The value of children in African countries – insights from studies on infertility

A number of studies have explored motives for parenthood in the Western industrialized world. These studies have documented that children are mostly desired for reasons relating to happiness and personal well-being. To date, limited data pertaining to parenthood motives in African countries exist. Insight into the value of children can, however, be derived from studies on infertility, as the negative repercussions of involuntary childlessness reflect the value of children to parents and the community. According to these studies children secure conjugal ties, offer social security, assist with labour, confer social status, secure rights of property and inheritance, provide continuity through re-incarnation and maintaining the family lineage, and satisfy emotional needs. Parenthood therefore appears to have more and, arguably, deeper roots in African communities when compared to industrialized countries.     

The CBFA2T3/ACSF3 locus is recurrently involved in IGH chromosomal translocation t(14;16)(q32;q24) in pediatric B-cell lymphoma with germinal center phenotype

Translocations involving immunoglobulin (IG) loci are the hallmarks of several subtypes of B-cell lymphoma. Common to these translocations is that cellular proto-oncogenes come under the influence of IG regulatory elements leading to deregulated expression. In case of a breakpoint in the IGH switch region, oncogene activation can take place on both derivative chromosomes, which means that in principle one translocation can result in concurrent activation of two genes. By fluorescence in situ hybridization (FISH), we identified a case of leukemic B-cell lymphoma in a child with an IGH break and unknown partner. Subsequent long-distance inverse PCR revealed fusion of IGH Sl in 14q32 and the 50 region of CBFA2T3 in 16q24.3, suggesting presence of the t(14;16)(q32;q24.3). Candidate oncogenes targeted through this translocation are CBFA2T3 and ACSF3, which could be activated on der(16) and der(14), respectively. FISH screening of a population-based cohort of B-cell lymphomas from a prospective trial for the treatment of lymphoma in childhood (BFM-NHL) identified additionally a follicular lymphoma Grade 3/diffuse large B-cell lymphoma with IGH-CBFA2T3/ACSF3 juxtaposition. Both lymphomas shared expression of CD10 and CD20 in the absence of TdT, suggesting a germinal center (GC) B-cell origin. Our data indicate that the CBFA2T3/ACSF3 locus is a novel recurrent oncogenic target of IGH translocations, which might contribute to the pathogenesis of pediatric GC-derived B-cell lymphoma.     

Validity of the patient health questionnaire-9 in assessing major depressive disorder during inpatient spinal cord injury rehabilitation

Bombardier CH, Kalpakjian CZ, Graves DE, Dyer JR, Tate DG, Fann JR. Validity of the Patient Health Questionnaire-9 in assessing major depressive disorder during inpatient spinal cord injury rehabilitation.ObjectiveTo investigate the validity of the Patient Health Questionnaire-9 (PHQ-9) depression screening measure in people undergoing acute inpatient rehabilitation for spinal cord injury (SCI).DesignWe performed a blinded comparison of the PHQ-9 administered by research staff with the major depression module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID) conducted by a mental health professional.SettingInpatient rehabilitation units.ParticipantsParticipants (N=142) were patients undergoing acute rehabilitation for traumatic SCI who were at least 18 years of age, English speakers, and without severe cognitive, motor speech, or psychotic disorders. We obtained the SCID on 173 (84%) of 204 eligible patients. The final sample of 142 patients (69%) consisted of those who underwent both assessments within 7 days of each other.InterventionsNot applicable.Main Outcome MeasuresPHQ-9 and SCID major depression module.ResultsParticipants were on average 42.2 years of age, 78.2% men, and 81.7% white, and 66.9% had cervical injuries. The optimal PHQ-9 cutoff (≥11) resulted in 35 positive screens (24.6%). Key indices of criterion validity were as follows: sensitivity, 1.00 (95% confidence interval [CI], .73–1.00); specificity, .84 (95% CI, .76–.89); Youden Index, .84; positive predictive value, .40 (95% CI, .24–.58); and negative predictive value, 1.00 (95% CI, .96–1.00). The area under the receiver operator curve was .92, and κ was .50. Total PHQ-9 scores were inversely correlated with subjective health state and quality of life since SCI.ConclusionsThe PHQ-9 meets criteria for good diagnostic accuracy compared with a structured diagnostic assessment for major depressive disorder even in the context of inpatient rehabilitation for acute traumatic SCI.     

Heritable changes in regional cortical thickness with age

It is now well established that regional indices of brain structure such as cortical thickness, surface area or grey matter volume exhibit spatially variable patterns of heritability. However, a recent study found these patterns to change with age during development, a result supported by gene expression studies. Changes in heritability have not been investigated in adulthood so far and could have important implications in the study of heritability and genetic correlations in the brain as well as in the discovery of specific genes explaining them. Herein, we tested for genotype by age (G ×A) interactions, an extension of genotype by environment interactions, through adulthood and healthy aging in 902 subjects from the Genetics of Brain Structure (GOBS) study. A “jackknife” based method for the analysis of stable cortical thickness clusters (JASC) and scale selection is also introduced. Although additive genetic variance remained constant throughout adulthood, we found evidence for incomplete pleiotropy across age in the cortical thickness of paralimbic and parieto-temporal areas. This suggests that different genetic factors account for cortical thickness heritability at different ages in these regions.     

Targeting the p53 pathway in retinoblastoma with subconjunctival Nutlin-3a

Retinoblastoma is a rare childhood cancer of the retina that begins in utero and is diagnosed in the first years of life. The goals of retinoblastoma treatment are ocular salvage, vision preservation, and reduction of short- and long-term side effects without risking mortality because of tumor dissemination. To identify better chemotherapeutic combinations for the treatment of retinoblastoma, several groups have developed genetic mouse models and orthotopic xenograft models of human retinoblastoma for preclinical testing. Previous studies have implicated the MDMX protein in the suppression of the p53 pathway in retinoblastoma and shown that the MDM2/MDMX antagonist, Nutlin-3a, can efficiently induce p53-mediated cell death in retinoblastoma cell lines. However, Nutlin-3a cannot be administered systemically to treat retinoblastoma, because it has poor penetration across the blood-ocular barrier. Therefore, we developed an ocular formulation of Nutlin-3a, Nutlin-3a(OC), and tested the pharmacokinetics and efficacy of this new formulation in genetic and human retinoblastoma orthotopic xenograft models of retinoblastoma. Here, we show that Nutlin-3a(OC) specifically and efficiently targets the p53 pathway and that the combination of Nutlin-3a(OC) with systemic topotecan is a significantly better treatment for retinoblastoma than currently used chemotherapy in human orthotopic xenografts. Our studies provide a new standardized approach to evaluate and prioritize novel agents for incorporation into future clinical trials for retinoblastoma.     

Introduction to genetic analysis workshop 17 summaries

Genetic Analysis Workshop 17 (GAW17) was held on October 13-16, 2010, in Boston, Massachusetts. The focus of GAW17 was on methods and challenges of the analysis of next-generation sequence data using a mini-exome data set. Two different study designs were simulated, unrelated individuals and large families, each with the same sample size. GAW17 was attended by 274 participants from 19 countries. The 166 contributions were organized into 15 discussion groups of 5-13 articles each. This supplement to Genetic Epidemiology provides further details on GAW17, and primary findings are highlighted in the individual group summary articles. In addition, the supplement includes two methodological articles (one on statistical approaches for collapsing methods and one on machine learning methods) to give an overview of the methods that many of the workshop participants used. We conclude the supplement with a discussion of critical aspects in the analysis of next-generation sequencing data.