bluuebunny/crossref_metadata_2025 huggingface dataset:
MELOGEN: an EST database for melon functional genomics
Authors: Gonzalez-Ibeas Daniel , Blanca José , Roig Cristina , González-To Mireia , Picó Belén , Truniger Verónica , Gómez Pedro , Deleu Wim , Caño-Delgado Ana , Arús Pere , Nuez Fernando , Garcia-Mas Jordi , Puigdomènech Pere , Aranda Miguel A
Published: September 2007

Background

Melon (Cucumis melo L.) is one of the most important fleshy fruits for fresh consumption. Despite this, few genomic resources exist for this species. To facilitate the discovery of genes involved in essential traits, such as fruit development, fruit maturation and disease resistance, and to speed up the process of breeding new and better adapted melon varieties, we have produced a large collection of expressed sequence tags (ESTs) from eight normalized cDNA libraries from different tissues in different physiological conditions.

Results

We determined over 30,000 ESTs that were clustered into 16,637 non-redundant sequences or unigenes, comprising 6,023 tentative consensus sequences (contigs) and 10,614 unclustered sequences (singletons). Many potential molecular markers were identified in the melon dataset: 1,052 potential simple sequence repeats (SSRs) and 356 single nucleotide polymorphisms (SNPs) were found. Sixty-nine percent of the melon unigenes showed a significant similarity with proteins in databases. Functional classification of the unigenes was carried out following the Gene Ontology scheme. In total, 9,402 unigenes were mapped to one or more ontology. Remarkably, the distributions of melon and Arabidopsis unigenes followed similar tendencies, suggesting that the melon dataset is representative of the whole melon transcriptome. Bioinformatic analyses primarily focused on potential precursors of melon micro RNAs (miRNAs) in the melon dataset, but many other genes potentially controlling disease resistance and fruit quality traits were also identified. Patterns of transcript accumulation were characterised by Real-Time-qPCR for 20 of these genes.

Conclusion

The collection of ESTs characterised here represents a substantial increase on the genetic information available for melon. A database (MELOGEN) which contains all EST sequences, contig images and several tools for analysis and data mining has been created. This set of sequences constitutes also the basis for an oligo-based microarray for melon that is being used in experiments to further analyse the melon transcriptome.
Living with an imperfect cell wall: compensation of femAB inactivation in Staphylococcus aureus
Authors: Hübscher Judith , Jansen Andrea , Kotte Oliver , Schäfer Juliane , Majcherczyk Paul A , Harris Llinos G , Bierbaum Gabriele , Heinemann Matthias , Berger-Bächi Brigitte
Published: September 2007

Background

Synthesis of the Staphylococcus aureus peptidoglycan pentaglycine interpeptide bridge is catalyzed by the nonribosomal peptidyl transferases FemX, FemA and FemB. Inactivation of the femAB operon reduces the interpeptide to a monoglycine, leading to a poorly crosslinked peptidoglycan. femAB mutants show a reduced growth rate and are hypersusceptible to virtually all antibiotics, including methicillin, making FemAB a potential target to restore β-lactam susceptibility in methicillin-resistant S. aureus (MRSA). Cis-complementation with wild type femAB only restores synthesis of the pentaglycine interpeptide and methicillin resistance, but the growth rate remains low. This study characterizes the adaptations that ensured survival of the cells after femAB inactivation.

Results

In addition to slow growth, the cis-complemented femAB mutant showed temperature sensitivity and a higher methicillin resistance than the wild type. Transcriptional profiling paired with reporter metabolite analysis revealed multiple changes in the global transcriptome. A number of transporters for sugars, glycerol, and glycine betaine, some of which could serve as osmoprotectants, were upregulated. Striking differences were found in the transcription of several genes involved in nitrogen metabolism and the arginine-deiminase pathway, an alternative for ATP production. In addition, microarray data indicated enhanced expression of virulence factors that correlated with premature expression of the global regulators sae, sarA, and agr.

Conclusion

Survival under conditions preventing normal cell wall formation triggered complex adaptations that incurred a fitness cost, showing the remarkable flexibility of S. aureus to circumvent cell wall damage. Potential FemAB inhibitors would have to be used in combination with other antibiotics to prevent selection of resistant survivors.
Architecture of Burkholderia cepacia complex σ70 gene family: evidence of alternative primary and clade-specific factors, and genomic instability
Authors: Menard Aymeric , de los Santos Paulina Estrada , Graindorge Arnault , Cournoyer Benoit
Published: September 2007

Background

The Burkholderia cepacia complex (Bcc) groups bacterial species with beneficial properties that can improve crop yields or remediate polluted sites but can also lead to dramatic human clinical outcomes among cystic fibrosis (CF) or immuno-compromised individuals. Genome-wide regulatory processes of gene expression could explain parts of this bacterial duality. Transcriptional σ70 factors are components of these processes. They allow the reversible binding of the DNA-dependent RNA polymerase to form the holoenzyme that will lead to mRNA synthesis from a DNA promoter region. Bcc genome-wide analyses were performed to investigate the major evolutionary trends taking place in the σ70 family of these bacteria.

