bluuebunny/crossref_metadata_2025 huggingface dataset:
Amodiaquine failure associated with erythrocytic glutathione in Plasmodium falciparum malaria
Authors: Zuluaga Lina , Pabón Adriana , López Carlos , Ochoa Aleida , Blair Silvia
Published: April 2007

Objective

To establish the relationship between production of glutathione and the therapeutic response to amodiaquine (AQ) monotherapy in Plasmodium falciparum non-complicated malaria patients.

Methodology

Therapeutic response to AQ was evaluated in 32 patients with falciparum malaria in two townships of Antioquia, Colombia, and followed-up for 28 days. For every patient, total glutathione and enzymatic activity (glutathione reductase, GR, and γ-glutamylcysteine synthetase, γ-GCS) were determined in parasitized erythrocytes, non-infected erythrocytes and free parasites, on the starting day (day zero, before ingestion of AQ) and on the day of failure (in case of occurrence).

Results

There was found an AQ failure of 31.25%. Independent of the therapeutic response, on the starting day and on the day of failure, lower total glutathione concentration and higher GR activities in parasitized erythrocytes were found, compared with non-infected erythrocytes (p < 0.003). In addition, only on the day of failure, γ-GCS activity of parasitized erythrocytes was higher, compared with that of healthy erythrocytes (p = 0.01). Parasitized and non-parasitized erythrocytes in therapeutic failure patients (TF) had higher total glutathione on the starting day compared with those of adequate clinical response (ACR) (p < 0.02). Parasitized erythrocytes of TF patients showed lower total glutathione on the failure day, compared with starting day (p = 0.017). No differences was seen in the GR and γ-GCS activities by compartment, neither between the two therapeutic response groups nor between the two treatment days.

Conclusion

This study is a first approach to explaining P. falciparum therapeutic failure in humans through differences in glutathione metabolism in TF and ACR patients. These results suggest a role for glutathione in the therapeutic failure to antimalarials.
A computational model of skeletal muscle metabolism linking cellular adaptations induced by altered loading states to metabolic responses during exercise
Authors: Dash Ranjan K , DiBella John A , Cabrera Marco E
Published: April 2007

Background

The alterations in skeletal muscle structure and function after prolonged periods of unloading are initiated by the chronic lack of mechanical stimulus of sufficient intensity, which is the result of a series of biochemical and metabolic interactions spanning from cellular to tissue/organ level. Reduced activation of skeletal muscle alters the gene expression of myosin heavy chain isoforms to meet the functional demands of reduced mechanical load, which results in muscle atrophy and reduced capacity to process fatty acids. In contrast, chronic loading results in the opposite pattern of adaptations.

Methods

To quantify interactions among cellular and skeletal muscle metabolic adaptations, and to predict metabolic responses to exercise after periods of altered loading states, we develop a computational model of skeletal muscle metabolism. The governing model equations – with parameters characterizing chronic loading/unloading states- were solved numerically to simulate metabolic responses to moderate intensity exercise (WR ≤ 40% VO2 max).

Results

Model simulations showed that carbohydrate oxidation was 8.5% greater in chronically unloaded muscle compared with the loaded muscle (0.69 vs. 0.63 mmol/min), while fat oxidation was 7% higher in chronically loaded muscle (0.14 vs. 0.13 mmol/min), during exercise. Muscle oxygen uptake (VO2) and blood flow (Q) response times were 29% and 44% shorter in chronically loaded muscle (0.4 vs. 0.56 min for VO2 and 0.25 vs. 0.45 min for Q).

Conclusion

The present model can be applied to test complex hypotheses during exercise involving the integration and control of metabolic processes at various organizational levels (cellular to tissue) in individuals who have undergone periods of chronic loading or unloading.
LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro
Authors: Huang Tien-sheng , Myklebust Line M , Kjarland Endre , Gjertsen Bjørn Tore , Pendino Frederic , Bruserud Øystein , Døskeland Stein Ove , Lillehaug Johan R
Published: April 2007

Background

Relapse due to chemoresistant residual disease is a major cause of death in acute myelogenous leukemia (AML). The present study was undertaken to elucidate the molecular mechanisms of chemoresistance by comparing differential gene expression in blasts from patients with resistant relapsing AML and chemosensitive AML.

Results

About 20 genes were identified as preferentially expressed in blasts pooled from patients with resistant disease, as compared to chemosensitive AML blasts, based on differential gene expression screening. Half of these genes encoded proteins related to protein translation, of these a novel protein related to the ribosomal stalk protein P0. Other upregulated mRNAs coded for cytochrome C oxidase III, the transcription factors ERF-2/TIS11d, and the p75 and p52 splice variants of Lens Epithelial Derived Growth Factor (LEDGF). Analysis of blasts from single patients disclosed that LEDGF/p75 was the most consistently upregulated mRNA in resistant AML. Transfection experiments demonstrated that LEDGF/p75 and p52b antagonized daunorubicin-induced and cAMP-induced apoptosis in an AML cell line. Also HEK-293 cells were protected against daunorubicin by LEDGF/p75 and p52b, whereas LEDGF/p52 splice variants lacking exon 6 had proapoptotic effects. Interestingly, full length LEDGF/p75 protected against truncated pro-apoptotic LEDGF/p75.

