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Te choice of design ards; to use research to infuence health policy also depends on the need to generalize from and practice; and to monitor and report on the one setting to another; results are more likely processes purchase 50 mg minocycline with mastercard, the outputs purchase 50 mg minocycline visa, the outcomes and impact generic minocycline 50 mg fast delivery. Although curiosity-driven investi- for instance, to assess the efcacy of drugs and gations have an essential place in the research vaccines (governed by physiological factors), but landscape, this report places high value on stud- observational studies are ofen used to resolve ies that address major health concerns and which operational questions about how drugs and respond to present and future gaps in service vaccines are best delivered by health services coverage and fnancial risk protection. Standard (infuenced by local systems and behaviours). To address the research age, it has also highlighted the co-benefts for priorities, once they have been chosen, inves- health of research done in other sectors, such as tigations are needed throughout the research 133 Research for universal health coverage cycle: measuring the size of the health problem; is easier in a common research language, understanding its cause(s); devising solutions; which would require a uniform and systematic translating the evidence into policy, practice approach to the classifcation, collection and and products; and evaluating efectiveness afer collation of data. Tose with a stake in Its purpose is to transmit the facts and fndings the research process are diverse; they include of health research in a standard way to sponsors, decision-makers, implementers, civil society, governments and the public; to identify gaps and funding agencies, pharmaceutical companies, opportunities for research, which are vital in set- product development partnerships, and research- ting research priorities; to carry out compara- ers themselves. Te roles of national and inter- ble analyses of the quality and productivity of national research funding agencies – who have research output; to identify instances of research substantial leverage – include promoting high collaboration; and to streamline peer review and standards of objectivity, rigour and account- scientifc recruitment. Te new trend is that Efective research requires transparent and long-established “north–south” links are being accountable methods for allocating funds, and supplemented by “south–south” collaboration. However, it is the people who do research tinue to be important because, for example, the who are most critical to the success of the research burden of noncommunicable diseases, up to now enterprise. Consequently, the process of build- largely a concern of the rich world, is growing ing research capacity should be spearheaded by in low-income countries. High-income countries staf recruitment and training, with mechanisms also have a pool of trained researchers from low- to retain the best researchers. Codes of between diferent kinds of international linkages research ethics have been written to uphold hon- is becoming less relevant. Connections of all esty, objectivity, integrity, justice, accountability, sorts are needed to enhance peer-to-peer learn- intellectual property, professional courtesy and ing, to foster joint research endeavours, and to fairness, and good stewardship of research on share resources. Te essential codes of practice as forces in research, initiating a multinational are already in use in many countries. Although collaboration, rather than simply joining as an internationally agreed standards will ofen need invited participant, is a statement of growing to be updated and adjusted to local circum- research confdence. When the too few formal publications of routine opera- fndings of research are turned into policy and tional research. Translational research could be boosted with Although a wide range of fundamental and stronger incentives for the research community. Incentives should Implementation and operational research, and make reference, not only to publications in high- health policy and systems research – bringing impact scientifc and medical journals, but also to scientists and decision-makers together – are measures of infuence on policy and practice. In making the link between research and To accelerate the process, research should be policy, private for-proft research companies (in strengthened not only in academic centres but