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Biomedical subjects

Christopher J Smith

Publications and source records attributed to Christopher J Smith.

At least 19 recordsLinked to original sources
PubMed2006

Lack of evidence for association of the serotonin transporter gene SLC6A4 with autism.

BACKGROUND: The serotonin transporter (5-HTT) has long been considered likely to play a role in autism. Hyperserotonemia has been consistently found in a proportion of autistic patients, and the use of selective serotonin reuptake inhibitors (SSRIs) can have a positive effect in treating some symptoms of autism. Specific variants of the 5-HTT gene, SLC6A4, especially the insertion-deletion 5-HTTLPR promoter locus, have been found to modulate its expression and transporter function. METHODS: We examined the transmission of the short or long allele of 5-HTTLPR locus to affected individuals, using a large cohort of 352 families. In addition, we screened five single nucleotide polymorphisms (SNPs) in the 5' region of SLC6A4 previously reported to be positively associated with autism, as well as 4 additional SNPs also in the 5' region. RESULTS: No association of the 5-HTTLPR locus with autism was found. Furthermore, no evidence for association of any of the nine SNPs covering the SLC6A4 gene, or any of their haplotypes, was observed in our study. Using obsessive-compulsive behaviors (OCB), severe OCBs or rigid-compulsive subsets of our cohort gave the same negative results. CONCLUSIONS: SLC6A4 variants do not appear to be significantly involved in the liability to autism.

Autistic Disorder↗
PubMed2006

Seasonality effects on schizophrenic births in multiplex families in a tropical island.

Many studies have found that individuals with schizophrenia have been born in winter months in disproportionately high numbers. Temperature and weather effects, such as hot summers or cold winters, have been among the suggested explanations for this seasonality effect. We studied the relationship between schizophrenia and season of birth in Puerto Rico, a tropical island with mild seasonal variation of temperature and virtually no cold periods. Our sample consisted of 132 subjects (57 with schizophrenia, 75 without) from 24 multiplex families. Schizophrenic family members were significantly more likely to be born during the winter months (21/57; 36.8%) than their unaffected relatives (16/75; 21.3%). These results suggest that extreme temperatures are not a sufficient explanation for the seasonality effect and that other factors associated with seasonality may have an effect on the later development of schizophrenia. The fact that a seasonality effect was found in a group likely to have an increased genetic loading for schizophrenia suggests that seasonality may be associated with a second, environmental "hit" in a "two-hit hypothesis" of schizophrenia.

Adult↗
PubMed2006

Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample.

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees--263 of European ancestry (EA) and 146 of African American ancestry (AA)--together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 all-possible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Z(lr)] threshold >/=2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >2.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families.

Adolescent↗
PubMed2005

Variability of familial risk of Alzheimer disease across the late life span.

CONTEXT: The role of genetic factors in Alzheimer disease (AD) varies across the late life span, complicating efforts to quantify the risk of AD for relatives of probands with AD. OBJECTIVES: To visualize the changing levels of familial risk according to proband onset age and the age of the at-risk relative and to determine the familiality of age at onset in AD. DESIGN: A retrospective, informant-based family study. SETTING, PATIENTS, AND OTHER PARTICIPANTS: Siblings and parents of probands with AD (relatives = 4687; probands = 904), ascertained at geriatric clinic and nursing home settings, and of elderly probands without dementia (relatives = 7649; probands = 1525) who were spouses of probands, participants at senior centers, or nursing home residents without dementia. MAIN OUTCOME MEASURES: Informant-based assessments of AD in the relatives were used to generate 3-dimensional surfaces representing the patterns of risk of AD across the late life span depending on the specific onset age of the proband with AD (or assessment age of the elderly proband without dementia). We then constructed a 3-dimensional, age-specific, 10-year hazard rate ratio (HRR) surface representing the relative risk of AD in relatives of probands with AD with smoothly shifting levels of onset age compared with relatives of elderly probands without dementia. RESULTS: The HRR surface peaked (HRR, 13.0) for younger sexagenarian relatives related to probands with AD with onset age in their early 60s. The HRRs dropped sharply both as the proband age at onset and the age of the relative increased. For relatives aged in their late 80s, the HRR fell lower than 2.0 regardless of proband onset age and their lower-limit 95% confidence intervals were less than 1.0. CONCLUSIONS: The role of genetic risk factors decreases with increasing onset age of the proband with AD regardless of the age of the relatives themselves. The familiality of onset age is greatly reduced at later ages. The role of environmental risk factors in AD likely increases with onset age.

