bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications
Authors: Chang David H. , Liu Nancy , Klimek Virginia , Hassoun Hani , Mazumder Amitabha , Nimer Stephen D. , Jagannath Sundar , Dhodapkar Madhav V.
Published: March 2006

Natural killer T (NKT) cells are CD1d-restricted glycolipid reactive innate lymphocytes that play an important role in protection from pathogens and tumors. Pharmacologic approaches to enhance NKT cell function will facilitate specific NKT targeting in the clinic. Here we show that lenalidomide (LEN), a novel thalidomide (Thal) analog, enhances antigen-specific expansion of NKT cells in response to the NKT ligand α-galactosylceramide (α-GalCer) in both healthy donors and patients with myeloma. NKT cells activated in the presence of LEN have greater ability to secrete interferon-γ. Antigen-dependent activation of NKT cells was greater in the presence of dexamethasone (DEX) plus LEN than with DEX alone. Therapy with LEN/Thal also led to an increase in NKT cells in vivo in patients with myeloma and del5q myelodysplastic syndrome. Together these data demonstrate that LEN and its analogues enhance CD1d-mediated presentation of glycolipid antigens and support combining these agents with NKT targeted approaches for protection against tumors.
Gimap4 accelerates T-cell death
Authors: Schnell Silke , Démollière Corinne , van den Berk Paul , Jacobs Heinz
Published: March 2006

Gimap4, a member of the newly identified GTPase of the immunity-associated protein family (Gimap), is strongly induced by the pre–T-cell receptor in precursor T lymphocytes, transiently shut off in double-positive thymocytes, and reappears after TCR-mediated positive selection. Here, we show that Gimap4 remains expressed constitutively in the cytosol of mature T cells. A C-terminal IQ domain binds calmodulin in the absence of calcium, and conserved PKC phosphorylation motifs are targets of concanavalin A (ConA)– or PMA/ionomycin-induced PKC activation. To address the role of Gimap4 in T-cell physiology, we completed the genomic organization of the gimap4 locus and generated a Gimap4-null mutant mouse. Studies in these mice revealed no critical role of Gimap4 in T-cell development but in the regulation of apoptosis. We have found that Gimap4 accelerates the execution of programmed cell death induced by intrinsic stimuli downstream of caspase-3 activation and phosphatidylserine exposure. Apoptosis directly correlates with the phosphorylation status of Gimap4.
Effective treatment of a murine model of adult T-cell leukemia using 211At-7G7/B6 and its combination with unmodified anti-Tac (daclizumab) directed toward CD25
Authors: Zhang Zhuo , Zhang Meili , Garmestani Kayhan , Talanov Vladimir S. , Plascjak Paul S. , Beck Barbara , Goldman Carolyn , Brechbiel Martin W. , Waldmann Thomas A.
Published: March 2006

Adult T-cell leukemia (ATL) consists of an overabundance of T cells, which express CD25. Therapeutic efficacy of astatine-211 (211At)–labeled murine monoclonal antibody 7G7/B6 alone and in combination with daclizumab was evaluated in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice given injections of MET-1 human T-cell leukemia cells. Daclizumab and 7G7/B6 are directed toward different epitopes of CD25. Either a single dose of 12 μCi (0.444 MBq) 211At-7G7/B6 per mouse given intravenously or receptor-saturating doses of daclizumab given at 100 μg weekly for 4 weeks intravenously inhibited tumor growth as monitored by serum levels of human β-2 microglobulin (β2μ) and by prolonged survival of leukemia-bearing mice compared with the control groups (P < .001). The combination of 2 agents enhanced the antitumor effect when compared with groups treated with 12 μCi (0.444 MBq) of 211At-7G7/B6 (P < .05) or daclizumab alone (P < .05). The median survival duration of the PBS group was 62.6 days and 61.5 days in the radiolabeled nonspecific antibody 211At-11F11–treated group. In contrast, 91% of mice in the combination group survived through day 94. These results that demonstrate a significantly improved therapeutic efficacy by combining 211At-7G7/B6 with daclizumab support a clinical trial of this regimen in patients with ATL.
Differential regulation of T-cell growth by IL-2 and IL-15
Authors: Cornish Georgina H. , Sinclair Linda V. , Cantrell Doreen A.
Published: March 2006

Although interleukin 2 (IL-2) and IL-15 signal through the common gamma chain (γc) and through IL-2 receptor β–chain (CD122) subunits, they direct distinct physiologic and immunotherapeutic responses in T cells. The present study provides some insight into why IL-2 and IL-15 differentially regulate T-cell function by revealing that these cytokines are strikingly distinct in their ability to control protein synthesis and T-cell mass. IL-2 and IL-15 are shown to be equivalent mitogens for antigen-stimulated CD8+ T cells but not for equivalent growth factors. Antigen-primed T cells cannot autonomously maintain amino acid incorporation or de novo protein synthesis without exogenous cytokine stimulation. Both IL-2 and IL-15 induce amino acid uptake and protein synthesis in antigen-activated T cells; however, the IL-2 response is strikingly more potent than the IL-15 response. The differential action of IL-2 and IL-15 on amino acid uptake and protein synthesis is explained by temporal differences in signaling induced by these 2 cytokines. Hence, the present results show that cytokines that are equivalent mitogens can have different potency in terms of regulating protein synthesis and cell growth.
The neuropathologic phenotype of experimental ovine BSE is maintained after blood transfusion
Authors: Sisó Sílvia , González Lorenzo , Houston Fiona , Hunter Nora , Martin Stuart , Jeffrey Martin
Published: March 2006

