Clinical and genetic differences between bipolar disorder type 1 and 2 in multiplex families.

The two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes. Historically, BD-II was perceived as a less severe form of BD-I. Recent research has challenged this concept of a severity continuum. Studies in large samples of unrelated patients have described clinical and genetic differences between the subtypes. Besides an increased schizophrenia polygenic risk load in BD-I, these studies also observed an increased depression risk load in BD-II patients. The present study assessed whether such clinical and genetic differences are also found in BD patients from multiplex families, which exhibit reduced genetic and environmental heterogeneity. Comparing 252 BD-I and 75 BD-II patients from the Andalusian Bipolar Family (ABiF) study, the clinical course, symptoms during depressive and manic episodes, and psychiatric comorbidities were analyzed. Furthermore, polygenic risk scores (PRS) for BD, schizophrenia, and depression were assessed. BD-I patients not only suffered from more severe symptoms during manic episodes but also more frequently showed incapacity during depressive episodes. A higher BD PRS was significantly associated with suicidal ideation. Moreover, BD-I cases exhibited lower depression PRS. In line with a severity continuum from BD-II to BD-I, our results link BD-I to a more pronounced clinical presentation in both mania and depression and indicate that the polygenic risk load of BD predisposes to more severe disorder characteristics. Nevertheless, our results suggest that the genetic risk burden for depression also shapes disorder presentation and increases the likelihood of BD-II subtype development.

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families.

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (padj < 0.006) and schizophrenia (padj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.

El estudio Andalusian Bipolar Family (ABiF): protocolo y descripción de la muestra / The Andalusian Bipolar Family (ABiF) Study: Protocol and sample description

Introducción: Se presenta la primera descripción del estudio denominado Andalusian Bipolar Family (ABiF). Se trata de una investigación longitudinal con familias procedentes de Andalucía (España), que comenzó en 1997, con el objetivo de dilucidar las causas geneticomoleculares del trastorno afectivo bipolar. Desde entonces, esta cohorte ha contribuido a una serie de hallazgos clave, que han sido publicados en revistas internacionales. Sin embargo, el conocimiento sobre las bases genéticas del trastorno en estas familias sigue siendo limitado. Método: El estudio consta de dos fases: en la fase inicial se reclutaron 100 familias con múltiples afectados de trastorno bipolar y otros trastornos del ánimo. La segunda fase del proyecto, actualmente en curso, comenzó en 2013 con el objetivo de realizar un seguimiento de la cohorte de familias reclutadas originalmente. Los objetivos del estudio de seguimiento son: I) recoger nuevos datos clínicos longitudinales; II) realizar una evaluación neuropsicológica detallada, y III) obtener una extensa colección de biomateriales para futuros estudios moleculares. Resultados: El estudio ABiF, por tanto, generará unos recursos valiosos para futuras investigaciones sobre la etiología del trastorno afectivo bipolar; particularmente con respecto a las causas de la alta carga genética del trastorno en las familias con múltiples afectados. Discusión: Se discute el valor de este enfoque en relación con las nuevas tecnologías para la identificación de factores genéticos de alta penetrancia. Estas nuevas tecnologías incluyen la secuenciación del exoma y del genoma completo, y el uso de células madre pluripotentes inducidas u organismos modelo para la determinación de consecuencias funcionales

Introduction: Here, we present the first description of the Andalusian Bipolar Family (ABiF) Study. This longitudinal investigation of families from Andalusia, Spain commenced in 1997 with the aim of elucidating the molecular genetic causes of bipolar affective disorder. The cohort has since contributed to a number of key genetic findings, as reported in international journals. However, insight into the genetic underpinnings of the disorder in these families remains limited. Method: In the initial 1997-2003 study phase, 100 multiplex bipolar disorder and other mood disorder families were recruited. The ongoing second phase of the project commenced in 2013, and involves follow-up of a subgroup of the originally recruited families. The aim of the follow-up investigation is to generate: I) longitudinal clinical data; II) results from detailed neuropsychological assessments; and III) a more extensive collection of biomaterials for future molecular biological studies. Results: The ABiF Study will thus generate a valuable resource for future investigations into the aetiology of bipolar affective disorder; in particular the causes of high disease loading within multiply affected families. Discussion: We discuss the value of this approach in terms of new technologies for the identification of high-penetrance genetic factors. These new technologies include exome and whole genome sequencing, and the use of induced pluripotent stem cells or model organisms to determine functional consequences

