Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth

The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multi- forme (GBM) cell lines and primary culture models are reported. Dose–response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repop- ulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR func- tions. DP68-induced interstrand DNA cross-links were dem- onstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell–cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced anti- glioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collec- tively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DN

Grip strength is strongly associated with height, weight and gender in childhood:a cross sectional study of 2241 children and adolescents providing reference values

QuestionWhat are reference values for grip strength in children and adolescents based on a large and heterogeneous study population? What is the association of grip strength with age, gender, weight, and height in this population?DesignCross-sectional study.ParticipantsParticipants were recruited from schools in the northern provinces of the Netherlands. The study included healthy children and adolescents ranging in age from 4 to 15 years.Outcome measuresAll children had their height (cm) and weight (kg) measured and were allowed a total of four attempts using the Jamar hand dynamometer: twice with each hand. Grip strength scores (kg) were recorded for the dominant and non-dominant hands.ResultsThe study population comprised 2241 children and adolescents. Reference values for both genders are provided according to age and dominance. Grip strength shows a linear and parallel progression for both genders until the age of 11 or 12, after which grip strength development shows an acceleration that is more prominent in boys.ConclusionThere is a significant difference in grip strength with each ascending year of age in favour of the older group, as well as a trend for boys to be stronger than girls in all age groups between 4 and 15 years. Weight and especially height have a strong association with grip strength in children

Alternative Markers of Performance in Simulation: Where We Are and Where We Need To Go

This article on alternative markers of performance in simulation is the product of a session held during the 2017 Academic Emergency Medicine Consensus Conference â Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes.â There is a dearth of research on the use of performance markers other than checklists, holistic ratings, and behaviorally anchored rating scales in the simulation environment. Through literature review, group discussion, and consultation with experts prior to the conference, the working group defined five topics for discussion: 1) establishing a working definition for alternative markers of performance, 2) defining goals for using alternative performance markers, 3) implications for measurement when using alternative markers, identifying practical concerns related to the use of alternative performance markers, and 5) identifying potential for alternative markers of performance to validate simulation scenarios. Five research propositions also emerged and are summarized.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142535/1/acem13321_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142535/2/acem13321.pd

The Influence of Hand Preference on Grip Strength in Children and Adolescents; A Cross-Sectional Study of 2284 Children and Adolescents

Introduction In adults the preferred hand is often considered to be around 10% stronger than the non-preferred hand. Whether the same is true for children and adolescents remains unclear. The objective of this study is therefore to determine whether there is a difference in grip strength between the preferred and non-preferred hand in developing children, to establish whether this difference is similar for children of a different gender or hand preference, and whether there is a difference in grip strength of the preferred hand of left-preferent (LP) and right-preferent (RP) children. Design Cross-sectional study. Participants Participants were recruited from schools in the northern provinces of the Netherlands. The study included healthy children and adolescents in the age range of 4-17 years. Outcome Measures Each child was allowed a total of four attempts using the JAMAR hand dynamometer, two attempts with each hand. All individual attempts were scored. Hand preference was determined by asking which hand was used to write, or in the case of 4- and 5-year-olds, which hand was used to draw a shape. Results The study population comprised 2284 children and adolescents. RP boys and girls scored significantly higher with their preferred hand, the difference amounting to 9.5 and 10.1% respectively. LP girls scored significantly higher with their preferred hand, but this difference was only 3.0%. For LP boys no significant difference was found in favor of either hand. LP children score higher with the non-preferred hand and tie scores on both hands more often than RP children. Conclusion The 10% rule of hand preference is applicable to RP children ranging in age between 4 and 17 years, but not to LP children. In contrast to LP boys, LP girls are generally significantly stronger with their preferred hand

Sensory Measurements: Coordination and Standardization

Do sensory measurements deserve the label of “measurement”? We argue that they do. They fit with an epistemological view of measurement held in current philosophy of science, and they face the same kinds of epistemological challenges as physical measurements do: the problem of coordination and the problem of standardization. These problems are addressed through the process of “epistemic iteration,” for all measurements. We also argue for distinguishing the problem of standardization from the problem of coordination. To exemplify our claims, we draw on olfactory performance tests, especially studies linking olfactory decline to neurodegenerative disorders

Evidence for the Predominance of Mid-Tropospheric Aerosols as Subtropical Anvil Cloud Nuclei

NASA's recent Cirrus Regional Study of Tropical Anvils and Cirrus Layers–Florida Area Cirrus Experiment focused on anvil cirrus clouds, an important but poorly understood element of our climate system. The data obtained included the first comprehensive measurements of aerosols and cloud particles throughout the atmospheric column during the evolution of multiple deep convective storm systems. Coupling these new measurements with detailed cloud simulations that resolve the size distributions of aerosols and cloud particles, we found several lines of evidence indicating that most anvil crystals form on mid-tropospheric rather than boundary-layer aerosols. This result defies conventional wisdom and suggests that distant pollution sources may have a greater effect on anvil clouds than do local sources

What are emergency ambulance services doing to meet the needs of people who call frequently? A national survey of current practice in the United Kingdom

Background Emergency ambulance services are integral to providing a service for those with unplanned urgent and life-threatening health conditions. However, high use of the service by a small minority of patients is a concern. Our objectives were to describe: service-wide and local policies or pathways for people classified as Frequent Caller; call volume; and results of any audit or evaluation. Method We conducted a national survey of current practice in ambulance services in relation to the management of people who call the emergency ambulance service frequently using a structured questionnaire for completion by email and telephone interview. We analysed responses using a descriptive and thematic approach. Results Twelve of 13 UK ambulance services responded. Most services used nationally agreed definitions for ‘Frequent Caller’, with 600–900 people meeting this classification each month. Service-wide policies were in place, with local variations. Models of care varied from within-service care where calls are flagged in the call centre; contact made with callers; and their General Practitioner (GP) with an aim of discouraging further calls, to case management through cross-service, multi-disciplinary team meetings aiming to resolve callers’ needs. Although data were available related to volume of calls and number of callers meeting the threshold for definition as Frequent Caller, no formal audits or evaluations were reported. Conclusions Ambulance services are under pressure to meet challenging response times for high acuity patients. Tensions are apparent in the provision of care to patients who have complex needs and call frequently. Multi-disciplinary case management approaches may help to provide appropriate care, and reduce demand on emergency services. However, there is currently inadequate evidence to inform commissioning, policy or practice development