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Chapter 46: Behavioral Phenotypes of Neurodevelopmental Disorders 637 7 motrin 400 mg on-line advanced pain treatment center edgewood ky. Abstr Eur J Child Adolesc Psychiatry 1992;1[Suppl]:1–61 purchase motrin 600 mg on-line arizona pain treatment center mcdowell. Behavioral phenotypes in organic genetic disease:pres- 31. Cognitive function in Lesch–Ny- idential address to the Society for Pediatric Research, May 1, han disease (in press). A window onto the Prader–Willi and Angelman syndromes. Brain 1999;122: Prader–Willi syndrome:genes, brain, and behavior. Angelman syndrome result- Dis Child 2000;82:222–225. Discovery of genes involved with learning and memory: clinical manifestations and genetic counselling. J Med Genet an experimental synthesis of Hirshian and Benzerian perspectives. Human haploinsufficiency:one for sor- lamic paraventricular nucleus and its oxytocin neurons (putative row, two for joy. Behavioral phenotypes in mental retardation syn- syndrome. Compulsive and impulsive symptoms disorders,, vol 1. San Francisco:Annual Meeting of the American Psychiatric Asso- Assessment, diagnosis and treatment of the developmental disorders. Diagnostic cri- symptoms in Prader–Willi and 'Prader–Willi-Like' patients. Oxford: of Prader–Willi syndrome:comparison of genetic subtypes. Phenotype-genotype nosis and treatment of the developmental disorders. New York:Ox- correlation in 20 deletion and 20 non-deletion Angelman syn- ford University Press, 1998:306–318. Cam- derline mental retardation with prominent behavioral disturb- bridge, MA:MIT Press, 1999:27–42. Understanding the molecular basis of fragile monoamine metabolism. Behavioural measurement in mental handicap: a guide 44. Oxford:Society for the Study of Behavioural X mental retardation 2 (FMR2) protein in mammalian brain. The greeting behavior of apoptotic neurodegeneration and fetal alcohol syndrome. Savants:mentally retarded individuals with special skills. Analysis of neocortex in three males sociated with a sex-linked human neurological disorder and exces- with fragile X syndrome. The crystal structure of human sis, treatment, and research, second ed. Baltimore:Johns Hopkins hypoanthine-guanine phosphoribosyltransferase with bound University Press, 1996. J Au- profile of Williams syndrome:a complex pattern of strengths and tism Dev Disord 1994;24:67–81. Genome structure dence of dysfunction of brain neurotransmitters in the and cognitive map of Williams syndrome. Hypersociability in Williams syn- markedly reduced in Lesch–Nyhan disease in vivo. J Child Psychol Psychiatry 1998;39: binding of WIN 35,428 correlates with HPRT level and extent 183–189. Cognitive modularity ers of serotonin, dopamine, and norepinephrine mediate seroto- and genetic disorders. HPRT-deficient Williams syndrome:how intact is 'intact'? Child Dev 1997;68: (Lesch–Nyhan) mouse embryos derived from germ line coloniza- 246–262. Mouse models of dows to the soul:evidence of domain-specific sparing in Williams hypoxanthine phosphoribosyltransferase deficiency. A potential animal zygosity implicated in impaired visuospatial constructive cogni- model for Lesch–Nyhan syndrome through introduction of tion. Behavioral differences syndrome:use of chromosomal microdeletions as a tool to dissect between neonatal and adult-6-hydroxydopamine treated rats to cognitive and physical phenotypes Am J Hum Genet 1999;64: dopamine gonists:relevance to neurological symptoms in clinical 118–125.

