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1.
Mol Psychiatry ; 25(11): 3109-3111, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30862939

RESUMEN

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

2.
Mol Psychiatry ; 23(4): 963-972, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28461698

RESUMEN

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Trastornos Psicóticos/genética , Esquizofrenia/genética , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/psicología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Trastornos Psicóticos/complicaciones , Esquizofrenia/complicaciones
3.
Curr Top Microbiol Immunol ; 383: 27-54, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24220751

RESUMEN

Microbicides are topically applied, user controlled dosage forms that are being developed to prevent the transmission of HIV during coitus. Early candidates focused on coitally dependent dosage forms such as gels and creams. More recent development has focused on broadening the coitally dependent options through the introduction of films and fast dissolving tablets. Additionally, it has become important to have longer acting products to minimize the burden of user compliance and thus vaginal rings have been developed providing sustained delivery of antiretroviral drugs. This chapter discusses the history of microbicides along with a detailed description of coitally dependent products, gels, films, tablets diaphragms, as well as coitally independent dosage forms such as vaginal rings and the introduction of a new technology, electrospun fibers.


Asunto(s)
Fármacos Anti-VIH/farmacología , Sistemas de Liberación de Medicamentos/instrumentación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Ensayos Clínicos como Asunto , Formas de Dosificación , Sistemas de Liberación de Medicamentos/métodos , Infecciones por VIH/virología , VIH-1/fisiología , Humanos
4.
Psychol Med ; 43(5): 1023-31, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-22975221

RESUMEN

BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.


Asunto(s)
Trastornos del Conocimiento/epidemiología , Infecciones por Citomegalovirus/epidemiología , Herpes Simple/epidemiología , Modelos Estadísticos , Pruebas Neuropsicológicas/estadística & datos numéricos , Esquizofrenia/epidemiología , Adulto , Negro o Afroamericano/genética , Negro o Afroamericano/psicología , Anticuerpos Antivirales/sangre , Encéfalo/virología , Estudios de Casos y Controles , Enfermedad Crónica , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/virología , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/sangre , Escolaridad , Empleo , Femenino , Predisposición Genética a la Enfermedad , Herpes Simple/sangre , Humanos , Masculino , Análisis Multivariante , Fenotipo , Análisis de Componente Principal , Esquizofrenia/genética , Esquizofrenia/virología , Simplexvirus/inmunología
5.
Mol Psychiatry ; 17(12): 1316-27, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22005930

RESUMEN

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Neurocalcina/genética , Trastornos Psicóticos/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Apolipoproteínas E/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 4/genética , ADN Intergénico/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/diagnóstico
6.
Genes Immun ; 13(3): 245-52, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22170232

RESUMEN

The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn's disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single-nucleotide polymorphism (SNP) genotyping and from imputation of classical human leukocyte antigen (HLA) types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD and 1428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67 × 10(-13)). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRß1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68 × 10(-13)). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC vs control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRß1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with UC.


Asunto(s)
Cromosomas Humanos Par 6 , Colitis Ulcerosa/genética , Predisposición Genética a la Enfermedad , Cadenas beta de HLA-DR/genética , Alelos , Sustitución de Aminoácidos , Enfermedad de Crohn/genética , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple
7.
Am J Med Genet B Neuropsychiatr Genet ; 156B(4): 462-71, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21480485

RESUMEN

Issues of multiple-testing and statistical significance in genomewide association studies (GWAS) have prompted statistical methods utilizing prior data to increase the power of association results. Using prior findings from genome-wide linkage studies on bipolar disorder (BPD), we employed a weighted false discovery approach (wFDR; [Roeder et al. 2006. Am J Hum Genet 78(2): 243­252]) to previously reported GWAS data drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Using this method, association signals are up or down-weighted given the linkage score in that genomic region. Although no SNPs in our sample reached genome-wide significance through the wFDR approach, the strongest single SNP result from the original GWAS results (rs4939921 in myosin VB) is strongly up-weighted as it occurs on a linkage peak of chromosome 18. We also identify regions on chromosome 9, 17, and 18 where modestly associated SNP clusters coincide with strong linkage scores, implicating them as possible candidate regions for further analysis. Moving forward, we believe the application of prior linkage information will be increasingly useful to future GWAS studies that incorporate rarer variants into their analysis.


Asunto(s)
Trastorno Bipolar/genética , Ligamiento Genético/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 18 , Cromosomas Humanos Par 9 , Interpretación Estadística de Datos , Estudio de Asociación del Genoma Completo/métodos , Humanos
8.
J Laryngol Otol ; 135(9): 815-819, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34294168

RESUMEN

OBJECTIVE: To review patient satisfaction with the change in practice towards telephone consultations during and after the coronavirus disease 2019 pandemic for head and neck cancer follow up. METHOD: A retrospective analysis was conducted of head and neck cancer telephone appointments during a six-month period in a tertiary referral centre. RESULTS: Patients found the telephone consultations beneficial (98 per cent), with 30 per cent stating they were relieved to not have to attend hospital. Patients who travelled further, those with lower stage disease and patients with a greater interval from initial treatment were most satisfied with the telephone consultations. Sixty-eight per cent of patients stated they would be happy to have telephone consultations as part of their regular follow up after the pandemic. CONCLUSION: Patients found the telephone consultations beneficial and 30 per cent considered them preferable to face-to-face appointments. This study demonstrates that telephone consultations can be used as an adjunct to face-to-face appointments in an effort to reduce hospital attendances whilst maintaining close follow up.


Asunto(s)
Cuidados Posteriores , Neoplasias de Cabeza y Cuello/terapia , Satisfacción del Paciente , Derivación y Consulta , Adulto , Cuidados Posteriores/métodos , Cuidados Posteriores/psicología , Cuidados Posteriores/normas , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Satisfacción del Paciente/estadística & datos numéricos , Estudios Retrospectivos , Teléfono , Centros de Atención Terciaria
10.
Schizophr Res ; 109(1-3): 70-9, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19264455

RESUMEN

While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.


Asunto(s)
Negro o Afroamericano/genética , Familia , Ligamiento Genético , Esquizofrenia/genética , Mapeo Cromosómico , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
11.
Science ; 255(5045): 717-20, 1992 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-1738844

RESUMEN

Forensic scientists commonly assume that DNA fingerprint patterns are infrequent in the general population and that genotypes are independent across loci. To test these assumptions, the number of matching DNA patterns in two large databases from the Federal Bureau of Investigation (FBI) and from Lifecodes was determined. No deviation from independence across loci in either database was apparent. For the Lifecodes database, the probability of a three-locus match ranges from 1 in 6,233 in Caucasians to 1 in 119,889 in Blacks. When considering all trios of five loci in the FBI database, there was only a single match observed out of more than 7.6 million comparisons. If independence is assumed, the probability of a five-locus match ranged from 1.32 x 10(-12) in Southeast Hispanics to 5.59 x 10(-14) in Blacks, implying that the minimum number of possible patterns for each ethnic group is several orders of magnitude greater than their corresponding population sizes in the United States. The most common five-locus pattern can have a frequency no greater than about 10(-6). Hence, individual five-locus DNA profiles are extremely uncommon, if not unique.


Asunto(s)
Dermatoglifia del ADN , Medicina Legal , Población Negra/genética , Bases de Datos Factuales , Reacciones Falso Positivas , Frecuencia de los Genes , Genotipo , Hispánicos o Latinos/genética , Humanos , Polimorfismo Genético , Probabilidad , Secuencias Repetitivas de Ácidos Nucleicos , Estados Unidos , Población Blanca/genética
12.
Science ; 249(4975): 1416-20, 1990 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-2205919

RESUMEN

Variable number of tandem repeat (VNTR) loci are extremely valuable for the forensic technique known as DNA fingerprinting because of their hypervariability. Nevertheless, the use of these loci in forensics has been controversial. One criticism of DNA fingerprinting is that the VNTR loci used for the "fingerprints" violate the assumption of Hardy-Weinberg equilibrium (H-W), making it difficult to calculate the probability of observing a genotype in the population. If one can assume H-W, the probability of observing the pair of alleles constituting an individual's genotype can be calculated by taking the product of the alleles' frequencies in the population and multiplying by two if the alleles are different. The evidence cited against assuming H-W is homozygote excess, which is presumed to be caused by an undetected mixture of two or more populations with limited interpopulational mating and distinct allele frequencies. For most VNTR loci, measurement error makes it impossible to test these claims by standard methods. The Lifecodes database of three VNTR loci used for forensics was used to show that the claimed excess of homozygotes is not necessarily real because many heterozygotes with similar allele sizes are misclassified as homozygotes. A simple test of H-W that takes such misclassifications into account was developed to test for an overall excess or dearth of heterozygotes in the sample (the complement of homozygote dearth or excess). The application of this test to the Lifecodes database revealed that there was no consistent evidence of violation of H-W for the Caucasian, black, or Hispanic populations.


Asunto(s)
ADN/genética , Técnicas Genéticas , Homocigoto , Paternidad , Heterocigoto , Humanos , Técnicas In Vitro , Modelos Genéticos , Fenotipo , Secuencias Repetitivas de Ácidos Nucleicos
13.
Science ; 287(5454): 848-51, 2000 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-10657297

RESUMEN

Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.


Asunto(s)
Tumor del Cuerpo Carotídeo/genética , Grupo Citocromo b/genética , Mutación de Línea Germinal , Complejos Multienzimáticos/genética , Oxidorreductasas/genética , Paraganglioma/genética , Succinato Deshidrogenasa/genética , Alelos , Secuencia de Aminoácidos , Cuerpo Carotídeo/metabolismo , Tumor del Cuerpo Carotídeo/metabolismo , Cromosomas Humanos Par 11/genética , Grupo Citocromo b/química , Grupo Citocromo b/metabolismo , Complejo II de Transporte de Electrones , Ligamiento Genético , Impresión Genómica , Haplotipos , Heterocigoto , Humanos , Pérdida de Heterocigocidad , Mitocondrias/metabolismo , Datos de Secuencia Molecular , Complejos Multienzimáticos/química , Complejos Multienzimáticos/metabolismo , Mutación Missense , Oxidorreductasas/química , Oxidorreductasas/metabolismo , Paraganglioma/metabolismo , Polimorfismo Conformacional Retorcido-Simple , Succinato Deshidrogenasa/química , Succinato Deshidrogenasa/metabolismo
14.
Am J Transplant ; 8(8): 1729-36, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18557726

RESUMEN

Thymus transplantation shows promise for the treatment of athymia in complete DiGeorge anomaly. This report reviews the effects of dose of thymus tissue, ABO compatibility, HLA matching, culture conditions, age of donor and immunosuppression of recipient on immune outcomes at 1 year after transplantation. Forty-nine athymic subjects have been treated with cultured postnatal allogeneic thymus tissue; 36 (73%) survive with only one subject on immunosuppression at 1.5 years. Of 31 surviving subjects more than 1 year after transplantation, 30 (97%) developed naive T cells, T-cell proliferative responses to mitogens and a diverse T-cell receptor beta variable (TCRBV) repertoire. The dose of thymus tissue, HLA matching and use of immunosuppression had nonsignificant effects on these outcome variables. Removal of deoxyguanosine from culture medium and length of culture did not adversely affect outcomes. Use of thymus tissue from donors over 1 month of age, versus under 1 month, resulted in higher total T-cell numbers (p = 0.03). However, this finding must be confirmed in a prospective trial. Although subtle immune effects may yet be associated with some of the factors tested, it is remarkable that consistently good immune outcomes result despite variation in dose, HLA matching and use of immunosuppression.


Asunto(s)
Síndrome de DiGeorge/cirugía , Timo/trasplante , Sistema del Grupo Sanguíneo ABO , Femenino , Antígenos HLA , Humanos , Lactante , Recién Nacido , Masculino , Resultado del Tratamiento
15.
Theriogenology ; 69(6): 724-7, 2008 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-18280563

RESUMEN

The objective was to compare the effects of treating bovine semen with two trypsin products (the porcine pancreas extract and a recombinant) and a control (no trypsin) on in vitro embryo production. Our hypothesis was that the trypsin treatments would not cause any significant difference in fertilization and embryo development as compared to the control. Semen was washed through a gradient system containing a porcine-origin trypsin, a recombinant bovine-sequence trypsin, or the control (no trypsin). Oocytes (n=3036) were collected from abbatoir-derived ovaries, matured for 24h, and allocated into three groups: porcine trypsin (n=1040), recombinant trypsin (n=972), and control (n=1024). Ova were inseminated with 1 x 10(6) motile sperm/mL and cultured for 18-24h. Thereafter, presumptive zygotes were cultured for 7 days in 50 microL G1/G2 micro-droplets under mineral oil. Overall, sperm motility was lower before than after each treatment (mean of 51.4% versus 70.2%, respectively; P<0.001); however, motility was not significantly different among the three groups (porcine-origin trypsin=68.8%, recombinant trypsin=69.0%, and control=72.6%). Similarly, there was no significant difference among these groups for cleavage rates (70.1, 70.9, and 73.9%), or the number of morula/blastocyst stage embryos (53.4, 53.3, and 48.7%). In conclusion, treatment of bovine sperm with either porcine-origin trypsin or recombinant trypsin prior to insemination had no detrimental effects on in vitro embryo development.


