bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic analysis of the entomopathogenic nematode Heterorhabditis bacteriophora TTO1
Authors: Bai Xiaodong , Adams Byron J , Ciche Todd A , Clifton Sandra , Gaugler Randy , Hogenhout Saskia A , Spieth John , Sternberg Paul W , Wilson Richard K , Grewal Parwinder S
Published: April 2009

Background

The entomopathogenic nematode Heterorhabditis bacteriophora and its symbiotic bacterium, Photorhabdus luminescens, are important biological control agents of insect pests. This nematode-bacterium-insect association represents an emerging tripartite model for research on mutualistic and parasitic symbioses. Elucidation of mechanisms underlying these biological processes may serve as a foundation for improving the biological control potential of the nematode-bacterium complex. This large-scale expressed sequence tag (EST) analysis effort enables gene discovery and development of microsatellite markers. These ESTs will also aid in the annotation of the upcoming complete genome sequence of H. bacteriophora.

Results

A total of 31,485 high quality ESTs were generated from cDNA libraries of the adult H. bacteriophora TTO1 strain. Cluster analysis revealed the presence of 3,051 contigs and 7,835 singletons, representing 10,886 distinct EST sequences. About 72% of the distinct EST sequences had significant matches (E value < 1e-5) to proteins in GenBank's non-redundant (nr) and Wormpep190 databases. We have identified 12 ESTs corresponding to 8 genes potentially involved in RNA interference, 22 ESTs corresponding to 14 genes potentially involved in dauer-related processes, and 51 ESTs corresponding to 27 genes potentially involved in defense and stress responses. Comparison to ESTs and proteins of free-living nematodes led to the identification of 554 parasitic nematode-specific ESTs in H. bacteriophora, among which are those encoding F-box-like/WD-repeat protein theromacin, Bax inhibitor-1-like protein, and PAZ domain containing protein. Gene Ontology terms were assigned to 6,685 of the 10,886 ESTs. A total of 168 microsatellite loci were identified with primers designable for 141 loci.

Conclusion

A total of 10,886 distinct EST sequences were identified from adult H. bacteriophora cDNA libraries. BLAST searches revealed ESTs potentially involved in parasitism, RNA interference, defense responses, stress responses, and dauer-related processes. The putative microsatellite markers identified in H. bacteriophora ESTs will enable genetic mapping and population genetic studies. These genomic resources provide the material base necessary for genome annotation, microarray development, and in-depth gene functional analysis.
Structure-Function analysis of the CTLA-4 interaction with PP2A
Authors: Teft Wendy A , Chau Thu A , Madrenas Joaquín
Published: April 2009

Background

CTLA-4 functions primarily as an inhibitor of T cell activation. There are several candidate explanations as to how CTLA-4 modulates T cell responses, but the exact mechanism remains undefined. The tail of CTLA-4 does not have any intrinsic enzymatic activity but is able to associate with several signaling molecules including the serine/threonine phosphatase PP2A. PP2A is a heterotrimeric molecule comprised of a regulatory B subunit associated with a core dimer of a scaffolding (A) and a catalytic (C) subunit.

Results

Here, we performed an analysis of the human CTLA-4 interface interacting with PP2A. We show that PP2A interacts with the cytoplasmic tail of CTLA-4 in two different sites, one on the lysine rich motif, and the other on the tyrosine residue located at position 182 (but not the tyrosine 165 of the YVKM motif). Although the interaction between CTLA-4 and PP2A was not required for inhibition of T cell responses, it was important for T cell activation by inverse agonists of CTLA-4. Such an interaction was functionally relevant because the inverse agonists induced IL-2 production in an okadaic acid-dependent manner.

Conclusion

Our studies demonstrate that PP2A interacts with the cytoplasmic tail of human CTLA-4 through two motifs, the lysine rich motif centered at lysine 155 and the tyrosine residue 182. This interaction and the phosphatase activity of PP2A are important for CTLA-4-mediated T cell activation.
Looking for a pattern: An MEG study on the abstract mismatch negativity in musicians and nonmusicians
Authors: Herholz Sibylle C , Lappe Claudia , Pantev Christo
Published: April 2009

Background

The mismatch negativity (MMN) is an early component of event-related potentials/fields, which can be observed in response to violations of regularities in sound sequences. The MMN can be elicited by simple feature (e.g. pitch) deviations in standard oddball paradigms as well as by violations of more complex sequential patterns. By means of magnetoencephalography (MEG) we investigated if a pattern MMN could be elicited based on global rather than local probabilities and if the underlying ability to integrate long sequences of tones is enhanced in musicians compared to nonmusicians.

Results

A pattern MMN was observed in response to violations of a predominant sequential pattern (AAAB) within a standard oddball tone sequence consisting of only two different tones. This pattern MMN was elicited even though the probability of pattern deviants in the sequence was as high as 0.5. Musicians showed more leftward-lateralized pattern MMN responses, which might be due to a stronger specialization of the ability to integrate information in a sequence of tones over a long time range.