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Whether voluntary exercise in exists that they have greater plasticity than do mature cells buy generic motrin 400mg on-line knee pain treatment yoga. In a recent study granule cells from the inner and Electrophysiology outer layer of the dentate gyrus were compared order motrin 600mg amex pain treatment lung cancer. The researchers found that the putative Chapter 8: Neurogenesis in Adult Brain 115 young cells had a lower threshold for LTP and were unaf- APA. Gage for comments on the manu- fected by GABA-A inhibition, suggesting enhanced plastic- script. In REFERENCES our studies we have found newly generated cells throughout the granule cell layer. Autoradiographic and histological evidence that a cell is a newborn neuron is by labeling the cell when of postnatal neurogenesis in rats. Autoradiographic and histological studies would be made from such a labeled cell and compared with of postnatal neurogenesis. A longitudinal investigation of the preexisting neurons. Indeed, performance postnatal neurogenesis in some brain regions. Neurogenesis in the adult rat: electron is stimulated, such as by running or enrichment, than in microscopic analysis of light radioautographs. This link may between neurogenesis and behavior 1092–1094. Neuronal production, migration, physiologically measurable changes occur in the brain region and differentiation in a vocal control nucleus of the adult female canary brain. De novo generation of neuronal cells from the adult mouse brain. Several areas of interest emerge when considering the thera- 7. Generation of neurons and astrocytes peutic potential for neurogenesis. First, a strategy that takes from isolated cells of the mammalian central nervous system. Proliferating subventricular zone cells opportunity for cellular transplantation to replace cells that in the adult mammalian forebrain can differentiate into neurons and glia. Genesis of olfac- supports that ability of adult stem cells to survive grafting tory receptor neurons in vitro: regulation of progenitor cell divi- to the adult brain, the fate of the grafted cells appears to sions by fibroblast growth factors. Identification of accurately replace cells in damaged areas of the brain signifi- a neural stem cell in the adult mammalian central nervous sys- tem. Subventricular zone astro- mechanisms that control fate decisions is required in order cytes are neural stem cells in the adult mammalian brain. A second strategy emerges as a direct result of the fact 13. Proliferation and differentiation of progenitor cells throughout the intact adult that the adult brain retains stem cells in situ throughout rat spinal cord. By understanding the internal factors, molecules and 14. Subgranular zone of the dentate gyrus of young rabbits as a secondary matrix. To this end, cell number could be am- resolution autoradiographic study. Dev Neurosci 1982;5: plified, direction of migration could be targeted, and finally 345–358. In all cases a more complete understanding 10409–10414. More hippocampal neu- rons in adult mice living in an enriched environment. Nature a prerequisite for the use of this process in rational strategies 1997b;386:493–495. Environmental stimu- lation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Hippocampal neurogenesis This work was supported by NIA, NINDS, the Lookout in adult Old World primates. Proc Natl Acad Sci USA 1999; Fund, Pasarow Foundation, Holfelder Foundation, and 96:5263–5267. Adult spinal cord stem hippocampus of the adult macaque monkey. Proc Natl Acad Sci cells generate neurons after transplantation in the adult dentate USA 1999;96:5768–5773. Intrinsic and extrinsic factors regulating vertebrate 23.

Am J Med Genet 1997;74:380– tein tau antigenicity is prominent in all types of tangles purchase motrin 400 mg free shipping pediatric pain treatment guidelines. Abnormal tau proteins tauopathy with presenile dementia is localized to chromosome in progressive supranuclear palsy: similarities and differences 17 order 400 mg motrin with mastercard pain treatment medicine clifton springs ny. J Neuropathol Exp dementia is linked to chromosome 17q21-q22: a genetic and Neurol 1996;55:534–539. Frontotemporal dementia degeneration, olivopontocerebellar atrophy and Shy-Drager and parkinsonism linked to chromosome 17: a new group of syndrome). Neurodegenerative disorders with tau (PHFtau) in Niemann-Pick type C disease is similar to extensive tau pathology: a comparative study and review. Acta Neuropathol (Berl) 1995; Neurol 1996;40:139–148. Neurofibrillary tan- ple system tauopathy with presenile dementia: a disease with Chapter 94: Tau Protein and Tauopathy 1351 abundant neuronal and glial tau filaments. Proc Natl Acad Sci high molecular weight tau present in the peripheral nervous USA 1997;94:4113–4118. Neuroscience 1984;11: and association of A beta 40 with cored plaques. Proc Natl Acad Sci USA 1981; mer neurofibrillary tangles in diseases other than senile and 78:3269–3273. Frequency of stages of Alzheimer-related tion of axonal microtubules. Paired helical filaments in electron microscopy of