Author: neuroscience research

Experimental Ad36 infection of mice improves hyperglycemia, despite a 60% fat diet and without reducing adiposity. Signaling studies suggest that in these mice, Ad36 improves glycemic control by increasing glucose uptake by BAY 43-9006 adipose tissue and skeletal muscle and by reducing hepatic glucose output. Mechanistic in vitro studies show that Ad36 increases insulin independent glucose uptake in diabetic and non-diabetic human adipose tissue explants and in human primary muscle cell culture in a dose dependent Vemurafenib manner. Ad36 requires Ras mediated activation of phosphatidyl inositol 3-kinase , to increase cellular glucose uptake. Collectively, these data reveal anti-hyperglycemic properties of Ad36,that are clinically relevant to humans, and offer a tool to develop new anti-diabetic agents. Harnessing certain properties of viruses for beneficial purposes has been creatively used for several years. For example, anti-bacterial properties of bacteriophage virus , the oncolytic ability of a mutant adenovirus , or the use of Herpes simplex virus and several other viruses for lysing cancer cells , have been used alone, or with various synergistic drugs. Clearly, infection with Ad36 is not a viable treatment option. Instead, identifying the viral protein responsible for Ad36- induced glucose disposal is the next step in harnessing the antihyperglycemic potential of the virus for therapeutic purpose. Adenoviruses have a set of several early genes that encode proteins for evading the host immune system and changing cell function for favorable viral replication, and several late genes, that encode structural proteins required for viral particle assembly. This study identified the Ad36 gene that mediates the glucose disposal induced by the virus. Considering that Ad36 requires Ras/PI3K pathway for enhancing glucose uptake , we focused on E4orf1 gene of the virus that up-regulates this pathway. The E4orf1 gene of Ad36 is transcribed from the first open reading frame of Ad36 early gene 4, and yields a 17 kDa, 125 amino acid protein, and has a PBM through which it interacts with other proteins containing PDZ regions for scaffolding. E4orf1 is necessary and sufficient for Ad36 to activate the PI3K pathway , and its PBM is required for the effect. E4orf1 protein of Ad9, a closely related adenovirus, stimulates Ras-mediated PI3K activation , via the interaction of its PBM with Dlg1 protein. In Ad36 infected animals, E4orf1 is expressed in adipose tissue or livers , and its expression in the liver positively correlates with glycemic improvement in mice. This background provided the rationale to test the role of E4orf1 as the mediator of Ad36-induced glucose uptake, as outlined below.

Magnetic resonance imaging has been rated by leading general internists to be, together with computed tomography , the most important medical innovation of the last 25 years. However, MR imaging can be severely hampered by CT99021 GSK-3 inhibitor claustrophobia induced by confinement in the long narrow bore of conventional scanners and further unpleasant aspects of the examination such as scanner noise and vibration. Anxious patients suffer from claustrophobia during MR imaging in up to 35% of all cases , and claustrophobic events can lead to abortion of imaging or require sedation for its completion. This situation decreases diagnostic yield, limits patient acceptance, and reduces workflow. Moreover, conscious sedation to alleviate claustrophobia involves significant risks. Thus, claustrophobia is a common challenge for performing MR imaging and has been investigated in CPI-613 supply several large nonrandomized studies. It was found that between 1 and 15% of all MR examinations in unselected patients on conventional scanners cannot be completed because of claustrophobia or require conscious sedation to be completed. Cognitive behavioral treatment, as by exposure to claustrophobic stimuli, is one effective approach to face the problem. Structured empathic attention by trained staff and instructing patients to self-hypnotic relaxation have also shown to reduce anxiety during MR imaging and other medical procedures. However, such options may not usually be available. Another approach to lower the rate of claustrophobic events is thus to improve the design of MR scanners. Two recent concepts are a more open panoramic scanner and a short-bore configuration. We compared these two scanner configurations in a randomized controlled trial in patients with an increased risk for claustrophobic events in MR imaging. An event for the primary hypothesis was defined as the inability of a patient to complete an examination on the assigned MR scanner due to claustrophobia. Events were assessed by two research staff members who had to be present during MR imaging and thus could not be blinded to the study group. Secondary objectives were to analyze the duration of MR imaging, the time at which events occur during the MR examination, the predictive value of validated questionnaires and patient characteristics for claustrophobic events , and follow-up results. Recent short-bore and open panoramic scanners have the potential to reduce claustrophobia which is a common problem in MR imaging. In this first randomized controlled trial on claustrophobia in MRI both, short-bore and open, scanners showed disappointing event rates of more than 25%, irrespective of patient characteristics and the anatomical region being examined.

This same type of toxicity was observed in the rabbit IV infusions, in which the 5 minute LY2109761 TGF-beta inhibitor infusion of 60 mg/kg was the maximum-tolerated dose. At the end of the infusion of the dose, lethargy, labored breathing and narcosis were observed. All animals appeared to fully recover within 30�C60 minutes after the end of the infusion, again, coincident with the rapidly Axitinib decreasing plasma ST-246 concentrations. Oral administration had not elicited any dose limiting toxicity at 100 mg/kg in rabbits. In NHP, mild ataxia was observed in three out of four animals at the end of the infusion of the 30 mg/kg dose, but in none of the other doses or dosing regimens. In fact, ST-246 had been administered orally daily at 300 mg/kg for as long as three months and had been welltolerated at that dose. As was observed in mice and rabbits, the clinical signs were observed only at the end of the infusion of the highest dose. In NHP this was at the 30 mg/kg dose administered over 4 hours, coincident with the peak plasma concentrations, and resolved after a short period of time. Taken together, the observations of clinical signs at peak plasma concentrations in mice, rabbits, and cynomolgus monkeys after IV infusions of the highest dose level over the shortest time period and resolution of these toxicities coincident with the decrease in plasma concentrations strongly indicate that this observed toxicity was related to the high peak plasma concentrations. Further, the toxicity appears to be reversible, and was not observed when the plasma concentrations were kept at lower concentrations by slower infusion of equivalent doses of ST-246. Although the mechanism of this toxicity is not yet known, the same ataxia was previously observed after oral administration of doses in NHP, where the mean Cmax was approximately 20 mg/mL, similar to that observed after the 4-hour IV infusion of ST-246. This CNS toxicity was also observed at lower doses in the dog, where the maximum-tolerated dose for repeat dose administration for ST-246 was 30 mg/kg. A comparison of the ST-246 concentrations in the CSF and brain between NHP and dogs after comparable doses showed that the concentrations were much higher in the dogs, possibly explaining the unique sensitivity. In each of the species where this toxicity was observed, further investigations demonstrated that slower infusions eliminated the clinical observations, indicating that IV infusions in humans can be conducted safely by initiating any studies with low doses administered as slow IV infusions.

