An electrophysiological study of the hyperstriatal visual projection area in the young chicken.

The structural organisation of avian visual pathways is discussed, and particular reference is made to the retino- thalamo-hyperstriatal projection. The appearance of the young (1-2 week old) chicken forebrain in Nissl-stained transverse sections is discussed, and an interpretation of the structure and nomenclature of the hyperstriatal complex is presented and compared with the interpretations found in the literature. An analysis is then presented of field and single unit potentials recorded from the hyperstriatal complex of the 1-2 week old chicken following electrical stimulation of the contralateral and ipsilateral retina and optic papilla. The retino-hyperstriatal projection was found to be topographically organised - thus, the inferior retina was found to project to the posterior regions of the Wulst, and the superior retina to anterior regions of the Wulst. A complex dorsoventral lamination of visual inputs to the hyperstriatum was revealed. Stimulation of the contralateral anterior retina resulted in early field potentials (mean peak latency, MPL: 14.3+0.7 mS) located in the hyper striatum intercalatus accessorium (IHA), followed by later activity spreading throughout superficial regions of the hyperstriatum accessorium (HA) (MPL: 18.5 + 1.6mS). Similarly, stimulation of the contralateral posterior retina resulted in early potentials (MPL: 14.9 + 1.6mS) in IHA, and late potentials (MPL: 17.2 + 0.9mS) spreading throughout deep regions of HA. It was concluded that IHA was the main visual thalamo-receptive lamina within the hyperstriatal complex. Stimulation of the ipsilateral optic papilla resulted in a single field potential response (MPL: 21.8 + 3.0mS), located in ventral HA, overlapping ventral areas of the contralaterally responsive region of HA. The responses of 220 single cells recorded from the hyperstriatum following electrical stimulation of the contralateral and ipsilateral optic papilla were analysed. 123 (56%) of these cells responded to the stimulation. Within the responsive sample, four classes of cell were identified: 85% responded exclusively to contralateral stimulation; 3% responded exclusively to ipsilateral stimulation; 8% responded to both contralateral and ipsilateral stimulation with different latencies (independent binocular); and 4% responded to both contralateral and ipsilateral stimulation with identical latencies (coincident binocular). The single cell responses showed excellent spatiotemporal correlation with the evoked field potentials. Comparison of these results with those obtained by other workers from the owl and pigeon indicated some similarities between the organisation of the thalamofugal pathway in chicken and owl, but also that at present, no single species should be assumed to be typical of the avian class

Biomarkers in Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)

PURPOSE OF REVIEW: Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis, a rare autoimmune disease characterised by fibrosis and vasculopathy. The variety of phenotypes in SSc-ILD have inspired multiple studies aimed at the identification of biomarkers which can provide disease-specific information but due to the complex pathogenesis of SSc-ILD, it has been challenging to validate such markers. We provide a comprehensive update on those most studied along with emerging biomarkers. RECENT FINDINGS: We review the up-to-date findings with regard to the use of well-studied molecular biomarkers in SSc-ILD along with novel biomarkers offering promise as prognostic markers such as IGFBP-2 and IGFBP-7, the adipokine CTRP9, endothelial progenitor cells, and cellular markers such as CD21lo/neg B cells. Expression profiling data is being used in SSc patients to determine genetic and epigenetic clusters which shed further light on mechanisms involved in the pathogenesis of SSc-ILD and are likely to uncover novel biomarkers. SUMMARY: With the exception of autoantibodies, there are no routinely measured biomarkers in SSc-ILD and reliable validation of the many potential biomarkers is lacking. Identifying biomarkers which can offer diagnostic and prognostic certainty may help patients to receive preventative treatment as part of a personalised medicine approach

Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need

Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality resulting from early internal-organ involvement. Clinicians therefore tend to focus on early diagnosis and treatment of potentially life-threatening cardiorespiratory and renal disease. However, the rapidly progressive painful, itchy skin tightening that characterizes dcSSc is the symptom that has the greatest effect on patients' quality of life, and there is currently no effective disease-modifying treatment for it. Considerable advances have been made in predicting the extent and rate of skin-disease progression (which vary between patients), including the development of techniques such as molecular analysis of skin biopsy samples. Risk stratification for progressive skin disease is especially relevant now that haematopoietic stem-cell transplantation is a treatment option, because stratification will inform the balance of risk versus benefit for each patient. Measurement of skin disease is a major challenge. Results from clinical trials have highlighted limitations of the modified Rodnan skin score (the current gold standard). Alternative patient-reported and other potential outcome measures have been and are being developed. Patients with early dcSSc should be referred to specialist centres to ensure best-practice management, including the management of their skin disease, and to maximize opportunities for inclusion in clinical trials