The Andalusian Bipolar Family (ABiF) Study: Protocol and sample description. / El estudio Andalusian Bipolar Family (ABiF): protocolo y descripción de la muestra.

INTRODUCTION: Here, we present the first description of the Andalusian Bipolar Family (ABiF) Study. This longitudinal investigation of families from Andalusia, Spain commenced in 1997 with the aim of elucidating the molecular genetic causes of bipolar affective disorder. The cohort has since contributed to a number of key genetic findings, as reported in international journals. However, insight into the genetic underpinnings of the disorder in these families remains limited. METHOD: In the initial 1997-2003 study phase, 100 multiplex bipolar disorder and other mood disorder families were recruited. The ongoing second phase of the project commenced in 2013, and involves follow-up of a subgroup of the originally recruited families. The aim of the follow-up investigation is to generate: i) longitudinal clinical data; ii) results from detailed neuropsychological assessments; and iii) a more extensive collection of biomaterials for future molecular biological studies. RESULTS: The ABiF Study will thus generate a valuable resource for future investigations into the aetiology of bipolar affective disorder; in particular the causes of high disease loading within multiply affected families. DISCUSSION: We discuss the value of this approach in terms of new technologies for the identification of high-penetrance genetic factors. These new technologies include exome and whole genome sequencing, and the use of induced pluripotent stem cells or model organisms to determine functional consequences.

Needs, Perceived Support, and Hospital Readmissions in Patients with Severe Mental Illness.

People with severe mental illness have multiple and complex needs that often are not addressed. The purpose of this study was to analyse needs and support perceived and the relationship with hospital readmission. We assessed 100 patients with severe mental illness at discharge from an acute inpatient unit in terms of needs (Camberwell Assessment of Needs), clinical status (The Brief Psychiatric Rating Scale), and social functioning (Personal and Social Performance); we also followed up these patients for 1 year. The group of patients who were readmitted had more total needs than did the non-readmitted, in addition to more unmet needs, although the differences were not significant. The highest risk factor for rehospitalisation was the number of previous admissions. In addition, the help of informal carers in alleviating psychological distress was associated with the risk of readmission. The main conclusion concerns the role of the psychological support provided by informal networks in preventing readmission.

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. METHODS: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. RESULTS: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. LIMITATIONS: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. CONCLUSIONS: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.

Factors associated with use of community mental health services by schizophrenia patients using multilevel analysis.

BACKGROUND: Persons with schizophrenia and related disorders may be particularly sensitive to a number of determinants of service use, including those related with illness, socio-demographic characteristics and organizational factors. The objective of this study is to identify factors associated with outpatient contacts at community mental health services of patients with schizophrenia or related disorders. METHODS: This cross-sectional study analyzed 1097 patients. The main outcome measure was the total number of outpatient consultations during one year. Independent variables were related to socio-demographic, clinical and use of service factors. Data were collected from clinical records. RESULTS: The multilevel linear regression model explained 46.35% of the variance. Patients with significantly more contacts with ambulatory services were not working and were receiving welfare benefits (p = 0.02), had no formal education (p = 0.02), had a global level of severity of two or three (four being the most severe) (p < 0.001), with one or more inpatient admissions (p < 0.001), and in contact with both types of professional (nurses and psychiatrists) (p < 0.001). The patients with the fewest ambulatory contacts were those with diagnoses of persistent delusional disorders (p = 0.04) and those who were attended by four of the 13 psychiatrists (p < 0.001). CONCLUSIONS: As expected, the variables that explained the use of community service could be viewed as proxies for severity of illness. The most surprising finding, however, was that a group of four psychiatrists was also independently associated with use of ambulatory services by patients with schizophrenia or related disorders. More research is needed to carefully examine how professional support networks interact to affect use of mental health.

