bluuebunny/crossref_metadata_2025 huggingface dataset:
Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma
Authors: Lin Ying-Wei , Nichols Rebecca A. , Letterio John J. , Aplan Peter D.
Published: November 2005

NOTCH1 is frequently mutated in human precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). In the current study, we found that 13 of 19 cell lines and 29 of 49 primary tumors from SCL/LMO1, OLIG2/LMO1, OLIG2, LMO1, NUP98/HOXD13, and p27-/-/SMAD3+/- mice had Notch1 mutations in either the heterodimerization (HD) or the glutamic acid/serine/threonine (PEST) domain but not both. Thymocytes from clinically healthy SCL/LMO1 mice aged 5 weeks did not have Notch1 mutations, whereas thymocytes from clinically healthy SCL/LMO1 mice aged 8 to 12 weeks did have Notch1 mutations and formed tumors upon transplantation into nude mice. Remarkably, all of the HD domain mutations that we identified were single-base substitutions, whereas all of the PEST domain mutations were insertions or deletions, half of which mapped to 1 of 2 mutational “hot spots.” Taken together, these findings indicate that Notch1 mutations are very frequent events that are acquired relatively early in the process of leukemic transformation and are important for leukemic cell growth. (Blood. 2006;107: 2540-2543)
Nitric oxide generation from hydroxyurea: significance and implications for leukemogenesis in the management of myeloproliferative disorders
Authors: Burkitt Mark J. , Raafat Alaeddin
Published: November 2005

The use of myelosuppressive agents to reduce the risk of thrombosis in patients with polycythemia vera (PV) and essential thrombocythemia (ET) has been associated with an increased risk of transformation to acute myeloid leukemia (AML). Whereas chlorambucil, busulfan, and radiophosphorus (32P) have been demonstrated to increase the risk of transformation, the leukemogenic potential of hydroxyurea (HU) continues to be a matter of debate. Clinical studies have suggested that HU may cause a small increase in the risk of AML, but it has proven difficult to establish whether AML is actually caused by HU or arises during the natural progression of PV and ET. Reports that HU undergoes metabolic activation to species that induce mutation appear to support the notion that it is leukemogenic. Here, we suggest that the ability of HU to induce mutation in cell culture studies results from the generation of nitrogen dioxide via the autoxidation of nitric oxide, a product of HU metabolism. However, we argue that autoxidation would not occur in vivo, leading to the conclusion that generation of the mutagen nitrogen dioxide is peculiar to cell culture systems and has little relevance to the use of HU in the management of PV and ET.
Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation—a randomized double-blind placebo-controlled study
Authors: Boeckh Michael , Kim Hyung W. , Flowers Mary E. D. , Meyers Joel D. , Bowden Raleigh A.
Published: November 2005

Varicella-zoster virus (VZV) disease occurs in 30% of allogeneic hematopoietic cell transplant recipients who had a history of VZV infection. A safe and effective prevention strategy has not been established. In a double-blind controlled trial, 77 hematopoietic cell transplant recipients at risk for VZV reactivation were randomized to acyclovir 800 mg twice daily or placebo given from 1 to 2 months until 1 year after transplantation. VZV disease at 1 year was the primary end point; VZV disease after discontinuation of prophylaxis, VZV-specific T-cell immunity, herpes simplex virus (HSV) infection, cytomegalovirus (CMV) disease, survival, and safety were secondary end points. Acyclovir significantly reduced VZV infections at 1 year after transplantation (HR, 0.16; 95% CI, 0.035-0.74; P = .006). In the postintervention observation period, this difference was not statistically significant (2 years: HR, 0.52; 95% CI, 0.21-1.3; 5 years: HR, 0.76; 95% CI, 0.36-1.6). There was no statistically significant difference in reconstitution of VZV-specific T-helper cell responses, HSV infections, CMV disease, chronic graft-versus-host disease, and overall survival between the groups. Acyclovir was well tolerated. Post-study VZV disease predominantly occurred in patients with continued need for systemic immunosuppression. In conclusion, acyclovir effectively and safely prevents VZV disease during the first year after hematopoietic cell transplantation. Periods of prophylaxis longer than 12 months may be beneficial for those hematopoietic cell transplant recipients on continued immune suppression.
MiMiR: a comprehensive solution for storage, annotation and exchange of microarray data
Authors: Navarange Mahendra , Game Laurence , Fowler Derek , Wadekar Vihar , Banks Helen , Cooley Nicola , Rahman Fatimah , Hinshelwood Justin , Broderick Peter , Causton Helen C
Published: November 2005

Background

The generation of large amounts of microarray data presents challenges for data collection, annotation, exchange and analysis. Although there are now widely accepted formats, minimum standards for data content and ontologies for microarray data, only a few groups are using them together to build and populate large-scale databases. Structured environments for data management are crucial for making full use of these data.

Description

The MiMiR database provides a comprehensive infrastructure for microarray data annotation, storage and exchange and is based on the MAGE format. MiMiR is MIAME-supportive, customised for use with data generated on the Affymetrix platform and includes a tool for data annotation using ontologies. Detailed information on the experiment, methods, reagents and signal intensity data can be captured in a systematic format. Reports screens permit the user to query the database, to view annotation on individual experiments and provide summary statistics. MiMiR has tools for automatic upload of the data from the microarray scanner and export to databases using MAGE-ML.

