bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of core promoter sequences in the mechanism of swarmer cell-specific silencing of gyrB transcription in Caulobacter crescentus
Authors: England Jennifer C , Gober James W
Published: May 2005

Background

Each Caulobacter crescentus cell division yields two distinct cell types: a flagellated swarmer cell and a non-motile stalked cell. The swarmer cell is further distinguished from the stalked cell by an inability to reinitiate DNA replication, by the physical properties of its nucleoid, and its discrete program of gene expression. Specifically, with regard to the latter feature, many of the genes involved in DNA replication are not transcribed in swarmer cells.

Results

We show that for one of these genes involved in DNA replication, gyrB, its pattern of temporal expression depends upon an 80 base pair promoter region with strong resemblance to the Caulobacter crescentus σ73 consensus promoter sequence; regulation does not appear to be affected by the general strength of the promoter activity, as mutations that increased its conformity with the consensus did not affect its cell-cycle expression pattern. Transcription from the gyrB promoter in vitro required only the presence of the σ73 RNA polymerase (from E. coli) and the requisite nucleoside triphosphates, although a distinct binding activity, present in crude whole-cell extracts, formed a complex gyrB promoter DNA. We also assayed the effect on gyrB expression in strains containing mutations in either smc or dps, two genes encoding proteins that condense DNA. However we found there was no change in the temporal pattern of gyrB transcription in strains containing deletions in either of these genes.

Conclusion

These experiments demonstrate that gyrB transcription does not require any auxiliary factors, suggesting that temporal regulation is not dependent upon an activator protein. Swarmer-specific silencing may not be attributable to the observed physical difference in the swarmer cell nucleoid, since mutations in either smc or dps, two genes encoding proteins that condense DNA, did not alter the temporal pattern of gyrB transcription in strains containing deletions in either of these genes. Rather a repressor that specifically recognizes sequences in the gyrB promoter region that are also probably essential for transcription, is likely to be responsible for controlling cell cycle expression.
General practitioners' conceptions about treatment of depression and factors that may influence their practice in this area. A postal survey
Authors: Andersson Stig J , Troein Margareta , Lindberg Gunnar
Published: May 2005

Background

The way GPs work does not appear to be adapted to the needs of depressive patients. Therefore we wanted to examine Swedish GPs' conceptions of depressive disorders and their treatment and GPs' ideas of factors that may influence their manner of work with depressive patients.

Methods

A postal questionnaire to a stratified sample of 617 Swedish GPs.

Results

Most respondents assumed antidepressive drugs effective and did not assume that psychotherapy can replace drugs in depression treatment though many of them looked at psychotherapy as an essential complement. Nearly all respondents thought that clinical experiences had great importance in decision situations, but patients' own preferences and official clinical guidelines were also regarded as essential. As influences on their work, almost all surveyed GPs regarded experiences from general practice very important, and a majority also emphasised experiences from private life. Courses arranged by pharmaceutical companies were seen as essential sources of knowledge. A majority thought that psychiatrists did not provide sufficient help, while most respondents perceived they were well backed up by colleagues.

Conclusion

GPs tend to emphasize experiences, both from clinical work and private life, and overlook influences of collegial dealings and ongoing CME as well as the effects of the pharmaceutical companies' marketing activities. Many GPs appear to need more evidence based knowledge about depressive disorders. Interventions to improve depression management have to be supporting and interactive, and should be combined with organisational reforms to improve co-operation with psychiatrists.
Suppression of colitis-related mouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands
Authors: Kohno Hiroyuki , Suzuki Rikako , Sugie Shigeyuki , Tanaka Takuji
Published: May 2005

Background

It is generally assumed that inflammatory bowel disease (IBD)-related carcinogenesis occurs as a result of chronic inflammation. We previously developed a novel colitis-related mouse colon carcinogenesis model initiated with azoxymethane (AOM) and followed by dextran sodium sulfate (DSS). In the present study we investigated whether a cyclooxygenase (COX)-2 inhibitor nimesulide and ligands for peroxisome proliferator-activated receptors (PPARs), troglitazone (a PPARγ ligand) and bezafibrate (a PPARα ligand) inhibit colitis-related colon carcinogenesis using our model to evaluate the efficacy of these drugs in prevention of IBD-related colon carcinogenesis.

Methods

Female CD-1 (ICR) mice were given a single intraperitoneal administration of AOM (10 mg/kg body weight) and followed by one-week oral exposure of 2% (w/v) DSS in drinking water, and then maintained on the basal diets mixed with or without nimesulide (0.04%, w/w), troglitazone (0.05%, w/w), and bezafibrate (0.05%, w/w) for 14 weeks. The inhibitory effects of dietary administration of these compounds were determined by histopathological and immunohistochemical analyses.

Results

Feeding with nimesulide and troglitazone significantly inhibited both the incidence and multiplicity of colonic adenocarcinoma induced by AOM/DSS in mice. Bezafibrate feeding significantly reduced the incidence of colonic adenocarcinoma, but did not significantly lower the multiplicity. Feeding with nimesulide and troglitazone decreased the proliferating cell nuclear antigen (PCNA)-labeling index and expression of β-catenin, COX-2, inducible nitric oxide synthase (iNOS) and nitrotyrosine. The treatments increased the apoptosis index in the colonic adenocarcinoma. Feeding with bezafibrate also affected these parameters except for β-catenin expression in the colonic malignancy.

