bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequencing of the tumor necrosis factor-alpha gene promoter
Authors: Fonseca João Eurico , Cavaleiro João , Teles José , Sousa Elsa , Andreozzi Valeska L , Antunes Marília , Amaral-Turkman Maria A , Canhão Helena , Mourão Ana F , Lopes Joana , Caetano-Lopes Joana , Weinmann Pamela , Sobral Marta , Nero Patrícia , Saavedra Maria J , Malcata Armando , Cruz Margarida , Melo Rui , Braña Araceli , Miranda Luis , Patto José V , Barcelos Anabela , da Silva José Canas , Santos Luís M , Figueiredo Guilherme , Rodrigues Mário , Jesus Herberto , Quintal Alberto , Carvalho Teresa , da Silva José A Pereira , Branco Jaime , Queiroz Mário Viana
Published: April 2007

The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-α) promoter genotype/haplotype markers. Each patient's disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-α gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-α promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.
Receptor for advanced glycation end products Glycine 82 Serine polymorphism and risk of cardiovascular events in rheumatoid arthritis
Authors: Carroll Lisa , Frazer Ian H , Turner Malcolm , Marwick Thomas H , Thomas Ranjeny
Published: April 2007

Patients with rheumatoid arthritis (RA) are at risk of excess mortality, predominantly owing to cardiovascular (CV) events. The receptor for advanced glycation end products (RAGE) has been implicated in the perpetuation of the chronic inflammatory response in vascular disease. A Gly82→Ser polymorphism in the RAGE gene, which is associated with enhanced RAGE signaling, is present more frequently in patients with RA than the general population. To investigate whether RAGE Gly82→Ser polymorphism is associated with CV events in RA, we examined CV events, CV risk factors, features of RA and RAGE Gly82→Ser polymorphism in 232 patients with RA attending a tertiary referral hospital. CV events, the duration and severity of RA, and risk factors for CV disease were determined using patient questionnaires, chart review, laboratory analysis and radiographs. DNA was typed for HLA–DRB1 genes and RAGE Gly82→Ser polymorphism. The RAGE Ser82 allele, which is in linkage disequilibrium with the RA susceptibility allele HLA–DRB1*0401, was carried by 20% of patients. More than 20% of the cohort had suffered a vascular event; a shorter duration of RA, but not the RAGE genotype, was significantly associated with CV events. However, a history of statin use was protective. Thus, the RAGE Ser82 allele, associated with enhanced RAGE signaling, does not predispose to CV events in RA. However, treatment of hyperlipidemia with statins reduces the probability of a CV event.
The interferon induced with helicase domain 1 A946T polymorphism is not associated with rheumatoid arthritis
Authors: Marinou Ioanna , Montgomery Douglas S , Dickson Marion C , Binks Michael H , Moore David J , Bax Deborah E , Wilson Anthony G
Published: April 2007

An important feature of autoimmune diseases is the overlap of pathophysiological characteristics. Clustering of autoimmune diseases in families suggests that genetic variants may contribute to autoimmunity. The aim of the present study was to investigate the role of the interferon induced with helicase domain 1 (IFIH1) A946T (rs1990760 A>G) variant in rheumatoid arthritis (RA), as this was recently associated with susceptibility to type 1 diabetes. A total of 965 Caucasians with RA and 988 healthy controls were genotyped for IFIH1 A946T. Gene expression of IFIH1 was measured in peripheral blood leukocytes using real-time PCR. Genotypes were equally distributed in both RA cases and healthy controls (odds ratio for allele C = 0.9, 95% confidence interval = 0.8–1.0, P = 0.3). No association was detected after stratification by sex, age at onset, rheumatoid factor status, anti-cyclic citrullinated peptide status or radiological joint damage. Levels of IFIH1 mRNA were approximately twofold higher in blood leucocytes of RA cases compared with healthy controls (P < 0.0001). These results indicate that the IFIH1 is upregulated in RA but that the A946T variant does not contribute significantly to the genetic background of RA.
Treatment of posttraumatic and focal osteoarthritic cartilage defects of the knee with autologous polymer-based three-dimensional chondrocyte grafts: 2-year clinical results
Authors: Ossendorf Christian , Kaps Christian , Kreuz Peter C , Burmester Gerd R , Sittinger Michael , Erggelet Christoph
Published: April 2007

