bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of algorithms for high throughput detection of genomic copy number variation in oligonucleotide microarray data
Authors: Baross Ágnes , Delaney Allen D , Li H Irene , Nayar Tarun , Flibotte Stephane , Qian Hong , Chan Susanna Y , Asano Jennifer , Ally Adrian , Cao Manqiu , Birch Patricia , Brown-John Mabel , Fernandes Nicole , Go Anne , Kennedy Giulia , Langlois Sylvie , Eydoux Patrice , Friedman JM , Marra Marco A
Published: October 2007

Background

Genomic deletions and duplications are important in the pathogenesis of diseases, such as cancer and mental retardation, and have recently been shown to occur frequently in unaffected individuals as polymorphisms. Affymetrix GeneChip whole genome sampling analysis (WGSA) combined with 100 K single nucleotide polymorphism (SNP) genotyping arrays is one of several microarray-based approaches that are now being used to detect such structural genomic changes. The popularity of this technology and its associated open source data format have resulted in the development of an increasing number of software packages for the analysis of copy number changes using these SNP arrays.

Results

We evaluated four publicly available software packages for high throughput copy number analysis using synthetic and empirical 100 K SNP array data sets, the latter obtained from 107 mental retardation (MR) patients and their unaffected parents and siblings. We evaluated the software with regards to overall suitability for high-throughput 100 K SNP array data analysis, as well as effectiveness of normalization, scaling with various reference sets and feature extraction, as well as true and false positive rates of genomic copy number variant (CNV) detection.

Conclusion

We observed considerable variation among the numbers and types of candidate CNVs detected by different analysis approaches, and found that multiple programs were needed to find all real aberrations in our test set. The frequency of false positive deletions was substantial, but could be greatly reduced by using the SNP genotype information to confirm loss of heterozygosity.
Limited genetic diversity in Salmonella enterica Serovar Enteritidis PT13
Authors: Olson Adam B , Andrysiak Ashleigh K , Tracz Dobryan M , Guard-Bouldin Jean , Demczuk Walter , Ng Lai-King , Maki Anne , Jamieson Frances , Gilmour Matthew W
Published: October 2007

Background

Salmonella enterica serovar Enteritidis has emerged as a significant foodborne pathogen throughout the world and is commonly characterized by phage typing. In Canada phage types (PT) 4, 8 and 13 predominate and in 2005 a large foodborne PT13 outbreak occurred in the province of Ontario. The ability to link strains during this outbreak was difficult due to the apparent clonality of PT13 isolates in Canada, as there was a single dominant pulsed-field gel electrophoresis (PFGE) profile amongst epidemiologically linked human and food isolates as well as concurrent sporadic strains. The aim of this study was to perform comparative genomic hybridization (CGH), DNA sequence-based typing (SBT) genomic analyses, plasmid analyses, and automated repetitive sequence-based PCR (rep-PCR) to identify epidemiologically significant traits capable of subtyping S. Enteritidis PT13.

Results

CGH using an oligonucleotide array based upon chromosomal coding sequences of S. enterica serovar Typhimurium strain LT2 and the Salmonella genomic island 1 successfully determined major genetic differences between S. Typhimurium and S. Enteritidis PT13, but no significant strain-to-strain differences were observed between S. Enteritidis PT13 isolates. Individual loci (safA and fliC) that were identified as potentially divergent in the CGH data set were sequenced in a panel of S. Enteritidis strains, and no differences were detected between the PT13 strains. Additional sequence-based typing was performed at the fimA, mdh, manB, cyaA, citT, caiC, dmsA, ratA and STM0660 loci. Similarly, no diversity was observed amongst PT13 strains. Variation in plasmid content between PT13 strains was observed, but macrorestriction with Bgl II did not identify further differences. Automated rep-PCR patterns were variable between serovars, but S. Enteritidis PT13 strains could not be differentiated.

Conclusion

None of the methods identified any significant variation between PT13 strains. Greater than 11,300 base pairs of sequence for each of seven S. Enteritidis PT13 strains were analyzed without detecting a single polymorphic site, although diversity between different phage types of S. Enteritidis was observed. These data suggest that Canadian S. Enteritidis PT13 strains are highly related genetically.
Abdominal obesity exhibits distinct effect on inflammatory and anti-inflammatory proteins in apparently healthy Japanese men
Authors: Nishida Makoto , Moriyama Toshiki , Sugita Yoshiro , Yamauchi-Takihara Keiko
Published: October 2007

Background

Since visceral fat tissue is known to release various inflammatory and anti-inflammatory cytokines, abdominal obesity may play a key role in the inflammation associated with metabolic syndrome (MetS). However, few studies have determined precise relationships of abdominal obesity with inflammatory markers in MetS. To clarify the importance of abdominal obesity in sub-clinical inflammation, we examined the changes of inflammatory markers in clustering of MetS components with or without abdominal obesity.

Methods

Subjects consisted of 326 apparently healthy Japanese men (age: 30 to 59 years) who underwent health examination in the Osaka University Health Care Center. MetS components were assessed and serum levels of high sensitive C-reactive protein (hs-CRP), interleukin (IL)-6 and adiponectin were examined in all subjects.

Results

Subjects with abdominal obesity (waist circumference ≥ 85 cm) showed higher serum hs-CRP and IL-6 levels and a lower adiponectin level than those without abdominal obesity. Serum levels of hs-CRP and IL-6 significantly increased in association with clustering of MetS components in the subjects with abdominal obesity, but not in those without abdominal obesity. On the other hand, serum adiponectin level exhibited a little change with clustering of MetS components in the subjects with abdominal obesity. Significant negative correlation between adiponectin and hs-CRP was observed in the subjects with abdominal obesity, however this correlation was not detected in obese subjects defined by body mass index ≥ 25.

