bluuebunny/crossref_metadata_2025 huggingface dataset:
A systems biology approach to investigate the effect of pH-induced gene regulation on solvent production by Clostridium acetobutylicum in continuous culture
Authors: Haus Sylvia , Jabbari Sara , Millat Thomas , Janssen Holger , Fischer Ralf-Jörg , Bahl Hubert , King John R , Wolkenhauer Olaf
Published: January 2011

Background

Clostridium acetobutylicum is an anaerobic bacterium which is known for its solvent-producing capabilities, namely regarding the bulk chemicals acetone and butanol, the latter being a highly efficient biofuel. For butanol production by C. acetobutylicum to be optimized and exploited on an industrial scale, the effect of pH-induced gene regulation on solvent production by C. acetobutylicum in continuous culture must be understood as fully as possible.

Results

We present an ordinary differential equation model combining the metabolic network governing solvent production with regulation at the genetic level of the enzymes required for this process. Parameterizing the model with experimental data from continuous culture, we demonstrate the influence of pH upon fermentation products: at high pH (pH 5.7) acids are the dominant product while at low pH (pH 4.5) this switches to solvents. Through steady-state analyses of the model we focus our investigations on how alteration in gene expression of C. acetobutylicum could be exploited to increase butanol yield in a continuous culture fermentation.

Conclusions

Incorporating gene regulation into the model of solvent production by C. acetobutylicum enables an accurate representation of the pH-induced switch to solvent production to be obtained and theoretical investigations of possible synthetic-biology approaches to be pursued. Steady-state analyses suggest that, to increase butanol yield, alterations in the expression of single solvent-associated genes are insufficient; a more complex approach targeting two or more genes is required.
Systems biological approach on neurological disorders: a novel molecular connectivity to aging and psychiatric diseases
Authors: Ahmed Shiek SSJ , Ahameethunisa Abdul R , Santosh Winkins , Chakravarthy Srinivasa , Kumar Suresh
Published: January 2011

Background

Systems biological approach of molecular connectivity map has reached to a great interest to understand the gene functional similarities between the diseases. In this study, we developed a computational framework to build molecular connectivity maps by integrating mutated and differentially expressed genes of neurological and psychiatric diseases to determine its relationship with aging.

Results

The systematic large-scale analyses of 124 human diseases create three classes of molecular connectivity maps. First, molecular interaction of disease protein network generates 3632 proteins with 6172 interactions, which determines the common genes/proteins between diseases. Second, Disease-disease network includes 4845 positively scored disease-disease relationships. The comparison of these disease-disease pairs with Medical Subject Headings (MeSH) classification tree suggests 25% of the disease-disease pairs were in same disease area. The remaining can be a novel disease-disease relationship based on gene/protein similarity. Inclusion of aging genes set showed 79 neurological and 20 psychiatric diseases have the strong association with aging. Third
and lastly, a curated disease biomarker network was created by relating the proteins/genes in specific disease contexts, such analysis showed 73 markers for 24 diseases. Further, the overall quality of the results was achieved by a series of statistical methods, to avoid insignificant data in biological networks.

Conclusions

This study improves the understanding of the complex interactions that occur between neurological and psychiatric diseases with aging, which lead to determine the diagnostic markers. Also, the disease-disease association results could be helpful to determine the symptom relationships between neurological and psychiatric diseases. Together, our study presents many research opportunities in post-genomic biomarkers development.
BiologicalNetworks - tools enabling the integration of multi-scale data for the host-pathogen studies
Authors: Kozhenkov Sergey , Sedova Mayya , Dubinina Yulia , Gupta Amarnath , Ray Animesh , Ponomarenko Julia , Baitaluk Michael
Published: January 2011

Background

Understanding of immune response mechanisms of pathogen-infected host requires multi-scale analysis of genome-wide data. Data integration methods have proved useful to the study of biological processes in model organisms, but their systematic application to the study of host immune system response to a pathogen and human disease is still in the initial stage.

Results

To study host-pathogen interaction on the systems biology level, an extension to the previously described BiologicalNetworks system is proposed. The developed methods and data integration and querying tools allow simplifying and streamlining the process of integration of diverse experimental data types, including molecular interactions and phylogenetic classifications, genomic sequences and protein structure information, gene expression and virulence data for pathogen-related studies. The data can be integrated from the databases and user's files for both public and private use.

Conclusions

The developed system can be used for the systems-level analysis of host-pathogen interactions, including host molecular pathways that are induced/repressed during the infections, co-expressed genes, and conserved transcription factor binding sites. Previously unknown to be associated with the influenza infection genes were identified and suggested for further investigation as potential drug targets. Developed methods and data are available through the Java application (from BiologicalNetworks program athttp://www.biologicalnetworks.org) and web interface (athttp://flu.sdsc.edu).
Toxoplasmosis in a patient who was immunocompetent: a case report
Authors: Taila Aneta K , Hingwe Ameet S , Johnson Laura E
Published: January 2011

Introduction

Toxoplasma gondii is an obligate intracellular protozoan that infects up to one-third of the world's population. Although this case is not the first of its kind, it is clinically important since it will help doctors keep a broad differential diagnosis in mind when attending to similar patients.

