bluuebunny/crossref_metadata_2025 huggingface dataset:
VWRPY motif–dependent and –independent roles of AML1/Runx1 transcription factor in murine hematopoietic development
Authors: Nishimura Motohiro , Fukushima-Nakase Yoko , Fujita Yasuko , Nakao Mitsushige , Toda Shogo , Kitamura Nobuo , Abe Tatsuo , Okuda Tsukasa
Published: September 2003

AML1/Runx1 is a frequent target of leukemia-associated gene aberration, and it encodes a transcription factor essential for definitive hematopoiesis. We previously reported that the AML1 molecules with trans-activation subdomains retained can rescue in vitro hematopoietic defects of AML1-deficient mouse embryonic stem (ES) cells when expressed by using a knock-in approach. Extending this notion to in vivo conditions, we found that the knock-in ES cell clones with AML1 mutants, which retain trans-activation subdomains but lack C-terminal repression subdomains including the conserved VWRPY motif, contribute to hematopoietic tissues in chimera mice. We also found that germline mice homozygous for the mutated AML1 allele, which lacks the VWRPY motif, exhibit a minimal effect on hematopoietic development, as was observed in control knock-in mice with full-length AML1. On the other hand, reduced cell numbers and deviant CD4 expression were observed during early T-lymphoid ontogeny in the VWRPY-deficient mice, whereas the contribution to the thymus by the corresponding ES cell clones was inadequate. These findings demonstrate that AML1 with its trans-activating subdomains is essential and sufficient for hematopoietic development in the context of the entire mouse. In addition, its trans-repression activity, depending on the C-terminal VWRPY motif, plays a role in early thymocyte development.
Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity
Authors: Chung Chun-Shiang , Song Grace Y , Lomas Joanne , Simms H Hank , Chaudry Irshad H , Ayala Alfred
Published: August 2003

Signaling through the Fas/Fas ligand (FasL) pathway plays a central role in immune-cell response and function; however, under certain pathological conditions such as sepsis, it may contribute to the animal’s or patient’s morbidity and mortality. To determine the contribution of FasL to mortality, we conducted survival studies by blocking Fas/FasL with Fas receptor fusion protein (FasFP) in vivo. C3H/HeN mice received FasFP or the saline vehicle (veh) immediately (0 h) or delayed (12 h), after sepsis induced by cecal ligation and puncture (CLP). Subsequently, we examined the effect of FasFP treatment (12 h post-CLP) on macrophage apoptosis and functional capacities. Peritoneal and splenic macrophages and Kupffer cells from sham-veh-, CLP-veh-, sham-FasFP-, or CLP-FasFP-treated mice were harvested 24 h after CLP and stimulated with lipopolysaccharide (LPS) for 24 h. The results indicate that only delayed (12 h) but not 0 h administration of FasFP demonstrated a significant increase in survival. The ability of all macrophage populations to release interleukin (IL)-6 was significantly depressed, and IL-10 release was augmented after CLP. FasFP treatment attenuated the increased IL-10 release in Kupffer cells. However, althogh enhanced susceptibility to LPS-induced apoptosis could be suppressed in CLP mouse Kupffer cells by FasFP, FasFP did not change the peritoneal or splenic macrophage response. Furthermore, FasFP attenuated the elevated plasma levels of liver enzymes after sepsis. These data indicate that in vivo inhibition of Fas/FasL signaling has tissue-specific effects on the induction of macrophage apoptosis, functional changes, and liver damage, which may contribute to the host’s ability to ward off a septic challenge.
Many chemokines including CCL20/MIP-3α display antimicrobial activity
Authors: Yang De , Chen Qian , Hoover David M , Staley Patricia , Tucker Kenneth D , Lubkowski Jacek , Oppenheim Joost J
Published: August 2003

Previous studies have demonstrated that β-defensins exhibit chemotactic activity by sharing the chemokine receptor CCR6 with the CC chemokine ligand CCL20/macrophage-inflammatory protein-3α (MIP-3α). Structural analysis of CCL20/MIP-3α revealed that most of the positively charged residues are concentrated at one area of its topological surface, a characteristic considered to be important for the antimicrobial activity of defensins. Here, we report that similar to defensins, CCL20/MIP-3α has antimicrobial effects on Escherichia coli, Pseudomonas aeruginosa, Moraxella catarrhalis, Streptococcus pyogenes, Enterococcus faecium, Staphylococcus aureus, and Candida albicans. Additionally, by screening a total of 30 human chemokines, we have identified an additional 17 human chemokines, which exhibit antimicrobial activity in vitro. Collectively, about two-thirds of the chemokines investigated so far has the capacity to kill microorganisms in vitro, suggesting that antimicrobial activity may be another host-defense function for certain chemokines. Comparison of the structural characteristics between antimicrobial and nonantimicrobial chemokines suggests that topological formation of a large, positively charged electrostatic patch on the surface of the molecule is likely to be a common structural feature of antimicrobial chemokines.
Expression of IL-2 receptor β and γ chains by human gingival fibroblasts and up-regulation of adhesion to neutrophils in response to IL-2
Authors: Ozawa Akiko , Tada Hiroyuki , Tamai Riyoko , Uehara Akiko , Watanabe Kouichi , Yamaguchi Takahiro , Shimauchi Hidetoshi , Takada Haruhiko , Sugawara Shunji
Published: August 2003