Conclusion

Inflammatory status is not exaggerated by clustering of MetS components in the subjects without abdominal obesity. Abdominal obesity may exhibit distinct effect on inflammatory and anti-inflammatory proteins and modulate inflammatory network in MetS.
Human Immunodeficiency Virus Type 1 Nef protein modulates the lipid composition of virions and host cell membrane microdomains
Authors: Brügger Britta , Krautkrämer Ellen , Tibroni Nadine , Munte Claudia E , Rauch Susanne , Leibrecht Iris , Glass Bärbel , Breuer Sebastian , Geyer Matthias , Kräusslich Hans-Georg , Kalbitzer Hans Robert , Wieland Felix T , Fackler Oliver T
Published: October 2007

Background

The Nef protein of Human Immunodeficiency Viruses optimizes viral spread in the infected host by manipulating cellular transport and signal transduction machineries. Nef also boosts the infectivity of HIV particles by an unknown mechanism. Recent studies suggested a correlation between the association of Nef with lipid raft microdomains and its positive effects on virion infectivity. Furthermore, the lipidome analysis of HIV-1 particles revealed a marked enrichment of classical raft lipids and thus identified HIV-1 virions as an example for naturally occurring membrane microdomains. Since Nef modulates the protein composition and function of membrane microdomains we tested here if Nef also has the propensity to alter microdomain lipid composition.

Results

Quantitative mass spectrometric lipidome analysis of highly purified HIV-1 particles revealed that the presence of Nef during virus production from T lymphocytes enforced their raft character via a significant reduction of polyunsaturated phosphatidylcholine species and a specific enrichment of sphingomyelin. In contrast, Nef did not significantly affect virion levels of phosphoglycerolipids or cholesterol. The observed alterations in virion lipid composition were insufficient to mediate Nef's effect on particle infectivity and Nef augmented virion infectivity independently of whether virus entry was targeted to or excluded from membrane microdomains. However, altered lipid compositions similar to those observed in virions were also detected in detergent-resistant membrane preparations of virus producing cells.

Conclusion

Nef alters not only the proteome but also the lipid composition of host cell microdomains. This novel activity represents a previously unrecognized mechanism by which Nef could manipulate HIV-1 target cells to facilitate virus propagation in vivo.
Application of a zona pellucida binding assay (ZBA) in the domestic cat benefits from the use of in vitro matured oocytes
Authors: Hermansson Ulrika , Axnér Eva , Holst Bodil Ström
Published: October 2007

Background

Zona pellucida binding assays (ZBAs) have proven useful in determining the fertilising ability of spermatozoa in several species. Most ZBAs use fresh or salt-stored oocytes collected from fresh ovaries but because ovaries are not easy to obtain on a regular basis, chilled and frozen-thawed ovaries have been tested, with varying results. The present study tested the hypothesis that cat spermatozoa, either fresh or frozen-thawed, can bind to homologous zona pellucida of oocytes retrieved from frozen-thawed queen ovaries to a similar extent as they can bind to the zona pellucida of fresh,in vitromatured oocytes.

Methods

Ovaries were collected from queens after routine ovario-hysterectomy and either stored in NaCl at -20°C until use (treatment animals), or used fresh (controls). Cumulus-oocyte complexes (COCs) were retrieved by ovarian slicing from either source and used directly (immature oocytes from frozen-thawed ovaries; treatment animals) or afterin vitromaturation (IVM) (fresh ovaries; controls) for 24 hours in TCM 199, supplemented with 1 IU hCG/mL and 0.5 IU eCG/mL and 0.5% bovine serum albumin (BSA). The oocytes were incubated for 4 hours in 5% CO2in air at 38°C and 100% humidity in the presence of 5 × 106fresh or frozen-thawed spermatozoa/mL. Representative samples of oocytes were processed for scanning electron microscopy (SEM).

Results

Both fresh and frozen-thawed spermatozoa bound to thein vitromatured zona pellucida but significantly fewer, or no, spermatozoa bound to frozen-thawed, immature zona pellucida (P < 0.001). Also, more fresh spermatozoa than frozen-thawed spermatozoa bound to the zona pellucida (P < 0.001). The zona pellucida surface differed in morphology (SEM), within vitromatured oocytes showing a dense surface with few fenestrations in contrast to their frozen-thawed, immature counterparts, where fenestrations were conspicuously larger.

Conclusion

In conclusion, under the conditions of the present study, immature oocytes recovered from ovaries frozen immersed in NaCl at -20°C are less suitable for use in feline ZBA.
Recent Advances in the Genetics of Autoimmune Diseases
Authors: ALARCÓN‐RIQUELME MARTA E.
Published: October 2007

Abstract:  Autoimmune diseases in general are complex genetic diseases where genes and environment interact in unknown ways. In recent years technologies have advanced our knowledge and new genes are being identified very rapidly. We can expect that most genes of major importance for the various autoimmune diseases will be discovered in the coming 5 years. The real challenge comes when we try to understand the mechanisms through which these genes confer disease susceptibility and how the interaction with environment takes place such that clinical expression of the disease results.
Profiling Meta‐Analysis Reveals Primarily Gene Coexpression Concordance between Systemic Lupus Erythematosus and Rheumatoid Arthritis
Authors: SILVA GUILHERME L. , JUNTA CRISTINA M. , MELLO STEPHANO S. , GARCIA PAULA S. , RASSI DIANE M. , SAKAMOTO‐HOJO ELZA T. , DONADI EDUARDO A. , PASSOS GERALDO A. S.
Published: October 2007

