Treatment of Working Memory in a Patient with Moderate Aphasia

Working memory (WM) is the cognitive system that functions for the temporary storage, activation, and manipulation of information in support of complex, goal-directed behavior (Baddeley, 2003; Kane, Conway, Hambrick, & Engle, 2007). This system is limited in capacity, and it includes an attentional or central executive component that serves to block interference, resolve conflict, and flexibly manage its capacity limitations (Baddeley, 2003; Just & Carpenter, 1992; Kane et al., 2007). It has been suggested that WM deficits may contribute to language performance impairments in aphasia (Caspari, Parkinson, LaPointe, & Katz, 1998; Friedmann & Gvion, 2003; Wright, Downey, Gravier, Love, & Shapiro, 2007; Wright & Shisler, 2005). Accordingly, clinical researchers have begun to study whether aphasia treatment targeted at WM or related processes may be efficacious

Plasmalemmal Vesicle Associated Protein-1 (PV-1) is a marker of blood-brain barrier disruption in rodent models

<p>Abstract</p> <p>Background</p> <p><it>Plasmalemmal vesicle associated protein-1 </it>(<it>PV-1</it>) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of <it>PV-1 </it>to determine whether localized <it>PV-1 </it>induction is conserved across species and disease state.</p> <p>Results</p> <p>We demonstrate that <it>PV-1 </it>is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, <it>PV-1 </it>is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated.</p> <p>Conclusion</p> <p>Our results confirm that <it>PV-1 </it>is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of <it>PV-1 </it>expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.</p

Data on the histological and immune cell response in the popliteal lymph node in mice following exposure to metal particles and ions

AbstractHip implants containing cobalt–chromium (CoCr) have been used for over 80 years. In patients with metal-on-metal (MoM) hip implants, it has been suggested that wear debris particles may contribute to metal sensitization in some individuals, leading to adverse reactions. This article presents data from a study in which the popliteal lymph node assay (PLNA) was used to assess immune responses in mice treated with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3, and NiCl2) or Cr2O3 particles with metal salts (“A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay” (B.E. Tvermoes, K.M. Unice, B. Winans, M. Kovochich, E.S. Fung, W.V. Christian, E. Donovan, B.L. Finley, B.L. Kimber, I. Kimber, D.J. Paustenbach, 2016) [1]). Data are presented on (1) the chemical characterization of TiO2 particles (used as a particle control), (2) clinical observations in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (3) PLN weight and weight index (WI) in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (4) histological changes in PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (5) percentages of immune cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, and (6) percentages of proliferating cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts

Characterization of TEM1/endosialin in human and murine brain tumors

<p>Abstract</p> <p>Background</p> <p><it>TEM1/endosialin </it>is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of <it>TEM1/endosialin </it>in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models.</p> <p>Methods</p> <p><it>In situ </it>hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize <it>TEM1/endosialin </it>expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in <it>TEM1/endosialin </it>expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown <it>in vitro</it>. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude <it>TEM1/endosialin </it>knockout (KO) and wildtype (WT) mice.</p> <p>Results</p> <p><it>TEM1/endosialin </it>was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated <it>TEM1/endosialin </it>expression in 79% of tumors. Robust <it>TEM1/endosialin </it>expression occurred in 31% of glioblastomas (grade IV astroctyomas). <it>TEM1/endosialin </it>expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, αSMA and fibronectin in clinical specimens. <it>In vitro</it>, <it>TEM1/endosialin </it>was upregulated in human endothelial cells cultured in matrigel. Vascular <it>Tem1/endosialin </it>was induced in intracranial U87MG GBM xenografts grown in mice. <it>Tem1/endosialin </it>KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although <it>Tem1/endosialin </it>KO tumors were significantly more vascular than the WT counterparts.</p> <p>Conclusion</p> <p><it>TEM1/endosialin </it>was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of <it>TEM1/endosialin </it>did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of <it>TEM1/endosialin </it>and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies.</p

Early Life Activation of the Aryl Hydrocarbon Receptor and Persistent Alterations in CD8+ T Cell Responses to Viral Infection

