bluuebunny/crossref_metadata_2025 huggingface dataset:
An observational study of changes to long‐term medication after admission to an intensive care unit*
Authors: Campbell A. J. , Bloomfield R. , Noble D. W.
Published: October 2006

Many patients admitted to intensive care units consume long‐term medication. New drugs may be commenced during intensive care intended for the short term or longer. Patients are often cared for by several teams during hospital admission and long‐term medication may inadvertently be permanently discontinued. Following admission, new therapies relevant only in the short term could be continued beyond intensive care and hospital discharge. We conducted a retrospective analysis of drug prescription by examining patients' notes and charts before, during and after intensive care admission. Of 197 drugs prescribed up to intensive care admission to 59 patients, 112 (57%) were stopped. Ninety‐nine of these were not reintroduced by intensive care discharge and 34 were not reintroduced by hospital discharge. Of 154 drugs commenced during intensive care, 96 (62%) had no listed reason for their introduction. Twenty‐eight were continued beyond hospital discharge, some without apparent ongoing indication. Reliable mechanisms to prevent prescription errors are required.
An open‐label, unit dose‐finding study of AMG 531, a novel thrombopoiesis‐stimulating peptibody, in patients with immune thrombocytopenic purpura
Authors: Newland Adrian , Caulier Marie T. , Kappers‐Klunne Mies , Schipperus Martin R. , Lefrere Francois , Zwaginga Jaap J. , Christal Jenny , Chen Chien‐Feng , Nichol Janet L.
Published: October 2006

The objective of this open label, phase 1–2, multicentre trial was to evaluate the safety of AMG 531, a novel thrombopoiesis‐stimulating peptibody, and its effect on platelet counts in adults with immune thrombocytopenic purpura. Four patients were assigned to each of four unit‐dose cohorts: 30, 100, 300 or 500 μg, administered subcutaneously on days 1 and 15 (or day 22 if the day 15 platelet count was >50 × 109/l). Safety was assessed by adverse event (AE) monitoring, clinical laboratory studies and antibody assays. Platelet response was defined as a platelet count double the baseline value and between 50 and 450 × 109/l. Sixteen patients (10 women) were enrolled. The 500‐μg cohort was discontinued because the first patient's platelet count became unacceptably high. AEs were generally expected and mild or moderate; the most frequent was headache (eight of 16 patients). Two patients experienced serious AEs related to AMG 531 (severe headache and elevated serum lactic dehydrogenase; thrombocytopenia). Platelet responses occurred with all doses and with a dose equivalent to ≥1 μg/kg in eight of 11 patients. In summary, patients tolerated AMG 531 well at the doses tested. No anti‐AMG or antithrombopoietin antibodies were detected. Doses equivalent to ≥1 μg/kg increased platelet counts.
Recombinant factor VIIa in paediatric bleeding disorders – a 2006 review
Authors: MATHEW P. , YOUNG G.
Published: October 2006

Summary.  Recombinant factor VIIa (rFVIIa) has been used in haemophilia bleeding since its introduction in 1996. It has been found to be safe and effective in the majority of patients with haemophilia who have developed inhibitors. There is increasing use of rFVIIa in many off‐label bleeding conditions, but there is a paucity of randomized studies regarding the use of rFVIIa in children. This review will attempt to address and summarize the studies focusing on the role of rFVIIa in both haemophilia and non‐haemophilia bleeding conditions in children. rFVIIa has been administered as both bolus and continuous infusions, and at varying doses. Furthermore, adverse events have not reportedly increased in children despite growing experience with its use in the paediatric population.
Epidemiology of inhibitor formation with recombinant factor VIII replacement therapy
Authors: PEERLINCK K. , HERMANS C.
Published: October 2006

Summary.  This article reviews the epidemiology of inhibitor formation in patients receiving recombinant factor VIII (rFVIII) replacement therapy for haemophilia A. Data from pivotal trial programmes, post‐marketing surveillance studies, and pharmacovigilance studies for all available rFVIII products were reviewed. To date, no comparative studies have been performed, and in the non‐comparative studies, there were differences in the patient population enrolled and study design (including the number of patient exposure days). In the absence of comparative clinical trials, it is not possible to make comparisons between inhibitor data for the various rFVIII products. This review of the epidemiological data shows that across the pivotal trial programmes for rFVIII products, the observed incidence of inhibitors was in the range of 15–32% in previously untreated patients (PUPs) and 0.9–2.9% in previously treated patients (PTPs). High‐titre inhibitors (peak >5 BU) were detected in 10–16% of PUPs and 0–2.3% of PTPs. Several initiatives proposed to help standardize collection and interpretation of inhibitor data for patients receiving rFVIII treatment are described. Such standardization would help to clarify the epidemiology of inhibitor formation across FVIII treatments.
Management of acute bleeding in a patient with congenital afibrinogenaemia
Authors: VAKALOPOULOU S. , RIZOPOULOU D. , ZAFIRIADOU E. , PERIFANIS V. , TZIOMALOS K. , LEFKOU E. , HILL M. , DOLAN G. , GARIPIDOU V.
Published: October 2006

