Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.

Unrecognized visual field deficits in children with primary central nervous system brain tumors.

Visual field deficits can be a consequence of brain tumor location or treatment. The prevalence of unrecognized visual field deficits in children diagnosed with brain tumors is not known. All children at a single tertiary care pediatric children's hospital diagnosed with a primary brain tumor were tested for visual field deficits by a child neurologist and neuro-ophthalmologist over 16 months. Children with reproducible visual field deficits on two separate occasions were included in the analysis. Patients with optic glioma, craniopharyngioma, or previously known visual field deficits were excluded. Fourteen of 92 (15.2%) children (average 8.9 years, 8 girls) had undiagnosed visual field deficits. Average time between diagnosis of tumor and unrecognized visual field deficit was 3.7 years (range 0-13 years). Unrecognized visual field deficits were not associated with age (P = 0.27) or gender (P = 0.38). Visual field deficits were attributed to direct tumor infiltration (n = 8), postoperative complications (n = 5) and post-radiation edema (n = 1). Deficits included bitemporal hemianopsia (n = 2), homonymous hemianopsia (n = 9), quadrantanopsia (n = 2), and concentric visual field loss (n = 1.) Tumor location included temporal lobe (n = 9), parietal lobe (n = 2), posterior fossa (n = 2), hypothalamic-chiasmatic (n = 2) and multifocal areas (n = 4). Children with temporal lobe tumors were more likely to have unrecognized visual field deficits (P = 0.004). In all 14 patients, visual field deficits were determined by examination only and were not reported by either the patient or caregiver regardless of age. The prevalence of unrecognized visual field deficits in children with brain tumors can be surprisingly high. Serial neuro-ophthalmologic evaluation of children with brain tumors is often required to diagnose a visual field deficit since patient or caregiver reporting may be limited.

Properties of the COPD assessment test in a cross-sectional European study.

A short, easy-to-use health status questionnaire is needed in the multidimensional assessment of chronic obstructive pulmonary disease (COPD) in routine practice. The performance of the eight-item COPD assessment test (CAT) was analysed in 1,817 patients from primary care in seven European countries. The CAT has a scoring range of 0-40 (high score representing poor health status). Mean CAT scores indicated significant health status impairment that was related to severity of airway obstruction, but within each Global Initiative for Obstructive Lung Disease stage (I to IV) there was a wide range of scores (I: 16.2 ± 8.8; II: 16.3 ± 7.9; III: 19.3 ± 8.2; and IV: 22.3 ± 8.7; I versus II, p = 0.88; II versus III, p<0.0001; III versus IV, p = 0.0001). CAT scores showed relatively little variability across countries (within ± 12% of the mean across all countries). Scores were significantly better in patients who were stable (17.2 ± 8.3) versus those suffering an exacerbation (21.3 ± 8.4) (p<0.0001); and in patients with no (17.3 ± 8.1) or one or two (16.6 ± 8.2) versus three or more (19.7 ± 8.5) comorbidities (p<0.0001 for both). The CAT distinguished between classes of other impairment measures and was strongly correlated with the St George's Respiratory Questionnaire (r = 0.8, p<0.0001). The CAT is a simple and easy-to-use questionnaire that distinguishes between patients of different degrees of COPD severity and appears to behave the same way across countries.

Retail sales of inhalation devices in European countries: so much for a global policy.

OBJECTIVE: To evaluate the retail sales of pressurised metered-dose inhalers (pMDIs), dry-powder inhalers (DPIs) and liquids for nebulisation in 16 European countries. METHODS: Retail sales data relating to pMDIs, DPIs and liquids for nebulisation delivering short- and long-acting bronchodilators, corticosteroids and combinations between 2002 and 2008 were obtained from the IMS sales database. The IMS database ensured that wholesalers' stock sales accurately matched that of retail pharmacies and included purchases by panel pharmacies directly from pharmaceutical manufacturers, specialist wholesalers and distribution cooperatives. RESULTS: Mean inhaler retail sales (expressed as percentages of total sales) were 47.5% for pMDIs, 39.5% for DPIs and 13% for nebulisers. The distribution of inhaler sales differed significantly between the countries with pMDI sales greatest in the United Kingdom and Hungary compared to other countries, where DPI sales prevailed. Sales of nebulisation liquids were high in Italy. The pMDI was the most frequently prescribed inhaler for bronchodilators. In contrast, retail sales of DPIs were similar to those of pMDIs for inhaled corticosteroids, and higher in the case of inhalers with combined long-acting ß(2)-agonist and corticosteroid. CONCLUSION: We found a high degree of variability in inhaler prescription between European countries. Differing health policies, costs, health insurance issues, pharmaceutical/commercial aspects and prescribers' and patients' preferences may explain this variation. We suggest a need for more uniform, outcome-led inhaler prescribing practice across Europe to improve the efficacy and cost effectiveness of the treatment of obstructive airways diseases.

Health-related quality of life in patients by COPD severity within primary care in Europe.