Conclusion

MiMiR facilitates microarray data management, annotation and exchange, in line with international guidelines. The database is valuable for underpinning research activities and promotes a systematic approach to data handling. Copies of MiMiR are freely available to academic groups under licence.
Commensurate distances and similar motifs in genetic congruence and protein interaction networks in yeast
Authors: Ye Ping , Peyser Brian D , Spencer Forrest A , Bader Joel S
Published: November 2005

Background

In a genetic interaction, the phenotype of a double mutant differs from the combined phenotypes of the underlying single mutants. When the single mutants have no growth defect, but the double mutant is lethal or exhibits slow growth, the interaction is termed synthetic lethality or synthetic fitness. These genetic interactions reveal gene redundancy and compensating pathways. Recently available large-scale data sets of genetic interactions and protein interactions in Saccharomyces cerevisiae provide a unique opportunity to elucidate the topological structure of biological pathways and how genes function in these pathways.

Results

We have defined congruent genes as pairs of genes with similar sets of genetic interaction partners and constructed a genetic congruence network by linking congruent genes. By comparing path lengths in three types of networks (genetic interaction, genetic congruence, and protein interaction), we discovered that high genetic congruence not only exhibits correlation with direct protein interaction linkage but also exhibits commensurate distance with the protein interaction network. However, consistent distances were not observed between genetic and protein interaction networks. We also demonstrated that congruence and protein networks are enriched with motifs that indicate network transitivity, while the genetic network has both transitive (triangle) and intransitive (square) types of motifs. These results suggest that robustness of yeast cells to gene deletions is due in part to two complementary pathways (square motif) or three complementary pathways, any two of which are required for viability (triangle motif).

Conclusion

Genetic congruence is superior to genetic interaction in prediction of protein interactions and function associations. Genetically interacting pairs usually belong to parallel compensatory pathways, which can generate transitive motifs (any two of three pathways needed) or intransitive motifs (either of two pathways needed).
The yeast kinome displays scale free topology with functional hub clusters
Authors: Lee Robin EC , Megeney Lynn A
Published: November 2005

Background

The availability of interaction databases provides an opportunity for researchers to utilize immense amounts of data exclusively in silico. Recently there has been an emphasis on studying the global properties of biological interactions using network analysis. While this type of analysis offers a wide variety of global insights it has surprisingly not been used to examine more localized interactions based on mechanism. In as such we have particular interest in the role of key topological components in signal transduction cascades as they are vital regulators of healthy and diseased cell states.

Results

We have used publicly available databases and a novel software tool termed Hubview to model the interactions of a subset of the yeast interactome, specifically protein kinases and their interaction partners. Analysis of the connectivity distribution has inferred a fat-tailed degree distribution with parameters consistent with those found in other biological networks. In addition, Hubview identified a functional clustering of a large group of kinases, distributed between three separate groupings. The complexity and average degree for each of these clusters is indicative of a specialized function (cell cycle propagation, DNA repair and pheromone response) and relative age for each cluster.

Conclusion

Using connectivity analysis on a functional subset of proteins we have evidence that reinforces the scale free topology as a model for protein network evolution. We have identified the hub components of the kinase network and observed a tendency for these kinases to cluster together on a functional basis. As such, these results suggest an inherent trend to preserve scale free characteristics at a domain based modular level within large evolvable networks.
Large-scale genetic variation of the symbiosis-required megaplasmid pSymA revealed by comparative genomic analysis of Sinorhizobium meliloti natural strains
Authors: Giuntini Elisa , Mengoni Alessio , De Filippo Carlotta , Cavalieri Duccio , Aubin-Horth Nadia , Landry Christian R , Becker Anke , Bazzicalupo Marco
Published: November 2005

Background

Sinorhizobium meliloti is a soil bacterium that forms nitrogen-fixing nodules on the roots of leguminous plants such as alfalfa (Medicago sativa). This species occupies different ecological niches, being present as a free-living soil bacterium and as a symbiont of plant root nodules. The genome of the type strain Rm 1021 contains one chromosome and two megaplasmids for a total genome size of 6 Mb. We applied comparative genomic hybridisation (CGH) on an oligonucleotide microarrays to estimate genetic variation at the genomic level in four natural strains, two isolated from Italian agricultural soil and two from desert soil in the Aral Sea region.

Results

From 4.6 to 5.7 percent of the genes showed a pattern of hybridisation concordant with deletion, nucleotide divergence or ORF duplication when compared to the type strain Rm 1021. A large number of these polymorphisms were confirmed by sequencing and Southern blot. A statistically significant fraction of these variable genes was found on the pSymA megaplasmid and grouped in clusters. These variable genes were found to be mainly transposases or genes with unknown function.

Conclusion

The obtained results allow to conclude that the symbiosis-required megaplasmid pSymA can be considered the major hot-spot for intra-specific differentiation in S. meliloti.
Prevalence of physical and verbal aggressive behaviours and associated factors among older adults in long-term care facilities
Authors: Voyer Philippe , Verreault René , Azizah Ginette M , Desrosiers Johanne , Champoux Nathalie , Bédard Annick
Published: November 2005

Background

Verbal and physical aggressive behaviours are among the most disturbing and distressing behaviours displayed by older patients in long-term care facilities. Aggressive behaviour (AB) is often the reason for using physical or chemical restraints with nursing home residents and is a major concern for caregivers. AB is associated with increased health care costs due to staff turnover and absenteeism.