Autologous chondrocyte implantation (ACI) is an effective clinical procedure for the regeneration of articular cartilage defects. BioSeed®-C is a second-generation ACI tissue engineering cartilage graft that is based on autologous chondrocytes embedded in a three-dimensional bioresorbable two-component gel-polymer scaffold. In the present prospective study, we evaluated the short-term to mid-term efficacy of BioSeed-C for the arthrotomic and arthroscopic treatment of posttraumatic and degenerative cartilage defects in a group of patients suffering from chronic posttraumatic and/or degenerative cartilage lesions of the knee. Clinical outcome was assessed in 40 patients with a 2-year clinical follow-up before implantation and at 3, 6, 12, and 24 months after implantation by using the modified Cincinnati Knee Rating System, the Lysholm score, the Knee injury and Osteoarthritis Outcome Score, and the current health assessment form (SF-36) of the International Knee Documentation Committee, as well as histological analysis of second-look biopsies. Significant improvement (p < 0.05) in the evaluated scores was observed at 1 and/or 2 years after implantation of BioSeed-C, and histological staining of the biopsies showed good integration of the graft and formation of a cartilaginous repair tissue. The Knee injury and Osteoarthritis Outcome Score showed significant improvement in the subclasses pain, other symptoms, and knee-related quality of life 2 years after implantation of BioSeed-C in focal osteoarthritic defects. The results suggest that implanting BioSeed-C is an effective treatment option for the regeneration of posttraumatic and/or osteoarthritic defects of the knee.
Increased serum levels of macrophage migration inhibitory factor in patients with primary Sjögren's syndrome
Authors: Willeke Peter , Gaubitz Markus , Schotte Heiko , Maaser Christian , Domschke Wolfram , Schlüter Bernhard , Becker Heidemarie
Published: April 2007

The objective of this study was to analyse levels of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) in patients with primary Sjögren's syndrome (pSS) and to examine associations of MIF with clinical, serological and immunological variables. MIF was determined by ELISA in the sera of 76 patients with pSS. Further relevant cytokines (IL-1, IL-6, IL-10, IFN-γ and TNF-α) secreted by peripheral blood mononuclear cells (PBMC) were determined by ELISPOT assay. Lymphocytes and monocytes were examined flow-cytometrically for the expression of activation markers. Results were correlated with clinical and laboratory findings as well as with the HLA-DR genotype. Healthy age- and sex-matched volunteers served as controls. We found that MIF was increased in patients with pSS compared with healthy controls (p < 0.01). In particular, increased levels of MIF were associated with hypergammaglobulinemia. Further, we found a negative correlation of MIF levels with the number of IL-10-secreting PBMC in pSS patients (r = -0.389, p < 0.01). Our data indicate that MIF might participate in the pathogenesis of primary Sjögren's syndrome. MIF may contribute to B-cell hyperactivity indicated by hypergammaglobulinemia. The inverse relationship of IL-10 and MIF suggests that IL-10 works as an antagonist of MIF in pSS.
Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study
Authors: Broeks Annegien , Braaf Linde M , Huseinovic Angelina , Nooijen Anke , Urbanus Jos , Hogervorst Frans BL , Schmidt Marjanka K , Klijn Jan GM , Russell Nicola S , Van Leeuwen Flora E , Van 't Veer Laura J
Published: April 2007

Introduction

Radiation exposure at a young age is one of the strongest risk factors for breast cancer. Germline mutations in genes involved in the DNA-damage repair pathway (DDRP) may render women more susceptible to radiation-induced breast cancer.

Methods

We evaluated the contribution of germline mutations in the DDRP genes BRCA1, BRCA2, CHEK2 and ATM to the risk of radiation-induced contralateral breast cancer (CBC). The germline mutation frequency was assessed, in a case-only study, in women who developed a CBC after they had a first breast cancer diagnosed before the age of 50 years, and who were (n = 169) or were not (n = 78) treated with radiotherapy for their first breast tumour.

Results

We identified 27 BRCA1, 5 BRCA2, 15 CHEK2 and 4 truncating ATM germline mutation carriers among all CBC patients tested (21%). The mutation frequency was 24.3% among CBC patients with a history of radiotherapy, and 12.8% among patients not irradiated for the first breast tumour (odds ratio 2.18 (95% confidence interval 1.03 to 4.62); p = 0.043). The association between DDRP germline mutation carriers and risk of radiation-induced CBC seemed to be strongest in women who developed their second primary breast tumour at least 5 years after radiotherapy. Those patients had an odds ratio of 2.51 (95% confidence interval 1.03 to 6.10; p = 0.049) of developing radiation-induced breast cancer, in comparison with non-carriers.

Conclusion

This study shows that carriers of germline mutations in a DDRP gene have an increased risk of developing (contralateral) breast cancer after radiotherapy; that is, over and above the risk associated with their carrier status. The increased risk indicates that knowledge of germline status of these DDRP genes at the time of breast cancer diagnosis may have important implications for the choice of treatment.
Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk
Authors: Baynes Caroline , Healey Catherine S , Pooley Karen A , Scollen Serena , Luben Robert N , Thompson Deborah J , Pharoah Paul DP , Easton Douglas F , Ponder Bruce AJ , Dunning Alison M ,   the SEARCH breast cancer study
Published: April 2007

Introduction

Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk.

Methods

We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene.

Results

No significant breast cancer associations were detected with any individual or combination of tag SNPs.

Conclusion

It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.
Effects of epinephrine and vasopressin on end-tidal carbon dioxide tension and mean arterial blood pressure in out-of-hospital cardiopulmonary resuscitation: an observational study
Authors: Mally Stefan , Jelatancev Alina , Grmec Stefek
Published: April 2007

Introduction

Clinical data considering vasopressin as an equivalent option to epinephrine in cardiopulmonary resuscitation (CPR) are limited. The aim of this prehospital study was to assess whether the use of vasopressin during CPR contributes to higher end-tidal carbon dioxide and mean arterial blood pressure (MAP) levels and thus improves the survival rate and neurological outcome.