Age Factors↗
PubMed2005

Investigation of the metabolic fate of 2-, 3- and 4-bromobenzoic acids in bile-duct-cannulated rats by inductively coupled plasma mass spectrometry and high-performance liquid chromatography/inductively coupled plasma mass spectrometry/electrospray mass spectrometry.

Inductively coupled plasma mass spectrometry (ICPMS) has been used to determine the rate and routes of excretion of bromine following the intraperitoneal administration (50 mg kg(-1)) of 2-, 3- and 4-bromobenzoic acids to male bile-duct-cannulated rats. Analysis of urine and bile for (79/81)Br using ICPMS showed that all three bromobenzoic acids were rapidly excreted (82-98%) within 48 h of dosing, primarily via the urine. High-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC/ICPMS) was then used to obtain metabolite profiles for bile and urine. These profiles revealed that extensive metabolism had taken place, with the unchanged bromobenzoic acids forming a minor part of the total of compound-related material detected. Concomitant MS studies, supplemented by alkaline hydrolysis, enabled the identification of the major metabolite of all three of the bromobenzoic acids as a glycine conjugate. Ester glucuronide conjugates were also identified, but formed only a small proportion of total.

Animals↗
PubMed2005

Fine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family.

A locus involved in schizophrenia and related disorders in a Puerto Rican family has previously been mapped to chromosome 5p. The maximum two-point log of the odds (LOD) score of 3.72 was obtained for marker D5S111, and increased to 4.37 by multipoint analysis, assuming autosomal dominant inheritance with 90% penetrance. Additional genotyping and haplotype analysis placed the novel locus on 5p13.2-p13.3 within the interval between markers D5S1993 and D5S631. In the current study, we saturated the interval between markers D5S1993 and D5S631 with densely spaced polymorphic markers, genotyped these markers in the most informative branch of the family, and narrowed the critical region to 2.8 Mb. G-protein-coupled receptor gene [somatostatin and angiotensin-like peptide receptor (SALPR)] is one of the candidate genes within the critical interval. Sequence analysis of the coding region and the putative promoter of somatostatin and angiotensin-like peptide receptor did not reveal functionally significant variants in affected family members, although several polymorphisms were detected.

Chromosome Mapping↗
PubMed2005

A longitudinal study of R2* and R2 magnetic resonance imaging relaxation rate measurements in murine liver after a single administration of 3 different iron oxide-based contrast agents.

OBJECTIVE: The objective of this study was to investigate the duration of R2* and R2 enhancement in murine liver in vivo after administration of a single dose of 3 different iron oxide-based contrast agents. MATERIALS AND METHODS: Murine liver R2* and R2 were quantified longitudinally postadministration of 2.5 mgFe/kg ferumoxides, 2.5 mgFe/kg ferumoxytol, 2.5 or 5 mgFe/kg feruglose, or saline over 50 days. Changes in R2* and R2 were evaluated histologically using Perl's staining and by atomic absorption spectrometry. RESULTS: All 3 contrast agents significantly increased liver R2* and R2 4 hours after challenge. After 10 days, R2* and R2 for both the ferumoxides and ferumoxytol cohorts had recovered to saline control levels, whereas the faster R2* and R2 of the feruglose cohort was sustained and significantly faster than control at day 50. Histology revealed feruglose in both Kupffer and endothelial cells, whereas both ferumoxides and ferumoxytol were associated with the Kupffer cells. CONCLUSION: Compared with ferumoxides and ferumoxytol, feruglose exhibits prolonged R2* and R2 enhancement of murine liver.

Animals↗
PubMed2005

Peyronie's disease: the epidemiology, aetiology and clinical evaluation of deformity.

There is a wide variety of topics covered in this section. The epidemiology, aetiology and clinical evaluation of the deformity in Peyronie's disease is described, followed by a discussion of recent advances in the biology of diabetes-associated bladder complications. Bladder cancer and its molecular prognostic factors are presented, and the section ends with an in-depth presentation of an evidence-based approach to the understanding of the pharmacological class effect in the management of prostatic diseases.

Free Radicals↗
PubMed2004

Application of inductively coupled plasma mass spectrometry and high-performance liquid chromatography--with parallel electrospray mass spectrometry to the investigation of the disposition and metabolic fate of 2-, 3- and 4-iodobenzoic acids in the rat.