To investigate the role of human gingival fibroblasts (HGF), the major constituents of gingival tissue in periodontal inflammatory disease, the expression of interleukin-2 receptor (IL-2R) α, β, and γ chains was examined. Immunohistochemistry showed a pronounced accumulation of CD8+ T cells in the inflamed lamina propria of gingival tissue from patients with adult periodontitis. HGF express IL-2Rβ and IL-2Rγ at mRNA and protein levels, but the expression of IL-2Rα could not be detected, as assessed by reverse transcriptase-polymerase chain reaction and flow cytometry. IL-2Rβ, and -γ expressed on HGF were functionally active, as addition of neutralizing anti-IL-2Rβ and -γ antibodies caused inhibition of the IL-2-induced production of monocyte chemoattractant protein-1 (MCP-1), and addition of IL-2 induced phosphorylation of Janus tyrosine kinase 3, which is critical in signaling through IL-2Rγ in HGF. The IL-2-induced MCP-1 production was significantly inhibited by pretreatment with neutralizing antibody to IL-15. Addition of IL-2 also induced a marked up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of HGF, which in turn, significantly augmented the adhesion of human neutrophils, which were inhibited by an anti-ICAM-1 antibody. These results suggest that HGF express functional IL-2Rβγ, respond to IL-2 from infiltrated T cells, and actively participate in the inflammatory process in the periodontal region and that IL-15 produced by HGF sustains IL-2-mediated signaling in HGF.
Several gene programs are induced in ciprofloxacin-treated human lymphocytes as revealed by microarray analysis
Authors: Eriksson Emily , Forsgren Arne , Riesbeck Kristian
Published: August 2003

Fluoroquinolones have immunomodulatory properties and interfere with cytokine production. The aim of this study was to characterize the extent of the superinduced mRNA levels in activated human lymphocytes incubated with ciprofloxacin (5 and 80 μg/ml) using a cytokine gene expression microarray from R&D Systems (Abingdon, UK). Several gene transcripts (n=104) were up-regulated in cells treated with ciprofloxacin at 80 μg/ml, whereas 98 transcripts were down-regulated out of 847 total genes included on the microarray. The increased mRNAs were distributed between major gene programs, including interleukins (36.5%), signal-transduction molecules (13.5%), adhesion molecules (10.6%), tumor necrosis factor and transforming growth factor-β superfamilies (10.6%), cell-cycle regulators (9.6%), and apoptosis-related molecules (8.7%). To determine the specficity of the microarray, a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), which contained a panel of 12 different cytokine mRNAs, was used. Eleven out of the 12 gene transcripts were up-regulated in the specific RT-PCR, whereas only eight were found to be increased in the microarray. A microarray from Clontech (Hampshire, UK), containing 588 different genes, was also included. Results obtained with this broad-coverage expression array slightly differed compared with the other microarray. We conclude that the fluoroquinolone ciprofloxacin at high concentrations interferes with several gene programs, which is in accordance with a mammalian stress response. From a technical point of view, a discrepancy may exist between data obtained by different microarrays and more specific methods such as quantitative RT-PCR.
Expression of the chemokine IP-10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation
Authors: Harvey Charles E , Post Jeffrey J , Palladinetti Patricia , Freeman Anthony J , Ffrench Rosemary A , Kumar Rakesh K , Marinos George , Lloyd Andrew R
Published: August 2003

The factors influencing lymphocyte trafficking to the liver lobule during chronic hepaititis C virus (HCV) infection are currently not well defined. Interferon-γ-inducible protein 10 (IP-10), a chemokine that recruits activated T lymphocytes, has recently been shown by in situ hybridization to be expressed in the liver during chronic HCV infection. This study sought to define the cellular source of IP-10 in the liver by immunohistochemistry, to examine the expression of its receptor, CXCR3, on T lymphocytes isolated from blood and liver tissue, and to correlate IP-10 expression with the histological markers of inflammation and fibrosis. IP-10 was expressed by hepatocytes but not by other cell types within the liver, and the most intense immunoreactivity was evident in the areas of lobular inflammation. The IP-10 receptor was expressed on a significantly higher proportion of T lymphocytes in the liver compared with blood. CD8 T lymphocytes, which predominate in the liver lobule, were almost uniformly CXCR3-positive. The expression of IP-10 mRNA correlated with lobular necroinflammatory activity but not with inflammation or fibrosis in the portal tracts. These findings suggest that IP-10 may be induced by HCV within hepatocytes and may be important in the pathogenesis of chronic HCV infection, as recruitment of inflammatory cells into the lobule is an important predictor of disease progression.
Lactobacilli and streptococci induce inflammatory chemokine production in human macrophages that stimulates Th1 cell chemotaxis
Authors: Veckman Ville , Miettinen Minja , Matikainen Sampsa , Lande Roberto , Giacomini Elena , Coccia Eliana M , Julkunen Ilkka
Published: August 2003

