The WPPSI was used in a Manhattan, N.Y., public school because administrators, teachers, and parents had asked for help in understanding children who had difficulty in learning to read well, despite special efforts to help them. A preventive intervention DrOgraM was begun based on a clinical study of every first grader. :Forty children were predicted to make normal progress; BC, a "high risk" group, gave evidence on neurological and perceptual examinations that they might have learning problems; an 12 children were omitted. High risk cases were those with a discrepancy between expectancy and achievement. Comparisons were made of the total groups of high risk and normal progress children, of samples matched for TO and sex, and of subgroups based upon diagnosis within the Intervention (high risk) group. Despite the small diagnostic subgroups, some tentative conclusions can be drawn; (1) the WPPST produced rich clinical material best unders+ool in conjunction with the diagnostic subgroups; (2) the quantitative and qualitative wPPFT material helps in the selection and diagnostic processes and in planning intervention; and (3) it is inadvisable to assume that learning disability is a homogeneous condition manifesting itself in a characteristic cognitive pattern in first grade. WPPSI Profiles for some typical cases and for the diagnostic subgroups are included. (CV) U.S. DEPARTMENT OF HEALTH, EDUCATION & WELFARE OFFICE OF CA THIS DOCUMENT HAS EDU BEEN TION CEPRODUCED EXACTLY A5 RECEIVED FROM THE PERSON OR ORGANIZATION ORIGIN STING IT. POINTS OF SARIL VIEW R O OPINIONS S STATED DO N,T NECESY REPRENT OFFICIAL OFFICE OF EDUCATION POSITION OR POLICY Clinical-Diagnostic Use of the WPPSI in Predicting Learning Disabilities in Grade One Rosa A. Hagin, Ph.D. Archie A. Silver, M.D. Carol J. Corwin, B.A. * From the Department of Psychiatry, New York University Medical School. ClinAcal-Diagnostic Use of the WPPSI in Predicting Learning Disabilities in Grade One Assessment of cognitive functioning is a basic aspect of the diagnosis of learning disability. This paper describes the use of the Wechsler Preschool and Primary Scale of Intelligence for this purpose with children whom it has been our privilege to study as an intact Troup of first graders during the past school year. These children attend a public school located on 33rd Street in Manhattan, almost in the shadow of Mew York University Medical Center where our Language Research Unit is housed. The project was initiated in response to a request by school administrators, teachers, and parents for help in understanding children who were not learning to read well, despite such efforts as an afterschool tutoring program, provision of textbooks emphasizing urban content, "linguistically-based" readers, and special groups for children for whom English was a second language. This was not an idle complaint. Survey of group test scores indicated that in 1968: 61% of the first graders had earned scores in the lowest two categories of the Metropolitan Readiness test 40% of the second graders scored below second grade on reading tests given near the end of second grade 58% of the sixth graders scored below grade on reading tests given near the end of sixth grade decided to offer a preventive program based upon clinical study of every first grader. This study would utilize methods developed over the past twenty years at our Language Research Unit, with an interdisciplinary approach to diagnosis forming the basis for treatment planning. The intervention aspect, and as much of the diagnostic work as possible,

Neuron differentiation is a complex process involving various cell–cell interactions, and multiple signaling pathways. We showed previously that CD40 is expressed and functional on mouse and human neurons. In neurons, ligation of CD40 protects against serum withdrawal-induced injury and plays a role in survival and differentiation. CD40 deficient mice display neuron dysfunction, aberrant neuron morphologic changes, and associated gross brain abnormalities. Previous studies by Tone and colleagues suggested that five isoforms of CD40 exist with two predominant isoforms expressed in humans: signal-transducible CD40 type I and a C-terminal truncated, non-signal-transducible CD40 type II. We hypothesized that differential expression of CD40 isoform type I and type II in neurons may modulate neuron differentiation. Results show that adult wild-type, and CD40−/− deficient mice predominantly express CD40 type I and II isoforms. Whereas adult wild-type mice express mostly CD40 type I in cerebral tissues at relatively high levels, in age and gender-matched CD40−/− mice CD40 type I expression was almost completely absent; suggesting a predominance of the non-signal-transducible CD40 type II isoform. Younger, 1 day old wild-type mice displayed less CD40 type I, and more CD40 type II, as well as, greater expression of soluble CD40 (CD40L/CD40 signal inhibitor), compared with 1 month old mice. Neuron-like N2a cells express CD40 type I and type II isoforms while in an undifferentiated state, however once induced to differentiate, CD40 type I predominates. Further, differentiated N2a cells treated with CD40 ligand express high levels of neuron specific nuclear protein (NeuN); an effect reduced by anti-CD40 type I siRNA, but not by control (non-targeting) siRNA. Altogether these data suggest that CD40 isoforms may act in a temporal fashion to modulate neuron differentiation during brain development. Thus, modulation of neuronal CD40 isoforms and CD40 signaling may represent important therapeutic modalities for neurodegenerative and neurodevelopmental disorders, as well as, for enhancement of neurogenesis.