Results

Twenty σ70 paralogous genes were detected in the Burkholderia cenocepacia strain J2315 (Bcen-J2315) genome, of which 14 were of the ECF (extracytoplasmic function) group. Non-ECF paralogs were related to primary (rpoD), alternative primary, stationary phase (rpoS), flagellin biosynthesis (fliA), and heat shock (rpoH) factors. The number of σ70 genetic determinants among this genome was of 2,86 per Mb. This number is lower than the one of Pseudomonas aeruginosa, a species found in similar habitats including CF lungs. These two bacterial groups showed strikingly different σ70 family architectures, with only three ECF paralogs in common (fecI-like, pvdS and algU). Bcen-J2315 σ70 paralogs showed clade-specific distributions. Some paralogs appeared limited to the ET12 epidemic clone (ecfA2), particular Bcc species (sigI), the Burkholderia genus (ecfJ, ecfF, and sigJ), certain proteobacterial groups (ecfA1, ecfC, ecfD, ecfE, ecfG, ecfL, ecfM and rpoS), or were broadly distributed in the eubacteria (ecfI, ecfK, ecfH, ecfB, and rpoD-, rpoH-, fliA-like genes). Genomic instability of this gene family was driven by chromosomal inversion (ecfA2), recent duplication events (ecfA and RpoD), localized (ecfG) and large scale deletions (sigI, sigJ, ecfC, ecfH, and ecfK), and a phage integration event (ecfE).

Conclusion

The Bcc σ70 gene family was found to be under strong selective pressures that could lead to acquisition/deletion, and duplication events modifying its architecture. Comparative analysis of Bcc and Pseudomonas aeruginosa σ70 gene families revealed distinct evolutionary strategies, with the Bcc having selected several alternative primary factors, something not recorded among P. aeruginosa and only previously reported to occur among the actinobacteria.
Lysis of tubercle bacilli in fresh and stored sputum specimens: implications for diagnosing tuberculosis in stored and paucibacillary specimens by PCR
Authors: Pathak Divya , Chakravorty Soumitesh , Hanif Mahmud , Tyagi Jaya Sivaswami
Published: September 2007

Background

Nucleic acid amplification techniques are being used increasingly in diagnosing tuberculosis. In developing countries clinical samples are often stored for subsequent analysis since molecular tests are conducted at only a limited number of laboratories. This study was conducted to assess the speed at which mycobacteria undergo autolysis and free DNA is detected in the supernatant during low-temperature storage.

Results

Eighty-seven smear positive sputa from tuberculosis patients were analysed immediately and after storage at -20°C. Timelines of 1 and 2 months were selected to assess the maximum extent of DNA loss that occurred during storage. All samples remained PCR- and smear-positive at 1 month and only 1 sample turned negative after 2 months. Bacterial lysis in the specimens was demonstrated by PCR analysis of supernatant fractions; 53% of the freshly analysed samples contained mycobacterial DNA in supernatants. PCR positivity increased significantly during storage (to 69% and 77% after 1 and 2 months of storage, respectively, P < 0.0001). Storage-associated bacterial lysis was accompanied by a decrease in smear grade status in 28 of 87 samples (P < 0.0001 after 2 months of storage) and a significant storage-associated reduction in bacterial numbers in the remaining samples.

Conclusion

We conclude that (i) freshly isolated sputum contains both intact and lysed mycobacteria, (ii) lysis increased during storage and (iii) supernatant fractions routinely discarded during sample processing contain mycobacterial DNA. We propose that supernatant is a valuable sample for PCR for both fresh and stored specimens, particularly those with a low bacterial load in addition to conventional sediment.
A qualitative study of primary care clinicians' views of treating childhood obesity
Authors: Walker Olivia , Strong Mark , Atchinson Rebecca , Saunders Joanna , Abbott Jo
Published: September 2007

Background

The prevalence of childhood obesity is rising and the UK Government have stated a commitment to addressing obesity in general. One method has been to include indicators relating to obesity within the GP pay-for-performance Quality and Outcomes Framework (QOF) contract. This study aimed to explore general practitioners' and practice nurses' views in relation to their role in treating childhood obesity.

Methods

We interviewed eighteen practitioners (twelve GPs and six nurses) who worked in general practices contracting with Rotherham Primary Care Trust. Interviews were face to face and semi structured. The transcribed data were analysed using framework analysis.

Results

GPs and practice nurses felt that their role was to raise the issue of a child's weight, but that ultimately obesity was a social and family problem. Time constraint, lack of training and lack of resources were identified as important barriers to addressing childhood obesity. There was concern that the clinician-patient relationship could be adversely affected by discussing what was often seen as a sensitive topic. GPs and practice nurses felt ill-equipped to tackle childhood obesity given the lack of evidence for effective interventions, and were sceptical that providing diet and exercise advice would have any impact upon a child's weight.

