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By G. Jorn. Brooks Institute.

Ethanol with- cal perfusion and metabolic rate is associated with reduced drawal seizures have been linked to neurotoxicity in these performance on cognitive tests that engage the frontal cortex patients (225) buy generic innopran xl 40 mg. Similarly cheap innopran xl 80mg, cerebellar metabolic deficits are associated white matter loss was particularly associated with ethanol with behavioral evidence of cerebellar dysfunction (236) discount innopran xl 40 mg amex. Although cortical atrophy has been described in ethanol-dependent patients with good nutritional status (227), the Wernicke-Korsakoff syndrome Behavioral Studies and hepatic cirrhosis are generally associated with more prominent MRI volumetric deficits in cortical and limbic The most profound cognitive deficits associated with alco- structures than ethanol-dependent patients who are other- holism are the memory impairments arising from nutri- wise healthy (228). Although the factors that might predispose individuals to develop alcohol- most severe consequences of alcoholism for cognition may ism. One risk factor, antisocial personality disorder, appears not reflect the direct toxic effects of ethanol on the brain, to be independently associated with reductions in frontal many patients exhibit cognitive deficits independent of cortex gray matter volume (229). Thus, the observation that these factors that reflect the combined impact of age, famil- frontal gray matter volume loss is present in young ethanol- ial vulnerability for alcoholism, adaptations to ethanol dependent patients could reflect a combination of the vul- effects on the brain, perhaps degree of liver injury (244), nerability to alcoholism and atrophic effects of ethanol de- presence of comorbid depression, and ethanol-related neu- pendence (214). Cognitive function is further compromised in those patients who continue to drink, due to the direct effects of ethanol on cognition (246). The familial vulnerability to alcoholism and traits associ- Magnetic Resonance Spectroscopy ated with that vulnerability are associated cognitive deficits Magnetic resonance spectroscopy (MRS) has been applied and educational achievement (247). Although reductions to the evaluation of structural deficits in alcoholic patients in attention, planning, visual-spatial learning, and impulse in a limited fashion. Proton-MRS ([1H]MRS) enables the control have been described in children of alcoholics (248), measurement of N-acetyl-aspartate (NAA), a constituent of these findings are not universal (249). One study found reductions in the NAA/ be largely accounted for by comorbid traits such as antisocial creatine ratio in the frontal cortex and cerebellum of personality, similar to both MRI and event-related potential ethanol-dependent patients (230,231). A phosphorus-MRS (ERP) findings in alcohol dependent patients (250,251). Familial his- these effects contribute to its complex array of behavioral tory of alcoholism appears to compound the negative conse- effects in animals and humans. Direct effects of ethanol on quences of social drinking on cognitive function (253). Further, the cellular consequences of exposure to a familial alcoholism history (254). Thus it is possible that ethanol are modulated by ethanol-sensitive regulatory en- cognitive responses to ethanol may also contribute to the zymes, such as PKA and PKC. In this regard, there is growing evidence that the in patients (255). Ethanol-dependent patients show many interplay of the prefrontal cortex (PFC) and limbic struc- impairments in cognitive function. Deficits in the level of tures including the nucleus accumbens (NAc) and amygdala performance and efficiency of verbal skills, learning and generally plays an important role in reward (266,267). Cognitive deficits the output of the NAc including NMDA receptor antago- may reflect in part the degree of neurotoxicity related to nism, GABA facilitation, and enhancement in 5-HT and alcoholism. For example, young ethanol-dependent patients dopamine release (267). Drugs that antagonize the inhibi- may show normal brain volumes on MRI and normal cogni- tory effects of ethanol in the NAc, such as naltrexone (268), tive function (257,258). With repeated episodes of ethanol may play an important role in the treatment of alcoholism withdrawal and advancing age, cognitive deficits become even if opiate receptors are not a major site of action for more pronounced (259). Cognitive function improves over the initial year of so- Abnormalities in PFC development may be an important briety; however, the domains of cognitive function do not factor influencing the vulnerability to alcoholism, in part recover