Conclusion

Dietary administration of nimesulide, troglitazone and bezafibrate effectively suppressed the development of colonic epithelial malignancy induced by AOM/DSS in female ICR mice. The results suggest that COX-2 inhibitor and PPAR ligands could serve as an effective agent against colitis-related colon cancer development.
Reevaluation of the 22-1-1 antibody and its putative antigen, EBAG9/RCAS1, as a tumor marker
Authors: Reimer Tatiana A , Anagnostopoulos Ioannis , Erdmann Bettina , Lehmann Insa , Stein Harald , Daniel Peter , Dörken Bernd , Rehm Armin
Published: May 2005

Background

Tumor-associated antigens are appreciated as diagnostic markers, but they have also prompted tremendous efforts to develop tumor-specific immunotherapy. A previously cloned tumor-associated antigen, EBAG9, was initially defined by reactivity with the monoclonal antibody 22-1-1. Functionally, the EBAG9-encoded gene-product was believed to induce apoptosis in activated immune cells. However, using a cell-biological approach we identified EBAG9 as a Golgi-resident modulator of O-linked glycan expression, the latter product was then recognized by the 22-1-1 antibody. Secondly, EBAG9 expression was found physiologically in all murine tissues examined. This raised the question if EBAG9 is tumor-specific and mediates apoptosis itself or through O-linked glycans generated, among them the cognate 22-1-1 antigen Tn.

Methods

We have used immunohistochemistry to detect the expression of 22-1-1 and EBAG9 in various tissues. Correlation between expression of both antigens in cell lines was analysed by immunoblot and flow cytometry. Apoptosis was studied by using flow cytometry and Caspase-Glo™ 3/7 assay kit. Cellular distribution of EBAG9 was analysed by electron and confocal microscopy.

Results

Here, we compared expression of the 22-1-1 and EBAG9-defined antigens in normal and neoplastic tissues in situ. In contrast to 22-1-1 staining, EBAG9 is a ubiquitously expressed antigen in all normal and cancerous tissues. Functional studies on the role of 22-1-1 reactive material did not support any evidence for apoptosis induction. Employing electron and confocal microscopy, a refined subcellular localization of EBAG9 at the Golgi was obtained.

Conclusion

We suggest that the estrogen-inducible EBAG9 gene-product and the 22-1-1 defined antigen are structurally and functionally separate antigens.
Changes in elderly women's health-related quality of life following discontinuation of hormone replacement therapy
Authors: Heller Debra A , Gold Carol H , Ahern Frank M , Pringle Kristine E , Brown Theresa V , Glessner Margaret R
Published: May 2005

Background

Many women have discontinued hormone replacement therapy (HRT) in view of recent findings. The goal of this study was to determine if HRT discontinuation is associated with changes in health-related quality of life (HRQOL) in elderly women.

Methods

We studied women enrolled in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly (PACE) program, linking prescription claims with data from a longitudinal mail survey. HRQOL measures included the number of days out of the last 30 that physical health was not good and analogous measures for mental health, pain, and interference with activities, as well as a composite "healthy days" measure developed by CDC. Longitudinal analyses focused on 2,357 women who completed surveys in both 2002 and 2003, and who used HRT at baseline (mean age = 75.5, range = 65–102). Propensity scores were used to match HRT continuers and discontinuers according to HRT type, demographics, and baseline HRQOL. Analysis of covariance was used to compare HRQOL change in continuers and discontinuers.

Results

Between 2002 and 2003, 43% of HRT users discontinued therapy. Analysis of covariance to examine HRQOL change revealed complex interactions with age. Discontinuers aged 65–74 reported greater increases in days in which mental health was not good (p < .05), fewer "healthy days" (p < .05), more days in which health interfered with activities (p < .01), and more days with pain (p < .01). Among women aged 75–84, HRT discontinuers reported more days in which physical health was not good (p < .01); no other significant effects were observed in this group. Relative to HRT continuers, discontinuers aged 85 and older experienced apparent HRQOL improvements following cessation, with fewer days in which physical health was not good (p < .01), fewer days of poor mental health (p < .05), and more "healthy days" (p < .01).

Conclusions

These results suggest that there are substantial age differences in response to HRT discontinuation. While women aged 65–74 experienced apparent declines in HRQOL following HRT cessation, women aged 85 and older experienced relative improvements. The HRQOL declines observed among younger women underscore the importance of communication between clinicians and patients throughout the discontinuation process. These results also demonstrate the value of HRQOL surveillance as a component of health program administration.
The transition from learner to provider/teacher: The learning needs of new orthopaedic consultants
Authors: McKinstry Brian , Macnicol Malcolm , Elliot Katy , Macpherson Stuart
Published: May 2005

Background

Given the relatively sudden change from learner to teacher-provider that new consultants experience and the likely clinical and managerial challenges this may pose, there is a relative dearth of research into the problems they may have in relation to their new roles, or how supported they feel by senior colleagues acting in a mentoring role. This research sought to determine new consultants views on the quality and relevance of their training, its relationship to their confidence in clinical and managerial skills and their views on mentorship by senior colleagues.