Conclusion

GPs and practice nurses felt that their role in obesity management was centred upon raising the issue of a child's weight, and providing basic diet and exercise advice. Clinicians may find it difficult to make a significant impact on childhood obesity while the evidence base for effective management remains poor. Until the lack of effective interventions is addressed, implementing additional targets (for example through the QOF) may not be effective.
Protocol of a prospective study on the diagnostic value of transcranial duplex scanning of the substantia nigra in patients with parkinsonian symptoms
Authors: Vlaar Annemarie MM , Bouwmans Angela EP , van Kroonenburgh Marinus JPG , Mess Werner H , Tromp Selma C , Wuisman Piet GWM , Kessels Alfons GH , Winogrodzka Ania , Weber Wim EJ
Published: September 2007

Background

Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD.

We have therefore set out to conduct a prospective study testing the diagnostic accuracy of TCD in patients with a parkinsonism of unclear origin.

Methods/Design

We will enrol 250 consecutive patients, who are referred to neurology outpatient clinics of two teaching hospitals, for analysis of clinically unclear parkinsonism. Patients, whose parkinsonism is clearly diagnosable at the first visit, will be excluded from the study. All patients will undergo a TCD of the substantia nigra. As a surrogate gold standard we will use the consensus clinical diagnosis reached by two independent, blinded, movement disorder specialist neurologists after 2 years follow-up. At the time of TCD, patients will also undergo a SPECT scan of the brain.

Discussion

As this prospective trial enrols only patients with an early-stage parkinsonism, it will yield data on the diagnostic accuracy of TCD that is relevant to daily clinical practice: The neurologist needs a diagnostic tool that provides additional information in patients with a clinically indefinable parkinsonian syndrome. The above described observational longitudinal study was designed to explicitly study this aspect in the diagnostic process.

Trial registration

(ITRSCC) NCT00368199
Over-expression of 14-3-3zeta is an early event in oral cancer
Authors: Matta Ajay , Bahadur Sudhir , Duggal Ritu , Gupta Siddhartha D , Ralhan Ranju
Published: September 2007

Background

The functional and clinical significance of 14-3-3 proteins in human cancers remain largely undetermined. Earlier, we have reported differential expression of 14-3-3ζ mRNA in oral squamous cell carcinoma (OSCC) by differential display.

Methods

The clinical relevance of 14-3-3ζ protein in oral tumorigenesis was determined by immunohistochemistry in paraffin embedded sections of oral pre-malignant lesions (OPLs), OSCCs and histologically normal oral tissues and corroborated by Western Blotting. Co-immunoprecipitation assays were carried out to determine its association with NFκB, β-catenin and Bcl-2.

Results

Intense immunostaining of 14-3-3ζ protein was observed in 61/89 (69%) OPLs and 95/120 (79%) OSCCs. Immunohistochemistry showed significant increase in expression of 14-3-3ζ protein from normal mucosa to OPLs to OSCCs (ptrend < 0.001). Significant increase in expression of 14-3-3ζ protein was observed as early as in hyperplasia (p = 0.009), with further elevation in moderate and severe dysplasia, that was sustained in OSCCs. These findings were validated by Western blotting. Using Co-immunoprecipitation, we demonstrated that 14-3-3ζ protein binds to NFκB, β-catenin and Bcl-2, suggesting its involvement in cellular signaling, leading to proliferation of oral cancer cells.

Conclusion

Our findings suggest that over-expression of 14-3-3ζ is an early event in oral tumorigenesis and may have an important role in its development and progression. Thus, 14-3-3ζ may serve as an important molecular target for designing novel therapy for oral cancer.
Identification of MSRA gene on chromosome 8p as a candidate metastasis suppressor for human hepatitis B virus-positive hepatocellular carcinoma
Authors: Lei Ke-Feng , Wang Yan-Fang , Zhu Xiao-Qun , Lu Peng-Cheng , Sun Bing-Sheng , Jia Hu-Liang , Ren Ning , Ye Qing-Hai , Sun Hui-Chuan , Wang Lu , Tang Zhao-You , Qin Lun-Xiu
Published: September 2007

Background

The prognosis of patients with hepatocellular carcinoma (HCC) still remains very dismal, which is mainly due to metastasis. In our previous studies, we found that chromosome 8p deletions might contribute to metastasis of HCC. In this study, we aimed to identify the candidate metastatic suppressor gene on chromosome 8p.

Methods

Oligo-nucleotide microarrays which included 322 genes on human chromosome 8p were constructed to analyze the difference in gene expression profiles between HCC tissues with and without metastasis. The leading differentially expressed genes were identified and selected for further analysis by real-time PCR and Western blotting. Recombinant expression plasmid vectors for each target gene were constructed and transfected into HCC cells and its in vitro effects on proliferation and invasion of HCC cells were also investigated.

Results

Sixteen leading differentially expressed genes were identified from the HCC tissues with metastasis compared with those without metastasis (p < 0.01, q < 16 %). Among of the 10 significantly down-regulated genes in HCC with metastasis, methionine sulfoxide reductase A (MSRA) had the lowest p value and false discovery rate (FDR), and was considered as a potential candidate for metastasis suppressor gene. Real-time PCR and Western blotting confirmed that the mRNA and protein expression levels of MSRA were significantly decreased in HCC with metastasis compared with those without metastasis (p < 0.001), and MSRA mRNA level in HCCLM6 cells (with high metastatic potential) was also much lower than that of other HCC cell lines. Transfection of a recombinant expression plasmid vector and overexpression of MSRA gene could obviously inhibit cell colony formation (4.33 ± 2.92 vs. 9.17 ± 3.38, p = 0.008) and invasion (7.40 ± 1.67 vs. 17.20 ± 2.59, p= 0.0001) of HCCLM6 cell line.

