955 resultados para School of Medicine Initiative
Resumo:
Nanoparticles and low-temperature plasmas have been developed, independently and often along different routes, to tackle the same set of challenges in biomedicine. There are intriguing similarities and contrasts in their interactions with cells and living tissues, and these are reflected directly in the characteristics and scope of their intended therapeutic solutions, in particular their chemical reactivity, selectivity against pathogens and cancer cells, safety to healthy cells and tissues and targeted delivery to diseased tissues. Time has come to ask the inevitable question of possible plasma–nanoparticle synergy and the related benefits to the development of effective, selective and safe therapies for modern medicine. This perspective paper offers a detailed review of the strengths and weakenesses of nanomedicine and plasma medicine as a stand-alone technology, and then provides a critical analysis of some of the major opportunities enabled by synergizing nanotechnology and plasma technology. It is shown that the plasma–nanoparticle synergy is best captured through plasma nanotechnology and its benefits for medicine are highly promising.
Resumo:
Large scale exome sequencing studies have revealed regions of the genome, which contribute to the castrate resistant prostate cancer (CRPC) phenotype. [1],[2],[3] Such studies have identified mutations in genes, which may have diagnostic/prognostic potential, or which may be targeted therapeutically. Two of these genes include the androgen receptor (AR) and speckle-type POZ protein (SPOP) genes. However, the findings from these exome sequencing studies can only be translated therapeutically once the functional consequences of these mutations have been determined. Here, we highlight the recent study by An et al. [4] which investigated the functional effects of mutations in the SPOP gene that were identified in the aforementioned exome sequencing studies, particularly in the context of SPOP-mediated degradation of the AR.
Resumo:
Prescription medicine samples (or starter packs) are provided by pharmaceutical manufacturers to prescribing doctors as one component in the suite of marketing products used to convince them to prescribe a particular medicine [1,2]. Samples are generally newer, more expensive treatment options still covered by patent [3,4]. Safe, effective, judicious and appropriate medicine use (quality use of medicines) [5] could be enhanced by involving community pharmacists in the dispensing of starter packs. Doctors who use samples show a trend towards prescribing more expensive medicines overall [6] and also prescribe more medicines [7]. Cardiovascular health and mental health are Australian National Health Priority Areas [8] and account for approximately 30% and 17%, respectively, of annual government Pharmaceutical Benefits System (PBS) in 2006 [9]. The PBS is Australia's universal prescription subsidy scheme [9]. Antihypertensives were a major contributor to the estimated 80 000 medicine-related hospital admissions in Australia in 1999 [10] and also internationally [11,12]. The aim of this study was to pilot an alternative model for supply of free sample or starter packs of prescription medicines and ascertain if it is a viable model in daily practice.
Resumo:
Background Heatwaves have a significant impact on population health including both morbidity and mortality. In this study we examined the association between heatwaves and emergency hospital admissions (EHAs) for renal diseases in children (aged 0–14 years) in Brisbane, Australia. Methods Daily data on EHAs for renal diseases in children and exposure to temperature and air pollution were obtained for Brisbane city from January 1, 1996 to December 31, 2005. A time-stratified case-crossover design was used to compare the risks for renal diseases between heatwave and non-heatwave periods. Results There were 1565 EHAs for renal diseases in children during the study period. Heatwaves exhibited a significant impact on EHAs for renal diseases in children after adjusting for confounding factors (odds ratio: 3.6; 95% confidence interval: 1.4–9.5). The risk estimates differed with lags and the use of different heatwave definitions. Conclusions There was a significant increase in EHAs for renal diseases in children during heatwaves in Brisbane, a subtropical city where people are well accustomed to warm weather. This finding may have significant implications for pediatric renal care, particularly in subtropical and tropical regions.
Resumo:
Objective: To study the anisotropic mechanical properties of the thoracic aorta in porcine. Methods: Twenty-one porcine thoracic aortas were collected and categorized into three groups. The aortas were then cut through in their axial directions and expanded into two-dimensional planes. Then, by setting the length direction of the planar aortas (i.e., axial directions of the aortas) as 0°, each planar aorta was counterclockwisely cut into 8 samples with orientation of 30°, 45°, 60°, 90°, 120°, 135°, 150° and 180°, respectively. Finally, the uniaxial tensile tests were applied on three groups of samples at the loading rates of 1, 5 and 10 mm/min, respectively, to obtain the elastic modulus and ultimate stress of the aorta in different directions and at different loading rates. Results: The stress-strain curves exhibited different viscoelastic behaviors. With the increase of sample orientations, the elastic modulus gradually increased from 30°, reached the maximum value at 90°, and then gradually decreased till 180°. The variation trend of ultimate stress was similar to that of elastic modulus. Moreover, different loading rates showed a significant influence on the results of elastic modulus and ultimate stress, but a weak influence on the anisotropic degree. Conclusions: The porcine thoracic aorta is highly anisotropic. This research finding provides parameter references for assignment of material properties in finite element modeling, and is significant for understanding biomechanical properties of the arteries.