Alz- and nonuniformity in the dendrite. Microtubule densities and total numbers in selected Alzheimer paired helical filaments: abnormal phosphorylation axons of the crayfish abdominal nerve cord. Projection domains of MAP2 mer paired helical filament. Acta Neuropathol 1996;92:42– implications for the microtubule-associated protein tau: locali- 48. Lab Invest 1991;64: phorylated tau protein segregates to the somatoaxonal compart- 693–702. Tau pathol- factor-induced neurite outgrowth in PC12 cells involves the coordinate induction of microtubule assembly and assembly- ogy in two Dutch families with mutations in the microtubule- promoting factors. Ultrastructure tubule protein levels during cellular morphogenesis in nerve and biochemical composition of paired helical filaments in corti- growth factor-treated PC12 cells. Microtubule formation and sequencing of the cDNA encoding a core protein of the paired neurite growth in cerebellar macroneurons which develop in helical filament of Alzheimer disease: identification as the micro- vitro: evidence for the involvement of the microtubule-associ- tubule-associated protein tau. Proc Natl Acad Sci USA 1988;85: ated proteins, MAP-1a, HMW-MAP2 and Tau. A protein is tightly bound to paired helical filaments. Neuron 1988;1: factor essential for microtubule assembly. Modulation of gragment of tau derived from the core of the paired helical the dynamic instability of tubulin assembly by the microtubule- filament of Alzheimer disease. Proc Natl Acad Sci USA 1988; associated protein tau. Epitopes that span the sense oligonucleotides in primary cerebellar neurons. Nature tau molecule are shared with paired helical filaments. A68: a major subunit of oligonucleotides on neurite formation of cultured cerebellar ma- paired helical filaments and derivatized forms of normal tau. Straight and paired helical filaments in Alzheimer nization in small-calibre axons of mice lacking tau protein. The distribution of tau tivity, and impairment in fear conditioning in tau-deficient in the mammalian central nervous system. Dephosphoryla- associated protein tau containing four tandem repeats: differen- tion of tau protein and Alzheimer paired helical filaments by tial expression of tau protein mRNAs in human brain. Expression of separate isoforms of human filament tau. Tau protein binds to microtubules recapitulates phosphorylation during development. Proc Natl through a flexible array of distributed weak sites. Identification of a novel microtubule in human, primate, and rat brain: evidence that a pool of tau binding and assembly domain in the developmentally regulated is highly phosphorylated in vivo and is rapidly dephosphorylated inter-repeat region of tau. Biopsy-derived between the proline-rich and repeat regions of tau enhance mi- adult human brain tau is phosphorylated at many of the same crotubule binding and assembly. Proc Natl Acad Sci USA 1992;89:1983– phosphorylation at specific sites. Sequen- specific functional impairments in distinct tau isoforms of he- tial phosphorylation of tau by glycogen synthase kinase-3beta reditary FTDP-17.

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Hunt years of middle age and among the elderly motrin 600 mg cheap joint pain treatment in ayurveda, and several stud- was quoted as saying generic 400mg motrin amex pain research treatment impact factor, 'The question is not whether there ies have noted a slight upturn in the riskfor alcohol depen- are three or four million [addicts], but that the number is dence during the last decades of life, at least among men several million rather than only several hundred thousand' (27). Nonetheless, these exceptions help prove the more (25). The view espoused by Newman and Cates (25) actually A recent intriguing discovery about male–female differ- was much more harsh. They wrote, 'The great disparity of ences in drug use within the United States is that a male the findings of studies using different methods of enumera- excess is found at the earliest stages of drug involvement; tion generally ensures that data will be found to support any boys are more likely than girls to be exposed to opportunities position, and contradictory information is simply ignored. However, once presented with the oppor- They concluded, 'Objectives of studies that are intended tunity, they are equally likely to try a drug (28). Further- to measure the incidence and prevalence of addiction must more, once drug use has started, women are almost as likely be reassessed in terms of experience. It is necessary to ask as men to become drug-dependent (12. Analyses of retrospective estimate the number of active drug users in populations data from the Epidemiologic Catchment Area studies and at the state level, with sample sizes for the U. National the National Comorbidity Survey have highlighted corre- Household Survey on Drug Abuse growing from under sponding differences in the experiences of successive birth 10,000 respondents per year in the early 1990s to more than 70,000 respondents per year in the early twenty-first cohorts born during the first two-thirds of the twentieth