Assessing the Influence of Brain-based Instructional Methods and Its Impact on Systemic Change for Learning Communities

Background: As scholars who prepare future school leaders to be innovative instructional leaders for their learning communities, we are on the verge of a curriculum design revolution. The application of brain research findings promotes educational reform efforts to systemically change the way in which children experience school. However, most educators, school leaders, board members, and policy makers are ill prepared to reconsider the implications for assessment, pedagogy, school climate, daily schedules, and use of technology. This qualitative study asked future school leaders to reconsider how school leadership preparedness programs prepared them to become instructional leaders for the 21st century. The findings from this study will enhance the field of school leadership, challenging the current emphasis placed on standardized testing, traditional school calendars, assessments, monocultural instructional methods, and meeting the needs of diverse learning communities. [See PDF for complete abstract]

Progenitor cells as remote "bioreactors": Neuroprotection via modulation of the systemic inflammatory response.

Acute central nervous system (CNS) injuries such as spinal cord injury, traumatic brain injury, autoimmune encephalomyelitis, and ischemic stroke are associated with significant morbidity, mortality, and health care costs worldwide. Preliminary research has shown potential neuroprotection associated with adult tissue derived stem/progenitor cell based therapies. While initial research indicated that engraftment and transdifferentiation into neural cells could explain the observed benefit, the exact mechanism remains controversial. A second hypothesis details localized stem/progenitor cell engraftment with alteration of the loco-regional milieu; however, the limited rate of cell engraftment makes this theory less likely. There is a growing amount of preclinical data supporting the idea that, after intravenous injection, stem/progenitor cells interact with immunologic cells located in organ systems distant to the CNS, thereby altering the systemic immunologic/inflammatory response. Such distant cell "bioreactors" could modulate the observed post-injury pro-inflammatory environment and lead to neuroprotection. In this review, we discuss the current literature detailing the above mechanisms of action for adult stem/progenitor cell based therapies in the CNS.

Regulation of hepatic cytochrome P450 expression in mice with intestinal or systemic infections of citrobacter rodentium.

We reported previously that infection of C3H/HeOuJ (HeOu) mice with the murine intestinal pathogen Citrobacter rodentium caused a selective modulation of hepatic cytochrome P450 (P450) gene expression in the liver that was independent of the Toll-like receptor 4. However, HeOu mice are much more sensitive to the pathogenic effects of C. rodentium infection, and the P450 down-regulation was associated with significant morbidity in the animals. Here, we report that oral infection of C57BL/6 mice with C. rodentium, which produced only mild clinical signs and symptoms, produced very similar effects on hepatic P450 expression in this strain. As in HeOu mice, CYP4A mRNAs and proteins were among the most sensitive to down-regulation, whereas CYP4F18 was induced. CYP2D9 mRNA was also induced 8- to 9-fold in the C57BL/6 mice. The time course of P450 regulation followed that of colonic inflammation and bacterial colonization, peaking at 7 to 10 days after infection and returning to normal at 15 to 24 days as the infection resolved. These changes also correlated with the time course of significant elevations in the serum of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-alpha, as well as of interferon-gamma and IL-2, with serum levels of IL-6 being markedly higher than those of the other cytokines. Intraperitoneal administration of C. rodentium produced a rapid down-regulation of P450 enzymes that was quantitatively and qualitatively different from that of oral infection, although CYP2D9 was induced in both models, suggesting that the effects of oral infection on the liver are not due to bacterial translocation.

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans.

OBJECTIVE: To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. METHODS: A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. RESULTS: The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P=8.16x10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P=7.61x10(-8)) and DPB1*0901 (P=2.55x10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P=7.58x10(-17)/4.84x10(-16)) or anticentromere autoantibodies (P=1.12x10(-3)/3.2x10(-5)), respectively. CONCLUSION: The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies.

Direct visualization of the putative portal in the Kaposi's sarcoma-associated herpesvirus capsid by cryoelectron tomography.

Genetic and biochemical studies have suggested the existence of a bacteriophage-like, DNA-packaging/ejecting portal complex in herpesviruses capsids, but its arrangement remained unknown. Here, we report the first visualization of a unique vertex in the Kaposi's sarcoma-associated herpesvirus (KSHV) capsid by cryoelectron tomography, thus providing direct structural evidence for the existence of a portal complex in a gammaherpesvirus. This putative KSHV portal is an internally localized, umbilicated structure and lacks all of the external machineries characteristic of portals in DNA bacteriophages.