Conclusion

The results indicate that auditory grouping and the probability distribution of possible patterns within a sequence influence the expectations about upcoming tones, and that the MMN might also be based on global statistical knowledge instead of a local memory trace. The results also show that auditory grouping based on sequential regularities can occur at a much slower presentation rate than previously presumed, and that probability distributions of possible patterns should be taken into account even for the construction of simple oddball sequences.
Daptomycin in experimental murine pneumococcal meningitis
Authors: Mook-Kanamori Barry B , Rouse Mark S , Kang Cheol-In , van de Beek Diederik , Steckelberg James M , Patel Robin
Published: April 2009

Background

Daptomycin, a lipopeptide antibiotic, could be an alternative to vancomycin for treatment of pneumococcal meningitis. We determined the activity of daptomycin versus vancomycin, with dexamethasone as an adjuvant, in a murine model of pneumococcal meningitis.

Methods

Ninety-six 25–30 gram mice were inoculated intracisternally with serotype 3 Streptococcus pneumoniae modified by the integration of a luminescent lux operon. All mice were treated with either dexamethasone 1 mg/kg intraperitoneally every 6 hours alone or in combination with either vancomycin or daptomycin, also administered intraperitoneally. Serum antimicrobial concentrations were selected to approximate those achieved in humans. Following treatment, bioluminescence and cerebrospinal fluid (CSF) bacterial concentrations were determined. Caspase-3 staining was used to assess apoptosis on brain histopathology.

Results

Sixteen hours post intracisternal inoculation, bacterial titers in CSF were 6.8 log10 cfu/ml. Amongst the animals given no antibiotic, vancomycin 50 mg/kg at 16 and 20 hours or daptomycin 25 mg/kg at 16 hours, CSF titers were 7.6, 3.4, and 3.9 log10 cfu/ml, respectively, at 24 hours post infection (p-value, < 0.001 for both vancomycin or daptomycin versus no antibiotic); there was no significant difference in bactericidal activity between the vancomycin and daptomycin groups (p-value, 0.18). CSF bioluminescence correlated with bacterial titer (Pearson regression coefficient, 0.75). The amount of apoptosis of brain parenchymal cells was equivalent among treatment groups.

Conclusion

Daptomycin or vancomycin, when given in combination with dexamethasone, is active in the treatment of experimental pneumococcal meningitis.
Role of educational level in the relationship between Body Mass Index (BMI) and health-related quality of life (HRQL) among rural Spanish women
Authors: García-Mendizábal María José , Carrasco José Miguel , Pérez-Gómez Beatriz , Aragonés Nuria , Guallar-Castillón Pilar , Rodríguez-Artalejo Fernando , López-Abente Gonzalo , Pollán Marina
Published: April 2009

Background

The impact of obesity on health-related quality of life (HRQL) has been little explored in rural areas. The goal of this study is to ascertain the association between obesity and HRQL among Spanish women living in a rural area, and the influence of their educational level.

Methods

Cross-sectional study with personal interview of 1298 women (aged 18 to 60) randomly selected from the electoral rolls of 14 towns in Galicia, a region in the north-west of Spain. HRQL was assessed using the SF-36 questionnaire. The association between body mass index (BMI) and suboptimal scores in the different HRQL dimensions was summarised using odds ratios (ORs), obtained from multivariate logistic regression models. Separate analyses were conducted for women who had finished their education younger than 16 years old and women with secondary education to assess differences in the relationship between BMI and HRQL according to educational level.

Results

Among women with primary or lower education, obesity was associated with a higher prevalence of suboptimal values in the following dimensions: Physical functioning (OR: 1.97; 95%CI: 1.22–3.18); Role-physical (OR: 1.81; 95%CI: 1.04–3.14); General health (OR: 1.76; 95%CI: 1.10–2.81); and Role-emotional (OR: 2.52; 95%CI: 1.27–5.03). In women with higher education, physical functioning was the only dimension associated with obesity (OR: 2.02: 95%CI 0.83–4.97).

Conclusion

The impact of obesity on women's HRQL is greater among those with a lower educational level. This group registered higher prevalence of obesity and poorer self-perceived health.
Antimicrobial effect of farnesol, a Candida albicans quorum sensing molecule, on Paracoccidioides brasiliensis growth and morphogenesis
Authors: Derengowski Lorena S , De-Souza-Silva Calliandra , Braz Shélida V , Mello-De-Sousa Thiago M , Báo Sônia N , Kyaw Cynthia M , Silva-Pereira Ildinete
Published: April 2009

Background

Farnesol is a sesquiterpene alcohol produced by many organisms, and also found in several essential oils. Its role as a quorum sensing molecule and as a virulence factor of Candida albicans has been well described. Studies revealed that farnesol affect the growth of a number of bacteria and fungi, pointing to a potential role as an antimicrobial agent.

Methods

Growth assays of Paracoccidioides brasiliensis cells incubated in the presence of different concentrations of farnesol were performed by measuring the optical density of the cultures. The viability of fungal cells was determined by MTT assay and by counting the colony forming units, after each farnesol treatment. The effects of farnesol on P. brasiliensis dimorphism were also evaluated by optical microscopy. The ultrastructural morphology of farnesol-treated P. brasiliensis yeast cells was evaluated by transmission and scanning electron microscopy.

Results

In this study, the effects of farnesol on Paracoccidioides brasiliensis growth and dimorphism were described. Concentrations of this isoprenoid ranging from 25 to 300 μM strongly inhibited P. brasiliensis growth. We have estimated that the MIC of farnesol for P. brasiliensis is 25 μM, while the MLC is around 30 μM. When employing levels which don't compromise cell viability (5 to 15 μM), it was shown that farnesol also affected the morphogenesis of this fungus. We observed about 60% of inhibition in hyphal development following P. brasiliensis yeast cells treatment with 15 μM of farnesol for 48 h. At these farnesol concentrations we also observed a significant hyphal shortening. Electron microscopy experiments showed that, despite of a remaining intact cell wall, P. brasiliensis cells treated with farnesol concentrations above 25 μM exhibited a fully cytoplasmic degeneration.