Renal Disease and Systemic Sclerosis: an Update on Scleroderma Renal Crisis

Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) with a mortality of 20% at 6 months. Once the leading cause of mortality in scleroderma (SSc), it remains a serious complication, often necessitating level three care for patients affected. Whilst renal outcomes have significantly improved following the advent of angiotensin-converting enzyme inhibitor (ACEi) therapy, SRC remains a precarious challenge for clinicians, due to lack of preventative measures and the fact that patients can rapidly decline despite best medical management. Large cohort studies spanning decades have allowed clear identification of phenotypes particularly at risk of developing SRC thus allowing enhanced monitoring and early identification in those individuals. Novel urinary biomarkers for renal disease in SSc may offer a new window for early identification of SRC patients and response to treatment. Multiple studies have demonstrated increased activity of complement pathways in SRC with some anecdotal cases exhibiting serological response to treatment with eculizumab where ACEi and therapeutic plasma exchange (TPE) were not successful. Endothelin-1 blockade, a therapeutic strategy in other SSc vasculopathies, has shown potential as a target but clinical trials are yet to show a clear treatment benefit. Clear guidelines for the management of SRC are in place to standardise care and facilitate early collaboration between rheumatology and renal physicians. Outcomes following renal transplant have improved but the mortality of SRC remains high, indicating the need for continued exploration of the mechanisms precipitating and exacerbating SRC in order to develop novel therapies

Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells - Activation of protein kinase B by wortmannin-sensitive and -insensittve mechanisms

Previous studies using L6 myotubes have suggested that glycogen synthase kinase-3 (GSK-3) is phosphoryl ated and inactivated in response to insulin by protein kinase B (PKB, also known as Akt or RAG) (Cross, D, A, E., Alessi, D, R., Cohen, P., Andjelkovic, M., and Hemmings, B, A. (1995) Nature 378, 785-789), In the present study, marked increases in the activity of PKB have been shown to occur in insulin-treated rat epididymal fat cells with a time course compatible with the observed decrease in GSK-3 activity, Isoproterenol, acting primarily through beta(3)-adrenoreceptors, was found to decrease GSK-3 activity to a similar extent (approximately 50%) to insulin, However, unlike the effect of insulin, the inhibition of GSK by isoproterenol was not found to be sensitive to inhibition by the phosphatidylinositol 3'-kinase inhibitors, wortmannin or LY 294002, The change in GSK-3 activity brought about by isoproterenol could not be mimicked by the addition of permeant cyclic AMP analogues or forskolin to the cells, although at the concentrations used, these agents were able to stimulate lipolysis. Isoproterenol, but again not the cyclic AMP analogues, was found to increase the activity of PKB, although to a lesser extent than insulin. While wortmannin abolished the stimulation of PKB activity by insulin, it was without effect on the activation seen in response to isoproterenol, The activation of PKB by isoproterenol was not accompanied by any detectable change in the electrophoretic mobility of the protein on SDS-polyacrylamide gel electrophoresis. It would therefore appear that distinct mechanisms exist for the stimulation of PKB by insulin and isoproterenol in rat fat cells

Scanning the Landscape of High School Alternatives

Interest in high school alternatives has grown over the last few decades as communities, school districts, states, and public agencies seek effective strategies to improve the educational and employment outcomes of young people and better serve students whose needs are not met through the traditional school system.To better understand this developing field, the Annie E. Casey?Foundation?asked Education Northwest to?conduct a systematic scan of?high school?alternative models and approaches across the United States. Based on interviews and surveys with program leaders, researchers, funders, and other experts in the field, this report outlines important considerations and recommendations for successful high school alternatives.The report describes strategies to build better systems to support high school alternatives—including shifts in mindsets and narratives, policies and budgets, and effective practices—that empower young people to transform their lives and build momentum for their future

BISON: bio-interface for the semi-global analysis of network patterns

BACKGROUND: The large amount of genomics data that have accumulated over the past decade require extensive data mining. However, the global nature of data mining, which includes pattern mining, poses difficulties for users who want to study specific questions in a more local environment. This creates a need for techniques that allow a localized analysis of globally determined patterns. RESULTS: We developed a tool that determines and evaluates global patterns based on protein property and network information, while providing all the benefits of a perspective that is targeted at biologist users with specific goals and interests. Our tool uses our own data mining techniques, integrated into current visualization and navigation techniques. The functionality of the tool is discussed in the context of the transcriptional network of regulation in the enteric bacterium Escherichia coli. Two biological questions were asked: (i) Which functional categories of proteins (identified by hidden Markov models) are regulated by a regulator with a specific domain? (ii) Which regulators are involved in the regulation of proteins that contain a common hidden Markov model? Using these examples, we explain the gene-centered and pattern-centered analysis that the tool permits. CONCLUSION: In summary, we have a tool that can be used for a wide variety of applications in biology, medicine, or agriculture. The pattern mining engine is global in the way that patterns are determined across the entire network. The tool still permits a localized analysis for users who want to analyze a subportion of the total network. We have named the tool BISON (Bio-Interface for the Semi-global analysis Of Network patterns)

Effects of the Oral Angiotensin II Type 2 Receptor Agonist C21 in Sugen-Hypoxia Induced Pulmonary Hypertension in Rats

Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p 100 μm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment