Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus

<p>Abstract</p> <p>Background</p> <p>Sublethal doses of whole brain irradiation (WBI) are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ) of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS) has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE) inhibitor, ramipril, as a mitigator of radiation injury in this context.</p> <p>Methods</p> <p>Adult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks.</p> <p>Results</p> <p>Ramipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats.</p> <p>Conclusions</p> <p>Our results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory disruption of neurogenic signaling within SGZ microenvironment, and suggest that angiotensin II may participate in maintaining the basal rate of granule cell neurogenesis.</p

Neglected Tropical Diseases and the Millennium Development Goals-why the "other diseases" matter: reality versus rhetoric

Since 2004 there has been an increased recognition of the importance of Neglected Tropical Diseases (NTDs) as impediments to development. These diseases are caused by a variety of infectious agents - viruses, bacteria and parasites - which cause a diversity of clinical conditions throughout the tropics. The World Health Organisation (WHO) has defined seventeen of these conditions as core NTDs. The objectives for the control, elimination or eradication of these conditions have been defined in World Health Assembly resolutions whilst the strategies for the control or elimination of individual diseases have been defined in various WHO documents. Since 2005 there has been a drive for the expanded control of these diseases through an integrated approach of mass drug administration referred to as Preventive Chemotherapy via community-based distribution systems and through schools. This has been made possible by donations from major pharmaceutical companies of quality and efficacious drugs which have a proven track record of safety. As a result of the increased commitment of endemic countries, bilateral donors and non-governmental development organisations, there has been a considerable expansion of mass drug administration. In particular, programmes targeting lymphatic filariasis, onchocerciasis, schistosomiasis, trachoma and soil transmitted helminth infections have expanded to treat 887. 8 million people in 2009. There has been significant progress towards guinea worm eradication, and the control of leprosy and human African trypanosomiasis. This paper responds to what the authors believe are inappropriate criticisms of these programmes and counters accusations of the motives of partners made in recently published papers. We provide a detailed response and update the information on the numbers of global treatments undertaken for NTDs and list the success stories to date

POISEUILLE FLOW OF A POWER-LAW FLUID BETWEEN COAXIAL CYLINDERS

An analytical expression is derived, which permits direct evaluation of the volumetric flow rate or the pressure gradient for the laminar flow of a power-law fluid in a concentric annulus. The derivation is valid for tangential as well as axial flow, provided a parameter q, in the problem formulation, is substituted by appropriate binary values. The final flow rate solution is in the form of an elegant algebraic equation (not a definite integral) and holds for all values of the power-law index (not merely reciprocal integers). Attention is focused on the tangential pressure flow problem, where the zero-shear plane does not coincide with the location of the maximum velocity

Unified conceptual approach to targeting and design of water and hydrogen networks

An algorithm is proposed to target the minimum freshwater for fixed flow rate (FF) problems in single-contaminant water networks. The approach is based on an extension of the limiting composite curve concept proposed earlier for fixed contaminant-load (FC) problems. The targeting method is elegant, noniterative, and can be applied to FF problems involving regeneration to minimize waste discharge. To design networks that achieve the minimum freshwater targets set for FF problems, an algorithm is presented based on the principle of nearest neighbors. The principle simply states that the sources to be chosen to satisfy a particular water demand must be the nearest available neighbors in terms of contaminant concentration. A significant advantage of the approach is that the same targeting concepts can be profitably used to determine the minimum makeup utility in hydrogen networks. Furthermore, hydrogen networks may be designed by the unified conceptual approach using the nearest neighbors algorithm. The hydrogen networks may then be evolved to account for the pressure constraints imposed by compressors or improved by regeneration through purification processes such as pressure-swing adsorption. (c) 2005 American Institute of Chemical Engineers