Summary.  Congenital afibrinogenaemia is a rare bleeding disorder characterized by absence of fibrinogen and varying bleeding tendency. Treatment with fibrinogen concentrates is considered to be the best choice for afibrinogenaemic patients who experience bleeding. We report the case of a 22‐year‐old Greek patient who presented with large muscular haematomas and was treated with fibrinogen concentrates. The efficacy of this treatment and the problems that arose during his hospitalization are being discussed.
Influence of factor VIII on overall coagulability and fibrinolytic potential of haemophilic plasma as measured by global assay: monitoring in haemophilia A
Authors: GOLDENBERG N. A. , HATHAWAY W. E. , JACOBSON L. , MCFARLAND K. , MANCO‐JOHNSON M. J.
Published: October 2006

Summary.  The objectives of the present study were to evaluate the analytical sensitivity of the recently developed Clot Formation and Lysis (CloFAL) global assay for factor VIII (FVIII) deficiency, both in vitro and ex vivo, to determine whether this global assay is influenced by FVIII inhibitors, and to investigate the coagulative response to FVIII replacement in haemophilia A patients using the CloFAL assay in comparison with FVIII activity. Among adults and children alike, the CloFAL assay coagulation index (CI) was significantly decreased in FVIII‐deficient vs. healthy subjects (adults median CI: 2% vs. 94% respectively; children median CI: 3% vs. 63%; P < 0.001 for each), and correlated significantly with activated partial thromboplastin time‐based FVIII activity across all individuals (r = 0.78; P < 0.001). The CloFAL assay was analytically sensitive to deficient FVIII activity and also influenced by the presence of von Willebrand factor. Severe haemophilia A patients without inhibitory antibodies to FVIII showed considerable heterogeneity in CloFAL assay waveforms, despite a uniformly diminished CI of 0–1%. During FVIII infusion half‐life studies in patients with severe haemophilia A, the CloFAL assay demonstrated a marked rise in coagulability 30 min following infusion, with progressive decrease in coagulability towards baseline over the ensuing 48‐h period. In each case, the profile of coagulative response to FVIII infusion as determined by CloFAL assay CI differed qualitatively from that measured by FVIII activity. These findings indicate that the CloFAL assay may be useful as an adjunctive test to FVIII activity measurements in the therapeutic monitoring of haemophilia A.
Screening for factor XI deficiency amongst pregnant women of Ashkenazi Jewish origin
Authors: KADIR R. A. , KINGMAN C. E. C. , CHI C. , O'CONNELL N. M. , RIDDELL A. , LEE C. A. , ECONOMIDES D. L.
Published: October 2006

Summary.  A pilot study was conducted over a 6‐month period to evaluate antenatal screening for factor XI (FXI) deficiency amongst Ashkenazi Jewish women booking for their pregnancy in a single obstetric unit. Fifty‐four women of Ashkenazi Jewish origin were recruited during their visit for the routine first trimester ultrasound scan. They completed a questionnaire about their personal bleeding symptoms and had blood taken for FXI levels (FXI:C). Seven (13%) women had partial FXI deficiency. Five (9%) were newly diagnosed, and in the remaining two, the diagnosis was known previously. One infant with severe FXI deficiency was identified as a result of maternal testing. This study has shown that FXI deficiency is common amongst women of Ashkenazi Jewish origin and supports its antenatal screening in this population. However, further studies are required to evaluate its cost‐effectiveness and the effect on pregnancy outcome.
Rituximab treatment of mild haemophilia A with inhibitors: a proposed treatment protocol
Authors: DUNKLEY S. , KERSHAW G. , YOUNG G. , WARBURTON P. , LINDEMAN R. , MATTHEWS S. , RENNISSON F.
Published: October 2006

Summary.  Inhibitors are an uncommon complication of mild haemophilia A but represent a severe disease, typically with high titre inhibitors and an associated high rate of bleeding. We present data from three patients with MHAI who were successfully treated with Rituximab alone and unequivocally prove that such inhibitors respond to this agent. A treatment protocol is suggested.
Distribution and microhabitats of native and non‐native gammarids (Amphipoda, Crustacea) in Brittany, with particular reference to the endangered endemic sub‐species Gammarus duebeni celticus
Authors: Piscart Christophe , Manach Alain , Copp Gordon H. , Marmonier Pierre
Published: October 2006

Aim  To assess temporal changes in gammarid distribution in Brittany and microhabitat‐use overlap between the endangered endemic Gammarus duebeni celticusStock & Pinkster, 1970, the expanding natives G. pulex (Linnaeus, 1758) and Echinogammarus berilloni (Catta, 1878), and the introduced G. tigrinus Sexton, 1939.

Location  Brittany and adjacent regions in western France.

Methods  The spatial and temporal patterns in distribution of gammarids at the scale of Brittany were studied using 351 sites. Longitudinal distributions (from the source to the estuary of the river) and microhabitat‐use (substratum type and water velocity) were also considered in selected rivers.

Results  At the regional scale, all species occurred together less often than expected statistically, with significant deviations from expected for G. pulex vs. both G. duebeni celticus and G. tigrinus, and for E. berilloni vs. both G. duebeni celticus and G. tigrinus. However, at the microhabitat scale, E. berilloni occurred significantly more often than expected with the endemic G. duebeni celticus, and this appears to be due to similar substratum and water velocity preferences, although at both the regional and microhabitat scales E. berilloni prefers wider streams than G. duebeni celticus. This study reveals a decline in the endangered G. duebeni celticus since 1970.

