Corporate Financing in Great Britain

Background: The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA). Methodology/Principal Findings: The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 mu M, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 mu M. Conclusions/Significance: The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer

On a Constitutive Material Model to Capture Time Dependent Behaviour of Cortical Bone

It is commonly known that cortical bone exhibits viscoelastic-viscoplastic behavior which affects the biomechanical response when an implant is subjected to an external load. In addition, long term effects such as creep, relaxation and remodeling affect the success of the implant over time. Constitutive material models are commonly derived from data obtained in\ua0in vitro\ua0experiments. However during function, remodeling of bone greatly affects the bone material over time. Hence it is essential to include long term\ua0in vivo\ua0effects in a constitutive model of bone. This paper proposes a constitutive material model for cortical bone incorporating viscoelasticity, viscoplasticity, creep and remodeling to predict stress-strain at various strain rates as well as the behavior of bone over time\ua0in vivo. The rheological model and its parameters explain the behavior of bone subjected to longitudinal loading. By a proper set of model parameters, for a specific cortical bone, the present model can be used for prediction of the behavior of this bone under specific loading conditions. In addition simulation with the proposed model demonstrates excellent agreement to\ua0in vitro\ua0and\ua0in vivo\ua0experimental results in the literature

An in vitro Study of Drug-induced Degranulation of Human HMC-1 Mast Cells and Rat RBL-2H3 Cells

ABSTRACT Neither codeine nor compound 48/80 produced any significant basophil or mast cell degranulation, whereas the calcium ionophore A23187 triggered a degranulation of both cell lines. In conclusion, none of the cell lines are useful as relevant, robust and reproducible in vitro models to study drug-induced mast cell degranulation.

Mining metadata from unidentified ITS sequences in GenBank: A case study in Inocybe (Basidiomycota)

<p>Abstract</p> <p>Background</p> <p>The lack of reference sequences from well-identified mycorrhizal fungi often poses a challenge to the inference of taxonomic affiliation of sequences from environmental samples, and many environmental sequences are thus left unidentified. Such unidentified sequences belonging to the widely distributed ectomycorrhizal fungal genus <it>Inocybe </it>(<it>Basidiomycota</it>) were retrieved from GenBank and divided into species that were identified in a phylogenetic context using a reference dataset from an ongoing study of the genus. The sequence metadata of the unidentified <it>Inocybe </it>sequences stored in GenBank, as well as data from the corresponding original papers, were compiled and used to explore the ecology and distribution of the genus. In addition, the relative occurrence of <it>Inocybe </it>was contrasted to that of other mycorrhizal genera.</p> <p>Results</p> <p>Most species of <it>Inocybe </it>were found to have less than 3% intraspecific variability in the ITS2 region of the nuclear ribosomal DNA. This cut-off value was used jointly with phylogenetic analysis to delimit and identify unidentified <it>Inocybe </it>sequences to species level. A total of 177 unidentified <it>Inocybe </it>ITS sequences corresponding to 98 species were recovered, 32% of which were successfully identified to species level in this study. These sequences account for an unexpectedly large proportion of the publicly available unidentified fungal ITS sequences when compared with other mycorrhizal genera. Eight <it>Inocybe </it>species were reported from multiple hosts and some even from hosts forming arbutoid or orchid mycorrhizae. Furthermore, <it>Inocybe </it>sequences have been reported from four continents and in climate zones ranging from cold temperate to equatorial climate. Out of the 19 species found in more than one study, six were found in both Europe and North America and one was found in both Europe and Japan, indicating that at least many north temperate species have a wide distribution.</p> <p>Conclusion</p> <p>Although DNA-based species identification and circumscription are associated with practical and conceptual difficulties, they also offer new possibilities and avenues for research. Metadata assembly holds great potential to synthesize valuable information from community studies for use in a species and taxonomy-oriented framework.</p

Implant stability and bone remodeling up to 84 days of implantation with an initial static strain. An in vivo and theoretical investigation

ObjectivesWhen implants are inserted, the initial implant stability is dependent on the mechanical stability. To increase the initial stability, it was hypothesized that bone condensation implants will enhance the mechanical stability initially and that the moderately rough surface will further contribute to the secondary stability by enhanced osseointegration. It was further hypothesized that as the healing progresses the difference in removal torque will diminish. In addition, a 3D model was developed to simulate the interfacial shear strength. This was converted to a theoretical removal torque that was compared to the removal torque obtained invivo. Material and methodsCondensation implants, inducing bone strains of 0.015, were installed into the left tibia of 24 rabbits. Non-condensation implants were installed into the right tibia. All implants had a moderately rough surface. The implants had an implantation time of 7, 28, or 84days before the removal torque was measured. The interfacial shear strength at different healing time was estimated by the means of finite element method. ResultsAt 7days of healing, the condensation implant had an increased removal torque compared to the non-bone-condensation implant. At 28 and 84days of healing, there was no difference in removal torque. The simulated interfacial shear strength ratios of bone condensation implants at different implantation time were in line with the invivo data. ConclusionsModerately rough implants that initially induce bone strain during installation have increased stability during the early healing period. In addition, the finite element method may be used to evaluate differences in interlocking capacity