Conclusion

Our results provide evidence for an association between the overexpression of genes encoding survival proteins like LEDGF/p75 and chemo-resistance in acute myelogenous leukemia. LEDGF/p75 has previously not been shown to protect against chemotherapy, and is a potential drug target in AML.
Process and formulation variables in the preparation of injectable and biodegradable magnetic microspheres
Authors: Zhao Hong , Gagnon Jeffrey , Häfeli Urs O
Published: April 2007

The aim of this study was to prepare biodegradable sustained release magnetite microspheres sized between 1 to 2 μm. The microspheres with or without magnetic materials were prepared by a W/O/W double emulsion solvent evaporation technique using poly(lactide-co-glycolide) (PLGA) as the biodegradable matrix forming polymer. Effects of manufacturing and formulation variables on particle size were investigated with non-magnetic microspheres. Microsphere size could be controlled by modification of homogenization speed, PLGA concentration in the oil phase, oil phase volume, solvent composition, and polyvinyl alcohol (PVA) concentration in the outer water phase. Most influential were the agitation velocity and all parameters that influence the kinematic viscosity of oil and outer water phase, specifically the type and concentration of the oil phase. The magnetic component yielding homogeneous magnetic microspheres consisted of magnetite nanoparticles of 8 nm diameter stabilized with a polyethylene glycole/polyacrylic acid (PEG/PAA) coating and a saturation magnetization of 47.8 emu/g. Non-magnetic and magnetic microspheres had very similar size, morphology, and size distribution, as shown by scanning electron microscopy. The optimized conditions yielded microspheres with 13.7 weight% of magnetite and an average diameter of 1.37 μm. Such biodegradable magnetic microspheres seem appropriate for vascular administration followed by magnetic drug targeting.
The training and expectations of medical students in Mozambique
Authors: Sousa Fernando , Schwalbach João , Adam Yussuf , Gonçalves Luzia , Ferrinho Paulo
Published: April 2007

Background

This paper describes the socio-economic profile of medical students in the 1998/99 academic year at the Universidade Eduardo Mondlane (UEM) Medical Faculty in Maputo. It aims to identify their social and geographical origins in addition to their expectations and difficulties regarding their education and professional future.

Methods

The data were collected through a questionnaire administered to all medical students at the faculty.

Results

Although most medical students were from outside Maputo City and Maputo Province, expectations of getting into medical school were already associated with a migration from the periphery to the capital city, even before entering medical education. This lays the basis for the concentration of physicians in the capital city once their term of compulsory rural employment as junior doctors is completed.

The decision to become a doctor was taken at an early age. Close relatives, or family friends seem to have been an especially important variable in encouraging, reinforcing and promoting the desire to be a doctor.

The academic performance of medical students was dismal. This seems to be related to several difficulties such as lack of library facilities, inadequate financial support, as well as poor high school preparation.

Only one fifth of the students reported receiving financial support from the Mozambican government to subsidize their medical studies.

Conclusion

Medical students seem to know that they will be needed in the public sector, and that this represents an opportunity to contribute to the public's welfare. Nevertheless, their expectations are, already as medical students, to combine their public sector practice with private medical work in order to improve their earnings.
Diabetes, minor depression and health care utilization and expenditures: a retrospective database study
Authors: Nichols Lori , Barton Phoebe L , Glazner Judith , McCollum Marianne
Published: April 2007

Background

To estimate the prevalence of minor depression among US adults with diabetes, health care resource utilization, and expenditures by people with diabetes with and without minor depression.

Methods

Among adult 2003 Medical Expenditure Panel Survey respondents, diabetes was identified by diagnosis code and self-report. Depression was identified by diagnosis code plus ≥ one antidepressant prescription. Odds of having depression was estimated in people with diabetes and the general population, adjusted for sociodemographic variables (e.g., age, sex, race/ethnicity). Multivariate regressions evaluated factors associated with utilization and log-transformed expenditures for ambulatory care, hospitalizations, emergency visits, and prescriptions.

Results

In 2003, 1932 respondents had diabetes, 435/1932 had diabetes and minor depression. Adults with diabetes were more likely than the general population to have depression (adjusted OR 1.81, 95% CI 1.56, 2.09). People with diabetes with versus without comorbid depression were more likely to be women, have lower incomes and health status, and more diabetes complications (all p < 0.05). In unadjusted analyses, ambulatory care visits were higher for those with versus without depression (17.9 vs. 11.4, p = 0.04), as were prescriptions (60.7 vs. 38.1, p = 0.05). In adjusted analyses, depression was not associated with increased resource use or higher expenditures in any category. Increased number of comorbid conditions was associated with increased resource use in all categories, and increased expenditures for ambulatory care and prescriptions.

