A randomized clinical trial to reduce asthma morbidity among inner-city children: results of the National Cooperative Inner-City Asthma Study buy generic clomiphene online women's health new dimensions. Svoren BM clomiphene 50 mg mastercard atraso menstrual 07 dias, Butler D, Levine BS, Anderson BJ, Laffel LM. Reducing acute adverse outcomes in youths with type 1 diabetes: a randomized, controlled trial. Szczepanski R, Gebert N, Hümmelink R, Könning J, Schmidt S, Runde B, et al. Toelle BG, Peat JK, Salome CM, Mellis CM, Bauman AE, Woolcock AJ. Evaluation of a community-based asthma management program in a population sample of schoolchildren. An education intervention for childhood asthma by Aboriginal and Torres Strait Islander health workers: a randomised controlled trial. Van de Wiel NMH, Matthys W, Cohen-Kettenis P, van Engeland H. Application of the Utrecht Coping Power Program and care as usual to children with disruptive behavior disorders in outpatient clinics: A comparative study of cost and course of treatment. Van Der Veek SMC, Derkx BHF, Benninga MA, Boer F, De Haan E. Cognitive behavior therapy for pediatric functional abdominal pain: a randomized controlled trial. Velsor-Friedrich B, Militello LK, Richards MH, Harrison PR, Gross IM, Romero E, et al. Effects of coping-skills training in low-income urban African-American adolescents with asthma. Walders N, Kercsmar C, Schluchter M, Redline S, Kirchner HL, Drotar D. An interdisciplinary intervention for undertreated pediatric asthma. Watson WT, Gillespie C, Thomas N, Filuk SE, McColm J, Piwniuk MP, et al. Small-group, interactive education and the effect on asthma control by children and their families. Weisz JR, Southam-Gerow MA, Gordis EB, Connor-Smith JK, Chu BC, Langer DA, et al. Cognitive-behavioral therapy versus usual clinical care for youth depression: an initial test of transportability to community clinics and clinicians. Willems DCM, Joore MA, Hendriks JJE, Wouters EFM, Severens JL. Cost-effectiveness of a nurse-led telemonitoring intervention based on peak expiratory flow measurements in asthmatics: results of a randomised controlled trial. Willems DC, Joore MA, Hendriks JJ, van Duurling RA, Wouters EF, Severens JL. Process evaluation of a nurse-led telemonitoring programme for patients with asthma. Willems DC, Joore MA, Hendriks JJ, Nieman FH, Severens JL, Wouters EF. The effectiveness of nurse-led telemonitoring of asthma: results of a randomized controlled trial. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that 63 suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Xu C, Jackson M, Scuffham PA, Wootton R, Simpson P, Whitty J, et al. A randomized controlled trial of an interactive voice response telephone system and specialist nurse support for childhood asthma management. Young NL, Foster AM, Parkin PC, Reisman J, MacLusky I, Gold M, et al. Assessing the efficacy of a school-based asthma education program for children: a pilot study. Grimshaw J, McAuley LM, Bero LA, Grilli R, Oxman AD, Ramsay C, et al. Systematic reviews of the effectiveness of quality improvement strategies and programmes. Linking clinical variables with health-related quality of life. Barr RD, Pai MK, Weitzman S, Feeny D, Furlong W, Rosenbaum P, et al. A multiattribute approach to health-status measurement and clinical management illustrated by an application to brain tumors in childhood. Assessment of health-related quality of life in children: a review of conceptual, methodological, and regulatory issues. Quality-of-life measures in chronic diseases of childhood. Measuring Health Outcomes in Pediatric Populations: Issues in Psychometrics and Application. Quality of Life and Pharmacoeconomics in Clinical Trials. The measurement of quality of life in young children. Reducing emergency admissions: are we on the right track? Centre of Health Economics, University of York; 2010. The experience of being the parent of a technology-dependent child. Health care professional support for self-care management in chronic illness: insights from diabetes research. Exploring reactions to a guided self-management intervention in a randomised controlled trial for IBS with reference to prior experience of managing a long term condition. Transfer of asthma management responsibility from parents to their school-age children. Craig P, Dieppe P, Macintyre S, Michie S, Nazareth I, Petticrew M, et al. Developing and evaluating complex interventions: the new Medical Research Council guidance.
Knowledge translation on ageing and health: a framework for policy development buy clomiphene 25 mg with amex women's health clinic kingston. Planning buy clomiphene with american express women's health boutique houston, monitoring and evaluation framework for capacity strengthening in health research (ESSENCE Good practice docu- ment series. Where there is no health research: what can be done to fll the global gaps in health research? Global strategy and plan of action on public health, innovation and intellectual property. Research and development to meet health needs in developing countries: strengthening global fnancing and coordination. Report of the Consultative Expert Working Group on Research and Development: Financing and Coordination. Research and development − coordination and fnancing. Public health, innovation and intellectual property rights: report of the Commission on Intellectual Property Rights, Innovation and Public Health. Promoting access to medical technologies and innovation: intersections between public health, intellectual property and trade. Geneva, World Health Organization, World Intellectual Property Organization and World Trade