Methods

Detailed postal questionnaire to new consultants using open and closed questions.

Open questionnaire to established consultants to validate new consultant responses.

Results

Respondents felt their clinical training was good and were generally confident in most clinical skills although some perceived deficiencies in more complex procedures and specialist areas. Most lacked confidence in many managerial skills. These perceptions were verified by established consultants. Although no relationship was found between total training time or quality of training with confidence, extra training in specific sub-specialities improved confidence in these areas. While most established consultants thought that mentorship would be useful for new consultants, only 52% of them shared this view.

Conclusion

Training and experience in management should be given greater emphasis. There may be a need for specific, targeted training in complex procedures for doctors who experience lack of confidence in these areas. Mentorship should be offered to new consultants and recognised in the job-plan of the new consultant contract.
The effect of geometry and abduction angle on the stresses in cemented UHMWPE acetabular cups – finite element simulations and experimental tests
Authors: Korhonen Rami K , Koistinen Arto , Konttinen Yrjö T , Santavirta Seppo S , Lappalainen Reijo
Published: May 2005

Background

Contact pressure of UHMWPE acetabular cup has been shown to correlate with wear in total hip replacement (THR). The aim of the present study was to test the hypotheses that the cup geometry, abduction angle, thickness and clearance can modify the stresses in cemented polyethylene cups.

Methods

Acetabular cups with different geometries (Link®: IP and Lubinus eccentric) were tested cyclically in a simulator at 45° and 60° abduction angles. Finite element (FE) meshes were generated and two additional designs were reconstructed to test the effects of the cup clearance and thickness. Contact pressures at cup-head and cup-cement interfaces were calculated as a function of loading force at 45°, 60° and 80° abduction angles.

Results

At the cup-head interface, IP experienced lower contact pressures than the Lubinus eccentric at low loading forces. However, at higher loading forces, much higher contact pressures were produced on the surface of IP cup. An increase in the abduction angle increased contact pressure in the IP model, but this did not occur to any major extent with the Lubinus eccentric model. At the cup-cement interface, IP experienced lower contact pressures. Increased clearance between cup and head increased contact pressure both at cup-head and cup-cement interfaces, whereas a decreased thickness of polyethylene layer increased contact pressure only at the cup-cement interface. FE results were consistent with experimental tests and acetabular cup deformations.

Conclusion

FE analyses showed that geometrical design, thickness and abduction angle of the acetabular cup, as well as the clearance between the cup and head do change significantly the mechanical stresses experienced by a cemented UHMWPE acetabular cup. These factors should be taken into account in future development of THR prostheses. FE technique is a useful tool with which to address these issues.
Patterns of walking for transport and exercise: a novel application of time use data
Authors: Tudor-Locke Catrine , Bittman Michael , Merom Dafna , Bauman Adrian
Published: May 2005

Background

Walking for exercise is a purposeful or structured activity that can be captured relatively easily in surveys focused on leisure time activity. In contrast, walking for transport is an incidental activity that is likely to be missed using these same assessment approaches. Therefore, the purpose of this analysis was to utilize 1997 Australian Bureau of Statistics (ABS) Time Use Survey diary data to describe nationally representative patterns of walking for transport and for exercise.

Methods

Household members ≥ 15 years of age were recruited from over 4,550 randomly selected private dwellings in Australia. Time use diaries were collected for two designated days during all four seasons over the calendar year. 3,471 males and 3,776 females (94% household response rate and 84% person response rate) provided 14,315 diary days of data. The raw diary data were coded and summarized into bouts and minutes that included walking for transport and for exercise.

Results

Walking for transport was indicated on a higher proportion of days compared to walking for exercise (20 vs. 9%). Based on participant sub-samples ('doers'; those actually performing the activity) walking for transport was performed over 2.3 ± 1.4 bouts/day (12.5 minutes/bout) for a total of ≈28 mins/day and walking for exercise over 1.2 ± 0.5 bouts/day (47 minutes/bout) for a total of ≈56 mins/day.

Conclusion

Although walking for transport is typically undertaken in multiple brief bouts, accumulated durations approximate public health guidelines for those who report any walking for transport.
Benign breast disease, recent alcohol consumption, and risk of breast cancer: a nested case–control study
Authors: Tamimi Rulla M , Byrne Celia , Baer Heather J , Rosner Bernie , Schnitt Stuart J , Connolly James L , Colditz Graham A
Published: May 2005

Introduction

Alcohol consumption is a well-established risk factor for breast cancer. Some studies have suggested that the risk of breast cancer associated with alcohol consumption is greater for women with a history of benign breast disease (BBD). We hypothesized that among women with biopsy-confirmed BBD, recent alcohol consumption would increase the risk of breast cancer in women with proliferative breast disease to a greater extent than in women with nonproliferative breast disease.

Methods

We conducted a nested case–control study in the Nurses' Health Study I and II. The cases (n = 282) were women diagnosed with incident breast cancer, with a prior biopsy-confirmed breast disease. The controls (n = 1,223) were participants with a previous BBD biopsy, but without a diagnosis of breast cancer. Pathologists reviewed benign breast biopsy slides in a blinded fashion and classified the BBD as nonproliferative, proliferative without atypia, or atypical hyperplasia, according to standard criteria.