Iatrogenic transmission by blood transfusion has been described in cases of human variant Creutzfeldt-Jakob disease (vCJD), experimental ovine bovine spongiform encephalopathy (BSE), and natural sheep scrapie, demonstrating that blood in these prion diseases is infectious. However, the possible effect of the transfusion, derived from differences in the inoculum (blood) and the route of infection (intravenous), on the pathologic phenotype of the disease in the recipients is not known. This study describes the neuropathologic phenotype of PrPd accumulation in sheep succumbing to neurologic disease after blood transfusion from donors experimentally infected with BSE; these were either clinically or subclinically affected at the time of donation. We demonstrate that blood can become infectious at early stages of ovine BSE infection and that the PrPd immunohistochemical phenotype is maintained after transfusion. This suggests that a change in the pathologic phenotype of vCJD would not be expected as a result of exposure to infected blood.
Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence
Authors: Datta Abhik , Bellon Marcia , Sinha-Datta Uma , Bazarbachi Ali , Lepelletier Yves , Canioni Danielle , Waldmann Thomas A. , Hermine Olivier , Nicot Christophe
Published: March 2006

The antiviral thymidine analog azidothymidine (AZT) is used to treat several virus-associated human cancers. However, to date the mechanism of AZT action remains unclear and thus, reasons for treatment failure are unknown. Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of poor prognosis. Here, we report that enduring AZT treatment of T-cell leukemia virus I–infected cells, in vitro and in vivo in ATL patients, results in inhibition of telomerase activity, progressive telomere shortening, and increased p14ARF expression. In turn, this elicits stabilization and reactivation of the tumor suppressor p53-dependent transcription, increased expression of the cyclin-dependent kinase inhibitor p21Waf1, and accumulation of p27kip1, thereby inducing cellular senescence and tumor cell death. While ATL patients carrying a wild-type p53 enter remission following treatment with AZT, those with a mutated p53 did not respond, and patients' disease relapse was associated with the selection of a tumor clone carrying mutated inactive p53.
Stem Cell and Related Therapies: Nurses and midwives representing all parties
Authors: Cedar S H
Published: March 2006

Nurses and midwives are part of health care in all the stages of our lives from preconception to death. Recent scientific advances have introduced new techniques of screening and diagnosis linked to stem cell isolation and therapies. These could affect us at any age and therefore nurses will be involved as carers and patients advocates for these techniques. In this article stem cell techniques and therapies are outlined, as well as some of the ethical challenges faced by various nursing groups, whether in adult, learning difficulties, mental health, paediatric, primary care, public health or health visiting areas. Nurses have to understand the ethical issues and the rights of all parties (donor, recipient and families), which may conflict with each other, to be able to weigh up the benefits and costs to each group involved. Answers have to be found on a case-by-case basis within local moral frameworks and law. Nurses represent all parties in these therapies and act as advocates for every patient group. They need to act in an interprofessional environment to promote the best interests of all their clients, both clinically and ethically.
Nurses’ Attitudes Towards People with Dementia: the semantic differential technique
Authors: Norbergh Karl-Gustaf , Helin Yvonne , Dahl Annika , Hellzén Ove , Asplund Kenneth
Published: March 2006

One important aspect of the nurse-patient relationship is nurses’ attitudes towards their patients. Nurses’ attitudes towards people with dementia have been studied from a wide range of approaches, but few authors have focused on the structure of these attitudes. This study aimed to identify a structure in licensed practical nurses’ attitudes towards people with dementia.

Twenty-one group dwelling units for people with dementia at 11 nursing homes participated in the study. A total of 1 577 assessments of 178 patients were sent out to 181 respondents and 1 237 answers were returned. The semantic differential technique was used. The scale had 57 bipolar pairs of adjectives that estimate an unknown number of dimensions of nurses’ attitudes towards an identified patient. The assessments were analysed using entropy-based measures of association combined with structural plots. The analysis revealed four dimensions, which related to licensed practical nurses’ opinions of the patients: an ethical and aesthetic dimension; an ability to understand; an ability to experience; and an ability for social interaction. The results of the study indicated that, on the positive to negative attitude continuum, the nurses’ attitudes fell at the positive to neutral end. This is an important finding owing to the personhood perspective, from which it is reasonable to assume that, with a more positive attitude to people with dementia, the prerequisites for person-centred care will improve.
Decision Making in Acute Care: A practical framework supporting the ‘best interests’ Principle
Authors: Bailey Susan
Published: March 2006

The best interests principle is commonly utilized in acute care settings to assist with decision making about life-saving and life-sustaining treatment. This ethical principle demands that the decision maker refers to some conception of quality of life that is relevant to the individual patient. The aim of this article is to describe the factors that are required to be incorporated into an account of quality of life that will provide a morally justifiable basis for making a judgement about the future quality of life, and therefore the best interests, of critically ill patients who are mentally incompetent. This account consists of three major components - pain and suffering, body functioning, and autonomy - and is applicable in situations where very limited information is available to guide decision making. This framework helps to make decisions about the provision of life-saving treatment that are as consistent as possible in all patient situations.
Patients’ Dignity in a Rehabilitation Ward: ethical challenges for nursing staff
Authors: Stabell Aase , Nåden Dagfinn
Published: March 2006