Organization, 2013. Multi-stakeholder technical meeting on implementation options recommended by the WHO Consultative Expert Working Group on Research & Development (CEWG): Financing and Coordination. Nonthaburi and Cambridge, MA, International Health Policy Program Thailand and Harvard Global Health Institute, Bellagio, Rockefeller Foundation, 2012. Bulletin of the World Health Organization, 2011,89:88-89. Current priorities in health research funding and lack of impact on the number of child deaths per year. Tropical Medicine & International Health, 2012,17:1409-1411. Implementing new health interventions in developing countries: why do we lose a decade or more? Closing the gaps: from science to action in maternal, newborn, and child health in Africa. The Paris Declaration on Aid Efectiveness and the Accra Agenda for Action. Paris, Organisation for Economic Co-operation and Development, 2013 (http://www. Busan, Global Partnership for Efective Development Cooperation, 2011. A framework for mandatory impact evaluation to ensure well informed public policy decisions. Ottawa, International Development Research Centre, 2012. Estimating the economic benefts from medical research in the UK. New York, NY, Albert & Mary Lasker Foundation, 2000. Exceptional returns: the value of investing in health R&D in Australia II. Canberra, The Australian Society for Medical Research, 2008. Efect of a US National Institutes of Health programme of clinical trials on public health and costs. Systematic review of methods for evaluating healthcare research economic impact. Payback arising from research funding: evaluation of the Arthritis Research Campaign. An assessment of the impact of the NHS Health Technology Assessment Programme. Health Technology Assessment, 2007,11:iii-iv, ix–xi, 1–180. Assessing the impact of health technology assessment in the Netherlands. International Journal of Technology Assessment in Health Care, 2008,24:259-269. A systematic evaluation of payback of publicly funded health and health services research in Hong Kong. How can payback from health services research be assessed? Journal of Health Services Research & Policy, 1996,1:35-43. The economic and social benefts of HRB funded research. The role of public-sector research in the discovery of drugs and vaccines. The New England Journal of Medicine, 2011,364:535-541. Strengthening capacity for health research in Africa. Best days for public health are ahead of us, says WHO Director-General. Address to the Sixty-ffth World Health Assembly, Geneva, 21 May 2012. Overcoming gaps to advance global health equity: a symposium on new directions for research. South-South collaboration in health biotechnology: growing partnerships amongst developing coun- tries. New Delhi and Ottawa, Academic Foundation and International Development Research Centre, 2012. The yellow on the armband indicates that the child is malnourished (© UNICEF/NYHQ2011-2139/Esteve). Key points ■ Research illuminates the path to universal health coverage and to better health. This chapter illustrates this with 12 case-studies which investigate questions on issues ranging from the prevention and control of specific diseases to the functioning of health systems. Second, what specifc question is being asked, and where is this question placed in the cycle of research from understanding causes to applying solutions? Tird, what is the most appropriate study design for addressing the question at hand? In particular, they highlight the range of methods that are commonly used in health research, from observational studies to randomized controlled trials. They illustrate the diversity of problems for which research can offer solutions, the benefits of having evidence from multiple sources, the nature of the research cycle, the relationship between study design and strength of inference, the challenge of applying research findings from one setting to another, and the link between research, policy and practice.
Suppression of the renin- lum ina discount clomiphene amex the women's health big book of exercises pdf download, giving the appearance of a bloodless glom erulus buy generic clomiphene 50 mg online women's health clinic waco tx. O n occa- angiotensin system occurs, probably in response to vasoconstric- sion, the m esangium , severely affected, m ay expand. The glom erular lesion leads to and fibrinlike m aterial and foam cells m ay be present, and epithe- proteinuria, which m ay be heavy. Renal hem odynam ic changes lial crescents have been described in rare instances. Decreased sodium and uric acid excre- tion m ay be caused by increased proxim al tubular reabsorption. The m echanism for the m arked hypocalciuria is not known. Investigators have sought m ethods to prevent preeclam psia (eg, salt restriction, prophylactic diuretics, and high-protein Smaller studies 11 10/319 50/284 (<200 women) (3. O ne approach that has been exten- sively investigated in the last 10 years is Larger studies: therapy with low-dose aspirin. It was EPHREDA (1990) 5/156 8/74 hypothesized that such therapy reversed the Hauth (1993) 5/303 17/303 im balance between prostacyclin and throm - Italian (1993) 12/565 9/477 Sibai (1993) 69/1570 94/1565 boxane that m ay be responsible for som e of Viinikka (1993) 9/103) 11/105) the m anifestations of the disease. Several CLASP (1994) 313/4659 352/4650 large trials now have been com pleted, and Odds ratio m ost have had negative results. Shown here All larger trials 6 413/7356 491/7174 Overall results is an overview of the effects of aspirin on 25% SD 6 proteinuric preeclam psia reported from all All trials 17 423/7675 541/7458 odds reduction (5. O