A new susceptibility locus for bipolar affective disorder in PAR1 on Xp22.3/Yp11.3.

We present the findings of a linkage study of bipolar affective disorder (BPAD) that involve the pseudoautosomal region 1 of the human sex chromosomes. We analyzed a substantial subset of pedigrees (89 families of German and Spanish origin; 661 participants; 298 affected individuals) from the large collection of BPAD-affected families with which a genomewide linkage analysis was previously performed and where the pseudoautosomal regions were poorly covered. Nonparametric linkage (Z(lr)) scores were calculated. The highest Z(lr) scores were obtained on Xp22.3/Yp11.3 in the Spanish subsample (DXS1071; Z(lr) = 3.54, P(empirical) = 0.0009 for the broad definition of affection sttuts; Z(lr) = 2.63, P(empirical) = 0.0129 for the medium definition of affection status; Z(lr) = 2.12, P(empirical) = 0.0429 for the narrow definition of affection status). Empirical P-values are adjusted using the Bonferroni correction to account for the testing of three affection status definitions. This region has not drawn much attention in previous linkage studies of BPAD. On the basis of these results, Xp22.3/Yp11.3 should now be considered a candidate region for BPAD.

Mood-incongruent psychosis in bipolar disorder: conditional linkage analysis shows genome-wide suggestive linkage at 1q32.3, 7p13 and 20q13.31.

OBJECTIVE: The majority of research into functional psychosis has proceeded under the assumption that schizophrenia and bipolar disorder are distinct entities with separate underlying disease processes and treatments. This view has been increasingly challenged in both clinical and genetic studies. Findings in recent association studies at two specific genes suggest that the occurrence of mood-incongruent psychotic features may indicate a relatively homogeneous subset of the bipolar phenotype. We examined this hypothesis. METHODS: Caucasian affected individuals were ascertained from Europe (the United Kingdom, the Republic of Ireland, Germany, Italy and Andalusia). Consensus best-estimate diagnoses were assigned by two independent raters according to all available information. There was no cross-site evaluation of inter-rater reliability. Families multiply affected by bipolar spectrum mood disorder were selected, comprising 383 affected relative pairs. Individuals were considered to be affected if they were diagnosed with DSM-IV bipolar I disorder or schizoaffective disorder, bipolar type. Multipoint, affected relative pair covariate linkage analysis was performed. RESULTS: Significant familiality of incongruent psychosis was observed [intra-class correlation coefficient (ICC) = 0.309; p = 0.001, one-tail]. Covariate linkage analysis provided three regions with genome-wide suggestive evidence for linkage on chromosomes 1q32.3 (LOD = 4.15, expected 0.12 times per genome scan), 7p13 (LOD = 3.32) and 20q13.31 (LOD = 2.98). No region in our analysis met criteria for genome-wide significance. CONCLUSION: Our results provide molecular support for the hypothesis that genes may exist for specific forms of bipolar illness, dependent on the presence or absence of incongruent psychosis. Our findings suggest that researchers should take account of mood-congruence/incongruence of psychotic features in studies of bipolar disorder.

Abnormal neuroendocrine response to clomipramine in hereditary affective psychosis.