Conclusion

People with diabetes are twice as likely to have depression as the general population. Screening for and treatment of depression is warranted, as is additional research into a causal relationship between diabetes and depression.
DNA vaccine constructs against enterovirus 71 elicit immune response in mice
Authors: Tung Wong Siew , Bakar Sazaly Abu , Sekawi Zamberi , Rosli Rozita
Published: April 2007

Background

Enterovirus 71 (EV71) is a major causative viral agent responsible for large outbreaks of hand, foot and mouth disease (HFMD), a common rash illness in children and infants. There is no effective antiviral treatment for severe EV71 infections and no vaccine is available. The objectives of this study were to design and construct a DNA vaccine against Enterovirus 71 using the viral capsid protein (VP1) gene of EV71 and to verify the functionality of the DNA vaccine in vitro and in vivo.

Methods

The VP1 gene of EV71 from two local outbreak isolates were amplified using PCR and then inserted into a eukaryotic expression vector, pVAX1. The 3.9 kb recombinant constructs were transformed into competent E. coli cells and the positive clones were screened and selected using PCR analysis, restriction digestion analysis and DNA sequencing. The constructs were then tested for protein expression in Vero cells. Subsequently, in the in vivo studies, female Balb/c mice were immunized with the DNA vaccine constructs. Enzyme Linked Immunosorbent Assay (ELISA) and virus neutralizing assay were performed to detect the presence of anti-VP1 IgG in mice and its neutralizing effect against the EV71.

Results

The pVAX1 vector was successfully cloned with the VP1 gene from each of the isolate (S2/86/1 and 410/4) in the correct orientation and in-frame. The DNA vaccine constructs with the VP1 gene were shown to be expressed in a cell-free in vitro expression system. The VP1 protein was successfully expressed in the mammalian cell line and was detected using RT-PCR, Indirect Immunofluorescence Assay (IFA) and western blotting. The anti-VP1 IgG levels in mice immunized with the DNA vaccine constructs increased after the first booster but declined following the second booster. The anti-VP1 IgG in the mice immunized with the DNA vaccine constructs exhibited neutralising activity against EV71.

Conclusion

The promising results obtained in the present study have prompted further testing to improve the expression and immunogenicity of this potential EV71 DNA vaccine.
Therapy of established B16-F10 melanoma tumors by a single vaccination of CTL/T helper peptides in VacciMax®
Authors: Mansour Marc , Pohajdak Bill , Kast W Martin , Fuentes-Ortega Antar , Korets-Smith Ella , Weir Genevieve M , Brown Robert G , Daftarian Pirouz
Published: April 2007

Background

Melanoma tumors are known to express antigens that usually induce weak immune responses of short duration. Expression of both tumor-associated antigens p53 and TRP2 by melanoma cells raises the possibility of simultaneously targeting more than one antigen in a therapeutic vaccine. In this report, we show that VacciMax®(VM), a novel liposome-based vaccine delivery platform, can increase the immunogenicity of melanoma associated antigens, resulting in tumor elimination.

Methods

C57BL/6 mice bearing B16-F10 melanoma tumors were vaccinated subcutaneously 6 days post tumor implantation with a mixture of synthetic peptides (modified p53: 232–240, TRP-2: 181–188 and PADRE) and CpG. Tumor growth was monitored and antigen-specific splenocyte responses were assayed by ELISPOT.

Results

Vaccine formulated in VM increased the number of both TRP2- and p53-specific IFN-γ producing splenocytes following a single vaccination. Vaccine formulated without VM resulted only in enhanced IFN-γ producing splenocytes to one CTL epitopes (TRP2:180–188), suggesting that VM overcomes antigen dominance and enhances immunogenicity of multiple epitopes. Vaccination of mice bearing 6-day old B16-F10 tumors with both TRP2 and p53-peptides formulated in VM successfully eradicated tumors in all mice. A control vaccine which contained all ingredients except liposomes resulted in eradication of tumors in no more than 20% of mice.

Conclusion

A single administration of VM is capable of inducing an effective CTL response to multiple tumor-associated antigens. The responses generated were able to reject 6-day old B16-F10 tumors.
Late-acting dominant lethal genetic systems and mosquito control
Authors: Phuc Hoang Kim , Andreasen Morten H , Burton Rosemary S , Vass Céline , Epton Matthew J , Pape Gavin , Fu Guoliang , Condon Kirsty C , Scaife Sarah , Donnelly Christl A , Coleman Paul G , White-Cooper Helen , Alphey Luke
Published: April 2007

Background

Reduction or elimination of vector populations will tend to reduce or eliminate transmission of vector-borne diseases. One potential method for environmentally-friendly, species-specific population control is the Sterile Insect Technique (SIT). SIT has not been widely used against insect disease vectors such as mosquitoes, in part because of various practical difficulties in rearing, sterilization and distribution. Additionally, vector populations with strong density-dependent effects will tend to be resistant to SIT-based control as the population-reducing effect of induced sterility will tend to be offset by reduced density-dependent mortality.