ICP-MS, HPLC-ICP-MS and HPLC-ICP-MS/ESI-MS have been applied to determine the disposition and metabolic fate of 2-, 3- and 4-iodobenzoic acids following intraperitoneal administration at 50 mg kg(-1) to male bile duct cannulated rats. Quantitative excretion balance studies based on the determination of the total iodine content of urine and bile showed that all three iodobenzoic acids were rapidly excreted. Recoveries ranging from 95 to 105% of the administered doses were achieved within 24 h of administration. Metabolite profiles for urine and bile showed extensive metabolism with unchanged iodobenzoic acids forming a minor part of the total. A combination of alkaline hydrolysis and MS enabled the identification of the major metabolites of all three iodobenzoic acids as glycine and ester glucuronide conjugates with very little if any of the parent compounds excreted unchanged.

Animals↗
PubMed2004

Familial symptom domains in monozygotic siblings with autism.

Autism is characterized by a triad of symptom domains (impaired social interaction, communication deficits, and repetitive behaviors) that vary significantly in their clinical presentation across the population. Within families with more than one affected member, however, discrepant findings exist with regard to symptom variability. Reduced intrafamily variance is of particular importance because it supports an underlying model of genetic heterogeneity in the transmission of autism, and the identification of familial clinical subtypes can be used to select more homogeneous samples for linkage analysis in the future. This study examines whether there are specific features of autism that show decreased variance within 16 families with monozygotic siblings concordant for autism. Evidence for familiality was defined as significantly decreased variance of symptom levels within monozygotic siblingships as compared to between siblingships. Using regression analysis, we demonstrated significant aggregation of symptoms within monozygotic siblingships for two of the three main symptom domains in autism: impairments in communication and social interaction showed significant familiality. Within the repetitive behavior domain, only the categories of circumscribed interests and preoccupation with part-objects showed reduced variance within siblingships. In addition, with the exception of a negative association between the social and behavior domains, partial correlation coefficients did not reveal significant associations between the levels of different symptom domains within families, suggesting that the levels of clinical features seen in autism may be a result of mainly independent genetic traits. Because of presumed genetic heterogeneity and the wide clinical variation seen in autism and other pervasive developmental disorders, selecting probands according to specific features known to show reduced variance within families may provide more homogeneous samples for genetic analysis and strengthen the power to detect the specific genes involved in autism.

Autistic Disorder↗
PubMed2004

Analysis of alpha- and beta-carbolines in mainstream smoke of reference cigarettes by gas chromatography-mass spectrometry.

The levels of 2-amino-9H-pyrido[2,3-b]indole (AalphaC or 2-amino-alpha-carboline), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAalphaC or 2-amino-3-methyl-alpha-carboline), 9H-pyrido[3,4-b]indole (norharman), and 1-methyl-pyrido[3,4-b]indole (harman) have been determined in the mainstream smoke condensate from three reference cigarettes, namely Kentucky reference 1R5F, Kentucky reference 2R4F, and CORESTA CM4. The amino-alpha-carbolines, and norharman and harman (beta-carbolines) can be classified as heterocyclic aromatic amines (HAAs) and are listed as biologically active agents in the mainstream smoke of cigarettes. For the analysis, the mainstream smoke condensate from cigarettes was collected on a filter pad, the analytes were isolated using solid-phase extraction (SPE), and quantified without derivatization on a GC-MS. Total amounts of carbolines found in the condensate increased from ultralight 1R5F to full-flavor CM4 cigarettes. The level of harman was about 250 ng/cigarette for the 1R5F cigarette and about 1025 ng/cigarette for the CM4 cigarette. Norharman was typically three times more abundant than harman. The AalphaC was found at about 10 times lower level compared to harman, and MeAalphaC was about 50 times lower than harman. The use of reference cigarettes can provide a common measure for laboratories to assess carboline amounts among cigarette brands.

Carbolines↗
PubMed2004

Cyclic nucleotides.

The natural occurrence of cyclic nucleotides in higher plants, formerly a topic of fierce debate, is now established, as is the presence of nucleotidyl cyclases and cyclic nucleotide phosphodiesterases capable of their synthesis and breakdown. Here we describe the significant properties of cyclic nucleotides, also outlining their second messenger functions and the history of plant cyclic nucleotide research over its first three decades. Findings of the last five years are detailed within the context of the functional role of cyclic nucleotides in higher plants, with particular emphasis upon nucleotidyl cyclases and cyclic nucleotide-responsive protein kinases, -binding proteins and -gated ion channels, with future objectives and strategies discussed.