CLL is a heterogeneous disease with a highly variable clinical course and a number of molecular prognostic markers have been identified to help determine that course. Among these are VLA-4 and CD38, two surface molecules that are believed not only to be mere markers of disease aggressiveness but also to play a role in CLL pathogenesis. VLA-4 is the exclusive member of the a4 integrin subfamily expressed by CLL cells and has recently been identified as a negative prognostic marker in this disease. VLA-4 plays a key role in the retention of hematopoietic progenitors in BM stroma, which is required for normal early B cell development. The second prognostic indicator, CD38, is a promiscuous glycoprotein that functions as an ectoenzyme, a surface receptor, and an adhesion molecule. In CLL, CD38 ligation in the presence of IL-2 induces the survival and proliferation of the tumor cells. Furthermore, CLL cells expressing CD38 are thought to have enhanced migratory capacity. Because VLA-4 and CD38 BAY 73-4506 expression have been described to be highly associated in CLL, we sought to determine their functional consequences in the context of supportive BM niches. For this we employed in vivo adoptive transfers of human leukemic cells into immunodeficient mice, in vitro flow cytometrical phenotyping of peripheral blood – and BM-derived CLL cells, and stromal cell co-culture experiments. Moreover, the extent of BM infiltration in CLL patients was correlated to the VLA-4 and CD38 status. Our data suggest that VLA-4 but not CD38 expression plays a prominent role in the homing of high-risk CLL cells to supportive BM niches and in human BM infiltration but only a limited role in supportive CLL cell-stromal cell interactions in vitro. Emerging evidence suggests that the proliferation and survival of CLL cells is dependent on their interplay with accessory cells and molecular factors in supportive niches. It is therefore essential to define the molecular mechanisms underlying the trafficking of CLL cells into these niches. Among the plenitude of prognostic markers supposed to have a pathophysiological influence, VLA-4 and CD38 may be key players regulating tissue invasion and infiltration in CLL. Since the majority of CLL samples show associated VLA-4 and CD38 expression, their individual roles in CLL cell migration and interactions with supportive accessory cells are still unclear. Therefore, in this study, we particularly analyzed samples with discordant VLA-4/CD38 expression. Collectively, our data argue for a higher propensity of high-risk CLL cells to infiltrate supportive BM niches as a result of their VLA-4 rather than CD38 expression, but only a limited role of VLA-4 in malignant cell-GSK212 stroma interactions.

Preliminary results demonstrate that a specific blocker of CCR5 and CCR1 chemokine receptors, called met-RANTES, was able to decrease the experimental PD severity. However the mechanisms involved in such modulation, the ideal dose of met- RANTES to achieve the maximum remission of experimental PD, as well potential side effects concerning the infectious aspects of the disease remain unknown. Therefore, we initially performed a dose-response analysis of experimental PD outcome following met-RANTES therapy. The alveolar bone loss and inflammatory cell influx were used as the disease severity parameters, and the bacterial load in the periodontal tissues was used to monitor the control of infection. Except for the 0.05 mg dose, all the other doses resulted in a significant decrease of experimental PD severity. Interestingly, as a general rule a dose-response effect was identified in the attenuation of inflammatory cells influx, while a Kinase Inhibitor Library similar inhibition of bone resorption was achieved with the doses ranging from 0.5 up to 5 mg. The effectiveness of the met-RANTES in the control of inflammation-associated tissue damage is in agreement with previous studies , but deeper TWS119 comparisons with other models are impaired by the relatively low number of previous studies, performed in quite different experimental models usually investigating one or at most two different met-RANTES doses within a narrow interval. Interestingly, the PD treatment with 5 mg of met-RANTES dose impaired the control of periodontal infection, evidencing to distinct situations, where similar protective effects from the tissue destruction viewpoint are associated with distinct infectious outcomes. Therefore, in order to investigate the mechanisms underlying such differential response, the experimental groups receiving met-RANTES doses of 0.5 and 5 mg were selected for the further analysis. The first scenario, represented by the 0.5 mg met-RANTES protocol, can be interpreted as a clinically desired situation, where the tissue damage was minimized without interfering with host defense process. In fact, the 0.5 mg met-RANTES dose was effective in reducing F4/80 and CD3 cells , which present CCR1 and CCR5 receptor in its membranes, and also was observed a reduction in the tissue levels of pro-inflammatory cytokines IL-1b, TNF-a and IL-6. These cytokines are classically implicated in the onset and progression of PD by its role in osteoclastogenic process , being the reduction in its levels compatible with the attenuation of the experimental disease severity observed. Accordingly, met- RANTES therapy target cells from the monocytic lineage, characteristic sources of IL-1b, TNF-a and IL-6.