The purpose of this study was to explore the challenges met by nursing staff in a rehabilitation ward. The overall design was qualitative: data were derived from focus interviews with groups of nurses and analyzed from a phenomenological-hermeneutic perspective. The main finding was that challenges emerge on two levels of ethics and rationality: an economic/administrative level and a level of care. An increase in work-load and the changing potential for patient rehabilitation influence the care that nurses can provide in rehabilitating patients, and therefore also affect patients’ feelings of self-worth and dignity. Some patients wish to maintain their independence and autonomy, whereas others seem to ‘lose themselves’. Independence and autonomy are associated with dignity, but their lack is contrary to it.
Cancer Patients’ Perception of Being or Not Being Confirmed
Authors: Nåden Dagfinn , Sæteren Berit
Published: March 2006

The aim of this study was to obtain in-depth knowledge about caring confirmation of patients with cancer, from the patients’ point of view. The research topic was: what is the significance for patients of their being confirmed by nursing personnel? Fifteen men and women between 43 and 80 years of age participated in this study. The method of data collection used was qualitative research interviewing. A hermeneutic approach was used to interpret the data, in which Kvale’s self-perception, the ‘common sense’ level, and theoretical levels were applied. The results are summarized in three areas: an outer confirmation, an inner confirmation, and a lack of the latter. Outer confirmation meant being understood and taken seriously; the maintenance of human dignity and worth indicated inner confirmation. A lack of inner confirmation is primarily manifest in terms of patients’ mental, spiritual and existential concerns. In relation to the theory of Eriksson, these patients were confirmed at the level of having and being, but seldom at the level of becoming.
Bridging Western Ethics and Japanese Local Ethics by Listening to Nurses’ Concerns
Authors: Izumi Shigeko
Published: March 2006

Among Japanese nurses ethics is perceived as being distant and unrelated to their practice, although this is filled with ethical concerns and the making of ethical decisions. The reasons for this dissociation are the primacy of western values in modern Japanese health care systems and the suppression of Japanese nurses’ indigenous ethical values because of domination by western ethics. A hermeneutic study was conducted to listen to the ethical voices of Japanese nurses. Seven ethical concerns were revealed. Although some of these concerns may seem to share similar values with western ethical principles, the basis for the concerns was unique and rooted in the Japanese cultural value system. The meanings of each concern are explicated in conjunction with related background meanings. Listening and trying to understand these nurses’ voices in their own context suggests a way of bridging the gap between abstract and universal ethics and practical and local ethics.
The Society for Academic Emergency Medicine's 2004–2005 Emergency Medicine Faculty Salary and Benefit Survey
Authors: Kristal Steven Lee , Randall‐Kristal Karen A. , Thompson Bruce M.
Published: March 2006

Objectives:
To report on the sixth survey of the Society for Academic Emergency Medicine (SAEM) of emergency medicine faculty salaries, benefits, work hours, and department demographics for all programs accredited by the Residency Review Committee for Emergency Medicine (RRC‐EM).

Methods:
Data represent compensation paid for the 2004–2005 academic year. Responses were collected by SAEM, and blinded program and individual faculty data were entered into a customized version of a relational database program with a built‐in statistical package. Salary data were sorted by criteria such as program region, faculty title, American Board of Emergency Medicine certification, academic rank, years since completing residency, program size, and whether data were reported to the American Association of Medical Colleges (AAMC). Demographic data were analyzed with regard to numerous criteria including department staffing levels, emergency department (ED) volumes, ED length of stay, department income sources, salary incentive components, research funding, and specific type and value of fringe benefits offered. Data were compared with previous SAEM studies.

Results:
Sixty‐one of 132 (46%) accredited programs responded, yielding data on 1,213 full‐time faculty from all four AAMC regions. Mean salaries were reported as follows: all faculty, $189,848; first‐year faculty, $153,855; programs reporting data to AAMC, $183,605; programs not reporting data to AAMC, $204,383; core faculty, $197,259; and noncore faculty, $164,215. Mean salaries as reported by AAMC region were as follows: Northeast, $192,864; South, $182,768; Midwest, $192,224; and West, $195,732. Full‐time emergency medicine residency program faculty are reported to be working an average of 1,032 total clinical hours per year. Workweeks average 22 clinical hours per week and 22 nonclinical hours per week, with 5.1 weeks of time off per year.

Conclusions:
Reported salaries for full‐time emergency medicine residency faculty continue to rise overall but fell for the first time in one region (the Midwest). Academic rank continues to correlate directly with salary. Fellowship training continues to show a negative correlation with salary. Significant regional differences in salaries have been present in all six SAEM surveys.
Testing Positive for Methadone and Either a Tricyclic Antidepressant or a Benzodiazepine Is Associated with an Accidental Overdose Death: Analysis of Medical Examiner Data
Authors: Chan Gar Ming , Stajic Marina , Marker Elizabeth K. , Hoffman Robert S. , Nelson Lewis S.
Published: March 2006

Objectives:
Patients in emergency departments who use methadone frequently use tricyclic antidepressants (TCAs) and/or benzodiazepines (BZDs). This is a potentially dangerous drug combination. The authors hypothesized that the presence of methadone and a TCA, a BZD, or both is associated with an “accidental” overdose (AOD) death more often than a death from any other cause.