Cyclic AMP↗
PubMed2004

Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.

OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region. METHOD: Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families. RESULTS: Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci. CONCLUSIONS: A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.

Aspartic Acid↗
PubMed2003

A comparison of the quantitative methods for the analysis of the platinum-containing anticancer drug [cis-[amminedichloro(2-methylpyridine)]platinum(II)] (ZD0473) by HPLC coupled to either a triple quadrupole mass spectrometer or an inductively coupled plasma mass spectrometer.

The use of high performance liquid chromatography coupled with inductively coupled plasma mass spectrometry (HPLC-ICPMS) as means for the quantitative determination of ZD0473, a platinum anticancer drug, and its related biologically active "aqua" compounds in biofluid samples is described. The performance of the resulting HPLC-ICPMS method was compared with that of a conventional HPLC-triple quadrupole mass spectrometer-based (HPLC-MS/MS) system for properties such as limit of detection, linearity, and reproducibility using spiked samples. The methods were then applied to the determination of plasma ultrafitrate concentrations of ZD0473 in dog plasma samples obtained following intravenous and oral administration at 0.5 and 6 mg/kg, respectively. These experiments showed that both methods were capable of providing accurate and precise results but that the HPLC-ICPMS method had advantages of extended linear range and superior sensitivity, providing a limit of quantification of 0.1 ng/mL for ZD0473, as compared to 5 ng/mL using the current HPLC-MS/MS method. In addition, by using a single combined HPLC-ICPMS/MS/MS system, it was possible to determine the relative MS/MS response of the aqua compounds for the first time.

Animals↗
PubMed2003

Obsessive-compulsive behaviors in parents of multiplex autism families.

Parents of autistic probands with high and low rates of repetitive behaviors were compared for rates of obsessive-compulsive traits and disorder. The rate of repetitive behaviors was assessed using the Autism Diagnostic Interview-Revised (ADI-R) in 176 autistic probands from 57 multiplex families. Obsessive-compulsive disorder (OCD) in parents was determined by direct interview using a parental history questionnaire, with screening for obsessive-compulsive traits using the Yale-Brown Obsessive-Compulsive Scale checklist. Children who had high total scores on the repetitive behavior domain of the ADI-R were significantly more likely to have one or both parents with obsessive-compulsive traits or disorder compared with children who had low total scores on this domain. Children with high scores on D1/D2 of the ADI-R (narrow restricted interests and rituals) were significantly more likely to have one or both parents with OCD, especially fathers, than those with low D1/D2. The occurrence of obsessive-compulsive traits or disorder in parents of autistic children in multiplex families is significantly more likely if autistic children have a high occurrence of repetitive behaviors. Dichotomizing autistic probands by severity and type of repetitive behaviors (circumscribed interests and compulsive rituals) may yield more homogenous groups, which could be helpful in genetic linkage studies.

Adult↗
PubMed2003

Familial patterns of risk in very late-onset Alzheimer disease.

BACKGROUND: The incidence of Alzheimer disease (AD) peaks after 85 years of age. Although genetic factors are implicated in AD with substantially earlier onset, the familial characteristics of high-incidence very late-onset AD (VLOAD, defined here as AD with onset age >/=85 years) remain unknown. METHODS: We collected information pertaining to the cognitive status and demographics of 809 parents and siblings of 144 VLOAD probands, 4235 parents and siblings of 793 earlier-onset AD probands, and 7646 parents and siblings of 1493 nondemented elderly probands. Cumulative risks and 5-year interval-specific hazard rate ratios were calculated for AD in relatives of the 2 AD proband groups and relatives of the nondemented elderly group. RESULTS: The cumulative risk for AD in the relatives of VLOAD probands was significantly different than that in the relatives of earlier-onset AD probands (P<.001), but not in the relatives of nondemented elderly probands. Also, the relatives of earlier-onset AD probands had hazard rate ratios ranging from 19.7 in those aged 50 to 54 years to 1.2 in those aged 90 to 94 years. Rates successively dropped as age intervals increased. CONCLUSIONS: At least through the middle of the ninth decade of life, relatives of VLOAD probands have a lower risk for AD than those of earlier-onset AD probands. In addition, the relatively increased risk of relatives of earlier-onset AD probands is highest at younger ages and diminishes with increasing age. In counseling family members of patients with AD concerned about their own risk, the onset age of the patient and the age of the concerned relative should be considered. Very late-onset AD may be a good target for investigating environmental factors associated with AD.

Age Factors↗