Case presentation

We present the case of a 20-year-old man of Middle Eastern heritage presenting with only generalized lymphadenopathy who was diagnosed with acute toxoplasmosis.

Conclusion

This case illustrates the important fact that toxoplasmosis can present with just simple lymphadenopathy, and thus can be confused with other infections such as Epstein-Barr virus and other mononucleosis-like illnesses such as cytomegalovirus, HIV with acute retroviral syndrome, cat scratch disease, leishmaniasis and syphilis. This case underlines why appropriate testing should be performed in confusing cases, and helps increase the knowledge about the diagnosis of this disease.
Determinants of patient satisfaction with ophthalmic services
Authors: Ziaei Hossain , Katibeh Marzieh , Eskandari Armen , Mirzadeh Monir , Rabbanikhah Zahra , Javadi Mohammad Ali
Published: January 2011

Background

This cross-sectional study was conducted during summer 2008 at an academic ophthalmic hospital to assess patient satisfaction with care services and examine the impact of different dimensions on overall satisfaction.

Findings

Clients of ophthalmic services were selected by systematic random sampling. Overall satisfaction was measured as the primary outcome using a validated patient satisfaction questionnaire (PSQ-18). Different domains were evaluated using PSQ-18 (technical quality, interpersonal manner, communication, financial aspects, time spent for patients, convenience and accessibility); an additional domain, physical setting of the hospital, was evaluated by complementary questions. A general linear model was used to assess the adjusted impact of each quality dimension on the overall satisfaction. Accessibility and technical quality had the strongest association with the overall satisfaction. This regression model could predict an overall satisfaction of 60%.

Conclusions

In comparable settings, if care providers wish to improve the quality of health services from a patients' perspective, they should give priority to improving accessibility and technical quality. Further studies are recommended to discover complementary predictors in formation of overall satisfaction.

Previous publication

Some parts of this article are translated form Farsi originally published in Bina Journal of Ophthalmology. (2009; 14 (3): 289-297). The original work is at: http://binajournal.org/index.php/bina/article/view/96.
Insecticide resistance in Aedes aegypti populations from Ceará, Brazil
Authors: Lima Estelita Pereira , Paiva Marcelo Henrique Santos , de Araújo Ana Paula , da Silva Éllyda Vanessa Gomes , da Silva Ulisses Mariano , de Oliveira Lúcia Nogueira , Santana Antonio Euzébio G , Barbosa Clarisse Nogueira , de Paiva Neto Clovis C , Goulart Marilia OF , Wilding Craig Stephen , Ayres Constância Flávia Junqueira , de Melo Santos Maria Alice V
Published: January 2011

Background

Organophosphates and pyrethroids are used widely in Brazil to control Aedes aegypti, the main vector of dengue viruses, under the auspices of the National Programme for Dengue Control. Resistance to these insecticides is widespread throughout Brazil. In Ceará the vector is present in 98% of districts and resistance to temephos has been reported previously. Here we measure resistance to temephos and the pyrethroid cypermethrin in three populations from Ceará and use biochemical and molecular assays to characterise resistance mechanisms.

Results

Resistance to temephos varied widely across the three studied populations, with resistance ratios (RR95) of 7.2, 30 and 192.7 in Juazeiro do Norte, Barbalha and Crato respectively. The high levels of resistance detected in Barbalha and Crato (RR95 ≥ 30) imply a reduction of temephos efficacy, and indeed in simulated field tests reduced effectiveness was observed for the Barbalha population. Two populations (Crato and Barbalha) were also resistant to cypermethrin, whilst Juazeiro do Norte showed only an altered susceptibility. The Ile1011Met kdr mutation was detected in all three populations and Val1016Ile in Crato and Juazeiro do Norte. 1011Met was significantly associated with resistance to cypermethrin in the Crato population. Biochemical tests showed that only the activity of esterases and GSTs, among the tested detoxification enzymes, was altered in these populations when compared with the Rockefeller strain.

Conclusions

Our results demonstrate that two A. aegypti populations from Ceará are under strong selection pressure by temephos, compromising the field effectiveness of this organophosphate. Our results also provide evidence that the process of reducing resistance to this larvicide in the field is difficult and slow and may require more than seven years for reversal. In addition, we show resistance to cypermethrin in two of the three populations studied, and for the first time the presence of the allele 1016Ile in mosquito populations from northeastern Brazil. A significant association between 1011M et and resistance was observed in one of the populations. Target-site mechanisms seem not to be implicated in temephos resistance, reinforcing the idea that for the studied populations, detoxification enzymes most likely play a major role in the resistance to this insecticide.
Do IGF-I concentrations better reflect growth hormone (GH) action in children with short stature than the results of GH stimulating tests? Evidence from the simultaneous assessment of thyroid function
Authors: Smyczyńska Joanna , Stawerska Renata , Lewiński Andrzej , Hilczer Maciej
Published: January 2011

Background

The diagnosis of growth hormone (GH) deficiency (GHD) in short children seems unquestionable when both GH peak in stimulating tests (GHST) and IGF-I concentration are decreased. However, the discrepancies between the results of GHST and IGF-I secretion are observed. It seems purposeful to determine the significance of GHST and IGF-I assessment in diagnosing GHD. The relationship between GH secretion and thyroid function, as well as GH influence on the peripheral thyroxine (T4) to triiodothyronine (T3) deiodination, mediated by IGF-I, were identified. Thus, clear differences in thyroid function between GH-deficient and non-GH-deficient subjects should exist.