Aggregate planning in supply chains by pinch analysis

This work presents a novel extension of the targeting methods front pinch analysis to aggregate planning in supply chains. Aggregate planning aims at meeting demand over a specified time horizon in a way that maximizes profit through optimal levels of production, capacity, subcontracting, inventory, and stockouts. It is demonstrated how minimum production rates for a given demand forecast may be targeted through composite curves on a time versus material quantity plot. The grand composite curve (GCC) representation may be conveniently used to depict how surpluses and shortages in inventory fluctuate over time. The pinch corresponds to the point of minimum lead time and zero inventory. An example problem is used to illustrate the approach. The initial aggregate plan from pinch analysis exactly matches the solution reported in literature obtained by solving a linear programming formulation. On the other hand, the final aggregate plans from the pinch targeting method are superior to the solution in literature, as they are more realistic. It may be concluded that the production composite determined by the pinch targeting method provides either the best aggregate plan or an excellent starting point to reduce computational time for a solution by mixed integer linear programming

GENERALIZED ANNULAR COUETTE-FLOW OF A POWER-LAW FLUID

The steady laminar axial flow of a power-law non-Newtonian fluid in the annular space between two long coaxial cylinders, with one of them in motion and an imposed pressure gradient, is studied. The pressure gradient may assist or oppose the drag on the fluid due to the moving cylinder. Expressions for the volume rate of flow are derived analytically for two cases, one in which there is a maximum or minimum in the velocity profile within the annular region of interest and another in which there is not. A quantitative criterion is established to distinguish between these two cases. The solutions allow direct calculation of the volumetric flow rate for all values of the annulus aspect ratio, the power-law index, and the dimensionless pressure gradient parameter

Targeting and design of water networks for fixed flowrate and fixed contaminant load operations

Water-using processes are typically modeled as either fixed flowrate operations or fixed contaminant load operations. A new method for targeting the minimum freshwater and pinch in a single-contaminant water network is proposed, which can be applied to both kinds of operations. The method consists of plotting separate source and demand composites with flowrate as the horizontal axis and contaminant load unusually as the vertical axis. It is elegant, non-iterative, and can handle hybrid problems where both kinds of operations coexist. To design minimum freshwater networks for fixed flowrate problems, an algorithm is presented based on a newly developed principle of nearest neighbors. The principle simply states that the source streams to be chosen to satisfy a particular water demand must be the nearest available neighbors in terms of contaminant concentration. To design minimum freshwater networks for fixed contaminant load problems, the nearest neighbors algorithm is applied to process units that lie across the pinch. Units that lie entirely on one side of the pinch are satisfied by the cleanest source available on that side of the pinch. In other words, below-pinch units are satisfied by freshwater and above-pinch units are satisfied by the cleanest available stream above the pinch. Designs based on this methodology, apart from meeting the minimum freshwater target, also minimize the water flowing through the process units resulting in reduced network capital cost. (C) 200

Targeting for multiple resources

The source composite curve is useful in simultaneously setting targets for the minimum freshwater requirement and minimum effluent treatment. The source composite curve also helps in reducing waste production for a variety of applications. In this paper, a methodology is developed to target multiple resources through the source composite curve in order to minimize the operating cost of the overall process. It is observed that it is not necessary to maximize the usage of the resource with the minimum unit cost. Hence, a prioritized cost for each resource is devised to select appropriate resources that minimize the operating cost subject to the availability of the resources

MODELING VARYING-HEAT-TRANSFER-AREA BATCH PROCESSES

Analytical equations are developed for heating and cooling of liquid batches, where the volume changes with time. Both reacting and nonreacting batches, as well as isothermal and nonisothermal exchange media, are considered. The operations of evaporation and exothermic chemical reaction are discussed as typical examples of batch heating and batch cooling. Previous effort at modeling varying-heat-transfer-area batch processes involved the use of a chart, and the calculations required graphical/numerical integration in the case of a nonisothermal exchange medium; here, analytical solutions are presented for the time dependence of the batch volume and the heat transfer rate. Furthermore, the previously made assumption of the arithmetic mean for the temperature driving force is shown to be unnecessary, as the log-mean temperature difference leads to a simple, appropriate analysis