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Biomedical subjects

P Sandor

Publications and source records attributed to P Sandor.

At least 19 recordsLinked to original sources
PubMed2004

Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples: 17q25 is a putative susceptibility region.

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 contributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P=.002). The original families, as well as two additional pedigrees, were genotyped for 25 single-nucleotide polymorphisms (SNPs), with a focus on three genes in the indicated region that could play a role in the development of GTS, on the basis of their function and expression profile. Multiple three-marker haplotypes spanning all three genes studied provided highly significant association results (P<.001). An independent sample of 96 small families with one or two children affected with GTS was also studied. Of the 25 SNPs, 3 were associated with GTS at a statistically significant level. The transmission/disequilibrium test for a three-site haplotype moving window again provided multiple positive results. The background linkage disequilibrium (LD) of the region was studied in eight populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. In conclusion, our findings warrant the further investigation of 17q25 as a candidate susceptibility region for GTS.

C-Reactive Protein↗
PubMed2000

Delevoyin C, a tetranortriterpenoid from Entandrophragma delevoyi.

The hexane extract of the bark of Entandrophragma delevoyi has yielded a novel tetranortriterpenoid, delevoyin C. This compound contains a cyclobutanyl ring incorporating C-19 and a cycloheptanyl ring C including C-30. Gedunin and 11beta-Acetoxygedunin were isolated from the hexane extract of the wood.

Hexanes↗
PubMed2000

An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries.

We have established a multisite, international database of 3,500 individuals diagnosed with Tourette syndrome (TS). The male:female ratio is 4.3:1 for the total sample, with wide variation among sites; the male excess occurs at every site. Anger control problems, sleep difficulties, coprolalia, and self-injurious behavior only reach impressive levels in individuals with comorbidity. Anger control problems are strongly correlated with comorbidity, regardless of site, region, or whether assessed by neurologists or psychiatrists. The mean age at onset of tics is 6.4 years. At all ages, about 12% of individuals with TS have no reported comorbidity. The most common reported comorbidity is attention-deficit-hyperactivity disorder. Males are more likely to have comorbid disorders than females. The earlier the age at onset, the greater the likelihood of a positive family history of tics. An understanding of the factors producing these and other variations might assist in better subtyping of TS. Because behavioral problems are associated with comorbidity, their presence should dictate a high index of suspicion of the latter, whose treatment may be at least as important as tic reduction. The established database can be used as the entry point for further research when large samples are studied and generalizability of results is important.

Adolescent↗
PubMed1999

The Tourette syndrome diagnostic confidence index: development and clinical associations.

BACKGROUND: The clinical characteristics of Tourette syndrome (TS) present challenges for the systematic determination of whether individuals are affected and severity. Vocal and motor tics wax and wane, decrease over time, and may be voluntarily suppressible, and therefore may be absent at interview. Current instruments measure symptoms at interview or rate symptom severity only. METHOD: To minimize error in case ascertainment and produce an instrument measuring lifetime likelihood of having had TS, clinical members of the American Tourette Syndrome Association International Genetic Collaboration developed the Diagnostic Confidence Index (DCI). The expert group worked collaboratively with progressive revision in consensus workshops using existing diagnostic criteria as guidelines. The DCI produces a score from 0 to 100 that is a measure of the likelihood of having or ever having had TS. RESULTS: The DCI was administered to 280 consecutive patients with TS attending a TS clinic; 264 (94%) completed it, indicating high feasibility and acceptability. Its correlation with other instruments and associations with psychopathology provide support for its being a lifetime measure of TS. CONCLUSIONS: The DCI is a useful, practicable instrument in the clinic or research practice allowing an assessment of lifetime likelihood of TS. Further work is needed to test the DCI's psychometric properties, such as its validity and reliability in populations of interest.

Adolescent↗
PubMed1999

Genome scan for linkage to Gilles de la Tourette syndrome.

Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics. Despite clear evidence for a genetic predisposition to TS from family, twin, and adoption studies, there have been no confirmed linkage findings. In this article we test for linkage to TS in multigenerational families segregating TS using a panel of 386 markers with the largest interval between any two markers being 28 cM and an average distance between markers of 10 cM. We tested for linkage using an autosomal dominant model with reduced penetrance and using nonparametric methods. No significant evidence for linkage was found with parametric analysis. A logarithm of the odds (LOD) score of greater or equal to one under the autosomal dominant model was observed in 24 of these markers in at least one of the families tested. No LOD scores greater than two were observed with any of the markers. For the nonparametric analysis, eight markers were observed with a P-value less than 0.00005 for significance evidence of linkage in at least one family. However caution should be used in the interpretation of the nonparametric analyses as this statistic (the affected-pedigree-member method) is know to have a high false-positive rate. Further support for linkage in these regions is required before linkage can be assumed.

Female↗
PubMed1999

Catechol-O-methyltransferase and Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics. Individuals with TS often have symptoms of obsessive compulsive disorder (OCD) and these symptoms are thought to be an alternative expression of the TS gene(s) in TS families. In this paper we test for linkage of the functional polymorphism in the catechol-O-methyltransferase (COMT) gene to TS and OCD in five multi-generational families ascertained through a TS proband. This polymorphism (valine to methionine at codon 158) has been previously reported to influence the activity of COMT by three to four-fold and has recently been reported to be associated with OCD.1 We tested for linkage using an autosomal dominant model with reduced penetrance and non-parametric methods. No significant evidence for linkage was found for the COMT gene and the TS/CMT, or OCD phenotypes in these pedigrees.

Catechol O-Methyltransferase↗
PubMed1999

Aggressive behaviour in children with Tourette syndrome and comorbid attention-deficit hyperactivity disorder and obsessive-compulsive disorder.

BACKGROUND: Aggressive behaviour, defined as sudden, explosive outbursts of rage, has been reported as a clinical problem in approximately 23% to 40% of Tourette syndrome (TS) patients (1-5). Attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) are also reported in 50% to 70% of TS patients (6). OBJECTIVE: To investigate whether aggressive behaviour was associated with TS directly or found primarily in TS with comorbid ADHD or OCD. METHOD: Aggressive behaviour in 33 nonmedicated patients with TS (ages 6 to 14 years) and 6 healthy control subjects (ages 7 to 12 years) was examined by semistructured interview and multiinformant questionnaires. RESULTS: Aggression subscales on Achenbach's Child Behavior Checklist (CBCL) completed by parents and Teacher's Report Form (TRF) completed by teachers distinguished the TS-only and control groups from the group with TS + Comorbidity (P < 0.046, and P < 0.016) after adjusting for tic severity and age. The conduct disorder subscale on the Conners Parent Rating Scale (CPRS) was also significantly higher (P < 0.005) in the TS + comorbidity group than in the TS-only or control groups, with more problems reported in the older children. CONCLUSIONS: These findings provide additional evidence that aggressive behaviour observed in children with TS may be associated with comorbid ADHD or OCD (6), independent of tic severity or age. This is consistent with the clinical observation that most TS patients have only minimal symptoms, which do not interfere with their daily functioning.

Adolescent↗
PubMed1998

Combination of LC-MS and LC-NMR as a Tool for the Structure Determination of Natural Products

Application of both LC-MS and LC-NMR to a partially purified extract of Vernonia fastigiataled to the direct identification of antibacterial sesquiterpene lactones 1-9 without isolation of individual compounds. The rapid structural analysis of both major and minor components of this class of compounds demonstrated the power of structure-guided screening as a complementary method to assay-guided screening.

Journal Article↗
PubMed1998

Autonomic correlates of antidepressant treatment using heart-rate variability analysis.