Main conclusions  The longitudinal and local distributions of G. duebeni celticus, and the higher‐than‐expected co‐occurrence of the species with G. pulex, suggest that the decline of the endemic species may be due to changes in the environment and/or interference from native G. pulex, which is expanding its range in Brittany. The results are discussed as regards to the consequences for regional biodiversity.
Clinical nurse specialists as entrepreneurs: constrained or liberated
Authors: Austin Lynn , Luker Karen , Ronald Martin
Published: October 2006

Aims.  This qualitative study explored the experiences of two groups of clinical nurse specialists – continence advisors and tissue viability nurses – working in primary care in the UK. In particular, the study focused on how clinical nurse specialists’ relationships with other health‐care professionals had an impact on their role.

Background.  Clinical nurse specialists are recognized worldwide as having expertise in a given field, which they use to develop the practice of others. Additionally, clinical nurse specialists share many of the characteristics of entrepreneurs, which they use to develop services related to their speciality. However, little research has been conducted in relation to clinical nurse specialists’ experiences as they attempt to diversify nursing practice.

Design/methods.  An ethnographic approach was adopted comprising many elements of Glaserian grounded theory. Data were collected via participant observation and face‐to‐face interviews with 22 clinical nurse specialists.

Findings.  Services provided by clinical nurse specialists were not static, clinical nurse specialists being the main drivers for service developments. However, clinical nurse specialists encountered difficulties when introducing new ideas. Given their role as advisors, clinical nurse specialists lacked authority to bring about change and were dependent on a number of mechanisms to bring about change, including ‘cultivating relationships’ with more powerful others, most notably the speciality consultant.

Conclusions.  The UK government has pledged to ‘liberate the talents of nurses’ so that their skills can be used to progress patient services. This study highlights the fact that a lack of collaborative working practices between health‐care professionals led to clinical nurse specialists being constrained.

Relevance to clinical practice.  Health‐care organizations need to provide an environment in which the entrepreneurial skills of clinical nurse specialists may be capitalized on. In the absence of an outlet for their ideas regarding service developments, clinical nurse specialists may remain dependent on the mechanisms witnessed in this study for some time.
Carer reports of health status among adults with intellectual/developmental disabilities in Taiwan living at home and in institutions
Authors: Wang K.‐Y. , Hsieh K. , Heller T. , Davidson P. W. , Janicki M. P.
Published: October 2006

Background  The aim of the present study was to assess the health status of a cohort of adults with intellectual/developmental disabilities (I/DD) residing in family homes or institutions in Taiwan and to examine whether morbidity varied with age, sex, existing diagnosis [Down syndrome (DS), seizures, cerebral palsy (CP), intellectual disability (ID) level] and residential status.

Methods  Systematic randomization based on geographic areas was employed for sampling selection. Primary carers were interviewed to provide health‐related information on individuals with I/DD aged 33 years or older living in institutions (n = 614) or living with their family (n = 514) in Taiwan.

Results  Cardiovascular, neurological, visual and hearing impairments increased with age; while gastrointestinal, endocrine, infectious and dermatological diseases did not, after adjusting for sex, level of ID, presence of DS, seizures or CP, across settings. Institution cohorts were more likely to have infectious diseases, skin diseases, hepatitis or to be hepatitis carriers, and to have psychiatric disorders.

Conclusions  Organ system morbidity increased with age and generally was influenced by the same factors as have been reported for cohorts in western countries. The results also suggest that disease/condition outcomes may vary or be influenced differentially by residential setting.
Dispersal ecology versus host specialization as determinants of ectoparasite distribution in brood parasitic indigobirds and their estrildid finch hosts
Authors: BALAKRISHNAN CHRISTOPHER N. , SORENSON MICHAEL D.
Published: October 2006

Brood parasitic birds offer a unique opportunity to examine the ecological and evolutionary determinants of host associations in avian feather lice (Phthiraptera). Brood parasitic behaviour effectively eliminates vertical transfer of lice between parasitic parents and offspring at the nest, while at the same time providing an opportunity for lice associated with the hosts of brood parasites to colonize the brood parasites as well. Thus, the biology of brood parasitism allows a test of the relative roles of host specialization and dispersal ecology in determining the host–parasite associations of birds and lice. If the opportunity for dispersal is the primary determinant of louse distributions, then brood parasites and their hosts should have similar louse faunas. In contrast, if host‐specific adaptations limit colonization ability, lice associated with the hosts of brood parasites may be unable to persist on the brood parasites despite having an opportunity for colonization. We surveyed lice on four brood parasitic finch species (genus Vidua), their estrildid finch host species, and a few ploceid finches. While Brueelia lice were found on both parasitic and estrildid finches, a molecular phylogeny showed that lice infesting the two avian groups belong to two distinct clades within Brueelia. Likewise, distinct louse lineages within the amblyceran genus Myrsidea were found on estrildid finches and the parasitic pin‐tailed whydah (Vidua macroura), respectively. Although common on estrildid finches, Myrsidea lice were entirely absent from the brood parasitic indigobirds. The distribution and relationships of louse species on brood parasitic finches and their hosts suggest that host‐specific adaptations constrain the ability of lice to colonize new hosts, at least those that are distantly related.
Topoisomerases of kinetoplastid parasites: why so fascinating?
Authors: Das Benu Brata , Sengupta Tanushri , Ganguly Agneyo , Majumder Hemanta K.
Published: October 2006

