bluuebunny/crossref_metadata_2025 huggingface dataset:
Practice or Profits
Authors: Jianakoplos Nancy Ammon , Shields Martin
Published: June 2012

This article investigates whether the outcomes of National Football League (NFL) preseason games are predictors of regular season NFL performance. Using data from the 2002-2010 NFL seasons, the empirical analysis does not find that either a team’s preseason winning percentage or a win in the third preseason game is a significant indicator of the team’s regular season winning percentage. This result contrasts with previous findings that preseason game performance did provide an indicator of regular season performance for the 1970-1991 NFL seasons. Preliminary evidence is presented that suggests that the change in the importance of preseason performance in predicting regular season performance started around 1994.
Customer Discrimination and Fernandomania
Authors: Nutting Andrew W.
Published: June 2012

This article tests for customer discrimination by examining attendance boosts associated with the Los Angeles Dodgers pitcher and Mexican national Fernando Valenzuela. Fernando’s starts were associated with higher attendance at games beginning in 1981 and as late as 1987, and as late as 1985 for games outside of Los Angeles. Attendance increased more when games were played in Metropolitan Statistical Area (MSA)s with larger Mexican populations. Attendance also increased more in MSAs with larger non-Mexican Hispanic populations, especially when such Hispanics did not claim a specific Latin American country of origin. Larger Asian populations led to significantly lower attendance at Fernando’s starts.
Financial Risk Management
Authors: Rascher Daniel A. , Brown Matthew T. , Nagel Mark S. , McEvoy Chad D.
Published: June 2012

One of the absolutes in professional sports, and a reason for its success, is the uncertainty of the outcome of individual games, seasons, and championships. This uncertainty impacts a team’s attendance and financial operation. While leagues cultivate uncertainty through various rules such as salary caps, revenue sharing, and the amateur draft, individual franchises have to manage the result of variability in annual revenues. Not only is this due to the parity in a league but also from injuries and changes in player quality that are unexpected. Whether uncertainty or winning or the perfect combination of the two, some aspects that affect revenues can be controlled by team management more so than others. Even though on-the-field success is not easily controlled by team management, the overall quality of the experience can be impacted from, among other things, a quality stadium with comfortable seating and delectable food. This research shows that the variability in annual team revenues decreases (relative to total revenues) once a team moves into a new stadium, all else equal. The increase in predictability lowers financial risk, impacting the cost of financing and other practical operational issues like game-day staffing.
Limb Wounding and Antisepsis
Authors: Eardley William G. P. , Watts Sarah A. , Clasper Jon C.
Published: June 2012

Extremity injury and contamination as consequence are features of high-energy wounding. A leading cause of disability and the commonest cause of late complications, prevention of wound infection determines the ultimate outcome in these populations. Multiple variables influence the development of infection, one of which is the dressing used on the wound. Antiseptic-soaked gauze dressings feature in the early management of limb trauma despite a lack of evidence to support this. Iodine and chlorhexidine are ubiquitous in other aspects of health care however, and a plethora of studies detail their role in skin antisepsis, the recommendations from which are often anecdotally applied to acute wounding. To contextualize the role for antiseptic dressing use in acute, significant limb injury this review explores the evidence for the use of chlorhexidine and iodine in skin antisepsis. The paucity of experimental data available for antiseptic use in early wound management and the need for further research to address this evidence void is highlighted.
Treatment of Chronic Osteomyelitis Secondary to Hydatid Disease of Bone Using Gentamycin Beads
Authors: Obeidat Moutasem M. , Mustafa Ziad
Published: June 2012

Hydatid disease of bone is rare. It remains asymptomatic over a long period. It is usually detected after a pathological fracture or secondary infection or following the onset of compressive myelopathy in cases of vertebral lesions. Secondary infection of hydatid disease of bone could be difficult to treat. The authors present a case of chronic osteomyelitis of the proximal aspect of the left femur in a 37-year-old male patient secondary to hydatid disease of bone. It was treated by aggressive debridement, gentamycin beads, and bone graft to fill the defect. No recurrence of the hydatid lesion or infection was detected after 2 years. This case showed that in addition to aggressive debridement, gentamycin beads may be valuable in eradicating the infection in such a case.
Onyx Embolization of High-Flow Spontaneous Cervical Vertebral Arteriovenous Fistula
Authors: Gordhan Ajeet
Published: June 2012

Background and Importance: High-flow spontaneous vertebral arteriovenous shunts in patients with fibromuscular disease (FMD) are rare. Onyx embolizaton of the recipient veins with shunt disconnection and preservation of the affected vertebral artery in a patient with FMD has not been reported. Clinical Presentation: A 59-year-old female presented with progressive dizziness, pre-syncopal episodes, and tinnitus. Catheter-based angiography identified features of fibromuscular dysplasia and a high-flow right cervical vertebral artery arteriovenous shunt. Onyx embolization of the principle draining veins was performed with initial detachable coil placement. Complete disconnection of the shunt was achieved without sacrifice of the parent vertebral artery. Conclusion: Spontaneous high-flow vertebral arteriovenous shunts can be successfully occluded with Onyx/detachable coil embolization of the principle recipient veins.
Current Debate on the Role of Embolic Protection Devices
Authors: Bornak Arash , Milner Ross
Published: June 2012