Abstract:  Consensus gene expression profiling by meta‐analysis of 4,500 cDNA sequence microarray data obtained from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) was assembled and systematically analyzed. The normalized data were statistically analyzed by the significance analysis of microarray (SAM) program (false discovery rate ≤ 0.01). Patient data input was realized together, in the Cluster and Tree‐View program, using the unsupervised function. Individual expression signatures permitted a hierarchical clustering of samples, separately identifying SLE and RA patients and the transcriptome profiling featured modules of the specifically induced or repressed and the comodulated genes. Gene expression profiling meta‐analysis showed that patients with SLE or RA share gene modulation but also present genes whose expression patterns are exclusive (induced or repressed) in corroboration with their clinical features. Among the genes that were differentially expressed, we found those that could play specific roles in these two diseases. This approach permits a clearer understanding of the molecular basis of SLE and RA concordance/divergence.
MICA Gene Polymorphism in the Pathogenesis of Type 1 Diabetes
Authors: GAMBELUNGHE G. , BROZZETTI A. , GHADERI M. , CANDELORO P. , TORTOIOLI C. , FALORNI A.
Published: October 2007

Abstract:  Type 1 diabetes mellitus (T1DM) is a typical autoimmune disease and results from the destruction of insulin‐producing β cells of the pancreas. It develops in the presence of genetic susceptibility, even though more than 85% of patients with T1DM do not have a close relative with the disorder. The etiology of T1DM is complex, and both genetic and environmental factors play important roles. A permissive genetic background is required for the development of the islet autoimmune process. The strongest genetic association idengified is that with HLA class II genes located on the short arm of chromosome 6. It is well known that both HLA DRB1*04‐DQA1*0301‐DQB1*0302 (DR4‐DQ8) and DRB1*03‐DQA1*0501‐DQB1*0201 (DR3‐DQ2) are positively, and DRB1*15‐DQA1*0102‐DQB1*0602 is negatively, associated with T1DM. However, only a minority of the subjects carrying the high‐risk haplotypes/genotypes develops the disease, which suggests that additional genes play a crucial role in conferring either protection or susceptibility to T1DM. Major histocompatibility complex (MHC) class I chain–related A (MICA) is located in a candidate susceptibility region and activates natural killer (NK) cells, T cells and γδ CD8 T cells by its receptor NKG2D. The polymorphism of the MICA gene is associated with T1DM in different populations as demonstrated in several papers published in the last 7 years.
HCV‐Related Immunocytoma and Type II Mixed Cryoglobulinemia‐Associated Autoantigens
Authors: SIMULA MARIA PAOLA , CAGGIARI LAURA , GLOGHINI ANNUNZIATA , DE RE VALLI
Published: October 2007

Abstract: Hepatitis C virus (HCV) is a hepatotropic virus causing hepatocellular damage and chronic liver inflammation that progressively can lead to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotropic, as demonstrated by its capacity to replicate in lymphocytes, by the recurrent detection of organ‐ and non‐organ‐specific autoantibodies in HCV‐infected patients, and by the strong association found between HCV infection and type II mixed cryoglobulinemic syndrome (MC‐II). Moreover, accumulating data ascribe an etiopathogenetic role in the development of B cell non‐Hodgkin's lymphomas (NHL) to HCV. All these findings account for the profound effect of HCV infection in the host's immune system. The unique virus–host interactions that culminate in the generation and sustained production of autoantibodies and cryoglobulins have not been delineated. It appears that chronic antigenic stimulation could cause the emergence of specific B cell clones that produce cryoglobulins; moreover, B cell activation and/or deregulation could originate as a result of HCV binding to CD81 tetraspanin or as a consequence of its ability to replicate in B cells. In a previous study we demonstrated that, in MC‐II HCV‐positive patients, cryoprecipitated monoclonal IgMs, and B cell receptors (BCR) of overexpanded B cell clones share the same combinatory region. Moreover, these IgMs were reactive against both the Fc region of human IgG and the HCV‐NS3 antigen. NS3 and Fc epitopes have been idengified by epitope excision approach. One of the idengified NS3 epitopes has been used to immunize a mouse and the monoclonal antibody obtained showed the same cross‐reactivity as patients' IgMs. The characterization of antigenic specificity of this antibody may be useful to idengify antigens that can stimulate B cell proliferation in HCV‐infected individuals.
Genetic Control of Immune Response in Carriers of the 8.1 Ancestral Haplotype
Authors: CANDORE GIUSEPPINA , CAMPAGNA ANNA MARIA , CUPPARI IRENE , CARLO DANIELE DI , MINEO CLAUDIA , CARUSO CALOGERO
Published: October 2007

Abstract:  Ancestral haplotype (AH) 8.1(HLA‐A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) seems to be associated with susceptibility to autoimmune diseases. Different mechanisms are probably involved in increasing autoimmunity, such as unbalanced cytokine production and the lack of C4A protein. So AH 8.1 modifies immune response in many ways. In this study we demonstrate that IgG2 serum levels were significantly lower in 8.1 AH carriers than in 8.1 AH non‐carriers. On the contrary, as regards IgG1, IgG3, IgG4 serum levels, no significant differences were observed between the two groups. In AH 8.1 carriers low IgG2 levels might take to slower clearance of the infectious agent and hence to a lasting presence of it. The persistence of infectious antigens could determine an increased production of autoantibodies with a higher risk of cross‐reactions.
Genetics and New Treatment Modalities for Familial Mediterranean Fever
Authors: BHAT ANUPAMA , NAGUWA STANLEY M. , GERSHWIN M. ERIC
Published: October 2007