Methods

The goals of this secondary analysis of a cross-sectional study are to determine the prevalence of verbal and physical aggressive behaviours and to identify associated factors among older adults in long-term care facilities in the Quebec City area (n = 2 332).

Results

The same percentage of older adults displayed physical aggressive behaviour (21.2%) or verbal aggressive behaviour (21.5%), whereas 11.2% displayed both types of aggressive behaviour. Factors associated with aggressive behaviour (both verbal and physical) were male gender, neuroleptic drug use, mild and severe cognitive impairment, insomnia, psychological distress, and physical restraints. Factors associated with physical aggressive behaviour were older age, male gender, neuroleptic drug use, mild or severe cognitive impairment, insomnia and psychological distress. Finally, factors associated with verbal aggressive behaviour were benzodiazepine and neuroleptic drug use, functional dependency, mild or severe cognitive impairment and insomnia.

Conclusion

Cognitive impairment severity is the most significant predisposing factor for aggressive behaviour among older adults in long-term care facilities in the Quebec City area. Physical and chemical restraints were also significantly associated with AB. Based on these results, we suggest that caregivers should provide care to older adults with AB using approaches such as the progressively lowered stress threshold model and reactance theory which stress the importance of paying attention to the severity of cognitive impairment and avoiding the use of chemical or physical restraints.
Bright light treatment of depression for older adults [ISRCTN55452501]
Authors: Loving Richard T , Kripke Daniel F , Elliott Jeffrey A , Knickerbocker Nancy C , Grandner Michael A
Published: November 2005

Background

The incidence of insomnia and depression in the elder population is significant. It is hoped that use of light treatment for this group could provide safe, economic, and effective rapid recovery.

Methods

In this home-based trial we treated depressed elderly subjects with bright white (8,500 Lux) and dim red (<10 Lux) light for one hour a day at three different times (morning, mid-wake and evening). A placebo response washout was used for the first week. Wake treatment was conducted prior to the initiation of treatment, to explore antidepressant response and the interaction with light treatment. Urine and saliva samples were collected during a 24-hour period both before and after treatment and assayed for aMT6s and melatonin respectively to observe any change in circadian timing. Subjects wore a wrist monitor to record light exposure and wrist activity. Daily log sheets and weekly mood (GDS) and physical symptom (SAFTEE) scales were administered. Each subject was given a SCID interview and each completed a mood questionnaire (SIGH-SAD-SR) before and after treatment. Also, Hamilton Depression Rating (SIGH-SAD version) interviews were conducted by a researcher who was blind to the treatment condition. A control group of healthy, age-matched, volunteers was studied for one day to obtain baseline data for comparison of actigraphy and hormone levels.

Results

Eighty-one volunteers, between 60 and 79 years old, completed the study. Both treatment and placebo groups experienced mood improvement. Average GDS scores improved 5 points, the Hamilton Depression Rating Scale (HDRS) 17 scores (extracted from the self-rated SIGH-SAD-SR) improved 6 points. There were no significant treatment effects or time-by-treatment interactions. No significant adverse reactions were observed in either treatment group. The assays of urine and saliva showed no significant differences between the treatment and placebo groups. The healthy control group was active earlier and slept earlier but received less light than the depressed group at baseline.

Conclusion

Antidepressant response to bright light treatment in this age group was not statistically superior to placebo. Both treatment and placebo groups experienced a clinically significant overall improvement of 16%.
Prevalence of mental disorders and torture among Tibetan refugees: A systematic review
Authors: Mills Edward J , Singh Sonal , Holtz Timothy H , Chase Robert M , Dolma Sonam , Santa-Barbara Joanna , Orbinski James J
Published: November 2005

Background

Many Tibetan refugees flee Tibet in order to escape physical and mental hardships, and to access the freedoms to practice their culture and religion. We aimed to determine the prevalence of mental illnesses within the refugee population and determine the prevalence of previous torture reported within this population.

Methods

We performed a systematic literature search of 10 electronic databases from inception to May 2005. In addition, we searched the internet, contacted all authors of located studies, and contacted the Tibetan Government-in-exile, to locate unpublished studies. We included any study reporting on prevalence of mental illness within the Tibetan refugee populations. We determined study quality according to validation, translation, and interview administration. We calculated proportions with exact confidence intervals.

Results

Five studies that met our inclusion criteria (total n = 410). All studies were conducted in North India and 4 were specifically in adult populations. Four studies provided details on the prevalence of torture and previous imprisonment within the populations. The prevalence of post-traumatic stress disorder ranged from 11–23%, anxiety ranged from 25–77%, and major depression ranged from 11.5–57%.