The role of embolic protection devices (EPDs) during percutaneous arterial revascularization is still debated. This article discusses the use, the limitations, and issues of the variety of EPDs in different vascular beds, with a particular focus on the lower extremity arterial interventions.
Race, Probation Violations, and Structured Secure Detention Decision Making in Three Jurisdictions
Authors: Leiber Michael J. , Boggess Lyndsay N.
Published: June 2012

The relationships between race and probation violations with preadjudication secure detention decision and detention hearings are examined in three jurisdictions in a Midwestern state that use a detention screening instrument. Interpretations of consensus theory and the racial or symbolic threat thesis with an emphasis on race stereotyping serve as the theoretical background for the study. The results reveal race to be influential in detention decisions in one jurisdiction, while involvement in probation violations is associated with the initial detention decision in all three jurisdictions. Implications for future research and for assessing whether the structuring of detention decision-making results in greater equality in detention proceedings for minority youth relative to White youth are discussed.
Reporting Physical Assault
Authors: Zaykowski Heather
Published: June 2012

Although numerous studies have explored youth formal and informal help-seeking, including reporting to the police and disclosing victimization experiences to others, there has been little discussion in how other experiences with violence, such as witnessing and perpetrating violence, may impact responses to victimization. The current study uses multinomial probit analyses to explore how multiple victimizations, violent behavior, and witnessing violence impact youth decisions to call the police, report to school authorities, or informally disclose their victimization. The results suggest that, accounting for alternative responses to victimization, reporting to the police is inhibited by the respondent’s violent background and witnessing violence.
School Improvement
Authors: Pollock Katina , Winton Sue
Published: June 2012

Maple Leaf School is a large English elementary school in Ontario, Canada. Wanda Miller, the principal, has been at the school for 2 years. Upon arrival, she engaged the teachers in a collaborative exercise to determine their school goal (as required by the province). Character education was selected. The district insisted that the school adopt an academic goal instead. Wanda determined that character education would be the school’s primary goal and writing its secondary one. Since then, students’ behavior and the school’s climate have improved markedly, but test scores have declined. This case focuses on the tension between a locally identified, collaboratively determined school focus and conflicting district and provincial demands.
All Seem to Need Immediate Attention—What Should I Do First? A Successful Principal in a New School Assignment at Secundaria Revolución
Authors: Torres-Arcadia Celina , Flores-Kastanis Eduardo
Published: June 2012

This case provides emerging school administrators the opportunity to learn about the school system in Mexico. The case relates to a successful principal in her new school assignment. Martha Miramontes is an experienced and successful principal who quickly identified a number of challenges in her new campus. Even though each problem can be solved with a particular strategy, for the first time, Martha is facing a situation where all problems seem to require immediate attention. She knows she can address all problems, but decisions must be made in relation to which problem should be tackled first. Where should she start? This case explores possible sequence of actions of an experienced principal facing multiple problems in the setting of a Mexican Public Secundaria.
Probability of failure on demand of safety systems: impact of partial test distribution
Authors: Brissaud Florent , Barros Anne , Bérenguer Christophe
Published: June 2012

In accordance with the IEC  61508 functional safety standard, safety-related systems operating in a low demand mode need to be proof tested to reveal any ‘dangerous undetected failures’. Proof tests may be full (i.e. complete) or partial (i.e. incomplete), depending on their ability to detect all the system failures or only a part of them. Following a partial test, some failures may then be left latent until the full test, whereas after a full test (and overhaul), the system is restored to an as-good-as-new condition. A partial-test policy is defined by the efficiency of the partial tests, and the number and distribution (periodic or non-periodic) of the partial tests in the full test time interval.

Non-approximate equations are introduced for probability of failure on demand (PFD) assessment of a Moo N architecture (i.e. k-out-of- n: G) systems subject to partial and full tests. Partial tests may occur at different time instants (periodic or not) until the full test. The time-dependent, average, and maximum system unavailability (PFD(t), PFDavg, and PFDmax) are investigated, and the impact of the partial test distribution on average and maximum system unavailability are analysed, according to system architecture, component failure rates, and partial test efficiency.
‘Uppity civilians’ and ‘cyber-vigilantes’: The role of the general public in policing cyber-crime
Authors: Huey Laura , Nhan Johnny , Broll Ryan
Published: June 2012