Abstract:  Familial Mediterranean fever (FMF) is the most common of a rare group of disorders collectively termed familial hereditary periodic fever syndromes, also known as autoinflammatory syndromes. FMF is clinically characterized by intermittent bouts of fever with peritonitis and abdominal pain, pleuritis, arthritis, or erysipelas‐like rashes. Amyloidosis due to chronic inflammation progressing to renal failure is one of the most serious potential complications of this disease. Individuals with FMF have identifiable genetic defects in the Mediterranean fever (MEFV) gene, which codes for the protein pyrin. Pyrin normally blunts neutrophil‐mediated inflammation, likely via interleukin‐1 (IL‐1) downregulation, but is defective in FMF. Potential treatments include colchicine, with case reports of benefits with catecholamine blockade (prazosin), tumor necrosis factor (TNF) antagonism (etanercept, thalidomide), and IL‐1 receptor blockade (anakinra).
Current State of Biologicals in the Management of Systemic Vasculitis
Authors: LAMPRECHT PETER , TILL ANDREAS , STEINMANN JÖRG , ARIES PEER M. , GROSS WOLFGANG L.
Published: October 2007

Abstract: Conventional immunosuppressive treatment of systemic vasculitides has improved their often fatal outcome, but is burdened by cytotoxic side effects and frequent relapses. Recent advances in the therapy of systemic vasculitides with biologicals have helped to establish new options for patients resistant to conventional treatment. Moreover, early intervention aiming to interfere with specific targets important in the break of tolerance and/or persistence of the autoimmune response might further improve the prognosis of autoimmune vasculitides such as antineutrophil cytoplasmic autoantibody (ANCA)‐associated vasculitides (AAV).In vitroandin vivostudies suggest that the interaction of ANCA and cytokine (TNF‐α, IL‐1)‐primed neutrophils results in premature neutrophil activation and degranulation, subsequent endothelial cell damage, and further leukocyte recruitment. For one of the AAV, Wegener's granulomatosis, recentex vivodata have provided evidence that WG‐granulomata might provide the necessary “proinflammatory environment” for the break of tolerance and display features of lymphoid‐like tissue neoformation, in which autoimmunity to “Wegener's autoantigen” proteinase 3 PR3 could be sustained. Blocking TNF‐α and eliminating autoreactive B cells seem promising treatment targets to interfere with these fundamental disease processes. While the recombinant TNF‐α receptor/IgG1 fusion protein etanercept, in addition to standard therapy with subsequent tapering of standard medications, was found to be not effective for maintenance of remission, open clinical studies suggest a beneficial effect of the anti‐TNF‐α antibody infliximab in addition to standard therapy for the induction of remission in patients with refractory AAV. Peripheral B cell depletion with the anti‐CD20 antibody rituximab also induced remissions in AAV in uncontrolled trials.
Bromocriptine during Pregnancy in Systemic Lupus Erythematosus
Authors: JARA LUIS J. , CRUZ‐CRUZ POLITA , SAAVEDRA MIGUEL A. , MEDINA GABRIELA , GARCÍA‐FLORES ADRIANA , ANGELES ULISES , MIRANDA‐LIMÓN JUAN M.
Published: October 2007

Abstract:  Bromocriptine (BRC) prevents postpartum flare in lupus patients. However, its potential role in protecting lupus pregnancy from maternal–fetal complications has not been studied. The objective of the study was to explore the role of oral BRC during pregnancy in patients with systemic lupus erythematosus (SLE). Pregnant SLE patients were randomized into two groups: group 1 received BRC 2.5 mg/day and prednisone 10 mg/day; group 2 received prednisone 10 mg/day. These treatments were administered from 25 to 35 weeks of gestation. Prolactin (PRL) levels were determined at 25, 30, and 35 weeks. The SLE Pregnancy Disease Activity Index, maternal–fetal outcome including preterm birth, fetal loss, premature rupture of membrane (PRM), low birth weight, and preeclampsia/eclampsia were evaluated. We studied 20 patients (10 in each group). A significant decrease of PRL levels in group 1 compared to group 2 at week 30 and at week 35 was found. No patients in the BRC group had flares and three from group 2 had SLE activity. None of the patients in group 1 had PRM but three patients in group 2 did. Eighty percent of pregnancies ended in birth at term in group 1 and 50% in group 2. There was no fetal loss in both groups. Mean birth weight was higher in group 1 than in group 2 (P < NS). BRC was well tolerated. This is the first clinical trial of BRC in SLE pregnancy. Our pilot study suggests that BRC may play a role in the prevention of maternal–fetal complications, such as PRM, preterm birth, and active disease.
Efficacy and Safety of Intravenous Immunoglobulin in Patients with Metastatic Melanoma
Authors: SCHACHTER JACOB , KATZ URIEL , MAHRER ARIE , BARAK DOV , DAVID LIAT ZIEGEL BEN , NUSBACHER JACOB , SHOENFELD YEHUDA
Published: October 2007

Abstract:  We have previously reported studies performed both in vitro and in laboratory animals, as well as a case study in humans, suggesting that intravenous immunoglobulin (IVIG) may be beneficial in the treatment of malignancies, including metastatic melanoma. As part of a phase II open label trial, we have administered IVIG to nine patients with metastatic melanoma who had been heavily treated. In two of nine (22%) patients treated every 3 weeks with IVIG (1 g/kg body weight), the disease stabilized. One patient had stable disease for 8 months; the other for 3 months. No serious adverse events (AEs) attributable to IVIG were observed. We conclude that IVIG therapy may be useful for the treatment of metastatic melanoma. Furthermore, we suggest that the effects of IVIG therapy might be enhanced by its use as an adjuvant in patients without evidence of disease following surgery.
Autoantibody Production in Anti‐TNF‐α‐Treated Patients
Authors: ALESSANDRI CRISTIANO , SCRIVO ROSSANA , SPINELLI FRANCESCA ROMANA , CECCARELLI FULVIA , MAGRINI LEONARDO , PRIORI ROBERTA , VALESINI GUIDO
Published: October 2007