Macrophages have a central role in innate-immune responses to bacteria. In the present work, we show that infection of human macrophages with Gram-positive pathogenic Streptococcus pyogenes or nonpathogenic Lactobacillus rhamnosus GG enhances mRNA expression of inflammatory chemokine ligands CCL2/monocyte chemoattractant protein-1 (MCP-1), CCL3/macrophage-inflammatory protein-1α (MIP-1α), CCL5/regulated on activation, normal T expressed and secreted, CCL7/MCP-3, CCL19/MIP-3β, and CCL20/MIP-3α and CXC chemokine ligands CXCL8/interleukin (IL)-8, CXCL9/monokine induced by interferon-γ (IFN-γ), and CXCL10/IFN-inducible protein 10. Bacteria-induced CCL2, CCL7, CXCL9, and CXCL10 mRNA expression was partially dependent on ongoing protein synthesis. The expression of these chemokines and of CCL19 was dependent on bacteria-induced IFN-α/β production. CCL19 and CCL20 mRNA expression was up-regulated by IL-1β or tumor necrosis factor α (TNF-α), and in addition, IFN-α together with TNF-α further enhanced CCL19 gene expression. Synergy between IFN-α and TNF-α was also seen for CXCL9 and CXCL10 mRNA expression. Bacteria-stimulated macrophage supernatants induced the migration of T helper cell type 1 (Th1) cells, suggesting that in human macrophages, these bacteria can stimulate efficient inflammatory chemokine gene expression including those that recruit Th1 cells to the site of inflammation. Furthermore, L. rhamnosus-induced Th1 chemokine production could in part explain the proposed antiallergenic properties of this bacterium.
ADAM-17-independent shedding of L-selectin
Authors: Walcheck Bruce , Alexander Shelia R , St. Hill Catherine A , Matala Erik
Published: August 2003

L-selectin is expressed by leukocytes and facilitates their adhesion under flow along the walls of blood vessels. As do a variety of membrane proteins, L-selectin undergoes ectodomain shedding. Using approaches that monitor full-length L-selectin in short-term assays, it has been determined that L-selectin shedding is defective in tumor necrosis factor α-converting enzyme (ADAM-17)-deficient cells. In this study, we examined the steady-state levels of L-selectin on ADAM-17-deficient cells using a monoclonal antibody to the cytoplasmic region of L-selectin, which allows for the detection of total L-selectin (full-length and the membrane-associated cleavage fragment). We demonstrate that ADAM-17-deficient cells generate a 6-kDa transmembrane fragment of L-selectin. Although inducible L-selctin shedding by phorbol 12-myristate 13-acetate stimulation was not observed by these cells in short-term assays, basal turnover did occur, resulting in the production of soluble L-selectin, as determined by enzyme-linked immunosorbent assay. L-selectin turnover was greatly increased upon ADAM-17 reconstitution. Truncating the juxtamembrane region of L-selectin blocked ADAM-17-independent shedding as did a hydroxymate metalloprotease inhibitor. Together, these findings demonstrate that a metalloprotease activity separate from ADAM-17 can use the cleavage domain of L-selectin. We speculate that separate proteolytic mechanisms of L-selectin shedding may regulate distinct antiadhesive mechanisms, such as inducible shedding for the rapid dissociation of cell–cell interactions and constitutive shedding for the homeostatic maintenance of high serum levels of soluble L-selectin, a potential adhesion buffer.
Nitric oxide-mediated inhibition of caspase-dependent T lymphocyte proliferation
Authors: Mahidhara Raja S , Hoffman Rosemary A , Huang Sulan , Wolf-Johnston Amanda , Vodovotz Yoram , Simmons Richard L , Billiar Timothy R
Published: August 2003

Nitric oxide (NO), a pleiotropic signaling molecule produced at sites of inflammaion, is a powerful inhibitor of lymphocyte proliferation. Caspases, central effector proteases in apoptosis, have recently been implicated as critical mediators of T cell activation. We and others have shown that NO can inhibit caspases by S-nitrosylation, which is reversible by the reducing agent dithiothreitol (DTT). The purpose of the present study was to determine whether NO inhibits lymphocyte proliferation by modulating caspase activity. Caspase inhibition with z-VAD-fmk blocked T cell proliferation. NO-dependent inhibition of T cell proliferation was associated with an inhibition of caspase activity and activation, and this effect was reversible by DTT. Previous studies demonstrated inhibition of apoptosis through S-nitrosylation of caspases; the present studies extend this effect to inhibition of caspase-dependent T cell proliferation.
Enhancement by neutrophils of collagen degradation by corneal fibroblasts
Authors: Li Qin , Fukuda Ken , Lu Ying , Nakamura Yoshikuni , Chikama Tai-ichiro , Kumagai Naoki , Nishida Teruo
Published: August 2003

Activated corneal fbroblasts and infiltrated leukocytes are thought to contribute to corneal ulceration. The potential roles of neutrophil-fibroblast and cell-matrix interactions in the degradation of stromal collagen associated with corneal ulceration have now been investigated with the use of three-dimensional cultures of rabbit cells in collagen gels. Degradation of collagen fibrils during culture was measured by spectrophotometric determination of released hydroxyproline. Whereas corneal fibroblasts alone degraded collagen fibrils to a small extent, neutrophils did not. However, the addition of neutrophils or neutrophil–conditioned medium (CM) to cultures of corneal fibroblasts resulted in a marked increase in the amount of collagen degraded by the fibroblasts. The effect of CM from neutrophils cultured in collagen gels on collagen degradation by corneal fibroblasts was greater than that of medium conditioned by neutrophils in monolayer culture. Immunoblot as well as reverse transcription and real-time polymerase chain reaction analyses revealed that neutrophil–CM stimulated the synthesis of matrix metalloproteinase (MMP)-1 and MMP-3 by corneal fibroblasts. The stimulatory effect of neutrophils on collagen degradation by corneal fibroblasts was inhibited by the synthetic MMP inhibitor ilomastat and by interleukin-1 (IL-1) receptor antagonist. These results suggest that factors secreted by collagen-stimulated neutrophils augment collagen degradation by corneal fibroblasts through a stimulatory effect on MMP synthesis and that IL-1 released by neutrophils may contribute to this effect.
Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools
Authors: Greil Richard , Anether Gabriele , Johrer Karin , Tinhofer Inge
Published: August 2003