The distributed nature of the Internet requires that security issues be addressed through collaborative efforts within and across various sets of public and private actors. Drawing on nodal governance theory, this article explores one aspect of the role that the general public can and does play in the field of cyber-security: civilian policing of the Internet. In particular, we examine the motives and actions of regular citizens, who use their computer skills to identify, track and collect information on the activities of suspected criminal offenders. Whereas some groups use such information to engage in vigilante acts, the groups that we study work cooperatively with police, collecting information to pass onto criminal justice agencies. We suggest that these collectives and their members are a potentially useful, if under-valued, component of cyber-security networks.
Healthy ageing: the role of health care services
Authors: Howse Kenneth
Published: June 2012

The implications of the imminent surge in population ageing for the work of health care services in high-income countries remain unclear. It is widely expected, however, that the prevention and management of chronic disease will increasingly dominate their workload, and that this is likely to require a major shift in the way that care is delivered. This paper argues that the central contribution of health care services to a healthy ageing strategy is to drive improvements in the prevention and management of chronic disease, and it explores some of the implications of this view in the light of evidence mainly from the UK.
Vaccinations and preventive screening services for older adults: opportunities and challenges in the USA
Authors: Shenson Douglas , Anderson Lynda , Slonim Amy , Benson William
Published: June 2012

Vaccinations and disease-screening services occupy an important position within the constellation of interventions designed to prevent, forestall or mitigate illness: they straddle the worlds of clinical medicine and public health. This paper focuses on a set of clinical preventive services that are recommended in the USA for adults aged 65 and older, based on their age and gender. These services include immunisations against influenza and pneumococcal disease, and screening for colorectal and breast cancers. We explore opportunities and challenges to enhance the delivery of these interventions, and describe some recently developed models for integrating prevention efforts based in clinician offices and in communities. We also report on a state-level surveillance measure that assesses whether older adults are ‘up to date’ on this subset of preventive services. To better protect the health of older Americans and change the projected trajectory of medical costs, expanded delivery of recommended vaccinations and disease screenings is likely to remain a focus for both US medicine and public health.
STI epidemiology in the global older population: emerging challenges
Authors: Minichiello Victor , Rahman Saifur , Hawkes Gail , Pitts Marian
Published: June 2012

This paper reviews the evidence concerning the epidemiology of sexually transmitted infections (STIs) with a particular focus on older people. Evidence from North America, Australia, China and Korea clearly shows increasing rates of many STIs in the population group aged 50 years and older. Similar changes are identified in three studies conducted in sub-Saharan Africa. There is a significant lack of detailed epidemiological data from Asia-Pacific and many African countries. There is also a lack of health education and health programmes directed towards older people. It is likely that sexual ageism is the dynamic that underpins this lack of focus and resources for older people.
Factors impacting on the well-being of older residents in rural communities
Authors: Inder Kerry J , Lewin Terry J , Kelly Brian J
Published: June 2012

Background:

In Australia, rural areas have higher proportions of older persons than metropolitan areas, where ageing poses many challenges related to social isolation, reduced mobility, more chronic disease and comorbidity, greater socio-economic disadvantage, limited access to services, and economic restructuring. Although Australian national data indicate an age-dependent decline in the prevalence of mental disorders, physical ill health is clearly associated with mental disorder in the elderly. There are conflicting findings regarding rural–urban differences in the prevalence of mental disorder, reflecting the complexity of definitions of rurality, and the geographic, ethnic and cultural diversity that underpins location and its influence on health outcomes.

Aims:

This study aims to investigate the determinants of well-being in a sample of older adults from rural and remote communities, with particular focus on the role of social factors.

Methods:

Baseline cross-sectional survey data were used from the Australian Rural Mental Health Study, a population-based longitudinal cohort of adults aged 18–85 years randomly selected from electoral rolls. We compared measures of mental health and well-being in adults aged 65 years and over with middle-aged and younger adults living in rural and regional New South Wales. Factors associated with positive well-being and psychological distress in the older group were examined using multivariate logistic regressions, reporting adjusted odds ratios (AOR) and 99% confidence intervals (CI).

Results:

Of the 2,624 participants, 722 (28%) were aged between 65 and 85 years. Well-being was generally higher among those aged 65 years or older, compared with younger groups, with the notable exception of perceived physical health. Among those aged 65 years or older, poorer well-being was independently associated with older age (AOR 0.29, 99% CI 0.13–0.64), one or more chronic diseases (AOR 0.34, 99% CI 0.17–0.69), and a history of depression, stress or anxiety (AOR 0.31, 99% CI 0.12–0.76). Having increased community and personal support (AOR 4.7, 99% CI 2.5–8.9) significantly increased well-being in the older participants. A comparable profile emerged for the predictors of psychological distress, with higher trait neuroticism also making a substantial contribution (AOR 6.4, 99% CI 2.3–7.8).