Abstract:  Targeting tumor necrosis factor alpha (TNF‐α) has offered an additional therapeutic strategy against several rheumatic inflammatory disorders. The current use of TNF‐α inhibitors allows physicians who manage these diseases and patients themselves to testify to an extraordinary efficacy, even though caution for possible adverse events must be maintained. Among these, the occurrence of autoimmune phenomena, encompassing new autoantibody formation and triggering of clinical manifestations, continues to be noted in published reports. Here, we review the current knowledge regarding the autoimmune phenomena linked to anti‐TNF‐α therapy in patients with rheumatic inflammatory disorders.
Anti‐IL‐17A Autovaccination Prevents Clinical and Histological Manifestations of Experimental Autoimmune Encephalomyelitis
Authors: UYTTENHOVE CATHERINE , SOMMEREYNS CAROLINE , THÉATE IVAN , MICHIELS THOMAS , VAN SNICK JACQUES
Published: October 2007

Abstract:  Excessive or inappropriate production of IL‐17A has been reported in diseases such as rheumatoid arthritis, asthma, and multiple sclerosis. The potential clinical relevance of these correlations was suggested by the protective effects of anti‐IL‐17A monoclonal antibodies in various mouse disease models. However, the chronic nature of the corresponding human afflictions raises great challenges for Ab‐based therapies. An alternative to passive Ab therapy is autovaccination. Covalent association of self‐cytokines with foreign proteins has been reported to induce the production of antibodies capable of neutralizing the biological activity of the target cytokine. We recently reported that cross‐linking of IL‐17A to ovalbumin produced highly immunogenic complexes that induced long‐lasting IL‐17A‐neutralizing antibodies. Vaccinated SJL mice were completely protected against experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein peptide (PLP 139–151), and a monoclonal anti‐IL‐17A Ab (MM17F3), derived from C57Bl/6 mice vaccinated against IL‐17A‐OVA, also prevented disease development. Here we report that this Ab also protects C57Bl/6 mice from myelin oligdendrocyte glycoprotein (MOG)‐induced EAE. Histological analysis of brain sections of C57Bl/6 mice treated with MM17F3 showed a complete absence of inflammatory infiltrates and evidence for a marked inhibition of chemokine and cytokine messages in the spinal cord. These results further extend the analytical and therapeutic potential of the autovaccine procedure.
Interleukin‐20 as a Target in Psoriasis Treatment
Authors: STENDERUP KARIN , ROSADA CECILIA , WORSAAE ANNE , CLAUSEN JES THORN , NORMAN DAM TOMAS
Published: October 2007

Abstract:  Interleukin‐20 (IL‐20) is a new member of the IL‐10 cytokine family discovered by a structural algorithm. IL‐20 transgenic mice displayed skin abnormalities reminiscent of psoriasis, a finding that has prompted the investigation of this new interleukin in relation to this disease. This article reviews the role of IL‐20 and its implication in psoriasis. It is shown that IL‐20 and its receptors are found in human skin and that IL‐20 is involved in proliferation, angiogenesis, and chemotaxis, all characteristics of psoriasis. We demonstrated that IL‐20 induced the thickening of human epidermis in vivo; however, this thickening does not seem to be related to a direct effect of IL‐20 on hyperproliferation since the growth of normal human epidermal keratinocytes (NHEKs) cultured in vitro was not affected by IL‐20. On the other hand, in vitro, IL‐20 stimulated human peripheral blood mononuclear cells (PBMCs) to produce proinflammatory cytokines and, in vivo, IL‐20 in combination with PBMCs induced psoriasis. This may suggest that IL‐20 indirectly exerts its proliferative effects on keratinocytes via immune cells present in the skin. Finally, we found that blocking IL‐20 signaling in psoriasis improves psoriasis, suggesting that IL‐20 is a potential target in psoriasis treatment.
Rapid and Deep Control of Inflammation in Rheumatoid Arthritis with Infliximab and Its Correlation with Acute‐Phase Reactants
Authors: SCALI J.J. , VISENTINI S. , SALOMÓN J. , SEVILLA D. , JU Y.C. , MORALES E. , UGARTE L. , TACHDJIAN A. , PACHECO G. , VEIGA S.
Published: October 2007