Methods:
A retrospective chart review of New York City Office of Chief Medical Examiner data for 2003 was performed. Decedents who tested positive for methadone that were classified as an AOD death, as determined by the medical examiner, were compared with deaths from all other causes for the presence of a TCA, a BZD, or both. A logistical regression was performed to develop a multivariate model identifying additional variables associated with a methadone‐positive AOD death. A p‐value of <0.05 was considered significant, and 95% confidence intervals (CIs) were calculated.

Results:
In 2003, there were 5,817 medical examiner cases, of which 500 (8.6%) were methadone positive. Of the methadone‐positive cases, 493 were available for analysis; 95 (19.3%) were TCA positive and 158 (32.0%) were BZD positive. The odds of having an AOD death in methadone‐positive decedents testing TCA positive, BZD positive, or both were 2.11 (95% CI = 1.32 to 3.37; p < 0.01) for TCAs, 1.66 (95% CI = 1.12 to 2.45; p < 0.02) for BZDs, and 4.34 (95% CI = 1.97 to 9.56; p < 0.001) for both. The multivariate logistic regression of analytes revealed the following covariates associated with an AOD death as well: amitriptyline, cocaine, morphine, or opiates.

Conclusions:
Among the methadone‐positive cases, testing positive for a TCA, a BZD, or both was associated with an AOD death.
Age Effect on Efficacy and Side Effects of Two Sedation and Analgesia Protocols on Patients Going through Cardioversion: A Randomized Clinical Trial
Authors: Parlak Mine , Parlak Ismet , Erdur Bulent , Ergin Ahmet , Sagiroglu Emel
Published: March 2006

Background:
Cardioversion (CV), a painful procedure, requires sedation and analgesia. Although several sedation agents currently are in use for CV, data on age‐specific efficacy and side effects of midazolam and propofol have been limited.

Objectives:
To compare the efficacy and side effects of midazolam and propofol in patients of two different age groups, younger than 65 years and 65 years and over, who were going through CV.

Methods:
Seventy consented patients with CV indications caused by atrial fibrillation were included in this clinical trial. The participants were placed into four groups by using a stratified randomization method: patients aged younger than 65 years who were receiving midazolam (n= 12) or propofol (n= 11) and patients 65 years and over who were receiving midazolam (n= 25) or propofol (n= 22). Medications were administered by slow intermittent bolus injections. During CV, time to reach Ramsay Sedation Scale level 5 (RSS‐5; induction time); time to reach RSS‐2 (recovery time); and side effects including desaturation, apnea, and changes in hemodynamic parameters were recorded by a person blinded to the patient treatment allocation.

Results:
Mean induction time was similar in all four groups. Mean recovery time (min ± SD) was shorter in both propofol groups when compared with both midazolam groups: 18.8 (± 4.06) and 40.33 (± 20.8) in the group younger than 65 years and 18.2 (± 5.12) and 54.2 (± 20.85) in the group 65 years or older, respectively (p < 0.001). Older participants in each medication group needed less medication than younger patients. There were no hemodynamic differences between the groups. Desaturation was higher in both midazolam groups as compared with individuals in the age‐matched propofol groups (both p < 0.05). Patient reactions were less in propofol groups with similar joules during CV procedures than were those in the midazolam groups.

Conclusions:
Propofol appears to be a better choice for CV sedation in elders because of its short recovery time, fewer side effects, and its more comfortable sedative effect.
Resident‐As‐Teacher: A Suggested Curriculum for Emergency Medicine
Authors: Farrell Susan E. , Pacella Charissa , Egan Daniel , Hogan Victoria , Wang Ernest , Bhatia Kriti , Hobgood Cherri D.
Published: March 2006

Resident teaching is a competency that must be recognized, developed, and assessed. The ACGME core competencies include the role of physician as educator to “educate patients and families” and to “facilitate the learning of students and other health care professionals.” Residents spend a significant proportion of their time in teaching activities, and students report achieving much of their clinical learning from their interactions with residents. Although many residents enjoy their critical role as teacher, many do not feel well prepared to teach. This article summarizes a preliminary curriculum of modules for a resident teacher‐training program for emergency medicine residents. The goal of these modules is to provide learning objectives and an initial structure through which residents could improve basic teaching skills. Many of these skills are adaptable to residents' interactions with each other and with students, other healthcare professionals, and patients. Each module and corresponding teaching exercises can be found at http:www.saem.org
Childhood Soccer Injuries Treated in U.S. Emergency Departments
Authors: Adams Annette L. , Schiff Melissa A.
Published: March 2006

Objectives:
Soccer, an increasingly popular sport among children in the United States, is a common precipitant to injury‐related emergency department (ED) visits. The authors estimated the number of children treated in EDs for soccer‐related injuries and described the nature of these injuries.