Conclusions:

Despite increased rates of chronic illness and poorer physical health, older rural Australians reported better well-being than younger groups, possibly reflecting a survivor effect or perhaps a generational effect, in terms of greater resilience or stoicism in the older generation. Higher levels of perceived community and personal support improve current well-being and are protective for moderate to high psychological distress.
Overcoming docetaxel resistance in prostate cancer: a perspective review
Authors: Hwang Clara
Published: June 2012

The treatment of metastatic castrate-resistant prostate cancer has been historically challenging, with few therapeutic successes. Docetaxel was the first cytotoxic therapy associated with a survival benefit in castrate-resistant prostate cancer. Toxicity is typical of other cytotoxic agents, with myelosuppression being the dose-limiting toxicity and neurotoxicity also a notable side effect for some patients. Unfortunately, a significant proportion of men with castrate-resistant prostate cancer will not respond to docetaxel-based therapy and all patients will ultimately develop resistance. Because it is an effective therapy, docetaxel is likely to remain an important part of the treatment arsenal against metastatic prostate cancer for the foreseeable future, despite its toxicities and limitations. Overcoming docetaxel resistance has been a challenge since docetaxel was first established as front-line therapy for metastatic castrate-resistant prostate cancer. Recent studies have shown that several new drugs, including cabazitaxel and abiraterone, are effective after docetaxel failure, dramatically changing the therapeutic landscape for these patients. In addition, a greater understanding of the mechanisms underlying docetaxel resistance has led to several new treatment approaches which hold promise for the future. This review will discuss recent therapeutic advances in metastatic castrate-resistant prostate cancer as well as ongoing clinical trials.
The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies
Authors: Hurvitz Sara A. , Kakkar Reva
Published: June 2012

The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumab- and lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.
Health Considerations for Children With Congenital Heart Disease in School
Authors: O’Brien Patricia , Evangelista Juli-anne , Green Angela , Uzark Karen
Published: June 2012

School participation for children with congenital heart disease (CHD) can be challenging. Despite advances in treatment that have increased survival to adulthood and decreased morbidity, concerns remain about their health and safety in the school environment. This article, the first in a two-part series, provides an overview of the health issues involving school-age children with CHD. School nurses are in a unique position to advocate for the child’s health care needs in the school setting, facilitate communication with the health care team, educate school personnel, and participate in the individualized educational planning process.
For My Own Benefit or for the Benefit of Others
Authors: Reutner Leonie , Wänke Michaela
Published: June 2012

Persuading people to follow a behavioral recommendation can be attempted by outlining the negative consequences for those performing this behavior or by outlining the negative consequences for others. Prior research has shown that reminding people of money (e.g., touching money) leads to higher self-sufficiency resulting in more self-focused and less social behavior. Consequently, the authors show that touching money also affects the persuasiveness of arguments focusing on the self versus other people. After reading an argument outlining the negative consequences of a behavior (e.g., smoking) for the person performing that behavior (e.g., premature skin aging), participants reported stronger intentions to abstain from that behavior when they had previously touched money compared to a control group. In contrast, following arguments that stressed the negative consequences the behavior had for other people (e.g., children imitating smoking behavior), participants who had touched money reported less inclination for behavioral change compared to a control group.
Outcome of the Dynamic Helical Hip Screw System for Intertrochanteric Hip Fractures in the Elderly Patients
Authors: O'Malley Natasha T. , Deeb Andrew-Paul , Bingham Karilee W. , Kates Stephen L.
Published: June 2012

Introduction:

The dynamic helical hip system (DHHS; Synthes, Paoli, Pennsylvania) differs from the standard dynamic sliding hip screw (SHS) in that in preparing for its insertion, reaming of the femoral head is not performed, thereby preserving bone stock. It also requires less torque for insertion of the helical screw. The associated plate has locking options to allow locking screw fixation in the femoral shaft, thereby decreasing the chance of the plate pulling off. While biomechanical studies have shown improved resistance to cutout and increased rotational stability of the femoral head fragment when compared with traditional hip lag screws, there is limited information on clinical outcome of the implant available in the literature.

Methods:

We report a single surgeon series of 87 patients who were treated for their per-trochanteric hip fractures with this implant to evaluate their clinical outcome and compare it with a cohort of 344 patients who were treated with the standard SHS. All data were prospectively collected, most as part of a structured Geriatric Fracture Care Program.

Results:

The 2 groups were similar demographically, and medically, with similar rates of in-hospital complications and implant failure. Failure in the DHHS group was attributable to use of the implant outside its indications and repeated fall of the patient.