dds ratios (area proportional therapy therapy to am ount of inform ation contributed) and better worse 99% confidence interval (CI) are plotted for various trials. A black square to the left of the solid vertical line suggests a benefit (how- ever, this indication is significant at 2p >0. Another preventive strategy Study that has been extensively investigated, with M arya et al. The rationale for this approach is Lopez-Jaramillo et al. A recent meta-analysis of 14 trials of calcium supple- 0. In contrast, a large randomized trial of calcium supple- mentation in 4589 low-risk women failed to demonstrate a benefit of calcium therapy. Close surveillance is best accom plished in the hospital in all but the m ildest cases. Close monitoring of maternal and fetal conditions M aternal hypertension should be treated to avoid cerebrovascular and cardiovascular Hospitalization in most cases com plications. M agnesium sulfate is the treatm ent of choice for seizure prophylaxis and usually is instituted im m ediately after delivery. W hen the fetus is m ature, delivery is indi- Lower blood pressure for maternal safety cated in all cases. W hen the fetus is im m ature, the decision to deliver is m ade after careful- Seizure prophylaxis with magnesium sulfate ly assessing both the m aternal and fetal condition. W hen m aternal health is in jeopardy, Timely delivery delivery is necessary, even with a prem ature fetus. FIGURE 10-38 ANTIHYPERTENSIVE THERAPY Som e controversy exists regarding when to institute antihypertensive therapy in wom en IN PREECLAM PSIA with preeclam psia. The basis for this controversy is that decreased uteroplacental perfusion is believed to be im portant in the pathophysiology of this disorder, and concern exists that lowering m aternal blood pressure m ay com prom ise uteroplacental blood flow and lead to Decreased uteroplacental blood flow and placental fetal distress. Furtherm ore, lowering m aternal blood pressure does not cure preeclam psia. Lowering blood pressure does not prevent or cure For m ost physicians, this treatm ent threshold is at approxim ately 150/100 m m H g. Lowering blood pressure is appropriate for maternal safety: maintain blood pressure at 130–150/85–100 mm Hg. FIGURE 10-39 ANTIHYPERTENSIVE THERAPY IN PREECLAM PSIA W hen blood pressure increases acutely and delivery is likely within the next 24 hours, use of a parenteral antihypertensive agent is preferable. Intravenous hydralazine or labetalol are acceptable Imminent delivery Delivery postponed agents for pregnant wom en, and both have been used successfully in preeclam psia. Calcium channel blockers should be used with Hydralazine (intravenous, intramuscular) Methyldopa caution because they m ay act synergistically with m agnesium sul- Labetalol (intravenous) Labetalol, other blockers fate, resulting in precipitous decreases in blood pressure. Rarely, Calcium channel blockers Calcium channel blockers agents such as diazoxide m ay be needed; however, when hyperten- Diazoxide (intravenous) Hydralazine sion is severe, m aternal safety takes priority over pregnancy status. M ethyldopa is one of the safest drugs in preg- nancy and has been used extensively with excellent m aternal and fetal outcom e. Labetalol and other blockers have been used suc- cessfully in preeclam psia. Calcium channel blockers also m ay be used as either second- or third-line agents. Lim ited experience exists with blockers or cloni- dine, although anecdotal reports suggest these agents are safe. W om en with preexisting or chronic hypertension Diastolic BP, mm Hg during pregnancy have a favorable prognosis, unless preeclam psia <90 90–100 ≥ 100 develops. The risk of superim posed preeclam psia is about 25%. W om en with this com plication are at greater risk for fetal com pli- Consider careful Continue treatment Indicates significant cations during pregnancy, including prem ature delivery, growth decrease in hypertension: BP medication consider stopping work; restriction, and perinatal m ortality. In those wom en with uncom plicat- Third trimester ed chronic hypertension (solid line), blood pressure decreases in the Increased surveillance for preeclampsia first trimester, then may decrease even further in the second trimester. Check BP every 2 weeks An increase in both systolic and diastolic blood pressure m ay occur during the third trim ester to levels at prepregnancy or early first trim ester. In those wom en who develop superim posed preeclam psia FIGURE 10-41 (broken lines), blood pressure often decreases in the first trim ester. Ideally, patients There is often a failure to decrease further in the second trim ester, with chronic hypertension should be evaluated before pregnancy so however, and blood pressures may actually begin to increase slightly. W om en can be counseled regarding the need for possible develops. Blood pres- sure (BP) m edications m ay require adjustm ent, depending on the m agnitude of the pregnancy-related changes in blood pressure. In the latter half of pregnancy, close surveillance for early signs of preeclam psia increases the likelihood the condition will be diag- nosed before it progresses to a severe stage. FIGURE 10-42 ANTIHYPERTENSIVE THERAPY The overall treatm ent goals of chronic hypertension in pregnancy are to ensure a success- FOR CHRONIC HYPERTENSION ful full-term delivery of a healthy infant without jeopardizing m aternal well-being. The DURING PREGNANCY level of blood pressure control that is tolerated in pregnancy m ay be higher, because the risk of exposure of the fetus to additional antihypertensive agents m ight outweigh the ben- efits to the m other (for the duration of pregnancy) of having a norm al blood pressure. Methyldopa M ost antihypertensive agents have been evaluated only sporadically during gestation, and blockers (labetalol) careful follow-up of children exposed in utero to m any of the agents is lacking. The only antihypertensive agent for which such follow-up exists is m ethyldopa. Because no adverse Calcium channel blockers effects have been docum ented in offspring of exposed m others, m ethyldopa is considered Hydralazine to be one of the safest drugs during pregnancy. Diuretics can be used at low doses, particu- larly in salt-sensitive hypertensive patients on chronic diuretic therapy.