Resumo:
Objective: To compare the differences in the hemodynamic parameters of abdominal aortic aneurysm (AAA) between fluid-structure interaction model (FSIM) and fluid-only model (FM), so as to discuss their application in the research of AAA. Methods: An idealized AAA model was created based on patient-specific AAA data. In FM, the flow, pressure and wall shear stress (WSS) were computed using finite volume method. In FSIM, an Arbitrary Lagrangian-Eulerian algorithm was used to solve the flow in a continuously deforming geometry. The hemodynamic parameters of both models were obtained for discussion. Results: Under the same inlet velocity, there were only two symmetrical vortexes in the AAA dilation area for FSIM. In contrast, four recirculation areas existed in FM; two were main vortexes and the other two were secondary flow, which were located between the main recirculation area and the arterial wall. Six local pressure concentrations occurred in the distal end of AAA and the recirculation area for FM. However, there were only two local pressure concentrations in FSIM. The vortex center of the recirculation area in FSIM was much more close to the distal end of AAA and the area was much larger because of AAA expansion. Four extreme values of WSS existed at the proximal of AAA, the point of boundary layer separation, the point of flow reattachment and the distal end of AAA, respectively, in both FM and FSIM. The maximum wall stress and the largest wall deformation were both located at the proximal and distal end of AAA. Conclusions: The number and center of the recirculation area for both models are different, while the change of vortex is closely associated with the AAA growth. The largest WSS of FSIM is 36% smaller than that of FM. Both the maximum wall stress and largest wall displacement shall increase with the outlet pressure increasing. FSIM needs to be considered for studying the relationship between AAA growth and shear stress.
Resumo:
AMPA receptors are an important class of ionotropic glutamate receptors which participate in fast excitatory synaptic transmission in most brain areas. They have a pivotal role in adjustment of cell membrane excitability as their cell membrane expression levels is altered in brain physiology such as in learning and memory formation. AMPA receptor function and trafficking is regulated by several proteins, such as transmembrane AMPA receptor regulatory proteins (TARPs). NMDA-type glutamate receptors are important target molecules of ethanol. The role of AMPA receptors in the actions of ethanol has not been clarified as thoroughly. Furthermore, the regulation of AMPA receptor synthesis and their possible adaptation in neurons with altered inhibitory mechanisms are poorly understood. In this thesis work AMPA receptor pharmacology, trafficking and synaptic localization was studied using patch-clamp electrophysiology. Both native and recombinant AMPA receptors were studied. Hippocampal slices from transgenic Thy1alfa6 mice with altered inhibition were used to study adaptation of AMPA receptors. Ethanol was found to inhibit AMPA receptor function by increasing desensitization of the receptor, as the steady-state current was inhibited more than the peak current. Ethanol inhibition was reduced when cyclothiazide was used to block desensitization and when non-desensitizing mutant receptors were studied. Ethanol also increased the rate of desensitization, which was increased further by the coexpression of TARP-proteins. We found that the agonist binding capability is important for trafficking AMPA receptors from endoplasmic reticulum to the cell membrane. TARP rescues the surface expression of non-binding AMPA receptor mutants in HEK293 cells, but not in native neurons. Studies with Thy1alfa6 mice revealed that decreased inhibition decrease AMPA receptor mediated excitation keeping the neurotransmission in balance. Thy1alfa6 mice also had lower sensitivity to electroshock convulsions, presumably due to the decreased AMPA receptor function. The results suggest that during alcohol intoxication ethanol may inhibit AMPA receptors by increasing the rate and the extent of desensitization. TARPs appear to enhance ethanol inhibition. TARPs also participate in trafficking of AMPA receptors upon their synthesis in the cell. AMPA receptors mediate also long-term adaptation to altered neuronal excitability, which adds to their well-known role in synaptic plasticity.