Methods

Analysis comprised 800 children (541 boys), age 11.6 ± 3.1 years (mean ± SD), with short stature, in whom two (2) standard GHST (with clonidine and with glucagon) were performed and IGF-I, free T4 (FT4), free T3 (FT3) and TSH serum concentrations were assessed. The patients were qualified to the following groups: GHD - decreased GH peak in GHST and IGF-I SDS (n = 81), ISS - normal GH peak and IGF-I SDS (n = 347), low GH - normal IGF-I SDS, and decreased GH peak (n = 212), low IGF - decreased IGF-I SDS, and normal GH peak (n = 160). The relationships among the results of particular tests were evaluated.

Results

In the groups with decreased IGF-I concentrations (GHD Group and low IGF Group), the more severe deficit of height was observed, together with higher TSH and FT4 but lower FT3 levels than in groups with normal IGF-I concentrations (ISS Group and low GH Group), independently of the results of GHST. TSH, FT4 and FT3 concentrations were - respectively - similar in two groups with decreased IGF-I secretion, as well as in two groups with normal IGF-I levels. Significant correlations were found between patients' height SDS and IGF-I SDS, between FT3 and IGF-I SDS (positive), and between FT4 and IGF-I SDS (negative), with no correlation between GH peak and any of the parameters analyzed.

Conclusion

The assessment of thyroid function in children with short stature provides the evidence that measurement of IGF-I concentration may be a procedure reliable at least to the some degree in diagnosing GHD as the results of GHST.
Implementation of a new cost efficacy method for blood irradiation using a non dedicated device
Authors: Pinnarò Paola , Soriani Antonella , D'Alessio Daniela , Giordano Carolina , Foddai Maria Laura , Pinzi Valentina , Strigari Lidia
Published: January 2011

Objectives

To implement a new cost efficacy internal Service for blood component irradiation, we carried out specific procedures and quality assurance reports using the linear accelerators (LINACs) of the Regina Elena Institute (IRE) Radiotherapy Department instead of a dedicated device.

Methods

The technical aspects, quality assurance and regulatory requirements of the internal procedure to set up a local irradiated blood bank have been defined. The LINACs of the IRE Radiotherapy Department were used to deliver a mean dose of 32 Gy and dose accuracy was checked with gafchromic film. The overall time/cost of this procedure was compared with the previous procedure, out-sourcing the irradiation of blood components.

Results

A total of 1996 blood component units were internally irradiated in the first year. Moreover, reducing the overall procedure time by a third. Overall cost/bag of external and internal procedures was approx. 66 € and 11 €, respectively. Thus the average saving of cost/bag was higher than 80%. The use of gafchromic films in all irradiated blood component bags allowed the accuracy of the dose delivered to blood to be checked.

Conclusions

By utilizing LINACs installed in the Radiotherapy Department it is possible to provide an internal blood component irradiation service, capitalizing on internal resources without any inconvenience/discomfort to patients undergoing radiotherapy and satisfying governmental regulatory requirements. The internal irradiation procedures has proven to be safe and feasible, and along with the significant cost/time reduction suggests that it is more advantageous than external procedures.
Antimicrobial resistance among Escherichia coli that cause childhood community-acquired urinary tract infections in Northern Italy
Authors: Caracciolo Alessandra , Bettinelli Alberto , Bonato Claudio , Isimbaldi Clementina , Tagliabue Alessandro , Longoni Laura , Bianchetti Mario G
Published: January 2011

Abstracts

Background

Resistance rate of Escherichia coli against antimicrobials that are commonly prescribed in pediatric urinary tract infections is currently a matter of concern.

Methods

The antimicrobial susceptibility patterns of uropathogenic Escherichia coli strains to the common antibimcrobials ampicillin, cotrimoxazole, coamoxyclav, ceftazidime, ceftriaxone, nitrofurantoin, and gentamycin were determined in 177 children aged from 2 to 36 months. They presented with their first symptomatic community acquired urinary tract infection at the Department of Pediatrics, San Leopoldo Mandic Hospital, Merate-Lecco.

Results

High rates of ampicillin (inpatients: 50%; outpatients: 52%) resistance were identified. The resistance for cotrimoxazole (inpatients: 22%; outpatients: 15%) and especially coamoxyclav (inpatients: 6%; outpatients: 10%) was less pronounced than that to ampicillin. No resistance or less than 1% of resistance was identified for ceftazidime, ceftriaxone, nitrofurantoin, and gentamycin both in inpatients and in outpatients.