Conclusion

MSRA gene on chromosome 8p might possess metastasis suppressor activity in HCC.
The effect of body weight on altered expression of nuclear receptors and cyclooxygenase-2 in human colorectal cancers
Authors: Delage Barbara , Rullier Anne , Capdepont Maylis , Rullier Eric , Cassand Pierrette
Published: September 2007

Background

Epidemiological studies on risk factors for colorectal cancer (CRC) have mainly focused on diet, and being overweight is now recognized to contribute significantly to CRC risk. Overweight and obesity are defined as an excess of adipose tissue mass and are associated with disorders in lipid metabolism. Peroxisome proliferator-activated receptors (PPARs) and retinoid-activated receptors (RARs and RXRs) are important modulators of lipid metabolism and cellular homeostasis. Alterations in expression and activity of these ligand-activated transcription factors might be involved in obesity-associated diseases, which include CRC. Cyclooxygenase-2 (COX-2) also plays a critical role in lipid metabolism and alterations in COX-2 expression have already been associated with unfavourable clinical outcomes in epithelial tumors. The objective of this study is to examine the hypothesis questioning the relationship between alterations in the expression of nuclear receptors and COX-2 and the weight status among male subjects with CRC.

Method

The mRNA expression of the different nuclear receptor subtypes and of COX-2 was measured in 20 resected samples of CRC and paired non-tumor tissues. The association between expression patterns and weight status defined as a body mass index (BMI) was statistically analyzed.

Results

No changes were observed in PPARγ mRNA expression while the expression of PPARδ, retinoid-activated receptors and COX-2 were significantly increased in cancer tissues compared to normal colon mucosa (P ≤ 0.001). The weight status appeared to be an independent factor, although we detected an increased level of COX-2 expression in the normal mucosa from overweight patients (BMI ≥ 25) compared to subjects with healthy BMI (P = 0.002).

Conclusion

Our findings show that alterations in the pattern of nuclear receptor expression observed in CRC do not appear to be correlated with patient weight status. However, the analysis of COX-2 expression in normal colon mucosa from subjects with a high BMI suggests that COX-2 deregulation might be driven by excess weight during the colon carcinogenesis process.
A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model
Authors: Munoz Lenka , Ranaivo Hantamalala Ralay , Roy Saktimayee M , Hu Wenhui , Craft Jeffrey M , McNamara Laurie K , Chico Laura Wing , Van Eldik Linda J , Watterson D Martin
Published: September 2007

Background

An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38α MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (Aβ) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38α MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes.

Methods

A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model.

Results

A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38α MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits.

Conclusion

The p38α MAPK pathway is quantitatively important in the Aβ-induced production of proinflammatory cytokines in hippocampus, and brain p38α MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.
The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists
Authors: Huang Da Wei , Sherman Brad T , Tan Qina , Collins Jack R , Alvord W Gregory , Roayaei Jean , Stephens Robert , Baseler Michael W , Lane H Clifford , Lempicki Richard A
Published: September 2007

The DAVID Gene Functional Classification Tool http://david.abcc.ncifcrf.gov uses a novel agglomeration algorithm to condense a list of genes or associated biological terms into organized classes of related genes or biology, called biological modules. This organization is accomplished by mining the complex biological co-occurrences found in multiple sources of functional annotation. It is a powerful method to group functionally related genes and terms into a manageable number of biological modules for efficient interpretation of gene lists in a network context.
Variation in the frequency and characteristics of incidental focus on form
Authors: Loewen Shawn
Published: September 2007

Recently there has been a call for an integration of meaning-focused and form-focused instruction in the second language (L2) classroom, in order to promote both learners’ fluency and accuracy. Incidental focus on form, in which linguistic items are focused on briefly within meaning-focused activities, is one way such an integration might occur. The present study investigates 12 ESL classes in Auckland, New Zealand in order to compare the frequency and characteristics of incidental focus on form episodes (FFEs) occurring in these classes. A total of 32 hours of meaning-focused classroom interaction was observed and recorded. Characteristics of the FFEs, such as Type, Linguistic Focus and Source, were coded and analysed. Incidental focus on form was found to occur in all classes; however, the frequency of FFEs as well as the characteristics varied significantly among the classes. Furthermore, the number of FFEs that each student participated in varied considerably. The implications of such variation for both research and teaching are discussed.
The relationship between experience, education and teachers’ use of incidental focus-on-form techniques
Authors: Mackey Alison , Polio Charlene , McDonough Kim
Published: September 2007

This paper reports the findings of an empirical study that explored whether ESL teachers’ use of incidental focus-on-form techniques was influenced by their level of experience. The results showed that experienced ESL teachers used more incidental focus-on-form techniques than inexperienced teachers. A follow-up study investigated whether inexperienced ESL teachers’ awareness and use of incidental focus-on-form techniques could be influenced by education, specifically, their participation in a teacher education workshop. Overall, the studies demonstrate the importance of taking experience and education into account in research on teacher-initiated incidental focus on form.
The effects of explicit feedback on the development of pragmatic proficiency
Authors: Takimoto Masahiro
Published: September 2007