Resumo:
Some leucine-rich repeat (LRR) -containing membrane proteins are known regulators of neuronal growth and synapse formation. In this work I characterize two gene families encoding neuronal LRR membrane proteins, namely the LRRTM (leucine-rich repeat, transmembrane neuronal) and NGR (Nogo-66 receptor) families. I studied LRRTM and NGR family member's mRNA tissue distribution by RT-PCR and by in situ hybridization. Subcellular localization of LRRTM1 protein was studied in neurons and in non-neuronal cells. I discovered that LRRTM and NGR family mRNAs are predominantly expressed in the nervous system, and that each gene possesses a specific expression pattern. I also established that LRRTM and NGR family mRNAs are expressed by neurons, and not by glial cells. Within neurons, LRRTM1 protein is not transported to the plasma membrane; rather it localizes to endoplasmic reticulum. Nogo-A (RTN4), MAG, and OMgp are myelin-associated proteins that bind to NgR1 to limit axonal regeneration after central nervous system injury. To better understand the functions of NgR2 and NgR3, and to explore the possible redundancy in the signaling of myelin inhibitors of neurite growth, I mapped the interactions between NgR family and the known and candidate NgR1 ligands. I identified high-affinity interactions between RTN2-66, RTN3-66 and NgR1. I also demonstrate that Rtn3 mRNA is expressed in the same glial cell population of mouse spinal cord white matter as Nogo-A mRNA, and thus it could have a role in myelin inhibition of axonal growth. To understand how NgR1 interacts with multiple structurally divergent ligands, I aimed first to map in more detail the nature of Nogo-A:NgR1 interactions, and then to systematically map the binding sites of multiple myelin ligands in NgR1 by using a library of NgR1 expression constructs encoding proteins with one or multiple surface residues mutated to alanine. My analysis of the Nogo-A:NgR1 -interactions revealed a novel interaction site between the proteins, suggesting a trivalent Nogo-A:NgR1-interaction. Our analysis also defined a central binding region on the concave side of NgR1's LRR domain that is required for the binding of all known ligands, and a surrounding region critical for binding MAG and OMgp. To better understand the biological role of LRRTMs, I generated Lrrtm1 and Lrrtm3 knock out mice. I show here that reporter genes expressed from the targeted loci can be used for maping the neuronal connections of Lrrtm1 and Lrrtm3 expressing neurons in finer detail. With regard to LRRTM1's role in humans, we found a strong association between a 70 kb-spanning haplotype in the proposed promoter region of LRRTM1 gene and two possibly related phenotypes: left-handedness and schizophrenia. Interestingly, the responsible haplotype was linked to phenotypic variability only when paternally inherited. In summary, I identified two families of neuronal receptor-like proteins, and mapped their expression and certain protein-protein interactions. The identification of a central binding region in NgR1 shared by multiple ligands may facilitate the design and development of small molecule therapeutics blocking binding of all NgR1 ligands. Additionally, the genetic association data suggests that allelic variation upstream of LRRTM1 may play a role in the development of left-right brain asymmetry in humans. Lrrtm1 and Lrrtm3 knock out mice developed as a part of this study will likely be useful for schizophrenia and Alzheimer s disease research.
Resumo:
Aims: To gain insight on the immunological processes behind cow’s milk allergy (CMA) and the development of oral tolerance. To furthermore investigate the associations of HLA II and filaggrin genotypes with humoral responses to early oral antigens. Methods: The study population was from a cohort of 6209 healthy, full-term infants who in a double-blind randomized trial received supplementary feeding at maternity hospitals (mean duration 4 days): cow’s milk (CM) formula, extensively hydrolyzed whey formula or donor breast milk. Infants who developed CM associated symptoms that subsided during elimination diet (n=223) underwent an open oral CM challenge (at mean age 7 months). The challenge was negative in 112, and in 111 it confirmed CMA, which was IgE-mediated in 83. Patients with CMA were followed until recovery, and 94 of them participated in a follow-up study at age 8-9 years. We investigated serum samples at diagnosis (mean age 7 months, n=111), one year later (19 months, n=101) and at follow-up (8.6 years, n=85). At follow-up, also 76 children randomly selected from the original cohort and without CM associated symptoms were included. We measured CM specific IgE levels with UniCAP (Phadia, Uppsala, Sweden), and β-lactoglobulin, α-casein and ovalbumin specific IgA, IgG1, IgG4 and IgG levels with enzyme-linked immunosorbent assay in sera. We applied a microarray based immunoassay to measure the binding of IgE, IgG4 and IgA serum antibodies to sequential epitopes derived from five major CM proteins at the three time points in 11 patients with active IgE-mediated CMA at age 8-9 years and in 12 patients who had recovered from IgE-mediated CMA by age 3 