In the past decade, it was concluded from a number of investigations that death domain-containing members of the tumor necrosis factor-receptor (TNF-R) family and their ligands such as Fas/FasL and TNF-related apoptosis-inducing ligand (TRAIL)-R/TRAIL are essential for maintaining an intact immune system for surveillance against infection and cancer development and that nondeath domain-containing members such as CD30 or CD40 are involved in the fine tuning of this system during the selection process of the lymphaticsystem. In line with this conclusion are the observations that alterations in structure, function, and regulation of these molecules contribute to autoimmunity and cancer development of the lymphoid system. Besides controlling size and function of the lymphoid cell pool, Fas/FasL and TRAIL-R/TRAIL regulate myelopoiesis and the dendritic cell functions, and severe alterations of these lineages during the outgrowth and expansion of the lymphoid tumors have been reported. It is the aim of this review to summarize what is currently known about the complex role of these two death receptor/ligand systems in normal, disturbed, and neoplastic hemato-/lymphopoiesis and to point out how such knowledge can be used in developing novel, therapeutic options and the problems that will have to be faced along the way.
The polysaccharide capsule of Cryptococcus neoformans interferes with human dendritic cell maturation and activation
Authors: Vecchiarelli Anna , Pietrella Donatella , Lupo Patrizia , Bistoni Francesco , McFadden Diane C , Casadevall Arturo
Published: August 2003

The ability of encapsulated andacapsular strains of Cryptococcus neoformans to activate dendritic cells (DC) derived from monocytes stimulated with granulocyte macrophage-colony stimulating factor and interleukin-4 was evaluated. Profound differences in DC response to encapsulated and acapsular C. neoformans strains were observed. In particular, (i) the acapsular strain was easily phagocytosed by immature DC, and the process induced several molecular markers, such as major histocompatibility complex (MHC) class I and class II, CD40, and CD83, which are characteristic of mature DC; (ii) the encapsulated strain did not up-regulate MHC class I and class II and CD83 molecules; (iii) the soluble capsular polysaccharide glucuronoxylomannan (GXM) is unable to regulate MHC class I and class II molecules; (iv) the addition of monoclonal antibody to GXM (anti-GXM) to the encapsulated strain facilitated antigen-presenting cell maturation by promoting ingestion of C. neoformans via Fc receptor for immunoglobulin G (FcγR)II (CD32) and FcγRIII (CD16); (v) pertubation of FcRγII or FcγRIII was insufficient to promote DC maturation; and (vi) optimal DC maturation permitted efficient T cell activation and differentiation, as documented by the enhancement of lymphoproliferation and interferon-γ production. These results indicate that the C. neoformans capsule interferes with DC activation and maturation, indicating a new pathway by which the fungus may avoid an efficient T cell response.
Phospholipase C and phosphatidylinositol 3-kinase signaling are involved in the exogenous arachidonic acid-stimulated respiratory burst in human neutrophils
Authors: Liu Jiang , Liu Zhaoxia , Chuai Shaokun , Shen Xun
Published: August 2003

To define the role of phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI-3K), signaling pathways in arachidonic acid (AA)-stimulated respiratory burst in human neutrophils, the AA-stimulated respiratory burst, Ins(1,4,5)P3 production, PI-3K activation, and cytoplasmic Ca2+ mobilization were investigated. It was found that Ins(1,4,5)P3 production and PI-3K activity in AA-stimulated cells were increased in a dose-dependent manner. U73122, the PLC inhibitor, effectively inhibited the AA-stimulated respiratory burst and Ca2+ release from th intracellular calcium store but not the activity of PI-3K, indicating the independence of PI-3K signaling on PLC activation. Wortmannin, the PI-3K inhibitor, at the concentration sufficient to inhibit PI-3K activity, can only partially inhibit Ca2+ release from the internal store, indicating a partial regulation of PLC signaling by PI-3K and the existence of two pathways initiated by different PLC subfamilies. One is regulated by PI-3K activation, and the other is independent of PI-3K signaling. It was observed that AA could still induce a noncapacitative Ca2+ entry in the cells when Ca2+ release from the intracellular store was blocked by a PLC inhibitor, or a capacitative Ca2+ entry was induced by preincubation with thapsigargin. However, the AA-mediated, noncapacitative Ca2+ entry seems to play a little, if any, role in the stimulated respiratory burst. The present study suggests that the PLC signaling pathway, which may be activated by PLCβ and PLCγ, respectively, and the PI-3K signaling pathway are involved in the AA-stimulated respiratory burst in human neutrophil.
IL-4 primes human endothelial cells for secondary responses to histamine
Authors: Wierzbicki Tom , Iqbal Shehzad M , Cuvelier Susan L , Awong Geneve , Tibbles Lee Anne , Patel Kamala D
Published: August 2003

