11.2 deletion syndrome
Authors: Fernández L , Lapunzina P , Arjona D , López Pajares I , García‐Guereta L , Elorza D , Burgueros M , De Torres ML , Mori MA , Palomares M , García‐Alix A , Delicado A
Published: September 2005

The 22q11.2 deletion syndrome is commonly diagnosed using fluorescence in situ hybridization (FISH) with commercial probes. The chromosomal breakpoints and deletion size are subsequently characterized by short tandem repeat (STR) segregation tests or by further FISH probes. Recently, a multiplex ligation‐dependent probe amplification (MLPA) single tube assay was developed to detect deletions of the 22q11.2 region and other chromosomal regions associated with DiGeorge/velocardiofacial syndrome. We have compared the results of these three techniques in a group of 30 patients affected with 22q11.2 deletion syndrome. MLPA correctly called all patients who had been previously diagnosed by FISH. The MLPA results were concordant in all patients with the STR analysis in respect to deletion size. Furthermore, this novel technique resolved seven cases that were undetermined by STR analysis. These results confirm the efficiency of MLPA as a rapid, reliable, economical, high‐throughput method for the diagnosis of 22q11.2 deletion syndrome.