Conclusion:

This limited case series showed that the DHHS outcomes are comparable with that of the SHS. Whether there is any benefit to its use will require larger, prospective randomized controlled trials.
Comparison of Complications and Length of Hospital Stay Between Orthopedic and Orthogeriatric Treatment in Elderly Patients With a Hip Fracture
Authors: Wagner Pablo , Fuentes Paola , Diaz Andres , Martinez Felipe , Amenabar Pedro , Schweitzer Daniel , Botello Eduardo , Gac Homero
Published: June 2012

Hip fractures in the elderly individuals are a complex problem. Our objective was to determine whether orthogeriatric treatment is effective in terms of reducing length of hospital stay, morbidity, and mortality of elderly patients with a hip fracture compared with orthopedic (traditional) treatment. From July 2009 to May 2011, patients older than 65 years with a hip fracture were followed prospectively. They were co-treated by geriatric and orthopedic teams. This cohort was compared with a retrospective cohort followed from January 2007 to June 2009 that was managed by the orthopedic surgery team only. Epidemiology, pre- and postoperative hematocrit, and renal function were registered. Also, in-hospital and distant mortality data (determined by consulting the national registry), mortality-associated factors, postoperative complications, hospital stay length, and transfers to other services were registered. One hundred and eighty-three patients in the retrospective group and 92 in the prospective group were included in this study with a median follow-up of 26 months (interquartile range: 13-41). The average age was 84 years and 74% of patients were female. Intertrochanteric fracture accounted for 51% of the cases. There was no difference between groups with regard to hospital stay length, hematocrit at discharge, in-hospital mortality, long-term survival, or transfers to internal medicine or the intensive care unit. It did show differences in the transfer to the intermediate care unit, prolonged hospitalizations (>20 days), and diagnosis of delirium and anemia requiring transfusion. In the present study, orthogeriatric treatment is slightly more effective than traditional treatment in terms of morbidity, but there is no difference in hospital stay length or mortality. Further studies and longer follow-up are needed to draw more conclusions.
Effects of Reiki, Yoga, or Meditation on the Physical and Psychological Symptoms of Chemotherapy-Induced Peripheral Neuropathy
Authors: Clark Paul G. , Cortese-Jimenez Geronima , Cohen Eric
Published: June 2012

Three complementary approaches for managing physical and psychological symptoms related to chemotherapy-induced peripheral neuropathy were evaluated against an education-only control arm. This study included 26 participants who were randomly assigned to weekly, hour-long sessions of yoga, Reiki, meditation, or an educational control experience for 6 weeks. Each participant completed pre–post measures of neurotoxicity, quality of life, psychological distress, and mindfulness. Descriptive analysis of the data indicated that all experimental group participants demonstrated improved within-group scores on quality of life and neurotoxicity outcomes following intervention; however, the improvements were not statistically significant. Neurotoxicity worsened significantly in the control group, but there were no pre–post changes with respect to quality of life, psychological distress, or mindfulness. Effect sizes were large with respect to meditation and mindfulness and with Reiki and psychological distress. Moderate effect sizes with respect to yoga and neurotoxicity and quality of life offer promise for all 3 interventions in managing chemotherapy-induced peripheral neuropathy.
Radiation therapy for the management of patients with HTLV-1–associated adult T-cell leukemia/lymphoma
Authors: Simone Charles B. , Morris John C. , Stewart Donn M. , Urquhart Nicole E. , Janik John E. , Kreitman Robert J. , Lita Elena , Conlon Kevin , Wharfe Gilian , Waldmann Thomas A. , Kaushal Aradhana
Published: June 2012

Human T-cell leukemia virus type 1–associated adult T-cell leukemia/lymphoma (ATL) typically has survivals measured in months with chemotherapy. One prior published series (1983-1991) assessed local radiotherapy for ATL. Ten consecutive patients with pathologically confirmed ATL treated with radiotherapy were reviewed. Subtypes included acute (n = 7), smoldering (n = 2), and lymphomatous (n = 1). Patients received an average of 2.5 systemic therapy regimens before radiotherapy. Twenty lesions (cutaneous = 10, nodal = 8, extranodal = 2) were treated to a mean of 35.4 Gy/2-3 Gy (range, 12-60 Gy). At 9.0-month mean follow-up (range, 0.1-42.0 months), all lesions symptomatically and radiographically responded, with in-field complete responses in 40.0% (nodal 37.5% vs cutaneous 50.0%; P = .62). No patient experienced in-field progression. Nine patients developed new/progressive out-of-field disease. Median survival was 17.0 months (3-year survival, 30.0%). No Radiation Therapy Oncology Group acute grade ≥ 3 or any late toxicity was noted. This report is the first to use modern radiotherapy techniques and finds effective local control across ATL subtypes. Radiotherapy should be considered for symptomatic local progression of ATL.
Early posttransplantation donor-derived invariant natural killer T-cell recovery predicts the occurrence of acute graft-versus-host disease and overall survival
Authors: Rubio Marie-Thérèse , Moreira-Teixeira Lucia , Bachy Emmanuel , Bouillié Marie , Milpied Pierre , Coman Tereza , Suarez Felipe , Marcais Ambroise , Sibon David , Buzyn Agnès , Caillat-Zucman Sophie , Cavazzana-Calvo Marina , Varet Bruno , Dy Michel , Hermine Olivier , Leite-de-Moraes Maria
Published: June 2012