Methods

Two treatment groups of resuscitated patients in cardiac arrest were compared: in the epinephrine group, patients received 1 mg of epinephrine intravenously every three minutes only; in the vasopressin/epinephrine group, patients received 40 units of arginine vasopressin intravenously only or followed by 1 mg of epinephrine every three minutes during CPR. Values of end-tidal carbon dioxide and MAP were recorded, and data were collected according to the Utstein style.

Results

Five hundred and ninety-eight patients were included with no significant demographic or clinical differences between compared groups. Final end-tidal carbon dioxide values and average values of MAP in patients with restoration of pulse were significantly higher in the vasopressin/epinephrine group (p < 0.01). Initial (odds ratio [OR]: 18.65), average (OR: 2.86), and final (OR: 2.26) end-tidal carbon dioxide values as well as MAP at admission to the hospital (OR: 1.79) were associated with survival at 24 hours. Initial (OR: 1.61), average (OR: 1.47), and final (OR: 2.67) end-tidal carbon dioxide values as well as MAP (OR: 1.39) were associated with improved hospital discharge. In the vasopressin group, significantly more pulse restorations and a better rate of survival at 24 hours were observed (p < 0.05). Subgroup analysis of patients with initial asystole revealed a higher hospital discharge rate when vasopressin was used (p = 0.04). Neurological outcome in discharged patients was better in the vasopressin group (p = 0.04).

Conclusion

End-tidal carbon dioxide and MAP are strong prognostic factors for the outcome of out-of-hospital cardiac arrest. Resuscitated patients treated with vasopressin alone or followed by epinephrine have higher average and final end-tidal carbon dioxide values as well as a higher MAP on admission to the hospital than patients treated with epinephrine only. This combination vasopressor therapy improves restoration of spontaneous circulation, short-term survival, and neurological outcome. In the subgroup of patients with initial asystole, it improves the hospital discharge rate.
Cortisol levels in cerebrospinal fluid correlate with severity and bacterial origin of meningitis
Authors: Holub Michal , Beran Ondřej , Džupová Olga , Hnyková Jarmila , Lacinová Zdenka , Příhodová Jana , Procházka Bohumír , Helcl Miroslav
Published: April 2007

Introduction

Outcomes following bacterial meningitis are significantly improved by adjunctive treatment with corticosteroids. However, little is known about the levels and significance of intrathecal endogenous cortisol. The aim of this study was to assess cortisol as a biological and diagnostic marker in patients with bacterial meningitis.

Methods

Forty-seven consecutive patients with bacterial meningitis and no prior treatment were evaluated. For comparison, a group of 37 patients with aseptic meningitis and a group of 13 healthy control individuals were included.

Results

The mean age of the bacterial meningitis patients was 42 years, and the mean Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation II, and Sequential Organ Failure Assessment scores on admission were 12, 13 and 4, respectively. Altogether, 40 patients (85%) were admitted to the intensive care unit, with a median (interquartile range) length of stay of 8 (4 to 15) days. A bacterial etiology was confirmed in 35 patients (74%). The median (interquartile range) cortisol concentration in cerebrospinal fluid (CSF) was 133 (59 to 278) nmol/l. CSF cortisol concentrations were positively correlated with serum cortisol levels (r = 0.587, P < 0.001). Furthermore, CSF cortisol levels correlated with Acute Physiology and Chronic Health Evaluation II score (r = 0.763, P < 0.001), Sequential Organ Failure Assessment score (r = 0.650, P < 0.001), Glasgow Coma Scale score (r = -0.547, P < 0.001) and CSF lactate levels (r = 0.734, P < 0.001). CSF cortisol was only weakly associated with intrathecal levels of IL-6 (r = 0.331, P = 0.02) and IL-8 (r = 0.296, P < 0.05). CSF cortisol levels in bacterial and aseptic meningitis significantly differed (P < 0.001). The CSF cortisol concentration of 46.1 nmol/l was found to be the optimal cutoff value for diagnosis of bacterial meningitis.

Conclusion

CSF cortisol levels in patients with bacterial meningitis are highly elevated and correlate with disease severity. Moreover, our findings also suggest that intrathecal cortisol may serve as a valuable marker in discriminating between bacterial and aseptic meningitis.
The concentration of oxygen, lactate and glucose in the central veins, right heart, and pulmonary artery: a study in patients with pulmonary hypertension
Authors: Gutierrez Guillermo , Venbrux Anthony , Ignacio Elizabeth , Reiner Jonathan , Chawla Lakhmir , Desai Anish
Published: April 2007

Introduction

Decreases in oxygen saturation (SO2) and lactate concentration [Lac] from superior vena cava (SVC) to pulmonary artery have been reported. These gradients (ΔSO2 and Δ[Lac]) are probably created by diluting SVC blood with blood of lower SO2 and [Lac]. We tested the hypothesis that ΔSO2 and Δ[Lac] result from mixing SVC and inferior vena cava (IVC) blood streams.