Conclusion

Our review indicates that the prevalence of serious mental health disorders within this population is elevated. The reported incidence of torture and imprisonment is a possible contributor to the illnesses. Non-government organizations and international communities should be aware of the human rights abuses being levied upon this vulnerable population and the mental health outcomes that may be associated with it.
Role of cultivation media in the development of yeast strains for large scale industrial use
Authors: Hahn-Hägerdal Bärbel , Karhumaa Kaisa , Larsson Christer U , Gorwa-Grauslund Marie , Görgens Johann , van Zyl Willem H
Published: November 2005

The composition of cultivation media in relation to strain development for industrial application is reviewed. Heterologous protein production and pentose utilization by Saccharomyces cerevisiae are used to illustrate the influence of media composition at different stages of strain construction and strain development. The effects of complex, defined and industrial media are compared. Auxotrophic strains and strain stability are discussed. Media for heterologous protein production and for bulk bio-commodity production are summarized.
Cross-cultural validation and analysis of responsiveness of the QUALIOST®: QUAlity of Life questionnaire In OSTeoporosis
Authors: de la Loge Christine , Sullivan Kate , Pinkney Robert , Marquis Patrick , Roux Christian , Meunier Pierre Jean
Published: November 2005

Background

The QUALIOST® was designed for use with the SF-36 to measure established osteoporosis-specific quality of life (QoL). The reliability (internal consistency and test-retest) and validity of the questionnaire were established in a stand-alone psychometric validation study. The objective of this paper is to provide additional information on the instrument's responsiveness using clinical trial data, along with the reliability and validity of translated versions.

Methods

The Spinal Osteoporosis Therapeutic Intervention (SOTI) was an international clinical trial comparing strontium ranelate to placebo on the occurrence of new vertebral fracture in patients with postmenopausal osteoporosis. QoL was a secondary endpoint, assessed using the SF-36 and QUALIOST® at baseline and every six months, with the main analysis at 3-year follow-up. Questionnaire acceptability, analysis of the hypothesised structure, internal consistency reliability and responsiveness to clinical change over time were assessed at the 3-year follow up.

Results

1592 patients from 11 countries completed at least one QoL questionnaire. The psychometric properties of the questionnaires were assessed on cross-sectional (N = 1486) and longitudinal (N = 1288) data. Item discriminant validity of the QUALIOST® was excellent, as was item convergent validity, with 100% of item-scale correlations being above the 0.40 level. Internal consistency reliability was also extremely good, with high Cronbach's alpha scores above the 0.70 benchmark. Responsiveness results were consistent for all QUALIOST® scores, indicating that greater decreases in QoL corresponded to greater numbers of fractures experienced. QUALIOST® scores also differed according to the type of fracture suffered. This was demonstrated by increased effect sizes for more severe vertebral fractures (clinical vertebral and painful vertebral). In comparing responsiveness, the QUALIOST® scores were generally more consistent than those of the SF-36. Most notably, the QUALIOST® was more responsive with regard to painful vertebral fractures than the SF-36.

Conclusion

The QUALIOST® is a reliable and valid tool for measuring QoL in postmenopausal osteoporotic women. Being available in several validated language versions, it is ready to be used in a variety of settings, including international clinical trials.
The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study
Authors: Gao Fang , Melody Teresa , Daniels Darren F , Giles Simon , Fox Samantha
Published: November 2005

Introduction

Compliance with the ventilator care bundle affects the rate of ventilator-associated pneumonia. It was not known, however, whether compliance with sepsis care bundles has an impact on outcome. The aims of the present study were to determine the rate of compliance with 6-hour and 24-hour sepsis bundles and to determine the impact of the compliance on hospital mortality in patients with severe sepsis or septic shock.

Methods

We conducted a prospective observational study on 101 consecutive adult patients with severe sepsis or septic shock on medical or surgical wards, or in accident and emergency areas at two acute National Health Service Trust Teaching hospitals in England. The main outcome measures were: the rate of compliance with 6-hour and 24-hour sepsis care bundles adapted from the Surviving Sepsis Campaign guidelines on patients' clinical care; and the difference in hospital mortality between the compliant and the non-compliant groups.

Results

The median age of the patients was 69 years (interquartile range 51 to 78), and 53% were male. The sources of infection were sought and confirmed in 87 of 101 patients. The chest was the most common source (50%), followed by the abdomen (22%). The rate of compliance with the 6-hour sepsis bundle was 52%. Compared with the compliant group, the non-compliant group had a more than twofold increase in hospital mortality (49% versus 23%, relative risk (RR) 2.12 (95% confidence interval (CI) 1.20 to 3.76), P = 0.01) despite similar age and severity of sepsis. Compliance with the 24-hour sepsis bundle was achieved in only 30% of eligible candidates (21/69). Hospital mortality was increased in the non-compliant group from 29% to 50%, with a 76% increase in risk for death, although the difference did not reach statistical significance (RR 1.76 (95% CI 0.84 to 3.64), P = 0.16).