Heterogeneity between brain and substance for human corticotropin-releasing factor in late gesta- pituitary corticotropin-releasing factor receptors is due to differ- tional maternal plasma which could mask the ACTH-releasing ential glycosylation cheap clomiphene 50mg with amex pregnancy 12 weeks. Characterization of CRH pin-releasing factor receptor expressed in heart and skeletal mus- binding protein in human plasma by chemical cross-linking and cle purchase clomiphene once a day women's health center fishersville va. New tion of the cDNAs for human and rat corticotropin-releasing York: The New York Academy of Sciences,1987:48–66. Corticotropin-releasing factor receptors in the rat 49. Corticotropin-releasing central nervous system: characterization and regional distribu- factor-binding protein is a glycoprotein. The central distribution ing factor receptors in the brain-pituitary-immune axis. In: Stress, of a corticotropin-releasing factor (CRF)-binding protein predicts neuropeptides, and systemic disease. San Diego: Academic Press, multiple sites and modes of interaction with CRF. Chemical and biological Handbook of chemical neuroanatomy: neuropeptide receptors in the characterization of corticotropin-releasing factor. Catecholami- regulation of corticotropin-releasing factor receptors in the cen- nergic modulation of corticotropin-releasing factor and adreno- tral nervous,endocrine and immune systems. Age-related decreases chemical study of human corticotropin-releasing factor2 recep- in corticotropin-releasing factor (CRF) receptors in rat brain and tors. Effects of CRF on spontaneous and sensory-evoked for rapid screening of corticotropin-releasing factor receptor lig- activity of locus ceruleus neurons. Electrophysiology of corticotropin-releasing factor in ings of the 25th Annual Meeting of the Neuroscience Society, San nervous tissue. In: Corticotropin-releasing factor: basic and clinical Diego,1995. CRF effects on EEG activity: implications for the specific sub-cortical nuclei in rat brain: comparison with CRF1 modulation of normal and abnormal brain states. Corticotropin-releasing factor: endocrine and auto- receptor mRNAs are differentially distributed between the rat nomic integration of responses to stress. Trends Pharmacol Sci central nervous system and peripheral tissues. Characterization of corti- system by corticotropin-releasing factor. In: Corticotropin-releas- cotropin-releasing factor receptor-mediated adenylate cyclase ac- ing factor: basic and clinical studies of a neuropeptide. Boca Raton, tivity in the rat central nervous system. Central nervous system stimulation of protein carboxylmethylation in mouse pituitary action to influence gastrointestinal function and role in the gas- tumor cells. Mechanisms of basic and clinical studies of a neuropeptide. Boca Raton,FL: CRC action of CRF and other regulators of ACTH release in pituitary Press,1990:299–308. In: The hypothalamic-pituitary-adrenal axis revis- 61. In: Corticotropin-releasing factor: basic and clinical stud- 43. Psychopharmacology of affective disorders in the 79. The rationale for corticotropin-releasing hormone of dementia and monoamine metabolites. Biol Psychiatry 1989; receptor (CRH-R) antagonists to treat depression and anxiety. Role of corticotropin-releasing factor in neuropsy- cotropin-releasing factor-like immunoreactivity in cerebral cortex chiatric disorders and neurodegenerative diseases. CSF corticotropin-releasing hor- somatocrinin and amine contents in normal and parkinsonian mone in depressed patients and normal control subjects. Reduced corticotro- corticotropin-releasing factor: implications for affective disorders. Neuropeptide concentra- flammatory actions of corticotropin-releasing hormone in vivo. Responses to corticotropin- receptor subtypes and clinical indications. Curr Pharm Design releasing hormone in the hypercortisolism of depression and 1999;5:289–315. The corticotropin-releasing efficacy of a 4-(butylethylamino)pyrrolo[2,3-d]pyrimidine: a cen- hormone stimulation test in patients with panic disorder. Am J trally active corticotropin-releasing factor1 receptor antagonist. Design and synthesis factor-like immunoreactivity in senile dementia of the Alzheimer of a series of nonpeptide high-affinity human corticotropin-re- type. Abnormalities in tuitary ACTH release and peripheral inflammation. R121919: a novel nonpeptide corticotropin-releasing factor1 77. Neu- in major depression: the first 20 patients treated. GAGE AND HENRIETTE VAN PRAAG HISTORIC PERSPECTIVE ture. Under a variety of culture conditions with different factors, these isolated cells can be induced to differentiate The idea that the adult brain retains the capacity to generate into glia and neurons (6–9). This later observation provided new neurons has been proposed several times over the last a mechanism for the neurogenesis in the adult. Mature com- 40 years, and in each case both conceptual and technical mitted neurons were not dividing, but rather a population constraints have led to resistance. Joseph Altman first re- of immature stem-like cells exists in the brain and it is likely ported that some dividing cells in the adult brain survived that it is the proliferation and differentiation of this popula- and differentiated into cells with morphology similar to tion that is resulting in neurogenesis. With this conceptual neurons using tritiated thymidine autoradiography (1). When contrasting adult neurogenesis with the extensive we have learned is that development never ended in some neurogenesis in development, adult neurogenesis seemed areas of the brain.