Results

We investigated by mathematical modeling the effect of manipulating the stage of development at which death occurs (lethal phase) in an SIT program against a density-dependence-limited insect population. We found late-acting lethality to be considerably more effective than early-acting lethality. No such strains of a vector insect have been described, so as a proof-of-principle we constructed a strain of the principal vector of the dengue and yellow fever viruses, Aedes (Stegomyia) aegypti, with the necessary properties of dominant, repressible, highly penetrant, late-acting lethality.

Conclusion

Conventional SIT induces early-acting (embryonic) lethality, but genetic methods potentially allow the lethal phase to be tailored to the program. For insects with strong density-dependence, we show that lethality after the density-dependent phase would be a considerable improvement over conventional methods. For density-dependent parameters estimated from field data for Aedes aegypti, the critical release ratio for population elimination is modeled to be 27% to 540% greater for early-acting rather than late-acting lethality. Our success in developing a mosquito strain with the key features that the modeling indicated were desirable demonstrates the feasibility of this approach for improved SIT for disease control.
Effect of peppermint water on prevention of nipple cracks in lactating primiparous women: a randomized controlled trial
Authors: Sayyah Melli Manizheh , Rashidi Mohammad Reza , Delazar Abbas , Madarek Elaheh , Kargar Maher Mohammad Hassan , Ghasemzadeh Alieh , Sadaghat Kamran , Tahmasebi Zohreh
Published: April 2007

Background

Nipple pain and damage in breastfeeding mothers are common causes of premature breastfeeding cessation. Peppermint water is popularly used for the prevention of nipple cracks in the North West of Iran. The aim of this study was to determine the effectiveness of peppermint water in the prevention of nipple cracks during breastfeeding in comparison with the application of expressed breast milk (EBM).

Methods

One hundred and ninety-six primiparous breastfeeding women who gave birth between February and May 2005 in a teaching hospital in Tabriz, Iran, were randomized to receive either peppermint water or EBM. Each woman was followed for up to three visits or telephone calls within 14 days and then by telephone call at week six postpartum.

Results

Women who were randomized to receive peppermint water were less likely to experience nipple and areola cracks (9%) compared to women using EBM (27%; p < 0.01). Women who used the peppermint water on a daily basis were less likely to have a cracked nipple than women who did not use peppermint water (relative risk 3.6, 95%CI: 2.9, 4.3). Nipple pain in the peppermint water group was lower than the expressed breast milk group (OR 5.6, 95% CI: 2.2, 14.6; p < 0.005).

Conclusion

This study suggests that peppermint water is effective in the prevention of nipple pain and damage. Further studies are needed to assess the usefulness of peppermint water in conjunction with correct breastfeeding techniques.

Trial registration number: NCT00456404
Serum antioxidant micromineral (Cu, Zn, Fe) status of drug dependent subjects: Influence of illicit drugs and lifestyle
Authors: Hossain Kazi Jahangir , Kamal Md Mustafa , Ahsan Monira , Islam SK Nazrul
Published: April 2007

Background

Use of illicit drugs induces multiple nutrient deficiencies. Drug habit, sexual practice and socioeconomic factors influence the nutrient profile of drug dependent subjects. The literature on this issue is still insufficient. This study has tested the hypothesis that illicit drug use and lifestyle impair mineral status. To test this hypothesis, 253 men multiple drug users of age 18–45 years were recruited to investigate their serum copper, zinc and iron levels. Influence of illicit drugs and their lifestyle on the mineral levels was also examined. The study subjects were drug dependent who had shared needles and had sexual activity with multiple partners. Serum concentrations of the minerals were estimated by atomic absorption flame spectrometry.

Results

Results showed a significant increase in serum copper and zinc concentrations, and decrease in iron level in drug dependent subjects. The increase of copper level was found to be much higher than that of zinc. Period of drug abuse had made a significant positive influence on the copper and iron levels, but it was apparently reversed for zinc concentration. Multiple sexual partnerships had significant influence on zinc status. There also were significant relationships observed between body mass index (BMI) as well as certain socioeconomic factors, and mineral status of drug dependent subjects and non-drug dependent controls. A series of multiple linear regression analysis predicted mineral values for education, age and BMI. The group (drug dependent subject = 1, non-drug dependent control = 2) had a significant influence on these parameters. However, after controlling these factors, it was shown that illicit drug use significantly contributed to influence the serum mineral levels.

Conclusion

Illicit drug use impairs serum mineral value causing an increase in copper and zinc and a decrease in iron. Lifestyle and nutritional status of drug dependent subjects influence serum mineral concentrations.
Polarity and intracellular compartmentalization of Drosophila neurons
Authors: Rolls Melissa M , Satoh Daisuke , Clyne Peter J , Henner Astra L , Uemura Tadashi , Doe Chris Q
Published: April 2007

Background

Proper neuronal function depends on forming three primary subcellular compartments: axons, dendrites, and soma. Each compartment has a specialized function (the axon to send information, dendrites to receive information, and the soma is where most cellular components are produced). In mammalian neurons, each primary compartment has distinctive molecular and morphological features, as well as smaller domains, such as the axon initial segment, that have more specialized functions. How neuronal subcellular compartments are established and maintained is not well understood. Genetic studies in Drosophila have provided insight into other areas of neurobiology, but it is not known whether flies are a good system in which to study neuronal polarity as a comprehensive analysis of Drosophila neuronal subcellular organization has not been performed.

