252 research outputs found
Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: a new window to study experimental spontaneous pain?
Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment.
In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10 ”g/50 ”l; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1 mg/50 ”l; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7 T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72 mm volume coil for excitation.
The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5 g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats
Chemical and biological factors in the control Brucella and Brucellosis
Brucellosis is a highly contagious bacterial zoonosis that affects millions of people worldwide. Brucella is highly infectious, especially when aerosolized. The infection induces severe protracted diseases, which are both debilitating and incapacitating, hence, Brucella melitensis has been considered a potential biological warfare agent. In the battle against Brucella, it is crucial to know its chemical-structure and biochemistry-metabolic characteristics. It is well known that Brucella, as well as many other intracellular bacterial pathogens, has evolved to survive and even proliferate within monocytes and macrophages cells. Depending on the route of entry (complement, Fc, lectin or fibronectin receptors), the fate of the bacteria will vary; it may even segregate from the endocytic route towards the endoplasmic reticulum. This intracellular ânon regularâ behaviour of Brucella makes treatment difficult. Most antibiotics, although effective in vitro, do not actively pass through cellular membranes, or, once inside, may not reach the discrete intracellular niche where the bacteria is hidden. Therefore, complete eradication of the microorganisms is difficult to achieve, and the incidence of relapses is rather high. Taking these data into consideration, this review will evaluate the past, current and new trends in the control of brucellosis, paying special attention to the drug delivery systems as potential vectors for targeting these intracellular sites where the organisms are located
Denitrification and Nitrous Oxide Emissions in Annual Croplands, Perennial Grass Buffers, and Restored Perennial Grasslands
Liberación controlada de principios activos mediante el empleo de formulaciones galénicas
Drugs inside a conventional galenic form are distributed between specific biological targets and other anatomical tissues. With the aim to obtain a more rational and a better therapeutic, one of the most promising possibilities by using the concept of vector- ization: association of an active principle to an appropriate vector with the object to increase its action efficiency and efficacy. By this means, they do not just increase the affinity of the drug to the target but also active principle gets protected from a potentially hos- tile environment (hydrolytic enzymes, acid pH, etc.). The success in the extension of the applications of the vectorizaciĂłn depends more and more of an appropriate design, for what the fundamental objective of this revision will be the one of presenting the general char- acteristics and some of the current applications in these new galenic forms.Los principios activos incluidos en una
forma galénica convencional se distribuyen indistintamente
entre dianas biolĂłgicas especĂficas y otros tejidos
anatómicos. Con el fin de obtener una terapéutica
mĂĄs racional y mejor adaptada, una de las posibilidades
mĂĄs prometedoras es la que utiliza el concepto
de vectorizaciĂłn: asociaciĂłn del principio activo a un
vector apropiado, con objeto de aumentar la eficacia y
la especificidad de acciĂłn del mismo. De esta manera,
no solo aumenta la afinidad del fĂĄrmaco por la diana,
sino que ademĂĄs queda protegido de un ambiente
potencialmente hostil (enzimas hidrolĂticas, pH ĂĄcido,
etc.). El Ă©xito en la extensiĂłn de las aplicaciones de la
vectorización depende cada vez mås de un diseño
adecuado, por lo que el objetivo fundamental de esta
revisiĂłn serĂĄ la de presentar las caracterĂsticas generales
y algunas de las actuales aplicaciones de estas
nuevas formas farmacéuticas
Predicting haemodynamic networks using electrophysiology: The role of non-linear and cross-frequency interactions
Understanding the electrophysiological basis of resting state networks (RSNs) in the human brain is a critical step towards elucidating how inter-areal connectivity supports healthy brain function. In recent years, the relationship between RSNs (typically measured using haemodynamic signals) and electrophysiology has been explored using functional Magnetic Resonance Imaging (fMRI) and magnetoencephalography (MEG). Significant progress has been made, with similar spatial structure observable in both modalities. However, there is a pressing need to understand this relationship beyond simple visual similarity of RSN patterns. Here, we introduce a mathematical model to predict fMRI-based RSNs using MEG. Our unique model, based upon a multivariate Taylor series, incorporates both phase and amplitude based MEG connectivity metrics, as well as linear and non-linear interactions within and between neural oscillations measured in multiple frequency bands. We show that including non-linear interactions, multiple frequency bands and cross-frequency terms significantly improves fMRI network prediction. This shows that fMRI connectivity is not only the result of direct electrophysiological connections, but is also driven by the overlap of connectivity profiles between separate regions. Our results indicate that a complete understanding of the electrophysiological basis of RSNs goes beyond simple frequency-specific analysis, and further exploration of non-linear and cross-frequency interactions will shed new light on distributed network connectivity, and its perturbation in pathology
Strategies to design clinical studies to identify predictive biomarkers in cancer research
The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological frameworkâthe DESIGN guidelinesâto standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field
Monitoring of the winter populations of cereal aphids near Wageningen, the Netherlands, in 1982/1983
Petrophysical, Geochemical, and Hydrological Evidence for Extensive Fracture-Mediated Fluid and Heat Transport in the Alpine Fault's Hanging-Wall Damage Zone
Fault rock assemblages reflect interaction between deformation, stress, temperature, fluid, and chemical regimes on distinct spatial and temporal scales at various positions in the crust. Here we interpret measurements made in the hanging-wall of the Alpine Fault during the second stage of the Deep Fault Drilling Project (DFDP-2). We present observational evidence for extensive fracturing and high hanging-wall hydraulic conductivity (âŒ10â9 to 10â7 m/s, corresponding to permeability of âŒ10â16 to 10â14 m2) extending several hundred meters from the fault's principal slip zone. Mud losses, gas chemistry anomalies, and petrophysical data indicate that a subset of fractures intersected by the borehole are capable of transmitting fluid volumes of several cubic meters on time scales of hours. DFDP-2 observations and other data suggest that this hydrogeologically active portion of the fault zone in the hanging-wall is several kilometers wide in the uppermost crust. This finding is consistent with numerical models of earthquake rupture and off-fault damage. We conclude that the mechanically and hydrogeologically active part of the Alpine Fault is a more dynamic and extensive feature than commonly described in models based on exhumed faults. We propose that the hydrogeologically active damage zone of the Alpine Fault and other large active faults in areas of high topographic relief can be subdivided into an inner zone in which damage is controlled principally by earthquake rupture processes and an outer zone in which damage reflects coseismic shaking, strain accumulation and release on interseismic timescales, and inherited fracturing related to exhumation
Weber and church governance: religious practice and economic activity
The debate about the relationship between religion and economic activity in the wake of Weber has been cast largely in terms of belief and values. This article suggests an alternative focus on practice. It argues that taken for granted practices of church governance formed to-hand resources for the organization of economic activity. The argument is developed through an examination of the historical development of church governance practices in the Presbyterian Church of Scotland, with particular emphasis on the way in which theological belief gave rise to practices of accountability and record keeping. In turn such practices contributed to a âculture of organizationâ which had implications for economic activity. A focus on governance practices can help to illuminate enduring patterns of difference in the organization of economic activity
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