DNA topoisomerases are the key enzymes involved in carrying out high precision DNA transactions inside the cells. However, they are detrimental to the cell when a wide variety of topoisomerase‐targeted drugs generate cytotoxic lesions by trapping the enzymes in covalent complexes on the DNA. The discovery of unusual heterodimeric topoisomerase I in kinetoplastid family added a new twist in topoisomerase research related to evolution, functional conservation and their preferential sensitivity to Camptothecin. On the other hand, structural and mechanistic studies on kinetoplastid topoisomerase II delineate some distinguishing features that differentiate the parasitic enzyme from its prokaryotic and eukaryotic counterparts. This review summarizes the recent advances in research in kinetoplastid topoisomerases, their evolutionary significance and the death of the unicellular parasite Leishmania donovani induced by topoisomerase I inhibitor camptothecin.
Specificity of Streptococcus pyogenes NAD+ glycohydrolase in cytolysin‐mediated translocation
Authors: Ghosh Joydeep , Caparon Michael G.
Published: October 2006

The mechanism by which the cytolysin‐mediated translocation (CMT) pathway of the Gram‐positive pathogen Streptococcus pyogenes injects effector proteins into the cytosol of an infected host cell via the pore‐forming protein streptolysin O is unknown. Key questions include whether the pathway can discriminate between different substrates for translocation, and whether the effector protein plays an active or passive role in the translocation process. Here we show that CMT can discriminate between a known effector of the pathway, the S. pyogenes NAD+ glycohydrolase (SPN), and a second secreted protein, the mitogenic factor (MF), routing the former into the host cell cytosol and the latter into the extracellular milieu. Residues within the amino‐terminal 190 residues of SPN were essential for discrimination, as deletions within this domain produced proteins that retained full enzymatic activity, but were completely uncoupled from the translocation pathway. The enzymatic domain itself played a pivotal role in the discrimination as deletions within this domain also produced translocation incompetent proteins and the conversion of MF to a translocation‐competent form required fusion with both SPN domains in a contiguous orientation. These data establish that CMT is discriminatory, and that SPN is a multidomain protein that plays an active role in its translocation.
Lex marks the spot: the virulent side of SOS and a closer look at the LexA regulon
Authors: Kelley William L.
Published: October 2006

The SOS response that responds to DNA damage induces many genes that are under LexA repression. A detailed examination of LexA regulons using genome‐wide techniques has recently been undertaken in both Escherichia coli and Bacillus subtilis. These extensive and elegant studies have now charted the extent of the LexA regulons, uncovered many new genes, and exposed a limited overlap in the LexA regulon between the two bacteria. As more bacterial genomes are analysed, more curiosities in LexA regulons arise. Several notable examples include the discovery of a LexA‐like protein, HdiR, in Lactococcus lactis, organisms with two lexA genes, and small DNA damage‐inducible cassettes under LexA control. In the cyanobacterium Synechocystis, genetic and microarray studies demonstrated that a LexA paralogue exerts control over an entirely different set of carbon‐controlled genes and is crucial to cells facing carbon starvation. An examination of SOS induction evoked by common therapeutic drugs has shed new light on unsuspected consequences of drug exposure. Certain antibiotics, most notably fluoroquinolones such as ciprofloxacin, can induce an SOS response and can modulate the spread of virulence factors and drug resistance. SOS induction by β‐lactams in E. coli triggers a novel form of antibiotic defence that involves cell wall stress and signal transduction by the DpiAB two‐component system. In this review, we provide an overview of these new directions in SOS and LexA research with emphasis on a few themes: identification of genes under LexA control, the identification of new endogenous triggers, and antibiotic‐induced SOS response and its consequences.
FvVE1 regulates filamentous growth, the ratio of microconidia to macroconidia and cell wall formation in Fusarium verticillioides
Authors: Li Shaojie , Myung Kyung , Guse Diana , Donkin Brett , Proctor Robert H. , Grayburn W. Scott , Calvo Ana M.
Published: October 2006

The velvet gene, veA, co‐ordinates asexual and sexual development in the homothallic fungal species Aspergillus nidulans. Studies in Aspergillus parasiticus and Aspergillus fumigatus demonstrated that veA also regulates morphological differentiation in these species. Whether veA has the same role in morphogenesis in other fungal genera has not been investigated. In this work, we studied the role of the veA homologue, FvVE1, in the heterothallic fungus Fusarium verticillioides. Deletion of FvVE1 suppressed aerial hyphal growth and reduced colony surface hydrophobicity on solid media. In submerged cultures, FvVE1 deletion caused alterations in hyphal polarity, marked activation of conidiation and yeast‐like growth. The latter was promoted by shaking to increase aeration of cultures. In addition, FvVE1 deletion markedly increased the ratio of macroconidia to microconidia. Supplementation of osmotic stabilizers restored the wild‐type phenotype to deletion mutants, suggesting phenotypic alterations caused by FvVE1 deletion are related to cell wall defects. This is consistent with the hypersensitivity of FvVE1 deletion mutants to SDS and with the significant reduction in the mannoprotein content of mutants compared with the wild‐type strain. However, no dramatic cell wall alterations were observed when mutants were examined by transmission electron microscopy. Our data strongly suggest that FvVE1 is important for cell wall integrity, cell surface hydrophobicity, hyphal polarity and conidiation pattern.
Descriptive epidemiology of Down’s syndrome in Estonia
Authors: Reimand Tiia , Õunap Katrin , Zordania Riina , Ilus Tiiu , Uibo Oivi , Sitska Mari , Talvik Tiina
Published: October 2006