International Society of Magnetic Resonance in Medicine 2000;8: 25 purchase clomiphene 100 mg women's health issues depression. New York: John Wiley Electroencephalogr Clin Neurol 1990;75:350–357 buy 50 mg clomiphene with mastercard menstruation lasting 2 weeks. Functional interactions cortex on the MRI with transcranial magnetic stimulation and among neurons in inferior temporal cortex of the awake macaque. EEG patterns during ping of motor cortex: comparing echoplanar BOLD fMRI and cognitive tasks. Methodology and analysis of complex behav- transcranial magnetic stimulation. Co-planar stereotaxic atlas of the human human brain during cognition: a new method of reveals dynamic brain: 3-dimensional proportional system: an approach to cerebral patterns of correlation. Three-dimensional multi- ances during a bimanual visuomotor task. Methods and analysis modal image guidance for neurosurgery. IEEE Trans Med Imag- of stimulus- and response-locked data. Cortico-cortical associa- netic stimulation and functional magnetic resonance imaging: tions and EEG coherence: a two-compartment model. Elec- complementary approaches in the evaluation of cortical motor troencephalogr Clin Neurophysiol 1986;64:123–143. Echoplanar BOLD fMRI cortical regions: topography of EEG coherence. Electroencepha- of brain activation induced by concurrent transcranial magnetic logr Clin Neurophysiol 1986;63:242–250. A combined TMS/ multidimensional scaling and functional connectivity in the fMRI study of intensity-dependent TMS over motor cortex. Performance of a system for ulation during positron emission tomography: a new method for interleaving transcranial magnetic stimulation with steady state studying connectivity of the human cerebral cortex. Daily repeti- model to functional imaging in neuropsychiatric disorders: a tive transcranial magnetic stimulation (rTMS) improves mood principal component approach to modeling brain function in in depression. Network analy- transcranial magnetic stimulation (rTMS) changes relative perfu- sis of cortical visual pathways mapped with PET. Transcranial mag- in effective connectivity measured with PET. Hum Brain Map- netic stimulation with simultaneous undistorted functional mag- ping 1993;1:69–79. BOLD-fMRI 410 Neuropsychopharmacology: The Fifth Generation of Progress response to single-pulse transcranial magnetic stimulation rior parietal cortex in updating reaching movements to a visual (TMS). The distribution of induced currents in magnetic stimu- bral connectivity by PET during TMS. Analysis of the distribution of current of cerebral blood flow during rapid-rate transcranial magnetic induced by a changing magnetic field in a volume conductor. J Clin Neurophysiol 1991;8: cerning the roles of frequency and intensity in the antidepressant 102–111. Unilateral left prefrontal Electroencephalogr Clin Neurophysiol 1991;81:47–56. An accurate 3-D model for bilateral effects as measured with interleaved BOLD fMRI. Numerical recipes to magnetic stimulation reveals cortical reactivity and connectiv- in C: the art of scientific computing. Brain activity for 17 in visual imagery: convergent evidence from PET and rTMS. INNIS In positron emission tomography (PET) and single-photon ders must be addressed. Physical barriers include limited emission computed tomography (SPECT), tracers labeled anatomic resolution and the need for even higher sensitivity. Commercially available PET de- of magnitude greater than the sensitivities available with vices provide resolution of 2 to 2. Furthermore, magnetic resonance imaging (MRI) ( 10 4 M) or mag- the relatively high cost of imaging with SPECT, and espe- netic resonance spectroscopy (MRS) ( 10 3 to 10 5 M). Thus, the major barriers for conventional bismuth germanate-based scintillator is used the expanded use of PET are not physical or monetary, but can measure extrastriatal dopamine D1 receptors present at rather chemical in nature. Simply stated, the major barrier a concentration of approximately 10 9 M (4). Because to radiotracer imaging of molecular targets may well be the many molecules of relevance to neuropsychiatric disorders difficulties associated with developing the radiotracers are present at concentrations of less than 10 8 M, radio- themselves. Labeling the appropriate precursor typically is tracer imaging is the only currently available in vivo method not the major impediment. Almost all candidate ligands capable of quantifying these molecular targets. As described in the next section, the most common ography, Western blots, and Northern blots. Thus, the fu- obstacle to the development of in vivo tracers is the relatively ture possibilities of radiotracer imaging are broad and excit- small window of appropriate combinations of lipophilicity, ing—and include targets of receptors, signal transduction, molecular weight, and affinity. However, in brain, relatively low lipophilicity and Although in vivo molecular imaging is a promising tech- high affinity are required to achieve high ratios of specific nique, several barriers— physical, monetary, and