BACKGROUND: Blunting of prolactin response after serotonergic stimulation during a major depressive episode has been described by several investigators. In this study, the neuroendocrine responses to clomipramine were assessed in remitted patients suffering from hereditary depression. METHODS: Twenty remitted patients from 11 large families with multigenerational, multiple cases of major affective disorder (bipolar disorder n=15, recurrent depression n=5, according DSM-IV) and 12 healthy relatives were investigated. After intravenous application of 12.5 mg of the serotonin re-uptake inhibitor clomipramine, serum prolactin and cortisol levels were analysed. RESULTS: Patients and comparison group did not differ significantly with respect to age, baseline prolactin and cortisol concentrations. A gender effect was found in an exploratory analysis for prolactin but not for cortisol and therefore the data for prolactin were analysed separately. After clomipramine infusion, the increase of cortisol was significantly lower in patients than in the comparison group (P=.046). For prolactin, this effect could be found in the male (P=.012) as well as in the female (P=.007) subsample. CONCLUSIONS: These results suggest that blunted prolactin and cortisol responses to serotonergic stimulation are characteristic for remitted depressive patients with previous episodes of major affective disorders.

The Malaga schizophrenia case-register (RESMA): overview of methodology and patient cohort.

BACKGROUND: Little information has become available after psychiatric reforms regarding outcomes of persons with schizophrenia and related disorders cared for in community-based mental health facilities. AIMS: The aim of this study was to determine the consequences of psychiatric services in the users of mental health services in Malaga. METHOD: We describe the cohort and methods involved in the Schizophrenia Case Register (RESMA) in Malaga, Spain. All cases (n = 1,022) were users of public mental health services provided in the catchment area over one year. The majority were male (65%), single (68%), living with their original family (50%), with primary education (41%) and living on disability benefits (52%). RESULTS: Concerning use of services, the majority had out-patient contacts (89%). RESULT: s show a substantial overlap in the use of different services during the study period. CONCLUSION: The Malaga Schizophrenia Case Register provides sociodemographic, clinical and service use information for a large sample of patients with schizophrenia or related disorders. Results obtained from the cohort studied will be instrumental for the follow-up and evaluation of the mental health care reform.

Prevalencia y factores asociados a la pediculosis en niños del Jardín Infantil de la Universidad Nacional de Colombia / Pediculosis prevalence and associated risk factors in children of the nursery school, Bogotá, Colombia

Introducción. La pediculosis es una de las infestaciones crónicas más importante en escolares en el mundo.Objetivo. Estimar la prevalencia y describir la estacionalidad de la pediculosis durante siete meses en un jardín infantil y explorar su asociación con las variables socioeconómicas, las prácticas de higiene y las características del cabello. Materiales y métodos. Ciento setenta y ocho niños entre 3 y 60 meses de edaddel jardín infantil de la Universidad Nacional de Colombia participaron en el estudio. En cada niño se exploró la presencia de Pediculus humanus mensualmente por siete meses y se midió el grosor y la longitud del cabello al comienzo del seguimiento. Se realizó una encuesta a los cuidadores de los sujetos de estudio sobre prácticas higiénicas y condiciones socioeconómicas.Resultados. Se encontraron mayores prevalencias en el grupo de edad entre 48 a 59 meses, al principio del año escolar. Estos resultados sugieren una asociaciónpositiva entre la pediculosis y tener una longitud del cabello mayor de 11,5 centímetros [Razón de prevalencia (RP): 2,0; intervalo de confianza (IC) del 95 por ciento:0,82-4,8 ], el bañarse la cabeza menos de tres veces a la semana (RP: 1,58; IC 95 por ciento: 0,58-4,7), el compartir implementos de aseo (RP:1,31; IC 95 por ciento: 0,38-4,46) y el vivir más de cinco personas en la casa (RP; 2,04: IC 95 por ciento: 0,8-5,06). Conclusión. La infestación por P. humanus capitis tiene altas prevalencias en los escolares del jardín. Esta infestación se encuentra asociada a las malas prácticas higiénicas, al hacinamiento y la longitud del cabello.

