Clinical use of CCR5 inhibitors in HIV and beyond

Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV-infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick-borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation

Design and innovation in successful product competition

This paper presents results from a project entitled ‘MArket Demands that Reward Investment in Design’ (MADRID). Among other aims, MADRID seeks to identify the contribution of design and innovation to product competitiveness in different markets. The paper provides a conceptual analysis of the role of design and innovation in product competition. The concepts are employed to conduct an analysis of a sample of new and redesigned products using data from a previous study on the ‘Commercial Impacts of Design’ (CID). CID was a study of over 220 design and product development projects in British SMEs which had received government financial support for design. The key conclusions from this re-analysis of the CID data are: in commercially successful product development projects more attention had been paid than in the loss-making projects to genuine product improvements rather than just styling or costs; commercially successful product development projects involved a multi-dimensional approach to design with a focus on product performance, features and build quality and, where relevant, technical or design innovation. Loss-making projects tended to involve a narrow, often styling-oriented, approach to design with more attention paid to cost reduction than to performance, quality and innovation

Infarto do miocárdio e acidente vascular cerebral associados à alta temperatura e monóxido de carbono em área metropolitana do sudeste do Brasil

Muito se tem publicado e discutido acerca de fatores de risco ligados a estilo de vida e a fatores hereditários em Acidente Vascular Cerebral (AVC) e Infarto do Miocárdio (IM). Porém o estudo da influência de fatores ambientais como poluição por monóxido de carbono e temperatura na determinação nas ocorrências dessas patologias ainda é pouco discutido em nosso meio. Visando preencher esta lacuna, foi verificada a associação existente entre os valores de temperaturas máximas diárias e valores médio e máximo diários de monóxido de carbono e AVC e IM no Município de São Paulo, SP (Brasil). Foi coletada uma série histórica do número de casos novos de AVC e IM atendidos em Pronto Socorro de um hospital de clínicas e valores de temperatura e monóxido de carbono. Conclui-se que das internações anuais por IM, 2,1% são devidos à poluição atmosférica e 4,9% a altas temperaturas. Das internações anuais por AVC, 2,8% são devidas a altas temperaturas. Não foi identificado associação entre monóxido de carbono e AVC.Many studies have been published about the relationship between life style and genetic risk factors and stroke and heart attack, but there have been few about the relationship between atmospheric pollution, specifically with carbon monoxide, and temperature and stroke and heart attack. With a view to filling this gap the relationship between values of carbon monoxide concentration in the air, maximum and average by day, and maximum temperature by day and the number of new cases of CVA and IM admitted as emergencies at the biggest hospital complex of S. Paulo city was analysed. If was concluded, by the use of multivariable regression analysis, that 2.1% and 4.9% of heart attack admissions were due to carbon monoxide air pollution and high temperature, respectively. 2.8% of stroke admissions were due high temperature. Stroke and carbon monoxide were not associated in this population

An exact solution on the ferromagnetic Face-Cubic spin model on a Bethe lattice

The lattice spin model with $Q$--component discrete spin variables restricted to have orientations orthogonal to the faces of $Q$-dimensional hypercube is considered on the Bethe lattice, the recursive graph which contains no cycles. The partition function of the model with dipole--dipole and quadrupole--quadrupole interaction for arbitrary planar graph is presented in terms of double graph expansions. The latter is calculated exactly in case of trees. The system of two recurrent relations which allows to calculate all thermodynamic characteristics of the model is obtained. The correspondence between thermodynamic phases and different types of fixed points of the RR is established. Using the technique of simple iterations the plots of the zero field magnetization and quadrupolar moment are obtained. Analyzing the regions of stability of different types of fixed points of the system of recurrent relations the phase diagrams of the model are plotted. For $Q \leq 2$ the phase diagram of the model is found to have three tricritical points, whereas for $Q> 2$ there are one triple and one tricritical points.Comment: 20 pages, 7 figure

Critical behavior of the two-dimensional N-component Landau-Ginzburg Hamiltonian with cubic anisotropy

We study the two-dimensional N-component Landau-Ginzburg Hamiltonian with cubic anisotropy. We compute and analyze the fixed-dimension perturbative expansion of the renormalization-group functions to four loops. The relations of these models with N-color Ashkin-Teller models, discrete cubic models, planar model with fourth order anisotropy, and structural phase transition in adsorbed monolayers are discussed. Our results for N=2 (XY model with cubic anisotropy) are compatible with the existence of a line of fixed points joining the Ising and the O(2) fixed points. Along this line the exponent $\eta$ has the constant value 1/4, while the exponent $\nu$ runs in a continuous and monotonic way from 1 to $\infty$ (from Ising to O(2)). For N\geq 3 we find a cubic fixed point in the region $u, v \geq 0$, which is marginally stable or unstable according to the sign of the perturbation. For the physical relevant case of N=3 we find the exponents $\eta=0.17(8)$ and $\nu=1.3(3)$ at the cubic transition.Comment: 14 pages, 9 figure