Conclusion

Non-compliance with the 6-hour sepsis bundle was associated with a more than twofold increase in hospital mortality. Non-compliance with the 24-hour sepsis bundle resulted in a 76% increase in risk for hospital death. All medical staff should practise these relatively simple, easy and cheap bundles within a strict timeframe to improve survival rates in patients with severe sepsis and septic shock.
Sedative clearance during extracorporeal membrane oxygenation
Authors: Bhatt-Mehta Varsha , Annich Gail
Published: November 2005

The effects of polyvinyl chloride (PVC) tubing and membrane oxygenator (MO) on the concentrations of lorazepam and morphine in the neonatal extracorporeal membrane oxygenation (ECMO) circuit were evaluated using an in vitro model that included a closed ECMO circuit with a MO, heat exchanger, bladder and PVC tubing. The circuit was primed with blood, electrolytes, albumin and heparin and maintained at physiologic pH and temperature throughout by frequent measurement of blood gas pH and a temperature probe. Lorazepam and morphine were each studied separately in three separate, but identical circuits for 6 h on the day of circuit prime (new circuit) and then again for 6 h at 24 h (old circuit). Each circuit (new and old) was spiked once with lorazepam to a final concentration of 250 ng/mL or with morphine to a final concentration of 70 ng/mL in the circuit. Serial samples were drawn at baseline and every 30/60 min for 6 h at the site of injection and pre- and post-MO for each circuit. Lorazepam and morphine concentrations were analysed using gas chromatography with electron capture and gas chromatography with mass spectrometry, respectively. The concentrations of morphine and lorazepam at various sample sites and time points were expressed as a percentage of the original concentration.

This single-dose study shows that up to 50% of a dose of lorazepam and 40% of a dose of morphine may be extracted by PVC and MO during bypass, depending on the age of the circuit. As the circuits become older, this amount could increase. These data may explain, in part, the higher doses of lorazepam and morphine required to sedate patients during ECMO.
Cardiopulmonary bypass and mitral valve replacement during pregnancy
Authors: Sutton Steven W , Duncan Michael A , Chase Virginia A , Marcel Randy J , Meyers Thomas P , Wood Richard E
Published: November 2005

Gravid patient cardiopulmonary bypass remains a high- risk procedure with regard to fetal preservation. Maternal mortality is similar to that of the nonpregnant female at 1.5-5%. However, fetal mortality remains high at 16-33%, with an average of 19% over the past 25 years, with no correlation to gestational age. Teratogenesis is a major consideration in the first trimester. Variations in the timing of surgical intervention, gestational age, maternal health status, type of procedure, pre- or post- organogenesis, perfusion protocol, and pharmaceutical therapy are all factors that can influence fetomaternal outcome. In this report, we present a literature review along with our experience of a 26-year-old female who developed complications with her pregnancy at approximately 17 weeks gestation, with adverse neurological sequelae. The patient was 152 cm in height and weighed 48 kg, with a calculated body surface area of 1.40 M2. She had no prior history of cardiac disease and, upon admission to our institution, presented with a declining health status in pulmonary edema and was treated medically, with an ultimate requirement for mitral valve replacement. The total cardiopulmonary bypass time was 99 min with an aortic crossclamp time of 83 min. The literature, as expected, is limited to case reports and reviews since a controlled clinical trial during pregnancy is nonexistent, using extracorporeal circulation. This greatly challenges the medical staff in managing such difficult cases, with an incidence of heart disease during pregnancy of 1.2-3.7%.
PVC-plasticizer DEHP in medical products: do thin coatings really reduce DEHP leaching into blood?
Authors: Hildenbrand Sibylle L , Lehmann Hans-Dieter , Wodarz Roman , Ziemer Gerhard , Wendel Hans P
Published: November 2005

The hemocompatibility of artificial surfaces in extracorporeal blood circulation systems can be improved by coatings. According to the literature, heparin coatings should avoid the leaching of the plasticizer di(2-ethylhexyl) phthalate (DEHP) into the blood from components made from plasticized polyvinyl chloride (PVC). DEHP and its metabolites are known to impair the fertility of male rodents; effects on human fertility are assumed.

Three different surface coatings with and without heparin were examined in a Chandler Loop model at 37°C using fresh human blood to evaluate their hemocompatibility and barrier property to plasticizer.

The levels of toxic oxidation products of DEHP generated in the blood, particularly, were found as high as in the uncoated tubing. The coatings improved the hemocompatibility, but are not safe protection against the hazardous metabolites of DEHP.

For pregnant women, neonates and children, we would recommend using the available surface-coated plasticized PVC tubing sets, but free of DEHP.
Seventy-two hour gas exchange performance and hemodynamic properties of NOVALUNG®iLA as a gas exchanger for arteriovenous carbon dioxide removal
Authors: Zhou Xiaoqin , Loran David B , Wang Dongfang , Hyde Brannon R , Lick Scott D , Zwischenberger Joseph B
Published: November 2005

Objective: Acute respiratory failure is complicated by acidosis and altered end-organ perfusion. NOVA-LUNG®iLA is an interventional lung assist (ILA) device for arteriovenous carbon dioxide removal (AVCO2R). The present study was conducted to evaluate the device for short-term CO2 removal performance and hemodynamic response.

Methods: Six adult sheep received cannulation of the jugular vein and carotid artery. The ILA-AVCO2R circuit was placed on the sheep for 72 hours. Hemodynamics and PaCO2 were measured; CO2 removal was calculated while varying sweep gas flow rates (Qg), device blood flow rates (Qb), and PaCO2.

Results: Hemo-dynamic variables remained normal throughout the 72 hour study. CO2 removal increased with increases in Qgor Qb. Mean CO2 removal was 119.3 ml/min for Qb 1L/min, Qg 5 L/min, and PaCO2 40 - 50 mmHg.PaCO2 was directly proportional to CO2 clearance (R-0.72, p B/0.001).