Results

Women with nonproliferative breast disease consuming ≥ 15 g of alcohol per day had a nonsignificant 67% increased risk of breast cancer (odds ratio = 1.67; 95% confidence interval 0.65 to 4.34) compared with nondrinkers. There was no evidence that recent alcohol consumption increased the risk of breast cancer to a greater extent in women with proliferative BBD than among women with nonproliferative BBD (P for interactio n = 0.20).

Conclusion

Contrary to our a priori hypothesis, there was no evidence that recent alcohol consumption increased the risk of breast cancer to a greater extent among women with proliferative BBD than among women with nonproliferative BBD.
Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture
Authors: Pollmann Mary-Ann , Shao Qing , Laird Dale W , Sandig Martin
Published: May 2005

Introduction

Metastasis involves the emigration of tumor cells through the vascular endothelium, a process also known as diapedesis. The molecular mechanisms regulating tumor cell diapedesis are poorly understood, but may involve heterocellular gap junctional intercellular communication (GJIC) between tumor cells and endothelial cells.

Method

To test this hypothesis we expressed connexin 43 (Cx43) in GJIC-deficient mammary epithelial tumor cells (HBL100) and examined their ability to form gap junctions, establish heterocellular GJIC and migrate through monolayers of human microvascular endothelial cells (HMVEC) grown on matrigel-coated coverslips.

Results

HBL100 cells expressing Cx43 formed functional heterocellular gap junctions with HMVEC monolayers within 30 minutes. In addition, immunocytochemistry revealed Cx43 localized to contact sites between Cx43 expressing tumor cells and endothelial cells. Quantitative analysis of diapedesis revealed a two-fold increase in diapedesis of Cx43 expressing cells compared to empty vector control cells. The expression of a functionally inactive Cx43 chimeric protein in HBL100 cells failed to increase migration efficiency, suggesting that the observed up-regulation of diapedesis in Cx43 expressing cells required heterocellular GJIC. This finding is further supported by the observation that blocking homocellular and heterocellular GJIC with carbenoxolone in co-cultures also reduced diapedesis of Cx43 expressing HBL100 tumor cells.

Conclusion

Collectively, our results suggest that heterocellular GJIC between breast tumor cells and endothelial cells may be an important regulatory step during metastasis.
Alternative initiation and splicing in dicer gene expression in human breast cells
Authors: Irvin-Wilson Charletha V , Chaudhuri Gautam
Published: May 2005

Introduction

Dicer is a ribonuclease that mediates RNA interference both at the transcriptional and the post-transcriptional levels. Human dicer gene expression is regulated in different tissues. Dicer is responsible for the synthesis of microRNAs and short temporal (st)RNAs that regulate the expression of many genes. Thus, understanding the control of the expression of the dicer gene is essential for the appreciation of double-stranded (ds)RNA-mediated pathways of gene expression. Human dicer mRNA has many upstream open reading frames (uORFs) at the 5'-leader sequences (the nucleotide sequence between the 5'-end and the start codon of the major ORF), and we studied whether these elements at the 5'-leader sequences regulate the expression of the dicer gene.

Method

We determined the 5'-leader sequences of the dicer mRNAs in human breast cells by 5'-RACE and S1-nuclease protection analysis. We have analyzed the functions of the 5'-leader variants by reporter gene expression in vitro and in vivo.

Results

We found that the dicer transcripts in human breast cells vary in the sequence of their 5'-leader sequences, and that alternative promoter selection along with alternative splicing of the 5'-terminal exons apparently generate these variations. The breast cell has at least two predominant forms of dicer mRNAs, one of which has an additional 110 nucleotides at the 5'-end. Sequence comparison revealed that the first 80 nucleotides of these mRNA isoforms are encoded by a new exon located approximately 16 kb upstream of the reported start site. There are 30 extra nucleotides added to the previously reported exon 1. The human breast cells studied predominantly express two 5'-leader variants of dicer mRNAs, one with the exons 2 and 3 (long form) and the other without them (short form). By reporter gene expression analysis we found that the exon 2 and 3 sequences at the 5'-leader sequences are greatly inhibitory for the translation of the mRNA into protein.

Conclusion

Dicer gene expression in human breast cells is regulated by alternative promoter selection to alter the length and composition of the 5'-leader sequence of its mRNA. Furthermore, alternative splicing of its exon 2 and 3 sequences of their pre-mRNA creates a more translationally competent mRNA in these cells.
Effect of reproductive factors on stage, grade and hormone receptor status in early-onset breast cancer
Authors: Largent Joan A , Ziogas Argyrios , Anton-Culver Hoda
Published: May 2005

Introduction

Women younger than 35 years who are diagnosed with breast cancer tend to have more advanced stage tumors and poorer prognoses than do older women. Pregnancy is associated with elevated exposure to estrogen, which may influence the progression of breast cancer in young women. The objective of the present study was to examine the relationship between reproductive events and tumor stage, grade, estrogen receptor and progesterone receptor status, and survival in women diagnosed with early-onset breast cancer.

Methods

In a population-based, case–case study of 254 women diagnosed with invasive breast cancer at age under 35 years, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression with tumor characteristics as dependent variables and adjusting for age and education. Survival analyses also examined the relationship between reproductive events and overall survival.