Conclusion

Our data indicate that farnesol acts as a potent antimicrobial agent against P. brasiliensis. The fungicide activity of farnesol against this pathogen is probably associated to cytoplasmic degeneration. In concentrations that do not affect fungal viability, farnesol retards the germ-tube formation of P. brasiliensis, suggesting that the morphogenesis of this fungal is controlled by environmental conditions.
Role of hepatitis B surface antigen in the development of hepatocellular carcinoma: regulation of lymphoid enhancer-binding factor 1
Authors: Tian Xiaochen , Li Jinjun , Ma Zhang-Mei , Zhao Chao , Wan Da-Fang , Wen Yu-Mei
Published: April 2009

Background

There are around 350 million of hepatitis B surface antigen (HBsAg) carriers worldwide, and among them, high risk of developing hepatocellular carcinoma (HCC) has been identified by epidemiological studies. To date, the molecular role of HBsAg in HCC development has not been fully studied. We have previously reported that in cell cultures, HBsAg up-regulated the expression of lymphoid enhancer-binding factor 1 (LEF-1), a key component of the Wnt pathway. In this study we aimed to study this effect of HBsAg on LEF-1 in the development of HCC.

Methods

Expression of HBsAg, LEF-1 and its downstream effector genes were compared among 30 HCCs, their peritumor tissue counterparts and 9 normal control liver tissues by quantitative real-time PCR. In addition, immunohistochemical staining studies on HBsAg and LEF-1 expression were conducted among these samples.

Results

The expression of LEF-1 was compared between 13 HBsAg positive HCC tissues and 17 HBsAg negative HCC tissues. Simultaneous detection of LEF-1 and HBsAg was observed in HBsAg positive HCC tissues and, additionally, the simultaneous detection of HBsAg and LEF-1 was more pronounced in peritumor tissues, compared to that in the tumor tissues. The distribution of cellular LEF-1 in peritumor tissues was predominantly in the cytoplasm; while LEF-1 in the tumor tissues was located either exclusively in the nucleus or both in the nucleus and cytoplasm. By real-time PCR, the expression levels of LEF-1 downstream effector genes cyclin D1 and c-myc were higher in peritumor cells compared to that of the tumor cells. However, a 38 kDa truncated isoform of LEF-1, rather than the 55 kDa wild-type LEF-1, was significantly elevated in the HBsAg positive tumor cells.

Conclusion

Data indicate that deregulation of the Wnt pathway by HBsAg occurred in HBV-associated HCCs, but was more pronounced in the peritumor cells. It is speculated that HBsAg could stimulate proliferation and functional modification of hepatocytes via LEF-1 through the Wnt pathway at the pre-malignant stage.
RANKL increases the level of Mcl-1 in osteoclasts and reduces bisphosphonate-induced osteoclast apoptosis in vitro
Authors: Sutherland Karen A , Rogers Helena L , Tosh Denise , Rogers Michael J
Published: April 2009

Introduction

Bisphosphonates are the most widely used class of drug for inhibiting osteoclast-mediated bone loss, but their effectiveness at preventing joint destruction in rheumatoid arthritis has generally been disappointing. We examined whether the ability of bisphosphonates to induce osteoclast apoptosis and inhibit bone resorption in vitro is influenced by the cytokine receptor activator of nuclear factor-kappa B ligand (RANKL), an important mediator of inflammation-induced bone loss.

Methods

Rabbit osteoclasts were treated with the bisphosphonates clodronate or alendronate for up to 48 hours in the absence or presence of RANKL. Changes in cell morphology and induction of apoptosis were examined by scanning electron microscopy, whilst resorptive activity was determined by measuring the area of resorption cavities. Changes in the level of anti-apoptotic proteins, including Mcl-1, Bcl-2, and Bcl-x>L, were determined in rabbit osteoclasts and in cytokine-starved mouse osteoclasts by Western blotting.

Results

RANKL significantly attenuated the ability of both clodronate and alendronate to induce osteoclast apoptosis and inhibit bone resorption. Treatment of rabbit osteoclasts with RANKL was associated with an increase in the anti-apoptotic protein Mcl-1 but not Bcl-2. A role for Mcl-1 in osteoclast survival was suggested using osteoclasts generated from mouse bone marrow macrophages in the presence of RANKL + macrophage colony-stimulating factor (M-CSF) since cytokine deprivation of mouse osteoclasts caused a rapid loss of Mcl-1 (but not Bcl-2 or Bcl-xL), which preceded the biochemical and morphological changes associated with apoptosis. Loss of Mcl-1 from mouse osteoclasts could be prevented by factors known to promote osteoclast survival (RANKL, M-CSF, tumour necrosis factor-alpha [TNF-α], or lipopolysaccharide [LPS]).

