By A. Uruk. Delaware Valley College.

Efficacy of flumazenil in acute alcohol Res 1997;21:430–433 20mg arava visa. Interaction of pregnanolone and lies: a report from the COGA project generic 10 mg arava free shipping. J StudAlcohol 1996;57: pregnenolone sulfate with ethanol and pentobarbital arava 10mg free shipping. The neurosteroid, 3 alpha- with and without an alcoholic first-degree relative. Alcohol Clin hydroxy-5 alpha-pregnan-20-one, protects against bicuculline- Exp Res 1990;14:63–70. Ethanol-like discrimina- Alcohol Clin Exp Res 1995;19:510–516. Diazepam preference in males with and without an alpha-pregnan-20-one in female Macaca fascicularis monkeys. Alcohol Clin Exp Res 1991;15: Psychopharmacology 1996;124:340–346. Preferences for ethanol and diazepam hormones during the estrous cycle. Levels of gamma-aminobutyric lite allopregnanolone in women with premenstrual syndrome. Preliminary evidence effects of ethanol and 3 alpha-hydroxy-5 alpha-pregnan-20-one of reduced cortical GABA levels in localized 1H NMR spectra in relation to menstrual cycle phase in cynomolgus monkeys of alcohol dependent and hepatic encephalopathy patients. Plasma gamma-aminobu- strual distress in women at higher and lower risk for alcoholism. Prog Neuropsychopharmacol Biol Psychiatry 1997; 100. Basic aspects of GABA- Psychopharmacology 1997;130:69–78. GABA receptors are transmission at a calyx-type synapse. J Neurosci 1998;18: increased in brains of alcoholics. Role of GABAA receptors in the actions of alcohol 102. NMDA receptors amplify and in alcoholism: recent advances. Alcohol Alcohol 1994;29: calcium influx into dendritic spines during associative pre- and 115–129. Receptor binding sites nels and their role in neurotransmitter release. Cell Calcium and uptake activities mediating GABA neurotransmission in 1998;24:307–323. Effects of L-type voltage-sensitive calcium graphic studies of cerebral benzodiazepine-receptor binding in channel modulators on the discriminative stimulus effects of chronic alcoholics. Sedative-hypnotic drugs: interaction with calcium benzodiazepine receptors in type II alcoholics measured with channels. Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1439 107. Inhibition of dihydropyri- human 5-HT1D receptor-mediated functional responses in sta- dine-sensitive Ca2 channels by ethanol in undifferentiated bly transfected rat C6-glial cell lines: further evidence differ- and nerve growth factor-treated PC12 cells: interaction with entiating human 5-HT1D and 5-HT1B receptors. Ritanserin, a 5-HT2A/2C in up-regulation of dihydropyridine-sensitive calcium channels antagonist, reverses direct dopamine agonist-induced inhibition by ethanol. Genetic regulation of dihydro- expressed in HEK293 cells. Neuropharmacology 1997;36: pyridine-sensitive calcium channels in brain may determine sus- 713–720. Calcium currents and meta-chlorophenylpiperazine in healthy human subjects. Psy- peptide release from neurohypophyseal terminals are inhibited chiatry Res 1991;38:227–236. Ethanol effects on two treatment of alcohol dependence—a multi-center clinical trial. Serotonin transporter pro- mediates up-regulation of N-type calcium channels by ethanol. Dose-related ethanol- populations and in alcohol-dependent subjects.

Selective D1- and D2-dopamine receptor blockade macology 1998;19:161 buy arava 20mg. Predicting haloperi- [11C]SCH 23390 and [11C]raclopride discount 10 mg arava overnight delivery. Psychopharmacology dol occupancy of central dopamine D2 receptors from plasma (Berl) 1992;107:23–29 generic arava 20mg otc. Sustained decrease occupancy and plasma haloperidol levels. Relationship between dopa- phenylpropyl)piperazinyl decanoate, a long-acting ester deriva- mine D(2) occupancy, clinical response, and side effects: a dou- tive of GBR 12909. GBR12909 that suppress cocaine self-administration in non- 102. Relationship human primates substantially occupy dopamine transporters as between D2 occupancy and prolactin levels in first episode psy- measured by [11C]WIN35,428 PET scans. GBR12909 attenuates CIT binding to monoamine transporters in the monkey and amphetamine-induced striatal dopamine release as measured by human brain. Phasic versus tonic dopamine release and the modula- with risperidone. Elevated dopa decarboxyl- 5-HT2A receptor occupancy in schizophrenic patients. Am J ase activity in living brain of patients with psychosis. Single pho- receptor density and affinity: a PET study with [11C]raclopride ton emission computerized tomography imaging of amphet- in man. Increased striatal dopa- tron emission tomographic study. J Clin Psychopharmacol 1998; mine transmission in schizophrenia: confirmation in a second 18:82–83. Schizophrenia is associated receptor occupancy of olanzapine in schizophrenia: a PET inves- with elevated amphetamine-induced synaptic dopamine con- tigation. D2 dopamine receptor blockade and clinical response: a 123I 126. Increased base- IBZM SPET (single photon emission tomography) study. Psy- line occupancy of D2 receptors by dopamine in schizophrenia. Quantification of neuro- pancy in clozapine treated patients demonstrated by PET. Irreversible binding of chopharmacology (Berl) 1993;110:365–367. Psychotic propensity associated with four- pancy profile of loxapine determined using PET. Neuropsycho- fold elevated dopamine binding to D2-like receptors in caudate pharmacology 1996;15:562–566. Cerebral metabolite abnor- D2 receptor occupancy and plasma levels on low dose oral halo- malities correlate with clinical severity of HIV-1 cognitive motor peridol: a PET study. Brain elimination half-life levels and clinical effects in schizophrenia and schizoaffective of fluvoxamine measured by 19F magnetic resonance spectros- disorder. Brain pharmacokinetics D2 receptor occupancy with low-dose haloperidol treatment: a and tissue distribution in vivo of fluvoxamine and fluoxetine PET study [see comments]. Life Sci 1995;57: tion of the cerebral distribution of general anesthetics in vivo L103–L107. Neurol- optical imaging of protease activity for tumor detection. Neurology 2000;54: of gene expression using magnetic resonance imaging. Fluorescently detect- techniques in multiple sclerosis: clinical applications and clues able magnetic resonance imaging agents. A 'smart' magnetic resonance MR histograms differ between MS subtypes. Neurology 2000; imaging agent that reports on specific enzymatic activity. Imaging brain structure and function, resonance imaging in multiple sclerosis: correlation with attacks, infection and gene expression in the body using light. Nat Med 2000;6: disease in late onset families [see comments].

The identification of an OCD–tic subtype has tion generic arava 10mg with mastercard, 64% had a decrease of more than 50% in Y-BOCS already led to important new genetic and biological studies score buy 10 mg arava free shipping, and 33% had a decrease of more than 75% in Y- and has been directly relevant to treatment purchase 20 mg arava with amex. These results are at odds with fort to characterize pediatric autoimmune neuropsychiatric those of two other prospective longitudinal observational disorders and their relationship to genetic vulnerability to studies of the course of OCDthat have recently been initi- streptococcal infection offers a promising lead for furthering ated at our site. It is compulsive outpatients evaluated at the Yale–Brown clinics possible that we will increase our understanding of predic- and followed them prospectively during a 2-year period. Of tions of remission and relapse related to possible homogene- the 51 patients who started the study meeting full criteria, ous subtypes of illness. A review of these studies suggests 57% still met full criteria after 2 years. Survival analysis that the course of OCD, long thought to be chronic, may revealed a 47% probability of achieving at least partial re- be more episodic than previously believed, particularly in mission during the 2-year study period. It also appears that in some sub- tive