areas such as biotechnology, pharmaceuticals, also in public health programmes that are close etc. A growing number of health Te greater the contact between researchers and products are being created through partner- policy-makers, the greater will be the mutual ships between the public and private sectors, understanding. A variety of methods can be used making explicit links between various organi- to train decision-makers to use evidence from zations involved in the discovery, development research, and to train researchers to understand and delivery of new technologies. Te use of data Chapter 2 described the role of DNDi in coordi- (especially the large volume of data that are col- nating the development of anthelmintic drugs by lected routinely), evidence and information can several pharmaceutical companies. It has been pointed out that civil positions where they can help to frame policy- society has a role in setting research priorities, related questions which lend themselves to spe- but public engagement in research should be cifc research studies, and to challenge decisions wider in scope. Staf rotations between health the source of government funds for research, are ministries and research institutions are an aid entitled to share in all aspects of the investiga- to communication, and research staf employed tive process; their continued backing depends on explicitly to carry out knowledge translation will being able to listen to, understand, believe in and help to bridge the gap. Public engagement via Te application of research fndings is the media, policy debates and open evaluations, more likely if there are formal procedures for works towards these ends. Making data publicly translating evidence into practice. Guidance on coordination essarily generate a useful health product, a useful could be provided by an international body, such product does not necessarily infuence health as a reconstituted WHO Advisory Committee on policy. Tis is because research is only one of the Health Research (the frst such advisory commit- determinants of policy. Furthermore, the factors tee was established in 1956). Whichever body is that infuence health policy are not necessarily responsible, it must represent the views of all con- the same as those that help turn policy into prac- cerned – researchers, funding agencies, private tice (11, 12). In addition to scientifc evidence, companies, and civil society and their representa- other considerations are cultural values, human tive governments in the countries concerned. Because donors and national governments should meas- policy and practice are subject to various infu- ure their commitments to investing in health ences, and are decided in the face of multiple research against defned criteria. Chapter 4 listed competing interests, robust and unbiased evi- some of the proposals that have been made – for dence ought to be valued by decision-makers. Some Supporting research for form of assessment is needed to judge whether investments are commensurate with achieving universal health coverage, universal health coverage. An improved support research for universal health coverage: system of fnancing might be newly created, or monitoring, coordination and fnancing. A the potential to manage research funds and dis- network of observatories could compile, analyse tribute them for research in low- and middle- and present data on fnancial fows for health income countries. As we have argued throughout this could chart progress on research for universal report, research for universal health coverage health coverage by measuring each of the ele- recognizes that health, and particularly preven- ments of the results chain, from inputs and pro- tion, depends on actions taken outside the health cesses, through outputs and outcomes, to health sector – in agriculture, education, employment, impact (Chapter 1).