Abstract:  Rheumatoid arthritis (RA) is a chronic inflammatory disease with predominant joint involvement and possible systemic compromise, which leads to a handicapped status and poor quality of life. An optimal approach to treat RA requires early and intensive intervention with close monitoring of treatment response. Tumor necrosis factor (TNF) blockers are recommended in cases of active RA after the unsuccessful use of effective disease‐modifying antirheumatic drugs (DMARDs); even adding them to treatment or replacing these drugs. Anti‐TNF therapies have been demonstrated to reduce significant joint damage and to relieve symptoms during a prolonged time (see Scott and Kingsley, 2006). The efficacy of infliximab in an open‐label trial is summarized with respect to speed of onset of action, durability of response, and its correlation between clinical and laboratory parameters. Safety for long‐term treatment is also summarized. We studied 105 RA patients with more than 3 years' history of disease during 24 months on i.v. infliximab (75 completed study). We evaluated ACR responses at base line, and at 1, 6, 12, 16, 52, 77, and 104 weeks. Morning stiffness, swollen and tender joints, HAQ, SF‐36% (PCS/MCS), polymerase chain reaction (PCR), erythrosedimentation rate (ESR), transaminases, rheumatoid factor (RF) levels, hemogram, and adverse events profile were all assessed. The treatment offered rapid and sustained clinical improvements as revealed by ACR responses and marked changes in the parameters previously described. Important changes were made in functional status and acute‐phase reactants. Finally, infliximab was considered well tolerated and did not affect the safety profile of this trial.
Intravenous Immunoglobulin and Cytokines
Authors: LE POTTIER LAËTITIA , SAPIR TAL , BENDAOUD BOUTAHAR , YOUINOU PIERRE , SHOENFELD YEHUDA , PERS JACQUES‐OLIVIER
Published: October 2007

Abstract:  The presence of natural autoantibodies against cytokines has been reported in healthy individuals. Because circulating cytokines may be implicated in the clinical outcome of numerous diseases, the mode of action of intravenous immunoglobulin (IVIg) (pooled from sera over a thousand normal individuals) may involve immunomodulation of the cytokine network. We review the anti‐cytokine effects of IVIg as well as the consequences of IVIg infusions on cytokine production. Furthermore, IVIg exerts therapeutic effects in autoimmune diseases and lymphoid malignancies. These two conditions have in common an overproduction of BAFF (for B‐cell‐activating factor of the TNF family). The presence of antibodies with BAFF and APRIL (a proliferation‐inducing ligand) specificity was investigated. We found that IVIg recognizes BAFF and APRIL and that IVIg binding prevents BAFF from exerting its antiapoptotic effect on B cells. These anti‐BAFF IgGs might prevent the deleterious effects of BAFF in B‐cell‐mediated autoimmune diseases.
Impact of Steroids on Hepatitis C Virus Replication in Vivo and in Vitro
Authors: HENRY SCOT D. , METSELAAR HEROLD J. , VAN DIJCK JEROEN , TILANUS HUGO W. , VAN DER LAAN LUC J. W.
Published: October 2007

Abstract:  Chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation. Transplantation outcome is often compromised by a rapid re‐infection of the graft. Several factors have been implicated in the increased severity of recurrence, including steroid‐based immunosuppression. Evidence suggests that steroid boluses used to treat acute rejection are associated with an increase in HCV viral load and the severity of recurrence. Two possible mechanisms for a steroid‐mediated effect on HCV viral loads can be postulated, the first being a direct effect of steroids on the virus by enhancing its replication. The second, an indirect effect due to the suppression of the HCV immune response, allows unrestricted HCV replication. To investigate the direct effect of steroids on HCV replication, dexamethasone (Dex) and prednisolone (Pred) were tested in an in vitro replicon model. HCV replication was assessed on the basis of luciferase reporter expression (luminescence) and HCV RNA (RT‐PCR). At clinically relevant concentrations (1–10 nM), treatment with both Dex and Pred did not enhance, but resulted in a slight reduction of relative luciferase activity (HCV replication), which was independent of increased cellular protein content and reduced cell proliferation. This minor reduction of HCV replication was confirmed by RT‐PCR showing more than 41% reduction in HCV RNA levels. In conclusion, despite clinical evidence that the use of steroids aggravates recurrence of HCV, our in vitro study suggests that there is no direct stimulatory effect of steroids on the replication of HCV. As such, the increased viral loads after high‐dose steroid treatment are more likely due to a downregulation of the immune response. In such patients, a dampened immune response allows viruses like HCV to replicate free of immune‐mediated killing of their host cells. When a change occurs, such as a tapering or an alteration of immunosuppressant drugs, the immune system reinitiates and vigorously attempts to control the virus, resulting in acceleration of liver damage. Therefore, either steroid avoidance or maintaining low levels, coupled with a slow tapering of corticosteroids, may be beneficial to HCV‐infected transplantation recipients.
Natalizumab in the Treatment of Patients with Multiple Sclerosis
Authors: MARECKOVA HELENA , HAVRDOVA EVA , KRASULOVA EVA , VANKOVA ZDENKA , KOBEROVÁ MICHAELA , ŠTERZL IVAN
Published: October 2007

Abstract:  Multiple sclerosis (MS) usually develops in young adults with a complex predisposing genetic background. Polymorphisms in the gene for chemokine receptor CCR5 have been proposed to confer susceptibility to or protection from MS. Study of molecules participating in the inflammatory process contributed to the development of a new humanized monoclonal antibody, natalizumab, aimed at the adhesive molecule VLA‐4. Natalizumab (Biogen Idec/Elan) went through successful clinical studies and its clinical testing was also carried out in the Czech Republic. Twenty‐one patients with MS were included in the AFFIRM study (2‐year, placebo‐controlled study and consecutive 7‐month unblinded natalizumab treatment); immunophenotyping of the cerebrospinal fluid (CSF)– CD4+CCR5+CXCR3+ lymphocytes, using flow cytometer FACSCalibur and monoclonal antibodies (BD Biosciences), was done at the end of natalizumab treatment and 1 year after the therapy withdrawal. Compared to MS patients receiving other therapy, the patients treated with natalizumab had statistically significantly (P < 0.0001) higher levels of CCR5+ and lower levels of CD4+ T lymphocytes in CSF, whereas the levels of CXCR3+ lymphocytes were almost the same as in other patients. CCR5‐positive CSF lymphocytes decreased 1 year after treatment withdrawal. Natalizumab treatment alters the percentage of CCR5+ and CD4+ cells in CSF. In view of the excellent temporary clinical results of the therapy, which are yet to be assessed in the course of a longer time period, our results show a possible explanation for the therapeutic success of this drug as well as for the development of progressive multifocal leukoencephalopathy.
Mycophenolate Mofetil in Lupus Glomerulonephritis
Authors: IACCARINO LUCA , ARIENTI SILVIA , RAMPUDDA MARIAELISA , CANOVA MARIAGRAZIA , ATZENI FABIOLA , SARZI PUTTINI PIERCARLO , DORIA ANDREA
Published: October 2007