Methods:
Data from the 2000 National Electronic Injury Surveillance System All Injury Program were used to estimate the overall number and rate of soccer injuries in children, calculate injury rates per 1,000 children, and describe the body regions affected and types of injuries. Results were stratified by five‐year age groups (5–9 years, 10–14 years, and 15–19 years).

Results:
Approximately 144,600 children sustained soccer‐related injuries in 2000 for a rate of 2.36 injuries per 1,000 children. Injury rates increased with age (0.8, 5–9 year olds; 3.1, 10–14 year olds; 3.2, 15–19 year olds). Common types of injuries were strains/sprains (36.7%), fractures (23.0%), and contusions (20.9%). Fractures decreased with age; sprains/strains increased with age. Commonly injured body regions varied by age. Wrist and finger injuries were most common (12.7% and 12.4%, respectively) in the youngest group; in the 10–14‐year‐old group, ankle and wrist injuries were most common (15.7% and 13.6%, respectively). In the oldest age group, ankle injuries were most common (21.9%), followed by knee injuries (17.6%).

Conclusions:
Substantial numbers of children were treated in EDs for soccer‐related injuries. Injury types and affected body regions varied by age. Injury prevention efforts to reduce soccer‐related injuries may need to be age specific.
Ten‐year Experience with an Emergency Medicine Resident Research Project Requirement
Authors: Holmes James F. , Sokolove Peter E. , Panacek Edward A.
Published: March 2006

Background:
Controversy exists regarding the value and quality of required emergency medicine (EM) resident scholarly projects.

Objectives:
To describe the research designs and presentation rate at national scientific meetings and the publication rate of EM resident scholarly projects at a university‐based residency program.

Methods:
The authors reviewed the initial ten years (1993–2002) of resident scholarly projects from an EM residency program. Since the inception of the program, a formal research study has been required of all residents for residency graduation. Scholarly projects were reviewed and categorized by study design. Abstracts from the American Academy of Emergency Medicine (AAEM), American College of Emergency Physicians (ACEP), and Society for Academic Emergency Medicine (SAEM) annual meetings were searched to identify projects presented at any of these national meetings. A PubMed search for resident and faculty investigators was performed, and faculty and graduated residents were queried to identify all resident scholarly projects published in peer‐reviewed journals.

Results:
Eighty‐seven residents produced 90 scholarly projects. Study designs were prospective data collection, 42 (47%); retrospective chart review, 38 (42%); survey, 5 (6%); animal, 4 (4%); and computer program development, 1 (1%). Of the 80 projects collecting patient data, 72 were conducted at a single center; 6, at two centers; and 2, at five centers each. Of the 42 prospective clinical studies, 27 (64%) were observational and 15 (36%) were interventional. Forty‐six (51%) abstracts were presented at national meetings (SAEM, 20; ACEP, 19; AAEM, 3; and other, 4). Thirty‐six (40%) of the projects have been published in peer‐reviewed journals. Abstract presentation at national meetings (range, 13%–64% of projects per yr) and manuscript publication rates (range, 0–67% of projects per yr) were variable from year to year.

Conclusions:
Resident scholarly projects at one institution were equally likely to use a prospective or retrospective design, and most were conducted at a single center. More than half of the projects were presented at national research meetings, and more than a third were subsequently developed into manuscripts and published in peer‐reviewed journals. When an original research study is required for satisfying the scholarly requirement for EM residency graduation, resident projects can contribute to the EM literature.
Ventricular Fibrillation in Pediatric Cardiac Arrest
Authors: Smith Brian T. , Rea Tom D. , Eisenberg Mickey S.
Published: March 2006

Objectives:
After activating 9‐1‐1 for out‐of‐hospital cardiac arrest (CA), guidelines for children 1 year and older have evolved to include immediate automated external defibrillator (AED) use for witnessed arrest, and two minutes of cardiopulmonary resuscitation (CPR) followed by AED use for unwitnessed arrests. The best approach to resuscitation in a two‐tiered emergency medical services (EMS) system depends in part on how likely the patient is to present with ventricular fibrillation (VF). Therefore, the authors evaluated the frequency of VF with respect to age and other characteristics to further elucidate the role of the AED among pediatric CAs.

Methods:
The investigation was a retrospective cohort study of EMS‐treated, nontraumatic, out‐of‐hospital CA among persons aged 1–18 years in King County, Washington, between April 1, 1976, and December 31, 2003. The primary goal was to identify the proportion of patients presenting to EMS in VF, according to age. The association between other characteristics and the likelihood of VF was also evaluated. Finally, hospital survival according to cardiac rhythm at EMS arrival was evaluated.

Results:
Ventricular fibrillation was the presenting rhythm in 17.6% of cases (48/272). The proportion presenting with VF was 7.6% (10/131) among children aged 1–7 years and 27.0% (38/141) among children aged 8–18 years (p < 0.001). In multivariable models, VF was independently associated with age 8 years and older compared with 1–7 years (odds ratio, 3.19; 95% confidence interval [CI] = 1.46 to 6.97), witnessed arrest (odds ratio, 3.33; 95% CI = 1.63 to 6.82), and cardiac etiology (odds ratio, 2.89; 95% CI = 1.32 to 6.34). Survival was 31.3% (15/48) for VF and 10.7% (24/224) for nonshockable rhythm CAs.

