Radiation therapy with orthovoltage X-ray minibeams

A method for delivering therapeutic radiation to a target includes positioning a multi-aperture collimator on the skin within a trajectory of orthovoltage x-rays directed at the target, thus generating an array of minibeams, each of width between 0.1 mm to 0.6 mm. The skin is irradiated with the array. An effective beam of therapeutic radiation, which may be a solid beam, is delivered to the target at a predetermined tissue depth by merging adjacent orthovoltage x-ray minibeams sufficiently to form the effective beam. The effective beam may be formed proximal to the target. The depth at which the effective, preferably, solid, beam is formed is controlled by varying one or more of the spacing of the minibeams in the array, the minibeam width, the distance from the x-ray source to the collimator, and the x-ray source spot size. Planar minibeams can be arc-scanned while continuously modulating beam shape and intensity.Board of Regents, University of Texas Syste

Finding gene-environment interactions for Phobias

Phobias are common disorders causing a great deal of suffering. Studies of gene-environment interaction (G × E) have revealed much about the complex processes underlying the development of various psychiatric disorders but have told us little about phobias. This article describes what is already known about genetic and environmental influences upon phobias and suggests how this information can be used to optimise the chances of discovering G × Es for phobias. In addition to the careful conceptualisation of new studies, it is suggested that data already collected should be re-analysed in light of increased understanding of processes influencing phobias

From Marx to Gramsci to us: Laboratory to prison, and back

Marx and Gramsci remain two of the most constant presences and inspirations for those on the left. Yet there is a persistent sense that we have still to get them right. Perhaps this indicates that sources like this are now fully classics, to be returned, and returned to. In the case of Marx and Gramsci, a series of major works published in the Brill Historical Materialism series breaks new ground as well as returning to older controversies, both resolved and unresolved. Apart from remaining arguments concerning the status of materials unpublished in their own lifetimes, the major tension that emerges here is that between the task of immanent, contextual philology and the challenge of reading ‘Marx for today’ or ‘Gramsci for today’. The tension between text and context, and the question of what travels, conceptually persists

Structural role of the tyrosine residues of cytochrome c

The tertiary structures of horse, tuna, Neurospora crassa, horse [Hse65,Leu67]- and horse [Hse65,Leu74]-cytochromes c were studied with high-resolution 1H n.m.r. spectroscopy. The amino acid sequences of these proteins differ at position 46, which is occupied by phenylalanine in the horse proteins but by tyrosine in the remaining two, and at positions 67, 74 and 97, which are all occupied by tyrosine residues in horse and tuna cytochrome c but in the other proteins are substituted by phenylalanine or leucine, though there is only one such substitution per protein. The various aromatic-amino-acid substitutions do not seriously affect the protein structure

Cell Type-Specific Reduction of Beta Tubulin Isotypes Synthesized in the Developing Gerbil Organ of Corti

There are seven isotypic forms of the microtubule protein beta tubulin in mammals, but not all isotypes are synthesized in every cell type. In the adult organ of Corti, each of the five major cell types synthesizes a different subset of isotypes. Inner hair cells synthesize only betaI and betaII tubulin, while outer hair cells make betaI and betaIV tubulin. Only betaII and betaIV tubulin are found in inner and outer pillar cells, while betaI, betaII, and betaIV tubulin are present in Deiters cells, and betaI, betaII and betaIII tubulin are found in organ of Corti dendrites. During post-natal organ of Corti development in the gerbil, microtubules are elaborated in an orderly temporal sequence beginning with hair cells, followed by pillar cells and Deiters cells. Using beta tubulin isotype-specific antibodies, we show that, in the gerbil cochlea, the same three isotypes are present in each cell type at birth, and that a cell type-specific reduction in the isotypes synthesized occurs in hair cells and pillar cells at an unusually late stage in development. No beta tubulin isotypes were detected in mature afferent dendrites, but we show that this is because few microtubules are present in mature dendrites. In addition, we show that primary cilia in inner hair cells, a feature of early development, persist much later than previously reported. The findings represent the first description of developmental cell type-specific reductions in tubulin isotypes in any system

The Genesis 12–19 (G1219) Study: A Twin and Sibling Study of Gene–Environment Interplay and Adolescent Development in the UK

The Genesis 12–19 (G1219) Study is an ongoing longitudinal study of a sample of UK twin pairs, non-twin sibling pairs, and their parents. G1219 was initially designed to examine the role of gene–environment interplay in adolescent depression. However, since then data have continued to be collected from both parents and their offspring into young adulthood. This has allowed for longitudinal analyses of depression and has enabled researchers to investigate multiple phenotypes and to ask questions about intermediate mechanisms. The study has primarily focused on emotional development, particularly depression and anxiety, which have been assessed at multiple levels of analysis (symptoms, cognitions, and relevant environmental experiences). G1219 has also included assessment of a broader range of psychological phenotypes ranging from antisocial behaviors and substance use to sleep difficulties, in addition to multiple aspects of the environment. DNA has also been collected. The first wave of data collection began in the year 1999 and the fifth wave of data collection will be complete before the end of 2012. In this article, we describe the sample, data collection, and measures used. We also summarize some of the key findings to date

Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF

© 2016 BMJ Publishing Group Ltd & British Thoracic Society.Rationale Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose. Methods We explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung. Results We provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF. Conclusions Our data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-ofmechanism trial of this agent is currently underway. Trial registration number NCT01725139, pre-clinical

Black bone MRI with 3D reconstruction for the detection of skull fractures in children with suspected abusive head trauma.

PURPOSE: The purpose of this study was to determine the accuracy of "black bone" (BB) MRI for the detection of skull fractures in children with potential abusive head trauma. METHODS: A total of 34 pediatric patients were evaluated for potential abusive head trauma. All patients had both a non-contrast head CT (HCT) with multiplanar reformatted images and 3D volumetric reformatted images where available (gold standard) for fracture diagnosis and BB of the head with multiplanar reformatted images and 3D volumetric images. BB was performed using an ultrashort TE pointwise encoding time reduction with radial acquisition (PETRA) sequence at 1.5 T or 3 T. BB datasets were post-processed and 3D images created using Fovia's High Definition Volume Rendering® software. Two board-certified pediatric neuroradiologists independently reviewed the HCT and BB imaging, blinded to the findings from the other modality. RESULTS: Median patient age was 4 months (range 1.2-30 months). A total of 20 skull fractures in six patients (18% incidence of skull fractures) were detected on HCT. BB demonstrated 83% sensitivity (95%[CI] 36-99%), 100% specificity (95%[CI] 88-100%), 100% PPV (95%[CI] 46-100%), 97% NPV (95%[CI] 82-99%), and 97% accuracy (95%[CI] 85-99%) for diagnosis of a skull fracture. BB detected 95% (19/20) of the skull fractures detected by CT. CONCLUSION: A black bone MRI sequence may provide high sensitivity and specificity for detection of skull fractures in pediatric patients with abusive head trauma