Frecuencia de anticuerpos anti-Trypanosoma cruzi en pacientes portadores de marcapasos de la Clínica San Pedro Claver de Bogotá / Frequency of Trypanosoma cruzi infection in patients with implanted pacemaker

Introducción. En Colombia no se conoce cuál es el impacto de la infección por Trypanosoma cruzi en la producción de cardiopatía crónica expresada por bradiarritmias graves que requieren implante de marcapaso. Objetivo. Determinar la seroprevalencia de anticuerpos anti-Trypanosoma cruzi en pacientes con bloqueos de conducción o disfunción sinusal que requirieron implantación de marcapaso. Materiales y métodos. Mediante un estudio descriptivo de corte transversal (2004-2005) en 332 pacientes de la consulta de marcapaso de la clínica San Pedro Claver de Bogotá, se estimó la seroprevalencia de anticuerpos anti-Trypanosoma cruzi mediante las pruebas de inmunofluorescencia indirecta y ELISA. Se aplicó un formulario de recolección de datos epidemiológicos y de hallazgos de examen físico. El análisis estadístico se hizo mediante las pruebas de ji al cuadrado y T de Student. Resultados. La seroprevalencia anti-T. cruzi fue de 17,11 por ciento. Esta seropositividad se asoció con: menor edad al momento del implante del marcapaso (55,22+13,62 Vs. 59,82+17,19, p= 0,0013), con el reconocimiento de los triatominos (83,6 por ciento Vs. 39,6 por ciento, p<0,001) y con haber vivido antes de los 15 años en zonas endémicas para la enfermedad de Chagas. El paciente no conocía el diagnóstico de enfermedad de Chagas o éste no se sospechó clínicamente en el 60 por ciento de los casos. Conclusiones. La prevalencia de anticuerpos anti-T. cruzi en pacientes portadores de marcapaso es alta. La implantación de marcapasos se presentó más tempranamente en el grupo seropositivo. No hay adecuada sospecha clínica ni información al paciente sobre el diagnóstico de la enfermedad de Chagas.

Introduction. In Colombia the impact of infections of Trypanosoma cruzi are known to produce chronic cardiopathy and expressed by bradycardia. In Colombia the extent and impact of these infections has not been examined. Objective. The current study aimed to determine the prevalence of T. cruzi infection as measured by serology, in a population of patients with cardiopathy that required a permanent pacemaker as treatment for cardiac rhythm abnormalities and conduction blocking. Materials and methods. A cross sectional study sampled 332 patients from the pacemaker clinic at the San Pedro Claver Hospital in Bogotá, Colombia, for one year (2004-2005). Epidemiological and clinical data were obtained through interviews and physical examination were accomplished with chi-square and Students’ t tests. Results. Of patients with pacemakers, 17.1% had anti-T. cruzi antibodies (seropositive). At the time when the pacemaker was implanted, chronic Chagas’ disease patients were younger (55±13 years) than those patients with cardiopathy (60±17 years) with no anti-T. cruzi antibodies (p<0.01). The seropositive group was aware of the Chagas’ disease vector (83.6%) in contrast to the seronegative group (39.6%, p<0.001). In 60% of the patients of the seropositive group, no clinical signs of the disease were apparent. The geographical origin of the seropositive group were traced to regions in Colombia known to be endemic for Chagas´ disease transmission. Conclusion. Chagas´ disease prevalence is high in Colombian patients who required a permanent cardiac pacemaker. Chronic Chagas’ disease patients required pacemaker implant at a younger age in contrast with patients with other cardiac pathologies. The clinical recognition of Chagas´ disease associated with cardiopathy is low despite the epidemiological data.

The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q.

We present the first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder (BPAD), using a large linkage data set (52 families of European descent; 448 participants and 259 affected individuals). Our results provide the strongest interaction evidence between BPAD genes on chromosomes 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions (nonparametric LOD [NPL] scores of 7.55 on 2q and 7.63 on 6q; P<.0001 and P=.0001, respectively, after a genomewide permutation procedure). The second-best BPAD interaction evidence was observed between chromosomes 2q22-q24 and 15q26. Here, we also observed a symmetrical interaction (NPL scores of 6.26 on 2q and 4.59 on 15q; P=.0057 and .0022, respectively). We covered the implicated regions by genotyping additional marker sets and performed a detailed interaction linkage analysis, which narrowed the susceptibility intervals. Although the heterogeneity analysis produced less impressive results (highest NPL score of 3.32) and a less consistent picture, we achieved evidence of locus heterogeneity at chromosomes 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. Our results provide systematic insights in the framework of BPAD epistasis and locus heterogeneity, which should facilitate gene identification by the use of more-comprehensive cloning strategies.