Conclusions

Italian children affected with a community acquired urinary tract infection are initially managed orally with coamoxyclav or parenterally with ceftriaxone. The results of the present retrospective analysis support this attitude. Parenteral ceftriaxone or an aminoglycoside should be considered for patients on antimicrobial prophylaxis or recently prescribed antimicrobials.
Breastfeeding and transmission of cytomegalovirus to preterm infants. Case report and kinetic of CMV-DNA in breast milk
Authors: Chiavarini Manuela , Bragetti Patrizia , Sensini Alessandra , Cenci Elio , Castronari Roberto , Rossi Marta J , Fantauzzi Ambra , Minelli Liliana
Published: January 2011

Background

Breastfeeding has a major impact on CMV epidemiology. Postnatal CMV reactivation's incidence during lactation is nearby the maternal seroprevalence. Although perinatal CMV infection has practically no consequences in term newborn, it may cause, in some cases, a severe symptomatic disease in preterm newborns.

The aims of the present study are to evaluate the rate and clinical expression of CMV infection breast milk transmitted in preterm infants and to check the safety of the freezing treated breast milk.

Methods

The study included fifty-seven preterm infants and their CMV seropositive mothers. Fresh breast milk samples have been collected from 1stto 9thpostpartum week. Both fresh breast milk and 72, 96, 120 hours frozen samples have been examined, checking the presence of CMV; urine samples have been tested too.

Results

70.2% of tested mothers showed reactivation of the infection, and CMV-positive breast milk during the six weeks postpartum has been found. However, only one infant was infected by CMV, developing hepatic affection concomitantly with a multi-system involvement, as shown CMV DNA detection in urine, saliva, blood, gastric aspirate, and stools.

Conclusion

Freezing breast milk at -20°C and pasteurization may respectively reduce or eliminate the viral load.
Single- and double-stranded DNA binding proteins act in concert to conserve a telomeric DNA core sequence
Authors: Rhodin Edsö Jenny , Gustafsson Cecilia , Cohn Marita
Published: January 2011

Background

Telomeres are protective cap structures at the ends of the linear eukaryotic chromosomes, which provide stability to the genome by shielding from degradation and chromosome fusions. The cap consists of telomere-specific proteins binding to the respective single- and double-stranded parts of the telomeric sequence. In addition to the nucleation of the chromatin structure the telomere-binding proteins are involved in the regulation of the telomere length. However, the telomeric sequences are highly diverged among yeast species. During the evolution this high rate of divergency presents a challenge for the sequence recognition of the telomere-binding proteins.

Results

We found that the Saccharomyces castellii protein Rap1, a negative regulator of telomere length, binds a 12-mer minimal binding site (MBS) within the double-stranded telomeric DNA. The sequence specificity is dependent on the interaction with two 5 nucleotide motifs, having a 6 nucleotide centre-to-centre spacing. The isolated DNA-binding domain binds the same MBS and retains the same motif binding characteristics as the full-length Rap1 protein. However, it shows some deviations in the degree of sequence-specific dependence in some nucleotide positions. Intriguingly, the positions of most importance for the sequence-specific binding of the full-length Rap1 protein coincide with 3 of the 4 nucleotides utilized by the 3' overhang binding protein Cdc13. These nucleotides are very well conserved within the otherwise highly divergent telomeric sequences of yeasts.

Conclusions

Rap1 and Cdc13 are two very distinct types of DNA-binding proteins with highly separate functions. They interact with the double-stranded vs. the single-stranded telomeric DNA via significantly different types of DNA-binding domain structures. However, we show that they are dependent on coinciding nucleotide positions for their sequence-specific binding to telomeric sequences. Thus, we conclude that during the molecular evolution they act together to preserve a core sequence of the telomeric DNA.
(Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis
Authors: den Uyl Debby , Nurmohamed Mike T , van Tuyl Lilian HD , Raterman Hennie G , Lems Willem F
Published: January 2011

Introduction

Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms.

Methods

A systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized.

Results

Seventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation.

Conclusions

The current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk.
Risk factors and outcomes after unplanned extubations on the ICU: a case-control study
Authors: de Groot Robin I , Dekkers Olaf M , Herold Ingeborg HF , de Jonge Evert , Arbous M Sesmu
Published: January 2011

Introduction

Unplanned extubation (UE) is a frequent event during mechanical ventilation in critically ill patients and might be associated with increased morbidity and mortality. However, detailed knowledge of risk factors and outcomes after UE is lacking.

Methods

A case-control study was performed with a case to control ratio of 1:4. Incidence density sampling was applied. Seventy-four cases and 296 control patients were included.