OBJECTIVE: To assess the 24-hour temporal-domain heart-rate variability correlates of treatment with fluoxetine or doxepin for depression. METHOD: A randomized evaluation of fluoxetine and doxepin measured a 50% change in the Hamilton Depression Rating Scale (HDRS) score as a response to therapy and was correlated with measures of standard deviation of the mean of all 5-minute segments of normal electrocardiographic R-R intervals (SDANN), standard deviation of all normal R-R intervals (SDNN), root mean square of successive differences in R-R intervals (r-MSSD), and percentage difference between adjacent normal R-R intervals that are greater than 50 msec (pNN50) from 24-hour electrocardiogram (ECG) tapes. RESULTS: Ten out of 14 patients responded. Response was associated with an increase in SDANN of 17% (P < 0.05). Nonresponse was associated with a 17% decrease in SDANN and a 22% decrease in SDNN (both P < 0.05). No other measures correlated with therapeutic response. No heart-rate variability (HRV) differences between the 2 drug therapies were observed. CONCLUSION: Twenty-four-hour HRV measures may be useful in assessing response to antidepressant therapy.

Analysis of Variance↗
PubMed1998

Current status of genetic studies of Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (TS) is a familial, neuropsychiatric disorder characterized by chronic, intermittent motor and vocal tics. Despite strong evidence for a genetic basis of this disorder from family, twin, and adoption studies, no convincing evidence for genetic linkage has been reported. Numerous groups world-wide have searched for genetic susceptibility factors for TS, testing specific candidate genes in neurotransmitter systems as well as DNA markers with known locations. Several factors may complicate the search for genes for this disorder, including diagnostic uncertainties, definition of the TS phenotypic spectrum as it relates to genetic susceptibility, assortative mating, genetic heterogeneity, and unclear mode of inheritance. In this article, we review the evidence for the genetic basis of TS and the current status of genetic studies.

Adoption↗
PubMed1998

Clinical features distinguishing patients with Tourette's syndrome and obsessive-compulsive disorder from patients with obsessive-compulsive disorder without tics.

OBJECTIVE: It is not clear whether obsessive-compulsive disorder (OCD) in the context of Tourette's syndrome (TS) is the same as that disorder found in patients with OCD alone. This study evaluated the severity and characteristics of the obsessive-compulsive symptoms in adult patients with OCD and TS compared to adult patients with OCD alone. METHOD: Thirteen subjects with both DSM-III-R TS and OCD and 13 subjects with OCD alone were recruited. Obsessive-compulsive severity was determined by using the Yale-Brown Obsessive Compulsive Scale. The Tourette Syndrome Association Unified Tic Rating Scale was administered to determine tic severity, and the adult version of the Attention Deficit and Hyperactivity Checklist was used to detect a history of childhood attention-deficit hyperactivity disorder (ADHD). RESULTS: Subjects with OCD alone had very few obsessions and compulsions that were not also experienced by subjects with both TS and OCD. In contrast, subjects with TS and OCD were significantly more likely to report obsessions involving nonviolent images, excessive concern with appearance, and need for symmetry. Touching, blinking or staring, and counting compulsions were also significantly more common in this group. Eight subjects with OCD and TS had a childhood history of ADHD, compared to none of the pure OCD subjects. CONCLUSION: There are subtle but definite differences in symptomatology of subjects with pure OCD compared to those with OCD and TS consistent with putative differences in pathophysiology between the 2 groups, i.e., abnormalities in the serotonergic system in OCD patients and serotonergic and dopaminergic abnormalities in those with OCD and TS. These observations may be consistent with genetic heterogeneity within both OCD and TS.

Adult↗
PubMed1998

Effectiveness of fluoxetine and doxepin in treatment of melancholia in depressed patients.

It has been suggested that serotonin reuptake inhibitors (SSRIs) may be less effective than tricyclic antidepressants (TCAs) in treatment of melancholic depression. We treated 36 depressed ambulatory patients with doxepin or fluoxetine in a double-blind, randomized 6-week trial with placebo run-in. Seven patients treated with doxepin and 13 patients treated with fluoxetine met diagnostic criteria for melancholic depression. Average daily dose was 169.4 +/- 41.6 mg for doxepin and 36.8 +/- 18 mg for fluoxetine. We observed a 50% response rate in both treatment groups, using as outcome criterion reduction of Hamilton Depression Scale Score to less than 10. Regardless of how strict the definition of response, we found fluoxetine to be as effective as doxepin in our group of melancholic outpatients.