Asunto(s)
Bovinos/embriología , Fertilización In Vitro/veterinaria , Extractos Pancreáticos/farmacología , Espermatozoides/efectos de los fármacos , Tripsina/farmacología , Animales , Técnicas de Cultivo de Embriones/veterinaria , Desarrollo Embrionario/efectos de los fármacos , Femenino , Fertilización In Vitro/efectos de los fármacos , Masculino , Oocitos/fisiología , Proteínas Recombinantes/farmacología , Motilidad Espermática/efectos de los fármacos , Espermatozoides/fisiología , Porcinos , Cigoto/crecimiento & desarrollo
16.
Nat Genet ; 36(11): 1129-30; author reply 1131, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15514657
17.
Genes Brain Behav ; 5(2): 150-7, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16507006

RESUMEN

We hypothesize that circadian dysfunction could underlie, at least partially, the liability for bipolar 1 disorder (BD1). Our hypothesis motivated tests for the association between the polymorphisms of genes that mediate circadian function and liability for BD1. The US Caucasian patients with BD1 (DSM-IV criteria) and available parents were recruited from Pittsburgh and surrounding areas (n = 138 cases, 196 parents) and also selected from the NIMH Genetics Collaborative Initiative (n = 96 cases, 192 parents). We assayed 44 informative single-nucleotide polymorphisms (SNPs) from eight circadian genes in the BD1 samples. A population-based sample, specifically cord blood samples from local live births, served as community-based controls (n = 180). It was used as a contrast for genotype and haplotype distributions with those of patients. US patients with schizophrenia/schizoaffective disorder (SZ/SZA, n = 331) and available parents from Pittsburgh (n = 344) were assayed for a smaller set of SNPs based on the results from the BD1 samples. Modest associations with SNPs at ARNTL (BmaL1) and TIMELESS genes were observed in the BD1 samples. The associations were detected using family-based and case-control analyses, albeit with different SNPs. Associations with TIMELESS and PERIOD3 were also detected in the Pittsburgh SZ/SZA group. Thus far, evidence for association between specific SNPs at the circadian gene loci and BD1 is tentative. Additional studies using larger samples are required to evaluate the associations reported here.


Asunto(s)
Trastorno Bipolar/genética , Trastornos Cronobiológicos/complicaciones , Trastornos Cronobiológicos/genética , Ritmo Circadiano/genética , Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Factores de Transcripción ARNTL , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Relojes Biológicos/genética , Trastorno Bipolar/fisiopatología , Química Encefálica/genética , Estudios de Casos y Controles , Proteínas de Ciclo Celular , Trastornos Cronobiológicos/fisiopatología , Análisis Mutacional de ADN , Femenino , Regulación de la Expresión Génica/genética , Pruebas Genéticas , Genoma Humano/genética , Humanos , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Proteínas Circadianas Period , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/genética , Trastornos Psicóticos/fisiopatología , Esquizofrenia/fisiopatología , Factores de Transcripción/genética
18.
Biochim Biophys Acta ; 1278(1): 73-8, 1996 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-8611610

RESUMEN

Rates of pH-dependent micellization of multilamellar vesicles by the hydrophobic polyelectrolyte poly(2-ethylacrylic acid) (PEAA) have been measured turbidometrically. This polymer shows a strong ph-dependence in its affinity for phospholipid membranes, binding in increasing amounts as pH is lowered and ultimately solubilizing membranes to form mixed micelles (Tirrell, Takigawa and Seki (1985) Ann. N.Y. Acad. Sci. 446, 237). The rate of solubilization of dipalmitoylphosphatidylcholine (DPPC) vesicle suspensions by PEAA increases approximately linearly with reductions in pH below a threshold at pH 6.55. Interestingly, negatively-charged dipalmitoylphosphatidylglycerol membranes showed qualitatively similar behavior in the presence of PEAA, and incorporation of 10% or 20% dipalmitoylphosphatidic acid in DPPC membranes did not affect solubilization rates, demonstrating that membrane charge is not an important factor in determining micellization kinetics. Micellization of DPPC and dimyristoylphosphatidylcholine membranes occurs most rapidly at their respective gel-liquid crystalline transition temperatures (Tm); the rate enhancement is correlated with a peak in the temperature-dependent binding of a fluorescently-modified PEAA in slightly alkaline solutions in which no micellization is observed. The lateral compressibility of the membrane, which has a similar peak at Tm, is proposed to be an important determinant of the rate and extent of polymer adsorption, and consequently of the rate of micellization.