The aim of the study was to investigate the livebirth prevalence of Down’s syndrome (DS) in Estonia during the past 14 years, create a DS database and observe the effectiveness of prenatal screening. This is a population‐based descriptive study. The study subjects were children with DS diagnosis born between the years 1990 and 2003. We collected data from genetic centres in Estonia, from the databases of DS support groups, from institutions for disabled children and from the registers of family doctors/paediatricians. Prenatal screening for chromosomal anomalies for women aged ≥35 years was started in Estonia in 1995. Therefore, we divided the DS children into two groups: 112 born between 1990 and 1994 comprise group I, and 127 born between 1995 and 2003 comprise group II. Group II was further divided into two subgroups: IIa, from 1995 to 1998, when screening of advanced maternal age (≥35 years) commenced, and IIb, from 1999 to 2003, when screening of second trimester maternal serum for younger women commenced. Prenatally, 68 cases of DS were diagnosed between 1995 and 2003 in the whole of Estonia, and all of these pregnancies were terminated. This represents 34.9% of all delivered and prenatally detected DS cases from this period.

The overall livebirth prevalence was 1.17 per 1000 livebirths. The livebirth prevalence in group I was 1.25 and in group II was 1.09 per 1000 livebirths. The second trimester maternal serum screening with advanced maternal age screening was more effective than advanced maternal age screening alone. The livebirth prevalence in group IIa was 1.22 and in group IIb 0.99 per 1000 livebirths. Overall, regular trisomy was found in 90.4%, translocation in 6.3% and mosaicism in 2.9%. The overall male to female sex ratio of DS was 1.09.
Levels of IL‐15 in Serum and Cerebrospinal Fluid of Patients with Behçet's Disease
Authors: Hamzaoui K. , Hamzaoui A. , Ghorbel I. , Khanfir M. , Houman H.
Published: October 2006

Interleukin‐15 (IL‐15) is a novel proinflammatory cytokine, involved in the pathogenesis of inflammatory/autoimmune disease. The objective of our study was to measure serum and cerebrospinal fluid (CSF) IL‐15 levels in patients with Behçet's disease (BD). CSF/serum IL‐15 ratio was introduced to assess the origin of elevated IL‐15 levels. We measured serum and CSF‐IL‐15 levels in 40 patients with BD (20 patients in active stage). Inflammatory and non‐inflammatory neurological disease patients acted as controls. Active BD patients have significantly higher serum IL‐15 levels (median 10.4 pg/ml; range 5.3–17.4) compared with BD in remission (6.05 pg/ml; 4–10.4) and healthy controls (4.65 pg/ml; 3.9–6.2). Similar serum IL‐15 levels were found in active neuro‐BD and inflammatory neurological disease (9.5 pg/ml; 5–13). Elevated levels of IL‐15 were observed in CSF samples from neuro‐BD patients (11 pg/ml; 8.5–15) and inflammatory neurological disease patients (10 pg/ml; 6.5–14) compared with patients with non‐inflammatory neurological disease (4 pg/ml; 4–5.5; P < 0.001). Vascular cerebral BD lesions were associated with high CSF/serum IL‐15 ratio. Our findings suggest that IL‐15 is involved in BD inflammatory process, particularly in vasculitis foci, as an elevated CSF/serum IL‐15 ratio characterizes vascular cerebral lesions.
Is the Activity of Partially Agonistic MHC:Peptide Ligands Dependent on the Quality of Immunological Help?
Authors: Uhlin M. , Masucci M. , Levitsky V.
Published: October 2006

CD8+ cytotoxic T lymphocytes (CTL) are important for the immunological control of infections and tumours. Engagement of the T‐cell receptor (TCR) with major histocompatibility complex (MHC) class I/peptide complexes on antigen‐presenting cells (APC) is the key interaction, which initiates the process of T‐cell activation. Depending on the affinity of this interaction, different arrays of signalling pathways and functional outcomes can be activated in the specific T cells. Molecular alterations in the peptide bound to the MHC class I can lead to a lower affinity of the MHC:TCR interaction resulting in incomplete or qualitatively different T‐cell responses. Altered peptide ligands (APL) exhibiting such activity are referred to as partial agonists and often occur naturally through genetic instability, which affects T‐cell epitopes derived from rapidly mutating viruses or tumour‐associated cellular antigens. Partial agonists are usually viewed as peptide variants, which escape efficient CTL recognition. Our recent data suggest that APL can not only trigger incomplete activation but also induce and modulate intrinsic T‐cell programmes leading to the shut‐off of specific CTL responses. This APL‐induced suppression appears to be more prominent in the absence of immunological help, suggesting that under conditions of immune deregulation APL may actively inhibit CTL responses against infectious agents or tumours. In this review, we discuss experimental data supporting this model and possible role of APL‐induced immunosuppression in different pathological conditions.
Two Neisseria meningitidis Strains with Different Ability to Stimulate Toll‐Like Receptor 4 Through the MyD88‐Independent Pathway
Authors: Mogensen T. H. , Paludan S. R. , Kilian M. , Østergaard L.
Published: October 2006