chemi- to nonspecific binding. In contrast, the requirements for in cal—to its successful application in neuropsychiatric disor- vitro ligands are much less stringent because the blood–brain barrier can be removed by homogenization or tissue sectioning and most nonspecific binding washed Masahiro Fumita: Department of Psychiatry, Yale University School of away. The special requirements of in vivo probes (low mo- Medicine, New Haven, Connecticut. Innis: Departments of Psychiatry and Pharmacology, Yale lecular weight, high affinity, and just the right amount of University School of Medicine, New Haven, Connecticut. It is easy to understand that small molecular weight and a high degree of lipophilicity are required to pass the blood–brain barrier because it is composed of a lipid bilayer. However, lipophilicity has opposing effects on the brain uptake of a tracer. Increasing lipophilicity enhances the per- meability of the compound, but it also tends to increase plasma protein binding, thereby decreasing the concentra- tion of free drug available to cross the blood–brain barrier. From rat experiments in which 27 tracers of various chemi- cal classes were used, Levin (8) obtained the following sim- ple equation to derive a capillary permeability coefficient, FIGURE 31. Compartmental description of radioactively la- Pc, from an octanol/water partition coefficient, P, and the beled tracer uptake in brain. Because a higher lipophilicity is required for brain imaging tracers to In addition to a high degree of affinity and selectivity, several be taken up adequately in brain, the equation only partially other properties are required for useful in vivo tracers. High lipophilicity (higher value of log P) increases the binding to the plasma Combination of Small Molecular Weight, components (protein and cell membranes) (9) and reduces Appropriate Lipophilicity, and High the capillary permeability coefficient expressed relative to Affinity the total plasma concentration of drug (10,11). Therefore, both low lipophilicity and high lipophilicity decrease the Tissue uptake of a drug (whether radioactive or not) is often penetration of imaging agents across the blood–brain bar- analyzed within the theoretic framework of a compartment, rier, so that a parabolic curve is created (Fig.
The right histogram demonstrates a women over a period of only 1 year buy clomiphene on line amex womens health york pa. An increase of over 1 cheap clomiphene 25 mg mastercard menstruation kolik,500 mm3 in ventricular volume was demonstrated during reduced baseline (PRE AMP) Vh after administration of GBR con- sistent with an increase in baseline extracellular intrasynaptic DA this time but no detectable change in the total or regional concentration (PRE AMP) and the absence of a significant change in V after the administration of amphetamine (POST AMP). This suggests that determination of the pat- h ified from Villemagne VL, Wong DF, Yokoi F, Stephane M, Rice tern and rate of these changes longitudinally could be a KC, Matecka D, Clough DJ, Dannals RF, Rothman RB. GBR12909 future predictor of cognitive declines and dementia (136). Syn- Functional MRI (fMRI), a technique in which subjects apse1999;33:268–273. For example, the rCBF of cocaine- dependent subjects administered intravenous cocaine exhib- ited increases in the nucleus accumbens, subcallosal cortex, MAGNETIC RESONANCE SPECTROSCOPY and hippocampus and decreases in rCBF in the amygdala, temporal pole, and medial frontal cortex (137). Future stud- Magnetic resonance spectroscopy (MRS) provides surrogate ies utilizing this paradigm could additionally assess whether markers to determine clinical endpoints to evaluate new another compound administered before cocaine can antago- therapeutic interventions for specific diseases. Additionally, [19F]MRS has been explicitly employed to examine the pharmacokinetics of BIOMARKERS OF ALCOHOL ABUSE psychotropic medications containing a fluorine group such as fluvoxamine (130). This allows direct comparison of The synergistic combination of carbohydrate-deficient brain and plasma concentrations, and brain elimination transferrin (CDT), gamma-glutamyl transferase (GGT), 468 Neuropsychopharmacology: The Fifth Generation of Progress and mean red cell volume (MCV) functions as a possible the CNS could be administered as therapeutic agents to biomarker for alcohol abuse (138). CSF from treated patients and bioluminescent compounds responsive to the presence of the enzyme that should be NEWER MARKERS FOR DRUG absent could then be injected into experimental animals. DEVELOPMENT Detection of the bioluminescence in the experimental ani- mal would then indicate failure of the new drug to prevent Several techniques recently have been developed to provide the growth of the tumor or infection. Thus, this technique the means to assess the efficacy of newly developed potential offers the potential of surrogate markers to monitor the drugs. These procedures assist clinicians in both the (a) diag- presence of CNS tumors and infections. The appli- Simultaneous Optical and Magnetic cation of the following novel procedures to drug develop- Resonance Microscopy ment is the result of a collaborative effort jointly of the Simultaneous optical and magnetic resonance imaging National Institutes of Health (NIH), the United States (MRI) is being developed in experimental animals. MRI Food and Drug Administration (FDA), the Health Care contrast agents (143), such as fluorescently detectable mag- Financing Administration (HCFA), and private industry netic resonance imaging agents, are utilized to permit light (139). The protocols