Methods

This was a prospective, sequential, observational study of hemodynamically stable individuals with pulmonary artery hypertension (n = 9) who were about to undergo right heart catheterization. Catheters were advanced under fluoroscopic guidance into the IVC, SVC, right atrium, right ventricle, and pulmonary artery. Samples were obtained at each site and analyzed for SO2, [Lac], and glucose concentration ([Glu]). Analysis of variance with Tukey HSD test was used to compare metabolite concentrations at each site.

Results

There were no differences in SO2 or [Lac] between IVC and SVC, both being greater than their respective pulmonary artery measurements (P < 0.01 for SO2 and P < 0.05 for [Lac]). SO2 and [Lac] in right atrium, right ventricle, and pulmonary artery were similar. ΔSO2 was 4.4 ± 1.4% (mean ± standard deviation) and Δ[Lac] was 0.16 ± 0.11 mmol/l (both > 0; P < 0.001). Δ[Glu] was -0.19 ± 0.31 mmol/l, which was not significantly different from zero, with SVC [Glu] being less than IVC [Glu].

Conclusion

Mixing of SVC with IVC blood does not account for the development of ΔSO2 and Δ[Lac] in hemodynamically stable individuals with pulmonary artery hypertension. An alternate mechanism is mixing with coronary sinus blood, implying that ΔSO2 and Δ[Lac] may reflect changes in coronary sinus SO2 and [Lac] in this patient population.
Premortem clinical diagnoses and postmortem autopsy findings: discrepancies in critically ill cancer patients
Authors: Pastores Stephen M , Dulu Alina , Voigt Louis , Raoof Nina , Alicea Margarita , Halpern Neil A
Published: April 2007

Introduction

Limited data are available regarding the relationship of premortem clinical diagnoses and postmortem autopsy findings in cancer patients who die in an oncologic intensive care unit (ICU). The purposes of this study were to compare the premortem clinical and postmortem diagnoses of cancer patients who died in the ICU and to analyze any discrepancies between them.

Methods

This is a retrospective review of medical records and autopsy reports of all cancer patients who died in a medical-surgical ICU and had an autopsy performed between 1 January 1999 and 30 September 2005 at a tertiary care cancer center. Premortem clinical diagnoses were compared with the postmortem findings. Major missed diagnoses were identified and classified, according to the Goldman criteria, into class I and class II discrepancies.

Results

Of 658 deaths in the ICU during the study period, 86 (13%) autopsies were performed. Of the 86 patients, 22 (26%) had 25 major missed diagnoses, 12 (54%) patients had class I discrepancies, 7 (32%) had class II discrepancies, and 3 (14%) had both class I and class II discrepancies. Class I discrepancies were due to opportunistic infections (67%) and cardiac complications (33%), whereas class II discrepancies were due to cardiopulmonary complications (70%) and opportunistic infections (30%).

Conclusion

There was a discrepancy rate of 26% between premortem clinical diagnoses and postmortem findings in cancer patients who died in a medical-surgical ICU at a tertiary care cancer center. Our findings underscore the need for enhanced surveillance, monitoring, and treatment of infections and cardiopulmonary disorders in critically ill cancer patients.
Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis
Authors: Bozza Fernando A , Salluh Jorge I , Japiassu André M , Soares Marcio , Assis Edson F , Gomes Rachel N , Bozza Marcelo T , Castro-Faria-Neto Hugo C , Bozza Patrícia T
Published: April 2007

Introduction

The current shortage of accurate and readily available, validated biomarkers of disease severity in sepsis is an important limitation when attempting to stratify patients into homogeneous groups, in order to study pathogenesis or develop therapeutic interventions. The aim of the present study was to determine the cytokine profile in plasma of patients with severe sepsis by using a multiplex system for simultaneous detection of 17 cytokines.

Methods

This was a prospective cohort study conducted in four tertiary hospitals. A total of 60 patients with a recent diagnosis of severe sepsis were included. Plasma samples were collected for measurement of cytokine concentrations. A multiplex analysis was performed to evaluate levels of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-γ, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein-1 and tumour necrosis factor-α). Cytokine concentrations were related to the presence of severe sepsis or septic shock, the severity and evolution of organ failure, and early and late mortality.

Results

Concentrations of IL-1β, IL-6, IL-7, IL-8, IL-10, IL-13, interferon-γ, MCP-1 and tumour necrosis factor-α were significantly higher in septic shock patients than in those with severe sepsis. Cytokine concentrations were associated with severity and evolution of organ dysfunction. With regard to the severity of organ dysfunction on day 1, IL-8 and MCP-1 exhibited the best correlation with Sequential Organ Failure Assessment score. In addition, IL-6, IL-8 and G-CSF concentrations during the first 24 hours were predictive of worsening organ dysfunction or failure of organ dysfunction to improve on day three. In terms of predicting mortality, the cytokines IL-1β, IL-4, IL-6, IL-8, MCP-1 and G-CSF had good accuracy for predicting early mortality (< 48 hours), and IL-8 and MCP-1 had the best accuracy for predicting mortality at 28 days. In multivariate analysis, only MCP-1 was independently associated with prognosis.