Neisseria meningitidis causes acute severe diseases, including sepsis and meningitis, and more benign manifestations such as chronic meningococcemia or colonization of the upper respiratory tract. The inflammatory response, which contributes to the pathogenesis of meningococcal disease, is initiated by pattern recognition receptors, among which Toll‐like receptors (TLR)s have been ascribed a particularly important role. We have previously demonstrated that N. meningitidis induce proinflammatory cytokine expression through TLR2 and TLR4. Here we characterize the molecular basis for differential activation of the inflammatory response by two N. meningitidis strains. This difference was due to differential ability to activate signal transduction through TLR4, as HEK293 cells expressing TLR4 produced significantly different levels of interleukin‐8 in response to these strains. At the level of signal transduction, the two strains differed substantially in their ability to activate the pathway to nuclear factor κB in HEK293‐TLR4/MD2 cells at late, but not early, time points. TLR4 activates two signal transduction pathways: one dependent on the adaptor molecule MyD88 and one independent of MyD88, and these pathways induce distinct patterns of gene expression in response to TLR4 ligands. By using macrophages from TLR2−/− mice, we observed that the two strains differed in their ability to activate the TLR4‐induced MyD88‐independent pathway, but not the MyD88‐dependent pathway. This idea was further supported by experiments where either of the two pathways was inhibited and IL‐8 secretion was measured. These data therefore provide molecular insight into activation of the inflammatory response by N. meningitidis, which is one of the key events in the pathogenesis of meningococcal disease.
Cytokinin‐ and auxin‐induced stomatal opening is related to the change of nitric oxide levels in guard cells in broad bean
Authors: Xiao‐Ping She , Xi‐Gui Song
Published: October 2006

The relationship between cytokinin‐ and auxin‐induced stomatal opening and nitric oxide (NO) levels in guard cells in broad bean was studied. Results indicate that cytokinins and auxins reduced the levels of NO in guard cells and induced stomatal opening in darkness. In addition, cytokinins not only reduced NO levels in guard cells caused by sodium nitroprusside (SNP) in light but also abolished NO that had been generated by dark, and then promoted the closed stomata reopening, as did NO scavenger 2‐(4‐carboxyphenyl)‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide. However, unlike cytokinins, auxins not only had incapability to reduce NO levels by SNP but also could not abolish NO having been generated by dark, so auxins could not promote the closed stomata to reopen. The above‐mentioned effects of auxins were similar to that of nitric oxide synthase (enzyme commission 1.14.13.39) inhibitor NG‐nitro‐l‐Arg‐methyl ester. Hence, it is concluded that cytokinins reduced probably the levels of NO in guard cells via scavenging, and auxins reduced NO levels through restraining NO generation in all probability, and then induced stomatal opening in darkness.
Clinical predictors of suicidal acts after major depression in bipolar disorder: a prospective study
Authors: Galfalvy Hanga , Oquendo Maria A , Carballo Juan J , Sher Leo , Grunebaum Michael F , Burke Ainsley , John Mann J
Published: October 2006

Objective:  This study determined the clinical predictors of suicidal behavior during a 2‐year follow‐up of patients with bipolar disorder presenting with a major depressive episode (MDE).

Method:  Sixty four patients with DSM‐III‐R bipolar disorder were assessed at presentation for treatment of an MDE. Correlates of past suicidal behavior were determined by comparing patients with and without a history of suicide attempts using a t‐test, Wilcoxon test or chi‐squared test of independence on individual explanatory variables. Putative predictors of attempts during the follow‐up period were tested separately using Cox proportional hazards regression analysis.

Results:  Twelve of 64 patients had at least one suicide attempt in the follow‐up period, five of them attempted in the first 2 months and seven around or shortly after the 1‐year follow‐up visit. All attempters had a history of past suicide attempts. Most predictors of future suicidal behavior were correlates of past suicidal behavior. Family history of suicide acts and comorbid borderline personality disorder predicted early attempts, while younger age, high hostility scores, number of past attempts, subjective pessimism as reflected in depression and suicidal ideation, and few reported reasons for living predicted suicidal acts during the whole period.

Conclusion:  In this data set of bipolar patients we noted an intriguing picture of two clusters of suicide attempts. Hostility was the strongest risk factor. These findings may have implications in both the identification of at‐risk patients and the timing of clinical interventions including aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptomatology.
Decreased risk of suicides and attempts during long‐term lithium treatment: a meta‐analytic review
Authors: Baldessarini Ross J , Tondo Leonardo , Davis Paula , Pompili Maurizio , Goodwin Frederick K , Hennen John
Published: October 2006

Objectives:  To update and extend comparisons of rates of suicides and suicide attempts among patients with major affective disorders with versus without long‐term lithium treatment.

Methods:  Broad searching yielded 45 studies providing rates of suicidal acts during lithium treatment, including 34 also providing rates without lithium treatment. We scored study quality, tested between‐study variance, and examined suicidal rates on versus off lithium by meta‐analytic methods to determine risk ratios (RRs) and 95% confidence intervals (CI).

Results:  In 31 studies suitable for meta‐analysis, involving a total of 85,229 person‐years of risk‐exposure, the overall risk of suicides and attempts was five times less among lithium‐treated subjects than among those not treated with lithium (RR = 4.91, 95% CI 3.82–6.31, p < 0.0001). Similar effects were found with other meta‐analytic methods, as well as for completed versus attempted suicide, and for bipolar versus major mood disorder patients. Studies with higher quality ratings, including randomized, controlled trials, involved shorter exposures with somewhat lesser lithium superiority. Omitting one very large study or those involving lithium‐discontinuation had little effect on the results. The incidence‐ratio of attempts‐to‐suicides increased 2.5 times with lithium‐treatment, indicating reduced lethality of suicidal acts. There was no indication of bias toward reporting positive findings, nor were outcomes significantly influenced by publication‐year or study size.