Conclusion: NOVALUNG®iLA can provide near total CO2 removal with Qb 1 - 2 L/min,Qg 5 L/min, and minimal flow resistance (3.889/0.82 mmHg/L/min). PaCO2 correlates with CO2 removal and is dependent on Qb and Qg.
Management of Acute Undifferentiated Agitation in the Emergency Department: A Randomized Double‐Blind Trial of Droperidol, Ziprasidone, and Midazolam
Authors: Martel Marc , Sterzinger Ann , Miner James , Clinton Joseph , Biros Michelle
Published: November 2005

Objectives: To compare the efficacy of sedation, need for rescue sedation, rates of respiratory depression, and complications of droperidol, ziprasidone, and midazolam when used for the treatment of emergency department (ED) patients requiring sedation for acute undifferentiated agitation. Methods: A prospective, randomized, double‐blind trial of agitated ED patients requiring emergent sedation was performed. Patients were randomized to receive droperidol 5 mg, ziprasidone 20 mg, or midazolam 5 mg intramuscularly. Interval measurements were made at 0, 15, 30, 45, 60, and 120 minutes and included Altered Mental Status Scale (AMS) scores, oxygen saturations, and end‐tidal carbon dioxide levels. Results: A total of 144 patients were enrolled; 50 patients received droperidol, 46 received ziprasidone, and 48 received midazolam. Adequate sedation (mean AMS score <0) was achieved at 15 minutes in patients receiving midazolam (mean AMS score, −0.81) and 30 minutes for patients receiving droperidol (mean AMS score, −1.3) and ziprasidone (mean AMS score, −0.74). Rescue medication for sedation was necessary in 38 of 144 patients (droperidol, 5 of 50; ziprasidone, 9 of 46; midazolam, 24 of 48; p < 0.05). No cardiac dysrhythmias were identified in any treatment group. Respiratory depression that clinically required treatment with supplemental oxygen occurred in 21 of 144 patients (droperidol, 4 of 50; ziprasidone, 7 of 46; midazolam, 10 of 48; p = 0.20). No patients required endotracheal intubation. Conclusions: Acutely agitated ED patients sedated with droperidol or ziprasidone required rescue medications to achieve adequate sedation less frequently than those sedated with midazolam. The onset of adequate sedation is delayed with ziprasidone, relative to the other agents.
The Role of Leptin in the Development of the Cerebral Cortex in Mouse Embryos
Authors: Udagawa Jun , Hashimoto Ryuju , Suzuki Hiroaki , Hatta Toshihisa , Sotomaru Yusuke , Hioki Kyoji , Kagohashi Yukiko , Nomura Tatsuji , Minami Yasuhiro , Otani Hiroki
Published: November 2005

Leptin is detected in the sera, and leptin receptors are expressed in the cerebrum of mouse embryos, suggesting that leptin plays a role in cerebral development. Compared with the wild type, leptin-deficient (ob/ob) mice had fewer cells at embryonic day (E) 16 and E18 and had fewer 5-bromo-2′-deoxyuridine+ cells at E14 and E16 in the neuroepithelium. Intracerebroventricular leptin injection in E14 ob/ob embryos increased the number of neuroepithelium cells at E16. In cultured neurosphere cells, leptin treatment increased Hes1 mRNA expression and maintained neural progenitors. Astrocyte differentiation was induced by low-dose (0.1 μg/ml) but not high-dose (1 μg/ml) leptin. High-dose leptin decreased Id mRNA and increased Ngn1 mRNA in neurosphere cells. The neuropeptide Y mRNA level in the cortical plate was lower in ob/ob than the wild type at E16 and E18. These results suggest that leptin maintains neural progenitors and is related to glial and neuronal development in embryos.
Suppression of Adiponectin Gene Expression by Histone Deacetylase Inhibitor Valproic Acid
Authors: Qiao Liping , Schaack Jerome , Shao Jianhua
Published: November 2005

Valproic acid (VPA) has been used for the treatment of epilepsy and bipolar disorders for more than 30 yr. Obesity and insulin resistance are common side effects of VPA treatment. Adiponectin is an adipocyte-derived protein that plays an important role in controlling insulin sensitivity and glucose homeostasis. In this report, we examined the effects of VPA on adiponectin gene expression in C57BL/6J mice and in differentiated 3T3-L1 adipocytes. VPA treatment significantly decreased adiponectin protein and mRNA levels in both mice and 3T3-L1 adipocytes. The adipocyte study showed that VPA inhibited adiponectin gene expression in a dose- and time-dependent manner. Repression of adiponectin expression by VPA occurred at the transcription level and correlated with inhibition of histone deacetylase activity. Therapeutic concentrations of VPA increased overall histone acetylation and increased adiponectin promoter-driven luciferase expression in fibroblasts, but decreased adiponectin promoter activity in differentiated 3T3-L1 adipocytes. VPA treatment decreased adipogenic transcription factor CCAAT/enhancer binding protein-α (C/EBPα) levels and binding of C/EBPα to the adiponectin promoter without altering the levels of peroxisome proliferator-activated receptor-γ and steroid regulatory element binding protein-1. Furthermore, VPA did not suppress adiponectin gene expression in C/EBPα gene-deficient adipocytes that stably expressed exogenous peroxisome proliferator-activated receptor-γ2. Together, these results demonstrate that histone deacetylase inhibitor VPA suppresses adiponectin gene expression in mature adipocytes. The study also provides evidence that diminished C/EBPα protein level and decreased binding at the adiponectin promoter mediate the inhibitory effects of VPA on adiponectin gene transcription.
A Novel Role for Endogenous Pituitary Adenylate Cyclase Activating Polypeptide in the Magnocellular Neuroendocrine System
Authors: Gillard E. R. , León-Olea M. , Mucio-Ramírez S. , Coburn C. G. , Sánchez-Islas E. , de Leon A. , Mussenden H. , Bauce L. G. , Pittman Q. J. , Currás-Collazo M. C.
Published: November 2005