Almost all degenerative diseases of the CNS are associated with chronic inflammation. A central step in this process is the activation of brain mononuclear phagocyte cells, called microglia. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not fully understood. In the peripheral nervous system, recent studies suggest that an endogenous 'cholinergic anti-inflammatory pathway' regulates systemic inflammatory responses via alpha 7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. Here we report for the first time that cultured microglial cells express alpha 7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent, and immunohistochemistry analyses. Acetylcholine and nicotine pre-treatment inhibit lipopolysaccharide (LPS)-induced TNF-alpha release in murine-derived microglial cells, an effect attenuated by alpha 7 selective nicotinic antagonist, alpha-bungarotoxin. Furthermore, this inhibition appears to be mediated by a reduction in phosphorylation of p44/42 and p38 mitogen-activated protein kinase (MAPK). Though preliminary, our findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through alpha 7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties.

To address the lack of a simple and standardized instrument to assess overall illness severity of Tourette's disorder (TD), the authors developed and tested a 15-item scale to measure a broad range of common symptoms including tics, inattention, hyperactivity, obsessions, compulsions, aggression, and emotional symptoms. Independent investigators used the 15-item Tourette's Disorder Scale (TODS) to assess 60 TD patients who were taking part in a double-blind placebo-controlled multicenter 8-week treatment study. Interrater reliability, internal consistency, convergent and discriminant validity, and sensitivity to change were examined. The TODS was associated with good interrater reliability, excellent internal consistency, and favorable levels of validity and sensitivity to change. Individual TODS items showed good convergent and discriminant validity against other measures. The TODS is a simple, efficient way for clinicians and parents to rate the severity of multiple symptoms commonly found in patients with Tourette's disorder.

Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by both motor and vocal tics. The etiology of TS is poorly understood; however, evidence of genetic transmission arises from family and twin studies. A complex mode of inheritance has been suggested, likely involving contributions of several genes with different effect size. We describe here two unrelated families wherein balanced t(6;8) chromosomal translocations occur in individuals diagnosed with TS. In one of these families, the transmission of the translocation is associated with learning and behavioral difficulties; in the other family, one parent is unaffected and the other cannot be traced, thus transmission cannot be demonstrated and it is possible that the translocation may have occurred de novo. The breakpoint on chromosome 8 occurs within the q13 band in both families, suggesting that a gene or genes in this region might contribute to the TS phenotype. Existing linkage and cytogenetic data, suggesting involvement of chromosome 8 in TS families and individuals, further support this hypothesis. We have identified two YAC clones mapping distal and proximal to the chromosome 8 translocation site, as determined by fluorescent in situ hybridization (FISH). PCR amplification of genetic markers in this region, using isolated chromosomes from one of the patients, followed by BAC screening with the closest flanking genetic markers, has identified a 200-kb BAC, which, by FISH, we have demonstrated encompasses the chromosome 8 breakpoint in both families. The fact that the chromosomal breaks in the TS cases from both families occur within such a small region of chromosome 8 further supports the hypothesis that disruption of a gene or genes in this part of chromosome 8 contributes to the clinical phenotype.

To address the lack of a simple and standardized instrument to assess overall illness severity of Tourette's disorder (TD), the authors developed and tested a 15-item scale to measure a broad range Of common symptoms including tics, inattention, hyperactivity, obsessions, compulsions, aggression, and emotional symptoms. Independent investigators used the 15 item Tourette's Disorder Scale (TODS) to assess 60 TD patients who were taking part in a double-blind placebo-controlled multicenter 8-week treatment study. Interrater reliability, internal consistency, convergent and discriminant validity, and sensitivity to change were examined. The TODS was associated with good interrater reliability. excellent internal consistency, and favorable levels of validity and sensitivity to change. Individual TODS items showed good convergent and discriminant validity against other measures. The TODS is a simple, efficient way for clinicians and parents to rate the severity of multiple symptoms commonly found in patients with Tourette's disorder.

