A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder

OBJECTIVE: Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary. METHOD: In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score. RESULTS: Two regions with multipoint maximum lod scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak lod score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p. CONCLUSIONS: The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.     

Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype

OBJECTIVE: Longitudinal outcomes of bipolar disorder with onset in the late teenage years or in adulthood have been reported, but little is known about the natural history of childhood-onset mania. This study sought to provide rates and predictors of recovery and relapse in children with a prepubertal and early adolescent bipolar disorder phenotype. METHOD: Eighty-nine consecutively ascertained outpatient subjects (mean age=10.9 years [SD=2.7]) received comprehensive research assessments, including separate interviews of mothers about their children and of children about themselves, at baseline and at 6, 12, 18, and 24 months after baseline. The study phenotype required DSM-IV mania with elation and/or grandiosity as one criterion to distinguish the study phenotype from a diagnosis of mania based on criteria overlapping with those for attention deficit hyperactivity disorder and to ensure that subjects had at least one of the two cardinal features of mania (i.e., elation and/or grandiosity). Subjects were treated by their own community practitioners. RESULTS: The proportions of subjects who recovered from mania and who relapsed after recovery were 65.2% and 55.2%, respectively. The mean time to recovery was 36.0 weeks (SD=25.0). Relapse occurred after a mean of 28.6 weeks (SD=13.2). Living with an intact biological family significantly predicted rate of recovery, and a low level of maternal warmth significantly predicted rate of relapse. CONCLUSIONS: The relatively poor outcomes of these subjects may be related to their phenotypic resemblance to severely ill adults with bipolar disorder who have mixed mania, continuous rapid cycling, psychosis, and treatment-resistant psychopathology. A lower level of effectiveness of mood stabilizers in children cannot be ruled out. Although the significance of maternal warmth as a predictor is consistent with reports in adult mania, the significance of intact family as a predictor may be unique to childhood mania.     

Four-dimensional fetal echocardiography with spatiotemporal image correlation (STIC): a systematic study of standard cardiac views assessed by different observers.

OBJECTIVE: To test the agreement between observers and reproducibility of a technique to display standard cardiac views of the left and right ventricular outflow tracts from four-dimensional volume datasets acquired with Spatiotemporal Image Correlation (STIC). METHODS: A technique was developed to obtain dynamic multiplanar images of the left ventricular outflow tract (LVOT) and right ventricular outflow tract (RVOT) from volume datasets acquired with STIC. Volume datasets were acquired from fetuses with normal cardiac anatomy. Twenty volume datasets of satisfactory quality were pre-selected by one investigator. The data was randomly assigned for a blinded review by two independent observers with previous experience in fetal echocardiography. Only one volume dataset was used for each fetus. After a training session, the observers obtained standardized cardiac views of the LVOT and RVOT, which were scored on a scale of 1 to 5, based on diagnostic value and image quality (1=unacceptable, 2=marginal, 3=acceptable, 4=good, and 5=excellent). Median scores and interquartile range, as well as inter- and intraobserver agreement were calculated for each view. RESULTS: The mean menstrual age at the time of volume acquisition was 25.5+/-4.5 weeks. Median scores (interquartile range) for LVOT images, obtained by the first and second observers, were 3.5 (2.25-5.00) and 4 (3.00-5.00), respectively. The median scores (interquartile range) for RVOT images obtained by the first and second observers were 3 (3.00-5.00) and 3 (2.00-4.00), respectively. The interobserver intraclass correlation coefficient for the LVOT was 0.693 (95% CI 0.380-0.822), and 0.696 (95% CI 0.382-0.866) for the RVOT. For the intraobserver agreement analysis, observer 1 gave higher scores to the LVOT the second time the volumes were analyzed [LVOT: 3.50 (2.25-5.00) vs. 5.00 (4.00-5.00, p=0.008)]. CONCLUSION: STIC can be reproducibly used to evaluate fetal cardiac outflow tracts by independent examiners. Slightly better image quality rating scores during the intraobserver variability trial suggests the presence of a learning curve for the manipulation and analysis of volume data obtained by STIC.     

p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.

PURPOSE: Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used. EXPERIMENTAL DESIGN: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing. RESULTS: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion. CONCLUSIONS: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.     

Anemia and iron deficiency in pregnant Ghanaian women from urban areas.

OBJECTIVES: To determine the prevalence and identify risk factors for iron deficiency and anemia in pregnant Ghanaian women from urban areas. METHODS: A cross-sectional study of 452 healthy pregnant women receiving prenatal care in Accra, Ghana, was conducted. A sociodemographic health questionnaire was performed and hematologic parameters were measured. Logistic regression methods were used to identify risk factors for anemia and iron status. RESULTS: Complete data were available for 428 women. Anemia (hemoglobin <11 g/dL) was present in 144 (34%), iron deficiency (ferritin < or =16 microg/L) in 69 (16%), and iron deficiency anemia in 32 (7.5%) women. The adjusted odds ratio (OR) for anemia was 3.4 and 9.8 if iron deficiency and malaria parasitemia were present, respectively; the OR was 0.6 if women were at > or =36 weeks of pregnancy. The adjusted OR for iron deficiency was 2.7 if women were at > or =36 weeks of pregnancy and 0.12 if they had sickle trait. CONCLUSION: Although anemia and iron deficiency remain substantial problems in pregnant Ghanaian women from urban areas, their prevalence is less than previously reported.     

The role of constructed meaning in adaptation to the onset of life-threatening illness

Do the meanings inherent within a traumatic life event increase our understanding of differential mental health outcomes? In light of this question two central issues are addressed in this article: (1) what variables influence the meaning that is constructed in response to a crisis, and (2) how does this meaning affect the self and ultimately the adaptation/mental health outcome as indicated by the level of emotional distress? A theoretical model is evaluated via a comparative analysis that incorporates the data of 76 persons with cancer and 130 persons with HIV/AIDS. Three primary findings support this model and the significance of the role of meaning in response to a crisis: (1) the meaning constructed in response to a crisis can be operationalized and its role evaluated as a dimension of the adaptation process, (2) evidence indicates constructed meaning affects self-perception, which subsequently affects adaptation, and (3) the pattern of effects does not differ by illness type since analyses indicate meaning is central to individuals' responses regardless of differences in characteristics of the event.