Conclusions:
The proportion of children aged younger than 8 years presenting with VF is low compared with older children. The greatest increase in VF proportion occurs in children older than 12 years. Based on these results, the best approach for initial EMS resuscitation in a two‐tiered EMS system, CPR versus AED use, is uncertain among younger children. Inclusion of witness status into the decision process for younger children may more efficiently allocate AED use, a finding in accordance with 2005 guidelines.
Aldosterone Blockade Attenuates Urinary Monocyte Chemoattractant Protein-1 and Oxidative Stress in Patients with Type 2 Diabetes Complicated by Diabetic Nephropathy
Authors: Takebayashi Kohzo , Matsumoto Sachiko , Aso Yoshimasa , Inukai Toshihiko
Published: March 2006

Context: Aldosterone causes organic impairment by enhancement of oxidative stress and subsequent induction of proinflammatory cytokines and chemokines.

Objective: This study was designed to investigate the effect of spironolactone, an aldosterone blocker, on oxidative stress and the level of urinary monocyte chemoattractant protein (MCP)-1, a cysteine-cysteine chemokine that may contribute to progression of various nephropathies in type 2 diabetic patients with diabetic nephropathy.

Design, Setting, Patients and Other Participants, and Intervention: The patients were randomly assigned to two groups in which they received either spironolactone (50 mg/d; n = 23) or amlodipine (2.5 mg/d; n = 14).

Main Outcome Measures: Urinary 8-iso-prostaglandin (PG) F2α (a marker of oxidative stress), urinary MCP-1, and urinary albumin excretion (UAE) were measured at the start of administration (0 months) and after 3 months in each group. Baseline levels of these variables were also measured in 25 age-matched healthy subjects.

Results: There were significant positive correlations between log10-transformed (log) 8-iso-PGF2α and log MCP-1 levels in control and diabetic subjects and all subjects combined, but no correlations between log UAE and log 8-iso-PGF2α or log MCP-1 were found in any group. Significant decreases in 8-iso-PGF2α, MCP-1, and UAE were observed with spironolactone (P = 0.0001, P = 0.0041, and P = 0.0037, respectively), and systolic blood pressure significantly decreased after both spironolactone and amlodipine therapy (P = 0.00011 and P = 0.0051, respectively).

Conclusions: Our data suggest that urinary MCP-1 is correlated with oxidative stress as measured by urinary 8-iso-PGF2α and that spironolactone can decrease urinary MCP-1 and oxidative stress.
Interaction of SH2-Bβ with RET is involved in signaling of GDNF-induced neurite outgrowth
Authors: Zhang Yong , Zhu Wei , Wang Yong-Gang , Liu Xiu-Jie , Jiao Li , Liu Xuan , Zhang Zhao-Huan , Lu Chang-Lin , He Cheng
Published: March 2006

RET receptor signalling is essential for glial-cell-line-derived neurotrophic factor (GDNF)-induced survival and differentiation of various neurons such as mesencephalic neurons. To identify proteins that mediate RET-dependent signaling, yeast two-hybrid screening was performed with the intracellular domain of RET as bait. We identified a new interaction between RET and the adapter protein SH2-Bβ. Upon GDNF stimulation of PC12-GFRα1-RET cells (that stably overexpress GDNF receptor α1 and RET), wild-type SH2-Bβ co-immunoprecipitated with RET, whereas the dominant-negative SH2-Bβ mutant R555E did not. RET interacted with endogenous SH2-Bβ both in PC12-GFRα1-RET cells and in rat tissues. Mutagenesis analysis revealed that Tyr981 within the intracellular domain of RET was crucial for the interaction with SH2-Bβ. Morphological evidence showed that SH2-Bβ and RET colocalized in mesencephalic neurons. Furthermore, functional analysis indicated that overexpression of SH2-Bβ facilitated GDNF-induced neurite outgrowth in both PC12-GFRα1-RET cells and cultured mesencephalic neurons, whereas the mutant R555E inhibited the effect. Moreover, inhibition of SH2-Bβ expression by RNA interference caused a significant decrease of GDNF-induced neuronal differentiation in PC12-GFRα1-RET cells. Taken together, our results suggest that SH2-Bβ is a new signaling molecule involved in GDNF-induced neurite outgrowth.
NMDA induces post-transcriptional regulation of α2-guanylyl-cyclase-subunit expression in cerebellar granule cells
Authors: Jurado Sandra , Rodríguez-Pascual Fernando , Sánchez-Prieto José , Reimunde Francisco M. , Lamas Santiago , Torres Magdalena
Published: March 2006