Depression and AnxietyVolume 16, Issue 3 p. 89-92 Research Article Neuronal nicotinic receptor inhibition for treating mood disorders preliminary controlled evidence with mecamylamine† R. Douglas Shytle Ph.D., Corresponding Author R. Douglas Shytle Ph.D. [email protected] Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida Center for Infant and Child Development, University of South Florida College of Medicine, Tampa, Florida Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neurosurgery, University of South Florida College of Medicine, Tampa, Florida Department of Pharmacology, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaCenter for Aging and Brain Repair, Department of Neurosurgery, MDC-78, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33613Search for more papers by this authorArchie A. Silver M.D., Archie A. Silver M.D. Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida Center for Infant and Child Development, University of South Florida College of Medicine, Tampa, Florida Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this authorKathy H. Sheehan Ph.D., Kathy H. Sheehan Ph.D. Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this authorDavid V. Sheehan M.D., M.B.A., David V. Sheehan M.D., M.B.A. Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this authorPaul R. Sanberg Ph.D., D.Sc., Paul R. Sanberg Ph.D., D.Sc. Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida Center for Infant and Child Development, University of South Florida College of Medicine, Tampa, Florida Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neurosurgery, University of South Florida College of Medicine, Tampa, Florida Department of Pharmacology, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this author R. Douglas Shytle Ph.D., Corresponding Author R. Douglas Shytle Ph.D. [email protected] Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida Center for Infant and Child Development, University of South Florida College of Medicine, Tampa, Florida Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neurosurgery, University of South Florida College of Medicine, Tampa, Florida Department of Pharmacology, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaCenter for Aging and Brain Repair, Department of Neurosurgery, MDC-78, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33613Search for more papers by this authorArchie A. Silver M.D., Archie A. Silver M.D. Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida Center for Infant and Child Development, University of South Florida College of Medicine, Tampa, Florida Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this authorKathy H. Sheehan Ph.D., Kathy H. Sheehan Ph.D. Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this authorDavid V. Sheehan M.D., M.B.A., David V. Sheehan M.D., M.B.A. Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this authorPaul R. Sanberg Ph.D., D.Sc., Paul R. Sanberg Ph.D., D.Sc. Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida Center for Infant and Child Development, University of South Florida College of Medicine, Tampa, Florida Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida Department of Neurosurgery, University of South Florida College of Medicine, Tampa, Florida Department of Pharmacology, University of South Florida College of Medicine, Tampa, Florida Department of Neuroscience Program, University of South Florida College of Medicine, Tampa, FloridaSearch for more papers by this author First published: 30 October 2002 https://doi.org/10.1002/da.10035Citations: 62 † Financial Disclosure: RDS, AAS, and PRS are inventors on a patent owned by the University of South Florida, which covers the use of nicotinic receptor antagonists for the treatment of nicotine-responsive neuropsychiatric disorders. RDS, AAS, PRS, and DVS have served as scientific consultants for Layton BioScience, Inc., who own the tradename and marketing rights to mecamylamine (Inversine®). PRS has also served on the board of directors for Layton BioScience, Inc. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES Blomqvist O, Hernandez-Avila CA, Van Kirk J, Rose JE, Kranzler HR. 2002. Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol. Alcohol Clin Exp Res 26: 326– 331. Covey LS, Glassman AH, Stetner F. 1998. Cigarette smoking and major depression. J Addict Dis 17: 35– 46. Fryer JD, Lukas RJ. 1999. Antidepressants noncompetitively in-hibit nicotinic acetylcholine receptor function. J Neurochem 72: 1117– 1124. Gadow KD, Sprafkin J. 1997. Child and adolescent symptom inventory 4: norms manuals. Stony Brook, NY: Checkmate Plus, Inc. Hennings EC, Kiss JP, De Oliveira K, Toth PT, Vizi ES. 1999. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. J Neurochem 73: 1043– 1050. Lukas RJ, Ke L, Bencherif M, Eisenhour CM. 1996. Regulation by nicotine of its own receptors. Drug Dev Res 38: 136– 148. Papke RL, Sanberg PR, Shytle RD. 2001. Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes. J Pharmacol Exp Ther 297: 646– 656. Reid MS, Mickalian JD, Delucchi KL, Berger SP. 1999. A nicotine antagonist, mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent subjects. Neuropsychopharmacology 20: 297– 307. Rose JE, Behm FM, Westman EC. 1998. Nicotine-mecamylamine treatment for smoking cessation: the role of pre-cessation therapy. Exp Clin Psychopharmacol 6: 331– 343. Sanberg PR, Shytle RD, Silver AA. 1998. Treatment of Tourette's syndrome with mecamylamine [letter]. Lancet 352: 705– 706. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59: 22– 33. Shytle R, Silver A, Lukas R, Newman M, Sheehan D, Sanberg P. 2001. Nicotinic acetylcholine receptors as targets for antidepressants. Molec Psychiatry. In press. Sheehan D, Shytle RD, Newman M, Sanberg P, Silver AA. 1999. Development of the Tourette Disorder Scale (TODS). 39th Annual Meeting of the New Clinical Drug Evaluation Unit Program, Boca Raton, Florida. Shytle RD, Silver AA, Sanberg PR. 2000. Comorbid bipolar disorder in Tourette syndrome responds to nicotinic receptor antagonist, mecamylamine (Inversine®). Biol Psychiatry 48: 1028– 1031. Silver AA, Shytle RD, Sanberg PR. 2000. Mecamylamine in Tourette's syndrome: a two-year retrospective case. J Child Adolesc Psychopharmacol 10: 59– 68. Silver AA, Shytle RD, Sheehan KH, Sheehan DV, Ramos A, Sanberg PR. 2001. Multi-center double blind placebo controlled study of mecamylamine monotherapy for Tourette's disorder. J Am Acad Child Adolesc Psychiatry 40: 1103– 1110. Tizabi Y, Overstreet DH, Rezvani AH, Louis VA, Clark E, Jr., Janowsky DS, Kling MA. 1999. Antidepressant effects of nicotine in an animal model of depression. Psychopharmacology (Berl) 142: 193– 199. Young JM, Shytle RD, Sanberg PR, George TP. 2001. Mecamyl-amine: new therapeutic uses and toxicity/risk profile. Clin Ther 23: 532– 565. Citing Literature Volume16, Issue32002Pages 89-92 ReferencesRelatedInformation