Results

Compared with nulliparous women, women with three or more childbirths were more likely to be diagnosed with nonlocalized tumors (OR = 3.1, 95% CI = 1.3–7.7), and early age (<20 years) at first full-term pregnancy was also associated with a diagnosis of breast cancer that was nonlocalized (OR = 3.0, 95% CI = 1.2–7.4) and of higher grade (OR = 3.2, 95% CI 1.0–9.9). The hazard ratio for death among women with two or more full-term pregnancies, as compared with those with one full-term pregnancy or none, was 2.1 (95% CI = 1.0–4.5), adjusting for stage. Among parous women, those who lactated were at decreased risk for both estrogen receptor and progesterone receptor negative tumors (OR = 0.2, 95% CI = 0.1–0.5, and OR = 0.4, 95% CI = 0.2–0.8, respectively).

Conclusion

The results of the present study suggest that pregnancy and lactation may influence tumor presentation and survival in women with early-onset breast cancer.
Inspiratory oscillatory flow with a portable ventilator: a bench study
Authors: Frank Guenther E , Trimmel Helmut , Fitzgerald Robert D
Published: May 2005

Introduction

We observed an oscillatory flow while ventilating critically ill patients with the Dräger Oxylog 3000™ transport ventilator during interhospital transfer. The phenomenon occurred in paediatric patients or in adult patients with severe airway obstruction ventilated in the pressure-regulated or pressure-controlled mode. As this had not been described previously, we conducted a bench study to investigate the phenomenon.

Methods

An Oxylog 3000™ intensive care unit ventilator and a Dräger Medical Evita-4 NeoFlow™ intensive care unit ventilator were connected to a Dräger Medical LS800™ lung simulator. Data were registered by a Datex-S5™ Monitor with a D-fend™ flow and pressure sensor, and were analysed with a laptop using S5-Collect™ software. Clinical conditions were simulated using various ventilatory modes, using various ventilator settings, using different filters and endotracheal tubes, and by changing the resistance and compliance. Data were recorded for 258 combinations of patient factors and respirator settings to detect thresholds for the occurrence of the phenomenon and methods to overcome it.

Results

Under conditions with high resistance in pressure-regulated ventilation with the Oxylog 3000™, an oscillatory flow during inspiration produced rapid changes of the airway pressure. The phenomenon resulted in a jerky inspiration with high peak airway pressures, higher than those set on the ventilator. Reducing the inspiratory flow velocity was effective to terminate the phenomenon, but resulted in reduced tidal volumes.

Conclusion

Oscillatory flow with potentially harmful effects may occur during ventilation with the Dräger Oxylog 3000™, especially in conditions with high resistance such as small airways in children (endotracheal tube internal diameter <6 mm) or severe obstructive lung diseases or airway diseases in adult patients.
Factors that predict outcome of intensive care treatment in very elderly patients: a review
Authors: de Rooij Sophia E , Abu-Hanna Ameen , Levi Marcel , de Jonge Evert
Published: May 2005

Introduction

Advanced age is thought to be associated with increased mortality in critically ill patients. This report reviews available data on factors that determine outcome, on the value of prognostic models, and on preferences regarding life-sustaining treatments in (very) elderly intensive care unit (ICU) patients.

Methods

We searched the Medline database (January 1966 to January 2005) for English language articles. Selected articles were cross-checked for other relevant publications.

Results

Mortality rates are higher in elderly ICU patients than in younger patients. However, it is not age per se but associated factors, such as severity of illness and premorbid functional status, that appear to be responsible for the poorer prognosis. Patients' preferences regarding life-sustaining treatments are importantly influenced by the likelihood of a beneficial outcome. Commonly used prognostic models have not been calibrated for use in the very elderly. Furthermore, they do not address long-term survival and functional outcome.

Conclusion

We advocate the development of new prognostic models, validated in elderly ICU patients, that predict not only survival but also functional and cognitive status after discharge. Such a model may support informed decision making with respect to patients' preferences.
Large-scale 13C-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast
Authors: Blank Lars M , Kuepfer Lars , Sauer Uwe
Published: May 2005

Background

Quantification of intracellular metabolite fluxes by 13C-tracer experiments is maturing into a routine higher-throughput analysis. The question now arises as to which mutants should be analyzed. Here we identify key experiments in a systems biology approach with a genome-scale model of Saccharomyces cerevisiae metabolism, thereby reducing the workload for experimental network analyses and functional genomics.

Results

Genome-scale 13C flux analysis revealed that about half of the 745 biochemical reactions were active during growth on glucose, but that alternative pathways exist for only 51 gene-encoded reactions with significant flux. These flexible reactions identified in silico are key targets for experimental flux analysis, and we present the first large-scale metabolic flux data for yeast, covering half of these mutants during growth on glucose. The metabolic lesions were often counteracted by flux rerouting, but knockout of cofactor-dependent reactions, as in the adh1, ald6, cox5A, fum1, mdh1, pda1, and zwf1 mutations, caused flux responses in more distant parts of the network. By integrating computational analyses, flux data, and physiological phenotypes of all mutants in active reactions, we quantified the relative importance of 'genetic buffering' through alternative pathways and network redundancy through duplicate genes for genetic robustness of the network.

Conclusions

The apparent dispensability of knockout mutants with metabolic function is explained by gene inactivity under a particular condition in about half of the cases. For the remaining 207 viable mutants of active reactions, network redundancy through duplicate genes was the major (75%) and alternative pathways the minor (25%) molecular mechanism of genetic network robustness in S. cerevisiae.
Intractable hiccup as the initial presenting feature of systemic lupus erythematosus
Authors: Delèvaux I , André M , Marroun I , Lamaison D , Piette J-C , Aumaître O
Published: May 2005

An infarctus of medulla oblongata was discovered in a 44-year old man with an intractable hiccup and 10, 11th and 12th right cranial nerves palsies. Systemic lupus erythematosus (SLE) with antiphospholipid syndrome was subsequently diagnosed. Hiccup has withdrew with corticosteroid therapy and low-dose aspirin. The other cases of literature and pathophysiologic hypotheses are briefly reported.
Sweet’s syndrome as an initial presentation in systemic lupus erythematosus: a case report and review of the literature
Authors: Hou T-Y , Chang D-M , Gao H-W , Chen C-H , Chen H-C , Lai J-H
Published: May 2005

Malar or discoid rash is the most frequent specific cutaneous lesion for systemic lupus erythematosus (SLE). Neutrophilic dermatosis as an initial presentation in SLE is unusual. We describe a 38-year old female patient who primarily suffered from erythematous tender plaques and fever. Examination of skin biopsy of the plaques showed dense neutrophilic infiltration in the dermis. Polyarthritis, heavy proteinuria, photosensitivity and positive antinuclear antibodies (ANA. 1: 1280) concluded the diagnosis of SLE. The plaques disappeared completely after treatment with systemic corticosteroids. To our knowledge, this is the first reported SLE patient with Sweet’s syndrome as the initial presentation in literature review.
A case of lupus erythematosus profundus with unusual manifestations
Authors: Bacanli A , Uzun S , Ciftcioglu M A , Alpsoy E
Published: May 2005

We describe a 16-year old female with lupus erythematosus panniculitis with unusual manifestations. She had noted to have developed erythematous nodules and plaques in the right axilla and inguinal region at the age of one year. These lesions resolved gradually with scar formation. However, new lesions were noted at the same locations in the following years. Some of her lesions at the scalp and the left axillary regions developing within the last two years slowly enlarged showing an annular configuration and subsequently resulted in hair loss. The erythematous border of her lesion in the left axilla consisted of two parallel red lines. Histopathological and direct immunofluorescent findings were consistent with lupus erythematosus panniculitis. Similar clinical findings in the same locations were also observed in the mother.
Catalase and PPARg2 genotype and risk of systemic lupus erythematosus in Koreans
Authors: Eny K M , El-Sohemy A , Cornelis M C , Sung Y-K , Bae S-C
Published: May 2005

Catalase (CAT) and peroxisome proliferator activated receptor-g2 (PPARg2) are important regulators of oxidative stress and inflammation, which may contribute to the development of systemic lupus erythematosus (SLE). The objective of this study was to investigate the effects of genetic polymorphisms of CAT and PPARg2 on risk and severity of SLE in a Korean population. DNA was isolated from blood samples collected from 345 patients with SLE and 400 controls. Genotyping for the 2262C!T polymorphism of CAT and the Pro12Ala polymorphism of PPARg2 were performed by PCR-RFLP analysis. The severity of SLE was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI). No association was observed between genotypes for any of the clinical manifestations of SLE. CAT and PPARg2 genotypes were not associated with either risk or severity of SLE. For subjects who were carriers of the high activity Tallele for CATand have the Pro/Pro genotype for PPARg2, the odds ratio (95% confidence interval) for risk of SLE was 0.45 (0.23-1.08). Our results suggest that genetic polymorphisms of CAT and PPARg2 do not play a significant role in the development of SLE in a Korean population. A possible protective effect of a combined genotype warrants further investigation.
Major life stress, coping styles, and social support in relation to psychological distress in patients with systemic lupus erythematosus
Authors: Kozora E , Ellison M C , Waxmonsky J A , Wamboldt F S , Patterson T L
Published: May 2005

The objective of this study was to examine psychological processes in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients in relation to measures of life stress, coping styles, social support and cognitive ability. Fifty-two SLE patients without overt neuropsychiatric symptoms, 29 RA patients and 27 healthy controls completed measures of depression, mood, disease activity, perceived health, stressful life events, coping, and social support. Variables entered into the multiple regression analysis following principal component analysis were: group, major difficult event, major life threatening event, disengaging coping, emotional coping, social support, and cognitive impairment. Depressive symptoms were associated with SLE group status (P, 0.001), major life-threatening events (P, 0.01), disengage coping (P, 0.001) and emotional coping (P, 0.05). SLE group status (P, 0.05), disengage coping (P, 0.05) and emotional coping (P, 0.05) were associated with current distressed mood. SLE patients without overt, major neuropsychiatric symptoms had greater psychological distress compared to RA and control subjects. Increased depressive symptoms and distressed mood state in SLE patients were related to use of disengaging and emotional coping styles. These findings are limited to SLE patients with no overt neuropsychiatric illness and low disease activity, suggesting the need for future studies with a greater variety of SLE patients. Interventions aimed at improving active coping and minimizing emotional response to stress may lower psychological distress in SLE patients with mild disease.
Antiphospholipid antibodies are induced by in vitro fertilization and correlate with paraoxonase activity and total antioxidant capacity of plasma in infertile women
Authors: Alves J Delgado , Radway-Bright E L , Lee S , Grima B , Hothersall J , Ravirajan C T , Isenberg D A
Published: May 2005

