bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical value of daily routine chest radiographs in a mixed medical–surgical intensive care unit is low
Authors: Graat Marleen E , Choi Goda , Wolthuis Esther K , Korevaar Johanna C , Spronk Peter E , Stoker Jaap , Vroom Margreeth B , Schultz Marcus J
Published: December 2005

Introduction

The clinical value of daily routine chest radiographs (CXRs) in critically ill patients is unknown. We conducted this study to evaluate how frequently unexpected predefined major abnormalities are identified with daily routine CXRs, and how often these findings lead to a change in care for intensive care unit (ICU) patients.

Method

This was a prospective observational study conducted in a 28-bed, mixed medical–surgical ICU of a university hospital.

Results

Over a 5-month period, 2,457 daily routine CXRs were done in 754 consecutive ICU patients. The majority of these CXRs did not reveal any new predefined major finding. In only 5.8% of daily routine CXRs (14.3% of patients) was one or more new and unexpected abnormality encountered, including large atelectases (24 times in 20 patients), large infiltrates (23 in 22), severe pulmonary congestion (29 in 25), severe pleural effusion (13 in 13), pneumothorax/pneumomediastinum (14 in 13), and malposition of the orotracheal tube (32 in 26). Fewer than half of the CXRs with a new and unexpected finding were ultimately clinically relevant; in only 2.2% of all daily routine CXRs (6.4% of patients) did these radiologic abnormalities result in a change to therapy. Subgroup analysis revealed no differences between medical and surgical patients with regard to the incidence of new and unexpected findings on daily routine CXRs and the effect of new and unexpected CXR findings on daily care.

Conclusion

In the ICU, daily routine CXRs seldom reveal unexpected, clinically relevant abnormalities, and they rarely prompt action. We propose that this diagnostic examination be abandoned in ICU patients.
A compendium of Caenorhabditis elegans regulatory transcription factors: a resource for mapping transcription regulatory networks
Authors: Reece-Hoyes John S , Deplancke Bart , Shingles Jane , Grove Christian A , Hope Ian A , Walhout Albertha JM
Published: December 2005

Background

Transcription regulatory networks are composed of interactions between transcription factors and their target genes. Whereas unicellular networks have been studied extensively, metazoan transcription regulatory networks remain largely unexplored. Caenorhabditis elegans provides a powerful model to study such metazoan networks because its genome is completely sequenced and many functional genomic tools are available. While C. elegans gene predictions have undergone continuous refinement, this is not true for the annotation of functional transcription factors. The comprehensive identification of transcription factors is essential for the systematic mapping of transcription regulatory networks because it enables the creation of physical transcription factor resources that can be used in assays to map interactions between transcription factors and their target genes.

Results

By computational searches and extensive manual curation, we have identified a compendium of 934 transcription factor genes (referred to as wTF2.0). We find that manual curation drastically reduces the number of both false positive and false negative transcription factor predictions. We discuss how transcription factor splice variants and dimer formation may affect the total number of functional transcription factors. In contrast to mouse transcription factor genes, we find that C. elegans transcription factor genes do not undergo significantly more splicing than other genes. This difference may contribute to differences in organism complexity. We identify candidate redundant worm transcription factor genes and orthologous worm and human transcription factor pairs. Finally, we discuss how wTF2.0 can be used together with physical transcription factor clone resources to facilitate the systematic mapping of C. elegans transcription regulatory networks.

Conclusion

wTF2.0 provides a starting point to decipher the transcription regulatory networks that control metazoan development and function.
Systematic analysis of gene expression in human brains before and after death
Authors: Franz Henriette , Ullmann Claudia , Becker Albert , Ryan Margaret , Bahn Sabine , Arendt Thomas , Simon Matthias , Pääbo Svante , Khaitovich Philipp
Published: December 2005

Background

Numerous studies have employed microarray techniques to study changes in gene expression in connection with human disease, aging and evolution. The vast majority of human samples available for research are obtained from deceased individuals. This raises questions about how well gene expression patterns in such samples reflect those of living individuals.

Results

Here, we compare gene expression patterns in two human brain regions in postmortem samples and in material collected during surgical intervention. We find that death induces significant expression changes in more than 10% of all expressed genes. These changes are non-randomly distributed with respect to their function. Moreover, we observe similar expression changes due to death in two distinct brain regions. Consequently, the pattern of gene expression differences between the two brain regions is largely unaffected by death, although the magnitude of differences is reduced by 50% in postmortem samples. Furthermore, death-induced changes do not contribute significantly to gene expression variation among postmortem human brain samples.

Conclusion

We conclude that postmortem human brain samples are suitable for investigating gene expression patterns in humans, but that caution is warranted in interpreting results for individual genes.
A novel approach to identifying regulatory motifs in distantly related genomes
Authors: Van Hellemont Ruth , Monsieurs Pieter , Thijs Gert , De Moor Bart , Van de Peer Yves , Marchal Kathleen
Published: December 2005

Although proven successful in the identification of regulatory motifs, phylogenetic footprinting methods still show some shortcomings. To assess these difficulties, most apparent when applying phylogenetic footprinting to distantly related organisms, we developed a two-step procedure that combines the advantages of sequence alignment and motif detection approaches. The results on well-studied benchmark datasets indicate that the presented method outperforms other methods when the sequences become either too long or too heterogeneous in size.
iVici: Interrelational Visualization and Correlation Interface
Authors: Tarassov Kirill , Michnick Stephen W
Published: December 2005

We have developed an application, iVici, to analyze cellular networks represented as addressable symmetric or asymmetric two-dimensional matrices. iVici was designed to permit simultaneous visualization and correlation of multiple datasets, representing any relationship between a set of genes, mRNAs, or proteins. Visual overlay of datasets and addressable access to gene annotations permits comparison of networks of different types (for example protein-protein interactions and genetic networks) or investigation of the dynamic reorganization of a particular network.
Differential effects of statins on relevant functions of human monocyte-derived dendritic cells
Authors: Yilmaz Atilla , Reiss Christine , Weng Alexander , Cicha Iwona , Stumpf Christian , Steinkasserer Alexander , Daniel Werner G , Garlichs Christoph D
Published: December 2005

Statins were shown to possess immunomodulating properties, but the mechanisms of statin effects on the immune system are poorly understood. We analyzed the influence of statins on professional antigen-presenting dendritic cells (DC). Immature DC were cultivated from monocytes of healthy donors. DC maturation was induced by lipopolysaccharide (LPS; 1 μg/mL). Unstimulated and LPS-stimulated DC were treated with simvastatin or atorvastatin (0.1–1 μM). The expression of CD40, CD83, CD86, and human leukocyte antigen-DR on unstimulated and LPS-stimulated DC was reduced significantly by statins, and the expression of Toll-like receptor 2 (TLR2) and TLR4 on LPS-stimulated DC was enhanced temporarily. Statins caused a significant reduction of endocytosis of fluorescein isothiocyanate-dextran by DC. Statins significantly inhibited the basal secretion of interleukin (IL)-6, IL-8, IL-12, and tumor necrosis factor α from unstimulated DC, and their release from LPS-stimulated DC was enhanced. In mixed leukocyte reaction, preincubation of LPS-stimulated DC with statins significantly suppressed their clustering with T cells and their ability to induce T cell proliferation, CD71, and CD25 up-regulation on T cells and the secretion of interferon-γ and IL-2 from T cells. In conclusion, this study showed that statins suppressed endocytosis, basal secretion of proinflammatory cytokines, and the ability of DC to induce T cell proliferation, activation, and T helper cell type 1 differentiation. However, statin preincubation of LPS-stimulated DC caused a further increase in their secretion of proinflammatory cytokines.
Differential expression of adenosine receptors in human neutrophils: up-regulation by specific Th1 cytokines and lipopolysaccharide
Authors: Fortin Andrée , Harbour Danielle , Fernandes Maria , Borgeat Pierre , Bourgoin Sylvain
Published: December 2005

Four types of adenosine receptors have been identified in different tissues and cell types, namely, A1, A2A, A2B, and A3 receptors. We report that A2AR but not A2BR mRNA in freshly isolated polymorphonuclear neutrophils (PMN) is maximally up-regulated after 4 h stimulation with lipopolysaccharide (LPS) or tumor necrosis factor α (TNF-α) and to a lesser extent, with interleukin (IL)-1β. These effects were maintained up to 21 h. Consistent with changes in A2AR mRNA expression, up-regulation of A2AR protein was also detected after 4 h of LPS or TNF-α exposure. Up-regulation of A2AR protein expression was transient and returned to near basal levels after 12 h or 16 h stimulation with TNF-α or LPS, respectively. Conversely, IL-1β failed to promote A2AR protein expression. Suppression of thapsigargin-induced leukotriene synthesis by the selective A2AR agonist CGS-21680 was found to be more pronounced when PMN were cultured for 4 h with LPS or TNF-α. In contrast, the up-regulation of A2AR has no impact on CGS-21680-induced inhibition of phospholipase D activation and superoxide production in response to formyl-Met-Leu-Phe. These results demonstrate that the A2AR is up-regulated by specific T helper cell type 1 cytokines and LPS. Although this could represent a potential feedback mechanism to control inflammation, the effect of A2AR up-regulation varied depending on the stimulus used to stimulate PMN functional responses after their incubation with proinflammatory mediators.
Nitric oxide synthase localization in the rat neutrophils: immunocytochemical, molecular, and biochemical studies
Authors: Saini R , Patel S , Saluja R , Sahasrabuddhe A A , Singh M P , Habib S , Bajpai V K , Dikshit M
Published: December 2005

Nitric oxide (NO) modulates diverse functions of polymorphonuclear neutrophils (PMNs), but localization of NO synthase (NOS) and identification of its interacting proteins remain the least defined. The present study discerns subcellular distribution of NOS and caveolin-1, a prominent NOS-interacting protein in rat PMNs. Localization of NOS was explored by confocal and immunogold electron microscopy, and its activity was assessed by L-[3H] arginine and 4,5-diaminofluorescein diacetate (DAF-2DA). Reverse transcriptase-polymerase chain reaction using NOS primers and Western blotting demonstrated the presence of neuronal NOS (nNOS) and inducible NOS (iNOS) in PMNs. Immunocytochemical studies exhibited distribution of nNOS and iNOS in cytoplasm and nucleus, and L-[3H] citrulline formation and DAF fluorescence confirmed NOS activity in both fractions. NOS activity correlated positively with calmodulin concentration in both of the fractions. nNOS and iNOS colocalized with caveolin-1, as evidenced by immunocytochemical and immunoprecipitation studies. The results thus provide first evidence of nNOS and iNOS in the nuclear compartment and suggest NOS interaction with caveolin-1 in rat PMNs.
A role of PP1/PP2A in mesenteric lymph node T cell suppression in a two-hit rodent model of alcohol intoxication and injury
Authors: Li Xiaoling , Schwacha Martin G , Chaudry Irshad H , Choudhry Mashkoor A
Published: December 2005