Interleukin-4 (IL-4) is a multifunctional cytokine, which is involved in numerous disease states, including atopic asthma. IL-4 not only induces direct responses in cells but can also prime for secondary responses to stimuli. Little is known about the priming effects of IL-4 on endothelial cells; therefore, we chose to examine the ability of IL-4 to prime endothelial cells for platelet-activating factor (PAF) synthesis and prostaglandin E2 (PGE2) release. IL-4 alone did not enhance PAF synthesis or PGE2 release; however, pretreatment with IL-4 primed for PAF synthesis and PGE2 release in response to subsequent stimulation with histamine. In contrast, tumor necrosis factor α (TNF-α), oncostatin M (OSM), and IL-1β did not prime endothelial cells for PAF synthesis in response to histamine. The priming effects of IL-4 occurred without any detectable changes in the requirement for signaling pathways upstream of PGE2 release. IL-4 treatment increased the expression of mRNA for histamine receptor 1 (HR1) and shifted the inhibition curve for pyrilamine, a specific HR1 antagonist. In addition, the dose-response curve for histamine-induced elevations in intracellular calcium was shifted following IL-4 stimulation. Together, these data indicate that HR1 is up-regulated in IL-4-stimulated human umbilical vein endothelial cells (HUVEC) and suggest that this up-regulation may contribute to the enhanced responsiveness of IL-4-stimulated HUVEC to histamine.
Expression and function of chemokines during viral infections: from molecular mechanisms to in vivo function
Authors: Melchjorsen Jesper , Sørensen Louise N , Paludan Søren R
Published: August 2003

Recruitment and activation of leukocytes are important for elimination of microbes, including viruses, from infected areas. Chemokines constitute a group of bioactive peptides that regulate leukocyte migration and also contribute to activation of these cells. Chemokines are essential mediators of inflammation and important for control of viral infections. The profile of chemokine expression contributes to shaping the immune response during viral infection, whereas viral subversion of the chemokine system allows the virus to evade antiviral activities of the host. In this review, we discuss the role of chemokines in host-defense against virus infections, and we also look deeper into the virus-cell interactions that trigger chemokine expression as well as the cellular signaling cascades involved.
LF15-0195 generates tolerogenic dendritic cells by suppression of NF-κB signaling through inhibition of IKK activity
Authors: Yang Jinming , Bernier Suzanne M , Ichim Thomas E , Li Mu , Xia Xiaoping , Zhou Dejun , Huang Xuyan , Strejan Gill H , White David J , Zhong Robert , Min Wei-Ping
Published: August 2003

LF15-0195 (LF) is a potent, less toxic analog of the immunosuppressant 15-deoxyspergualine, which we previously reported to prevent graft rejection and to induce permanent tolerance in a murine cardiac transplantation model. However, the underlying mechanism of action of LF required elucidation. In this study, dendritic cells (DC) treated with LF before activation with tumor necrosis factor α (TNF-α)/lipopolysaccharide (LPS) failed to express maturation markers (major histocompatibility complex II, CD40, CD86) and interleukin-12. LF prevented, in a concentration-dependent manner, the activation and nuclear translocation of nuclear factor-κB (NF-κB) in DC following addition of TNF-α/LPS. Yet-activated and active IκB kinases (IKKs) were inhibited in cells pretreated with LF, thereby preventing the phosphorylation of IκB and release of NF-κB, a key regulator of genes associated with the maturation of DC. LF-induced inhibition of IKK activity was reversed in a dose-dependent manner by the overexpression of IKK. The T helper cell type 2 (Th2) differentiation of naïve T cells promoted by LF-treated DC in vitro correlates with Th2 polarization observed in transplant recipients made tolerant by LF. These data demonstrated that LF-induced blockade of NF-κB signaling at the level of IKK promoted the generation of tolerogenic DC that inhibited Th1 polarization and increased Th2 polarization in vitro and in vivo.
Clinical risk management and child mental health
Authors: Subotsky Fiona
Published: August 2003

Risk management is a requirement of clinical governance and a new paradigm for child and adolescent mental health services. Issues are different from those of adult services and a wide range need to be considered, which include not only the risk of harm to self, to others and from others but also from the system (by omission or commission) and to the staff. Systematic policy development, using information from audits, complaints, incidents and inquiries, will be helpful and interagency agreements necessary to promote coordination. The complex regulatory framework is discussed.
Work, employment and psychiatric disability
Authors: Boardman Jed
Published: August 2003

Unemployment is high among those with mental disorders, particularly severe mental disorders, and there are a range of social and economic barriers impeding their employment. In general, there is a lack of vocational rehabilitation services in the UK for people with both physical and mental illnesses, despite good evidence for the effectiveness of some work schemes. Here, the need is discussed for a national strategy for vocational rehabilitation that involves employment and health services, and covers both physical and mental disorders.
What should we tell people about dementia?
Authors: Pinner Gill , Bouman Walter Pierre
Published: August 2003

This article reviews what we should tell patients and carers about dementia. The attitudes and views of patients, carers and peer groups are examined, as is the practice of doctors and other professionals working in dementia care. Factors influencing the decision to disclose the diagnosis of dementia, including the degree of certainty of the diagnosis, the degree of insight of the patient and the severity of the dementia are considered. Advantages, disadvantages and ethical issues of disclosure are discussed, as well as when or whether and how to disclose the diagnosis. Flexible guidelines regarding the process of disclosure are introduced.
Dangerous severe personality disorder
Authors: Feeney Adrian
Published: August 2003