The present study evaluates the relative effectiveness of two types of input-based instruction, structured input instruction (a structured input task only) and structured input instruction with feedback (the structured input task + reactive explicit feedback) for teaching English polite requestive forms, involving 45 Japanese learners of English. Treatment group performance was compared to that of a control group on the pre-tests, post-tests, and follow-up tests: a discourse completion test, a role-play test, a listening judgement test, and an acceptability judgement test. The results of data analysis indicate that the two treatment groups performed better than the control group, and that the explicit reactive feedback was not always indispensable in the structured input task.
Exploring the relationship between characteristics of recasts and learner uptake
Authors: Sheen Younghee
Published: September 2007

This study presents a taxonomy of the recasts that arose in communicative ESL and EFL classrooms. The taxonomy is used to examine the relationship between different characteristics of recasts and learner uptake/repair. Characteristics that were significantly related to uptake were the length of recasts (short vs. long), the linguistic focus (pronunciation vs. grammar), the type of change (substitution vs. addition). Also, these features - along with mode (declarative vs. interrogative), the use of reduction (partial recasts) and the number of changes (one vs. multiple) - were associated with learner repair. These results are discussed in terms of a general distinction between implicit and explicit recasts and the extent to which recasts are salient to learners linguistically and pragmatically. The study suggests that explicit recasts lead to more uptake/repair because they are focused on a single linguistic feature and the reformulated item is salient to learners.
Researching and experiencing motivation: a plea for ‘balanced research’
Authors: Li Na
Published: September 2007

Intrigued by van Lier’s call for ‘balanced teaching’, I come up with a proposal of ‘balanced research’. In this paper, I describe my personal involvement in a four-month teaching/data-gathering experience (as a part of my doctoral research project on task motivation) which shows that it both necessitates and ends up involving such a ‘balanced’ approach. Meanwhile, ‘Exploratory Practice’, as a set of general principles for practitioner research, offers great support for my joint teacher/researcher enterprise as well.
Sex hormones and mental health
Authors: Golightly Louise , Young Allan
Published: September 2007

Hormones are widely considered to cause powerful psychological effects and because of this psychiatrists may be asked to advise general practitioners, consultants in other specialities or patients about the relationship between hormones (including sex hormones) and psychiatric disorder. Sex hormones may be relevant to psychiatry in three ways:

(a) Sex hormones may play a role in the pathophysiology of psychiatric disorders.

(b) These agents may be utilised for treatment of psychiatric disorder.

(c) Administration of sex hormones may cause psychiatric side-effects.
The Nature and Nurture of Common Autoimmunity
Authors: CASTIBLANCO JOHN , ANAYA JUAN‐MANUEL
Published: September 2007

Abstract:  Autoimmune diseases are a heterogeneous group of disorders where multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Although their heterogeneity is due to a collection of diverse conditions based on epidemiology, pathology, or diagnostic criteria, the underlying immunogenetic mechanism might be similar. Herein the nature and nurture of autoimmune diseases considered as a trait are reviewed, and a discussion is given on their multifactorial characteristics.
Immune Complex Pathophysiology
Authors: NYDEGGER URS E.
Published: September 2007

Abstract:  Antigen–antibody (Ab) interactions that lead to the formation of immune complexes (ICs) are subtle biochemical processes determining health or disease according to the outcome. Good laboratory practice (GLP)‐acknowledged IC detection methods reveal that plasma levels of up to 15 μg/mL heat‐aggregated immunoglobulin G (IgG) equivalents are normal, indicating the physiological role of ICs. Among the major variables that influence the equilibrium association constant Ka, are specificity and epitope density of the antigen, Ig class/subclass of the Ab, IC complement (C)‐activating capacity, Fc receptor (FcR) interaction, and cytokine activation pattern. The Ka of antigen–Ab binding at ∼20°C ranges from low affinity (105) to high affinity (107–1011). Beneficial ICs serve to remove and/or neutralize infectious or toxic antigens, following an infectious attack in immune and vaccinated hosts. Circulating ICs are more prone for benefit than tissue‐bound ICs, which reflect in situ formation and/or undesired deposition in tissues due to overflow from insufficient reticuloendothelial system (RES) removal. The classical textbook topic on ICs still holds true but is under revision because of the improved knowledge of effector systems, such as C, cytokine, and FcR apparatus. Therapeutic options to treat IC‐associated diseases include intravenous immunoglobulins (IVIG) at their onset and monoclonal antibodies (mAb) directed at C activation products and/or cytokines.
Immunodeficiency and Autoimmune Phenomena in Female Hyper‐IgM Syndrome
Authors: MELEGARI ALESSANDRA , MASCIA MARIA TERESA , SANDRI GILDA , CARBONIERI ANNA
Published: September 2007