Central release of vasopressin (VP) by the magnocellular neuroendocrine cells (MNCs) responsible for systemic VP release is believed to be important in modulating the activity of these neurons during dehydration. Central VP release from MNC somata and dendrites is stimulated by both dehydration and pituitary adenylate cyclase activating polypeptide (PACAP). Although PACAP is expressed in MNCs, its potential role in the magnocellular response to dehydration is unexplored. The current study demonstrates that prolonged dehydration increases immunoreactivity for PACAP-27, PACAP-38, and the type I PACAP receptor in the supraoptic nucleus (SON) of the rat. In addition, PACAP stimulates local VP release in the euhydrated rat SON in vitro, and this effect is reduced by the PACAP receptor antagonist PAC6–27 (100 nm), suggesting the participation of PACAP receptors. Concomitant with its effects on local VP release, PACAP also reduces basal glutamate and aspartate release in the euhydrated rat SON. Furthermore, somatodendritic VP release elicited by acute dehydration is blocked by PAC6–27, suggesting that endogenous PACAP participates in this response. Consistent with this, RIA revealed that local PACAP-38 release within the SON is significantly elevated during acute dehydration. These results suggest that prolonged activation of hypothalamic MNCs is accompanied by up-regulation of PACAP and the type I PACAP receptor in these cells and that somatodendritic VP release in response to acute dehydration is mediated by activation of PACAP receptors by endogenous PACAP released within the SON. A potential role for PACAP in promoting efficient, but not exhaustive, systemic release of VP from MNCs during physiological challenge is discussed.
Psychosocial Effects of Harboring an Untreated Unruptured Intracranial Aneurysm
Authors: Towgood Karren , Ogden Jenni A. , Mee Edward
Published: November 2005

OBJECTIVE:

The primary purpose of the study was to investigate the psychosocial effects of harboring a known but untreated unruptured intracranial aneurysm (UIA), information considered important to the decision of whether to treat or not treat an unruptured aneurysm.

METHODS:

Over a 24–month period, 70 Auckland Hospital patients with UIAs were identified. Of these, 30 completed treatment, 2 patients died before treatment, and 38 were either not treated or treatment was unable to be completed during the time frame of the study. Of this group of 38 untreated UIA patients, 23 were enrolled in the study and were assessed on a brief cognitive screen and a battery of psychosocial measures. Their performance was compared with a group of 26 treated UIA patients.

RESULTS:

Poorer functioning was reported by the untreated UIA group on most psychosocial measures when compared with the treated UIA group 6 months posttreatment, and 36% of untreated UIA patients presented with a pattern of significant psychosocial impairment when compared with the treated UIA group. Qualitative data from the current study suggested that a factor contributing to the poorer reported psychosocial functioning in the untreated group was past or current fear about their untreated UIA.

CONCLUSION:

A decrease in overall quality of life was found to be associated with harboring an identified but untreated UIA. Findings from the current study suggest that further investigation of psychosocial outcome in other groups of untreated UIA patients is warranted. Results also suggest that some untreated UIA patients might benefit from psychological intervention.
Evaluation of Fractionated Radiotherapy and Gamma Knife Radiosurgery in Cavernous Sinus Meningiomas: Treatment Strategy
Authors: Metellus Philipe , Regis Jean , Muracciole Xavier , Fuentes Stephane , Dufour Henry , Nanni Isabelle , Chinot Oliver , Martin Pierre-Marie , Grisoli Francois
Published: November 2005

OBJECTIVE:

To investigate the respective role of fractionated radiotherapy (FR) and gamma knife stereotactic (GKS) radiosurgery in cavernous sinus meningioma (CSM) treatment.

METHODS:

The authors report the long-term follow-up of two populations of patients harboring CSMs treated either by FR (Group I, 38 patients) or GKS radiosurgery (Group II, 36 patients). There were 31 females with a mean age of 53 years in Group I and 29 females with a mean age of 51.2 years in Group II. In 20 patients (Group I) and 13 patients (Group II), FR and GKS radiosurgery were performed as an adjuvant treatment. In 18 patients (Group I) and in 23 patients (Group II), FR and GKS radiosurgery were performed as first line treatment. In our early experience with GKS radiosurgery (1992, date of gamma knife availability in the department), patients with tumors greater than 3 cm, showing close relationship with the optic apparatus (<3 mm) or skull base dural spreading, were treated by FR. Secondarily, with the advent of new devices and our growing experience, these criteria have evolved.