Results

Here we use new and previously characterized markers to examine Drosophila neuronal compartments. We find that: axons and dendrites can accumulate different microtubule-binding proteins; protein synthesis machinery is concentrated in the cell body; pre- and post-synaptic sites localize to distinct regions of the neuron; and specializations similar to the initial segment are present. In addition, we track EB1-GFP dynamics and determine microtubules in axons and dendrites have opposite polarity.

Conclusion

We conclude that Drosophila will be a powerful system to study the establishment and maintenance of neuronal compartments.
Genetic interplay between the transcription factors Sp8 and Emx2 in the patterning of the forebrain
Authors: Zembrzycki Andreas , Griesel Gundula , Stoykova Anastasia , Mansouri Ahmed
Published: April 2007

Background

The forebrain consists of multiple structures necessary to achieve elaborate functions. Proper patterning is, therefore, a prerequisite for the generation of optimal functional areas. Only a few factors have been shown to control the genetic networks that establish early forebrain patterning.

Results and conclusion

Using conditional inactivation, we show that the transcription factor Sp8 has an essential role in the molecular and functional patterning of the developing telencephalon along the anteroposterior axis by modulating the expression gradients of Emx2 and Pax6. Moreover, Sp8 is essential for the maintenance of ventral cell identity in the septum and medial ganglionic eminence (MGE). This is probably mediated through a positive regulatory interaction with Fgf8 in the medial wall, and Nkx2.1 in the rostral MGE anlage, and independent of SHH and WNT signaling. Furthermore, Sp8 is required during corticogenesis to sustain a normal progenitor pool, and to control preplate splitting, as well as the specification of cellular diversity within distinct cortical layers.
Rheumatoid peripheral blood phagocytes are primed for activation but have impaired Fc-mediated generation of reactive oxygen species
Authors: Fairhurst Anna-Marie , Wallace Paul K , Jawad Ali SM , Goulding Nicolas J
Published: April 2007

Significant levels of circulating immune complexes (ICs) containing rheumatoid factors and immunoglobulin G in peripheral blood are a characteristic feature of rheumatoid arthritis (RA). ICs interact through Fcγ receptors (FcγR) to activate phagocytes in numerous inflammatory processes. The high concentration of neutrophils in synovial fluid during active phases of the disease, together with their destructive capacity, pose important questions as to their role in the pathogenesis of RA. Functional defects in RA or control peripheral blood neutrophil FcγRs were examined with a specific FcγR-mediated reactive oxygen species (ROS) assay. Heterologous cross-linking of FcγRIIa and FcγRIIIb on neutrophils resulted in a significantly decreased production of ROS by RA cells compared with controls matched for age and sex. However, expression and homologous ligation of receptors did not differ between these groups. These data suggest that neutrophil priming does occur before emigration into the joint and that blood neutrophils from patients with RA have a functional impairment in cooperative FcγR-mediated ROS generation. This may account for the increased susceptibility to bacterial infection that arises in patients with severe disease.
High abundance synovial fluid proteome: distinct profiles in health and osteoarthritis
Authors: Gobezie Reuben , Kho Alvin , Krastins Bryan , Sarracino David A , Thornhill Thomas S , Chase Michael , Millett Peter J , Lee David M
Published: April 2007

The development of increasingly high-throughput and sensitive mass spectroscopy-based proteomic techniques provides new opportunities to examine the physiology and pathophysiology of many biologic fluids and tissues. The purpose of this study was to determine protein expression profiles of high-abundance synovial fluid (SF) proteins in health and in the prevalent joint disease osteoarthritis (OA). A cross-sectional study of 62 patients with early OA (n= 21), patients with late OA (n= 21), and control individuals (n= 20) was conducted. SF proteins were separated by using one-dimensional PAGE, and the in-gel digested proteins were analyzed by electrospray ionization tandem mass spectrometry. A total of 362 spots were examined and 135 high-abundance SF proteins were identified as being expressed across all three study cohorts. A total of 135 SF proteins were identified. Eighteen proteins were found to be significantly differentially expressed between control individuals and OA patients. Two subsets of OA that are not dependent on disease duration were identified using unsupervised analysis of the data. Several novel SF proteins were also identified. Our analyses demonstrate no disease duration-dependent differences in abundant protein composition of SF in OA, and we clearly identified two previously unappreciated yet distinct subsets of protein profiles in this disease cohort. Additionally, our findings reveal novel abundant protein species in healthy SF whose functional contribution to SF physiology was not previously recognized. Finally, our studies identify candidate biomarkers for OA with potential for use as highly sensitive and specific tests for diagnostic purposes or for evaluating therapeutic response.
Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects
Authors: Tay Lee , Leon Francisco , Vratsanos George , Raymond Ralph , Corbo Michael
Published: April 2007