Invariant natural killer T (iNKT) cells can experimentally dissociate GVL from graft-versus-host-disease (GVHD). Their role in human conventional allogeneic hematopoietic stem cell transplantation (HSCT) is unknown. Here, we analyzed the post-HSCT recovery of iNKT cells in 71 adult allografted patients. Results were compared with conventional T- and NK-cell recovery and correlated to the occurrence of GVHD, relapse, and survival. We observed that posttransplantation iNKT cells, likely of donor origin, recovered independently of T and NK cells in the first 90 days after HSCT and reached greater levels in recipient younger than 45 years (P = .003) and after a reduced-intensity conditioning regimen (P = .03). Low posttransplantation iNKT/T ratios (ie, < 10−3) were an independent factor associated with the occurrence of acute GVHD (aGVHD; P = .001). Inversely, reaching iNKT/T ratios > 10−3 before day 90 was associated with reduced nonrelapse mortality (P = .009) without increased risk of relapse and appeared as an independent predictive factor of an improved overall survival (P = .028). Furthermore, an iNKT/T ratio on day 15 > 0.58 × 10−3 was associated with a 94% risk reduction of aGVHD. These findings provide a proof of concept that early postallogeneic HSCT iNKT cell recovery can predict the occurrence of aGVHD and an improved overall survival.
Recognition of highly restricted regions in the β-propeller domain of αIIb by platelet-associated anti-αIIbβ3 autoantibodies in primary immune thrombocytopenia
Authors: Kiyomizu Kazunobu , Kashiwagi Hirokazu , Nakazawa Tsuyoshi , Tadokoro Seiji , Honda Shigenori , Kanakura Yuzuru , Tomiyama Yoshiaki
Published: June 2012

Platelet-associated (PA) IgG autoantibodies play an essential role in primary immune thrombocytopenia (ITP). However, little is known about the epitopes of these Abs. This study aimed to identify critical binding regions for PA anti-αIIbβ3 Abs. Because PA anti-αIIbβ3 Abs bound poorly to mouse αIIbβ3, we created human-mouse chimera constructs. We first examined 76 platelet eluates obtained from patients with primary ITP. Of these, 26 harbored PA anti-αIIbβ3 Abs (34%). Further analysis of 15 patients who provided sufficient materials showed that the epitopes of these Abs were mainly localized in the N-terminal half of the β-propeller domain in αIIb (L1-W235). We could identify 3 main recognition sites in the region; 2 eluates recognized a conformation formed by the W1:1-2 and W2:3-4 loops, 5 recognized W1:2-3, and 4 recognized W3:4-1. The remaining 4 eluates could not be defined by the binding sites. Within these regions, we identified residues critical for binding, including S29 and R32 in W1:1-2; G44 and P45 in W1:2-3; and P135, E136, and R139 in W2:3-4. Of 11 eluates whose recognition sites were identified, 5 clearly showed restricted κ/λ-chain usage. These results suggested that PA anti-αIIbβ3 Abs in primary ITP tended to recognize highly restricted regions of αIIb with clonality.
Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004
Authors: Hasle Henrik , Abrahamsson Jonas , Forestier Erik , Ha Shau-Yin , Heldrup Jesper , Jahnukainen Kirsi , Jónsson Ólafur Gísli , Lausen Birgitte , Palle Josefine , Zeller Bernward
Published: June 2012

There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m2 and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of veno-occlusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541).
Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?
Authors: Pui Ching-Hon , Mullighan Charles G. , Evans William E. , Relling Mary V.
Published: June 2012

Improved supportive care, more precise risk stratification, and personalized chemotherapy based on the characteristics of leukemic cells and hosts (eg, pharmacokinetics and pharmacogenetics) have pushed the cure rate of childhood acute lymphoblastic leukemia to near 90%. Further increase in cure rate can be expected from the discovery of additional recurrent molecular lesions, coupled with the development of novel targeted treatment through high-throughput genomics and innovative drug-screening systems. We discuss specific areas of research that promise to further refine current treatment and to improve the cure rate and quality of life of the patients.
Have drug combinations supplanted stem cell transplantation in myeloma?
Authors: Palumbo Antonio , Cavallo Federica
Published: June 2012

The introduction of proteasome inhibitor and immunomodulatory drugs has considerably changed the treatment paradigm of multiple myeloma. Autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy and is considered the standard of care for patients younger than 65 years. Nevertheless, the favorable results shown by multidrug inductions, consolidations, and long-term maintenance approaches have challenged the role of ASCT. This article provides an overview of recent and ongoing clinical trials and aims to define the role of ASCT in the era of novel agents.
Cryptococcus pneumonia presenting in an immunocompetent host with pulmonary asbestosis: a case report
Authors: Guy Judah P. , Raza Shahzad , Bondi Elliot , Rosen Yale , Kim Dong-Sung , Berger Barbara J.
Published: June 2012

Introduction

Cryptococcal infections pose a diagnostic challenge in an immunocompetent host. Asbestos exposure has been associated with pulmonary aspergillosis. This case highlights an interesting presentation of cryptococcal lung inflammation with underlying asbestosis.