Conclusion

In this exploratory analysis we demonstrated that use of a multiple cytokine assay platform allowed identification of distinct cytokine profiles associated with sepsis severity, evolution of organ failure and death.
The metabolic and renal effects of adrenaline and milrinone in patients with myocardial dysfunction after coronary artery bypass grafting
Authors: Heringlake Matthias , Wernerus Marit , Grünefeld Julia , Klaus Stephan , Heinze Hermann , Bechtel Matthias , Bahlmann Ludger , Poeling Jochen , Schön Julika
Published: April 2007

Introduction

Myocardial dysfunction necessitating inotropic support is a typical complication after on-pump cardiac surgery. This prospective, randomized pilot study analyzes the metabolic and renal effects of the inotropes adrenaline and milrinone in patients needing inotropic support after coronary artery bypass grafting (CABG).

Methods

During an 18-month period, 251 patients were screened for low cardiac output upon intensive care unit (ICU) admission after elective, isolated CABG surgery. Patients presenting with a cardiac index (CI) of less than 2.2 liters/minute per square meter upon ICU admission – despite adequate mean arterial (titrated with noradrenaline or sodium nitroprusside) and filling pressures – were randomly assigned to 14-hour treatment with adrenaline (n = 7) or milrinone (n = 11) to achieve a CI of greater than 3.0 liters/minute per square meter. Twenty patients not needing inotropes served as controls. Hemodynamics, plasma lactate, pyruvate, glucose, acid-base status, insulin requirements, the urinary excretion of alpha-1-microglobuline, and creatinine clearance were determined during the treatment period, and cystatin-C levels were determined up to 48 hours after surgery (follow-up period).

Results

After two to four hours after ICU admission, the target CI was achieved in both intervention groups and maintained during the observation period. Plasma lactate, pyruvate, the lactate/pyruvate ratio, plasma glucose, and insulin doses were higher (p < 0.05) in the adrenaline-treated patients than during milrinone or control conditions. The urinary excretion of alpha-1-microglobuline was higher in the adrenaline than in the control group 6 to 14 hours after admission (p < 0.05). No between-group differences were observed in creatinine clearance, whereas plasma cystatin-C levels were significantly higher in the adrenaline than in the milrinone or the control group after 48 hours (p < 0.05).

Conclusion

This suggests that the use of adrenaline for the treatment of postoperative myocardial dysfunction – in contrast to treatment with the PDE-III inhibitor milrinone – is associated with unwarranted metabolic and renal effects.

Clinical trials registration: ClinicalTrials.gov NCT00446017.
CAGE-TSSchip: promoter-based expression profiling using the 5'-leading label of capped transcripts
Authors: Katayama Shintaro , Kanamori-Katayama Mutsumi , Yamaguchi Kazumi , Carninci Piero , Hayashizaki Yoshihide
Published: April 2007

Cap analysis gene expression (CAGE) technology has revealed numerous transcription start sites (TSSs) in mammals and has suggested complex promoter-based patterns of regulation. We developed the CAGE-TSSchip to detect promoter-based transcriptional activity. The CAGE-TSSchip is a customized oligonucleotide array that targets known TSSs identified by CAGE. A new labeling method, labeling capped transcripts from the 5'-end, had to be developed. The CAGE-TSSchip is accurate and sensitive, and represents the activity of each TSS.
Genome mapping and expression analyses of human intronic noncoding RNAs reveal tissue-specific patterns and enrichment in genes related to regulation of transcription
Authors: Nakaya Helder I , Amaral Paulo P , Louro Rodrigo , Lopes André , Fachel Angela A , Moreira Yuri B , El-Jundi Tarik A , da Silva Aline M , Reis Eduardo M , Verjovski-Almeida Sergio
Published: April 2007

Background

RNAs transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression. However, the complement of human genes in which introns are transcribed, and the number of intronic transcriptional units and their tissue expression patterns are not known.

Results

A survey of mRNA and EST public databases revealed more than 55,000 totally intronic noncoding (TIN) RNAs transcribed from the introns of 74% of all unique RefSeq genes. Guided by this information, we designed an oligoarray platform containing sense and antisense probes for each of 7,135 randomly selected TIN transcripts plus the corresponding protein-coding genes. We identified exonic and intronic tissue-specific expression signatures for human liver, prostate and kidney. The most highly expressed antisense TIN RNAs were transcribed from introns of protein-coding genes significantly enriched (p = 0.002 to 0.022) in the 'Regulation of transcription' Gene Ontology category. RNA polymerase II inhibition resulted in increased expression of a fraction of intronic RNAs in cell cultures, suggesting that other RNA polymerases may be involved in their biosynthesis. Members of a subset of intronic and protein-coding signatures transcribed from the same genomic loci have correlated expression patterns, suggesting that intronic RNAs regulate the abundance or the pattern of exon usage in protein-coding messages.