Asunto(s)
Acrilatos/química , Liposomas/química , Micelas , 1,2-Dipalmitoilfosfatidilcolina/química , Adsorción , Compuestos de Dansilo/química , Compuestos de Dansilo/metabolismo , Dimiristoilfosfatidilcolina/química , Concentración de Iones de Hidrógeno , Cinética , Nefelometría y Turbidimetría , Ácidos Fosfatidicos/química , Fosfatidilgliceroles/química , Espectrometría de Fluorescencia , Temperatura
19.
Arch Gen Psychiatry ; 54(7): 613-23, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9236545

RESUMEN

BACKGROUND: We studied the family psychiatric history of 125 youths with childhood-onset depressive disorder (a portion of whom developed bipolar disorder) and 55 psychiatric controls with nonaffective disorder. METHODS: Probands were classified according to prospectively observed clinical course in childhood. Family psychiatric history was determined by interviewers blind to probands' diagnosis, with mothers typically informing about themselves and about remaining first- and a all second-degree adult relatives. RESULTS: Families of affectively ill juveniles had 5-fold greater odds of lifetime depressive disorder and 2-fold greater odds of recurrent unipolar depressive disorder than did families of psychiatric controls. The higher risk of depression was most evident in first-degree and female relatives. Mothers of affectively ill youths were younger at onset of depression than were mothers of controls. Alcoholism and substance use disorders were more prevalent in relatives of affectively ill probands than in controls and cosegregated with familial depression. However, other covariates were more important at predicting patterns of familial depression. Familial illness patterns also varied somewhat with proband characteristics. CONCLUSIONS: Child probands with affective disorder identify families enriched with affective disorder (even compared with families of psychiatric controls), suggesting that juvenile- and adult-onset forms of this condition share the same diathesis. Rates of affective illness in the families of depressed youngsters also are notably higher than population-based estimates. The findings therefore indicate that very-early-onset affective disorder is familial and that pedigrees ascertained through affectively ill children are good candidates for family and genetic studies.


Asunto(s)
Trastorno Depresivo/epidemiología , Familia , Adolescente , Adulto , Edad de Inicio , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Niño , Comorbilidad , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/genética , Femenino , Humanos , Modelos Logísticos , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiología , Trastornos Mentales/genética , Probabilidad , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Recurrencia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Clase Social
20.
Biol Psychiatry ; 47(9): 794-803, 2000 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-10812038

RESUMEN

BACKGROUND: Eating disorders have not traditionally been viewed as heritable illnesses; however, recent family and twin studies lend credence to the potential role of genetic transmission. The Price Foundation funded an international, multisite study to identify genetic factors contributing to the pathogenesis of anorexia nervosa (AN) by recruiting affective relative pairs. This article is an overview of study methods and the clinical characteristics of the sample. METHODS: All probands met modified DSM-IV criteria for AN; all affected first, second, and third degree relatives met DSM-IV criteria for AN, bulimia nervosa (BN), or eating disorder not otherwise specified (NOS). Probands and affected relatives were assessed diagnostically with the Structured Interview for Anorexia and Bulimia. DNA was collected from probands, affected relatives and a subset of their biological parents. RESULTS: Assessments were obtained from 196 probands and 237 affected relatives, over 98% of whom are of Caucasian ancestry. Overall, there were 229 relative pairs who were informative for linkage analysis. Of the proband-relative pairs, 63% were AN-AN, 20% were AN-BN, and 16% were AN-NOS. For family-based association analyses, DNA has been collected from both biological parents of 159 eating-disordered subjects. Few significant differences in demographic characteristics were found between proband and relative groups. CONCLUSIONS: The present study represents the first large-scale molecular genetic investigation of AN. Our successful recruitment of over 500 subjects, consisting of affected probands, affected relatives, and their biological parents, will provide the basis to investigate genetic transmission of eating disorders via a genome scan and assessment of candidate genes.


Asunto(s)
Anorexia Nerviosa/genética , Adulto , Anorexia Nerviosa/diagnóstico , Anorexia Nerviosa/psicología , Índice de Masa Corporal , Bulimia/diagnóstico , Bulimia/genética , Bulimia/psicología , Femenino , Genoma Humano , Genotipo , Humanos , Entrevista Psicológica , Masculino , Escalas de Valoración Psiquiátrica , Control de Calidad , Medición de Riesgo , Autoevaluación (Psicología)
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