century. According to this evidence, the riskfor drug depen- dence has been markedly greater in persons born since World War II than in prior birth cohorts (17,29–31). RUBRIC 2, LOCATION (VARIATION): 'IN The location of cases in relation to geography also has THE POPULATION, IS THERE ANY been scrutinized in descriptive epidemiologic studies. Retrospectively constructed geographic spread of the epidemic of heroin use in the United States during the Vietnam War era. Data from age at onset of cases admitted to treatment facilities. An assessment of the diffusion of heroin abuse to medium-sized American cities. Washington, DC: Special Action Office for Drug Abuse Prevention, 1974, with permission. ESTIMATED PREVALENCE OF ILLICIT DRUG USE IN THE UNITED STATES Estimated Proportion Estimated with a Prevalence Number History of of Recent Survey of Survey Illicit Drug Illicit Drug Year Respondents Use (%) Use (%) 1971–72 3,760a 15–22a N/Aa 1979 7,224 31. Estimated geographic distribution of coca paste smoking among Chilean youth, 1999. Parental attention and risk of coca paste smoking in findings, 1998. Rockville, MD: Chile: preliminary data from the 1999 national school survey in Department of Health and Human Services, substance abuse and Chile. Rockville, MD: Department of Health and Human Services, Mental Health Services administration, 2000. In some instances, weaklinks in the chains of disease What is common to all these epidemiologic observations causation have been spotted by epidemiologists working is that they describe, but do not explain or account for, the with basic quantitative methods, such as cross-tabulation or observed variation. We know that men have been more plotting of incidence estimates, as was done for maternal likely to become drug-dependent than women, but the stud- age and riskfor Down syndrome. Complex diseases and ies that produced solid evidence on this variation have not conditions such as the drug dependence syndromes do not helped us explain why this is so. The same is true for the yield so readily; what might seem to be an apparently simple epidemiologic observations of birth cohort differences, 'chain' of causation actually turns out to be a complex which prompt speculation about the greater availability of 'web' of causation of multifactorial origin. The patterns of epidemic spread of cology, epidemiology sometimes can turn to the power of heroin use in the United States remain unexplained, and it randomized, controlled trials and multiple replications for is possible that the exclusive attention to treated cases in definitive evidence of the web of causation. However, a great the study of Hunt (24) may have produced a biased impres- many of the important questions in the intersection between sion of the temporal sequencing of spread through different epidemiology and neuropsychopharmacology cannot be an- areas. Finally, at one level, the north–south pattern of coca swered with randomized, controlled trials; in some instances paste smoking in Chile may be interpreted as a manifesta- of 'natural experiments,' the concept of replication leaves tion of proximity to the coca-producing countries, but no much to be desired. More be repeated, we have the experience of members of the U. Virtually all Vietnam impression left by initial descriptive observations of this veterans were exposed to the opportunity to try heroin type. When diagnostic interview schedule field study methods were used RUBRIC 3, CAUSES: 'IN THE POPULATION, to assess a large representative sample of Vietnam returnees, WHY DO SOME BECOME AFFECTED WHILE almost 20% of the study sample qualified as cases of active OTHERS ARE SPARED? Nevertheless, no more than a fraction continued to use heroin or remained Concepts and History heroin-dependent once they returned stateside to home. Studying Vietnam veter- toward explaining and accounting for the observed phe- ans who came home to urban areas known for heroin avail- nomena, rather than merely describing the patterns of oc- ability, they found substantially higher fractions returning currence. To the extent that the search for causes can lead to heroin use. Nonetheless, even in this study sample, a us toward more effective intervention maneuvers, work great many heroin users did not come backfrom Vietnam under this rubric merits a special status; many regard this to the United States and return to heroin dependence once search as one of the highest callings of epidemiology (33). These results challenge con- Nonetheless, numerous examples show that epidemiologic ventional notions of any inherent addictive quality, abuse research can have a considerable impact on the health of a potential, or dependence liability of heroin as a chemical population even before the search for causes is complete. HIV prevention controlled trial of exposure to heroin in otherwise drug- efforts directed toward the unsafe sex practices of gay men naıve¨ young adults. Recent evidence on the early onset of in the United States helped to change the dynamics of the drug use raises similar issues.

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