Results

Seventy-four UEs occurred in 69 patients, comprising 2% of all mechanically ventilated patients. Multivariable regression analysis revealed that the first and second categories of the Ramsay Sedation Scale score were associated with a high risk for an UE (odds ratios (ORs) 30 and 25, respectively). Male sex, subunit of the intensive care unit (ICU), length of stay in the ICU and midazolam use at time of UE were also risk factors for an UE. Patients with an UE had lower hospital mortality than mechanically ventilated patients without UE, 10% versus 30%, respectively. Forty-seven percent (n = 35) of the patients with an UE had to be reintubated.

Conclusions

The present study shows that the first and second categories of the Ramsay Sedation Scale were associated with a high risk for an UE. Also, male sex and use of midazolam at time of UE were identified as risk factors for an UE. However, compared with mechanically ventilated controls, no increased mortality was shown for UE patients. In UE patients without the need for subsequent reintubation, mortality was very low.
Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis
Authors: Paunel-Görgülü Adnana , Flohé Sascha , Scholz Martin , Windolf Joachim , Lögters Tim
Published: January 2011

Introduction

Deregulated apoptosis and overshooting neutrophil functions contribute to immune and organ dysfunction in sepsis and multiple organ failure (MOF). In the present study, we determined the role of soluble Fas (sFas) in the regulation of posttraumatic neutrophil extrinsic apoptosis and the development of sepsis.

Methods

Forty-seven major trauma patients, 18 with and 29 without sepsis development during the first 10 days after trauma, were enrolled in this prospective study. Seventeen healthy volunteers served as controls. Blood samples from severely injured patients were analyzed at day 1, day 5 and day 9 after major trauma. sFas levels, plasma levels of neutrophil elastase (PMNE) and levels of interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay and related to patients' Sequential Organ Failure Assessment (SOFA) score and Multiple Organ Dysfunction Score (MODS). Neutrophil apoptosis was determined by propidium iodide staining of fragmented DNA and flow cytometry. sFas-mediated effects on neutrophil apoptosis were investigated in cells cultured with agonistic anti-Fas antibodies in the presence of recombinant sFas, sFas-depleted serum or untreated serum from septic patients.

Results

Serum levels of sFas in patients who later developed sepsis were significantly increased at day 5 (P < 0.01) and day 9 (P < 0.05) after trauma compared with patients with uneventful recovery. Apoptosis of patient neutrophils was significantly decreased during the observation period compared with control cells. Moreover, Fas-mediated apoptosis of control neutrophils was efficiently inhibited by recombinant sFas and serum from septic patients. Depletion of sFas from septic patient sera diminished the antiapoptotic effects. In septic patients, sFas levels were positively correlated with SOFA at day 1 (r = 0.7, P < 0.001), day 5 (r = 0.62, P < 0.01) and day 9 (r = 0.58, P < 0.01) and with PMNE and leukocyte counts (r = 0.49, P < 0.05 for both) as well as MODS at day 5 (r = 0.56, P < 0.01) after trauma.

Conclusions

Increased sFas in patients with sepsis development impairs neutrophil extrinsic apoptosis and shows a positive correlation with the organ dysfunction scores and PMNE. Therefore, sFas might be a therapeutic target to prevent posttrauma hyperinflammation and sepsis.
Effect of norepinephrine dosage and calibration frequency on accuracy of pulse contour-derived cardiac output
Authors: Gruenewald Matthias , Meybohm Patrick , Renner Jochen , Broch Ole , Caliebe Amke , Weiler Norbert , Steinfath Markus , Scholz Jens , Bein Berthold
Published: January 2011

Introduction

Continuous cardiac output monitoring is used for early detection of hemodynamic instability and guidance of therapy in critically ill patients. Recently, the accuracy of pulse contour-derived cardiac output (PCCO) has been questioned in different clinical situations. In this study, we examined agreement between PCCO and transcardiopulmonary thermodilution cardiac output (COTCP) in critically ill patients, with special emphasis on norepinephrine (NE) administration and the time interval between calibrations.

Methods

This prospective, observational study was performed with a sample of 73 patients (mean age, 63 ± 13 years) requiring invasive hemodynamic monitoring on a non-cardiac surgery intensive care unit. PCCO was recorded immediately before calibration by COTCP. Bland-Altman analysis was performed on data subsets comparing agreement between PCCO and COTCP according to NE dosage and the time interval between calibrations up to 24 hours. Further, central artery stiffness was calculated on the basis of the pulse pressure to stroke volume relationship.

Results

A total of 330 data pairs were analyzed. For all data pairs, the mean COTCP (±SD) was 8.2 ± 2.0 L/min. PCCO had a mean bias of 0.16 L/min with limits of agreement of -2.81 to 3.15 L/min (percentage error, 38%) when compared to COTCP. Whereas the bias between PCCO and COTCP was not significantly different between NE dosage categories or categories of time elapsed between calibrations, interchangeability (percentage error <30%) between methods was present only in the high NE dosage subgroup (≥0.1 μg/kg/min), as the percentage errors were 40%, 47% and 28% in the no NE, NE < 0.1 and NE ≥ 0.1 μg/kg/min subgroups, respectively. PCCO was not interchangeable with COTCP in subgroups of different calibration intervals. The high NE dosage group showed significantly increased central artery stiffness.