Pan-European data on health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) are lacking. This cross-sectional epidemiological study evaluated health status in 1817 COPD patients from an 'all-comers' primary care population in seven European countries (87% stable disease; 13% with current exacerbation) using: St George's Respiratory Questionnaire-COPD specific (SGRQ-C), the short form health survey (SF-12) and the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale. Mean total score for SGRQ was 44.7 ± 19.4 showing marked impairment of HRQL. Scores differed little between countries (range 39.2-50.1). Impairment was associated with the severity of airway obstruction, but within each GOLD stage the variation (SD) was wide [Stage I: 38.5 ± 19.3 (n = 223); Stage II: 40.4 ± 18.1 (n = 868); Stage III: 50.2 ± 18.6 (n = 551); Stage IV: 58.6 ± 17.7 (n = 144)]. Patients suffering an exacerbation had a worse SGRQ score (54.9 ± 19.3) than those with stable disease (43.3 ± 19.0). The presence of ≥3 co-morbidities (CM) was also associated with a significantly worse score (49.9 ± 19.1) vs. 1-2 CM (42.1 ± 19.1) or no CM (42.3 ± 18.6). Findings with the SF-12 and FACIT-F results were consistent with those from the SGRQ-C. This large observational primary care study shows that health status is significantly impaired in COPD patients of all severities, even in those with mild airway obstruction. Within each GOLD stage of severity there is considerable heterogeneity in HRQL impairment among patients. (Study number: 111749).

Stratification of COPD patients by previous admission for targeting of preventative care.

BACKGROUND: Hospital admissions for exacerbations of chronic obstructive pulmonary disease (COPD) impact considerably on disease evolution and healthcare provision. Building on previous studies, this study postulated that COPD patients could be stratified by risk of admission to determine which groups provide the greatest burden on resources, and how interventions should be targeted to prevent admissions. METHODS: COPD admissions during 1997-2003 in three Strategic Health Authorities in England were analysed (n=80,291). Patients admitted during winter (1 November-31 March) were stratified into three groups according to the number of admissions during the previous year: 0 (NIL), 1-2 (MOD) or >or=3 (FRQ). Winter weeks were classified as "average", "above average", "high", or "very high" risk, compared with the long-term mean. RESULTS: The risk of admission during winter for FRQ and MOD patients was 40% and 12% respectively. NIL patients contributed to 70% of winter admissions, and 90% of the variation between "average" and "very high" weeks, versus 9% and 1% for MOD and FRQ. CONCLUSIONS: Patients with no previous admissions have lower individual risk, but contribute to a high overall utilisation of health care resources and should be targeted to prevent admissions. Focusing upon high-risk patients (frequent attenders or more severe) may only reduce a small proportion of admissions, and therefore clinicians should ensure that all COPD patients receive appropriate therapy to reduce risk of exacerbations.

Autoantibodies in Caribbean youth with diabetes mellitus.

The prevalence of diabetes and other autoantibodies in patients with recently diagnosed youth onset diabetes was evaluated. Fifty-seven patients (95% black, age 19 +/- 5 years, 36% male, diabetes duration 2.6 +/- 2.2 years) were clinically diagnosed as having type 1 (n = 35), type 2 (n = 13) and lipoatrophic diabetes (n = 3) while 6 remained untyped. GAD65 was the most common diabetes-associated autoantibody in patients with type 1A diabetes (12/17; 71%). The prevalence of any diabetes-associated autoantibodies decreased with diabetes duration (OR[95%CI]/yr after diagnosis 0.50[0.31,0.82]) and was not associated with age of onset, duration or gender. Rheumatoid factor (13/57; 23%), smooth muscle (6/57; 11%), gastric-parietal cell (5/57; 9%) and thyroid microsomal antibodies (5/57; 9%) were the most frequent non-diabetes associated autoantibodies and were more common in patients with type 1A diabetes. Only one patient had clinical autoimmune disease (hypothyroidism). Type 1A diabetes may constitute up to half the cases of newly diagnosed type 1 diabetes in Jamaican youth and is associated with a higher prevalence of other organ-specific autoantibodies.

A new perspective on concepts of asthma severity and control.

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. "Asthma control" refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patient's phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.

Atopic dermatitis: understanding the disease and its management.

OBJECTIVE: Atopic dermatitis (AD) is a common, chronic, inflammatory skin disease that can significantly reduce the quality of life of not only patients but also entire families. This review will focus on the currently available non-pharmacologic and pharmacologic treatments for the control and management of AD. RESEARCH DESIGN AND METHODS: A review of English-language articles from January 1953 to May 2006 was performed within the MEDLINE database. Search terms included, but were not limited to, atopic dermatitis, topical corticosteroids, and topical calcineurin inhibitors. Studies evaluating the diagnosis, physical and psychological burden, and underlying pathophysiology of AD were included. Particular focus was placed on literature presenting key safety and efficacy data from clinical trials involving AD treatment. RESULTS: Although good skin care and trigger avoidance are fundamental to AD management, most patients also require pharmacologic intervention. Topical therapies comprise the foundation of AD treatment. In particular, topical corticosteroids have been a mainstay in AD treatment for several decades and the newer topical calcineurin inhibitors have become a valuable addition to the therapeutic armamentarium. TCIs are a safe and effective AD treatment; they limit the number of disease flares, extend the time between flares, and provide a steroid-sparing option that may be of particular benefit in the pediatric population. The use of more potent therapies, such as systemic (oral/injected) agents or phototherapy, is typically limited to the treatment of severe, refractory disease. Additionally, owing to the increased risk for bacterial, viral, and fungal infections in patients with AD, topical or systemic antimicrobials are an important component of treatment. LIMITATIONS: Case reports and small-scale studies were typically not included in this analysis and owing to the limited number of trials evaluating TCSs, consensus statements and comprehensive review articles were used to obtain information pertaining to the use of this treatment in AD. CONCLUSIONS: AD is a common, chronic disease requiring a long-term management strategy that incorporates preventive measures and a multipronged treatment approach.