This study examined the role of protein phosphatase type-1 (PP1), type-2A (PP2A), and mitogen-activated protein kinase phosphatase-1 (MKP-1) in altered mesenteric lymph node (MLN) T cell function in a two-hit model of alcohol (EtOH) intoxication and burn injury. Male rats (250 g) were gavaged with EtOH to achieve a blood EtOH level of ∼100 mg/dL prior to burn or sham injury (25% total body surface area). MLN T cells harvested 24 h after injury show a significant decrease in p38 and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation in T cells from rats receiving a combined insult of EtOH intoxication and burn injury compared with rats receiving EtOH intoxication or burn injury alone. Treatment of cells with inhibitors of PP1/PP2A [calyculin A (CA) and okadaic acid (OA)] prevented the suppression in T cells p38 and ERK-1/2 activation. In addition, the suppression in interleukin-2 and interferon-γ production was attenuated in T cells cultured in the presence of CA and OA. MKP-1 inhibitor triptolide did not prevent the suppression in T cells p38/ERK-1/2 and cytokine production. Furthermore, there was a significant decrease in PP1α phosphorylation (Thr320) and an increase in PP2A (Tyr307) phosphorylation in T cells following a combined insult of EtOH intoxication and burn injury. As phosphorylation of PP1 at Thr320 and PP2A at Tyr307 led to an inhibition of their enzymatic activities, the decrease in the PP1α phosphorylation correlates with an increase in its enzyme activity. Thus, these results suggest that activation of PP1 is likely to play a predominant role in T cell suppression following a combined insult of EtOH intoxication and burn injury.
An in vitro Shwartzman reaction-like response is augmented age-dependently in human peripheral blood mononuclear cells
Authors: Motegi Akira , Kinoshita Manabu , Sato Kengo , Shinomiya Nariyoshi , Ono Satoshi , Nonoyama Shigeaki , Hiraide Hoshio , Seki Shuhji
Published: December 2005

A lethal human septic shock model, mouse generalized Shwartzman reaction (GSR), was elicited by two consecutive lippolysaccharide (LPS) injections (24 h apart) in which interferon-γ (IFN-γ) induced by interleukin (IL)-12 played a critical role in the priming phase, and tumor necrosis factor (TNF) was an important effector molecule in the second phase. We recently reported IL-12/LPS-induced mouse GSR age-dependently enhanced. We herein demonstrate that human peripheral blood mononuclear cells (PBMC) from healthy adults/elderly, cultured with IL-12 for 24 h and with LPS for an additional 24 h, produced a much larger amount of TNF (which increased age-dependently) than did PBMC without IL-12 priming. Whereas macrophages mainly produced TNF following LPS stimulation, macrophages and lymphocytes were necessary for a sufficient TNF production. IL-12-induced IFN-γ up-regulated Toll-like receptor 4 (TLR-4) on macrophages of adults. Although the PBMC from children produced a substantial amount of IFN-γ after IL-12 priming, the GSR response, with augmented TNF production and an up-regulated TLR-4 expression of macrophages, was not elicited by LPS stimulation. CD56+ natural killer cells, CD56+T cells, and CD57+T cells (NK-T cells), which age-dependently increased in PBMC, produced much larger amounts of IFN-γ after IL-12 priming than that of conventional CD56−CD57−T cells and also induced cocultured macrophages to produce TNF by subsequent LPS stimulation. The elder septic patients were consistently more susceptible to lethal shock with enhanced serum TNF levels than the adult patients. The NK cells, NK-T cells, and macrophages, which change proportionally or functionally with aging, might be involved in the enhanced GSR response/septic shock observed in elderly patients.
Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population
Authors: Grimaldi Maria Paola , Candore Giuseppina , Vasto Sonya , Caruso Marco , Caimi Gregorio , Hoffmann Enrico , Colonna-Romano Giuseppina , Lio Domenico , Shinar Yael , Franceschi Claudio , Caruso Calogero
Published: December 2005

