Studies towards improved focusing methods of photoelectron autoradiography

Since the discovery of radioactivity, due to the photographic action of the emitted radiations, by Becquerel in 1896, the photographic plate has been an important tool in the detection of electrons. Although overshadowed by electronic counting devices, it still plays an important role, since the developed image gives a more detailed distribution of the radioisotope in the specimen under observation. The technique of autoradiography utilises the photographic action of all the emitted ionizing radiations for locating the radioactive material in a sample, and was first used by Lacassagne and Lattes (l ) in 1925. The general procedure is to introduce the active isotope into the system and to select the specimen to be studied, which is then placed in contact with a suitable photographic material and left for exposure. After processing, the location of the radioactive material can be deduced by studying the image, but the latter is not sharp since it is difficult to achieve intimate contact between the specimen and recording film. This method gives autoradiographs with a resolution of 50 to 100 microns(2) . An improved method was achieved by Evans(3), who floated sections of his material on to a photographic plate which was then dried out and left for exposure. The resolving power of this method was estimated to be 5 to 6 microns. Belanger and Leblond(4) obtained similar resolution by coating sections with liquefied emulsion at 37° C. These methods suffer from many disadvantages. The activity has to be firmly fixed in the emulsion so that subsequent treatment will not leach it out; also there is a danger of artifacts caused by diffusion and pressure, and the inactive substances in the specimen often render the emulsion grains developable. In the stripping plate technique described by pe1c(5) and others, the emulsion is mounted on a thin support (cellulose esters have been used) and the latter shields the emulsion from abrasion and chemical action, but this advantage is gained at the expense of resolution. There have been many refinements of the method. Berriman, Herz, and Stevens(6) using a new, fine grain emulsion 4 microns thick on top of ordinary emulsion have obtained a resolution of 200 lines per mm. Gomberg(7) has developed a method called wet process autoradiography and claims a resolution down to 1 micron, but there is a corresponding loss in resolution when a protective coating is used to shield the one micron thick sensitized layer, formed on the surface of the specimen, from direct interaction with the chemicals used in forming the film. None of these methods employs direct magnification, although Fink(8) mechanically enlarged the specimen between lead sheets in a rolling mill, before the autoradiograph was taken. Optical magnification of the image is employed, but when this is greater than 10x, the silver grains appear as groups of hazy smudges, irregularly distributed, and no longer give a true picture. The only way to get direct magnification is to use a focusing method, in which the electrons emitted from the specimen pass through a suitable magnetic field and form an image on the photographic plate some distance from the specimen. In this method the whole system is in vacuo. Emission microscopes, in which the object constitutes the source of electrons, have been used for a long time, but these did not employ a radioisotope as a source of electrons. According to Lawrence(0) , sections have been placed in magnetic fields in an attempt "to pull the /3 -rays straight out and get real cell definition" but magnetic fields are not intense enough for this. In 1947, Marton and Abelson(10) described a method called tracer micography in which monoenergetic internal conversion electrons from a radioactive source were focused by a magnetic lens, producing a magnification of 1.6x. With their apparatus, using a 1 milli curie per mm2 source of Ga67 at a numerical aperture of 0.04 radians, satisfactory blackening of a plate was obtained after a 1 hour exposure. They obtained a best resolution of 30 microns, and proposed after-acceleration of the electrons to reduce exposure time, spherical aberration, and possibly chromatic aberration. At the same time, a similar instrument was developed in Edinburgh(11), (12) with which a resolution of 5 to 10 microns was obtained at a magnification of 7x. An attempt has been made to improve this instrument, and to study the principles on which its operation depends; also to evaluate the potential of such an instrument in the field of autoradiography. The work involved is described in the following chapters

Genetic Variants For Head Size Share Genes and Pathways With Cancer

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Dysregulation of specialized delay/interference-dependent working memory following loss of dysbindin-1A in schizophrenia-related phenotypes

Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A -/-, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A -/-showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A -/-provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects

Safe and Effective Intravenous Thrombolysis for Acute Ischemic Stroke Caused by Left Atrial Myxoma

Atrial myxoma may be associated with syncope or sudden death attributed to left-sided cardiac outflow obstruction or embolization caused by tumor dislodgement or thrombus formation. Definitive treatment for primary and secondary stroke prevention is surgical resection. The role of thrombolysis in acute brain ischemia in patients with atrial myxoma is not defined. There are few data available regarding safety and efficacy of thrombolytic therapy in acute ischemic strokes caused by atrial myxoma. Prior case reports described partial success using intra-arterial local thrombolysis; however, this is invasive and can be associated with significant complications. A previously reported case of systemic thrombolysis resulted in development of cerebral hemorrhage. We describe a young man who presented with syncope and a dense stroke developing as a complication of atrial myxoma, followed by a remarkable recovery after treatment with intravenous recombinant tissue plasminogen activator and urgent cardiac surgery. Contrary to some expert opinion, systemic thrombolytic therapy may be safely and effectively used to treat acute ischemic strokes from atrial myxoma. © 2009 National Stroke Association

A systematic review and meta-analysis on the effects of young offender treatment programs in Europe

Objectives To examine the effectiveness of young offender rehabilitation programs in Europe as part of an international project on the transnational transfer of approaches to reducing reoffending. Methods A literature search of approximately 27,000 titles revealed 25 controlled evaluations that fulfilled eligibility criteria, such as treatment of adjudicated young offenders below the age of 25, equivalence of treatment and control groups, and outcomes on reoffending. In total, the studies contained 7,940 offenders with a mean age of 17.9 years. Results Outcomes in the primary studies ranged widely from odds ratio (OR)?=?0.58 to 6.99, and the mean effect was significant and in favor of treatment (OR?=?1.34). Behavioral and cognitive-behavioral treatment ranked above average (OR?=?1.73), whereas purely deterrent and supervisory interventions revealed a slightly negative outcome (OR?=?0.85). Programs that were conducted in accordance with the risk–need–responsivity principles revealed the strongest mean effect (OR?=?1.90), which indicates a reduction of 16 % in reoffending against a baseline of 50 %. Studies of community treatment, with small samples, high program fidelity, and conducted as part of a demonstration project had larger effects; high methodological rigor was related to slightly smaller outcomes. Large effect size differences between evaluations from the UK and continental Europe disappeared when controlling for other study characteristics. Conclusions Overall, most findings agreed with North American meta-analyses. However, two-thirds of the studies were British, and in most European countries there was no sound evaluation of young offender treatment at all. This limits the generalization of results and underlines the policy need for systematic evaluation of programs and outcome moderators across different countries