Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

Male eyespan size is associated with meiotic drive in wild stalk-eyed flies (Teleopsis dalmanni).

This study provides the first direct evidence from wild populations of stalk-eyed flies to support the hypothesis that male eyespan is a signal of meiotic drive. Several stalk-eyed fly species are known to exhibit X-linked meiotic drive. A recent quantitative trait locus analysis in Teleopsis dalmanni found a potential link between variation in male eyespan, a sexually selected ornamental trait, and the presence of meiotic drive. This was based on laboratory populations subject to artificial selection for male eyespan. In this study, we examined the association between microsatellite markers and levels of sex ratio bias (meiotic drive) in 12 wild T. dalmanni populations. We collected two data sets: (a) brood sex ratios of wild-caught males mated to standard laboratory females and (b) variation in a range of phenotypic traits associated with reproductive success of wild-caught males and females. In each case, we typed individuals for eight X-linked microsatellite markers, including several that previously were shown to be associated with male eyespan and meiotic drive. We found that one microsatellite marker was very strongly associated with meiotic drive, whereas a second showed a weaker association. We also found that, using both independent data sets, meiotic drive was strongly associated with male eyespan, with smaller eyespan males being associated with more female-biased broods. These results suggest that mate preference for exaggerated male eyespan allows females to avoid mating with males carrying the meiotic drive gene and is thus a potential mechanism for the maintenance and evolution of female mate preference.

Comparison of curvilinear and linear ultrasound imaging probes for measuring cross-sectional area and linear dimensions.

The aim of the study was to determine whether different ultrasound probe/transducer configurations produce the same measurements. Two investigators undertook 10 scans of a general purpose semi-solid multi-tissue ultrasound phantom (phantom A) using two ultrasound scanners with a linear and curvilinear probe. From those 10 scans, two measurements of cross-sectional area (CSA), width and thickness were made. These measurements were then repeated with an open-top fluid-filled phantom, with 10% ethanol solution (phantom B). Intra- and inter-rater reliability were examined using Bland and Altman plots. Agreement between measurements made with the two probe types was also assessed using Bland and Altman plots. An independent samples t-test was used to compare statistical differences between probe type configuration. There was a significant difference (p < 0.05) and a tendency for increased measurements in CSA and width, and decreased measurements in thickness when using a curvilinear probe on phantom A, and these differences were not scanner specific. When imaging phantom B there were no significant differences in measurements between probe configurations; however there was a small bias for smaller CSA measurements with a curvilinear probe. In conclusion there are small differences in measurements obtained from different ultrasound probe configurations using a semi-solid phantom, but their clinical significance is unknown.

A review of the principles and use of lasers in lower limb problems.

Lasers present a unique light source with many clinical uses including a number of applications relevant to the lower extremity. In this article, the basic principles of lasers and their interactions with tissue will be reviewed. The article examines laser applications in skin and vascular disease including wound healing. The principles of laser safety are discussed, and relevant future developments are considered.

Private thoughts in public spheres: issues in reflection and reflective practices in nursing.

AIM: This paper aims to problematize the notions of reflection and reflective practice, particularly as they relate to private thoughts in public spheres and the constitution of personal and professional subjectivities. BACKGROUND/RATIONALE: Reflection and reflective practice, through the technologies of power and technologies of the self, permit the previously private thoughts of nurses to enter the public sphere where they are subject to surveillance, assessment, classification and control. Instead of raising serious concerns and debate about such practices, the plethora of literature, whilst using a bewildering array of ambiguous, diverse interpretations of reflection and reflective practice, has been united in claiming them as good for nurses and nursing. APPROACH: The paper draws on Foucauldian concepts of power-knowledge and discourse to interrogate radically the conceptualizations of reflection and reflective practice in contemporary nursing literature. CONCLUSIONS: The paper challenges the hegemonic discourse of reflection in nursing. It argues that new conceptualizations of reflection that acknowledge and value a diversity of perspectives, contexts and dimensions are needed.

Clinical supervision UK style: good for nurses and nursing?

British nursing has presented a particular view of clinical supervision and has made its availability an essential requirement for all nurses in the United Kingdom (UK). Through a plethora of literature, this view of clinical supervision has become widespread, as has the notion that it is good for nurses and nursing. In this paper, utilising a Foucauldian approach to discourse, power-knowledge and clinical gaze, I radically interrogate this seemingly unproblematic conceptualisation of clinical supervision and its rising popularity and influence.