Quantitation of C4a and C4b in systemic lupus erythematosus patients

The fourth component of human complement (C4) exists in blood as two major forms or isotypes which differ in their biochemical and functional properties. Because C4A preferentially transacylates onto amino groups, it has been postulated that this isotype is more important in the clearance of immune complexes. Patients having systemic lupus erythematosus (SLE), an autoimmune disease, have an increased incidence of C4A null genes and presumably decreased levels of C4A. Currently accepted methods for the detection of C4, however, cannot accurately quantitate C4A and C4B. Thus, their role in disease susceptibility and activity has not been studied. A novel immunoassay, which utilized heat-aggregated IgG to activate and capture C4, was developed for accurate quantitation of total C4, C4A and C4B by monoclonal antibody conjugates. Higher mean total C4 values were found in a healthy Black control population when compared to White controls. This appeared to be due to an increase in C4B. In SLE patients, mean total C4 levels were significantly lower than controls regardless of disease activity. Serial patient studies showed that the ratio of C4A:C4B remained relatively constant. When the patient group was compared to controls based on C4 null gene status, the mean levels of C4A were identical while C4B was decreased in the patients. This suggests that the common HLA-B8, Dr3 C4A*Q0 gene deletion found in SLE patients may also adversely affect genetic control of the C4B genes. Furthermore, low levels of C4A cannot fully account for disease development in SLE patients having C4A null genes. ^

Mechanisms of UV induced systemic immunosuppression: An essential role for interleukin-10

The recognition of the skin as an immunocompetent organ has focused attention on the complex interaction between ultraviolet radiation and the immune system. How UV-radiation, which hardly penetrates past the epidermis, induces systemic immune suppression is not entirely clear. We propose that suppressive cytokines, released by UV-irradiated keratinocytes, play a role in the induction of immune suppression. Injecting supernatants from UV-exposed murine keratinocytes into mice impairs their ability to mount a delayed-type hypersensitivity response against allogeneic histocompatibility antigens. We tested the hypothesis that the down regulation of the immune response by UV is precipitated by the release of IL-10 after keratinocytes are UV-irradiated. After UV exposure IL-10 mRNA was upregulated. Western analysis indicated immunoreactive IL-10 was secreted by UV-exposed keratinocytes. The addition of supernatants from UV-irradiated keratinocytes to Th1 clones diminished their IFN production, whereas the addition of supernatants from normal keratinocytes had no suppressive effect on IFN production. Furthermore, treating supernatants from UV-irradiated keratinocytes with anti-IL-10 antibodies blocked the induction of immune suppression. To determine if IL-10 was responsible for the immunosuppression seen after total-body UV irradiation, UV-exposed mice were treated with anti-IL-10 antibodies. Treating UV-irradiated mice with anti-IL-10 reversed the induction of immune suppression. These findings suggest that keratinocyte-derived IL-10 was mediating UV-induced suppression in vivo. We also tested the hypothesis that UV-induced suppressor cells are Th2 cells. Mice were injected with spleen cells from either normal or UV-exposed donor mice immunized with alloantigen. At the time of spleen cell infusion, the recipient mice were then resensitized. Spleen cells from UV-exposed mice suppressed DTH. Mice treated identically and injected with anti-IL-10 antibodies were able to generate a DTH response. Taken together these data suggest that the suppressor cells that are induced by UV radiation are Th2 cells which mediate their suppressive effect by release of IL-10. ^

Development of automated image analysis tools for verification of radiotherapy field accuracy with an electronic portal imaging device

The successful management of cancer with radiation relies on the accurate deposition of a prescribed dose to a prescribed anatomical volume within the patient. Treatment set-up errors are inevitable because the alignment of field shaping devices with the patient must be repeated daily up to eighty times during the course of a fractionated radiotherapy treatment. With the invention of electronic portal imaging devices (EPIDs), patient's portal images can be visualized daily in real-time after only a small fraction of the radiation dose has been delivered to each treatment field. However, the accuracy of human visual evaluation of low-contrast portal images has been found to be inadequate. The goal of this research is to develop automated image analysis tools to detect both treatment field shape errors and patient anatomy placement errors with an EPID. A moments method has been developed to align treatment field images to compensate for lack of repositioning precision of the image detector. A figure of merit has also been established to verify the shape and rotation of the treatment fields. Following proper alignment of treatment field boundaries, a cross-correlation method has been developed to detect shifts of the patient's anatomy relative to the treatment field boundary. Phantom studies showed that the moments method aligned the radiation fields to within 0.5mm of translation and 0.5$\sp\circ$ of rotation and that the cross-correlation method aligned anatomical structures inside the radiation field to within 1 mm of translation and 1$\sp\circ$ of rotation. A new procedure of generating and using digitally reconstructed radiographs (DRRs) at megavoltage energies as reference images was also investigated. The procedure allowed a direct comparison between a designed treatment portal and the actual patient setup positions detected by an EPID. Phantom studies confirmed the feasibility of the methodology. Both the moments method and the cross-correlation technique were implemented within an experimental radiotherapy picture archival and communication system (RT-PACS) and were used clinically to evaluate the setup variability of two groups of cancer patients treated with and without an alpha-cradle immobilization aid. The tools developed in this project have proven to be very effective and have played an important role in detecting patient alignment errors and field-shape errors in treatment fields formed by a multileaf collimator (MLC). ^