A proinflammatory genotype seems to contribute significantly to the risk of developing coronary heart disease (CHD). Conversely, the susceptibility alleles to inflammatory disease should be infrequent in the genetic background favoring longevity. In fact, in a modern environment, attainment of longevity is facilitated by an anti-inflammatory status. To evaluate whether inflammatory alleles of pyrin, the gene responsible for familial Mediterranean fever (FMF) may play an opposite role in CHD and in longevity, we examined three FMF-associated mutations, M694V (A2080G), M694I (G2082A), and V726A (T2177C), encoded by the FMF gene (MEFV) in 121 patients affected by acute myocardial infarction (AMI), in 68 centenarians, and in 196 age-matched controls from Sicily. None of the Sicilian subjects studied carried the V726A and the M694I FMF-related mutations. The proinflammatory M694V (A2080G) mutation was the only one we found, which was over-represented significantly in CHD patients and under-represented in oldest old, and intermediate values were in healthy, young controls. After adjustment for well-recognized AMI risk factors, the M694V allele still predicted a significant risk to develop AMI. So, according to these results, we suggest that carrying the proinflammatory M694V pyrin allele may increase the risk to develop AMI. Conversely, the wild-type pyrin genotype may predispose to a greater chance to live longer in a modern environment with reduced pathogen load and improved control of severe infections by antibiotics. All these data indicate a strong relationship among inflammation, genetics, CHD, and longevity.
Uric acid, a nucleic acid degradation product, down-regulates dsRNA-triggered arthritis
Authors: Zare Fariba , Magnusson Mattias , Bergström Tomas , Brisslert Mikael , Josefsson Elisabet , Karlsson Anna , Tarkowski Andrej
Published: December 2005

Uric acid, the naturally occurring degradation product of purine metabolism, is a danger signal, driving maturation of dendritic cells. It is well known that uric acid crystals display potent proinflammatory properties—the cause of gout—whereas the biological properties of soluble uric acid are less well documented. We have demonstrated previously that nucleic acids of endogenous and exogenous origin display proinflammatory properties. The aim of the present study was to assess the impact of soluble uric acid on in vivo inflammatory responses. Mice were administered with uric acid suspension in saline or saline alone prior to induction of neutrophil-mediated inflammation, delayed-type hypersensitivity, histamin-induced edema (measure of vasodilation capacity), as well as double-stranded (ds)RNA-triggered arthritis. Frequency and severity of arthritis were decreased significantly in mice exposed to dsRNA and simultaneously treated with uric acid as compared with saline-treated controls. Also, granulocyte-mediated inflammatory response and vasodilation capacity were reduced significantly in mice treated with uric acid as compared with their control group. The data suggest that down-regulation of inflammation was mediated by skewing the inflammatory response from the peripheral sites to the peritoneal cavity and down-regulating vasodilatatory capacity and thereby affecting leukocyte migration. In contrast, the T cell-mediated delayed-type hypersensitivity reaction was not affected significantly in mice exposed to uric acid. These findings demonstrate that uric acid displays a potent, distant anti-inflammatory effect in vivo. This property seems to be mediated by down-regulation of neutrophil influx to the site of inflammatory insult.
Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72
Authors: Johnson John D , Fleshner Monika
Published: December 2005

Heat shock proteins (Hsp) were first characterized as intracellular proteins, which function to limit protein aggregation, facilitate protein refolding, and chaperone proteins. During times of cellular stress, intracellular Hsp levels increase to provide cellular protection. Recently, it has been recognized that Hsp, particularly Hsp72, are also found extracellularly (eHsp72), where they exhibit potent immunomodulatory effects on innate and acquired immunity. Circulating eHsp72 levels also greatly increase during times of stress (i.e., when an organism is exposed to a physical/psychological stressor or suffers from various pathological conditions). It has been proposed that elevated eHsp72 serves a protective role by facilitating immunological responses during times of increased risk of pathogenic challenge and/or tissue damage. This review focuses on the in vivo releasing signals and immunomodulatory function(s) of endogenous eHsp72. In addition, we present data that emphasize the importance of caution when conducting in vitro immunological tests of Hsp72 function.
Demographic and health-related factors associated with complementary and alternative medicine (CAM) use in multiple sclerosis
Authors: Shinto L , Yadav V , Morris C , Lapidus J A , Senders A , Bourdette D
Published: December 2005

Complementary and alternative medicine (CAM) use is high among people with multiple sclerosis (MS), yet there are no reports on the association between CAM use and health-related quality of life (HRQL) in MS. To examine this relationship, a cross-sectional survey and SF-12 was used to collect demographic and HRQL data from 1667 survey respondents. Factors examined for their association with CAM use included, age, gender, race, self-reported disease severity, disease-modifying drug (DMT) use, MS duration, MS type, education level, physical and mental well-being. Multiple regression analysis revealed that female gender, high education level, longer MS duration, lower physical well-being and not using DMT were independent factors associated with both ‘ever’ and ‘current’ CAM use. The finding that a drop in physical component score (PCS) of the SF-12 is independently associated with an increased odds of ‘ever’ CAM use, ‘current’ CAM use, and ‘past’ CAM reflect an association of CAM use with PCS regardless of time of use. Although, temporality of this relationship cannot be established, as this was a cross-sectional study, a longitudinal study is warranted so that we can establish if HRQL is predictive for CAM use in MS.
Intrathecal baclofen for treatment of spasticity of multiple sclerosis patients
Authors: smail D Ben , Peskine A , Roche N , Mailhan L , Thiébaut J B , Bussel B
Published: December 2005