years. We used bioinformatic methods to analyze the microarray data. We studied T cell expression profile in peripheral blood mononuclear cell (PBMC) samples from 57 children aged 5-12 years (median 8.3): 16 with active CMA, 20 who had recovered from CMA by age 3 years, 21 non-atopic control subjects. Following in vitro β-lactoglobulin stimulation, we measured the mRNA expression in PBMCs of 12 T-cell markers (T-bet, GATA-3, IFN-γ, CTLA4, IL-10, IL-16, TGF-β, FOXP3, Nfat-C2, TIM3, TIM4, STIM-1) with quantitative real time polymerase chain reaction, and the protein expression of CD4, CD25, CD127, FoxP3 with flow cytometry. To optimally distinguish the three study groups, we performed artificial neural networks with exhaustive search for all marker combinations. For genetic associations with specific humoral responses, we analyzed 14 HLA class II haplotypes, the PTPN22 1858 SNP (R620W allele) and 5 known filaggrin null mutations from blood samples of 87 patients with CMA and 76 control subjects (age 8.0-9.3 years). Results: High IgG and IgG4 levels to β-lactoglobulin and α-casein were associated with the HLA (DR15)-DQB1*0602 haplotype in patients with CMA, but not in control subjects. Conversely, (DR1/10)-DQB1*0501 was associated with lower IgG and IgG4 levels to these CM antigens, and to ovalbumin, most significantly among control subjects. Infants with IgE-mediated CMA had lower β -lactoglobulin and α-casein specific IgG1, IgG4 and IgG levels (p<0.05) at diagnosis than infants with non-IgE-mediated CMA or control subjects. When CMA persisted beyond age 8 years, CM specific IgE levels were higher at all three time points investigated and IgE epitope binding pattern remained stable (p<0.001) compared with recovery from CMA by age 3 years. Patients with persisting CMA at 8-9 years had lower serum IgA levels to β-lactoglobulin at diagnosis (p=0.01), and lower IgG4 levels to β-lactoglobulin (p=0.04) and α-casein (p=0.05) at follow-up compared with patients who recovered by age 3 years. In early recovery, signal of IgG4 epitope binding increased while that of IgE decreased over time, and binding patterns of IgE and IgG4 overlapped. In T cell expression profile in response to β –lactoglobulin, the combination of markers FoxP3, Nfat-C2, IL-16, GATA-3 distinguished patients with persisting CMA most accurately from patients who had become tolerant and from non-atopic subjects. FoxP3 expression at both RNA and protein level was higher in children with CMA compared with non-atopic children. Conclusions: Genetic factors (the HLA II genotype) are associated with humoral responses to early food allergens. High CM specific IgE levels predict persistence of CMA. Development of tolerance is associated with higher specific IgA and IgG4 levels and lower specific IgE levels, with decreased CM epitope binding by IgE and concurrent increase in corresponding epitope binding by IgG4. Both Th2 and Treg pathways are activated upon CM antigen stimulation in patients with CMA. In the clinical management of CMA, HLA II or filaggrin genotyping are not applicable, whereas the measurement of CM specific antibodies may assist in estimating the prognosis.
Resumo:
Pheromones are chemical cues released and sensed by individuals of the same species, which are of major importance in regulating reproductive and social behaviors of mammals. Generally, they are detected by the vomeronasal system (VNS). Here, we first investigated and compared an essential genetic component of vomeronasal chemoreception, that is, TRPC2 gene, of four marine mammals varying the degree of aquatic specialization and related terrestrial species in order to provide insights into the evolution of pheromonal olfaction in the mammalian transition from land to water. Our results based on sequence characterizations and evolutionary analyses, for the first time, show the evidence for the ancestral impairment of vomeronasal pheromone signal transduction pathway in fully aquatic cetaceans, supporting a reduced or absent dependence on olfaction as a result of the complete adaptation to the marine habitat, whereas the amphibious California sea lion was found to have a putatively functional TRPC2 gene, which is still under strong selective pressures, reflecting the reliance of terrestrial environment on chemical recognition among the semiadapted marine mammals. Interestingly, our study found that, unlike that of the California sea lion, TRPC2 genes of the harbor seal and the river otter, both of which are also semiaquatic, are pseudogenes. Our data suggest that other unknown selective pressures or sensory modalities might have promoted the independent absence of a functional VNS in these two species. In this respect, the evolution of pheromonal olfaction in marine mammals appears to be more complex and confusing than has been previously thought. Our study makes a useful contribution to the current understanding of the evolution of pheromone perception of mammals in response to selective pressures from an aquatic environment.
Resumo:
S.J. Cox, S. Neethling and H. Wilson (2008) British Society of Rheology mid-winter meeting on The Rheology of Foams and Emulsions. Applied Rheology 18:93-95