The effect of abatacept, a selective T-cell co-stimulation modulator, on vaccination has not been previously investigated. In this open-label, single-dose, randomized, parallel-group, controlled study, the effect of a single 750 mg infusion of abatacept on the antibody response to the intramuscular tetanus toxoid vaccine (primarily a memory response to a T-cell-dependent peptide antigen) and the intramuscular 23-valent pneumococcal vaccine (a less T-cell-dependent response to a polysaccharide antigen) was measured in 80 normal healthy volunteers. Subjects were uniformly randomized to receive one of four treatments: Group A (control group), subjects received vaccines on day 1 only; Group B, subjects received vaccines 2 weeks before abatacept; Group C, subjects received vaccines 2 weeks after abatacept; and Group D, subjects received vaccines 8 weeks after abatacept. Anti-tetanus and anti-pneumococcal (Danish serotypes 2, 6B, 8, 9V, 14, 19F and 23F) antibody titers were measured 14 and 28 days after vaccination. While there were no statistically significant differences between the dosing groups, geometric mean titers following tetanus or pneumococcal vaccination were generally lower in subjects who were vaccinated 2 weeks after receiving abatacept, compared with control subjects. A positive response (defined as a twofold increase in antibody titer from baseline) to tetanus vaccination at 28 days was seen, however, in ≥ 60% of subjects across all treatment groups versus 75% of control subjects. Similarly, over 70% of abatacept-treated subjects versus all control subjects (100%) responded to at least three pneumococcal serotypes, and approximately 25–30% of abatacept-treated subjects versus 45% of control subjects responded to at least six serotypes.
Soluble Fas ligand inhibits angiogenesis in rheumatoid arthritis
Authors: Kim Wan-Uk , Kwok Seung-Ki , Hong Kyung-Hee , Yoo Seung-Ah , Kong Jin-Sun , Choe Jongseon , Cho Chul-Soo
Published: April 2007

The characteristics of rheumatoid arthritis (RA) pathology include the infiltration of inflammatory leukocytes, the proliferation of synovial cells, and the presence of extensive angiogenesis, referred to as rheumatoid pannus. Fas ligand is critical to the homeostatic regulation of the immune response, but its role in the angiogenic process of RA remains to be defined. In this study, we investigated whether soluble Fas ligand (sFasL) induces synoviocyte apoptosis and regulates angiogenesis of endothelial cells in RA. The levels of sFasL were elevated in the synovial fluids of RA patients when compared to those of osteoarthritis (OA) patients, and they correlated inversely with vascular endothelial growth factor165(VEGF165) concentrations. sFasL, ranging from 10 to 100 ng/ml, induced the apoptosis of RA fibroblast-like synoviocytes (FLS)in vitro, and thereby decreased VEGF165production. In addition, sFasL inhibited VEGF165-induced migration and chemotaxis of endothelial cells to basal levels in a manner independent of the Fas-mediated cell death. sFasL dose-dependently suppressed the VEGF165-stimulated increase in pAkt expression in endothelial cells, which might be associated with its anti-migratory effect on endothelial cells. Moreover, sFasL strongly inhibited neovascularization in the Matrigel plugin vivo. Our data suggest that sFasL shows anti-angiogenic activity within RA joints not only by inducing apoptosis of VEGF165-producing cells but also by blocking VEGF165-induced migration of endothelial cells, independent of Fas-mediated apoptosis.
Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity
Authors: Vincent-Salomon Anne , Gruel Nadège , Lucchesi Carlo , MacGrogan Gaëtan , Dendale Remi , Sigal-Zafrani Brigitte , Longy Michel , Raynal Virginie , Pierron Gaëlle , de Mascarel Isabelle , Taris Corinne , Stoppa-Lyonnet Dominique , Pierga Jean-Yves , Salmon Rémy , Sastre-Garau Xavier , Fourquet Alain , Delattre Olivier , de Cremoux Patricia , Aurias Alain
Published: April 2007

Introduction

Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC).

Methods

Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs.

Results

All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC.

Conclusion

Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.
N-terminal pro-brain natriuretic peptide as an early prognostic factor in cancer patients developing septic shock
Authors: Mokart Djamel , Sannini Antoine , Brun Jean-Paul , Faucher Marion , Blaise Didier , Blache Jean-Louis , Faucher Catherine
Published: April 2007

Introduction

The overall prognosis of critically ill patients with cancer has improved during the past decade. The aim of this study was to identify early prognostic factors of intensive care unit (ICU) mortality in patients with cancer.

Methods

We designed a prospective, consecutive, observational study over a one-year period. Fifty-one cancer patients with septic shock were enrolled.