study, by Steketee et al. However, a long-term prospec- of partial remission for at least a 2-month period was 53%, tive follow-up study of a large number of patients with and for full remission (no longer meeting criteria) at 5 years OCDis needed to confirm these observations. Rasmussen receives research support from Solvay Phar- maceuticals and Pfizer. The prevailing notion that the course of OCDis chronic and deteriorating has not been consistently borne out by the evidence, particularly in children followed prospectively. REFERENCES Furthermore, the natural course of this disorder appears to have been altered by the availability of effective pharmaco- 1. Lifetime preva- lence of specific psychiatric disorders in three sites. In their review of follow-up Psychiatry 1984;41:958–967. Weissman MM, Bland RC, Canino GJ et al, The cross-national can be categorized as (a) unremitting and chronic, (b) phasic epidemiology of obsessive-compulsive disorder J Clin Psychiatry with periods of complete remission, or (c) episodic with 1994;55:5–10. A follow-up study of obsessional neurotics in Hong Gen Psychiatry 1988;45:1094–1099. Obsessive-compulsive disorder in children and 1986;143:317–322. Washington, DC: American Psychiatric Association, 31. Obsessive compulsive disorder and primary unipolar 1989. Obsessive-compulsive disorders practical manage- pulsive disorder in adolescence: an epidemiologic study. Childhood obsessive- models of obsessive-compulsive disorder. In: Jenike MA, Baer compulsive disorder: a prospective follow-up study. Obsessive-compulsive disorders practical chol Psychiatry 1990;31:363–380. Structured clinical inter- obsessive-compulsive disorder in a community sample of young view for DSM-IV axis II personality disorders (SCID-II). J Am Acad Child Adolesc Psychiatry 1995;34: ington, DC: American Psychiatric Press, 1997. Obsessive-compulsive disorder in children and wood Cliffs, NJ: Prentice-Hall, 1980. Childhood Obsessive-Compulsive Rating Scale (Y-BOCS) reliability and rituals: normal development or obsessive-compulsive symp- validity. Efficacy and tolerabil- interval follow-up evaluation: a comprehensive method for as- ity of serotonin transport inhibitors in obsessive-compulsive dis- sessing outcome in prospective longitudinal studies. Obsessive- of course in obsessive-compulsive disorder. Psychiatry Res 1999; compulsive disorders practical management, third ed. A two- to seven- ogy of behavioral inhibition in children. Child Dev 1987;58: year follow-up study of 54 obsessive-compulsive children and 459. In: Jenike MA, Baer L, Minichiello WE, 85 patients with obsessive-compulsive disorder. Obsessive-compulsive disorders practical management, third 1994;151:441–442. Childhood movement disorders and for patients with obsessive-compulsive disorder. Pediatric autoimmune during the long-term course of unipolar major depressive disor- neuropsychiatric disorders associated with streptococcal infec- der. Clinical findings of significance to of obsessive-compulsive disorder.

Estimates generic arava 10 mg fast delivery, therefore arava 10 mg without a prescription, vary widely buy arava 20 mg visa, though median ing autism to an early developmental abnormality in the figures from extant studies suggest a rate 1. Thus, taken together, the PDDs may affect individuals with autism (8), much more frequently than 15 to 25 per 10,000 school-aged children. Given that autism expected by chance, though whether the presence of epilepsy is a lifelong condition, the prevalence in adults is likely to defines an etiologically meaningful autistic subgroup is un- be similar to that found in children. Two other biological traits that have been investigated are head size and brain morphology. Enlarged head size was Family and Twin Studies noted by Kanner in seven of the first 11 children he de- scribed in 1943. Subsequent studies have revealed that ap- Family and twin studies help to determine the pattern and proximately 20% of autistic individuals have macrocephaly strength of the heritability of a disorder. The recurrence ( 98th percentile for head circumference)(9,10), and the risk of autism for siblings of autistic probands is approxi- few published postmortem studies report that the brains of mately 4% to 5% (19), translating to a sibling relative risk autistic individuals are larger and heavier (megalencephalic) (sibling recurrence risk/population prevalence)of roughly than those of normal controls (11,12). The risk to second- and third-degree relatives tudinal studies of head circumference also suggest that while drops off dramatically to less than 1% (20). Twin studies, some enlargement may take place before birth, an increased which compare concordance rates between monozygotic rate of growth