Case presentation

A 63-year-old Mediterranean Caucasian woman presented with progressive dry cough of nine months duration. A computed tomography (CT) scan of her chest revealed multiple foci in the right infra-hilar region, which were seen as hot lung masses on a positron emission tomography (PET) scan. These multiple foci appeared metastatic in nature throughout both lung fields with early mediastinal invasion. A computed tomography (CT)-guided core biopsy was obtained from a dominant right lower lobe lung mass. Histology showed chronic granulomatous inflammation with numerous budding yeast forms that were GMS-, PAS-, and mucin-positive, consistent with cryptococcosis together with asbestos bodies (ferruginous). She was managed with fluconazole (400mg (6mg/kg) per day orally) daily. At her six-month follow up, she had marked improvement in her general condition along with a diminution of the lower lobe lung mass.

Conclusion

We report a clinical and radiological improvement in a patient treated for cryptococcal pneumonia. Asbestos exposure was likely to have been an important pathophysiological precursor to infection by environmental fungi.
SOX9 gene transfer via safe, stable, replication-defective recombinant adeno-associated virus vectors as a novel, powerful tool to enhance the chondrogenic potential of human mesenchymal stem cells
Authors: Venkatesan Jagadeesh K , Ekici Myriam , Madry Henning , Schmitt Gertrud , Kohn Dieter , Cucchiarini Magali
Published: June 2012

Introduction

Transplantation of genetically modified human bone marrow-derived mesenchymal stem cells (hMSCs) with an accurate potential for chondrogenic differentiation may be a powerful means to enhance the healing of articular cartilage lesions in patients. Here, we evaluated the benefits of delivering SOX9 (a key regulator of chondrocyte differentiation and cartilage formation) via safe, maintained, replication-defective recombinant adeno-associated virus (rAAV) vector on the capability of hMSCs to commit to an adequate chondrocyte phenotype compared with other mesenchymal lineages.

Methods

The rAAV-FLAG-hSOX9 vector was provided to both undifferentiated and lineage-induced MSCs freshly isolated from patients to determine the effects of the candidate construct on the viability, biosynthetic activities, and ability of the cells to enter chondrogenic, osteogenic, and adipogenic differentiation programs compared with control treatments (rAAV-lacZ or absence of vector administration).

Results

Marked, prolonged expression of the transcription factor was noted in undifferentiated and chondrogenically differentiated cells transduced with rAAV-FLAG-hSOX9, leading to increased synthesis of major extracellular matrix components compared with control treatments, but without effect on proliferative activities. Chondrogenic differentiation (SOX9, type II collagen, proteoglycan expression) was successfully achieved in all types of cells but strongly enhanced when the SOX9 vector was provided. Remarkably, rAAV-FLAG-hSOX9 delivery reduced the levels of markers of hypertrophy, terminal and osteogenic/adipogenic differentiation in hMSCs (type I and type X collagen, alkaline phosphatise (ALP), matrix metalloproteinase 13 (MMP13), and osteopontin (OP) with diminished expression of the osteoblast-related transcription factor runt-related transcription factor 2 (RUNX2); lipoprotein lipase (LPL), peroxisome proliferator-activated receptor gamma 2 (PPARG2)), as well as their ability to undergo proper osteo-/adipogenic differentiation. These effects were accompanied with decreased levels of β-catenin (a mediator of the Wnt signaling pathway for osteoblast lineage differentiation) and enhanced parathyroid hormone-related protein (PTHrP) expression (an inhibitor of hypertrophic maturation, calcification, and bone formation) via SOX9 treatment.

Conclusions

This study shows the potential benefits of rAAV-mediated SOX9 gene transfer to propagate hMSCs with an advantageous chondrocyte differentiation potential for future, indirect therapeutic approaches that aim at restoring articular cartilage defects in the human population.
CCL1 released from M2b macrophages is essentially required for the maintenance of their properties
Authors: Asai Akira , Nakamura Kiwamu , Kobayashi Makiko , Herndon David N , Suzuki Fujio
Published: June 2012

Increased susceptibility of mice 10–30 days postburn to MRSA infection is controlled through the intervention of CCL1-producing M2bMΦ, appearing in association with burn injuries.