Results

The ICU mortality rate was 51% (26 deaths). Among the 45 patients who benefited from transthoracic echocardiography evaluation, 17 showed right ventricular dysfunction, 18 showed left ventricular diastolic dysfunction, 18 showed left ventricular systolic dysfunction, and 11 did not show any cardiac dysfunction. During the first three days of ICU course, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were significantly higher in patients presenting cardiac dysfunctions compared to patients without any cardiac dysfunction. Multivariate analysis discriminated early prognostic factors (within the first 24 hours after the septic shock diagnosis). ICU mortality was independently associated with NT-proBNP levels at day 2 (odds ratio, 1.2; 95% confidence interval, 1.004 to 1.32; p = 0.022). An NT-proBNP level of more than 6,624 pg/ml predicted ICU mortality with a sensitivity of 86%, a specificity of 77%, a positive predictive value of 79%, a negative predictive value of 85%, and an accuracy of 81%.

Conclusion

We observed that critically ill cancer patients with septic shock have an approximately 50% chance of survival to ICU discharge. NT-proBNP was independently associated with ICU mortality within the first 24 hours. NT-proBNP could be a useful tool for detecting high-risk cancer patients within the first 24 hours after septic shock diagnosis.
The influence of volume and intensive care unit organization on hospital mortality in patients admitted with severe sepsis: a retrospective multicentre cohort study
Authors: Peelen Linda , de Keizer Nicolette F , Peek Niels , Scheffer Gert Jan , van der Voort Peter HJ , de Jonge Evert
Published: April 2007

Introduction

The aim of the study was to assess the influence of annual volume and factors related to intensive care unit (ICU) organization on in-hospital mortality among patients admitted to the ICU with severe sepsis.

Methods

A retrospective cohort study was conducted using the database of the Dutch National Intensive Care Evaluation (NICE) registry. Analyses were based on consecutive patients admitted between 1 January 2003 and 30 June 2005 who fulfilled criteria for severe sepsis within the first 24 hours of admission. A 13-item questionnaire was sent to all 32 ICUs across The Netherlands that participated in the NICE registry within this period in order to obtain information on ICU organization and staffing. The association between in-hospital mortality and factors related to ICU organization was investigated using logistic regression analysis, combined with generalized estimation equations to account for potential correlations of outcomes within ICUs. Correction for patient-related factors took place by including Simplified Acute Physiology Score II, age, sex and number of dysfunctioning organ systems in the analyses.

Results

Analyses based on 4,605 patients from 28 ICUs (questionnaire response rate 90.6%) revealed that a higher annual volume of severe sepsis patients is associated with a lower in-hospital mortality (P = 0.029). The presence of a medium care unit (MCU) as a step-down facility with intermediate care is associated with a higher in-hospital mortality (P = 0.013). For other items regarding ICU organization, no independent significant relationships with in-hospital mortality were found.

Conclusion

A larger annual volume of patients with severe sepsis admitted to Dutch ICUs is associated with lower in-hospital mortality in this patient group. The presence of a MCU as a step-down facility is associated with greater in-hospital mortality. No other significant associations between in-hospital mortality and factors related to ICU organization were found.
Minimally invasive cardiopulmonary bypass: does it really change the outcome?
Authors: Ranucci Marco , Isgrò Giuseppe
Published: April 2007

Introduction

Many innovative cardiopulmonary bypass (CPB) systems have recently been proposed by the industry. With few differences, they all share a philosophy based on priming volume reduction, closed circuit with separation of the surgical field suction, centrifugal pump, and biocompatible circuit and oxygenator. These minimally invasive CPB (MICPB) systems are intended to limit the deleterious effects of a conventional CPB. However, no evidence exists with respect to their effectiveness in improving the postoperative outcome in a large population of patients. This study aimed to verify the clinical impact of an MICPB in a large population of patients undergoing coronary artery revascularization.

Methods

We conducted a retrospective analysis of 1,663 patients treated with an MICPB. The control group (conventional CPB) was extracted from a series of 2,877 patients according to a propensity score analysis.

Results

Patients receiving an MICPB had a shorter intensive care unit (ICU) stay, had lower peak postoperative serum creatinine and bilirubin levels, and suffered less postoperative blood loss. Within a multivariable model, MICPB is independently associated with lower rates of atrial fibrillation (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.69 to 0.99) and ventricular arrhythmias (OR 0.45, 95% CI 0.28 to 0.73) and with higher rates of early discharge from the ICU (OR 1.31, 95% CI 1.06 to 1.6) and from the hospital (OR 1.46, 95% CI 1.18 to 1.8). Hospital mortality did not differ between groups.

Conclusion

MICPBs are associated with reduced morbidity. However, these results will need to be confirmed in a large, prospective, randomized, controlled trial.
Sense-antisense pairs in mammals: functional and evolutionary considerations
Authors: Galante Pedro AF , Vidal Daniel O , de Souza Jorge E , Camargo Anamaria A , de Souza Sandro J
Published: April 2007

Background

A significant number of genes in mammalian genomes are being found to have natural antisense transcripts (NATs). These sense-antisense (S-AS) pairs are believed to be involved in several cellular phenomena.