appears to occur during the early postnatal (MZ)and dizygotic (DZ)twins, estimate the heritability period (10,13). Magnetic resonance imaging (MRI) studies for autism to be greater than 90% (21,22). This enlargement, rather than being generalized, may be confined to discrete structures (16). One recent report, for Gender Differences example, found evidence linking abnormalities in caudate volume to ritualistic-repetitive behaviors in subjects with All epidemiologic studies of autism demonstrate a male pre- autism, a finding that is similar to reported relationships ponderance of the disorder. As our ability to measure these cor- Associated Medical Conditions relates becomes more precise, however, their value is likely A host of medical conditions have been reported to cause to increase. They may then serve the purpose of adding occasional cases of autism, including neurofibromatosis, tu- power to genetic studies by increasing phenotypic informa- berous sclerosis (TS), phenylketonuria, rubella, cerebral tion. For most of these disor- ders, however, whether they occur in autism more fre- quently than expected by chance is unclear. TS has the EPIDEMIOLOGY AND GENETIC strongest association; its population prevalence is 1/10,000, MECHANISMS and up to 25% of individuals with TS meet diagnostic crite- ria for autism or PDD (24)(discussed in more detail below). Prevalence Overall, it has been estimated that approximately 5% of The estimated prevalence of autism has increased since the autistic individuals have an associated medical condition mid-1980s from 3 to 5 cases per 10,000 to a current esti- that may play an etiologic role in the development of the mate of 6 to 10 per 10,000 (2,18). Chapter 41: The Molecular and Cellular Genetics of Autism 551 Environmental Determinants the differential gender distribution across IQs suggests ge- netic heterogeneity. The rapidly diminishing relative risk Investigators have repeatedly postulated that in utero events from first- to second- to third-degree relatives, combined might predispose a fetus to the development of autism. Early with the 4:1 MZ:DZ concordance ratio, indicates that twin studies, for example, suggested that obstetric complica- autism is likely to be due to multiple genes interacting in tions differentiated autistic twins from nonautistic co-twins variable combinations in additive, multiplicative, epistatic, (25). Subsequent examination of these and other data, how- or as yet unknown fashions (35). Estimates of the number ever, has shown that the obstetric complications are typically of genes involved have ranged from at least three (36)to quite minor, the association between autism and complica- more than 15 (37). Furthermore, other disorders composed tions is weak (26), and that the causality may be in- of isolated components of the autism phenotype (e. Similarly, some studies have reported genetics of autism will be complicated as well. The weight of evidence, GENETIC INVESTIGATIONS OF AUTISM however, either fails to support such associations or suggests that they account for only a small minority of autism cases Early genetic investigations of autism were hampered by a (29,30). Thus, although perinatal factors are reasonably in- number of constraints, including small sample sizes, incon- ferred in rare instances (e. The they appear to have either a negligible effect or a minor development of standardized diagnostic criteria and ad- effect of undetermined significance. Multicenter col- Estimates of the frequency of chromosomal abnormalities laborations can now gather large, consistently characterized in autism vary widely. Early studies reported rates as high samples, genome-wide screens are practical, sequence data as 20% (31), though recent surveys have reported lower are available for focused genetic investigations, and chromo- frequencies ranging from 3% to 8% (32–34; Wassink et somal studies are more exact and informative. These rates may increase, tions of autism, which are summarized below. Up to 10% of unexplained cases of MR, for example, have been found to be associated with cytoge- Genome-Wide and Focused Linkage and netic abnormalities detectable only by recently developed Association Studies subtelomeric probes, and similar abnormalities may be Four genome-wide linkage studies of autism have been pub- found in autism as well. All these studies have examined abnormalities currently associated with autism include the families containing at least two affected siblings [affected fragile X mutation, other sex chromosome abnormalities, sibling pair (ASP)families] and are summarized in Table and abnormalities of 15q11-q13 (the Prader-Willi/An- 41. The strongest single finding to emerge from these gelman syndrome (PW/AS)region).