Conclusions:  Risks of completed and attempted suicide were consistently lower, by approximately 80%, during treatment of bipolar and other major affective disorder patients with lithium for an average of 18 months. These benefits were sustained in randomized as well as open clinical trials.
Aggression and substance abuse in bipolar disorder
Authors: Grunebaum Michael F , Galfalvy Hanga C , Nichols C Matthew , Caldeira Nathilee A , Sher Leo , Dervic Kanita , Burke Ainsley K , Mann J John , Oquendo Maria A
Published: October 2006

Objectives:  The goal of this retrospective study was to examine factors differentiating persons with bipolar disorder who did or did not have comorbid lifetime substance use disorders (SUD) at an index assessment. We also explored the chronology of onset of mood and SUD.

Methods:  We studied 146 subjects with DSM‐defined bipolar disorder. Subgroups with and without lifetime SUD were compared on demographic and clinical measures.

Results:  Substance abuse disorders in this bipolar sample were associated with male sex, impulsive‐aggressive traits, comorbid conduct and Cluster B personality disorders, number of suicide attempts and earlier age at onset of a first mood episode. In a multivariable logistic regression analysis, male sex and aggression and possibly earlier age at mood disorder onset were associated with SUD. In those with or without SUD, the first mood episode tended to be depressive and to precede the onset of SUD.

Conclusions:  In persons with bipolar disorder, an earlier age of onset and aggressive traits appear to be factors associated with later development of comorbid SUD.
Individual Differences and Repeatability of Post‐prandial Changes of Plasma‐free Amino Acids in Young Horses
Authors: Hackl S. , Van Den Hoven R. , Zickl M. , Spona J. , Zentek J.
Published: October 2006

Few data are available on post‐prandial changes of plasma amino acids (AAs) in horses and on the repeatability and the individual variance on different sampling days. The objective of the present study was to measure pre‐ and post‐prandial concentrations of plasma AA in 10 yearling horses. Blood samples were taken on days 1 and 40 of the study before feeding of hay, oats and soya meal and over an 8 h post‐prandial period in 2‐h intervals. The plasma AAs were measured by high‐pressure liquid chromatography after ortho‐phthalaldehyde derivatization. Mean fasting concentrations of the AAs were not significantly influenced by the individuum and sampling day. Repeatability of the fasting AA levels in the individual horses on two different sampling days was only found for histidine, 3‐methylhistidine, methionine, tryptophan and taurine. While the absolute post‐prandial AA concentrations differed between sampling days, the relative changes were comparable. All AA concentrations except 3‐methylhistidine increased after feeding by 13% to more than 200% of their fasting values if the combined data of both days were analysed. Four hours after feeding the concentrations of arginine, asparagine, lysine, leucine, isoleucine and threonine, decreased more than 20%. Histidine, methionine, phenylalanine, valine, tryptophan, glutamine, glycine, tyrosine and taurine concentrations decreased by less than 20%. Concentrations of aspartic acid, glutamic acid, ornithine, serine and citrulline remained elevated. Most AA approached the fasting concentrations at 8 h, only glycine increased between 6 and 8 h after meal and 3‐methyl‐histidine concentrations were constant throughout the entire period. In conclusion, the pre‐prandial plasma AA in horses appeared less influenced by individuum or sampling day than post‐prandial plasma AA concentrations. Therefore, plasma AA concentrations should be interpreted only under well‐defined conditions, especially regarding the feeding regimen.
Investigations on the Association of D‐lactate Blood Concentrations with the Outcome of Therapy of Acidosis, and with Posture and Demeanour in Young Calves with Diarrhoea
Authors: Lorenz I. , Vogt S.
Published: October 2006

The objective of this prospective study was to elucidate whether amounts of bicarbonate needed for correction of acidosis and normalization of clinical signs are influenced by blood d‐lactate concentrations in calves with diarrhoea. In 73 calves up to 3 weeks old with acute diarrhoea and base excess values below −10 mmol/l correction of acidosis was carried out within 3.5‐h by intravenous administration of an amount of sodium bicarbonate which was calculated using the formula: HCO (mmol) = body mass (kg) × base deficit (mmol/l) × 0.6 (l/kg). Clinical signs, venous base excess, and plasma d‐lactate concentrations were monitored immediately following admission, following correction of acidosis at 4 h and 24 h after admission. The base excess and plasma d‐lactate concentrations throughout the study were −17.8 ± 4.0, −0.4 ± 0.4, −3.0 ± 5.5 mmol/l (base excess), and 10.0 ± 4.9, 9.8 ± 4.8, 5.4 ± 3.4 mmol/l (d‐lactate) for the three times of examination. Metabolic acidosis was not corrected in more than half of the calves (n = 43) by the calculated amount of bicarbonate, whereas the risk of failure to correct acidosis increases with d‐lactate concentrations. The study shows that calves with elevated d‐lactate concentrations do not need additional specific therapy, as d‐lactate concentrations regularly fall following correction of acidosis and restitution of body fluid volume, for reasons that remain unclear. However, calves with distinct changes in posture and demeanour need higher doses of bicarbonate than calculated with the factor of 0.6 in the formula mentioned above probably because of d‐hyperlactataemia.
Altered Homeostasis of Extracellular Matrix Proteins in Joints of Standardbred Trotters During a Long‐term Training Programme
Authors: Skiöldebrand E. , Heinegård D. , Olofsson B. , Rucklidge G. , Ronéus N. , Ekman S.
Published: October 2006