Results

Here, we generated a catalog of S-AS pairs occurring in the human and mouse genomes by analyzing different sources of expressed sequences available in the public domain plus 122 massively parallel signature sequencing (MPSS) libraries from a variety of human and mouse tissues. Using this dataset of almost 20,000 S-AS pairs in both genomes we investigated, in a computational and experimental way, several putative roles that have been assigned to NATs, including gene expression regulation. Furthermore, these global analyses allowed us to better dissect and propose new roles for NATs. Surprisingly, we found that a significant fraction of NATs are artifacts produced by genomic priming during cDNA library construction.

Conclusion

We propose an evolutionary and functional model in which alternative polyadenylation and retroposition account for the origin of a significant number of functional S-AS pairs in mammalian genomes.
Porcine transcriptome analysis based on 97 non-normalized cDNA libraries and assembly of 1,021,891 expressed sequence tags
Authors: Gorodkin Jan , Cirera Susanna , Hedegaard Jakob , Gilchrist Michael J , Panitz Frank , Jørgensen Claus , Scheibye-Knudsen Karsten , Arvin Troels , Lumholdt Steen , Sawera Milena , Green Trine , Nielsen Bente J , Havgaard Jakob H , Rosenkilde Carina , Wang Jun , Li Heng , Li Ruiqiang , Liu Bin , Hu Songnian , Dong Wei , Li Wei , Yu Jun , Wang Jian , Stærfeldt Hans-Henrik , Wernersson Rasmus , Madsen Lone B , Thomsen Bo , Hornshøj Henrik , Bujie Zhan , Wang Xuegang , Wang Xuefei , Bolund Lars , Brunak Søren , Yang Huanming , Bendixen Christian , Fredholm Merete
Published: April 2007

Background

Knowledge of the structure of gene expression is essential for mammalian transcriptomics research. We analyzed a collection of more than one million porcine expressed sequence tags (ESTs), of which two-thirds were generated in the Sino-Danish Pig Genome Project and one-third are from public databases. The Sino-Danish ESTs were generated from one normalized and 97 non-normalized cDNA libraries representing 35 different tissues and three developmental stages.

Results

Using the Distiller package, the ESTs were assembled to roughly 48,000 contigs and 73,000 singletons, of which approximately 25% have a high confidence match to UniProt. Approximately 6,000 new porcine gene clusters were identified. Expression analysis based on the non-normalized libraries resulted in the following findings. The distribution of cluster sizes is scaling invariant. Brain and testes are among the tissues with the greatest number of different expressed genes, whereas tissues with more specialized function, such as developing liver, have fewer expressed genes. There are at least 65 high confidence housekeeping gene candidates and 876 cDNA library-specific gene candidates. We identified differential expression of genes between different tissues, in particular brain/spinal cord, and found patterns of correlation between genes that share expression in pairs of libraries. Finally, there was remarkable agreement in expression between specialized tissues according to Gene Ontology categories.

Conclusion

This EST collection, the largest to date in pig, represents an essential resource for annotation, comparative genomics, assembly of the pig genome sequence, and further porcine transcription studies.
Assembly of the Candida albicans genome into sixteen supercontigs aligned on the eight chromosomes
Authors: van het Hoog Marco , Rast Timothy J , Martchenko Mikhail , Grindle Suzanne , Dignard Daniel , Hogues Hervé , Cuomo Christine , Berriman Matthew , Scherer Stewart , Magee BB , Whiteway Malcolm , Chibana Hiroji , Nantel André , Magee PT
Published: April 2007

Background

The 10.9× genomic sequence of Candida albicans, the most important human fungal pathogen, was published in 2004. Assembly 19 consisted of 412 supercontigs, of which 266 were a haploid set, since this fungus is diploid and contains an extensive degree of heterozygosity but lacks a complete sexual cycle. However, sequences of specific chromosomes were not determined.

Results

Supercontigs from Assembly 19 (183, representing 98.4% of the sequence) were assigned to individual chromosomes purified by pulse-field gel electrophoresis and hybridized to DNA microarrays. Nine Assembly 19 supercontigs were found to contain markers from two different chromosomes. Assembly 21 contains the sequence of each of the eight chromosomes and was determined using a synteny analysis with preliminary versions of the Candida dubliniensis genome assembly, bioinformatics, a sequence tagged site (STS) map of overlapping fosmid clones, and an optical map. The orientation and order of the contigs on each chromosome, repeat regions too large to be covered by a sequence run, such as the ribosomal DNA cluster and the major repeat sequence, and telomere placement were determined using the STS map. Sequence gaps were closed by PCR and sequencing of the products. The overall assembly was compared to an optical map; this identified some misassembled contigs and gave a size estimate for each chromosome.

Conclusion

Assembly 21 reveals an ancient chromosome fusion, a number of small internal duplications followed by inversions, and a subtelomeric arrangement, including a new gene family, the TLO genes. Correlations of position with relatedness of gene families imply a novel method of dispersion. The sequence of the individual chromosomes of C. albicans raises interesting biological questions about gene family creation and dispersion, subtelomere organization, and chromosome evolution.