Conclusions

RANKL protects osteoclasts from the apoptosis-inducing and anti-resorptive effects of bisphosphonates in vitro. The ability of RANKL (and other pro-inflammatory factors such as TNF-α and LPS) to increase the level of Mcl-1 in osteoclasts may explain the lack of effectiveness of some bisphosphonates in preventing inflammation-induced bone loss.
Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells
Authors: Kang Hee-Kap , Ecklund Diane , Liu Michael , Datta Syamal K
Published: April 2009

Introduction

Lupus patients need alternatives to steroids and cytotoxic drugs. We recently found that apigenin, a non-mutagenic dietary flavonoid, can sensitize recurrently activated, normal human T cells to apoptosis by inhibiting nuclear factor-kappa-B (NF-κB)-regulated Bcl-xL, cyclooxygenase 2 (COX-2), and cellular FLICE-like inhibitory protein (c-FLIP) expression. Because sustained immune activation and hyperexpression of COX-2 and c-FLIP contribute to lupus, we treated SNF1 mice that spontaneously develop human lupus-like disease with apigenin.

Methods

SNF1 mice with established lupus-like disease were injected with 20 mg/kg of apigenin daily and then monitored for development of severe nephritis. Histopathologic changes in kidneys, IgG autoantibodies to nuclear autoantigens in serum and in cultures of splenocytes, along with nucleosome-specific T helper 1 (Th1) and Th17 responses, COX-2 expression, and apoptosis of lupus immune cells were analyzed after apigenin treatment.

Results

Apigenin in culture suppressed responses of Th1 and Th17 cells to major lupus autoantigen (nucleosomes) up to 98% and 92%, respectively, and inhibited the ability of lupus B cells to produce IgG class-switched anti-nuclear autoantibodies helped by these Th cells in presence of nucleosomes by up to 82%. Apigenin therapy of SNF1 mice with established lupus suppressed serum levels of pathogenic autoantibodies to nuclear antigens up to 97% and markedly delayed development of severe glomerulonephritis. Apigenin downregulated COX-2 expression in lupus T cells, B cells, and antigen-presenting cells (APCs) and caused their apoptosis. Autoantigen presentation and Th17-inducing cytokine production by dendritic cells were more sensitive to the inhibitory effect of apigenin in culture, as evident at 0.3 to 3 μM, compared with concentrations (10 to 100 μM) required for inducing apoptosis.

Conclusions

Apigenin inhibits autoantigen-presenting and stimulatory functions of APCs necessary for the activation and expansion of autoreactive Th1 and Th17 cells and B cells in lupus. Apigenin also causes apoptosis of hyperactive lupus APCs and T and B cells, probably by inhibiting expression of NF-κB-regulated anti-apoptotic molecules, especially COX-2 and c-FLIP, which are persistently hyperexpressed by lupus immune cells. Increasing the bioavailability of dietary plant-derived COX-2 and NF-κB inhibitors, such as apigenin, could be valuable for suppressing inflammation in lupus and other Th17-mediated diseases like rheumatoid arthritis, Crohn disease, and psoriasis and in prevention of inflammation-based tumors overexpressing COX-2 (colon, breast).
Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer
Authors: Jacquemier Jocelyne , Charafe-Jauffret Emmanuelle , Monville Florence , Esterni Benjamin , Extra Jean Marc , Houvenaeghel Gilles , Xerri Luc , Bertucci François , Birnbaum Daniel
Published: April 2009

Introduction

Breast cancers are traditionally divided into hormone-receptor positive and negative cases. This classification helps to guide patient management. However, a subgroup of hormone-receptor positive patients relapse irrespective of hormonal therapy. Gene expression profiling has classified breast tumours into five major subtypes with significant different outcome. The two luminal subtypes, A and B, show high expression of ESR1, GATA3 and FOXA1 genes. Prognostic biomarkers for oestrogen receptor (ER)-positive cases include progesterone receptor (PR) and androgen receptor (AR), and proteins related to proliferation or apoptotic resistance. The aim of this study was to identify the best predictors of success of hormonal therapy.

Methods

By immunohistochemistry we studied 10 markers in a consecutive series of 832 cases of breast carcinoma treated at the Paoli-Calmettes Institute from 1990 to 2002 and deposited onto tissue microarrays (TMA). These markers were luminal-related markers ER, PR, AR, FOXA1 and GATA3 transcription factors, proliferation-related Ki67 and CCND1, ERBB2, anti-apoptotic BCL2 and P53. We also measured vascular peritumoural invasion (VPI), size, grade and lymph node involvement. For 143 cases, gene expression profiles were available. Adjuvant chemotherapy and hormonal therapy were given to high- and low-risk patients, respectively. The 162 events observed and taken into account were metastases.

Results

Molecular expression of the 10 parameters and subtype with ER status were strongly correlated. Of the 67 luminal A cases of this series, 63 were ER-positive. Multivariate analyses showed the highly significant prognostic value of VPI (hazard ratio (HR) = 2.47), Ki67 (HR = 2.9), P53 (HR = 2.9) and GATA3 (HR = 0.5) for the 240 patients who received hormonal therapy.

Conclusions

A panel of three antibodies (Ki67, P53 and GATA3) associated with VPI can significantly improve the traditional prognosticators in predicting outcome for ER-positive breast cancer patients receiving hormonal therapy.
Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells
Authors: Bollyky Paul L , Falk Ben A , Wu Rebecca P , Buckner Jane H , Wight Thomas N , Nepom Gerald T
Published: April 2009

The authors describe the immunoregulatory contributions of intact versus fragmented hyaluronan, a prominent component of the extracellular matrix.