The Draft Mental Health Bill was published in June 2002 and was widely criticised. There were particular concerns regarding the possible detention of those with personality disorders solely for the protection of the general public. Subsequently the Draft Bill was omitted from the Queen's speech in November 2002. The Department of Health has stated that it intends to push for the Bill's inclusion in the next Parliamentary year. This review attempts to summarise the present situation so as to inform the debate. It considers the relationship between personality disorder and risk, with examination of treatment models and the existing and proposed mental health legislation.
Managing criminal acts on the psychiatric ward: understanding the police view
Authors: Bayney Richard , Ikkos George
Published: August 2003

Success in preventing and responding to criminal behaviours on psychiatric wards may sometimes require cooperation between mental health services and local police services. This is especially so when seeking legal remedies through the criminal justice system. This article describes police perceptions of psychiatric services and psychiatric patients. It also reviews police procedures and factors that influence their response when the police are requested to intervene following an alleged criminal act by an in-patient. A case vignette is used to highlight the causes of tensions and guide the reader through the steps that might be considered when the issue of prosecution arises.
Psychiatric assertive outreach and learning disability services
Authors: Hassiotis Angela , Tyrer Peter , Oliver Patricia
Published: August 2003

Assertive outreach is a well-established method of managing patients with severe mental illness in the community. However, there is limited application and evidence of its efficacy in services for people with learning disabilities who also have mental illness. This paper elucidates current service provision for this group of patients and illustrates the pathways to mental health care available to them.
Roles for literature in medical education
Authors: Evans Martyn
Published: August 2003

The sustained study of literary texts and, to a lesser extent, of techniques of literary analysis offers a number of educational ‘goods' to the medical curriculum, to medical students and to the clinical practitioners they will one day become. In addition to the intrinsic goods of literature – the intense and direct experience of connecting with another's vision of the world – there are ‘instrumental’ goods augmenting the clinician's necessary physical understanding of patients' bodies with the equally necessary personal understanding of patients as individuals. These goods include (within the context of a medical curriculum genuinely located in higher education rather than in mere training) skills of communication, sensitive appreciation of the ethical dimensions of practice, the development of students' personal values and the stimulation of an enduring sense of wonder at embodied human nature.
Emerging challenges in using health information from the internet
Authors: Theodosiou Louise , Green Jonathan
Published: August 2003

In 2000, about 350 million adults used the internet and people increasingly take articles from websites to medical appointments. The quality and safety of websites vary widely and some users are reluctant to access mainstream sites. People are vulnerable to misinformation and exploitation: there is evidence that online purchases have caused morbidity and mortality. This paper reviews the current evidence on the dissemination of health information on the internet and the various strategies that are developing to assess and screen site quality. Such strategies include ‘quality assurance’ marking, specially designed search engines, and operational criteria for individuals to apply to sites. It also discusses the medical community's roles and responsibilities in relation to this burgeoning area.
Vagus nerve stimulation and refractory depression
Authors: Matthews Keith , Eljamel Muftah S.
Published: August 2003

As highlighted in the recent systematic review by Stimpson et al (2002), we know little about the relative efficacies of the treatment interventions that are routinely deployed for those with depressive disorders that have not responded to standard, first-line treatment approaches. Accepted practice is, at best, systematic ‘trial and error’, with sequential antidepressant monotherapy and/or combinations of antidepressant drugs with ‘augmenting agents'. This haphazard medicinal approach to managing the patient with poorly responsive depressive disorder is compounded by the lack of available information on the effectiveness and optimal role for psychological treatment methods. Given the high prevalence of depressive disorders and their frequent presentation to both primary and secondary care health services, it is a source of embarrassment that we remain so ignorant. Nevertheless, it is against this backdrop of uncertainty that we must now evaluate the relative merits of a novel intervention that has captured considerable media and lay interest: vagus nerve stimulation (VNS™).
Cultural adaptation of mental health measures: Improving the quality of clinical practice and research
Authors: Bhui Kamaldeep , Mohamud Salaad , Warfa Nasir , Craig Thomas J. , Stansfeld Stephen A.
Published: August 2003

The need for accurate information about the mental health problems of multicultural communities requires valid measures of mental health for use in a number of languages and cultural contexts. Measures of psychopathological symptoms leading to a diagnosis have been especially criticised for their universal application, without attention to their limitations across cultures. Yet, measures are crucial to assess recovery and the performance of services, and to take account of carer and user views. We summarise the main challenges in the cultural adaptation of such measures in our work with adults and adolescents of South Asian, African and Caribbean origin.
Towards a developmental understanding of violence
Authors: Fonagy Peter
Published: August 2003

Young offenders (under 20 years old) account for more than half of the violent crimes in the UK. Statistics on the onset of serious and violent delinquency show us that about half of persistent juvenile offenders are ‘active’ by age 12–13 years. Prevalence peaks between the ages of 17 and 18, but most serious delinquent offenders have started their offending careers much earlier.
‘Kind of Blue’: Creativity, mental disorder and jazz
Authors: Poole Rob
Published: August 2003