Power, knowledge, and the discourse of specialization in nursing.

The characterization of specialization in nursing varies across different time periods, contexts, persons, groups, and institutions. Therefore, it may be viewed as a discourse. The expression of this discourse is subject to contextual influences and social interests. For example, its perceived congruence or antagonism to other major discourses, such as specialization, medicine, and nursing, will impact on its expression and legitimization. This article explores the discourse of specialization in nursing, especially as it is expressed in the Australian and North American context, and focuses on the power and knowledge issues that relate to, and constitute, the discourse.

Reference ranges of bone mineral density for women in southern England: the impact of local data on the diagnosis of osteoporosis.

The construction of reference ranges that accurately represent the population at large is essential for the correct identification of osteoporosis from bone mineral density (BMD) measurements. In this study, reference data supplied by the manufacturer of the Lunar DPX+ bone densitometer were compared with data obtained locally. Lumbar spine, proximal femur and total body BMD measurements were made in an age-stratified random sample of 702 Southampton women aged 20 to 89 years. Relevant demographic and medical data were recorded for each subject using a questionnaire. Reference curves of BMD (mean +/- SD) were plotted against age for each measurement site and were found to be higher than the manufacturer's reference values at all ages and sites. Exclusion of women with factors known to affect bone mass only served to increase this discrepancy. According to World Health Organisation definitions, osteoporosis may be identified from BMD values alone. Based upon neck of femur BMD values, 100 (14.8%) of the women in this study group were categorized as osteoporotic using local young normal reference data, compared with only 39 (5.8%) using the manufacturer's data. By normalizing for age distribution, these findings were extrapolated to the local population where it was predicted that 26.0% and 10.1% of females over 50 years of age would be classified as osteoporotic using the respective reference ranges. This study clearly illustrates how the numbers of women diagnosed as osteoporotic vary with the use of different reference populations.

Affinity-purified Escherichia coli J5 lipopolysaccharide-specific IgG protects neutropenic rats against gram-negative bacterial sepsis.

Antibodies were raised in rabbits by immunization with the heat-killed J5 mutant of Escherichia coli O111 (Rc chemotype). Serum antibodies were separated into purified IgG and IgM by sequential affinity chromatography on protein G-Sepharose and anti-rabbit IgG-Sepharose columns. J5 lipopolysaccharide (LPS)-specific IgG was prepared by affinity chromatography of purified IgG on a J5 LPS-EAH Sepharose 4B affinity column. Purified IgM, IgG, and J5 LPS-specific IgG protected neutropenic rats against lethal challenge with Pseudomonas aeruginosa 12:4:4 (Fisher Devlin immunotype 6). Nine of 16 rats treated with the IgM fraction were protected (P < .001). Thirteen of 20 rats treated with the purified IgG and 6 of 8 treated with J5 LPS-specific IgG were protected compared with none of 25 treated with IgG made from the preimmune serum of the same rabbit (P < .001). These results demonstrate that purified J5 LPS-specific IgG protects against the lethal consequences of gram-negative bacteremia.

Truancy and illegal drug use, and knowledge of HIV infection in 932 14-16-year-old adolescents.

In a sample of 932 4th & 5th year comprehensive school adolescents, 41% had truanted in the current term. The truants, compared with their non-truanting peers, had three times the level of solvent misuse (14% compared with 4%), thrice the soft drug misuse (19% compared with 6%), and four times the involvement with hard drugs (9% compared with 2%). Truants were significantly more involved with other problematic behaviour and were found to score higher on all negative social indices, including parents who smoked. Despite the sample's relatively accurate knowledge about drugs and HIV infection, truants scored less well on these and other HIV-related issues. An extrapolation of the results indicates a significant number of adolescents at risk demanding urgent policy initiatives.

Cosmetic eye modified to retain vision.

A patient with bilateral ocular injuries with hypotony and light perception vision was fitted with scleral shells modified to allow light to pass through the central 4-mm area. This modification, allowing the patient to retain light perception with the prosthesis in place, aided in the rehabilitation of this patient by encouraging his independent ambulation, providing clues to time, place, and direction, and offering an enhanced cosmetic effect.