[Frequency of Trypanosoma cruzi infection in patients with implanted pacemaker]. / Frecuencia de anticuerpos anti-Trypanosoma cruzi en pacientes portadores de marcapasos de la Clínica San Pedro Claver de Bogotá.

INTRODUCTION: In Colombia the impact of infections of Trypanosoma cruzi are known to produce chronic cardiopathy and expressed by bradycardia. In Colombia the extent and impact of these infections has not been examined. OBJECTIVE: The current study aimed to determine the prevalence of T. cruzi infection as measured by serology, in a population of patients with cardiopathy that required a permanent pacemaker as treatment for cardiac rhythm abnormalities and conduction blocking. MATERIALS AND METHODS: A cross sectional study sampled 332 patients from the pacemaker clinic at the San Pedro Claver Hospital in Bogotá, Colombia, for one year (2004-2005). Epidemiological and clinical data were obtained through interviews and physical examination. Serological tests consisted of indirect inmunofluorescence assay and ELISA. Statistical analyses were accomplished with chi-square and Students t tests. RESULTS: Of patients with pacemakers, 17.1% had anti-T. cruzi antibodies (seropositive). At the time when the pacemaker was implanted, chronic Chagas disease patients were younger (55+/-13 years) than those patients with cardiopathy (60+/-17 years) with no anti-T. cruzi antibodies (p<0.01). The seropositive group was aware of the Chagas disease vector (83.6%) in contrast to the seronegative group (39.6%, p<0.001). In 60% of the patients of the seropositive group, no clinical signs of the disease were apparent. The geographical origin of the seropositive group were traced to regions in Colombia known to be endemic for Chagas disease transmission. CONCLUSION: Chagas disease prevalence is high in Colombian patients who required a permanent cardiac pacemaker. Chronic Chagas disease patients required pacemaker implant at a younger age in contrast with patients with other cardiac pathologies. The clinical recognition of Chagas disease associated with cardiopathy is low despite the epidemiological data.

Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24.

We present the findings of a large linkage study of bipolar affective disorder (BPAD) that involved genomewide analysis of 52 families (448 genotyped individuals) of Spanish, Romany, and Bulgarian descent and further fine mapping of the 1p34-p36, 4q28-q31, and 6q15-q24 regions. An additional sample of 56 German families (280 individuals) was included for this fine-mapping step. The highest nonparametric linkage scores obtained in the fine mapping were 5.49 for 4q31 and 4.87 for 6q24 in the Romany families and 3.97 for 1p35-p36 in the Spanish sample. MOD-score (LOD scores maximized over genetic model parameters) analysis provided significant evidence of linkage to 4q31 and at least borderline significance for the 1p and 6q regions. On the basis of these results and previous positive research findings, 4q31 and 6q24 should now be considered confirmed BPAD susceptibility loci, and 1p35-p36 is proposed as a new putative locus that requires confirmation in replication studies.

Increased levels of glucocorticoid receptors and enhanced glucocorticoid receptor auto-regulation after hydrocortisone challenge in B-lymphoblastoids from patients with affective disorders.