Abstract:  We report an unusual case that highlights the clinical problems associated with autoimmune phenomena. A female (born 1972) was referred to our hospital with systemic lupus erythematosus (SLE) diagnosis. During the follow‐up (7 years), we observed the appearance and the disappearance of a lot of autoantibodies detected. The history of recurrent bacterial sinopulmonary infections since puberty and enlargement of lymphonodes, elevated IgM, very low IgA and normal IgG levels, and the variable autoantibody profile oriented toward a “defective Ig class switch recombination” disorder: the hyper‐IgM syndrome. Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual and sometimes the differential diagnosis is difficult.
Veterinary Autoimmunity
Authors: GERSHWIN LAUREL J.
Published: September 2007

Abstract:  The first spontaneous animal model of autoimmunity was the New Zealand black mouse, discovered in 1959. Interestingly, although several models of induced autoimmunity were demonstrated in a variety of rodents, the recognition of autoimmune disease in dogs came somewhat later. Dog breeding and selection of traits within certain dog breeds have become an important enterprise with intensive husbandry and selection criteria being applied to each breed standard. This has resulted in breeding for specific phenotypic characteristics. This selection has inadvertently led to the propagation of a number of autoimmune diseases in dogs. For example, systemic lupus erythematosus (SLE), autoimmune hemolytic anemia and thrombocytopenia, autoimmune myasthenia gravis, and diabetes mellitus are now fairly common. In the final analysis, the appearance of autoimmunity in dogs reflects their breeding selection and illustrates the importance of genetics in the development of autoimmune disease.
Prediction and Prevention of Autoimmune Disease
Authors: ROSE NOEL R.
Published: September 2007

Abstract:  Biomarkers, represented by genetically determined traits or biologic changes predictive of disease onset or outcome, are increasingly employed by academic and industrial investigators. They can identify unusually susceptible populations or individuals, facilitate prognosis, forecast the outcome of therapy in clinical trials, or aid in developing improved treatments or preventative measures. All of these applications have been applied to the autoimmune diseases. As a case in point, we have through the years used biomarkers to predict susceptibility and the longer‐range outcome of thyroid autoimmunity employing, a number of different approaches. They have taught us valuable lessons for future broader applications of biomarkers. The clues for susceptibility include major histocompatibility complex (MHC) and non‐MHC genes combined with the fine specificity of thyroid autoantibodies in siblings of patients with juvenile thyroid disease. Together these biomarkers are highly predictive of later thyroid autoimmunity and subclinical thyroid dysfunction. For example, the progression from benign autoimmunity to clinical thyroid disease is marked by the appearance of autoantibodies to species‐restricted epitopes on thyroglobulin. Thus, predictive biomarkers aid in identifying individuals with inordinate risk of disease and provide opportunities for earlier interventions to arrest the disease process.
Two‐Step Mechanism of Virus‐induced Autoimmune Hemolytic Anemia
Authors: COUTELIER JEAN‐PAUL , DETALLE LAURENT , MUSAJI ANDREI , MEITE MORY , IZUI SHOZO
Published: September 2007

Abstract:  Viruses are associated with the development of autoantibody‐mediated blood autoimmune diseases. A two‐step mechanism could explain virus involvement in the development of experimental hemolytic anemia. Immunization of normal mice with rat erythrocytes results in an autoantibody production that could be enhanced by viral infection, without erythrocyte destruction. Inoculation of the same virus when autoantibodies are at high levels triggers clinical anemia. This results from macrophage activation by gamma‐interferon, leading to exacerbated erythrophagocytosis. Thus the development of anemia during the course of viral infection may require two independent stimuli, in which the first triggers autoantibody production and the second enhances the pathogenicity of these autoantibodies.
Autoimmune Diseases Are Connected with Disturbances in Cytokine Synthesis, and Therapy with IFN‐γ Blockers Is Their Main Pathogenetic Treatment
Authors: SKURKOVICH BORIS , SKURKOVICH SIMON
Published: September 2007

Abstract:  Development of autoimmune process in the organism is mainly due to disturbances in cytokine production. Hyperproduction of cytokines can be induced by certain viruses, bacteria, genetic factors, and other triggers. Cytokines act in an interrelated immune cascade with interferon‐γ (IFN‐γ) playing a central role. Blocking IFN‐γ is the safest and most effective method of treatment of TH1‐mediated autoimmune diseases, although blocking other cytokines in the cascade may lead to some therapeutic effect as well. Disturbances in the synthesis of IFN‐γ and, possibly, IFN‐α may lead to autoantigen formation. Antibodies to IFN‐γ have shown very pronounced therapeutic effect in multiple autoimmune conditions, especially in autoimmune skin diseases. Anticytokine therapy that we have pioneered may be the main pathogenetic method of treatment of a variety of autoimmune conditions.
Comparison of Two ELISA Assays for Anti‐Sp100 Determination
Authors: MANUEL LUCENA JOSÉ , MONTES CANO MARCOS , LUIS CARO JOSÉ , RESPALDIZA NIEVES , ALVAREZ ANTONIA , SÁNCHEZ‐ROMÁN JULIO , NÚÑEZ‐ROLDÁN ANTONIO , WICHMANN INGEBORG
Published: September 2007