RESULTS:

The median follow-up period was 88.6 months (range, 42–168 mo) for Group I and 63.6 months (range, 48–92 mo) for Group II. According to Sekhar's classification, 26 (68.4%) patients were Grade III to IV in Group I and 10 (27.8%) patients in Group II (P < 0.05); 23 (60.5%) patients had extensive lesions in Group I and 7 (19.4%) patients in Group II (P < 0.05). Mean tumor volume was 13.5 cm3 in Group I and 5.2 cm3 in Group II (P < 0.05). Actuarial progression-free survival was 94.7% and 94.4% in Group I and II, respectively. Clinically, improvement was seen for 24 (63.2%) patients in Group I and for 21 (53.8%) patients in Group II (P > 0.05). Radiologically, 11 (29%, Group I) patients and 19 (Group II, 52.7%) patients showed tumor shrinkage (P = 0.04). Transient morbidity was 10.5% in Group I and 2.8% in Group II. Permanent morbidity was 2.6% in Group I and 0% in Group II.

CONCLUSION:

FR and GKS radiosurgery are safe and efficient techniques in treatment of CSMs, affording comparable satisfactory long-term tumor control. However, GKS radiosurgery provides better radiological response, is far more convenient, and fits into most patients lives much better than FR. Therefore, in the authors' opinion, GKS radiosurgery should be advocated in first intention for patients with CSMs, whereas conventional radiotherapy should be reserved for cases that are not amenable to this technique, thus making these two therapeutic modalities not alternative but complementary tools in CS meningioma treatment strategy.
Intracranial Pressure Response to Induced Hypertension: Role of Dynamic Pressure Autoregulation
Authors: Hlatky Roman , Valadka Alex B. , Robertson Claudia S.
Published: November 2005

OBJECTIVE:

Induced hypertension is commonly used to improve cerebral perfusion, but this treatment may have the deleterious side effect of raising intracranial pressure (ICP). We tested the hypothesis that dynamic pressure autoregulation testing could identify patients who might develop increased ICP during induced hypertension.

METHODS:

Twenty-two studies were performed in 21 patients. Baseline dynamic testing of autoregulation by cuff deflation and carotid compression techniques was performed. After phenylephrine was infused to increase mean arterial pressure by 20 to 30 mm Hg, cuff deflation tests were repeated.

RESULTS:

The average increase in mean arterial pressure was 32.2 ± 16.1 mm Hg. This increase was accompanied by increased flow velocity (P < 0.001), brain tissue PO2 (P = 0.011), and regional cerebral blood flow (P = 0.008). Also, dynamic pressure autoregulation consistently improved (P = 0.015). Induced hypertension caused increased ICP (iICP) in 12 patients and a decrease in ICP (dICP) in 9. Baseline jugular venous oxygen saturation in the iICP group was 82 ± 10% compared with 70 ± 10% in dICP patients (P = 0.02). Baseline dynamic autoregulatory index for the cuff deflation tests (1.8 ± 1.4) and baseline transient hyperemic response ratio for the carotid compression tests (1.11 ± 0.07) were significantly lower in iICP patients (dICP group: autoregulatory index 3.2 ± 1.7, P = 0.06; transient hyperemic response ratio 1.26 ± 0.11, P = 0.009). Flow velocity increased more with the increase in blood pressure in the iICP group than in the dICP group: 19.0 ± 6.8 cm/s versus 10.2 ± 6.3 cm/s (P = 0.007).

CONCLUSION:

The patients who had an increase in ICP with induced hypertension had a greater degree of impairment of autoregulation and induced hypertension resulted in a greater increase in flow velocity.
Spinal Cord Stimulation Electrode Design: A Prospective, Randomized, Controlled Trial Comparing Percutaneous with Laminectomy Electrodes: Part II–Clinical Outcomes
Authors: North Richard B. , Kidd David H. , Petrucci Loredana , Dorsi Michael J.
Published: November 2005

OBJECTIVE:

Spinal cord stimulation, in use for more than 30 years, has evolved into an easily implemented technique involving percutaneous or laminectomy electrode placement. In a randomized comparison of four-contact percutaneous and four-contact insulated laminectomy electrodes placed at the same level in the dorsal, epidural midline, quantitative measures of stimulator performance revealed significant technical advantages for the laminectomy electrodes. Our prospective, randomized, controlled trial compares clinical results in these same patients.

METHODS:

Impartial third parties followed our series of 24 patients with failed back surgery syndrome to gather clinical outcome data. We defined “success” as at least 50% sustained relief of pain and patient satisfaction with the result of treatment.

RESULTS:

At a mean follow-up of 1.9 years, 10 of 12 patients receiving the laminectomy electrode and 5 of 12 patients receiving the percutaneous electrode reported a successful outcome (P < 0.05). Follow-up at a mean of 2.9 years showed that this result was maintained in 5 of 12 patients with the laminectomy electrode and 3 of 12 with the percutaneous electrode (not statistically significant). Many patients reported improvements in most activities of daily living, and loss of function was rare. In addition, 9 patients with laminectomy electrodes and 4 with percutaneous electrodes reducted or eliminated analgesic intake (P < 0.05), and 2 returned to work. No electrode migration was observed.

CONCLUSION:

Laminectomy electrode placement, although more invasive than percutaneous placement, yields significantly better clinical results in patients with failed back surgery syndrome at mean 1.9 years follow-up. In our small sample, however, the statistical significance of this advantage disappeared at mean 2.9 years follow-up.