Abstract:  Mycophenolate mofetil (MMF) is an immunosuppressive agent initially used in the treatment of transplant recipients. MMF has been used in renal, heart, and liver transplantation, where it seems more effective than other immunosuppressive regimens in reducing the incidence of acute rejection episodes. MMF has a variety of immunosuppressive effects, including selective suppression of T and B lymphocyte proliferation, and has been more recently used in many autoimmune inflammatory conditions. Systemic lupus erythematosus (SLE) is an autoimmune disease that can potentially involve any organ or system of the human body. Glomerulonephritis (GLN) has been recognized as the most frequent severe manifestation of SLE, leading to poor long‐term prognosis. In the treatment of lupus GLN, several therapeutic approaches, all including immunosuppressive drugs, such as cyclophosphamide, azathioprine, or cyclosporine A, have been used. The short‐ and long‐term toxicity of these drugs limits their use in a substantial number of patients. Over the last few years, MMF has emerged as an alternative therapeutic regimen in lupus GLN, mainly for patients refractory to other therapies. These studies have shown that it is highly effective and generally well tolerated.
Are Neuropeptides Important in Arthritis?
Authors: GRIMSHOLM O. , GUO YZ. , NY T. , RANTAPÄÄ‐DAHLQVIST S. , FORSGREN S.
Published: October 2007

Abstract:  Interference with the effects of neuropeptides may be of potential therapeutic value for the treatment of rheumatoid arthritis (RA). Two neuropeptides that can be discussed in this context are bombesin/gastrin‐releasing peptide (BN/GRP) and substance P (SP). In order to obtain new information on the possible importance of these two peptides, the patterns of immunohistochemical expression of BN/GRP and SP and their related receptors in the mouse knee joint from healthy and arthritic mice were examined. Positive staining for GRP receptor and the SP preferred receptor (the neurokinin‐1 receptor [NK‐1 R]) was observed in articular chondrocytes. On the whole, there was a decrease in immunoreactions for both the GRP‐ and the NK‐1 receptors in the articular chondrocytes in joints exhibiting severe arthritis. Staining for BN/GRP and GRP receptor was seen in the inflammatory infiltrates of the arthritic joints. New evidence for the occurrence of marked effects of BN/GRP concerning both the articular chondrocytes and the inflammatory process is obtained in this study. With these findings and previous observations of neuropeptide expression patterns and functions we discuss the possibility that interventions with the effects of BN/GRP, SP, and other neuropeptides might be worthwhile in RA.
A Long‐Term Follow‐up after Cardiac Transplantation in a Lupus Patient
Authors: TWEEZER‐ZAKS NURIT , ZANDMAN‐GODDARD GISELE , LIDAR MERAV , HAR‐ZAHAV YEDIAL , LIVNEH AVI , LANGEVITZ PNINA
Published: October 2007

Abstract:  Heart or heart–lung transplantations have only rarely been performed in patients with systemic lupus erythematosus (SLE), who like other patients with multi‐system autoimmune diseases are traditionally excluded from consideration for such transplantations. In view of the limited experience with heart transplantation in these patients, we report the successful transplantation outcome in a lupus patient and review the literature in relation to graft and recipient conditions.
Safety of Cyclosporin A in HCV‐Infected Patients
Authors: GALEAZZI MAURO , BELLISAI FRANCESCA , GIANNITTI CHIARA , MANGANELLI STEFANIA , MOROZZI GABRIELLA , SEBASTIANI GIAN DOMENICO
Published: October 2007

Abstract:  Because of the relatively high prevalence of both hepatitis C virus (HCV) infection and autoimmune disorders (ADs), it is not rare to encounter in daily clinical practice patients with ADs also carrying HCV. Corticosteroids and/or immunosuppressant drugs are needed to treat ADs, but they place HCV‐infected patients at risk of worsening the infection. So, rheumatologists have often refrained from using corticosteroids or immunosuppressants in AD when HCV–RNA is also present. Cyclosporin A (CsA) is an immunosuppressive agent used to treat a wide range of ADs, but there is a large evidences in the literature, both in vitro and in vivo, suggesting that CsA also exerts an inhibitory effect on HCV replication at standard therapeutic dose. Therefore, this evidence has opened new ways to improve the therapy and the prognosis in patients with HCV‐related liver diseases, including those with transplants. Recent reports, although limited in number, also suggest the safety of CsA in the treatment of patients with AD and concomitant HCV infection. In this review we also report our personal experience on the combination treatment with CsA and anti‐TNF‐α agents in rheumatoid arthritis.
Impact of Treatment with Infliximab on Serum Cytokine Profile of Patients with Rheumatoid and Psoriatic Arthritis
Authors: AMITAL HOWARD , BARAK VIVIAN , WINKLER ROBERT E. , RUBINOW ALAN
Published: October 2007