All scientific communities must keep themselves intellectually alive. It is important that we should attempt sometimes to tackle intriguing questions that are, strictly speaking, beyond the reach of robust, achievable, scientific methodologies. The small, flawed and inconclusive literature on the relationship between creativity and mental disorder, which includes contributions from some scientific heavyweights (e.g. Andreason, 1987; Post, 1994) represents a respectable attempt to use empirical methods to explore one such intriguing question. The fact that these matters are unlikely ever to be resolved does not discredit the effort.
Should neurosurgery for mental disorder be allowed to die out?
Authors: Persaud R. , Crossley D. , Freeman C.
Published: August 2003

The persistence of psychosurgery within the therapeutic armamentarium of psychiatry is something of an anachronism in the current era of evidence-based medicine. Robust evidence for efficacy does not exist and, indeed, can never realistically be gathered because of the extreme ethical difficulties of carrying out randomised controlled trials in this area. Yet there are undoubtedly patients who remain resistant to all conventional forms of treatment. Should they be denied what is possibly their last hope of recovery? Although the evidence is not watertight, modern neurosurgery is safer than ever before and appears to offer clinically meaningful symptom relief for ‘untreatable’ patients with chronic severe depression or obsessive–compulsive disorder (Matthews & Eljamel, 2003). The debate this month poses the question, ‘Should neurosurgery for mental disorder be allowed to die out?’ Dr Raj Persaud, consultant psychiatrist at the Maudsley hospital, argues in favour of the motion. The case in favour of retaining neurosurgery is made by two consultant psychotherapists, Dr David Crossley (Wrexham) and Dr Chris Freeman (Edinburgh).
Clinical interventions for treatment non-adherence in psychosis: Meta-analysis
Authors: Nosé Michela , Barbui Corrado , Gray Richard , Tansella Michele
Published: August 2003

Background

Studies investigating the efficacy of clinical interventions for reducing treatment non-adherence have generated contrasting findings, and treatment non-adherence remains common in clinical practice.

Aims

To systematically review whether there are effective clinical interventions that community psychiatric services can implement to reduce non-adherence.

Method

Systematic review and metaregression analysis of randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were used to assess the efficacy of interventions to enhance adherence.

Results

We reviewed 24 studies, more than half of which were RCTs. In 14 studies the experimental intervention was an educational programme. Five studies evaluated pre-discharge educational sessions, three studies explored the benefit of psychotherapeutic interventions and two studies looked at the effect of telephone prompts. The overall estimate of the efficacy of these interventions produced an odds ratio of 2.59 (95% Cl 2.21–3.03) for dichotomous outcomes, and a standardised mean difference of 0.36 (95% Cl 0.06–0.66) for continuous outcomes.

Conclusions

Community psychiatric services can potentially use effective clinical interventions, backed by scientific evidence, for reducing patient non-adherence.
Long-term outcome of late-onset schizophrenia: 5-year follow-up study
Authors: Brodaty Henry , Sachdev Perminder , Koschera Annette , Monk Dorothy , Cullen Breda
Published: August 2003

Background

There is controversy about whether late-onset schizophrenia is a precursor of cognitive decline.

Aims

To examine the long-term outcome of a group of patients with late-onset schizophrenia.

Method

Patients with onset of DSM–III–R schizophrenia at age 50 years or over, but without dementia, and a healthy control group were assessed at baseline (n=27 and n=34, respectively), after 1 year and after 5 years (n=19 and n=24, respectively) on measures of psychopathology, cognition and general functioning, and compared on rates of decline and incidence of dementia.

Results

Nine patients with late-onset schizophrenia and none of the control group were found to have dementia (5 Alzheimer type, 1 vascular, 3 dementia of unknown type) at 5-year follow-up. There appeared to be a subgroup of late-onset schizophrenia patients without signs of dementia at baseline or at 1 year follow-up who subsequently declined.

Conclusions

Late-onset schizophrenia may be a prodrome of Alzheimer-type dementia. More longitudinal studies are required to determine its nosological status.
Variations in the costs of child and adolescent psychiatric in-patient units
Authors: Beecham Jennifer , Chisholm Daniel , O'Herlihy Anne , Astin Jack
Published: August 2003

Background

Child and adolescent inpatient care is a highly specialised service, ideally requiring planning at a national level, but there are no routine data collections specifically for these services.

Aims

To estimate unit costs for child and adolescent psychiatric in-patient units and to analyse the variations in costs between units.

Method

Data collection alongside a national survey with cost estimations guided by principles drawn from economic theory. Bivariate and multivariate analyses are employed to identify cost influences.

Results

Fifty-eight units could provide sufficient data to allow calculation of the cost per in-patient day; mean=$197 (s.d.=71.6; 1999–2000 prices). The management sector, type of provision, number of rooms, capacity and location explained nearly half of the cost variation.