This study evaluates how strenuous training, age and lameness influence the release of cartilage oligomeric matrix protein (sf‐COMP), aggrecan and collagen type II into synovial fluid in 28 (19.5–40 months) Standardbred trotters (STB), during a long‐term training programme (24 months). All the horses were trained by the same trainer and were healthy on entering the training programme. Synovial fluid (sf) from the left middle carpal joint in each subject was sampled every third month. Enzyme‐linked immunosorbent assay was used to determine the concentrations of sf‐COMP, sf‐aggrecan and sf‐collagen type II. Concentration of sf‐COMP decreased with increasing age and total days of training. The concentration of sf‐COMP was found similarly related to both age and total days of training, so they could not be differentiated. It was also shown that the concentration of collagen type II degradation products increased with total days of training. The study shows that extensive and long‐term training programme induces metabolic changes in articular cartilage exemplified by reduced release and synthesis of COMP. This is most likely due to strenuous training leading to inappropriate load on the articular cartilage.
Anti‐oxidative Status and Semen Quality during Cooled Storage in Stallions
Authors: Pagl R. , Aurich C. , Kankofer M.
Published: October 2006

Activity of the anti‐oxidative enzymes glutathione peroxidase (GSH‐Px), superoxide dismutase (SOD) and catalase (CAT), content of thiobarbituric acid reactive substances (TBARS) and SH‐groups were determined in native stallion semen (n = 8 stallions). Semen was then diluted in Kenney extender, EquiPro®extender either with or without addition ofN‐acetyl cysteine or phosphate‐buffered saline (PBS) and stored for 72 h at 5°C. Correlations between initial activity of enzymes and development of semen motility and membrane integrity were calculated. Activities of GSH‐Px, SOD and CAT immediately after semen collections were 10.0 ± 0.6 picokatals, 0.40 ± 0.03 SOD units and 0.70 ± 0.05 nanokatals/106spermatozoa respectively. TBARS content was 0.06 ± 0.01 nmol and SH‐group content 1.7 ± 0.5 mmol/106spermatozoa. The loss of motile spermatozoa during storage did not differ between extenders.N‐acetyl cysteine had no effect on semen motility and membrane integrity. The loss in membrane‐intact spermatozoa was highest (P < 0.05) in semen diluted in PBS. Motility and membrane integrity after addition of extender were positively correlated with GSH‐Px and CAT, indicating that anti‐oxidative mechanisms contribute to the initial high percentage of motile and membrane‐intact spermatozoa. However, in these samples the decrease in semen quality was most pronounced. No correlations existed between initial activity of anti‐oxidative enzymes, peroxidation products and semen quality during storage. This indicates that once extender has been added, peroxidative damage to sperm membranes is not the predominant cause of losses in semen quality.
SERTRALINE PROTECTS AGAINST MONOCROTALINE‐INDUCED PULMONARY HYPERTENSION IN RATS
Authors: Li Xue‐Qin , Hong Yang , Wang Yun , Zhang Xin‐Hua , Wang Huai‐Liang
Published: October 2006

Serotonin (5‐HT), as a type of mitogen for smooth muscle cells, plays an important role in the development of pulmonary hypertension. It is known that selective serotonin re‐uptake inhibitors (SSRI) inhibit 5‐HT internalization. Therefore, the aim of the present study was to investigate the protective effect and mechanism of the SSRI sertraline against pulmonary hypertension.

Monocrotaline (MCT)‐induced chronic ‘inflammatory’ pulmonary hypertension in Wistar rats was established. Pulmonary haemodynamic measurement and lung tissue morphological investigations were undertaken. Serotonin transporter (SERT) mRNA was assayed by reverse transcription–polymerase chain reaction (RT‐PCR).

The results showed that pulmonary artery pressure (PAP) was significantly increased by MCT treatment from 12.6 ± 2.1 to 20.1 ± 3.4 mmHg (P < 0.01 vs control) and sertraline attenuated the MCT‐induced increase in PAP from 20.1 ± 3.4 to 16.4 ± 1.8 mmHg (P < 0.05 vs MCT). The right ventricular index was increased in the MCT‐treated group from 0.32 ± 0.04 to 0.51 ± 0.09 (P < 0.01 vs control) and was reduced to 0.42 ± 0.04 by sertraline (P < 0.05 vs MCT). The degree of muscularization of the pulmonary artery in the MCT‐treated group was significantly higher than control (P < 0.01) and was decreased by sertraline (P < 0.01 vs MCT). The RT‐PCR assay showed that MCT increased SERT mRNA expression from 0.86 ± 0.08 to 0.99 ± 0.06 (P < 0.05 vs control), which was attenuated by sertraline (0.82 ± 0.09; P < 0.05 vs MCT).

In conclusion, the SSRI sertraline protects against MCT‐induced pulmonary hypertension by decreasing PAP, right ventricular index and pulmonary artery remodelling, which may be related to a reduction in SERT mRNA.