Conclusion

We have identified diverse intronic RNA expression patterns, pointing to distinct regulatory roles. This gene-oriented approach, using a combined intron-exon oligoarray, should permit further comparative analysis of intronic transcription under various physiological and pathological conditions, thus advancing current knowledge about the biological functions of these noncoding RNAs.
Normalization of two-channel microarrays accounting for experimental design and intensity-dependent relationships
Authors: Dabney Alan R , Storey John D
Published: April 2007

In normalizing two-channel expression arrays, the ANOVA approach explicitly incorporates the experimental design in its model, and the MA plot-based approach accounts for intensity-dependent biases. However, both approaches can lead to inaccurate normalization in fairly common scenarios. We propose a method called efficient Common Array Dye Swap (eCADS) for normalizing two-channel microarrays that accounts for both experimental design and intensity-dependent biases. Under reasonable experimental designs, eCADS preserves differential expression relationships and requires only a single array per sample pair.
Deafblindness in French Canadians from Quebec: a predominant founder mutation in the USH1Cgene provides the first genetic link with the Acadian population
Authors: Ebermann Inga , Lopez Irma , Bitner-Glindzicz Maria , Brown Carolyn , Koenekoop Robert Karel , Bolz Hanno Jörn
Published: April 2007

Background

Usher syndrome type 1 (USH1) is the leading cause of deafblindness. In most populations, many private mutations are distributed across the five known USH1 genes. We investigated patients from the French Canadian population of Quebec (approximately 6 million people) that descends from about 8,500 French settlers who colonized the St Lawrence River valley between 1608 and 1759. We hypothesized that founder mutations in USH1 genes exist in this population.

Results

We have genetically characterized 15 patients from different regions of Quebec who were clinically diagnosed as USH1. Of these cases, 60% carried mutations of the USH1C gene, a genetic subtype that is rare outside the Acadian population. We have discovered a founder effect of the c.216G>A mutation, which has previously been designated the 'Acadian allele' because it accounts for virtually all Acadian USH1 cases. It represents 40% of disease alleles in Quebec, and a carrier of c.216G>A was identified in the general population. Mutations in other genes, except CDH23, are very rare.

Conclusion

Based on our findings, approximately 0.5% of congenitally deaf children in Quebec are at risk of developing retinal degeneration due to homozygosity for c.216G>A. Although the Acadians and French Canadians from Quebec are descended from French ancestors, they have always been considered genetically distinct. The genetic conditions common in Quebec are generally not found in Acadians, or they are due to different mutations. Our results, however, show that carriers of the c.216G>A allele haplotype belonged to the early founders of both the Acadian and the Quebec population.
Integration of Arabidopsis thaliana stress-related transcript profiles, promoter structures, and cell-specific expression
Authors: Ma Shisong , Bohnert Hans J
Published: April 2007

Background

Arabidopsis thaliana transcript profiles indicate effects of abiotic and biotic stresses and tissue-specific and cell-specific gene expression. Organizing these datasets could reveal the structure and mechanisms of responses and crosstalk between pathways, and in which cells the plants perceive, signal, respond to, and integrate environmental inputs.

Results

We clustered Arabidopsis transcript profiles for various treatments, including abiotic, biotic, and chemical stresses. Ubiquitous stress responses in Arabidopsis, similar to those of fungi and animals, employ genes in pathways related to mitogen-activated protein kinases, Snf1-related kinases, vesicle transport, mitochondrial functions, and the transcription machinery. Induced responses to stresses are attributed to genes whose promoters are characterized by a small number of regulatory motifs, although secondary motifs were also apparent. Most genes that are downregulated by stresses exhibited distinct tissue-specific expression patterns and appear to be under developmental regulation. The abscisic acid-dependent transcriptome is delineated in the cluster structure, whereas functions that are dependent on reactive oxygen species are widely distributed, indicating that evolutionary pressures confer distinct responses to different stresses in time and space. Cell lineages in roots express stress-responsive genes at different levels. Intersections of stress-responsive and cell-specific profiles identified cell lineages affected by abiotic stress.

Conclusion

By analyzing the stress-dependent expression profile, we define a common stress transcriptome that apparently represents universal cell-level stress responses. Combining stress-dependent and tissue-specific and cell-specific expression profiles, and Arabidopsis 5'-regulatory DNA sequences, we confirm known stress-related 5' cis-elements on a genome-wide scale, identify secondary motifs, and place the stress response within the context of tissues and cell lineages in the Arabidopsis root.
Comparative analysis indicates regulatory neofunctionalization of yeast duplicates
Authors: Tirosh Itay , Barkai Naama
Published: April 2007

Background

Gene duplication provides raw material for the generation of new functions, but most duplicates are rapidly lost due to the initial redundancy in gene function. How gene function diversifies following duplication is largely unclear. Previous studies analyzed the diversification of duplicates by characterizing their coding sequence divergence. However, functional divergence can also be attributed to changes in regulatory properties, such as protein localization or expression, which require only minor changes in gene sequence.