The composition of the ECM provides contextual cues to leukocytes in inflamed and healing tissues. One example of this is HA, where LMW–HA, generated during active inflammation, is a TLR ligand and an endogenous “danger signal,” and HMW–HA, predominant in healing or intact tissues, functions in an inverse manner. Our data suggest that HMW–HA actively promotes immune tolerance by augmenting CD4+CD25+ TReg function, and LMW–HA does not. Using a human iTReg model, we demonstrate that HMW–HA but not LMW–HA provides a costimulatory signal through cross–linking CD44 which promotes Foxp3 expression, a critical signaling molecule associated with TReg. This effect, in part, may be mediated by a role for intact HMW–HA in IL–2 production, as TReg are highly IL–2–dependent for their survival and function. We propose that HMW–HA contributes to the maintenance of immune homeostasis in uninjured tissue and effectively communicates an “all–clear” signal to down–regulate the adaptive immune system through TReg after tissue matrix integrity has been restored.
CD4 and CD8: an inside-out coreceptor model for innate immune cells
Authors: Gibbings Derrick , Befus A Dean
Published: April 2009

CD4 and CD8 enhancement of FcR-like signaling is discussed as a potential role when expressed by innate immune cells.

CD8 and CD4 are expressed by several cell types that do not express TCR. These include DCs, macrophages, monocytes, and NK cells. CD8+ monocytes and macrophages are abundant at the site of pathology in many rat disease models, particularly those involving immune complex-mediated pathology. Indeed, in some disease models, CD8+ macrophages correlate with severity of pathology or directly cause pathology or tumor cell killing. Evidence suggests CD8 or CD4 can enhance FcγR-dependent responses of human monocytes. Building on data that key components of TCR and FcγR signaling can substitute one another efficiently, we postulate that CD4 and CD8 operate with FcγR and potentially other receptors to enhance responses of T cells and various innate immune cells. Our model suggests CD8 on myeloid cells may contribute directly to tumor killing and tissue pathology by enhancing FcγR responses. Moreover, the model suggests a role for CD8 in cross-presentation of antibody-associated antigen by DCs and a new mechanism to regulate TCR sensitivity.
IL-21: a new player in the control of isotype switch in Peyer’s patches
Authors: Pistoia Vito , Cocco Claudia
Published: April 2009

Peyer’s patches (PP) are lymphoid follicles of the small intestine containing predominantly IgA+ B cells. In this JLB issue, IL-21 is reported to dampen TGF-β1-induced IgG2b but not IgA production by mouse B cells, possibly explaining why IgA+ B cells predominate in PP.
Galectin-8 provides costimulatory and proliferative signals to T lymphocytes
Authors: Tribulatti María Virginia , Cattaneo Valentina , Hellman Ulf , Mucci Juan , Campetella Oscar
Published: April 2009

CD4+ T cells are the main lymphocyte target of Galectin-8, which lowers their activation threshold and thus suggesting the lectin involvement in inflammatory diseases.

Galectin (Gal) constitute a family of carbohydrate-recognizing molecules ubiquitously expressed in mammals. In the immune system, they regulate many processes such as inflammation, adhesion, and apoptosis. Here, we report the expression in the spleen of the two same Gal-8 splice variants described previously in the thymus. Gal-8 was found to induce two separate biological activities on T lymphocytes: a robust naive CD4+ T cell proliferation in the absence of antigen and notably, a costimulatory signal that synergized the cognate OVA peptide in DO11.10 mice transgenic for TCROVA. The antigen-independent proliferation induced by Gal-8 displayed increased expression of pro- and anti-inflammatory cytokines, thus suggesting the polyclonal expansion of Th1 and Th2 clones. The costimulatory effect on antigen-specific T cell activation was evidenced when the Gal and the peptide were assayed at doses suboptimal to induce T cell proliferation. By mass spectra analysis, several integrins and leukocyte surface markers, including CD45 isoforms, as well as other molecules specific to macrophages, neutrophils, and platelets, were identified as putative Gal-8 counter-receptors. Gal-8 triggered pZAP70 and pERK1/2. Moreover, pretreatment with specific inhibitors of CD45 phosphatase or ERK1/2 prevented its antigen-dependent and -independent T cell-proliferative activities. This seems to be associated with the agonistic binding to CD45, which lowers the activation threshold of the TCR signaling pathway. Taken together, our findings support a distinctive role for locally produced Gal-8 as an enhancer of otherwise borderline immune responses and also suggest that Gal-8 might fuel the reactivity at inflammatory foci.
IFN-α amplifies human naïve B cell TLR-9-mediated activation and Ig production
Authors: Giordani L , Sanchez M , Libri I , Quaranta M G , Mattioli B , Viora M
Published: April 2009

CpG ODN drives B cells to differentiate into plasma cells; IFN-α amplifies the inductive effect of CpG ODN on B cells.