Conclusions

This study shows that NE dosage, but not the time interval between calibrations, has an impact on the agreement between PCCO and COTCP. Only in the measurements with high NE dosage (representing the minority of measurements) was PCCO interchangeable with COTCP.
Risk assessment in the first fifteen minutes: a prospective cohort study of a simple physiological scoring system in the emergency department
Authors: Merz Tobias M , Etter Reto , Mende Ludger , Barthelmes Daniel , Wiegand Jan , Martinolli Luca , Takala Jukka
Published: January 2011

Introduction

The survival of patients admitted to an emergency department is determined by the severity of acute illness and the quality of care provided. The high number and the wide spectrum of severity of illness of admitted patients make an immediate assessment of all patients unrealistic. The aim of this study is to evaluate a scoring system based on readily available physiological parameters immediately after admission to an emergency department (ED) for the purpose of identification of at-risk patients.

Methods

This prospective observational cohort study includes 4,388 consecutive adult patients admitted via the ED of a 960-bed tertiary referral hospital over a period of six months. Occurrence of each of seven potential vital sign abnormalities (threat to airway, abnormal respiratory rate, oxygen saturation, systolic blood pressure, heart rate, low Glasgow Coma Scale and seizures) was collected and added up to generate the vital sign score (VSS). VSSinitial was defined as the VSS in the first 15 minutes after admission, VSSmax as the maximum VSS throughout the stay in ED. Occurrence of single vital sign abnormalities in the first 15 minutes and VSSinitial and VSSmax were evaluated as potential predictors of hospital mortality.

Results

Logistic regression analysis identified all evaluated single vital sign abnormalities except seizures and abnormal respiratory rate to be independent predictors of hospital mortality. Increasing VSSinitial and VSSmax were significantly correlated to hospital mortality (odds ratio (OR) 2.80, 95% confidence interval (CI) 2.50 to 3.14, P < 0.0001 for VSSinitial; OR 2.36, 95% CI 2.15 to 2.60, P < 0.0001 for VSSmax). The predictive power of VSS was highest if collected in the first 15 minutes after ED admission (log rank Chi-square 468.1, P < 0.0001 for VSSinitial;,log rank Chi square 361.5, P < 0.0001 for VSSmax).

Conclusions

Vital sign abnormalities and VSS collected in the first minutes after ED admission can identify patients at risk of an unfavourable outcome.
Pulse pressure variation and stroke volume variation during increased intra-abdominal pressure: an experimental study
Authors: Jacques Didier , Bendjelid Karim , Duperret Serge , Colling Joëlle , Piriou Vincent , Viale Jean-Paul
Published: January 2011

Introduction

The aim of this study was to evaluate dynamic indices of fluid responsiveness in a model of intra-abdominal hypertension.

Methods

Nine mechanically-ventilated pigs underwent increased intra-abdominal pressure (IAP) by abdominal banding up to 30 mmHg and then fluid loading (FL) at this IAP. The same protocol was carried out in the same animals made hypovolemic by blood withdrawal. In both volemic conditions, dynamic indices of preload dependence were measured at baseline IAP, at 30 mmHg of IAP, and after FL. Dynamic indices involved respiratory variations in stroke volume (SVV), pulse pressure (PPV), and systolic pressure (SPV, %SPV and Δdown). Stroke volume (SV) was measured using an ultrasound transit-time flow probe placed around the aortic root. Pigs were considered to be fluid responders if their SV increased by 15% or more with FL. Indices of fluid responsiveness were compared with a Mann-Whitney U test. Then, receiver operating characteristic (ROC) curves were generated for these parameters, allowing determination of the cut-off values by using Youden's method.

Results

Five animals before blood withdrawal and all animals after blood withdrawal were fluid responders. Before FL, SVV (78 ± 19 vs 42 ± 17%), PPV (64 ± 18 vs 37 ± 15%), SPV (24 ± 5 vs 18 ± 3 mmHg), %SPV (24 ± 4 vs 17 ± 3%) and Δdown (13 ± 5 vs 6 ± 4 mmHg) were higher in responders than in non-responders (P < 0.05). Areas under ROC curves were 0.93 (95% confidence interval: 0.80 to 1.06), 0.89 (0.70 to 1.07), 0.90 (0.74 to 1.05), 0.92 (0.78 to 1.06), and 0.86 (0.67 to 1.06), respectively. Threshold values discriminating responders and non-responders were 67% for SVV and 41% for PPV.

Conclusions

In intra-abdominal hypertension, respiratory variations in stroke volume and arterial pressure remain indicative of fluid responsiveness, even if threshold values identifying responders and non-responders might be higher than during normal intra-abdominal pressure. Further studies are required in humans to determine these thresholds in intra-abdominal hypertension.
Genetic Factors Underlying the Risk of Thalidomide-Related Neuropathy in Patients With Multiple Myeloma
Authors: Johnson David C. , Corthals Sophie L. , Walker Brian A. , Ross Fiona M. , Gregory Walter M. , Dickens Nicholas J. , Lokhorst Henk M. , Goldschmidt Hartmut , Davies Faith E. , Durie Brian G.M. , Van Ness Brian , Child J. Anthony , Sonneveld Pieter , Morgan Gareth J.
Published: January 2011

Purpose

To indentify genetic variation that can modulate and predict the risk of developing thalidomide-related peripheral neuropathy (TrPN).

