Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting over a million people in the United States alone, and is characterized by rigidity, bradykinesia, resting ...tremor, and postural instability. Its main neuropathological feature is the loss of dopaminergic neurons of the substantia nigra pars compacta. However, the pathogenesis of this loss is not understood fully. One of the earliest biochemical changes seen in PD is a reduction in the levels of total glutathione, a key cellular antioxidant. Traditionally, it has been thought that this decrease in GSH levels is the consequence of increased oxidative stress, a process heavily implicated in PD pathogenesis. However, emerging evidence suggests that GSH depletion may itself play an active role in PD pathogenesis. This review aims to explore the contribution of GSH depletion to PD pathogenesis.--Martin, H. L., Teismann, P. Glutathione--a review on its role and significance in Parkinson's disease.
•Integrating PDMP into the EHR facilitates multiple factors of PDMP IS success.•Educational outreach and training should be coupled with registration mandates to promote actual PDMP use.•Expanding ...delegate access facilitates PDMP success due to physician's lack of time to check the system.
Prescription Drug Monitoring Programs (PDMP) help prevent prescription drug misuse and promote appropriate pain management. Despite these benefits and PDMP mandates in most states, PDMPs face challenges that hinder their success. This paper uses the Delone and McLean Information Success (IS) Model to review the current literature for barriers and facilitators to PDMP quality, use, intention to use and user satisfaction in the United States (U.S.).
Scopus, PubMed and Embase databases were searched due to their relevance to information technology, education and research.
There were 142 and 183 barriers and facilitators, respectively, found in 44 peer reviewed articles. Barriers to PDMP quality, use and user satisfaction include lack of interstate data sharing, access difficulties, lack of time, inability to delegate access, lack of knowledge or awareness of the PMDP, and lack of EHR integration. Facilitators to PDMP quality, use and user satisfaction include interstate data connections, real-time data updates, EHR integration, and access delegation.
Interstate data sharing, EHR integration and expanding access to delegates were common themes found. Some results were found to be contradictory such as mandating use.
PDMP users can use these findings to assess current barriers to PDMP success in the U.S. and draw possible solutions from the list of facilitators. Practitioners should consider the context of their state and organization when determining which facilitators would most promote PDMP IS success. Combining facilitators may be the best route to PDMP IS success in certain situations.
Parasite location has been proposed as an important factor in the behavioural changes observed in rodents infected with the protozoan Toxoplasma gondii. During the chronic stages of infection, ...encysted parasites are found in the brain but it remains unclear whether the parasite has tropism for specific brain regions. Parasite tissue cysts are found in all brain areas with some, but not all, prior studies reporting higher numbers located in the amygdala and frontal cortex. A stochastic process of parasite location does not, however, seem to explain the distinct and often subtle changes observed in rodent behaviour. One factor that could contribute to the specific changes is increased dopamine production by T. gondii. Recently, it was found that cells encysted with parasites in the brains of experimentally infected rodents have high levels of dopamine and that the parasite encodes a tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of this neurotransmitter. A mechanism is proposed that could explain the behaviour changes due to parasite regulation of dopamine. This could have important implications for T. gondii infections in humans.
The ubiquitous occurrence of antibiotics in aquatic environments raises concerns about potential adverse effects on aquatic ecology and human health, including the promotion of increased antibiotic ...resistance. This study examined the oxidation of three widely detected antibiotics (ciprofloxacin, lincomycin, and trimethoprim) by potassium permanganate KMnO4; Mn(VII). Reaction kinetics were described by second-order rate laws, with apparent second-order rate constants (k 2) at pH 7 and 25 °C in the order of 0.61 ± 0.02 M−1 s−1 (ciprofloxacin) < 1.6 ± 0.1 M−1 s−1 (trimethoprim) < 3.6 ± 0.1 M−1 s−1 (lincomycin). Arrhenius temperature dependence was observed with apparent activation energies (E a) ranging from 49 kJ mol−1 (trimethoprim) to 68 kJ mol−1 (lincomycin). Rates of lincomycin and trimethoprim oxidation exhibited marked pH dependences, whereas pH had only a small effect on rates of ciprofloxacin oxidation. The effects of pH were quantitatively described by considering parallel reactions between KMnO4 and individual acid−base species of the target antibiotics. Predictions from a kinetic model that included temperature, KMnO4 dosage, pH, and source water oxidant demand as input parameters agreed reasonably well with measurements of trimethoprim and lincomycin oxidation in six drinking water utility sources. Although Mn(VII) reactivity with the antibiotics was lower than that reported for ozone and free chlorine, its high selectivity and stability suggests a promising oxidant for treating sensitive micropollutants in organic-rich matrices (e.g., wastewater).
Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly ...understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395
Main Points
MHCII upregulation is necessary for dopaminergic cell death in a model of Parkinson's disease. The study supports the presence of an adaptive immune response in the pathogenesis of Parkinson's disease.
While institutional repositories are common in medical schools and academic health centers, they have been used by only a small number of health systems to track and promote their research and ...scholarly activity. This article describes how Providence System Library Services leveraged their existing institutional repository platform to substitute a virtual showcase for an annual in-person event.
Abstract High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells — including microglia and neurons. HMGB1 can ...contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.
Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are ...persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.
Toxicity is a major cause of failure in drug discovery and development, and whilst robust toxicological testing occurs, efficiency could be improved if compounds with cytotoxic characteristics were ...identified during primary compound screening. The use of high-content imaging in primary screening is becoming more widespread, and by utilising phenotypic approaches it should be possible to incorporate cytotoxicity counter-screens into primary screens. Here we present a novel phenotypic assay that can be used as a counter-screen to identify compounds with adverse cellular effects. This assay has been developed using U2OS cells, the PerkinElmer Operetta high-content/high-throughput imaging system and Columbus image analysis software. In Columbus, algorithms were devised to identify changes in nuclear morphology, cell shape and proliferation using DAPI, TOTO-3 and phosphohistone H3 staining, respectively. The algorithms were developed and tested on cells treated with doxorubicin, taxol and nocodazole. The assay was then used to screen a novel, chemical library, rich in natural product-like molecules of over 300 compounds, 13.6% of which were identified as having adverse cellular effects. This assay provides a relatively cheap and rapid approach for identifying compounds with adverse cellular effects during screening assays, potentially reducing compound rejection due to toxicity in subsequent in vitro and in vivo assays.
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