TLRs are a family of molecules that function as sensors for the detection of pathogens. TLR-9, expressed on B cells and pDCs, recognizes CpG motifs of unmethylated bacterial DNA and plays a role in the development of autoimmunity. The present study was designed to investigate the effects of IFN-α in combination with CpG ODN on the activation of CD27– naïve B cells and on Ig production. We provide evidence that CpG ODN not only induces a total and T-dependent, specific IgM response by naïve B cells but also their phenotypic differentiation in plasma cells, as demonstrated by the up-regulation of CD38 expression. We found that TLR-9 stimulation with CpG ODN induces IL-1β, TNF-α, IL-10, and IL-6 production. Interestingly, we also found that CpG ODN induces naïve B cell maturation into memory cells, as demonstrated by the induction of CD27, AID mRNA expression, and IgG production. More importantly, our results demonstrate that IFN-α amplifies the inductive effect of CpG ODN on naïve B activation and on Ig production through a mechanism involving TLR-9/MyD88-dependent signaling. Moreover, we found that IFN-α enhances the frequency of CpG ODN-induced memory B cells. Our results may contribute to clarify the events promoting IFN-α-induced amplification of naïve B cell activation via TLR-9 for a better understanding of the pathogenesis of autoimmune disorders and may guide treatments targeting this pathway within B cells.
Pivotal Advance: Expansion of small sputum macrophages in CF: failure to express MARCO and mannose receptors
Authors: Wright Adam K A , Rao Satish , Range Simon , Eder Christiane , Hofer Thomas P J , Frankenberger Marion , Kobzik Lester , Brightling Chris , Grigg Jonathan , Ziegler–Heitbrock Loems
Published: April 2009

In the airways of classical CF cases there is a high number of newly immigrated small macrophages, which are disabled with respect to scavenger receptor–mediated phagocytosis.

Macrophages in the airways form an important element of immune defense and inflammation. We analyzed induced sputum from airways of patients with CF for the types of macrophages present, their receptor expression, and phagocytic function. In samples from patients and age–matched controls, macrophages were analyzed by multicolor flow cytometry, scavenger receptor expression was studied at the protein and mRNA level, and receptor function was investigated using fluorescent particles. In adult patients with CF, we discovered a pronounced expansion of the small CD14+ DR+ CD68weak+ macrophages to 73 ± 18% compared with 16 ± 8% in healthy controls. Expression of the MARCO and CD206 (mannose receptor) was strongly reduced at the mRNA and protein level in sputum macrophages. Antibody–blocking studies showed that MARCO mediates phagocytosis of unopsonized particles. In line with reduced MARCO expression, sputum macrophages in CF showed a deficient uptake of particles (23±9% of cells) compared with healthy controls (71±15%). The deficiency of MARCO expression in the predominant small sputum macrophages in CF may lead to impaired clearance of inhaled particles with increased inflammation and damage to the CF lung.
Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-γ expression in activated human T cells
Authors: Aydemir Tolunay B , Liuzzi Juan P , McClellan Steve , Cousins Robert J
Published: April 2009

Dietary zinc supplement increases production of the tumor/infection-fighting cytokine IFN-γ in T cells by increasing zinc transport from the lysosomes to the cell cytoplasm.

The zinc transporter ZIP8 is highly expressed in T cells derived from human subjects. T cell ZIP8 expression was markedly up-regulated upon in vitro activation. T cells collected from human subjects who had received oral zinc supplementation (15 mg/day) had higher expression of the activation marker IFN-γ upon in vitro activation, indicating a potentiating effect of zinc on T cell activation. Similarly, in vitro zinc treatment of T cells along with activation resulted in increased IFN-γ expression with a maximum effect at 3.1 μM. Knockdown of ZIP8 in T cells by siRNA decreased ZIP8 levels in nonactivated and activated cells and concomitantly reduced secretion of IFN-γ and perforin, both signatures of activation. Overexpression of ZIP8 by transient transfection caused T cells to exhibit enhanced activation. Confocal microscopy established that ZIP8 is localized to the lysosome where ZIP8 abundance is increased upon activation. Loss of lysosomal labile zinc in response to activation was measured by flow cytometry using a zinc fluorophore. Zinc between 0.8 and 3.1 μM reduced CN phosphatase activity. CN was also inhibited by the CN inhibitor FK506 and ZIP8 overexpression. The results suggest that zinc at low concentrations, through inhibition of CN, sustains phosphorylation of the transcription factor CREB, yielding greater IFN-γ expression in T cells. ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN-γ regulation in T cells.
Government policy and the National Service Framework for Mental Health: modelling and costing services in England
Authors: Boardman Jed , Parsonage Michael
Published: April 2009

The National Service Framework for Mental Health (NSF–MH), published by the Department of Health in 1999, set an ambitious 10-year agenda for improving mental healthcare for working-age adults in England, based on seven quality standards covering all major services. The NSF–MH was supported by a series of other policy documents published by the government. This article illustrates a means of modelling the government's policy for adult mental health services to produce figures for the necessary services, staffing and financial resources required to meet the policy objectives. The findings of a report recently published by the Sainsbury Centre for Mental Health, which undertook a detailed assessment of what needs to be done to deliver these standards in terms of service provision, staffing and funding, is summarised and its implications examined.
Hyperthermia syndromes in psychiatry
Authors: Ahuja Niraj , Cole Andrew J.
Published: April 2009

Presence of fever in psychiatric patients may signify a number of potentially fatal conditions. Several of these are related to treatments (e.g. neuroleptic malignant syndrome with antipsychotics, serotonin syndrome with serotonergic antidepressants, and malignant hyperpyrexia with anaesthesia used for administration of electroconvulsive therapy) or exacerbated by them (e.g. malignant catatonia with antipsychotics). New classes of drug treatment may be changing the epidemiology of these disorders. We suggest that an initial diagnosis of hyperthermia syndrome is clinically useful as there are some important commonalities in treatment. We outline a systematic approach to identify a particular subtype of hyperthermia syndrome and the indications for more specific treatments where available.
The humanities in postgraduate medical education
Authors: Oyebode Femi
Published: April 2009

This article discusses the value of the medical humanities within the medical curriculum. It explores the place of the humanities in postgraduate psychiatric training, what a curriculum might look like and which texts it might be useful to include in courses. It also briefly discusses teaching methods that may be appropriate in a postgraduate setting. Many of the proposed ideas are potentially relevant to CPD courses.
Minimal – no, minimise – yes
Authors: Feeney Larkin
Published: April 2009

This commentary questions evidence put forward in support of minimal-medication approaches to the treatment of schizophrenia. Psychiatrists should indeed seek to minimise the amount of medication that they use in order to reduce the incidence of side-effects. However, there is strong evidence that antipsychotic medications do help people with psychosis towards recovery. In practice, psychiatrists do not rigidly follow guidelines recommending medication, but rather work with and support individuals in a broad-based way to make informed choices about their mental healthcare.
Changing the balance of psychosis treatment
Authors: Moncrieff Joanna
Published: April 2009

Antipsychotic medication is the primary form of treatment offered to people diagnosed with schizophrenia or psychosis, but it is associated with severe adverse effects, it is often experienced as unpleasant and its benefits may have been overstated. Therefore, it is important to evaluate research into approaches that aim to minimise the use of this medication. Existing studies suggest that such approaches can be successful and result in avoidance of antipsychotics in a high proportion of clients.
Family relationships in childhood and common psychiatric disorders in later life: systematic review of prospective studies
Authors: Weich Scott , Patterson Jacoby , Shaw Richard , Stewart-Brown Sarah
Published: April 2009

Background

Most evidence for associations between childhood adversity and adult mental illness is retrospective.

Aims

To evaluate prospective evidence of associations between poor parent–child relationships and common psychiatric disorders in later life.

Method

Systematic review of studies published between 1970 and 2008 including: (a) more than 100 participants; (b) measures of relationships in the home during childhood; (c) at least 10 years between assessment of exposures; and (d) measures of anxiety, depression, suicide, suicidal ideation or post-traumatic stress disorder (PTSD). Analysis was by narrative synthesis.

Results

Twenty-three papers were identified reporting data from 16 cohorts. Abusive relationships predicted depression, anxiety and PTSD. Maternal emotional unavailability in early life predicted suicide attempts in adolescence. Results of studies investigating less severe relationship problems were suggestive but not conclusive of causal association, due partly to methodological heterogeneity.

Conclusions

Given the prevalence and disabling nature of common psychiatric problems, these studies highlight the need to minimise harm associated with dysfunctional parent–child relationships.
Screening for depression in high-risk groups: prospective cohort study in general practice
Authors: Baas Kim D. , Wittkampf Karin A. , van Weert Henk C. , Lucassen Peter , Huyser Jochanan , van den Hoogen Henk , van de Lisdonk Eloy , Bindels Patrick E. , Bockting Claudi L. , Ruhé Henricus G. , Schene Aart H.
Published: April 2009

Background

Currently only about half of the people who have major depressive disorder are detected during regular health care. Screening in high-risk groups might be a possible solution.

Aims

To evaluate the effectiveness of selective screening for major depressive disorder in three high-risk groups in primary care: people with mental health problems, people with unexplained somatic complaints and people who frequently attend their general practitioner.

Method

Prospective cohort study among 2005 people in high-risk groups in three health centres in The Netherlands.

Results

Of the 2005 people identified, 1687 were invited for screening and of these 780 participated. Screening disclosed 71 people with major depressive disorder: 36 (50.7%) already received treatment, 14 (19.7%) refused treatment and 4 individuals did not show up for an appointment. As a final result of the screening, 17 individuals (1% of 1687) started treatment for major depressive disorder.

Conclusions

Screening for depression in high-risk populations does not seem to be effective, mainly because of the low rates of treatment initiation, even if treatment is freely and easily accessible.
In-patient and residential alternatives to standard acute psychiatric wards in England
Authors: Johnson Sonia , Gilburt Helen , Lloyd-Evans Brynmor , Osborn David P. J. , Boardman Jed , Leese Morven , Shepherd Geoff , Thornicroft Graham , Slade Mike
Published: April 2009

Background

Acute psychiatric wards have been the focus of widespread dissatisfaction. Residential alternatives have attracted much interest, but little research, over the past 50 years.

Aims

Our aims were to identify all in-patient and residential alternatives to standard acute psychiatric wards in England, to develop a typology of such services and to describe their distribution and clinical populations.

Method

National cross-sectional survey of alternatives to standard acute in-patient care.

Results

We found 131 services intended as alternatives. Most were hospital-based and situated in deprived areas, and about half were established after 2000. Several clusters with distinctive characteristics were identified, ranging from general acute wards applying innovative therapeutic models, through clinical crisis houses that are highly integrated with local health systems, to more radical voluntary sector alternatives. Most people using the alternatives had a previous history of admission, but only a few community-based services accepted compulsory admissions.