Patients and Methods

We analyzed DNA from 1,495 patients with multiple myeloma. Using a custom-built single nucleotide polymorphism (SNP) array, we tested the association of TrPN with 3,404 SNPs. The SNPs were selected in predicted functional regions within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and adverse effects associated with myeloma and its therapy. Patient cases and controls were derived from two large clinical trials that compared thalidomide with conventional-based treatment in myeloma patients (Medical Research Council Myeloma-IX and HOVON-50/GMMG-HD3).

Results

We report TrPN associations with SNPs—ABCA1 (rs363717), ICAM1 (rs1799969), PPARD (rs2076169), SERPINB2 (rs6103), and SLC12A6 (rs7164902)—where we show cross validation of the associations in both trials. To investigate whether TrPN SNP associations were related to exposure to thalidomide only or general drug-related peripheral neuropathy, we performed a second analysis on patients treated with vincristine. We report SNPs associated with vincristine neuropathy, with a seemingly distinct underlying genetic mechanism.

Conclusion

Our results are consistent with the hypothesis that an individual's risk of developing a peripheral neuropathy after thalidomide treatment can be mediated by polymorphisms in genes governing repair mechanisms and inflammation in the peripheral nervous system. These findings will contribute to the development of future neuroprotective strategies with thalidomide therapy and the better use of this important compound.
C-MYC Alterations and Association With Patient Outcome in Early-Stage HER2-Positive Breast Cancer From the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial
Authors: Perez Edith A. , Jenkins Robert B. , Dueck Amylou C. , Wiktor Anne E. , Bedroske Patrick P. , Anderson S. Keith , Ketterling Rhett P. , Sukov William R. , Kanehira Kazunori , Chen Beiyun , Geiger Xochiquetzal J. , Andorfer Cathy A. , McCullough Ann E. , Davidson Nancy E. , Martino Silvana , Sledge George W. , Kaufman Peter A. , Kutteh Leila A. , Gralow Julie R. , Harris Lyndsay N. , Ingle James N. , Lingle Wilma L. , Reinholz Monica M.
Published: January 2011

Purpose

Findings from the human epidermal growth factor receptor 2 (HER2) –positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial—North Central Cancer Treatment Group (NCCTG) N9831.

Patients and Methods

This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8.

Results

In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05).

Conclusion

We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.
Candidate Reference Measurement Procedures for Serum 25-Hydroxyvitamin D3 and 25-Hydroxyvitamin D2 by Using Isotope-Dilution Liquid Chromatography–Tandem Mass Spectrometry
Authors: Stepman Hedwig CM , Vanderroost An , Van Uytfanghe Katleen , Thienpont Linda M
Published: January 2011

BACKGROUND

25-hydroxyvitamin D [25(OH)D] assays are characterized by poor between-assay comparability. This result emphasizes the need for reference measurement procedures (RMPs) to establish calibration traceability and assist in method validation. We aimed at developing candidate RMPs on the basis of isotope- dilution liquid chromatography–tandem mass spectrometry (ID-LC-MS/MS) for separate quantification of serum 25(OH)D2 and 25(OH)D3.

METHODS

Hexa-deuterated 25(OH)D3/D2 was added to serum. This mixture was extracted with n-hexane and fractionated on Sephadex LH-20 before 2-dimensional LC-MS/MS. In the first dimension, both procedures used a C4 column; however, in the second dimension, the 25(OH)D2 procedure used a C18 and the 25(OH)D3 procedure used a Zorbax SB-CN column. Calibration was traceable to the NIST Standard Reference Material (SRM) 2972. Validation comprised assessment of interference and limit of quantification/detection. Imprecision and trueness were validated by analysis of the SRM 972 against specifications (CV <5% and bias <1.7%). The expanded uncertainty for quadruplicate measurements was estimated.

RESULTS

Testing of potentially interfering substances was negative. Interference by 3-epi-25(OH)D3 was resolved by sufficient chromatographic resolution. The limits of quantification/detection were 1.1 nmol/L and 0.09 pmol/L for 25(OH)D3 and 1.2 nmol/L and 0.05 pmol/L for 25(OH)D2. Mean total CVs and differences from the SRM 972 target (± 1-sided 95% CI) were 2.1% and 1.1% ± 1.5% [25(OH)D3] and 3% and 1.3% ± 0.6% [25(OH)D2], respectively. The respective expanded uncertainties were 3.4% and 3.9%.