Patients with 10–30 days postburn injury are greatly susceptible to infections. M1MΦ (IL-10−IL-12+ MΦ) are essential cells in host antibacterial innate immunity against MRSA infections. However, these effector cells are not easily generated in hosts who are carriers of M2bMΦ (IL-12−IL-10+CCL1+LIGHT+ MΦ). M2bMΦ are inhibitory on M1MΦ generation. In this study, the antibacterial resistance of mice, 10–30 days postburn injury against MRSA infection, was improved by the modulation of M2bMΦ activities. Unburned mice inoculated with MΦ preparations from mice, 10–30 days after burn injury, were susceptible to MRSA infection, whereas unburned mice, inoculated with MΦ preparations from the same mice that were previously treated with CCL1 antisense ODN, were resistant to the infection. M2bMΦ, isolated from Day 15 burn mice, lost their M2bMΦ properties 3 days after cultivation under frequent medium changes, whereas their M2bMΦ properties remained in the same cultures supplemented with rCCL1. In cultures, MΦ preparations from Day 15 burn mice treated with CCL1 antisense ODN did not produce CCL1 and did convert to M1MΦ after heat-killed MRSA stimulation. Also, Day 15 burn mice treated with the ODN became resistant against MRSA infection. These results indicate that CCL1 released from M2bMΦ is essentially required for the maintenance of their properties. The increased susceptibility of mice, 10–30 days after burn injury to MRSA infection, may be controlled through the intervention of CCL1 production by M2bMΦ appearing in association with severe burn injuries.
Transient CD8-memory contraction: a potential contributor to latent cytomegalovirus reactivation
Authors: Campbell Jonathan , Trgovcich Joanne , Kincaid Michelle , Zimmerman Peter D , Klenerman Paul , Sims Stuart , Cook Charles H
Published: June 2012

Heterologous antigen encounters can induce transient T-memory contraction, allowing cytomegaloviral recrudescence in latently infected immunocompetent hosts.

It is clear that latent CMV can reactivate in immunocompetent individuals, but the mechanism triggering such reactivations remains unclear. Recent clinical data suggest that reactivation can be subverted by CMV-specific T-memory. We therefore monitored CMV-specific T cells in immunocompetent mice with latent mCMV after a known reactivation trigger (LPS). LPS induced transient systemic contraction of mCMV-specific CD8 memory that was followed by transcriptional reactivation. Subsequent recovery of mCMV-specific T cells coincided with resumption of latency. These data suggest that bacterial antigen encounters can induce transient T-memory contraction, allowing viral recrudescence in hosts latently infected with herpes family viruses.
Identification of compounds with anti-convulsant properties in a zebrafish model of epileptic seizures
Authors: Baxendale Sarah , Holdsworth Celia J. , Meza Santoscoy Paola L. , Harrison Michael R. M. , Fox James , Parkin Caroline A. , Ingham Philip W. , Cunliffe Vincent T.
Published: June 2012

The availability of animal models of epileptic seizures provides opportunities to identify novel anticonvulsants for the treatment of people with epilepsy. We found that exposure of 2-day-old zebrafish embryos to the convulsant agent pentylenetetrazole (PTZ) rapidly induces the expression of synaptic-activity-regulated genes in the CNS, and elicited vigorous episodes of calcium (Ca2+) flux in muscle cells as well as intense locomotor activity. We then screened a library of ~2000 known bioactive small molecules and identified 46 compounds that suppressed PTZ-induced transcription of the synaptic-activity-regulated gene fos in 2-day-old (2 dpf) zebrafish embryos. Further analysis of a subset of these compounds, which included compounds with known and newly identified anticonvulsant properties, revealed that they exhibited concentration-dependent inhibition of both locomotor activity and PTZ-induced fos transcription, confirming their anticonvulsant characteristics. We conclude that this in situ hybridisation assay for fos transcription in the zebrafish embryonic CNS is a robust, high-throughput in vivo indicator of the neural response to convulsant treatment and lends itself well to chemical screening applications. Moreover, our results demonstrate that suppression of PTZ-induced fos expression provides a sensitive means of identifying compounds with anticonvulsant activities.
Frequent major errors in antimicrobial susceptibility testing of bacterial strains distributed under the Deutsches Krebsforschungszentrum Quality Assurance Program
Authors: Boot R
Published: June 2012

The Quality Assurance Program (QAP) of the Deutsches Krebsforschungszentrum (DKFZ) was a proficiency testing system developed to service the laboratory animal discipline. The QAP comprised the distribution of bacterial strains from various species of animals for identification to species level and antibiotic susceptibility testing (AST). Identification capabilities were below acceptable standards. This study evaluated AST results using the DKFZ compilations of test results for all bacterial strains showing the number of participants reporting the strain as resistant (R), sensitive (S) or intermediate susceptible (I) to each antibiotic substance used. Due to lack of information about methods used, it was assumed that what the majority of the participants reported (R or S) was the correct test result and that an opposite result was a major error (ME). MEs occurred in 1375 of 14,258 (9.7%) of test results and ME% ranged from 0% to 23.2% per bacterial group–agent group combination. Considerable variation in MEs was found within groups of bacteria and within groups of agents. In addition to poor performance in proper species classification, the quality of AST in laboratory animal diagnostic laboratories seems far below standards considered acceptable in human diagnostic microbiology.