Activation of N-methyl-D-aspartate (NMDA) glutamate receptors commonly affects gene expression in different neurons. We reported previously that chronic treatment of rat cerebellar granule cells with NMDA (24 hours) upregulates the expression of mRNA encoding the α2 subunit of the nitric-oxide-sensitive guanylyl cyclase. However, the molecular mechanisms involved in this process remained to be elucidated. Here, we have performed mRNA-decay experiments using the transcriptional inhibitor actinomycin D, providing evidence that the half-life of α2 mRNA is significantly prolonged in cells exposed to NMDA. The role of the 3′ untranslated region of the α2 transcripts in NMDA-induced mRNA stabilisation was examined and an association between the RNA-binding proteins AUF1 and ELAV-like protein 1 (HuR/HuA), and endogenous α2 mRNA was demonstrated in vivo, as revealed by coimmunoprecipitation experiments with specific antibodies against AUF1 and HuR. Further studies indicated that stimulation of the NMDA receptor induces a downregulation in AUF1 levels stabilising the α2 mRNA transcripts. These events are triggered through a mechanism that depends on formation of nitric oxide, and on the subsequent activation of guanylyl cyclase and cGMP dependent protein kinases.
Targeted wild-type and jerker espins reveal a novel, WH2-domain-dependent way to make actin bundles in cells
Authors: Loomis Patricia A. , Kelly Alexander E. , Zheng Lili , Changyaleket Benjarat , Sekerková Gabriella , Mugnaini Enrico , Ferreira Adriana , Mullins R. Dyche , Bartles James R.
Published: March 2006

The espin actin-bundling proteins, which are the target of deafness mutations, are present in the parallel actin bundles of stereocilia and microvilli and appear to increase their steady-state length. Here, we report a new activity of the espins, one that depends on their enigmatic WH2 domain: the ability to assemble a large actin bundle when targeted to a specific subcellular location. This activity was observed for wild-type espins targeted to the centrosome in transfected neuronal cells and for jerker espins targeted to the nucleolus in a wide variety of transfected cells as a result of the frameshifted peptide introduced into the espin C-terminus by the jerker deafness mutation. This activity, which appears specific to espins, requires two espin F-actin-binding sites and the actin-monomer-binding activity of the espin WH2 domain, but can be mimicked by adding a WH2 domain to an unrelated actin-bundling protein, villin. Espins do not activate the Arp2/3 complex in vitro, and bundle assembly is not indicative of in-vitro nucleation activity. Our results suggest a novel way to build actin bundles at specific sites in cells.
NFATc1 nucleocytoplasmic shuttling is controlled by nerve activity in skeletal muscle
Authors: Tothova Jana , Blaauw Bert , Pallafacchina Giorgia , Rudolf Rüdiger , Argentini Carla , Reggiani Carlo , Schiaffino Stefano
Published: March 2006

Calcineurin-NFAT signaling has been shown to control activity-dependent muscle gene regulation and induce a program of gene expression typical of slow oxidative muscle fibers. Following Ca2+-calmodulin stimulation, calcineurin dephosphorylates NFAT proteins and induces their translocation into the nucleus. However, NFAT nuclear translocation has never been investigated in skeletal muscle in vivo. To determine whether NFATc1 nucleocytoplasmic shuttling depends on muscle activity, we transfected fast and slow mouse muscles with plasmids coding for an NFATc1-GFP fusion protein. We found that NFATc1-GFP has a predominantly cytoplasmic localization in the fast tibialis anterior muscle but a predominantly nuclear localization in the slow soleus muscle, with a characteristic focal intranuclear distribution. Two hours of complete inactivity, induced by denervation or anaesthesia, cause NFATc1 export out of the nucleus in soleus muscle fibers, whereas electrostimulation of tibialis anterior with a low-frequency tonic impulse pattern, mimicking the firing pattern of slow motor neurons, causes NFATc1 nuclear translocation. The activity-dependent nuclear import and export of NFATc1 is a rapid event, as visualized directly in vivo by two-photon microscopy. The calcineurin inhibitor cain/cabin1 causes nuclear export of NFATc1 both in normal soleus and stimulated tibialis anterior muscle. These findings support the notion that in skeletal muscle NFATc1 is a calcineurin-dependent nerve activity sensor.
The Black and White Traveling Salesman Problem
Authors: Ghiani Gianpaolo , Laporte Gilbert , Semet Frédéric
Published: March 2006

The black and white traveling salesman problem (BWTSP) is defined on a graph G whose vertex set is partitioned into black and white vertices. The aim is to design a shortest Hamiltonian tour on G subject to cardinality and length constraints: both the number of white vertices as well as the length of the tour between two consecutive black vertices are bounded above. The BWTSP has applications in airline scheduling and in telecommunications. This paper proposes an integer linear formulation for the undirected BWTSP, as well as several classes of valid inequalities. An exact branch-and-cut algorithm is then developed. Extensive tests show that it can solve exactly instances involving up to 100 vertices. The algorithm can also be applied directly to solve unit demand vehicle routing problems of similar sizes.
Dynamic Mechanism Design for Online Commerce
Authors: Gallien Jérémie
Published: March 2006

This paper is a mechanism design study for a monopolist selling multiple identical items to potential buyers arriving over time. Participants in our model are time sensitive, with the same discount factor; potential buyers have unit demand and arrive sequentially according to a renewal process; and valuations are drawn independently from the same regular distribution. Invoking the revelation principle, we restrict our attention to direct dynamic mechanisms taking a sequence of valuations and arrival epochs as input. We define two properties (discreteness and stability), and prove under further distributional assumptions that we may at no cost of generality consider only mechanisms satisfying them. This effectively reduces the mechanism input to a sequence of valuations and leads to formulate the problem as a dynamic program (DP). As this DP is equivalent to a well-known infinite-horizon asset-selling problem, we finally characterize the optimal mechanism as a sequence of posted prices increasing with each sale. Remarkably, this result rationalizes somewhat the frequent restriction to dynamic pricing policies and impatient buyers assumption. Our numerical study indicates that, under various valuation distributions, the benefit of dynamic pricing over a fixed posted price may be small. Besides, posted prices are preferable to online auctions for a large number of items or high interest rate, but in other cases auctions are close to optimal and significantly more robust.
Firefighter Staffing Including Temporary Absences and Wastage
Authors: Fry Michael J. , Magazine Michael J. , Rao Uday S.
Published: March 2006