described in this section are likely to and magnetic resonance imaging microscopy at the same be instrumental in drug development for neuropsychiatric time (144). These compounds can be detected deep in tis- disorders in the future. Although External Imaging of Internal light microscopy can penetrate only 100 to 300 m beneath Bioluminescent and Fluorescent Signals the surface of organisms, MRI microscopy can penetrate 1 to 6 mm into an organism (144). For example, agents that Biological processes, such as the propagation of cancer cells, can be simultaneously recognized by MRI microscopy and are studied in animal models by the detection of biolumi- by fluorescent optical microscopy permit visualization of nescent (140) and fluorescent signals recorded externally structures 1 to 6 mm below the surface of an organism by means of sensitive photon detection systems (141). Other examples in- Diffusion-Based Optical Imaging clude the evaluation of potential agents to treat human can- cer and infection by assessing the behavior of cells from Procedures to measure light emitted into opaque structures patients in animals utilizing bioluminescent markers. The have been termed medical optical imaging (MOI), medical technique utilizes bioluminescent compounds bound to optical spectroscopy (MOS), near-infrared imaging (NIRI), specific enzymes that signal the proliferation of cancers and and near-infrared optical spectroscopy (NIOS) (146). Human subjects with cancer or infection are example, three-dimensional optical coherence tomography treated with agents to alter the expression of genes that (OCT) is a technique to image nontransparent biologic tis- produce the enzymes needed for the growth of the cancer sue by recording and analyzing light emitted into scattering or bacteria. Then animals are injected with (a) cells from media. OCT has been employed to visualize nerve fascicles the previously cancerous or infected tissue of treated hu- in experimental animals for the microsurgical anastomoses mans, and (b) bioluminescent markers that respond to the of vessels and nerves (147). An example of diffusion-based presence of the enzyme that was hopefully blocked in optical imaging is the use of optical tomography to detect the humans. Detection of the bioluminescent markers in intraventricular hemorrhage in premature infants by exter- the animals indicates the proliferation of the enzyme to be nal transmission of light emitted through the skull (146). This technique, which provides a human disease, including infections and malignancies surrogate for the clinical effects, is being applied to a variety (146). Hopefully, in the future they will be applied to CNS of human diseases including cancer and infection (http:// tumors and malignancies. By analogy, this procedure could be ap- plied to assess drugs developed to treat malignancy and in- Magnetic Resonance Microscopy fection of the CNS. For example, novel agents to alter the expression of the genes that code for the control of the Microscopic visualization of magnetic resonance images has production of enzymes required by cancer and infection of detected transgene expression in experimental animals. Chapter 34: Proof of Concept 469 Identification of pathologic processes, including the prolif- Biomarkers and surrogate endpoints: advancing clinical research eration of tumor cells in clinical settings (148), may be and applications program book. Bethesda, Maryland: National Institutes of Health, 1999;15–16. Surrogate endpoints in clinical trials: definition means to both detect the occurrence of malignancies and and operational criteria. Bioassay design and MTD setting: old methods cedure to human CNS malignancy is a goal to be attained and new approaches. Regul Toxicol Pharmacol 1995;21:44–51; in the future. Determination of appropriate dosage in clinical development guidance. In: Balant LP, Benitez J, Dahl Electron Paramagnetic Resonance SG, et al. Clinical pharmacology in psychiatry: finding the right dose of psychotropic drugs. Brussels: European Commission, Electron paramagnetic resonance (EPR) (149) imaging and 1998:307–322. Prog Neuro-Psychopharmacol Biol Psychiatr labels into the system of interest (150). Phase I clinical develop- of experimental animals (150) and to measure oxygen free ment and finding the dose: the role of the bridging study. In: radical generation in human endothelial cells exposed to SramekJJ, Cutler NR, Kurtz NM, et al. New York: John Wiley and anoxia and reoxygenation (151). Recent dose-effect studies regarding antidepres- (152), a process vital to the measurement of the progression sants. Clinical of pathologic processes (153), including cerebral ischemia pharmacology in psychiatry: finding the right dose of psychotropic (154) and malignancies. Debate resolved: there are differential effects of serotonin selective reuptake inhibitors on cytochrome P450 en- zymes. Comparison of the effects of low and high doses of venlafaxine on serotonin and Biomarkers and surrogate markers are tools currently uti- norepinephrine reuptake processes in patients with major depression and healthy volunteers. Int J Neuropsychopharmacol lized to develop new drugs. Currently drugs are being developed treatment-resistant unipolar depression. J Clin Psychopharmacol by the use of neuroendocrine markers including CSF, pro- 1994;14:419–423. Venlafaxine: measuring the lactin, GH, ACTH, and cortisol. Imaging studies provide onset of antidepressant action.