Abstract:  This article analyzes the serum cytokine profile of a nonrandomized group of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who are destined to be treated with infliximab following failure after failure of different disease‐modifiying antirheumatic drugs (DMARDs). Serial serum samples were collected from 11 patients with refractory RA, three with PsA and one with undifferentiated spondyloarthropathy. All were treated with the antitumor necrosis factor (TNF)α agent, infliximab, after failing to sustain a clinical remission with conventional DMARDs. Blood samples were obtained at different phases of their therapy. Serum levels of tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)‐1β, IL‐6, sIL‐2R, IL‐10, and IL‐1 receptor antagonist (IL‐1RA) were determined by commercial ELISA kits. Interestingly, only eight of the 11 patients with RA had elevated TNFα serum levels (at least once in their serial measurements). Only one was unresponsive to therapy and despite anti‐TNFα therapy her serum TNFα levels remained extremely high. Two RA patients who responded to infliximab had normal TNFα serum levels prior to and following infliximab administration. One RA patient improved after infliximab therapy despite unrelenting high serum levels of TNFα, IL‐6, and sIL‐2R. Patients with active PsA who responded to infliximab therapy had sustained high serum TNFα levels. In an unselected population of RA and PsA patients, we noticed diverse patterns of serum cytokine profiles. These results imply that the cytokine profiles of RA and PsA are diverse and their pathogenesis is heterogeneous.
Effects of Intravenous Immunoglobulins on Peripheral Blood Mononuclear Cell Activation in Vitro
Authors: STICHERLING MICHAEL , TRAWINSKI HENNING
Published: October 2007

Abstract:  The therapeutic effects of intravenous immunoglobulins (IVIGs) on different chronic inflammatory and autoimmune diseases is well appreciated, though clinical studies with high‐evidence levels are largely missing. Similar to the broad spectrum of diseases and their underlying etiopathogenic background, the mechanisms of action seem heterogenous and multifold. Several studies addressing in vitro and in vivo effects of IVIG on various immunological parameters have been described with partly contradictory results. In this study immunoglobulins and stabilizers present in commercial IVIG preparations were studied in regard to the in vitro proliferation and cytokine production of peripheral blood mononuclear cells when stimulated with phytohemagglutinin (PHA), interleukin 2, and tetanus toxoid. Whereas the immunoglobulins stimulate the proliferation of PBMCs and decrease IFNγ secretion, stabilizers of IVIG seem to inhibit the proliferation of PBMCs while increasing the secretion of IFN γ. These effects have to be taken into account when balancing the impact of IVIG dosage and infusion intervals and relating them to clinical side effects and therapeutic efficacy.
Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer
Authors: Herbst Roy S. , O'Neill Vincent J. , Fehrenbacher Louis , Belani Chandra P. , Bonomi Philip D. , Hart Lowell , Melnyk Ostap , Ramies David , Lin Ming , Sandler Alan
Published: October 2007

Purpose

Bevacizumab, a humanized anti–vascular endothelial growth factor monoclonal antibody, and erlotinib, a reversible, orally available epidermal growth factor receptor tyrosine kinase inhibitor, have demonstrated evidence of a survival benefit in the treatment of non–small-cell lung cancer (NSCLC). A single-arm phase I and II study of bevacizumab plus erlotinib demonstrated encouraging efficacy, with a favorable safety profile.

Patients and Methods

A multicenter, randomized phase II trial evaluated the safety of combining bevacizumab with either chemotherapy (docetaxel or pemetrexed) or erlotinib and preliminarily assessed these combinations versus chemotherapy alone, as measured by progression-free survival (PFS). All patients had histologically confirmed nonsquamous NSCLC that had progressed during or after one platinum-based regimen.

Results

One hundred twenty patients were randomly assigned and treated. No unexpected adverse events were noted. Fewer patients (13%) in the bevacizumab-erlotinib arm discontinued treatment as a result of adverse events than in the chemotherapy alone (24%) or bevacizumab-chemotherapy (28%) arms. The incidence of grade 5 hemorrhage in patients receiving bevacizumab was 5.1%. Although not statistically significant, relative to chemotherapy alone, the risk of disease progression or death was 0.66 (95% CI, 0.38 to 1.16) among patients treated with bevacizumab-chemotherapy and 0.72 (95% CI, 0.42 to 1.23) among patients treated with bevacizumab-erlotinib. One-year survival rate was 57.4% for bevacizumab-erlotinib and 53.8% for bevacizumab-chemotherapy compared with 33.1% for chemotherapy alone.

Conclusion

Results for PFS and overall survival favor combination of bevacizumab with either chemotherapy or erlotinib over chemotherapy alone in the second-line setting. No unexpected safety signals were noted. The rate of fatal pulmonary hemorrhage was consistent with previous bevacizumab trials. The toxicity profile of the bevacizumab-erlotinib combination is favorable compared with either chemotherapy-containing group.
The Namesake: Deepika Bahri is Touched by Mira Nair's Vivid, Sonorous Account of Immigrant Life in an Adopted Home City
Authors: Bahri Deepika
Published: October 2007

ABSTRACT In this review of Mira Nair's film adaptation of Jhumpa Lahiri's 2003 novel about an immigrant Indian family in New York, particular close attention is paid to the director's careful use of color, speech, and music to evoke with subtlety and power the experience of migration and its attendant mourning.
Days of Glory / Flanders: Emma Wilson on Two Prize-winning, Politically Ambitious French War Films
Authors: Wilson Emma
Published: October 2007

ABSTRACT Though the two films seem rather different—Bruno Dumont's Flanders dealing with an imaginary contemporary war, Rachid Bouchareb's Days of Glory concerned with forgotten incidents in World War II—the argument of this essay is that they share a sense, somewhat unusual among recent French filmmakers, of the political power of cinema.