at the same rate and recovery may be partial (260, by altering the interplay of PFC and NAc that underlies 261). Poor cognitive function at the time that treatment is reward. As noted above, the vulnerability to alcoholism, initiated appears to predict improved alcohol-related treat- particularly in the case of individuals with antisocial person- ment outcomes (262). However, progress in treatment may ality disorder or impulsive traits, appears to be associated be reflected in improved cognitive function (263). Consis- with behavioral, physiologic, and structural evidence of PFC tent with the view that treatment may modulate cognitive dysfunction. An important and unanswered question is, recovery, some cognitive deficits in recovering patients ap- How does PFC dysfunction contribute to the vulnerability pear to respond to cognitive rehabilitation (264). Hypotheses have been presented that suggest In summary, the behavioral studies describe the display that alcoholism is just one of several forms of impulsive of deficits in cognitive functions that may have implications behavior that these individuals fail to inhibit due to a general for circuitry dysfunction in alcoholism: executive function deficiency in behavioral inhibition or as a consequence of deficits associated with the prefrontal cortex, visual-spatial the failure to anticipate the negative consequences of alco- deficits associated with the parietal cortex, and learning/ holism (269,270). Overall, these studies reward dysfunction hypothesis resting on a consideration of are consistent with the findings related to reduced tissue the impact of PFC dysfunction on mechanisms underlying volume on MRI, reductions in cortical metabolism with reward. The PFC input into limbic structures responsible fluorodeoxyglucose (FDG)-PET (242), and information for reward is critical to the experience, anticipation, and processing deficits in ERP studies (265). The activation of PFC outputs plies a connection between alterations in brain structure, to limbic structure causes a release of glutamate that may function, and behavior related to alcoholism. From this perspective, PFC activation serves THE INTERPLAY OF THE NEURAL as a 'brake' on reward mechanisms. In fact, it is tempting CIRCUITRY AND NEUROCHEMISTRY OF to think of this PFC-NAc interplay as a pathway contribut- ALCOHOLISM: IMPLICATIONS FOR ing to the capacity of human judgment to restrain impulsive TREATMENT reward-related behavior. Yet abnormal PFC input would also be expected to disturb NAc function with respect to Ethanol has multiple specific effects on amino acid, mono- both the processing of rewarding stimuli generally and drugs amine, and neuropeptide neurotransmitter systems, and of abuse in particular. Thus, it may not be surprising that 1436 Neuropsychopharmacology: The Fifth Generation of Progress the familial vulnerability to alcoholism is associated with ality disorder and alcohol-induced aggression. Alcohol Clin Exp both PFC functional deficits and alterations in the capacity Res 1998;22:1898–1902.

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To defne such a set of indicators is worldwide; these provide the basis on which to another task for research innopran xl 40mg free shipping. Chapter 3 shows cheap 40mg innopran xl otc, Tere are already numerous indicators of by example generic innopran xl 80mg with amex, how research can address a wide health-service coverage that have been standard- range of questions about universal health cov- ized and validated, and they are widely used. Te erage and how it can provide answers to guide techniques for measurement have been greatly health policy and practice. Health systems fnancing: the path to universal coverage. Sustainable health fnancing, universal coverage and social health insurance. In: Fifty-eighth World Health Assembly, Geneva, 16−25 May 2005. Geneva, World Health Organization, 2005 (Document WHA58/2005/REC/1). The world health report 2008 − primary health care, now more than ever. United Nations General Assembly Resolution A/RES/67/81. Address at the Conference of Ministers of Finance and Health. Achieving value for money and accountability for health outcomes, Tunis, 4 July 2012. From the Earth Summit to Rio+20: integration of health and sustainable development. Universal health coverage: the third global health transition? Analysing changes in health fnancing arrangements in high-income countries. Improving health system efciency as a means of moving towards universal coverage. Paris, Organisation for Economic Co-operation and Development, 2010. Strengthening cost-efectiveness analysis in Thailand through the establishment of the health intervention and technology assessment program. Scaling up health policies