CONCLUSIONS

From the validation data, we conclude that we achieved our objective of 2 state-of-the-art candidate RMPs for serum 25(OH)D3 and 25(OH)D2.
The ERK2 Mitogen-Activated Protein Kinase Regulates the Timing of Oligodendrocyte Differentiation
Authors: Fyffe-Maricich Sharyl L. , Karlo J. Colleen , Landreth Gary E. , Miller Robert H.
Published: January 2011

Oligodendrocyte development is tightly controlled by a variety of extracellular growth and differentiation factors. The mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, are critical intracellular signaling molecules important for transducing these extracellular signals. The extracellular signal-regulated kinases (ERKs) are ubiquitously expressed, coordinately regulated, and highly similar, butErk2deletion in mice is embryonic lethal whereasErk1deletion is not. Several studies have suggested that MAPK signaling is important for oligodendrocyte differentiation, although specific roles for the two ERK isoforms have not been investigated. In this study, we deletedErk2in the developing mouse cortex from GFAP-expressing radial glia that generate neurons and oligodendrocytes.In vitroanalysis revealed that loss of ERK2 resulted in fewer galactocerebroside-expressing mature oligodendrocytes in cortical cultures.In vivo, a delay in the expression of the myelin protein MBP was observed in the corpus callosum at postnatal day 10 (P10). In contrast,Erk1deletion did not affect oligodendrocyte differentiation. By P21, MBP expression was restored to wild-type levels, demonstrating that the loss of ERK2 results in a delay but not a complete arrest in the appearance of differentiated oligodendrocytesin vivo. Importantly, both the proliferation and total number of oligodendrocyte progenitor cells (OPCs) appeared normal in theErk2conditional knock-out cortex, demonstrating that ERK2 plays a specific role in the timing of forebrain myelination but is not critical for the proliferation or survival of OPCs. Oligodendrocyte-specific deletion ofErk2also resulted in decreased levels of MBP, indicating a cell-autonomous effect of ERK2 in the oligodendrocyte lineage.
Opposing Gradients of Ribbon Size and AMPA Receptor Expression Underlie Sensitivity Differences among Cochlear-Nerve/Hair-Cell Synapses
Authors: Liberman Leslie D. , Wang Haobing , Liberman M. Charles
Published: January 2011

The auditory system transduces sound-evoked vibrations over a range of input sound pressure levels spanning six orders of magnitude. An important component of the system mediating this impressive dynamic range is established in the cochlear sensory epithelium, where functional subtypes of cochlear nerve fibers differ in threshold sensitivity, and spontaneous discharge rate (SR), by more than a factor of 1000 (Liberman, 1978), even though, regardless of type, each fiber contacts only a single hair cell via a single ribbon synapse. To study the mechanisms underlying this remarkable heterogeneity in threshold sensitivity among the 5–30 primary sensory fibers innervating a single inner hair cell, we quantified the sizes of presynaptic ribbons and postsynaptic AMPA receptor patches in >1200 synapses, using high-power confocal imaging of mouse cochleas immunostained for CtBP2 (C-terminal binding protein 2, a major ribbon protein) and GluR2/3 (glutamate receptors 2 and 3). We document complementary gradients, most striking in mid-cochlear regions, whereby synapses from the modiolar face and/or basal pole of the inner hair cell have larger ribbons and smaller receptor patches than synapses located in opposite regions of the cell. The AMPA receptor expression gradient likely contributes to the differences in cochlear nerve threshold and SR seen on the two sides of the hair cellin vivo(Liberman, 1982a); the differences in ribbon size may contribute to the heterogeneity of EPSC waveforms seenin vitro(Grant et al., 2010).
Multipotent Adult Progenitor Cells Prevent Macrophage-Mediated Axonal Dieback and Promote Regrowth after Spinal Cord Injury
Authors: Busch Sarah A. , Hamilton Jason A. , Horn Kevin P. , Cuascut Fernando X. , Cutrone Rochelle , Lehman Nicholas , Deans Robert J. , Ting Anthony E. , Mays Robert W. , Silver Jerry
Published: January 2011

Macrophage-mediated axonal dieback presents an additional challenge to regenerating axons after spinal cord injury. Adult adherent stem cells are known to have immunomodulatory capabilities, but their potential to ameliorate this detrimental inflammation-related process has not been investigated. Using anin vitromodel of axonal dieback as well as an adult rat dorsal column crush model of spinal cord injury, we found that multipotent adult progenitor cells (MAPCs) can affect both macrophages and dystrophic neurons simultaneously. MAPCs significantly decrease MMP-9 (matrix metalloproteinase-9) release from macrophages, effectively preventing induction of axonal dieback. MAPCs also induce a shift in macrophages from an M1, or “classically activated” proinflammatory state, to an M2, or “alternatively activated” antiinflammatory state. In addition to these effects on macrophages, MAPCs promote sensory neurite outgrowth, induce sprouting, and further enable axons to overcome the negative effects of macrophages as well as inhibitory proteoglycans in their environment by increasing their intrinsic growth capacity. Our results demonstrate that MAPCs have therapeutic benefits after spinal cord injury and provide specific evidence that adult stem cells exert positive immunomodulatory and neurotrophic influences.