Renin cleaves the 10 N -term inal am ino acids from SVR angiotensinogen generic minocycline 50mg online. This decapeptide (angiotensin I) is cleaved by angiotensin converting enzym e (ACE) cheap minocycline 50 mg line. The resulting angiotensin II + + com prises the 8 N -term inal am ino acids of angiotensin I discount 50mg minocycline amex. The pri- Angiotensinogen m ary am ino acid structures of angiotensins I and II are shown in DRVYIHPFHL DRVYIHPF single letter codes. Angiotensin II increases system ic vascular resis- Angiotensin I Angiotensin II tance (SVR), stim ulates aldosterone secretion from the adrenal gland (indicated in gray), and increases sodium (N a) absorption by + + renal tubules, as shown in Figures 2-15 and 2-17. These effects Aldo decrease urinary N a (and chloride excretion; UN aV). This apparatus brings into close apposition the afferent B (A) and efferent (E) arterioles with the macula densa (M D), a specialized region of the thick ascending limb (TAL). The extraglomerular mesangium (EM ), or lacis “Goormaghtigh appa- N ratus (cells),” forms at the interface of these components. M D cells express the Na-K-2Cl JG (sodium-potassium-chloride) cotransporter (NKCC2) at the apical membrane [10,11]. By N A way of the action of this transporter, M D cells sense the sodium chloride concentration of luminal fluid. By way of mechanisms that are unclear, this message is communicated to JG cells located in and near the arterioles (especially the afferent arteriole). These JG cells IM increase renin secretion when the NaCl concentration in the lumen is low. Cells in the G M D afferent arteriole also sense vascular pressure directly, by way of the mechanisms discussed in Figure 2-9. Both the vascular and tubular components are innervated by sympathetic nerves (N). Voltage-sen- Renin Sympathetic sitive Ca channels in the plasm a m em brane are activated by m em - Renin AC nerves brane stretch, which correlates with arterial pressure and is assum ed to m ediate baroreceptor-sensitive renin secretion. Renin ↑cAM P AT1 All secretion is also stim ulated when the concentration of sodium (N a) + and chloride (Cl) at the m acula densa (M D) decreases [12,14]. The – – + NO m ediators of this effect are less well characterized; however, som e ↑Ca ↑Ca studies suggest that the effect of N a and Cl in the lum en is m ore potent than is the baroreceptor m echanism. M any other fac- PGE2 – + PGI tors affect rates of renin release and contribute to the physiologic 2 M embrane depolarization regulation of renin. Renal nerves, by way of receptors coupled + + to adenylyl cyclase (AC), stim ulate renin release by increasing the M embrane production of cyclic adenosine m onophosphate (cAM P), which stretch reduces Ca release. Angiotensin II (AII) receptors (AT1 receptors) + inhibit renin release, as least in vitro. Prostaglandins E2 and I2 M D NaCl (PGE and PGI , respectively) strongly stim ulate renin release 2 2 Arterial through m echanism s that rem ain unclear. Atrial natriuretic peptide pressure (AN P) strongly inhibits renin secretion. Constitutive nitric oxide (N O ) synthase is expressed by m acula densa (M D) cells. N O appears to stim ulate renin secretion, an effect that m ay counteract inhibition of the renin gene by AII [17,18]. Aldosterone, the predom inant hum an m ineralocorticoid horm one, enters distal nephron cells through the plasm a m em - Cortisone brane and interacts with its receptor (the m ineralocorticoid receptor [M R], or Type I receptor). Interaction between aldosterone and this receptor initiates induction of new 11β HSD proteins that, by way of m echanism s that rem ain unclear, increase the num ber of sodium Cortisol Cortisol GR channels (EN aC) and sodium -potassium adenosine triphosphatase (N a-K ATPase) pum ps at the cell surface. This increases transepithelial N a (and potassium ) transport. Cortisol, ↑ ENaC the predom inant hum an glucocorticoid horm one, also enters cells through the plasm a Cortisone ↑ Na/K ATPase m em brane and interacts with its receptor (the glucocorticoid receptor [GR]). Cortisol, 11β HSD however, also interacts with m ineralocorticoid receptors; the affinity of cortisol and aldos- Cortisol terone for m ineralocorticoid receptors is approxim ately equal. In distal nephron cells, this M R interaction also stim ulates electrogenic N a transport. Cortisol norm ally circulates at concentrations 100 to 1000 tim es higher than the circulating concentration of aldosterone. Aldo Aldo In aldosterone-responsive tissues, such as the distal nephron, expression of the enzym e M R 11 -hydroxysteroid dehydrogenase (11 -H SD) perm its rapid m etabolism of cortisol so that only aldosterone can stim ulate N a transport in these cells. An inherited deficiency of the enzym e 11 -H SD (the syndrom e of apparent m ineralocorticoid excess, AM E), or inhi- Distal nephron cell bition of the enzym e by ingestion of licorice, leads to hypertension owing to chronic stim - ulation of distal N a transport by endogenous glucocorticoids. FIGURE 2-11 ↑ Preload Control of system ic hem odynam ics by the atrial natriuretic peptide (AN P) system. Increases in atrial stretch (PRELO AD) increase AN P + SLRRSSCFGGRLDRIGAQSGLGCNSFRY secretion by cardiac atria.

