Characterizing Osteosarcoma Through PTEN and PI3K: What p53 and Rb1 Can’t Tell Us

Attention has been given to the fact that overall survival of osteosarcoma has plateaued over the last 30 years despite the addition of chemotherapy regimens. Elucidating the involvement of p53 and Rb1 in osteosarcoma has not yielded many novel treatments, but recent studies have started to characterize how the PTEN and the PI3K pathway can contribute to osteosarcoma. PTEN is a tumor suppressor that regulates a variety of signal transduction pathways and cellular processes, mainly by antagonizing PI3K activity and shutting down the PI3K/Akt pathway. Loss of PTEN function with concurrent PI3K activation has been detected frequently in a multitude of cancers, including osteosarcoma. This chapter aims to characterize PTEN and the PI3K/Akt pathway in osteosarcoma, their effects on primary bone tumor behavior, and potential therapeutic targets

Family Physicians’ Attitudes and Practices Regarding Assessments of Medical Fitness to Drive in Older Persons

BACKGROUND: Higher crash rates per mile driven in older drivers have focused attention on the assessment of older drivers. OBJECTIVE: To examine the attitudes and practices of family physicians regarding fitness-to-drive issues in older persons. DESIGN: Survey questionnaire. PARTICIPANTS: The questionnaire was sent to 1,000 randomly selected Canadian family physicians. Four hundred sixty eligible physicians returned completed questionnaires. MEASUREMENTS: Self-reported attitudes and practices towards driving assessments and the reporting of medically unsafe drivers. RESULTS: Over 45% of physicians are not confident in assessing driving fitness and do not consider themselves to be the most qualified professionals to do so. The majority (88.6%) feel that they would benefit from further education in this area. About 75% feel that reporting a patient as an unsafe driver places them in a conflict of interest and negatively impacts on the patient and the physician–patient relationship. Nevertheless, most (72.4%) agree that physicians should be legally responsible for reporting unsafe drivers to the licensing authorities. Physicians from provinces with mandatory versus discretionary reporting requirements are more likely to report unsafe drivers (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.58 to 4.91), but less likely to perform driving assessments (OR, 0.58; 95% CI, 0.39 to 0.85). Most driving assessments take between 10 and 30 minutes, with much variability in the components included. CONCLUSIONS: Family physicians lack confidence in performing driving assessments and note many negative consequences of reporting unsafe drivers. Education about assessing driving fitness and approaches that protect the physician–patient relationship when reporting occurs are needed

The effect of octopaminergic compounds on the behaviour and transmission of Gyrodactylus

Background: The high transmission potential of species belonging to the monogenean parasite genus Gyrodactylus, coupled with their high fecundity, allows them to rapidly colonise new hosts and to increase in number. One gyrodactylid, Gyrodactylus salaris Malmberg, 1957, has been responsible for devastation of Altantic salmon (Salmo salar L.) populations in a number of Norwegian rivers. Current methods of eradicating G. salaris from river systems centre around the use of non-specific biocides, such as rotenone and aluminium sulphate. Although transmission routes in gyrodactylids have been studied extensively, the behaviour of individual parasites has received little attention. Specimens of Gyrodactylus gasterostei Gläser, 1974 and G. arcuatus Bychowsky, 1933, were collected from the skin of their host, the three-spined stickleback (Gasterosteus aculeatus L.), and permitted to attach to the substrate. The movements of individual parasites were recorded and analysed. Results: The behaviour patterns of the two species were similar and parasites were more active in red light and darkness than in white light. Four octopaminergic compounds were tested and all four inhibited the movements of parasites. Treatment ultimately led to death at low concentrations (0.2 μM), although prolonged exposure was necessary in some instances. Conclusions: Octopaminergic compounds may affect the parasite's ability to locate and remain on its host and these or related compounds might provide alternative or supplementary treatments for the control of G. salaris infections. With more research there is potential for use of octopaminergic compounds, which have minimal effects on the host or its environment, as parasite-specific treatments against G. salaris infections

Has the Level of Evidence of Podium Presentations at the Musculoskeletal Tumor Society Annual Meeting Changed Over Time?

BACKGROUND: Level of evidence (LOE) framework is a tool with which to categorize clinical studies based on their likelihood to be influenced by bias. Improvements in LOE have been demonstrated throughout orthopaedics, prompting our evaluation of orthopaedic oncology research LOE to determine if it has changed in kind. QUESTIONS/PURPOSES: (1) Has the LOE presented at the Musculoskeletal Tumor Society (MSTS) annual meeting improved over time? (2) Over the past decade, how do the MSTS and Orthopaedic Trauma Association (OTA) annual meetings compare regarding LOE overall and for the subset of therapeutic studies? METHODS: We reviewed abstracts from MSTS and OTA annual meeting podium presentations from 2005 to 2014. Three independent reviewers evaluated a total of 1222 abstracts for study type and LOE; there were 577 abstracts from MSTS and 645 from OTA. Changes in the distributions of study type and LOE over time were evaluated by Pearson chi-square test. RESULTS: There was no change over time in MSTS LOE for all study types (p = 0.13) and therapeutic (p = 0.36) study types during the reviewed decade. In contrast, OTA LOE increased over this time for all study types (p < 0.01). The proportion of Level I therapeutic studies was higher at the OTA than the MSTS (3% [14 of 413] versus 0.5% [two of 387], respectively), whereas the proportion of Level IV studies was lower at the OTA than the MSTS (32% [134 of 413] versus 75% [292 of 387], respectively) during the reviewed decade. The proportion of controlled therapeutic studies (LOE I through III) versus uncontrolled studies (LOE IV) increased over time at OTA (p < 0.021), but not at MSTS (p = 0.10). CONCLUSIONS: Uncontrolled case series continue to dominate the MSTS scientific program, limiting progress in evidence-based clinical care. Techniques used by the OTA to improve LOE may be emulated by the MSTS. These techniques focus on broad participation in multicenter collaborations that are designed in a comprehensive manner and answer a pragmatic clinical question