Conclusions

Alternatives to standard acute psychiatric wards represent an important, but previously undocumented and unevaluated, sector of the mental health economy. Further evidence is needed to assess whether they can improve the quality of acute in-patient care.
Metabolic profile of antipsychotic-naive individuals with non-affective psychosis
Authors: Fernandez-Egea Emilio , Bernardo Miguel , Donner Thomas , Conget Ignacio , Parellada Eduard , Justicia Azucena , Esmatjes Enric , Garcia-Rizo Clemente , Kirkpatrick Brian
Published: April 2009

Background

Some studies suggest individuals with schizophrenia have an increased risk of diabetes prior to antipsychotic use. Small sample sizes and the potential for confounding by hypercortisolaemia have decreased confidence in those results.

Aims

To examine diabetes-related factors in newly diagnosed, antipsychotic-naive people with non-affective psychosis.

Method

Participants with psychosis (the psychosis group;n= 50) and matched controls (the control group;n= 50) were given a 2 h oral glucose tolerance test. Fasting concentrations were also determined for adiponectin, interleukin-6 and C-reactive protein.

Results

Compared with the control group, the psychosis group had significant increases in 2 h glucose and interleukin-6 concentrations, and in the prevalence of abnormal glucose tolerance (16% of psychosis groupv.0% of control group). Adiponectin and C-reactive protein concentrations did not differ significantly between the two groups. These findings could not be attributed to differences in cortisol concentrations, smoking, gender, neighbourhood of residence, body mass index, aerobic conditioning, ethnicity, socioeconomic status or age.

Conclusions

Individuals with non-affective psychosis appear to have an increased prevalence of abnormal glucose tolerance prior to antipsychotic treatment, as well as abnormalities in a related inflammatory molecule. These underlying problems may contribute to the metabolic side-effects of antipsychotic medications.
Development and implementation of early intervention services for young people with psychosis: case study
Authors: Lester Helen , Birchwood Max , Bryan Stirling , England Elizabeth , Rogers Helen , Sirvastava Namita
Published: April 2009

Background

The development of early intervention services for young people with first-episode psychosis is a priority internationally.

Aims

To evaluate the development, implementation and impact of existing and newly formed early intervention services in England.

Method

Multiple-case study involving staff, users, carers and commissioners of 14 early intervention services.

Results

Service numbers increased in response to national policy directives. They were still actively working with 90.6% of service users 12 months after inception. They were highly valued by users and carers as providing a personal service that contrasted with previous experiences of care. Tensions between providing a quality service and meeting case-load targets linked to future funding led teams to adopt a series of survival strategies with some unintended consequences.

Conclusions

Early intervention services are highly valued by consumers and engage users effectively after 12 months. Implementation of these services is threatened unless sufficient consistent funding is made available.
Stalking among juveniles
Authors: Purcell Rosemary , Moller Bridget , Flower Teresa , Mullen Paul E.
Published: April 2009

Background

There is an almost total lack of empirical research on stalking among juveniles.

Aims

To examine the characteristics, nature and impacts of stalking by juveniles.

Method

Analysis of consecutive court applications for a restraining order against a juvenile because of stalking behaviours.

Results

A total of 299 juvenile stalkers were identified. The majority were male (64%) and their victims predominantly female (69%). Most pursued a previously known victim (98%), favouring direct means of contact via unwanted approaches (76%) and telephone calls or text messaging (67%). Threats (75%) and physical and sexual assaults (54%) were common. The contexts for juvenile stalking involved an extension of bullying (28%), retaliation for a perceived harm (22%), a reaction to rejection (22%), sexual predation (5%) and infatuation (2%).

Conclusions

Juvenile stalking is characterised by direct, intense, overtly threatening and all too often violent forms of pursuit. The seriousness that is afforded to adult forms of stalking should similarly apply to this behaviour among juveniles given the even greater rates of disruption to the victim's life and risks of being attacked.
Mental disorders and termination of education in high-income and low- and middle-income countries: epidemiological study
Authors: Lee S. , Tsang A. , Breslau J. , Aguilar-Gaxiola S. , Angermeyer M. , Borges G. , Bromet E. , Bruffaerts R. , de Girolamo G. , Fayyad J. , Gureje O. , Haro J. M. , Kawakami N. , Levinson D. , Browne M. A. Oakley , Ormel J. , Posada-Villa J. , Williams D. R. , Kessler R. C.
Published: April 2009

Background

Studies of the impact of mental disorders on educational attainment are rare in both high-income and low- and middle-income (LAMI) countries.

Aims

To examine the association between early-onset mental disorder and subsequent termination of education.

Method

Sixteen countries taking part in the World Health Organization World Mental Health Survey Initiative were surveyed with the Composite International Diagnostic Interview (n=41 688). Survival models were used to estimate associations between DSM–IV mental disorders and subsequent non-attainment of educational milestones.

Results

In high-income countries, prior substance use disorders were associated with non-completion at all stages of education (OR 1.4–15.2). Anxiety disorders (OR=1.3), mood disorders (OR=1.4) and impulse control disorders (OR=2.2) were associated with early termination of secondary education. In LAMI countries, impulse control disorders (OR=1.3) and substance use disorders (OR=1.5) were associated with early termination of secondary education.

Conclusions

Onset of mental disorder and subsequent non-completion of education are consistently associated in both high-income and LAMI countries.
Invited commentary on … Lithium levels in drinking water and risk of suicide
Authors: Young Allan H.
Published: April 2009

Lithium is a well-established treatment in psychiatry. The possibility that lithium from the environment may affect mental health has received little study. However, a recent study and an older report both suggest that higher levels of lithium in drinking water are associated with lower suicide rates. These intriguing data should provoke further research, which ultimately may benefit community mental health.