Prevalence of significant pathology on MRI of brain and orbits in patients presenting with visual disturbance.

PURPOSE: The aim of our study was to determine the frequency and variety of abnormalities detected on MRI studies of the brain and orbits (MRBO), in patients referred for investigation of visual disturbance from a tertiary ophthalmology centre in Ireland. A secondary objective was to assess the various imaging pathologies identified in this cohort of patients. METHODS: The inclusion criteria were patients who underwent an Magnetic resonance imaging (MRI) brain or MRI brain and orbits over a 12-month period for investigation of first episode of visual disturbance, who were over 18 years of age, with visual disturbance of unknown aetiology. Statistical analysis was performed to calculate the percentage of abnormalities and corresponding 95% confidence interval (CI). Additionally, logistic regression was used to investigate any association between age, gender and the pathologies which presented. RESULTS: 135 MRI brain and orbit examinations fulfilled the inclusion criteria. Abnormalities were identified on 86 of the 135 examinations (63.7%; 95% CI: 55.3% to 71.3%). Nonspecific T2 hyperintensities were identified on 28 (20.7%) of the examinations, 13 (9.6%) examinations showed images suggestive of demyelination and 11 (8.1%) showed optic neuropathy. The logistic regression analysis showed no evidence of an association between age (p = 0.223), gender (p = 0.307) and abnormalities in this study. CONCLUSION: This represents a relatively high detection rate of abnormalities on MRBO when compared with similar studies and shows the important role MRI has in patients with a visual disturbance.

Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.

DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in DNA-PK subunits (Ku70, Ku80, and DNA-PKcs) does not. Here we demonstrate that, similar to p53 deficiency, ataxia-telangiectasia-mutated (ATM) gene deficiency rescues the embryonic lethality and neuronal apoptosis, but not impaired lymphocyte development, associated with Lig4 deficiency. However, in contrast to p53 deficiency, ATM deficiency enhances deleterious effects of Lig4 deficiency on growth potential of embryonic fibroblasts (MEFs) and genomic instability in both MEFs and cultured progenitor lymphocytes, demonstrating significant differences in the interplay of p53 vs. ATM with respect to NHEJ. Finally, in dramatic contrast to effects on Lig4 deficiency, ATM deficiency causes early embryonic lethality in Ku- or DNA-PKcs-deficient mice, providing evidence for an NHEJ-independent role for the DNA-PK holoenzyme.

Increased accumulation of hybrid V(D)J joins in cells expressing truncated versus full-length RAGs.

RAG1 and RAG2 (RAGs) initiate V(D)J recombination by introducing breaks between two coding segments and flanking recombination signals (RSs). Nonhomologous end-joining (NHEJ) proteins then join the coding segments and join the RSs. In wild-type cells, both full-length and truncated ("core") RAGs lead to accumulation of "hybrid" V(D)J joins, in which an RS is appended to a different coding sequence. We now show that while hybrid joins do not accumulate in NHEJ-deficient cells that express full-length RAGs, they do accumulate in NHEJ-deficient cells that express the core RAGS; like those catalyzed by core RAGs in vitro, however, they are sealed on just one DNA strand. These results suggest a potential role for the non-core regions in repressing potentially harmful transposition events.

Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses.

The Kit receptor tyrosine kinase functions in hemato- poiesis, melanogenesis and gametogenesis. Kit receptor-mediated cellular responses include proliferation, survival, adhesion, secretion and differentiation. In mast cells, Kit-mediated recruitment and activation of phosphatidylinositol 3'-kinase (PI 3-kinase) produces phosphatidylinositol 3'-phosphates, plays a critical role in mediating cell adhesion and secretion and has contributory roles in mediating cell survival and proliferation. To investigate the consequences in vivo of blocking Kit-mediated PI 3-kinase activation we have mutated the binding site for the p85 subunit of PI 3-kinase in the Kit gene, using a knock-in strategy. Mutant mice have no pigment deficiency or impairment of steady-state hematopoiesis. However, gametogenesis is affected in several ways and tissue mast cell numbers are affected differentially. While primordial germ cells during embryonic development are not affected, Kit(Y719F)/Kit(Y719F) males are sterile due to a block at the premeiotic stages in spermatogenesis. Furthermore, adult males develop Leydig cell hyperplasia. The Leydig cell hyperplasia implies a role for Kit in Leydig cell differentiation and/or steroidogenesis. In mutant females follicle development is impaired at the cuboidal stages resulting in reduced fertility. Also, adult mutant females develop ovarian cysts and ovarian tubular hyperplasia. Therefore, a block in Kit receptor-mediated PI 3-kinase signaling may be compensated for in hematopoiesis, melanogenesis and primordial germ cell development, but is critical in spermatogenesis and oogenesis.

Amnesia is a deficit in relational memory.

Eye movements were monitored to assess memory for scenes indirectly (implicitly). Two eye movement-based memory phenomena were observed: (a) the repetition effect, a decrease in sampling of previously viewed scenes compared with new scenes, reflecting memory for those scenes, and (b) the relational manipulation effect, an increase in viewing of the regions where manipulations of relations among scene elements had occurred. In normal control subjects, the relational manipulation effect was expressed only in the absence of explicit awareness of the scene manipulations. Thus, memory representations of scenes contain information about relations among elements of the scenes, at least some of which is not accessible to verbal report. But amnesic patients with severe memory impairment failed to show the relational manipulation effect. Their failure to show any demonstrable memory for relations among the constituent elements of scenes suggests that amnesia involves a fundamental deficit in relational (declarative) memory processing.

Record of Volcanism Since 7000 B.C. from the GISP2 Greenland Ice Core and Implications for the Volcano-Climate System.

Sulfate concentrations from continuous biyearly sampling of the GISP2 Greenland ice core provide a record of potential climate-forcing volcanism since 7000 B.C. Although 85 percent of the events recorded over the last 2000 years were matched to documented volcanic eruptions, only about 30 percent of the events from 1 to 7000 B.C. were matched to such events. Several historic eruptions may have been greater sulfur producers than previously thought. There are three times as many events from 5000 to 7000 B.C. as over the last two millennia with sulfate deposition equal to or up to five times that of the largest known historical eruptions. This increased volcanism in the early Holocene may have contributed to climatic cooling.

Changes in Atmospheric Circulation and Ocean Ice Cover over the North Atlantic During the Last 41,000 Years.

High-resolution, continuous multivariate chemical records from a central Greenland ice core provide a sensitive measure of climate change and chemical composition of the atmosphere over the last 41,000 years. These chemical series reveal a record of change in the relative size and intensity of the circulation system that transported air masses to Greenland [defined here as the polar circulation index (PCI)] and in the extent of ocean ice cover. Massive iceberg discharge events previously defined from the marine record are correlated with notable expansions of ocean ice cover and increases in PCI. During stadials without discharge events, ocean ice cover appears to reach some common maximum level. The massive aerosol loadings and dramatic variations in ocean ice cover documented in ice cores should be included in climate modeling.

The atmosphere during the younger dryas.

One of the most dramatic climate change events observed in marine and ice core records is the Younger Dryas, a return to near-glacial conditions that punctuated the last deglaciation. High-resolution, continuous glaciochemical records, newly retrieved from central Greenland, record the chemical composition of the arctic atmosphere at this time. This record shows that both the onset and the termination of the Younger Dryas occurred within 10 to 20 years and that massive, frequent, and short-term (decadal or less) changes in atmospheric composition occurred throughout this event. Changes in atmospheric composition are attributable to changes in the size of the polar atmospheric cell and resultant changes in source regions and to the growth and decay of continental biogenic source regions.