Abstract:  Antibodies to Sp100 have been described not only in primary biliary cirrhosis (PBC), but also in other diseases. Two assays for detection of Sp100 levels by enzyme‐linked immunosorbent assay (ELISA) have been compared in a cohort of patients from our area: (a) Sp100 kit produced by IMTEC, Immunodiagnostica GmbH, and (b) Quanta Lite Sp100 kit produced by INOVA Diagnostics. We analyze here the correlation between the two assays and compare their efficiency in diagnosing PBC. We also comment on the exceptions derived from reactivity with other diseases. We studied 78 sera by IIF with the typical multiple nuclear dots (MND) pattern from patients who suffered from PBC, hepatopathies different from PBC, systemic lupus erythematosus (SLE), other connective tissue diseases (CTD), skeletal diseases, lung diseases, hematological disorders, a miscellaneous group, and a healthy IIF negative control group. The tests work equally well despite their different quantification system: (a) it is based on a standard curve; and (b) it is based on a single‐point antigen‐specific calibration. Some discrepancies could be explained by differences in the immunodominant epitope used in the ELISA. The main finding of this study is that the presence of MND/Sp100‐positive antibodies were detected not only in hepatic diseases, mainly PBC, but also in other clinical conditions, confirmed by both tests. Diagnosis of PBC must be established in the right clinical context, because other diseases recognizing the same epitope, mainly SLE, may also show high Sp100 levels. Sera from PBC patients with antimitochondrial antibodies (AMA) showed higher anti‐Sp100 than the AMA‐negative group.
The Effect of Open Heart Surgery on Tuberculin Skin Test Reactivity
Authors: STEIN MICHAL , SELA‐RAZON BATIA , LINDER ILAN , SOMEKH ELI
Published: September 2007

Abstract:  To examine whether treatment with cardiopulmonary bypass (CPB), which causes transient cellular immunity depression, influences tuberculin skin testing (TST) interpretation. The study was also aimed to assess the degree of cellular immunity depression following open heart surgery. Fifteen children from developing countries with latent tuberculosis (TST ≥10 mm), undergoing open heart surgery had their TST repeated within 48–72 h following surgery. We compared the size of skin test induration before and after surgery and the relation of postsurgery skin induration to time on CPB (pump time). There was no significant difference in the size of induration before and after surgery (mean: 14.7 mm versus 13 mm, respectively). Pump time ranged from 38 to 204 min (mean: 110 min). Two of the children had pump time over 3 h. The TST of both of them turned negative after surgery, as opposed to all other children (P= 0.01). Most patients retained skin test reactivity. Only patients with pump time longer than 3 h had a negative TST.
ENA Screen Chemiluminescence Immunoassay
Authors: SIGNORINI S. , KUTSCHERA I. , CAPUANO F. , LATTUADA L.
Published: September 2007

Abstract:  Recently, autoimmunity, due to an increase in examination requests, has become an independent area of laboratory research, which needs management optimization in terms of quality, time, and flexibility. Therefore, we have evaluated the screening of extractable nuclear antigens (ENA) antibodies both with a chemiluminescence immunoassay and the enzyme‐linked immunosorbent assay (ELISA) method, which was used in our laboratory, as a reference kit. The most important difference between these two methods is the possibility of processing serum samples with a random access system, which is different from batch methods.
Evaluation of the BioPlex 2200 ANA Screen for the Detection of Antinuclear Antibodies and Comparison with Conventional Methods
Authors: DESPLAT‐JEGO SOPHIE , BARDIN NATHALIE , LARIDA BRUNO , SANMARCO MARIELLE
Published: September 2007

Abstract:  BioPlex 2200 multiplexed assays system is an automatic method allowing detection of antinuclear antibodies (ANA). The aim of our study was to evaluate the determination of 13 autoantibodies against chromatinic and nonchromatinic nuclear antigens by the BioPlex 2200 system and to compare the results achieved by this method to those obtained with our routinely used immunoassays. One thousand and four serum samples consecutively sent for ANA detection were routinely tested by indirect immunofluorescence (IIF) on HEp2 cells. Among them, 321 were also analyzed by dsDNA enzyme immunoassay (EliA) test and 657 by double immunodiffusion (DID) for extractable nuclear antigen (ENA) antibodies. All the sera were evaluated by the BioPlex 2200 ANA screen kit allowing simultaneous detection of antibodies against the following antigens: dsDNA, chromatin, SSA‐52 kDa, SSA‐60 kDa, SSB, Sm, Sm/RNP, RNP‐A, RNP‐68 kDa, Scl70, centromere B, Jo‐1, and P ribosomal proteins. The kappa coefficient between BioPlex 2200 and routine tests for detection of ANA on HEp2 cells, anti‐dsDNA, and anti‐ENA antibodies was, respectively, 0.31, 0.66, and 0.61. The comparison with our routine tests showed numerous discrepancies between IIF ANA screening and BioPlex but a good concordance for detection of anti‐dsDNA and anti‐ENA specificities. BioPlex 2200 system is a rapid and sensitive method for simultaneous quantitative detection of several autoantibodies. It is perfectly well adapted to determine ANA antigenic specificities of samples found positive using initial IIF screening. The capability of this multiplexed technology to analyze simultaneously 13 ANA autoantibodies leads to the rapid availability of an “autoimmune connective tissue disease serologic profile.”
Redox‐Reactive Autoantibodies in Cerebrospinal Fluids
Authors: McINTYRE JOHN A. , HAMILTON RONALD L. , DeKOSKY STEVEN T.
Published: September 2007