Differences at brain SPECT between depressed females with and without adult ADHD and healthy controls: etiological considerations

<p>Abstract</p> <p>Background</p> <p>Comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and mood disorders is common. Alterations of the cerebellum and frontal regions have been reported in neuro-imaging studies of ADHD and major depression.</p> <p>Methods</p> <p>Thirty chronically depressed adult females of whom 16 had scores below, and 14 scores above, cut-offs on the 25-items Wender Utah Retrospective Scale (WURS-25) and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) were divided into subgroups designated "Depression" and "Depression + ADHD", respectively. Twenty-one of the patients had some audiological symptom, tinnitus and/or hearing impairment. The patients were investigated with other rating scales and ^99mTc-HMPAO SPECT. Controls for ^99mTc-HMPAO SPECT were 16 healthy females. SPECT was analyzed by both statistical parametric mapping (SPM2) and the computerized brain atlas (CBA). Discriminant analysis was performed on the volumes of interest generated by the CBA, and on the scores from rating scales with the highest group differences.</p> <p>Results</p> <p>The mean score of a depression rating scale (MADRS-S) was significantly lower in the "Depression" subgroup compared to in the "Depression + ADHD" subgroup. There was significantly decreased tracer uptake within the bilateral cerebellum at both SPM and CBA in the "Depression + ADHD" subgroup compared to in the controls. No decrease of cerebellar tracer uptake was observed in "Depression". Significantly increased tracer uptake was found at SPM within some bilateral frontal regions (Brodmann areas 8, 9, 10, 32) in the "Depression + ADHD" subgroup compared to in "Depression". An accuracy of 100% was obtained for the discrimination between the patient groups when thalamic uptake was used in the analysis along with scores from Socialization and Impulsivity scales.</p> <p>Conclusion</p> <p>The findings confirm the previous observation of a cerebellar involvement in ADHD. Higher bilateral frontal ^99mTc-HMPAO uptake in "Depression + ADHD" compared to in "Depression" indicate a difference between these subgroups. ^99mTc-HMPAO uptake mechanisms are discussed.</p

Эндотелийзависимые механизмы формирования кислородтранспортной функции крови при окислительном стрессе

ЭНДОТЕЛИЙЭПИТЕЛИЙКРОВЬКИСЛОРОДА АКТИВНЫЕ ФОРМЫОКСИДАТИВНЫЙ СТРЕССОБМЕН ВЕЩЕСТВАНТИОКСИДАНТЫАЗОТА ОКСИД

High Tumour Cannabinoid CB1 Receptor Immunoreactivity Negatively Impacts Disease-Specific Survival in Stage II Microsatellite Stable Colorectal Cancer

BACKGROUND: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome. METHODOLOGY/PRINCIPAL FINDINGS: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and ≥2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB(1)IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 85±5 and 66±8%; tumour interior, 86±4% and 63±8% for the CB(1)IR<2 and CB(1)IR≥2 groups, respectively. CONCLUSIONS/SIGNIFICANCE: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients

Simulation of the mechanical interlocking capacity of a rough bone implant surface during healing

Background: When an implant is inserted in the bone the healing process starts to osseointegrate the implant by creating new bone that interlocks with the implant. Biomechanical interlocking capacity is commonly evaluated in in vivo experiments. It would be beneficial to find a numerical method to evaluate the interlocking capacity of different surface structures with bone. In the present study, the theoretical interlocking capacity of three different surfaces after different healing times was evaluated by the means of explicit finite element analysis. Methods: The surface topographies of the three surfaces were measured with interferometry and were used to construct a 3D bone-implant model. The implant was subjected to a displacement until failure of the bone-to-implant interface and the maximum force represents the interlocking capacity. Results: The simulated ratios (test/control) seem to agree with the in vivo ratios of Halldin et al. for longer healing times. However the absolute removal torque values are underestimated and do not reach the biomechanical performance found in the study by Halldin et al. which might be a result of unknown mechanical properties of the interface. Conclusion: Finite element analysis is a promising method that might be used prior to an in vivo study to compare the load bearing capacity of the bone-to-implant interface of two surface topographies at longer healing times