We conducted a retrospective study of the case files of 64 multiple sclerosis (MS) patients presenting severe spasticity, who had received intrathecal (IT) baclofen test injections between 1992 and 2004 in a rehabilitation unit. In almost all cases of our series, IT baclofen was proposed to patients who were no longer able to walk. IT baclofen is a safe and effective treatment to reduce spasticity in MS patients. Despite an advanced stage of the disease at the time of pump placement, the complication rate was low and the efficacy of this treatment was maintained over time.
An interdisciplinary approach to evaluating the need for assistive technology reduces equipment abandonment
Authors: Verza R , Carvalho M L Lopes , Battaglia M A , Uccelli M Messmer
Published: December 2005

Assistive technology makes up a substantial portion of the direct cost of multiple sclerosis (MS). Equipment abandonment results in the needs of the disabled individual being unmet and places stress on the resources available for the funding of such equipment. The aim of the study was to demonstrate whether an interdisciplinary approach to evaluating and prescribing assistive technology reduces equipment abandonment in persons with MS. Data concerning assistive devices acquired by patients being followed at a rehabilitation centre in northern Italy from January 1997 to December 2002, were included in the study. Through December 1999, a physician in physical medicine and rehabilitation prescribed equipment based on a recommendation from the physical therapist. From 2000 to 2002, patients were evaluated following a standardized protocol implemented by an interdisciplinary team comprised of a physical therapist, occupational therapist, physician in physical medicine and rehabilitation and psychologist. Assistive technology obtained during the study period was divided into two datasets based on the year that the aid was obtained: pre-intervention (January 1997 to December 1999) and intervention (January 2000 to December 2002). The analysis included a comparison of the two datasets on number and types of equipment abandoned, timing of abandonment and reasons why devices were abandoned. Fifty-four subjects obtained 151 assistive devices during the study period, 67 devices during pre-intervention and 84 with the intervention. The majority of devices were abandoned immediately or within the first year following obtainment in both groups. A comparison of the number of devices obtained during pre-intervention with those obtained during the intervention showed that the rate of equipment abandonment decreased significantly from 37.3 to 9.5%. An interdisciplinary approach to evaluating assistive technology needs does decrease the risk of equipment abandonment, although it does not completely solve the problem.
Intrathecal synthesis of soluble HLA-G and HLA-I molecules are reciprocally associated to clinical and MRI activity in patients with multiple sclerosis
Authors: Fainardi E , Rizzo R , Melchiorri L , Castellazzi M , Paolino E , Tola M R , Granieri E , Baricordi O R
Published: December 2005

The aim of this study was to provide further insight into the effective contribution of classical soluble HLA-A, B and C class Ia (sHLA-I) and non-classical soluble HLA-G class Ib (sHLA-G) molecules in immune dysregulation occurring in multiple sclerosis (MS). We evaluated by enzyme-linked immunosorbent assay (ELISA) technique intrathecal synthesis and cerebrospinal fluid (CSF) and serum levels of sHLA-I and sHLA-G in 69 relapsing-remitting (RR), 21 secondary progressive (SP) and 13 primary progressive (PP) MS patients stratified according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. We also tested, as neurological controls, 91 patients with other inflammatory neurological disorders (OIND) and 92 with non-inflammatory neurological disorders (NIND). Eighty-two healthy volunteers served as further controls for sHLA-I and sHLA-G determinations. An intrathecal production of sHLA-I and sHLA-G detected by specific indexes was significantly more frequent in MS patients than in controls (p<0.01). An intrathecal synthesis of sHLA-I was prevalent in clinically (p<0.02) and MRI active (p<0.001) MS, whereas a CSF-restricted release of sHLA-G predominated in clinically (p<0.01) and MRI stable (p<0.001) MS. sHLA-I levels were low in the serum of clinically active (p<0.001) and high in the CSF of MRI active (p<0.01) MS. Conversely, sHLA-G concentrations were decreased in the serum of clinically stable MS (p<0.01) and increased in the CSF of MRI inactive MS (p<0.001). The trends towards a negative correlation observed between CSF and serum concentrations and intrathecal synthesis of sHLA-I and sHLA-G in patients without evidence of clinical and MRI activity confirmed that intrathecal production and fluctuations in CSF and serum concentrations of sHLA-I and sHLA-G were reciprocal in MS. Our results suggest that, in MS, a balance between classical sHLA-I and non-classical sHLA-G products modulating both MRI and clinical disease activity in opposite directions may exist.
Measuring and evaluating interferon b-induced antibodies in patients with multiple sclerosis
Authors: Ross C , Clemmesen K M , Sørensen P S , Koch-Henriksen N , Bendtzen K
Published: December 2005

