Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease

Alzheimer's disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP, PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain disease-causing mutations are thought to exist. We performed whole exome sequencing in a Turkish patient clinically diagnosed with Alzheimer's disease from a consanguineous family with a complex history of neurological and immunological disorders and identified a mutation in NOTCH3 (p.R1231C), previously described as causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Complete screening of NOTCH3 in a cohort of 95 early onset AD cases and 95 controls did not reveal any additional pathogenic mutations. Although the complex history of disease in this family precluded us to establish segregation of the mutation found with disease, our results show that exome sequencing is a rapid, cost-effective and comprehensive tool to detect genetic mutations, allowing for the identification of unexpected genetic causes of clinical phenotypes. As etiological based therapeutics become more common, this method will be key in diagnosing and treating disease.     

Radiation‐guided breast sentinel lymph node biopsies – is a handling delay for radiation protection necessary?

Singleton M, Firth M, Stephenson T, Morrison G & Baginska J
(2012) Histopathology  61, 277–282 Radiation‐guided breast sentinel lymph node biopsies – is a handling delay for radiation protection necessary? Aims: Radiation‐guided sentinel lymph node (SLN) biopsy is a well‐established procedure in many countries. However, histopathology protocols in different centres specify widely differing sample handling delays of between 0 and 72 h. Introducing a delay reduces the radiation exposure of pathologists, but has a detrimental effect on the quality and validity of histology. This study aims to show that a sample handling delay is not justified by the radiation doses to pathologists handling samples received directly from surgery. Methods and results: Radiation doses to the body and hands of pathologists handling samples delivered directly from theatres were measured using personal dose meters. These measurements were supplemented by dose assessments undertaken using dose‐rate measurements at 1 cm and 30 cm from Tc‐99m sources to simulate the processing of samples. The study has shown that radiation doses arising from a zero delay in sample handling represent a negligible radiation risk to pathologists and are well within relevant limits specified in the Ionising Radiations Regulations 1999. Conclusions: This study supports adoption of a zero‐delay SLN histopathology protocol. Centres must, however, complete a risk assessment that accounts for local practice and adopt simple precautions to keep doses to pathologists as low as reasonably achievable.     

Genome-wide association study confirms extant PD risk loci among the Dutch

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514,799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P = 1.63 × 10(-5), OR = 1.325 and BST1, rs12502586: P = 1.63 × 10(-3), OR = 1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3' and 5' ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P = 1.22 × 10(-4), OR = 1.51; HLA, rs4248166: P = 4.39 × 10(-5), OR = 1.36; and MAPT, rs3785880: P = 1.9 × 10(-3), OR = 1.19).     

Correlates of STI testing among vocational school students in the Netherlands

Background  

Adolescents are at risk for acquiring sexually transmitted infections (STIs). However, test rates among adolescents in the Netherlands are low and effective interventions that encourage STI testing are scarce. Adolescents who attend vocational schools are particularly at risk for STI. The purpose of this study is to inform the development of motivational health promotion messages by identifying the psychosocial correlates of STI testing intention among adolescents with sexual experience attending vocational schools.     

Precursor B-lymphoblastic transformation of grade I follicle center lymphoma

Part of the natural history of follicle center lymphoma (FCL) is transformation to a more aggressive neoplasm, almost always a diffuse large B-cell lymphoma. We describe a rare example of a precursor B-lymphoblastic transformation of grade I FCL occurring in a 45-year-old woman 12 years after initial presentation and 3 years after successful treatment for a diffuse large cell transformation. The lymphoblastic lymphoma shared the same immunoglobulin heavy chain gene rearrangement as the FCL as assessed by polymerase chain reaction amplification and direct sequencing, as well as identical kappa light chain gene rearrangements by Southern blot analysis. The immunoglobulin heavy chain variable gene sequences of both tumors showed numerous identical base substitutions compared with germline sequences and 3 additional mutations in the lymphoblastic lymphoma not present in the low-grade FCL. These results indicate origin of the lymphoblastic process from the mature follicle center B-cell clone, rather than divergent origin of the 2 tumors from a common immature B-cell precursor.     

Prevention of neonatal macrosomia in gestational diabetes by the use of intensive dietary therapy and home glucose monitoring

This study was undertaken to determine if intensive dietary therapy, home blood glucose monitoring, and the selective use of insulin can be effective in preventing fetal macrosomia. All patients were screened at 24 to 28 weeks' gestation using a modification of O'Sullivan's criteria. The 153 patients diagnosed as gestational diabetics by the study protocol were placed on a 1800 to 2000 Kcal American Diabetes Association diet and taught home glucose monitoring. Insulin therapy was initiated only if blood glucose control was inadequate. There were no significant differences (p greater than 0.05) between the study and reference populations in regard to mean birthweight or the incidence of macrosomia. Since our study criteria for diagnosing gestational diabetes were slightly different from those of the National Diabetes Data Group (NDDG), data from 99 patients meeting the NDDG criteria were analyzed in a similar manner. No significant differences were found between this subgroup and the reference population. Since only 7.2% of our study patients required insulin, we conclude that the incidence of fetal macrosomia in gestational diabetes can be kept equal to that of the general population by a program of intensive dietary therapy and home glucose monitoring, with insulin being used only therapeutically, not prophylactically.     

Interferences in collaboration between child psychiatrists and pediatricians: a fundamental difference in attitude toward childhood

The relationship between pediatrics and child psychiatry has been discussed at length. Opportunities seem to exist for cooperation between the two specialties, and yet difficulties exist. This study compared attitudes toward childhood held by pediatricians and child psychiatrists, as well as by residents at the beginning and end of training in pediatrics, psychiatry, and child psychiatry. The attitudinal assessment tool was a 30-item questionnaire consisting of literary quotations with which respondents were asked to agree or disagree. The results suggest that pediatricians view childhood more positively than do child psychiatrists. These attitudinal differences exist at the beginning of residency training. Recommendations are made regarding how to facilitate better collaboration between pediatricians and child psychiatrists.