The objectives of this study were to determine whether antiphosholipid antibodies are associated with in vitro fertilization (IVF), and assess the potential biological effects of these antibodies. Sera from seventy infertile women (18 before IVF, 13 submitted to one IVF cycle and 39 after three cycles) and 28 healthy controls were collected. Anticardiolipin (anti-CL) and antiphosphatidylserine (anti-PS) antibodies, paraoxonase (PON) and Total Anti-oxidant Capacity of plasma (TAC) were measured. Anti-CL and anti-PS titres were significantly increased in treated patients compared with patients before treatment or controls ( P < 0.001). There were no differences regarding anti-CL and anti-PS titres between controls and untreated patients nor when different types of infertility were considered. PON activity and TAC were significantly reduced in treated patients when compared to untreated and controls ( P < 0.001; P < 0.002). PON correlated inversely with anti-CL and anti-PS IgG ( r = 20.734; P < 0.001) and directly with TAC ( r = 0.720, P < 0.001). In conclusion PON activity is decreased in women submitted to IVF treatment and is associated with the presence of antiphospholipid antibodies. These factors might contribute to the increased oxidative status found in these patients.
Glutathione S-transferase genotype and risk of systemic lupus erythematosus in Koreans
Authors: Kang T-Y , El-Sohemy A , Cornelis M C , Eny K M , Bae S-C
Published: May 2005

Oxidative stress caused by poor detoxification efficiency of reactive oxygen species (ROS) may play a role in the development of systemic lupus erythematosus (SLE). Glutathione S-transferase (GST) is involved in the detoxification of ROS and genetic polymorphisms of GSTM1, GSTT1 and GSTP1 are associated with altered enzyme activity. The aim of this study was to determine whether GSTM1 (deletion), GSTT1 (deletion) and GSTP1 (Ile105! Val105) polymorphisms are associated with susceptibility to SLE or frequency of clinical manifestations according to the ACR diagnostic criteria. DNA was isolated from blood samples collected from 330 patients with SLE and 270 ageand sex-matched controls. GST genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No associations were observed between GSTM1, GSTT1, and GSTP1 genotypes and risk of SLE. Among SLE patients, the GSTM1 null genotype was associated with a lower frequency of hematological disorders ( P = 0.012), and a higher SSA(+)/SSB(2) autoantibody profile ( P = 0.042). Compared to SLE patients with the GSTT1 non-null genotype, those with the GSTT1 null genotype had a lower frequency of discoid rash ( P = 0.018), and nephritis ( P = 0.033). Our findings suggest that genetic polymorphisms of GSTM1, GSTT1, and GSTP1 do not influence the risk of SLE, but a deletion of either GSTM1 or GSTT1 may influence certain clinical manifestations of the disease.
Very early development of steroid-associated osteonecrosis of femoral head in systemic lupus erythematosus: prospective study by MRI
Authors: Nagasawa K , Tada Y , Koarada S , Horiuchi T , Tsukamoto H , Murai K , Ueda A , Yoshizawa S , Ohta A
Published: May 2005

The objective of this study was to define prospectively the early development of corticosteroid-induced osteonecrosis of femoral head (ONF) in patients with systemic lupus erythematosus (SLE) and to identify the association of initial steroid treatment with the development of early (silent) ONF. Forty-five patients who were newly diagnosed as having SLE and required 40 mg/day or more prednisolone were enrolled. To detect silent ONF, examinations using magnetic resonance imaging (MRI) were done three months after starting steroid therapy, followed by every year’s MRI and plain radiography for over five years. Clinical and laboratory data were compared between silent ONF and non-ONF groups. Of 45 patients, 15 (33%) developed silent ONF and five (11%) symptomatic ONF. It was of interest that MRI detected silent ONF very early (by three months) in 14 patients (93%). It should be noted that pulse therapy with 1000 mg/day methylprednisolone was found to be done very frequently (13 of 15, 87%) in the silent ONF group compared to non-ONF group (11 of 30, 37%) (P, 0.01) although other clinical features were not significantly different between both groups. High dose corticosteroids caused elevation of serum levels of total cholesterol, albumin, and leukocyte count in most of patients. The degree of elevation of those parameters at one or three months was more prominent in the silent ONF group. In particular, the change ratio of total cholesterol at one month was outstanding in the silent ONF group compared to non-ONF group (0.551 versus 0.374, P, 0.05). In conclusion, pathological ONF develops very early in one-third of SLE patients who received high dose corticosteroids and steroid pulse therapy could be a significant risk factor. An abrupt elevation of serum total cholesterol and/or sensitivity to steroids seem to be associated with the pathogenesis of ONF.
Estrogen receptor alpha gene polymorphism and systemic lupus erythematosus: a possible risk?
Authors: Kassi E , Vlachoyiannopoulos P G , Kominakis A , Kiaris H , Moutsopoulos H M , Moutsatsou P
Published: May 2005