Analysis of her1 and her7 Mutants Reveals a Spatio Temporal Separation of the Somite Clock Module

Somitogenesis is controlled by a genetic network consisting of an oscillator (clock) and a gradient (wavefront). The “hairy and Enhancer of Split”- related (her) genes act downstream of the Delta/Notch (D/N) signaling pathway, and are crucial components of the segmentation clock. Due to genome duplication events, the zebrafish genome, possesses two gene copies of the mouse Hes7 homologue: her1 and her7. To better understand the functional consequences of this gene duplication, and to determine possible independent roles for these two genes during segmentation, two zebrafish mutants her1hu2124 and her7hu2526 were analyzed. In the course of embryonic development, her1hu2124 mutants exhibit disruption of the three anterior-most somite borders, whereas her7hu2526 mutants display somite border defects restricted to somites 8 (+/−3) to 17 (+/−3) along the anterior-posterior axis. Analysis of the molecular defects in her1hu2124 mutants reveals a her1 auto regulatory feedback loop during early somitogenesis that is crucial for correct patterning and independent of her7 oscillation. This feedback loop appears to be restricted to early segmentation, as cyclic her1 expression is restored in her1hu2124 embryos at later stages of development. Moreover, only the anterior deltaC expression pattern is disrupted in the presomitic mesoderm of her1hu2124 mutants, while the posterior expression pattern of deltaC remains unaltered. Together, this data indicates the existence of an independent and genetically separable anterior and posterior deltaC clock modules in the presomitic mesdorm (PSM)

Effects of Acute Ketamine Infusion on Visual Working Memory: Event-related Potentials

Background Working memory (WM) deficits are a core feature of schizophrenia. Electrophysiological studies suggest that impaired early visual processing may contribute to impaired WM in the visual domain. Abnormal N-methyl-D-aspartate (NMDA) receptor function has been implicated both in WM and in early visual processing deficits in schizophrenia. We investigated whether ketamine, a noncompetitive NMDA antagonist, would replicate in healthy volunteers the WM performance and early visual processing abnormalities we and others have reported in patients with schizophrenia. Methods Forty-four healthy volunteers were randomly assigned to receive intravenous ketamine or placebo. During infusion, the effects of ketamine were recorded using standardized psychiatric scales. Visual evoked potentials (P100 and P300 components) were recorded during performance of a delayed matching to sample task. Results Ketamine induced mild psychosis-like symptoms and impaired WM performance. It also significantly increased the P100 amplitude, while P300 amplitude decreased in a load-dependent manner. Amplitudes of P100 during retrieval correlated with cognitive performance only in the placebo group. Conclusions We confirmed previous studies showing that ketamine reproduces the impairment of WM performance and smaller P300 amplitudes observed in schizophrenia. However, ketamine increased visual P100 amplitude in contrast to our observation of reduced P100 amplitudes in established schizophrenia. The effects of ketamine on WM and P300 are likely to involve impaired NMDA function, as these receptors are implicated in changes of synaptic strength underlying associative learning and memory. Increased P100 amplitude may reflect the secondary disinhibition of cortical glutamate release that occurs after NMDA blockade

Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states

Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer\u27s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, \u27shape connections\u27 between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus

The Fitness Cost of Antibiotic Resistance in Streptococcus pneumoniae: Insight from the Field

Laboratory studies have suggested that antibiotic resistance may result in decreased fitness in the bacteria that harbor it. Observational studies have supported this, but due to ethical and practical considerations, it is rare to have experimental control over antibiotic prescription rates.We analyze data from a 54-month longitudinal trial that monitored pneumococcal drug resistance during and after biannual mass distribution of azithromycin for the elimination of the blinding eye disease, trachoma. Prescription of azithromycin and antibiotics that can create cross-resistance to it is rare in this part of the world. As a result, we were able to follow trends in resistance with minimal influence from unmeasured antibiotic use. Using these data, we fit a probabilistic disease transmission model that included two resistant strains, corresponding to the two dominant modes of resistance to macrolide antibiotics. We estimated the relative fitness of these two strains to be 0.86 (95% CI 0.80 to 0.90), and 0.88 (95% CI 0.82 to 0.93), relative to antibiotic-sensitive strains. We then used these estimates to predict that, within 5 years of the last antibiotic treatment, there would be a 95% chance of elimination of macrolide resistance by intra-species competition alone.Although it is quite possible that the fitness cost of macrolide resistance is sufficient to ensure its eventual elimination in the absence of antibiotic selection, this process takes time, and prevention is likely the best policy in the fight against resistance