Abstract:  The oxidative stress associated with increased transitional metal concentrations in neurodegenerative diseases served as the impetus for our testing the status of redox‐reactive autoantibodies in the cerebrospinal fluids from autopsy‐confirmed Alzheimer's patients. Here we describe a novel family of autoantibodies capable of recognizing autoantigens subsequent to in vitro oxidation‐reduction (redox) reactions in the blood and spinal fluids of all normal individuals tested. Redox autoantibodies are not detected in conventional immunoassays, thereby differentiating them from natural and hidden autoantibodies described by others. Whereas blood‐borne redox autoantibodies can be IgG, IgM, and/or IgA, in spinal fluid the antibody isotype is limited to IgG. Autoantibodies in certain patients are reversible and disappear when exposed to oxidizing agents in vitro. One mechanism proposed to modulate the autoantibody unmasking–masking reactions relies upon redox‐driven nitrosylation of an amino acid‐containing aromatic ring, which is found within the complementarity‐determining regions (CDR) of the antibodies' antigen‐binding sites. The evolutionary persistence of this novel autoantibody family indicates that they are important for immunological homeostasis and suggests that they perform necessary physiological functions. The dramatic difference in the presence of such antibodies in normal versus Alzheimer's disease (AD) suggests an important immune system dysfunction in AD.
Automatic Analysis of Immunofluorescence Patterns of HEp‐2 Cells
Authors: HIEMANN RICO , HILGER NADJA , MICHEL JÖRG , NITSCHKE JÖRG , BÖHM ALEXANDER , ANDERER URSULA , WEIGERT MARTIN , SACK ULRICH
Published: September 2007

Abstract:  The standard screening test for the recognition of autoimmune diseases is the proof of autoantibodies in serum of patients by indirect immunofluorescence (IIF) based on HEp‐2 cells. Manual evaluation of this test is very subjective, slow, and there are no objective parameters as guidelines available. Interlaboratory tests showed occasionally large deviations in the test evaluation resulting in a high variance of results. The aim of this project is fast, objective, safe, and economical automatic analysis of HEp‐2 IIF patterns. Images of IIF patterns were completely and automatically captured using an inverse motorized fluorescence microscope. Thereby, device‐specific parameters were controlled automatically, too. For fast analysis of IIF patterns new algorithms of image processing were developed. Artifacts were recognized and excluded from analysis by the developed software. Analysis of more than 80,000 images clearly demonstrated full automatization and fast processing of IIF patterns. Additionally serum‐specific fluorescence could be easily distinguished from background. Even very weak but positive patterns can be recognized and used for diagnosis. A detailed separation into different basic patterns is possible. Objective, fast, and disease‐related economical analysis of HEp‐2 immunofluorescence patterns is feasible. The implemented software algorithms allowed a mathematical way of describing IIF patterns and can therefore be a useful tool for the needed standardization process.
Clinical Significance of Anti‐Histidyl‐tRNA Synthetase (Jo1) Autoantibodies
Authors: GOMARD‐MENNESSON EMELINE , FABIEN NICOLE , CORDIER JEAN‐FRANCOIS , NINET JACQUES , TEBIB JACQUES , ROUSSET HUGUES
Published: September 2007

Abstract:  The clinical significance of a discovery of anti‐histidyl‐tRNA synthetase (Jo1) autoantibodies patients was established in the early diagnosis of antisynthetase syndrome (ASS) as the common form of this pathology is characterized by interstitial lung disease (ILD), inflammatory muscle disease, and production of anti‐Jo1 autoantibodies. However, the specificity of such autoantibodies has to be evaluated in daily clinical practice. In this study, the clinical and prognostic profiles of 45 patients displaying anti‐Jo1 autoantibodies were determined. Among 36 patients with a titer of anti‐Jo1 autoantibodies above the cutoff value suggested by the manufacturer (40 AU/mL), three different groups were identified. The first group (n= 26) suffered from a complete or incomplete ASS and showed anti‐Jo1 autoantibodies mostly above 60 AU/mL. A second group (n= 7) suffered from another autoimmune disease, that is, a systemic lupus erythematosus, cutaneous lupus and rheumatoid arthritis, and Crohn's disease with anti‐Jo1 autoantibodies mostly below 60 AU/mL. The third group (n= 3) did not suffer from any autoimmune disease and presented anti‐Jo1 autoantibodies below 60 AU/mL. The nine doubtful cases (titer of anti‐Jo1 autoantibodies of 30–39 AU/mL) were from patients with no ASS nor myositis. Only 27 out of 45 patients showed antinuclear antibodies with 15 sera showing a pattern characteristic of anti‐Jo1 autoantibodies by indirect immunofluorescence on HEp2 cells. In conclusion, this study underlines the need to search for anti‐Jo1 autoantibodies even if antinuclear antibodies are negative by indirect immunofluorescence and underlines the usefulness of anti‐Jo1 antibodies of titer above 60 AU/mL in the diagnosis of complete or incomplete ASS.