The stress response is mediated by a negative feedback effect of glucocorticoids on corticosteroid receptors. Here, we examine the potential contribution of these receptors and their response to a glucocorticoid challenge to dysfunctions of the hypothalamic-pituitary-adrenal axis reported for patients with affective disorders. In a pilot-study, we established B-lymphoblastoid cell lines from patients suffering from affective disorders and healthy subjects and measured the quantity of glucocorticoid receptors at steady state conditions after 12-weeks cell culture. After short-term incubation with 0.1 microM hydrocortisone for 48 h, the decrease of glucocorticoid receptors was also investigated. After 12-weeks cell culture, we found a significantly higher number of cytosolic glucocorticoid receptors in B-lymphoblastoids from patients (B(max)=804.9+/-342.5 fmol/mg protein) compared to those from healthy subjects (B(max)=576.9+/-190.3 fmol/mg protein: p=0.045; t-test). The increase of the glucocorticoid receptor level in the group of patients could be attributed largely to the higher number of these receptors measured in B-lymphoblastoids of patients suffering from major depressive disorder. The in vitro regulation of glucocorticoid receptors in response to 0.1 microM hydrocortisone for 48 h resulted in a significantly larger decrease in cultures of B-lymphoblastoids derived from patients (to 32.9+/-7.5%) than in those from healthy subjects (to 45.8+/-8.2%). The stronger decrease of glucocorticoid receptors in the group of patients (p=0.0001; t-test) was independent of the duration of illness and medication, suggesting a trait-like characteristic of the response.

Safety and immunogenicity of oral killed whole cell recombinant B subunit cholera vaccine in Barranquilla, Colombia

In January and February 1992, an assessment was conducted of the safety and immunogenicity of two doses of a new oral cholera vaccine prepared from the recombinant B subunit of the toxin and from killed whole cells (rBS/WC) in 1 165 individuals between the ages of 12 months and 64 years in Barranquilla, Colombia. This was a randomized, double-blind placebo controlled study. Participants received two doses of either the vaccine or a placebo (killed Escherichia coli K12) over a two-week interval. Few symptoms were detected during the three days following administration of the initial dose and even fewer following the second. Sera obtained upon administration of the first dose and two weeks after administration of the second were tested for Vibrio cholera 01 Inaba vibriocidal antibodies and antitoxins. Geometric mean titers (GMT) of vibriocidal antibodies were found to increase two-fold in subjects receiving the vaccine. In the paired samples taken from vaccinated subjects, two-fold or greater increases were observed in 44 percent and four-fold or greater increases were observed in 34 percent, as compared to similar increases in 9.2 percent and 2.2 percent of the sera taken from those receiving the placebo (P 0.05). The GMTs of IgG and IgA antitoxins, as determined by ELISA, increased by factors of 4 and 3.2, respectively, in those receiving the vaccine, as compared to factors of 1.1 and 1.1 in those given the placebo (P 0.001 for IgG, P 0.01 for IgA) (AU)

Safety and immunogenicity of oral killed whole cell recombinant B subunit cholera vaccine in Barranquilla, Colombia

In January and February 1992, an assessment was conducted of the safety and immunogenicity of two doses of a new oral cholera vaccine prepared from the recombinant B subunit of the toxin and from killed whole cells (rBS/WC) in 1 165 individuals between the ages of 12 months and 64 years in Barranquilla, Colombia. This was a randomized, double-blind placebo controlled study. Participants received two doses of either the vaccine or a placebo (killed Escherichia coli K12) over a two-week interval. Few symptoms were detected during the three days following administration of the initial dose and even fewer following the second. Sera obtained upon administration of the first dose and two weeks after administration of the second were tested for Vibrio cholera 01 Inaba vibriocidal antibodies and antitoxins. Geometric mean titers (GMT) of vibriocidal antibodies were found to increase two-fold in subjects receiving the vaccine. In the paired samples taken from vaccinated subjects, two-fold or greater increases were observed in 44 percent and four-fold or greater increases were observed in 34 percent, as compared to similar increases in 9.2 percent and 2.2 percent of the sera taken from those receiving the placebo (P 0.05). The GMTs of IgG and IgA antitoxins, as determined by ELISA, increased by factors of 4 and 3.2, respectively, in those receiving the vaccine, as compared to factors of 1.1 and 1.1 in those given the placebo (P 0.001 for IgG, P 0.01 for IgA) (AU)

Published in Spanish in the BOSP. Vol. 119(2) August 1995