Obligatory role of hyperaemia and shear stress in microvascular adaptation to repeated heating in humans

The endothelium, a single layer of cells lining the entire circulatory system, plays a key role in maintaining vascular health. Endothelial dysfunction independently predicts cardiovascular events and improvement in endothelial function is associated with decreased vascular risk. Previous studies have suggested that exercise training improves endothelial function in macrovessels, a benefit mediated via repeated episodic increases in shear stress. However, less is known of the effects of shear stress modulation in microvessels. In the present study we examined the hypothesis that repeated skin heating improves cutaneous microvascular vasodilator function via a shear stress-dependent mechanism. We recruited 10 recreationally active males who underwent bilateral forearm immersion in warm water (42°C), 3 times per week for 30 min. During these immersion sessions, shear stress was manipulated in one arm by inflating a pneumatic cuff to 100 mmHg, whilst the other arm remained uncuffed. Vasodilatation to local heating, a NO-dependent response assessed using laser Doppler, improved across the 8 week intervention period in the uncuffed arm (cutaneous vascular conductance week 0 vs. week 4 at 41°C: 1.37 ± 0.45 vs. 2.0 ± 0.91 units, P= 0.04; 42°C: 2.06 ± 0.45 vs. 2.68 ± 0.83 units; P= 0.04), whereas no significant changes were evident in the cuffed arm. We conclude that increased blood flow, and the likely attendant increase in shear stress, is a key physiological stimulus for enhancing microvascular vasodilator function in humans

The evanescence and persistence of RBC alloantibodies in blood donors

BACKGROUND Blood donors represent a healthy population, whose red blood cell (RBC) alloantibody persistence or evanescence kinetics may differ from those of immunocompromised patients. A better understanding of the biologic factors impacting antibody persistence is warranted, as the presence of alloantibodies may impact donor health and the fate of the donated blood product. METHODS Donor/donation data collected from four US blood centers from 2012 to 2016 as part of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) were analyzed. Clinically significant antibodies from blood donors with more than one donation who underwent at least one follow-up antibody screen after the initial antibody identification were included. Of 632,378 blood donors, 481 (128 males and 353 females) fit inclusion criteria. RESULTS Antibody screens detected 562 alloantibodies, with 368 of 562 (65%) of antibodies being persistently detected and with 194 of 562 (35%) becoming evanescent. Factors associated with antibody persistence included antibody specificity, detection at the first donation, reported history of transfusion, and detection of multiple antibodies concurrently. Anti-D, C, and Fy(a) were most likely to persist, while anti-M, Jk(a), and S were most frequently evanescent. CONCLUSIONS These data provide insight into variables impacting the duration of antibody detection, and they may also influence blood donor center policies regarding donor recruitment/acceptance

Multi-centre testing and validation of current protocols for the identification of Gyrodactylus salaris (Monogenea)

Despite routine screening requirements for the notifiable fish pathogen Gyrodactylus salaris, no standard operating procedure exists for its rapid identification and discrimination from other species of Gyrodactylus. This study assessed screening and identification efficiencies under real-world conditions for the most commonly employed identification methodologies: visual, morphometric and molecular analyses. Obtained data were used to design a best-practice processing and decision-making protocol allowing rapid specimen throughput and maximal classification accuracy. True specimen identities were established using a consensus from all three identification methods, coupled with the use of host and location information. The most experienced salmonid gyrodactylid expert correctly identified 95.1% of G. salaris specimens. Statistical methods of classification identified 66.7% of the G. salaris, demonstrating the need for much wider training. Molecular techniques (internal transcribed spacer region-restriction fragment length polymorphism (ITS-RFLP)/cytochrome c oxidase I (COI) sequencing) conducted in the diagnostic laboratory most experienced in the analysis of gyrodactylid material, identified 100% of the true G. salaris specimens. Taking into account causes of potential specimen loss, the probabilities of a specimen being accurately identified were 95%, 87% and 92% for visual, morphometric and molecular techniques, respectively, and the probabilities of correctly identifying a specimen of G. salaris by each method were 81%, 58% and 92%. Inter-analyst agreement for 189 gyrodactylids assessed by all three methods using Fleiss' Kappa suggested substantial agreement in identification between the methods. During routine surveillance periods when low numbers of specimens are analysed, we recommend that specimens be analysed using the ITS-RFLP approach followed by sequencing of specimens with a "G. salaris-like" (i.e. G. salaris, Gyrodactylus thymalli) banding pattern. During periods of suspected outbreaks, where a high volume of specimens is expected, we recommended that specimens be identified using visual identification, as the fastest processing method, to select "G. salaris-like" specimens, which are subsequently identified by molecular-based techniques