Conclusions

Child and adolescent psychiatric in-patient units are an expensive resource, with personnel absorbing two-thirds of the total costs. Costs per in-patient day vary fourfold and the exploration of cost variations can inform commissioning strategies.
Invited commentary on: Variations in the costs of child and adolescent psychiatric in-patient units
Authors: Harrington Richard , Gowers Simon
Published: August 2003

The great majority of young people with mental health problems never need admission to hospital. A small number, however, require some kind of in-patient provision. In comparison with North America and many parts of Europe, such provision has now become relatively uncommon in the UK. Although the remaining services are widely believed to be costly, there are no national data collections that provide accurate economic data. To begin to meet this need, the Department of Health commissioned a national study to explore the costs of these units, which ran in parallel with the National In-patient Child and Adolescent Psychiatry Study (NICAPS).
Standardised Assessment of Personality – Abbreviated Scale (SAPAS): Preliminary validation of a brief screen for personality disorder
Authors: Moran Paul , Leese Morven , Lee Tennyson , Walters Paul , Thornicroft Graham , Mann Anthony
Published: August 2003

Background

There is a need for a brief and simple screen for personality disorders that can be used in routine psychiatric assessments.

Aims

To test the concurrent validity and test–retest reliability of a brief screen for personality disorder.

Method

Sixty psychiatric patients were administered a brief screening interview for personality disorder. On the same day, they were interviewed with an established assessment for DSM–IV personality disorder. Three weeks later, the brief screening interview was repeated in order to examine test–retest reliability.

Results

A score of 3 on the screening interview correctly identified the presence of DSM–IV personality disorder in 90% of participants. The sensitivity and specificity were 0.94 and 0.85 respectively.

Conclusions

The study provides preliminary evidence of the usefulness of the screen in routine clinical settings.
‘Still-face’ interactions between mothers with borderline personality disorder and their 2-month-old infants
Authors: Crandell Lisa E. , Patrick Matthew P. H. , Hobson R. Peter
Published: August 2003

Background

There is evidence that psychopathology in mothers may be associated with dysfunctional mother–infant interactions.

Aims

To investigate mother–infant relations when mothers have borderline personality disorder.

Method

Eight mothers with borderline personality disorder and twelve mothers without psychiatric disorder were videotaped interacting with their 2-month-old infants in three successive phases of interaction: face-to-face play; an episode when the mother adopted a ‘still face’ and was unreactive; and a period when play interactions were resumed. The videotapes were rated by judges blind to the diagnostic group of the mother.

Results

The mothers with borderline personality disorder were more intrusively insensitive towards their infants. During the still-face period, their infants showed increased looking away and dazed looks. Following this, mother–infant interactions were less satisfying and their infants showed dazed looks and lowering of affect.

Conclusions

The diagnosis of borderline personality disorder is associated with a particular pattern of mother–infant interaction. The infants' responses to the still-face challenge might suggest dysfunctional self-regulation, but the developmental significance remains to be assessed.
Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia
Authors: Spector Aimee , Thorgrimsen Lene , Woods Bob , Royan Lindsay , Davies Steve , Butterworth Margaret , Orrell Martin
Published: August 2003

Background

A recent Cochrane review of reality orientation therapy identified the need for large, well-designed, multi-centre trials.

Aims

To test the hypothesis that cognitive stimulation therapy (CST) for older people with dementia would benefit cognition and quality of life.

Method

A single-blind, multi-centre, randomised controlled trial recruited 201 older people with dementia. The main outcome measures were change in cognitive function and quality of life. An intention-to-treat analysis used analysis of covariance to control for potential variability in baseline measures.

Results

One hundred and fifteen people were randomised within centres to the intervention group and 86 to the control group. At follow-up the intervention group had significantly improved relative to the control group on the Mini-Mental State Examination (P=0.044), the Alzheimer's Disease Assessment Scale – Cognition (ADAS–Cog) (P=0.014) and Quality of Life – Alzheimer's Disease scales (P=0.028). Using criteria of 4 points or more improvement on the ADAS–Cog the number needed to treat was 6 for the intervention group.

Conclusion

The results compare favourably with trials of drugs for dementia. CST groups may have worthwhile benefits for many people with dementia.
Forty lives in the bebop business: Mental health in a group of eminent jazz musicians
Authors: Wills Geoffrey I.
Published: August 2003

Background

Above-average levels of psychopathology have been demonstrated convincingly in groups of outstanding individuals working in the arts. Currently, jazz musicians have not been studied in this regard.

Aims

To investigate any evidence of psychopathology in a group of eminent jazz musicians.

Method

Biographical material relating to 40 eminent American modern jazz musicians was reviewed and an attempt was made to formulate diagnoses using DSM–IV.

Results

Evidence was provided of levels of psychopathology in the sample of jazz musicians similar to those found in other previously investigated creative groups, with the exception of substance-related problems. An interesting connection between creativity and sensation-seeking was highlighted.

Conclusions

The link between psychopathology and creativity in the arts was given further weight. Future studies of jazz musicians using larger samples and making comparison with groups from different eras of music would give greater clarification to this area.
Ten books
Authors: David Anthony S.
Published: August 2003

Don't get me wrong – I've nothing against books. In fact, I think books are great. It's just that I get annoyed by the attitude conveyed by some psychiatrists that the only qualifications needed to be a decent psychiatrist are a classical education, some foreign travel and the contents of a few good books. A bit like the diplomatic service. Although this may have been acceptable once upon a time, it isn't now. We have had at least 100 years to benefit from advances in the biological and social sciences and specific research in our field, so it is time we considered novels as holiday and recreational reading and not a substitute for study. That is one of the arguments set in train when I received the invitation to do ‘Ten books'. Another acknowledges just how much I enjoy reading other people's choices, both for forcing me to expand the ever-growing list of books I really must read and for what they say about the choosers.