Neuropharmacology other intravenous anesthetics have sites of action n the gamma- 1976;15:149–156 discount 50mg clomiphene amex breast cancer zumbathon. Hypothalamic regulation of sleep in rats: an experi- spinal neurones in culture buy clomiphene 50 mg visa women's health ketone advanced. Forebrain inhibitory mechanisms: gamma-aminobutyric acid receptor-mediated chloride transport sleep patterns induced by basal forebrain stimulation in the be- in rat brain synaptoneurosomes. Ambient temperature-dependence of Soc Pharmacol Exp Ther 1993;39:105–108. Sleep induced by electrical Brain Res Bull 1984;12:295–305. Neuronal sensitivities in preoptic tissue 1963;24:188–198. State-altering effects of benzodiazepines and bar- 1988;20:871–878. Effects of microinjections of triazolam into the 56. Hypothalamic thermoregulatory ventrolateral preoptic area on sleep in the rat. Neurotransmitter speci- ential ascending projections of the dorsal and median raphe nuclei ficity of cell and fibers in the medial preoptic nucleus: an immu- in the rat. The organization of neural inputs to rats utilizing a push-pull cannula technique. Neuroendocrinology the medial preoptic nucleus of the rat. Sydney: Academic Press, 1985: hypothalamus and substantia nigra. Brainstem afferents to the tuberomamillary nucleus in the rat brain with special reference to 60. Firing of neurons in the preoptic/anterior monoaminergic innervation. Effects of electrical stimulation of the rostral raphe nuclei. Preoptic hypnogenic area and the reticular activating neuroanatomy, fifth ed. Responses evoked in midbrain reticu- ventrolateral preoptic neurons during sleep. Science 1996;271: lar formation neurons by stimulation of the medial and lateral 216–219. Life Sci 1996;59: gic neurons in the ventrolateral preoptic nucleus of the rat. Serotonergic afferents to nifedipine injections into the medial preoptic area. Evolving concepts of sleep induction by injection of propofol into the medial preoptic area cycle generation: From brain centers to neuronal populations. Effects of ethanol Chapter 132: Basic Mechanisms of Sedative/Hypnotics 1929 injection to the preoptic area on sleep and temperature in rats. Characterization of the hypnotic perature regulation in the preoptic area of rats. Pharmacol Bio- effects of triazolam microinjections into the medial preoptic area. Effects of microinjections of triazo- duces sleep when microinjected into the preoptic area of con- lam into medial preoptic area on sleep and brain temperature in scious rats. The central metabolism on sleep in rats with lesions of the preoptic area. Pharmacol Bio- of serotonin in the cat during insomnia: a neurophysiological chem Behav 1998;61:81–86. Arousal: revisiting the reticular activating system. Principles and practice of sleep cillations in the sleeping and aroused brain. Effects of basal forebrain stimulation thetized rats during feeding and sleeping. Am J Physiol 1964;206: on the waking discharge of neurons in the midbrain reticular 641–646. Localization of neuronal histamine in benzodiazepine-barbiturate interactions on behaviour and physi- rat brain. Postischemic diazepam is neuro- rior hypothalamic warming. Epidemiologic studies point to a consistent set of risk factors for insomnia. The increas- Disorders ing prevalence of insomnia with age may be explained in large part by increasing comorbidity with medical and psy- Insomnia can refer to either a symptom or clinical disorder. The incidence of in- The symptom of insomnia is the subjective complaint of somnia also increases with age and is greater in women than difficulty falling or staying asleep, poor quality sleep, or men. On the other hand, remission of insomnia decreases inadequate sleep duration, despite having an adequate op- with age and is less common in women. Two points in this definition deserve lence, incidence, and remission data indicate that insomnia specific attention. First, insomnia is a subjective complaint is often a chronic condition. Between 50% and 80% of not currently defined by laboratory test results or a specific individuals with insomnia at baseline have a persistent com- duration of sleep or wakefulness. Second, the insomnia plaint after follow-up intervals of 1 to 3. This distinguishes insomnia from sleep deprivation, which has different causes, consequences, and Impact of Insomnia clinical presentations. As a disorder, insomnia is a syndrome consisting of the insomnia complaint, together with specific Studies in working populations show that individuals com- diagnostic features (either clinical or laboratory), significant plaining of insomnia have more mood symptoms, gastroin- distress or functional impairment, and the absence of spe- testinal symptoms, headache, and pain (9). Health-related quality of life Prevalence of Insomnia Symptoms and is significantly lower for individuals with insomnia than for Disorders those without (11). Individuals with insomnia may also have higher rates of serious accidents or injuries (12) and inju- Insomnia symptoms and disorders are widely prevalent. The economic costs of insomnia are also number of recent epidemiologic studies indicate a preva- substantial. One recent estimate places the annual direct lence of 30% to 45% for insomnia symptoms in the prior year costs for insomnia-related problems at nearly $14 billion (1–3). The specific prevalence depends on the definition (including $11 billion related to nursing home care) (14). The prevalence of insomnia Insomnia has been identified as a significant risk factor for disorders is obviously much lower, in the range of 10% to institutionalization in the elderly in some studies (15), but not in others (3). Despite these morbidities, insomnia does not appear to be an independent risk factor for mortality Daniel J. Buysse: Department of Psychiatry, University of Pittsburgh (3,16).