Results

We developed a novel method to compare expression profiles from different organisms and applied it to analyze the expression divergence of yeast duplicated genes. The expression profiles of Saccharomyces cerevisiae duplicate pairs were compared with those of their pre-duplication orthologs in Candida albicans. Duplicate pairs were classified into two classes, corresponding to symmetric versus asymmetric rates of expression divergence. The latter class includes 43 duplicate pairs in which only one copy has a significant expression similarity to the C. albicans ortholog. These may present cases of regulatory neofunctionalization, as supported also by their dispensability and variability.

Conclusion

Duplicated genes may diversify through regulatory neofunctionalization. Notably, the asymmetry of gene sequence evolution and the asymmetry of gene expression evolution are only weakly correlated, underscoring the importance of expression analysis to elucidate the evolution of novel functions.
Statistical tools for synthesizing lists of differentially expressed features in related experiments
Authors: Blangiardo Marta , Richardson Sylvia
Published: April 2007

We propose a novel approach for finding a list of features that are commonly perturbed in two or more experiments, quantifying the evidence of dependence between the experiments by a ratio. We present a Bayesian analysis of this ratio, which leads us to suggest two rules for choosing a cut-off on the ranked list of p values. We evaluate and compare the performance of these statistical tools in a simulation study, and show their usefulness on two real datasets.
Ancient papillomavirus-host co-speciation in Felidae
Authors: Rector Annabel , Lemey Philippe , Tachezy Ruth , Mostmans Sara , Ghim Shin-Je , Van Doorslaer Koenraad , Roelke Melody , Bush Mitchell , Montali Richard J , Joslin Janis , Burk Robert D , Jenson Alfred B , Sundberg John P , Shapiro Beth , Van Ranst Marc
Published: April 2007

Background

Estimating evolutionary rates for slowly evolving viruses such as papillomaviruses (PVs) is not possible using fossil calibrations directly or sequences sampled over a time-scale of decades. An ability to correlate their divergence with a host species, however, can provide a means to estimate evolutionary rates for these viruses accurately. To determine whether such an approach is feasible, we sequenced complete feline PV genomes, previously available only for the domestic cat (Felis domesticus, FdPV1), from four additional, globally distributed feline species: Lynx rufus PV type 1, Puma concolor PV type 1, Panthera leo persica PV type 1, and Uncia uncia PV type 1.

Results

The feline PVs all belong to the Lambdapapillomavirus genus, and contain an unusual second noncoding region between the early and late protein region, which is only present in members of this genus. Our maximum likelihood and Bayesian phylogenetic analyses demonstrate that the evolutionary relationships between feline PVs perfectly mirror those of their feline hosts, despite a complex and dynamic phylogeographic history. By applying host species divergence times, we provide the first precise estimates for the rate of evolution for each PV gene, with an overall evolutionary rate of 1.95 × 10-8 (95% confidence interval 1.32 × 10-8 to 2.47 × 10-8) nucleotide substitutions per site per year for the viral coding genome.

Conclusion

Our work provides evidence for long-term virus-host co-speciation of feline PVs, indicating that viral diversity in slowly evolving viruses can be used to investigate host species evolution. These findings, however, should not be extrapolated to other viral lineages without prior confirmation of virus-host co-divergence.
Global analyses of mRNA translational control during early Drosophila embryogenesis
Authors: Qin Xiaoli , Ahn Soyeon , Speed Terence P , Rubin Gerald M
Published: April 2007

Background

In many animals, the first few hours of life proceed with little or no transcription, and developmental regulation at these early stages is dependent on maternal cytoplasm rather than the zygotic nucleus. Translational control is critical for early Drosophila embryogenesis and is exerted mainly at the gene level. To understand post-transcriptional regulation during Drosophila early embryonic development, we used sucrose polysomal gradient analyses and GeneChip analysis to illustrate the translation profile of individual mRNAs.

Results

We determined ribosomal density and ribosomal occupancy of over 10,000 transcripts during the first ten hours after egg laying.

Conclusion

We report the extent and general nature of gene regulation at the translational level during early Drosophila embryogenesis on a genome-wide basis. The diversity of the translation profiles indicates multiple mechanisms modulating transcript-specific translation. Cluster analyses suggest that the genes involved in some biological processes are co-regulated at the translational level at certain developmental stages.
A third-generation microsatellite-based linkage map of the honey bee, Apis mellifera, and its comparison with the sequence-based physical map
Authors: Solignac Michel , Mougel Florence , Vautrin Dominique , Monnerot Monique , Cornuet Jean-Marie
Published: April 2007

Background:

The honey bee is a key model for social behavior and this feature led to the selection of the species for genome sequencing. A genetic map is a necessary companion to the sequence. In addition, because there was originally no physical map for the honey bee genome project, a meiotic map was the only resource for organizing the sequence assembly on the chromosomes.