and services in low- and middle-income settings. Scaling up cervical cancer screening in the midst of human papillomavirus vaccination advocacy in Thailand. Economic evaluation of policy options for prevention and control of cervical cancer in Thailand. What are the economic consequences for households of illness and of paying for health care in low- and middle-income country contexts? WHO report on the global tobacco epidemic, 2011: warning about the dangers of tobacco. Drivers of tuberculosis epidemics: the role of risk factors and social determinants. Tuberculosis and poverty: the contribution of patient costs in sub-Saharan Africa – a systematic review. Reaching the poor: challenges for TB programmes in the Western Pacifc Region. Tuberculosis a comprehen- sive, international approach, 3rd ed. Economic impact of tuberculosis at the household level. The International Journal of Tuberculosis and Lung Disease, 1999,3:596-602. PMID:10423222 23 Research for universal health coverage 28. Socio-economic impact of tuberculosis on patients and family in India. The International Journal of Tuberculosis and Lung Disease, 1999,3:869-877. Costs of tuberculosis for households and health care providers in Dar es Salaam, Tanzania. Tropical Medicine & International Health, 2001,6:60-68. Social franchising of TB care through private GPs in Myanmar: an assessment of treatment results, access, equity and fnancial protection. Patient and household costs associated with tuber- culosis diagnosis in Lilongwe. Bulletin of the World Health Organization, 2007,85:580-585. Economic evaluation of public-private mix for tuberculosis care and control, India. Socio- economic profile and costs among tuberculosis patients. The International Journal of Tuberculosis and Lung Disease, 2009,13:698-704. Cost and cost-efectiveness of PPM-DOTS for tuberculosis control: evidence from India. Bulletin of the World Health Organization, 2006,84:437-445.

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Dopamine Transporter Imaging as a USE OF RADIOTRACER IMAGING IN Biological Marker in Parkinson Disease THERAPEUTIC DRUG DEVELOPMENT Imaging of a biological marker may provide information Radiotracer imaging can provide useful information about that is useful either for diagnosis or as a monitor of disease molecules that are either the direct target of or indirect progression generic 80mg innopran xl mastercard. In Parkinson disease cheap innopran xl 80mg with mastercard, the two most successful markers for the effects of therapeutic drugs generic 40 mg innopran xl overnight delivery. For example, imaging targets used as biological markers are measures of if both the tracer and therapeutic drug competitively bind dopamine synthesis with [18F]FDOPA and of dopamine to the same target, then imaging can provide direct informa- terminal innervation with ligands for dopamine transporter. In addition, the molecular target mea- progressive loss of dopamine neurons in the nigrostriatal sured by the tracer (e. Such measurements are possible with in vivo deposition). However, these tracers do not detect the same biological process. Whereas Measurement of Receptor Occupancy 18 [ F]FDOPA detects metabolic activities at dopamine nerve Molecular imaging can provide useful guidance for two as- terminals, the tracers for dopamine transporter simply mea- pects of drug administration: dose and dosing interval. Because of this differ- dose is most easily chosen with a known target occupancy ence, the sensitivity to detect the decrease in dopamine neu- 420 Neuropsychopharmacology: The Fifth Generation of Progress rons may be different. In fact, both human and animal ing mood disorders (67) and drug addiction (68). However, studies have indicated that the imaging of dopamine trans- only a small number of PET and SPECT studies have been porter is more sensitive to dopamine neuronal loss (59). Although tracers have been Dopamine transporter can be quantified with SPECT developed to image three major biochemical cascades [i. Therefore, imaging of the dopamine transporter in tide (PI), and arachidonate pathways], all existing ligands movement disorders is widely performed in many developed have moderate to significant technical limitations, and bet- countries. Some of these tracers are lipids, It is clinically important but sometimes difficult to differ- and their nonspecific binding is too high. In addition, be- entiate essential tremor and Parkinson disease. Dopamine cause most of these tracers do not bind to a single type of transporter imaging clearly distinguishes these two groups, protein but are metabolized by several enzymes, the inter- with only a small overlap (60,61). However, dopamine pretation of the results is not clear. Further, these