Estrogens and their receptors may play a role in the pathogenesis of systemic lupus erythematosus. Genetic alterations in the exon 8-coding region of the estrogen receptor alpha alter the intracellular signalling of estrogens, leading in enhanced or diminished activity. We investigated whether genetic alterations in exon 8 of ERa gene are associated with the occurrence and clinical features of lupus disease. The coding region of ERa exon 8 was subjected to mutation analysis using the polymerase chain reaction, denaturing gradient gel electrophoresis and sequence analysis, using DNA isolated from whole blood of 36 female patients and 38 healthy females. Clinical and laboratory parameters were available from the patients’ files. We identified the codon 594 polymorphism either in homozygous for the wild type gene (ACG/ACG) or heterozygous (ACG/ACA), both in patients and healthy females. Statistical analysis of the genotype and allele distribution revealed that there was a significant difference (ϰ2 test, P = 0.02 and P = 0.04, respectively) between patients and healthy women. Odds ratio estimate revealed that carriers of ACG/ACA genotype have three-fold higher risk of developing lupus disease (OR = 3.129, 95% CI 1.181-8.292). Moreover, in patients the heterozygous genotype was associated with rash, mouth ulcers and serositis (Fisher’s exact test, P = 0.055, P = 0.083, P = 0.065, respectively). The heterozygous patients were associated significantly with an early age at disease onset (ANOVA test, P, 0.05). We conclude that estrogen receptor alpha codon 594 genotype may influence the development of systemic lupus erythematosus at a younger age, as well as a certain disease clinical pattern.
A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging
Authors: Jeffery Douglas R , Chepuri Neraj , Durden David , Burdette Jonathon
Published: May 2005

Objective: To examine the safety of combination therapy with mitoxantrone (MITX) and interferon β-1b (IFNβ-1b) in patients with multiple sclerosis (MS) and a high on-therapy relapse rate and enhancing lesions on baseline magnetic resonance imaging (MRI) scan. Methods: Ten patients with worsening relapsing—remitting or secondary progressive MS were studied using monthly MRI with triple-dose gadolinium contrast. All patients must have been on IFNβ-1b for at least six months, have at least one enhancing lesion on a screening MRI, at least one relapse on IFNβ-1b in the six months prior to study entry and be neutralizing antibody negative. Monthly MRI scans using triple dose contrast and a 30-minute delay between contrast administration and scanning were carried out three times over two months to obtain baseline numbers of enhancing lesions each month. At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 3), and 5 mg/m2 at months 4 and 5. Dosing was continued at 5 mg/m2 every third month. Monthly MRI scanning was continued throughout the duration of MITX dosing. The primary outcome measure was the frequency of new enhancing lesions. Secondary outcome measures included relapse rate, and T1 hypointense and T2 lesion burden. Results: Following the addition of MITX to IFNβ-1b mean enhancing lesion frequency decreased 90% at month 7 (P=0.008) and enhancing lesion volume decreased by 96% (P=0.01). Relapse rates decreased 64% (P=0.004). T2 lesion burden and T1 hypointense lesion burden increased slightly during the baseline phase and decreased following MITX but the difference did not reach statistical significance. There were no serious adverse events on combination therapy and no drop-outs due to toxicity. Total white blood cell count was reduced at 14 days post-MITX infusion but returned to normal levels by day 21. There were no neutropenic fevers and there was no clinically significant elevation of liver function tests. Conclusions: While the number of patients in this study was small, the results suggest that the combination is safe and well tolerated. Disease activity was substantially reduced following the addition of MITX to IFNβ-1b.
Effect of pulsed magnetic field therapy on the level of fatigue in patients with multiple sclerosis - a randomized controlled trial
Authors: Mostert Stefan , Kesselring Jürg
Published: May 2005

Twenty-five multiple sclerosis patients, taking part in a rehabilitation program, were randomly assigned to treatment with pulsed magnetic field therapy (PMFT) or to sham therapy in order to study the additional effect of PMFTas part of a multimodal neurological rehabilitation program on fatigue. Patients demographic and disease specific characteristics were recorded. Level of fatigue was measured by fatigue sverity scale (FSS) at entrance and discharge and with a visual analog scale (VAS) immediate before and after a single treatment session. The ‘Magnetic Cell Regeneration’ system by Santerra was used for PMFT. A single treatment lasted 16 minutes twice daily over 3-4 weeks and consisted of relaxed lying on a PMF mattress. Sham intervention was conducted in an identical manner with the PMF-device off. Patients and statistics were blinded.

Level of fatigue measured by FSS was high at entrance in both treatment group (TG) and control group (CG) (5.6 versus 5.5). Over time of rehabilitation fatigue was reduced by 18% in TG and 7% in CG which was statistically not significant. There was a statistically significant immediate effect of the single treatment session witch 18% reduction of fatigue measured by VAS in TG versus 11% in CG.

Because of a high ‘placebo effect’ of simple bed rest, a only small and short lasting additional effect of PMFT and high costs of a PMF-device, we cannot recommend PMFTas an additional feature of a multimodal neurological rehabilitation program in order to reduce fatigue level of MS-patients.