They also contain rons and astrocytes for normal brain function buy minocycline 50 mg overnight delivery. We briefly distinctive 9-nm intermediate filaments composed of a review several basic facts about astrocytes and then selec- unique protein called glial fibrillary acidic protein (GFAP) 50mg minocycline with visa. Recent work has assessed the func- astrocytes and neurons generic 50 mg minocycline visa. We also discuss features of astrocyte tional significance of this defining astrocytic protein using function as they relate to synaptic plasticity and emerging genetic knockout experiments (9–11). Astrocytes in GFAP concepts in the pathophysiology of psychiatric disorders. STRUCTURAL AND PHYSIOLOGIC It is not known how GFAP deficiency causes these changes. PROPERTIES Astrocytes are strongly coupled to one another by gap junctions (13), aqueous pores that are permeable to ions and The form of astrocytes is important in thinking about their other molecules with a molecular weight less than 1,000. Astrocytes are stellate cells (hence their name) broad range of biologically important molecules, including with multiple fine processes. Astrocytes in white matter are nucleotides, sugars, amino acids, small peptides, cAMP, complex cells with 50 to 60 long branching processes that Ca2 and inositol triphosphate (IP ) have access to this 3 radiate from the cell body and terminate in end-feet at the pathway. Such intercellular communication is believed to pial surface, on blood vessels, or freely among axons; white mediate the coordinated action of adjacent but individual matter astrocytes are usually called fibrous astrocytes (4). Gap have profuse, short stubby processes that contact blood ves- junction permeability is strongly reduced by intracellular sels and the pial surface, and surround neurons. Astrocytic acidification or large increases in intracellular [Ca2 ]. These end-feet express glucose transporters of the tive than that of neurons. For example, astrocytes have a V m GluT 1 type (6) and are a likely site of glucose uptake. Although glial cells express a variety of synapse; the ensheathing membranes constitute about 80% K channels, inwardly rectifying K channels seem to be of total membrane surface and are devoid of organelles (7). These chan- nels are voltage sensitive and are open at membrane poten- tials more negative than about 80 mV, close to the ob- Pierre J. Magistretti: Institut de Physiologie, University of Lausanne served resting potential of astrocytes. Astrocytes express Medical School, Lausanne, Switzerland Bruce R. Ransom: Department of Neurology, University of Washington many other voltage-activated ion channels, previously Medical School, Seattle, Washington 98195 thought to be restricted to neurons (15). The significance 134 Neuropsychopharmacology: The Fifth Generation of Progress of voltage-activated Na and Ca2 channels in glial cells cyte function is still evolving and is not considered further is unknown. Because the ratio of Na to K channels is low here (23,24). Neural activity can rapidly increase [K ] , o in adult astrocytes, these cells are not capable of regenerative which is tightly regulated to a resting level of about 3 mM electrical responses like the action potential. A single action potential increases the instantaneous One consequence of the high K selectivity of astrocytes, [K ] by 0. For example, when [K ] is raised from 4 to 20 which is only exceeded under pathologic conditions (29). If o o mM, astrocytes depolarize by 25 mV, compared to only diffusion alone were responsible for dissipating K released 5 mV for neurons (16). Homeostatic control of [K ] is needed because brain o o ity. In contrast, natural stimulation, such as viewing visual [K ] can influence transmitter release (31), cerebral blood o targets of different shapes or orientations, can cause depolar- flow (32), ECS volume (33,34), glucose metabolism (35), izations of up to 10 mV in astrocytes of the visual cortex and neuronal activity (36). The accumulation of extracellular K that is second- act as an unstable positive feedback loop increasing excita- ary to neural activity may serve as a signal to glial cells that bility. For example, Astrocytes expedite the removal of evoked increases in small increases in [K ] cause breakdown of glycogen (18), [K ] and limit its accumulation to a maximum level of o o perhaps providing fuel for nearby active neurons (see the 10 to 12mM, the ceiling level seen with intense activity following). Neurons, and perhaps Neurons and glial cells do not make functional synaptic blood vessels, also participate in [K ] regulation, but glial o or gap junction contacts with one another; therefore, inter- mechanisms are probably most important. Two general actions between these cell types must occur via the narrow mechanisms of astrocyte K removal have been proposed extracellular space (ECS) between them (16). There may (39): 1) net K uptake into astrocytes (by transport mecha- be rare exceptions to this rule (19,20). In the mammalian nisms and/or Donnan forces) and 2) K redistribution central nervous system (CNS), the ECS is a uniform and through astrocytes, which is known as K spatial buffering. Brain ECS is a dynamic compartment in terms of its the nature of the [K ] increase as well as brain region (38). Because of If glial cells take up K during neural activity and release the extreme narrowness of the ECS, molecules released from it thereafter, a transient increase in glial [K ] should result.