Multidirectional projectional rigid neuro-endoscopy: prototype and initial experience.

INTRODUCTION: The role of neuro-endoscopy is emerging. Traditional endoscopy is complicated by limited 2D views that make surgical interventions difficult. We have developed a rigid endoscope with a variable direction view that provides 3D visualization. MATERIALS AND METHODS: A prototype of the EndActive endoscope was used to examine 2 brain/intraventricular models. A 360-degree view is controlled via integrated joystick. Alternatively, the computer can volumetrically capture the ventricular surface. The captured video image can be viewed later or processed to create a flat projection map. The performance of this endoscope was compared to standard endoscopy with fixed directions of view. To simulate endoscopy, the center of the first brain model had eight labeled projections. The model was inspected with the multidirectional endoscope, standard rigid endoscopes (0-, 30- and 70-degree), and via a projection map. Ten neurosurgeons proficient in neuro-endoscopy were recruited for the experiments. The second brain model was labeled with 32 intraventricular tumors. RESULTS: With a 0-degree endoscope, only the number directly opposite the site of entry was visualized. With increasing angles, additional numbers were visualized. The 70-degree endoscope allowed 4 of 8 numbers to be visualized. Using the multidirectional endoscope, all 8 numbers were visualized. The multidirectional endoscope was more accurate in identifying markers compared to standard endoscopy (p = 0.031). The mean endoscopy times using the multidirectional endoscope and standard endoscopy were 143 and 117 seconds, respectively (p = 0.243). The best performance was obtained when the flat projection map was read (p < 0.01). Using the endoscope prototype, an average of 30.8 (96%) tumors was identified on the brain model. CONCLUSION: The EndActive endoscope is a rigid endoscope that provides complete visualization of a 3D space by controlling an adjustable viewing direction. In our study, the multidirectional endoscope provided superior visualization compared to standard endoscopy.

Gunshot wounds to the head: gang- and non-gang-related injuries and outcomes.

PRIMARY OBJECTIVE: This study examined the differences between gang and non-gang-related incidents of penetrative missile injuries in terms of demographics, motivation, intra-cranial pathology, transit time, injury time and clinical outcome. RESEARCH DESIGN: Retrospective and prospective chart review. METHODS AND PROCEDURES: Between 1985-1992, 349 patients with penetrating missile injuries to the brain presenting to LAC-USC were studied. EXPERIMENTAL INTERVENTIONS: Inclusion criteria were implemented to keep the cohort as homogenous as possible. Patients excluded were those with multiple gunshot wounds, non-penetrating gunshot wounds to the head, systemic injuries and cases in which the motivation for the incident was unknown. MAIN OUTCOMES AND RESULTS: Gang-related shooting slightly out-numbered non-gang-related incidents. Demographic analysis showed both a male and Hispanic predominance for both gang- and non-gang-related victims and significant differences in gender, race and age. Occipital entrance sites were more common in the gang-related vs temporal entrance sites in the non-gang-related. Mean transit time to the emergency department for gang-related shootings was less than non-gang-related shootings (24.4 vs 27.8 minutes). Most shooting incidents took place between 6pm and 3am. No difference between survival and outcome was noted between gang and non-gang victims. CONCLUSIONS: Significant differences were found between gang- and non-gang-related shooting victims in terms of demographics, entrance site and transit time. No difference was found between injury time, survival and outcome between gang and non-gang populations.

Abducens length and vulnerability?

BACKGROUND: Several sources have attributed the vulnerability of the abducens nerve to its long intracranial course. However, other anatomic factors likely contribute to the apparent vulnerability of the abducens nerve to mass lesions and trauma. METHODS: The authors performed a two-part anatomic study of the abducens nerve. In the first part of the study, they compared the length of the abducens with another cranial nerve, the trochlear, at the autopsy of 26 pediatric patients. In the second part of the study, the authors used an endoscopic exposure of these two cranial nerves in a preserved human cadaver head. RESULTS: The abducens nerve was consistently approximately one-third the length of the trochlear nerve at all ages that they studied. The endoscopic views revealed the structural and vascular relationships of the abducens nerve in situ. CONCLUSIONS: The authors conclude from these findings and the literature that abducens nerve vulnerability results from factors other than its intracranial length.