Adult↗
PubMed1997

Linkage study of the dopamine D5 receptor gene and Gilles de la Tourette syndrome.

A defect in the dopamine system has been hypothesized as the etiological defect in Gilles de la Tourette syndrome (TS). In this report, we test the hypothesis that the dopamine D5 receptor locus (DRD5) is linked to the genetic susceptibility to TS in five families studied in Canada. We tested for linkage to the dopamine D5 receptor gene using a microsatellite polymorphism located in the same cosmid clone. Using an autosomal dominant model with reduced penetrance, we were able to exclude linkage in four of the five families for the TS and chronic multiple tics (CMT) phenotype. Also, no evidence for linkage was found using nonparametric methods in all five families.

Canada↗
PubMed1997

Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder.

Cardiovascular adverse effects are amongst the most serious observed with antidepressant drugs and are often due to effects on cardiac conduction and refractoriness. However, such electrophysiologic effects may not be evident when using conventional electrocardiographic measures. Forty patients with major depressive disorder (according to DSM-III-R criteria) were enrolled in a 6-week double-blind parallel group study of fluoxetine (N = 20) or doxepin (N = 20). Cardiac conduction (QRS duration) and repolarization (corrected QT interval, QTc), were measured using signal-averaged electrocardiograms and 12-lead electrocardiogram at baseline and after 2, 4, and 6 weeks of treatment. Patients taking doxepin (mean daily dosage at 6 weeks 169 +/- 42 mg) were similar to those taking fluoxetine (37 +/- 18 mg) for demographic variables and improvement in depression scores but volunteered more side effects (p = 0.011), especially dry mouth (p < 0.001) and dizziness/lightheadedness (p = 0.005). After 6 weeks, doxepin increased heart rate (69 +/- 12 to 81 +/- 13 beats per minute; p = 0.0003) and prolonged QTc (from 417 +/- 36 to 439 +/- 28 msec; p < 0.03); overall QRS duration was not prolonged but was correlated with serum doxepin concentrations (r = 0.78, p < 0.0001). Fluoxetine had no effect on QTc (428 +/- 24 msec at baseline vs. 430 +/- 24 msec at 6 weeks) or QRS duration (97 +/- 12 msec at baseline vs. 94 +/- 12 msec at 6 weeks). The standard 12-lead electrocardiogram showed no significant change in QRS or QTc for either drug. Using a sensitive measure of electrocardiographic effects, doxepin prolongs repolarization and may slow cardiac conduction. Fluoxetine has no measurable electrocardiographic effects, which suggests an increased safety margin for cardiac adverse effects. The ability of the signal-averaged electrocardiogram to resolve small changes in the electrocardiogram is useful in the assessment of drugs with subtle electrophysiologic effects.

Adult↗
PubMed1997

Cerebrocortical and medullary blood flow changes after general opiate receptor blockade during hemorrhagic shock in cats.

The effect of centrally induced opiate receptor blockade on regional cerebral blood flow (rCBF) was studied in anesthetized, ventilated cats during the course of hemorrhagic shock. The blood flow of the medulla and the parietal cortex was measured with the H2-gas clearance technique. Hemorrhagic shock was produced by lowering the systemic mean arterial pressure to 60 mmHg for 120 min by blood withdrawal. Central opiate receptor blockade was induced by 10 micrograms/kg intracerebroventricularly (i.c.v.) injected naloxone at the 60th min of the bleeding period. Cortical blood flow showed no improvement after i.c.v. naloxone administration. Medullary blood flow, however, increased significantly and approached the pre-bleeding control flow values following central opiate receptor blockade. The results indicate involvement of endogenous opioid mechanisms in the regulation of rCBF during hemorrhage and may provide an explanation for the previously described beneficial effects of naloxone in hemorrhagic shock.

Animals↗