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Environmental Medicine, 2014.The developing immune system is sensitive to early life environmental insults, which likely contribute to altered immune function later in life. However, how developmental exposures persistently alter immune function remains poorly understood. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that acts as an environmental sensor and binds many dioxins and polychlorinated biphenyls (PCBs), pollutants to which humans are constantly exposed. AhR also plays a role in the development and function of the immune system. Human and animal data demonstrate that early life exposure to AhR ligands correlates with long-lasting alterations in immune function, supporting the idea that AhR activation influences the developing immune system. Adult mice with developmental AhR activation have alterations in adaptive and innate immune responses to influenza A virus infection, including reduced clonal expansion and differentiation of CD8+ T cells. The mechanism by which early life AhR activation alters the function of CD8+ T cells at maturity is not known. Based on experimental evidence, some of which was generated as part of this thesis research project, functional alterations of CD8+ T cells are (1) due to direct AhR signaling in the offspring, (2) present long after maternal exposure to the exogenous AhR ligand has ceased, and (3) due to direct effects on hematopoietic cells. We hypothesize that AhR influences epigenetic regulation of the developing immune system. Epigenetic regulatory mechanisms alter gene expression in a heritable fashion, and include DNA methylation and various histone modifications. Work in this thesis project sought to determine whether developmental triggering of AhR alters DNA methylation in CD8+ T cells. We examined genome-wide DNA methylation profiles in CD8+ T cells from naïve and infected mice with and without developmental AhR activation. We discovered that AhR signaling leads to broad changes in DNA methylation, with areas of hyper- and hypomethylation observed across the genome. Further, we directly integrated these changes in DNA methylation with genome-wide differences in gene expression. This revealed that activation of the AhR during development leads to changes in gene expression following influenza virus infection, and differential DNA methylation may contribute to some of these transcriptional changes. These data suggest that altered epigenetic regulation, cued by developmental exposure to AhR agonists, may cause enduring changes in gene expression and T cell function. The immune system functions via complex interactions among different cell types. We therefore also explored the idea that AhR-mediated changes in CD8+ T cell function may not only occur as a result of direct effects in the CD8 lineage, but also reflect altered function of other immune cells that influence CD8+ T cell responses during infection. Adoptively transferring CD8+ T cells from developmentally exposed mice into unexposed hosts and the reverse transfer revealed that the defective CD8+ T cell response to influenza virus infection is due to both CD8+ T cell intrinsic and extrinsic changes following early life AhR signaling. This suggests that in addition to intrinsic effects on CD8+ T cells, developmental AhR signaling alters other cell types, such as antigen presenting cells (APCs), which then lead to a change in CD8+ T cell function. The effects of developmental activation of AhR on dendritic cells (DCs), professional APCs that play a key role in activating naïve T cells during infection, have not been previously examined. We found that the number of DCs was decreased following influenza virus infection in developmentally exposed mice. Furthermore, the functional capacity of the DCs was reduced following developmental exposure, in that they were less able to drive the proliferation and differentiation of naïve, virus-specific CD8+ T cells. Given that DCs are key initiators and regulators of adaptive immunity, the discovery that developmental activation of AhR perturbs DC function has broad implications for AhR-mediated alterations in immune function. These findings provide an important framework for understanding how the early life environment shapes immune function across the life span

Environmental cues received during development shape dendritic cell responses later in life.

Environmental signals mediated via the aryl hydrocarbon receptor (AHR) shape the developing immune system and influence immune function. Developmental exposure to AHR binding chemicals causes persistent changes in CD4+ and CD8+ T cell responses later in life, including dampened clonal expansion and differentiation during influenza A virus (IAV) infection. Naïve T cells require activation by dendritic cells (DCs), and AHR ligands modulate the function of DCs from adult organisms. Yet, the consequences of developmental AHR activation by exogenous ligands on DCs later in life has not been examined. We report here that early life activation of AHR durably reduces the ability of DC to activate naïve IAV-specific CD8+ T cells; however, activation of naïve CD4+ T cells was not impaired. Also, DCs from developmentally exposed offspring migrated more poorly than DCs from control dams in both in vivo and ex vivo assessments of DC migration. Conditional knockout mice, which lack Ahr in CD11c lineage cells, suggest that dampened DC emigration is intrinsic to DCs. Yet, levels of chemokine receptor 7 (CCR7), a key regulator of DC trafficking, were generally unaffected. Gene expression analyses reveal changes in Lrp1, Itgam, and Fcgr1 expression, and point to alterations in genes that regulate DC migration and antigen processing and presentation as being among pathways disrupted by inappropriate AHR signaling during development. These studies establish that AHR activation during development causes long-lasting changes to DCs, and provide new information regarding how early life environmental cues shape immune function later in life

The toxicity of crude 4-methylcyclohexanemethanol (MCHM): review of experimental data and results of predictive models for its constituents and a putative metabolite

<div><p></p><p>Crude 4-methylcyclohexanemethanol (MCHM) is an industrial solvent used to clean coal. Approximately 10 000 gallons of a liquid mixture containing crude MCHM were accidently released into the Elk River in West Virginia in January 2014. Because of the proximity to a water treatment facility, the contaminated water was distributed to approximately 300 000 residents. In this review, experimental data and computational predictions for the toxicity for crude MCHM, distilled MCHM, its other components and its putative metabolites are presented. Crude MCHM, its other constituents and its metabolites have low to moderate acute and subchronic oral toxicity. Crude MCHM has been shown not to be a skin sensitizer below certain doses, indicating that at plausible human exposures it does not cause an allergic response. Crude MCHM and its constituents cause slight to moderate skin and eye irritation in rodents at high concentrations. These chemicals are not mutagenic and are not predicted to be carcinogenic. Several of the constituents were predicted through modeling to be possible developmental toxicants; however, 1,4-cyclohexanedimethanol, 1,4-cyclohexanedicarboxylic acid and dimethyl 1,4-cyclohexanedicarboxylate did not demonstrate developmental toxicity in rat studies. Following the spill, the Centers for Disease Control and Prevention recommended a short-term health advisory level of 1 ppm for drinking water that it determined was unlikely to be associated with adverse health effects. Crude MCHM has an odor threshold lower than 10 ppb, indicating that it could be detected at concentrations at least 100-fold less than this risk criterion. Collectively, the findings and predictions indicate that crude MCHM poses no apparent toxicological risk to humans at 1 ppm in household water.</p></div