Author for correspondence: Klaus Bendtzen, Institute for Inflammation Research IIR 7521, Rigshospitalet University Hospital, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. E-mail: address: kben@mail.dk Administration of interferons (IFNs) may induce antibodies that interfere with therapeutic efficacy. We have optimized and validated methods for large-scale economic screening. Sera from patients with relapsing-remitting multiple sclerosis (MS) were investigated for binding antibody (BAb) by protein-G affinity-chromatography radioimmunoassay and a commercially available enzyme immunoassay (EIA). Neutralizing antibody (NAb) was investigated by cytopathic effect assays (CEA) using both fixed amount and serially diluted sera. BAb correlated with log10-transformed titres obtained by EIA (r=0.70, p<0.0001); the latter, however, failed to demonstrate low-level BAb. Comparison of clinical significance of NAb-positivity measured by biological assays with different sensitivities demonstrated an optimal odds ratio for relapse rate using 10 laboratory units (LU)/mL. Purification of IgG prior to CEA removed toxicity from toxic sera. The neutralizing capacity data correlated linearly with log10-transformed titres obtained by a Kawade 10-to-1 LU/mL CEA (r=0.77, p<0.0001). In conclusion, neutralizing capacity CEA utilizing a fixed amount of serum predicts differences in relapse rates in IFNβ-treated MS patients and correlates with NAb titres of the 10-to- 1 LU/mL CEA. Neutralizing capacity CEA is less laborious and more economical than titre-based NAb assays and suitable for large-scale screenings of MS patients.
Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis
Authors: Nocentini U , Pasqualetti P , Bonavita S , Buccafusca M , De Caro M F , Farina D , Girlanda P , Le Pira F , Lugaresi A , Quattrone A , Reggio A , Salemi G , Savettieri G , Tedeschi G , Trojano M , Valentino P , Caltagirone C
Published: December 2005

Cognitive dysfunction is considered one of the clinical markers of multiple sclerosis (MS). However, in the literature there are inconsistent reports on the prevalence of cognitive dysfunction, and separate data for the relapsing-remitting (RR) type of the disease are not always presented. In this study, we submitted 461 RRMS patients to a battery of neuropsychological tests to investigate their impairment in various cognitive domains. As a consequence of the exclusion criteria, the sample is not fully representative of the entire population of RRMS patients. In this selected sample, when only the eight scores of a core battery (Mental Deterioration Battery) were considered (with respective cutoffs), it emerged that 31% of the patients were affected by some degree of cognitive deficit. In particular, 15% had mild, 11.2% moderate and 4.8% had severe impairment. Information processing speed was the most frequently impaired area, followed by memory. When two other tests (SDMT and MCST) were added and cognitive domains were considered, it emerged that 39.3% of the patients were impaired in two or more domains. When four subgroups were obtained by means of cluster analysis and then compared, it emerged that information processing speed and memory deficits differentiated the still cognitively unimpaired from the mildly impaired MS patients.

Significant associations were found between cognitive and clinical characteristics. However, due to the large sample size, clinically irrelevant relationships may also have emerged. Even with the limitations imposed by the sample selection and the possible underestimation of the prevalence and severity of cognitive dysfunction, these results seem to provide further evidence that information processing speed deficit may be an early and important marker of cognitive impairment in MS patients.
Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis
Authors: Kallmann B A , Fackelmann S , Toyka K V , Rieckmann P , Reiners K
Published: December 2005

Evoked potentials (EP) have a role in making the diagnosis of multiple sclerosis (MS) but their implication for predicting the future disease course in MS is under debate. EP data of 94 MS patients examined at first presentation, and after five and ten years were retrospectively analysed. Patients were divided into two groups in relation to the prior duration of disease at the time point of first examination: group 1 patients (n-44) were first examined within two years after disease onset, and group 2 patients (n-50) at later time points. As primary measures sum scores were calculated for abnormalities of single and combined EP (visual (VEP), somatosensory (SEP), magnetic motor evoked potentials (MEP)). In patients examined early after disease onset (group 1), a significant predictive value for abnormal EP was found with MEP and SEP sum scores at first presentation correlating significantly with Expanded Disability Status Scale (EDSS) values after five years, while the VEP sum score was not. The cumulative number of abnormal MEP, SEP and VEP results also indicated higher degrees of disability (EDSS≥ 3.5) after five years. Combined pathological SEP and MEP findings at first presentation best predicted clinical disability (EDSS≥ 3.5) after five years (odds ratio 11.0). EP data and EDSS at first presentation were not significantly linked suggesting that EP abnormalities at least in part represented clinically silent lesions not mirrored by EDSS. For patients in later disease phases (group 2), no significant associations between EP data at first presentation and EDSS at five and ten years were detected. Together with clinical findings and MR imaging, combined EP data may help to identify patients at high risk of long-term clinical deterioration and guide decisions as to immunomodulatory treatment.
No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis
Authors: Petereit H F , Reske D , Pukrop R , Maas-Enriquez M , Japp G , Jongen P JH , Kölmel H W , Merkelbach S , Hartung H P , Heiss W D , Hommes O R
Published: December 2005

Intravenous immunoglobulins (IVIG) have been effective in reducing multiple sclerosis (MS) disease activity and improving disability scores. However, the mechanism by which this beneficial effect is achieved remains unclear. An effect of IVIG on pro- and anti-inflammatory cytokines- which are thought to play a role in the disease process- has been postulated in a number of animal and ex vivo studies. Hence, we performed a study on 34 patients with secondary progressive (SP) MS being treated with monthly IVIG or placebo for two years according to the protocol of the ESIMS study. Clinical outcome measures and cytokine production (interferon gamma, tumour necrosis factor alpha, interleukin-4 and -10) were recorded in all patients and compared with respect to the treatment group. Against our expectations, IVIG did not reduce the relapse rate or the progression of disability or cytokine production. Our data argue against an enduring immunomodulating effect of IVIG, at least in SPMS.
The effect of consent guidelines on a multiple sclerosis register
Authors: Ford Helen L
Published: December 2005

Background The 1998 Data Protection Act and guidelines from the General Medical Council on informed consent have caused concern for medical researchers and particularly those involved in the management of disease registers.

Objective The aim of this study was to determine rates of consent for a multiple sclerosis (MS) community-based register and to investigate authorization bias by examining the characteristics of those refusing consent.

Methods A consent letter was developed with the advice and support of an advisory group which included people with MS. All people with MS on the prevalent register (n=820) were informed about the register and its purposes and asked to indicate whether they would like their details to be removed from the register.

Results Thirty-four (4.1%) people with MS asked for their details to be removed from the register. There was a significant difference in disease course in this group with more patients with benign relapsing-remitting disease compared to the prevalent population. There was no significant difference in age or sex distribution. The proportion of people not giving consent was similar to a local stroke register. Prospectively all new patients have given written informed consent.

Conclusion Patients refusing consent may have different disease characteristics than those who consent. The potential for response bias needs to be considered in the development of a UK MS register.
The Sonya Slifka Longitudinal Multiple Sclerosis Study: methods and sample characteristics
Authors: Minden S L , Frankel D , Hadden L , Perloff J , Srinath K P , Hoaglin D C
Published: December 2005

The Sonya Slifka Longitudinal Multiple Sclerosis Study follows a population-based cohort of approximately 2000 people with multiple sclerosis (MS) to study demographic and clinical characteristics, course of illness, utilization and cost of health services, provider characteristics, use of MS specialists and disease modifying agents, and neurologic, economic and psychosocial outcomes. This report describes the study methodology, presents baseline demographic and clinical data, and evaluates the representativeness of the sample. A stratified random sample of persons with established and recently-diagnosed MS selected from the National Multiple Sclerosis Society (NMSS) mailing lists was supplemented with recently-diagnosed patients recruited through systematic nationwide outreach. Baseline data were collected by computer-assisted telephone interviews derived from standardized instruments; data collection continues at six-month intervals. The cohort was comparable to population-based and clinical samples with respect to demographics, course, relapse rate, symptoms, and severity of disability. Almost two-thirds of the cohort needed help with activities of daily living, three-quarters were limited in work or other activities, and half had emotional problems that compromised quality of life. The Slifka Study cohort is broadly representative of the MS population and the database can be used to address questions not answered by natural history studies, clinical databases, or population-based surveys.
Personality disorder and the outcome of depression:
Meta-analysis of published studies
Authors: Newton-Howes Giles , Tyrer Peter , Johnson Tony
Published: December 2005

Background

There is conflicting evidence about the influence of personality disorder
on outcome in depressive disorders.

Aims

Meta-analysis of studies in which a categorical assessment of personality
disorder or no personality disorder was made in people with depressive
disorders, and categorical outcome (recovered/not recovered) also
determined.

Method

Systematic electronic search of the literature for relevant publications.
Hand searches of Journal of Affective Disorders and
recent reviews, with subsequent meta-analysis of selected studies.

Results

Comorbid personality disorder with depression was associated with a
doubling of the risk of a poor outcome for depression compared with no
personality disorder (random effects model OR=2.18, 95% C11.70–2.80), a
robust finding maintained with only Hamilton-type depression criteria at
outcome (OR=2.20, 95% C11.61–3.01). All treatments apart from
electroconvulsive therapy (ECT) showed this poor outcome, and the ECT
group was small.

Conclusions

Combined depression and personality disorder is associated with a poorer
outcome than depression alone.
Obstetric variables associated with bipolar affective puerperal psychosis
Authors: Blackmore Emma Robertson , Jones Ian , Doshi Monica , Haque Sayeed , Holder Roger , Brockington Ian , Craddock Nick
Published: December 2005

Background

Previous cross-sectional studies have highlighted a number of obstetric variables that may be associated with the development of broadly defined puerperal (post-partum) psychosis. These include: (a) primiparity (b) pregnancy complications, (c) delivery complications, (d) Caesarean section, (e) female baby and (f) shorter gestation period.

Aims

To examine these risk factors in women with well-characterised bipolar affective puerperal psychosis.

Method

A sample of 129 women with bipolar affective puerperal psychosis were investigated using a design that takes advantage of within-subject comparisons of affected and unaffected deliveries.

Results

Two of the variables studied were independently associated with an episode of puerperal psychosis: primiparity (odds ratio=3.76,P<0.001) and delivery complications (odds ratio=2.68,P=0.022).

Conclusions

This study provides further evidence of the association between primiparity and puerperal psychosis and suggests that complications during delivery may be associated with a severe post-partum episode.
Efficacy of ethyl-eicosapentaenoic acid in bipolar depression:
Randomised double-blind placebo-controlled study
Authors: Frangou Sophia , Lewis Michael , McCrone Paul
Published: December 2005

Background

Epidemiological and clinical studies suggest that increased intake of
eicosapentaenoic acid (EPA) alleviates unipolar depression.

Aims

To examine the efficacy of EPA in treating depression in bipolar
disorder.

Method

In a 12-week, double-blind study individuals with bipolar depression were
randomly assigned to adjunctive treatment with placebo
(n=26) or with 1g/day (n=24) or 2
g/day (n=25) of ethyl-EPA. Primary efficacy was assessed
by the Hamilton Rating Scale for Depression (HRSD), with changes in the
Young Mania Rating Scale and Clinical Global Impression Scale (CGI) as
secondary outcome measures.

Results

There was no apparent benefit of 2g over 1g ethyl-EPA daily. Significant
improvement was noted with ethyl-EPA treatment compared with placebo in
the HRSD (P=0.04) and the CGI (P=0.004)
scores. Both doses were well tolerated.

Conclusions

Adjunctive ethyl-EPA is an effective and well-tolerated intervention in
bipolar depression.
Natural history of depression in the oldest old
Authors: Stek Max L. , Vinkers David J. , Gussekloo Jacobijn , Van Der Mast Roos C. , Beekman Aartjan T. F. , Westendorp Rudi G. J.
Published: December 2005

Background

Despite its negative consequences, little is known about the natural
history of depression in the oldest old.

Aims

To study the incidence, course and predictors of depression in the
general population of the oldest old.

Method

The Leiden 85-plus Study is a prospective population-based study of 500
people from their 85th to their 89th birthdays. Depressive symptoms were
annually assessed with the 15-item Geriatric Depression Scale, using a
cut-off of 4 points.

Results

During a mean follow-up of 3.9 years, the annual risk for the emergence
of depression was 6.8%. Poor daily functioning and institutionalisation
predicted depression. Among the 77 participants with depression at
baseline (prevalence 15%) the annual remission rate was ony 14%. In more
than half of the participants with a remission of depression, we observed
a relapse of depression during follow-up. No predictors of remission
could be identified.

Conclusions

Among the oldest old, depression is frequent and highly persistent. More
active case-finding and treatment would be potentially rewarding.
An ethical framework for psychiatry
Authors: Bloch Sidney , Green Stephen A.
Published: December 2005

Psychiatry has not reached a consensus hitherto concerning an optimal
theoretical framework for ethical decision-making and corresponding action.
Various theories have been considered, but found wanting. Moreover, classic
theories may contradict one another, contribute to confusion and immobilise
the clinician. We have examined major theories commonly applied in
bioethics, conferred with moral philosophers and psychiatrists and striven
to apply more recent insights drawn from moral philosophy. We report that
instead of pursuing a single theoretical framework, we should garner the
strengths of compatible approaches in a synergistic way. We propose a
particular complementarity of principlism – with its pragmatic focus on
respect for autonomy, beneficence, non-maleficence and justice – and care
ethics, avariant of virtue theory, which highlights character traits
pertinent to caring for vulnerable psychiatric patients.
Mental health, burnout and job satisfaction among mental health
social workers in England and Wales
Authors: Evans Sherrill , Huxley Peter , Gately Claire , Webber Martin , Mears Alex , Pajak Sarah , Medina Jibby , Kendall Tim , Katona Cornelius
Published: December 2005

Background

Previous research suggests that social workers experience high levels of
stress and burnout but most remain committed to their work.

Aims

To examine the prevalence of stress and burnout, and job satisfaction
among mental health social workers (MHSWs) and the factors responsible
for this.

Method

A postal survey incorporating the General Health Questionnaire, Maslach
Burnout Inventory, Karasek Job Content Questionnaire and a job
satisfaction measure was sent to 610 MHSWs in England and Wales.

Results

Eligible respondents (n=237) reported high levels of
stress and emotional exhaustion and low levels of job satisfaction; 111
(47%) showed significant symptomatology and distress, which is twice the
level reported by similar surveys of psychiatrists. Feeling undervalued
at work, excessive job demands, limited latitude in decision-making, and
unhappiness about the place of MHSWs in modern services contributed to
the poor job satisfaction and most aspects of burnout. Those who had
approved social worker status had greater dissatisfaction.

Conclusions

Stress may exacerbate recruitment and retention problems. Employers must
recognise the demands placed upon MHSWs and value their contribution to
mental health services.
Specialised care for early psychosis: Symptoms, social
functioning and patient satisfaction
Authors: Garety Philippa A. , Craig Tom K. J. , Dunn Graham , Fornells-Ambrojo Miriam , Colbert Susannah , Rahaman Nikola , Reed Jason , Power Paddy
Published: December 2005

Background

The provision of early intervention services for people with psychosis is
UK government policy, although evidence for benefit of such services is
sparse.

Aims

To evaluate the effects of a service providing specialised care for early
psychosis (the Lambeth Early Onset team) on clinical and social outcomes,
and on service user satisfaction.

Method

One hundred and forty-four people with psychosis, presenting to mental
health services for the first or second time (if previously failed to
engage in treatment), were randomly allocated to care by the early onset
team or to standard care. Information was obtained on symptoms, treatment
adherence, social and vocational functioning, satisfaction and quality of
life. Relapse and rehospitalisation data have been reported
separately.

Results

Outcomes for the participants treated by the early onset team were
significantly better at 18 months for aspects of social and vocational
functioning, satisfaction, quality of life and medication adherence.
Symptom improvement did not significantly differ between the groups.

Conclusions

The provision of specialised care for early psychosis can achieve better
outcomes. The study therefore provides support for current policy.