Results:

We present the genetic (meiotic) map here and describe the main features that emerged from comparison with the sequence-based physical map. The genetic map of the honey bee is saturated and the chromosomes are oriented from the centromeric to the telomeric regions. The map is based on 2,008 markers and is about 40 Morgans (M) long, resulting in a marker density of one every 2.05 centiMorgans (cM). For the 186 megabases (Mb) of the genome mapped and assembled, this corresponds to a very high average recombination rate of 22.04 cM/Mb. Honey bee meiosis shows a relatively homogeneous recombination rate along and across chromosomes, as well as within and between individuals. Interference is higher than inferred from the Kosambi function of distance. In addition, numerous recombination hotspots are dispersed over the genome.

Conclusion:

The very large genetic length of the honey bee genome, its small physical size and an almost complete genome sequence with a relatively low number of genes suggest a very promising future for association mapping in the honey bee, particularly as the existence of haploid males allows easy bulk segregant analysis.
Functional dissection of the ash2 and ash1 transcriptomes provides insights into the transcriptional basis of wing phenotypes and reveals conserved protein interactions
Authors: Beltran Sergi , Angulo Mireia , Pignatelli Miguel , Serras Florenci , Corominas Montserrat
Published: April 2007

Background

The trithorax group (trxG) genes absent, small or homeotic discs 1 (ash1) and 2 (ash2) were isolated in a screen for mutants with abnormal imaginal discs. Mutations in either gene cause homeotic transformations but Hox genes are not their only targets. Although analysis of double mutants revealed that ash2 and ash1 mutations enhance each other's phenotypes, suggesting they are functionally related, it was shown that these proteins are subunits of distinct complexes.

Results

The analysis of wing imaginal disc transcriptomes from ash2 and ash1 mutants showed that they are highly similar. Functional annotation of regulated genes using Gene Ontology allowed identification of severely affected groups of genes that could be correlated to the wing phenotypes observed. Comparison of the differentially expressed genes with those from other genome-wide analyses revealed similarities between ASH2 and Sin3A, suggesting a putative functional relationship. Coimmunoprecipitation studies and immunolocalization on polytene chromosomes demonstrated that ASH2 and Sin3A interact with HCF (host-cell factor). The results of nucleosome western blots and clonal analysis indicated that ASH2 is necessary for trimethylation of the Lys4 on histone 3 (H3K4).

Conclusion

The similarity between the transcriptomes of ash2 and ash1 mutants supports a model in which the two genes act together to maintain stable states of transcription. Like in humans, both ASH2 and Sin3A bind HCF. Finally, the reduction of H3K4 trimethylation in ash2 mutants is the first evidence in Drosophila regarding the molecular function of this trxG gene.
Taking a spiritual history
Authors: Culliford Larry
Published: April 2007

The rationale for assessing the spiritual needs of psychiatric patients is examined as a prelude to addressing the question of how to do this. A number of approaches are considered. The emphasis is on varieties of practical history-taking suitable for the repertoire of every psychiatrist in training and those engaged in CPD. Finally, some of the consequences of identifying spiritual needs in psychiatric patients are discussed.
How to approach a research ethics committee
Authors: Masterton George , Shah Prem
Published: April 2007

This article describes research ethics and the UK research ethics system for psychiatrists who are engaged in research or in supporting trainees with research projects. The emphasis on practical aspects should ensure that submissions to research ethics committees are improved, and consequently the likelihood of a successful outcome is increased.
Dangerous and severe personality disorder and in need of treatment
Authors: Mullen Paul E.
Published: April 2007

The Dangerous and Severe Personality Disorder Programme was born out of a populist law and order reaction, developed on false premises, but is now evolving into an exciting initiative for providing effective services to a group of offenders with mental illness who psychiatry, and the justice services, have so long ignored. Enthusiasm, flexibility and an evidence-based approach may yet lead to real progress towards the improved management of disturbed high-risk offenders, improving the psychological and social functioning of the offenders as well as delivering a safer community.
Dangerous and severe personality disorder: antecedents and origins
Authors: Maden Anthony
Published: April 2007

The origins of the Dangerous and Severe Pesonality Disorder (DSPD) Programme can be traced to developments in structured assessment and services for the cognitive–behavioural treatment of sexual and violent offenders in other countries. A comparison with these other services highlights the strengths and weaknesses of DSPD. The decision to use a medical model raises ethical and financial questions that may jeopardise the Programme's future.
Zuclopenthixol in adults with intellectual disabilities and aggressive behaviours
Authors: Haessler Frank , Glaser Thomas , Beneke Manfred , Pap Akos F. , Bodenschatz Ralf , Reis Olaf
Published: April 2007

We investigated the effects of zuclopenthixol on aggressive behaviour in patients with intellectual disabilities by randomly withdrawing it after a 6-week period of open treatment. Of the 49 patients responding to the treatment, 39 took part in a randomised withdrawal trial. The placebo subgroup (n=20) showed more aggressive behaviour as indicated by outcomes observed by external raters on the Modified Overt Aggression Scale than did the continuing subgroup (n=19). The results indicate that discontinuation of zuclopenthixol in this population leads to an increase in aggressive behaviour.