We examine the problem of determining the annual staffing level that minimizes total expected costs for a fire department, subject to minimum service-level-based staffing requirements. We develop a quantitative model that allows for stochastic temporary absences, permanent wastage, and limited hiring opportunities, and takes into account the unique firefighter work schedule. Our model is reminiscent of traditional newsvendor-type inventory models, but where the uncertainty is dependent on the decision variable. We derive easily implementable optimal staffing policies for both the continuous and discrete cases. We provide numerical results comparing our optimal solution to several heuristic staffing policies commonly used in practice, which show that our optimal policy can provide significant savings. We perform sensitivity analysis to generate managerial insights. We discuss an application of our model and analysis to the Cincinnati Fire Department.
Exact Simulation of Stochastic Volatility and Other Affine Jump Diffusion Processes
Authors: Broadie Mark , Kaya Özgür
Published: March 2006

The stochastic differential equations for affine jump diffusion models do not yield exact solutions that can be directly simulated. Discretization methods can be used for simulating security prices under these models. However, discretization introduces bias into the simulation results, and a large number of time steps may be needed to reduce the discretization bias to an acceptable level. This paper suggests a method for the exact simulation of the stock price and variance under Heston’s stochastic volatility model and other affine jump diffusion processes. The sample stock price and variance from the exact distribution can then be used to generate an unbiased estimator of the price of a derivative security. We compare our method with the more conventional Euler discretization method and demonstrate the faster convergence rate of the error in our method. Specifically, our method achieves an O(s-1/2) convergence rate, where s is the total computational budget. The convergence rate for the Euler discretization method is O(s-1/3) or slower, depending on the model coefficients and option payoff function.
Inventory Policies in a Decentralized Assembly System
Authors: Bernstein Fernando , DeCroix Gregory A.
Published: March 2006

We consider a system in which a single finished good is assembled from two components. Demand for the finished product is stochastic and stationary, and procurement and assembly lead times are constant. Unsatisfied demand is backordered. The inventory of each component or assembly is controlled by a separate firm using a base-stock policy. Each firm is charged holding costs on its own inventory, plus a share of the shortage cost due to backorders of the finished product.

We investigate the equilibrium base-stock levels that arise in this system under both echelon and local base-stock policies. In both cases, the component firms’ base-stock levels are economic complements. We then examine the effect on system performance when one firm uses information about other firms’ pipeline inventory. We find that, under echelon base-stock policies, all firms benefit with the use of pipeline information. In contrast, under local policies, using pipeline information may actually increase costs for some firms (including the firm that makes direct use of the information). Also, we compare the behavior of the decentralized system with that of the assembly system under centralized control. Finally, we describe a payment scheme between the final assembler and the suppliers that allows the decentralized system to achieve the centralized solution.
Sensitivity of Performance in the Erlang-A Queueing Model to Changes in the Model Parameters
Authors: Whitt Ward
Published: March 2006

This paper studies the M/M/s+M queue, i.e., the M/M/s queue with customer abandonment, also called the Erlang-A model, having independent and identically distributed customer abandon times with an exponential distribution (the +M), focusing on the case in which the arrival rate and the number of servers are large. The goal is to better understand the sensitivity of performance to changes in the model parameters: the arrival rate, the service rate, the number of servers, and the abandonment rate. Elasticities are used to show the percentage change of a performance measure caused by a small percentage change in a parameter. Elasticities are calculated using an exact numerical algorithm and simple finite-difference approximations. Insight is gained by applying fluid and diffusion approximations. The analysis shows that performance is quite sensitive to small percentage changes in the arrival rate or the service rate, but relatively insensitive to small percentage changes in the abandonment rate.
An Optimal Lot-Sizing and Offline Inspection Policy in the Case of Nonrigid Demand
Authors: Anily Shoshana , Grosfeld-Nir Abraham
Published: March 2006

A batch production process that is initially in the in-control state can fail with constant failure rate to the out-of-control state. The probability that a unit is conforming if produced while the process is in control is constant and higher than the respective constant conformance probability while the process is out of control. When production ends, the units are inspected in the order they have been produced. The objective is to design a production and inspection policy that guarantees a zero defective delivery in minimum expected total cost.

The inspection problem is formulated as a partially observable Markov decision process (POMDP): Given the observations about the quality of the items that have already been inspected, the inspector should determine whether to inspect the next unit or stop inspection and possibly pay shortage costs. We show that the optimal policy is of the control limit threshold (CLT) type: The observations are used to update the probability that the production process was still in control while producing the candidate unit for inspection. The optimal policy is to continue inspection if and only if this probability exceeds a CLT value that may depend on the outstanding demand and the number of uninspected items. Structural properties satisfied by the various CLT values are presented.