techniques have shown bilateral loss of dopamine transporter in hemi- Imaging of this signal transduction system was initially at- Parkinson disease (i. The binding of [11C]forskolin may be correlated with the Restoring dopamine levels with L-DOPA is still the core activation of adenylate cyclase (71). However, brain uptake medication treatment of Parkinson disease. Although palliative treat- PDE-IV is the major subtype in brain of PDE, which hydro- ment with L-DOPA is clearly of significant clinical benefit, lyzes cAMP into 5′-AMP. PDE-IV is composed of four current drug development is oriented toward neuroprotec- major enzyme subtypes, PDE-IV A, B, C, and D, and all tive treatments designed to slow the loss of dopamine neu- four subtypes are found in human brain (73). Rolipram rons and the consequent progression of symptoms. As a binds to and inhibits all four PDE-IV subtypes with high biological marker of dopamine terminal innervation of the affinity. In one report of a rat ex vivo study, [11C]rolipram striatum, dopamine transporter imaging may well be useful was a promising tracer exhibiting high specific brain uptake to monitor whether such new therapies actually slow the loss (72). Further evaluation of the binding selectivity and kinet- of dopamine neurons. In fact, SPECT imaging is sensitive to ics must be performed in nonhuman primates and humans and can quantify dopamine transporter loss in longitudinal subjects. Therefore, with appropriate Phosphoinositide System sample sizes, this imaging technique can quantify a relevant biological marker as a surrogate measure of the efficacy of Imahori and colleagues have studied the PI system in vivo putative neuroprotective therapies. They showed specific incorporation of the tracer in the chemical components of the rat PI system, such as phos- IMAGING POST-RECEPTOR SIGNAL phatidic acid, phosphatidylinositol, phosphatidylinositol 4- TRANSDUCTION phosphate, and phosphatidylinositol 4,5-bis-phosphate (74). Further, the tracer uptake was increased by an agonist The majority of the imaging studies performed to date have at the muscarinic ACh receptor, which is known to be cou- focused on the synapse: transporters as presynaptic targets, pled with the PI system (74). Therefore, two promising areas for expansion in the near Under these circumstances, intersubject variability in the future are post-receptor signal transduction and subsequent amount of tracer delivered to brain may be primarily deter- changes in gene expression. Abnormalities in second mes- mined by its binding to plasma components and not by senger systems have been postulated to play important neuronal activity of the PI system. If intersubject variability pathophysiologic roles in many psychiatric illnesses, includ- in f1 (the free fraction of tracer in plasma) is noted, tracer Chapter 31: In Vivo Molecular Imaging 421 uptake cannot be compared among different subjects. Several modalities are applied in cancer did indeed show such behavior (76). Further, whatever imaging, including (a) imaging oncogene products with ra- amount of a highly lipophilic tracer actually crosses the dioactively labeled antibodies, (b) imaging messenger RNAs blood–brain barrier tends to exhibit a high rate of nonspe- with labeled antisense oligonucleotides (81), (c) imaging cific binding. In summary, because of the difficulty in abso- reporter gene products with labeled reporter probes (82, lute quantification, the utility of this tracer as a quantitative 83), and (d) applying conventional techniques with labeled measure may be significantly limited. Because the blood–brain barrier presents a special obsta- cle in neuroimaging, most techniques successfully used in Arachidonate cancer imaging are difficult to apply in brain imaging. For The utility of [11C]arachidonate to detect in vivo activity this reason, the first approach with antibodies is not possible of phospholipase A2 has been studied rigorously. After intra- in brain imaging unless the integrity of the blood–brain venous injection, [11C]arachidonate is readily taken up barrier is disrupted, as in the case of brain tumors. By stimu- used, is also difficult because these multiply charged com- lating receptors that are linked to phospholipase A2, proba- pounds do not cross the blood–brain barrier in any appre- bly via the PI pathway, the labeled phospholipids are ciable amount. To make radioactively labeled oligonucleo- catalyzed to generate arachidonate, and the regionally local- tide probes pass the blood–brain barrier, complicated ized enhancement of phospholipid turnover increases the techniques are required, including the utilization of recep- uptake of [11C]arachidonate. The cholinomimetic arecoline tor-mediated transport (e.