Article AbstractLetter to the EditorSir: We would like to thank Dr. Schwartz for drawing attention to the possibility that the chronic use of transdermal nicotine to treat Tourette's disorder could pose a potential risk that was not mentioned in our article. As pointed out by Dr. Schwartz, a recent in vitro study found that nicotine induced angiogenesis and accelerated the growth of tumors and atheroma under laboratory conditions. However, these authors stated that their findings raise particular concerns about the effects of chronic nicotine use in humans at risk for pathologic angiogenesis as opposed to those without such risks.

Summary: Objective: To test the hypothesis that transdermal nicotine would be efficacious for the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). Method: This was a double-blind, placebo-controlled, randomized, pilot trial that compared the effects of daily transdermal nicotine (5 mg/16 hrs) to placebo in children and adolescents with ADHD. There was a three-day washout period of all psychotropic medication followed by a one-week treatment period. Results: All 10 subjects enrolled (six males, four females; mean age = 10 years, SEM = 0.8) completed the study. As assessed by the 48-item Conners Parent Rating Scale at endpoint and during the trial, there was a significantly greater reduction in ADHD symptoms on “Learning Problems” and “Hyperactivity” subfactors. Nausea, stomach ache, itching under patch and dizziness were the most frequently reported adverse effects associated with transdermal nicotine. Conclusions: While the results of this study support previous research indicating that nicotinic receptor modulation may be a potentially useful strategy for the treatment of ADHD, therapeutic uses of nicotine are limited due to side effects. Thus, future research should investigate ways of improving the therapeutic index of nicotinic ligands in the treatment of ADHD, such as testing selective nicotinic antagonists alone or in combination with cholinergic agonists.

OBJECTIVE:The safety and efficacy of mecamylamine as a monotherapy in children and adolescents with Tourette's disorder (TD) was investigated in an 8-week multicenter, double-blind, placebo-controlled study.METHOD:Eligible subjects included subjects with TD (DSM-IV), with a naturalistic mix of comorbid diagnoses, nonsmokers, aged 8 to 17 years, whose behavioral and emotional symptoms (according to parents) were more disturbing than tics. After a washout period of all psychotropic medication, subjects were randomly assigned to either mecamylamine (n = 29) or placebo (n = 32). Mecamylamine doses ranged from 2.5 to 7.5 mg/day. Primary efficacy measures included the Tourette's Disorder Scale-Clinician Rated (TODS-CR) and 21-point Clinical Global Improvement scale; secondary efficacy measures included the Yale Global Tic Severity Scale and a rage-attack scale (RAScal).RESULTS:Of the 61 subjects who were randomized, 50 (82%) completed at least 3 weeks on medication and 38 (62%) completed the full 8-week trial. Study withdrawals included 12/29 on mecamylamine and 11/32 on placebo. For the total sample, mecamylamine was no more effective than placebo on any of the outcome measures. However, an item analysis of the TODS-CR suggested that mecamylamine may have reduced sudden mood changes and depression in moderately to severely affected subjects. Except for a slight increase in heart rate during the 1st week in both the mecamylamine and the placebo groups, there where no significant mecamylamine-related changes in vital signs, electrocardiogram, complete blood cell count, or blood chemistry values.CONCLUSIONS:Mecamylamine, in doses up to 7.5 mg/day, is well tolerated in children and adolescents, but as a monotherapy it does not appear to be an effective treatment for tics or for the total spectrum of symptoms associated with TD. However, further studies should be conducted to investigate its possible therapeutic effects in subjects with comorbid mood disorders and as an adjunct to neuroleptic medication.