The Prevalence of Thyroid Cancer and Benign Thyroid Disease in Patients With Familial Adenomatous Polyposis May Be Higher Than Previously Recognized

PurposePatients with familial adenomatous polyposis (FAP) are at increased risk for colorectal cancer and extracolonic neoplasms. The prevalence of thyroid cancer (TC) and benign thyroid disease in this patient population is unclear, and guidelines for screening for TC in these patients are not well established. The purpose of this study was to report the prevalence of TC and benign thyroid disease in patients with FAP.MethodsThe prospectively maintained Hereditary Colorectal Cancer Family Registry at Memorial Sloan-Kettering Cancer Center was queried to identify patients with FAP and with TC and/or benign thyroid disease.ResultsSixty-six patients with FAP were identified. There were 30 men and 36 women, with a median age of 38.6 years. Four (6.1%) patients had a history of TC. All were women, with a mean age at TC diagnosis of 36.5 years. Three of the 4 TCs were papillary thyroid cancer. Two patients with TC presented with palpable nodules. An additional 6 (9.1%) patients with FAP had a history of benign thyroid disease, including nodules (3), hypothyroidism (2), cysts (2), goiter (1), and thyroiditis (1). Three of 4 patients with TC and all 6 patients with benign thyroid disease had other extracolonic manifestations associated with FAP.ConclusionsThe prevalences of TC (6.1%) and benign thyroid disease (9.1%) are increased in our patients with FAP and are higher than noted in some previous reports. Periodic thyroid ultrasound screening should be considered in patients with FAP to further elucidate the prevalence and for possible early detection of TC and benign thyroid disease in this population.     

The role of advocacy and empowerment in shaping service development for families raising children with developmental disabilities

IntroductionEmpowerment of families raising children with developmental disabilities (DDs) is essential to achieving rights‐based service development.MethodsIn this qualitative study, we investigated stakeholder perceptions on the role of advocacy and empowerment in developing caregiver interventions for families of children with DDs in a global context. Participants had experience with at least one intervention, namely the Caregiver Skills Training developed by the World Health Organization (WHO). Participants were clinicians, caregivers and researchers representing five continents, and representatives of WHO and Autism Speaks. Two focus group discussions and 25 individual interviews were conducted. Data were analysed thematically.ResultsThree themes were developed: empowerment as independence and as a right; the role and practices of advocacy; and using evidence to drive advocacy. Many professional participants defined empowerment within the realms of their expertise, focusing on caregivers'' individual skills and self‐confidence. Caregivers expressed that this expert‐oriented view fails to acknowledge their intuitive knowledge and the need for community‐level empowerment. Participants discussed the challenges of advocacy in light of competing health priorities. The gap between the rights of caregivers and the availability of services, for example, evidence‐based interventions, was highlighted as problematic. Scientific evidence was identified as a key for advocacy.ConclusionRights‐orientated empowerment of caregivers and advocacy may make vital contributions to service development for children with DDs in contexts worldwide.Patient and Public ContributionResearch questions were revised based on views presented during focus group discussions. Participant feedback on preliminary themes informed the development of the interview guides.     

Human leukocyte antigen non-class II determinants for type 1 diabetes in the Finnish population

We explored the contribution of non-class II HLA loci to type 1 diabetes genetic susceptibility in the Finnish population. We analyzed 11 markers covering a 4-Mb region telomeric to the DQB1 gene in Finnish nuclear families with parents carrying either the DR8-DQB1*04 (n=188) or the DRB1*0404-DQB1*0302 haplotypes (n=135). On the DRB1*0404-DQB1*0302 haplotype we found independent disease association of the D6S273 and C125 markers (p(corr) = 10(-4) and 0.0095, respectively). The C125*200 alleles on this haplotype conferred an increased disease risk (OR = 3.6; p = 0.003). The B*39 allele also showed disease association (OR = 2.6; p = 0.054). The C125*200 allele appeared at an increased frequency also on transmitted B39 positive DRB1*0404-DQB1*0302 haplotypes, suggesting an independent effect. In addition, the C143*417 allele on the DRB1*08-DQB1*04 haplotype was associated with decreased disease risk (OR = 0.48, p = 0.003). Our data confirm that non-class II HLA loci affect genetic susceptibility to type 1 diabetes. In addition to HLA B*39 the C125 locus contributes to disease risk on the Finnish DRB1*0404-DQB1*0302 haplotypes. Another locus close to D6S273 may also have an effect. For the first time we report that a locus near the C143 marker appear to affect disease association of the DRB1*08-DQB1*04 haplotype.     

Single-molecule fluorescence resonance energy transfer reveals a dynamic equilibrium between closed and open conformations of syntaxin 1

Protein conformational transitions form the molecular basis of many cellular processes, such as signal transduction and membrane traffic. However, in many cases, little is known about their structural dynamics. Here we have used dynamic single-molecule fluorescence to study at high time resolution, conformational transitions of syntaxin 1, a soluble N-ethylmaleimide-sensitive factor attachment protein receptors protein essential for exocytotic membrane fusion. Sets of syntaxin double mutants were randomly labeled with a mix of donor and acceptor dye and their fluorescence resonance energy transfer was measured. For each set, all fluorescence information was recorded simultaneously with high time resolution, providing detailed information on distances and dynamics that were used to create structural models. We found that free syntaxin switches between an inactive closed and an active open configuration with a relaxation time of 0.8 ms, explaining why regulatory proteins are needed to arrest the protein in one conformational state.     

Proteomic analysis of cerebrospinal fluid changes related to postmortem interval

BACKGROUND: The study of proteins with altered production in postmortem cerebrospinal fluid (CSF) compared with antemortem CSF may improve the understanding of biochemical changes that occur immediately after death. METHODS: Two CSF samples (1 antemortem and 1 postmortem) were collected from 7 patients and analyzed by 2-dimensional gel electrophoresis. An analysis was also performed to identify proteins that showed a correlation between concentration change and postmortem interval. Tandem mass spectrometry was used to identify the proteins. RESULTS: Fifty-four protein spots were identified that showed a consistent and significant change in concentration in the postmortem CSF of all 7 patients (>3.5-fold, P <0.01). The proteins in these spots derive from a variety of functional groups, including cytoskeletal proteins, enzymes involved in glycolysis, and proteins that prevent oxidative stress. Fourteen protein spots were found to have an increase in production that correlated with postmortem interval. CONCLUSIONS: Changes in protein production of postmortem vs antemortem CSF were studied. The proteins observed to change production in the postmortem CSF include several proteins previously observed as potential stroke biomarkers.     

Association between dopamine D4 receptor (DRD4) gene polymorphisms and novelty-elicited auditory event-related potentials in preschool children

We investigated associations of the exon III repeat and the -521 C/T polymorphisms of the DRD4 gene with novelty-elicited auditory ERP components and behavioral resistance to distraction in 57 healthy, typically developing 6-year-old children. Dopamine-related gene polymorphisms have previously been linked to processes directing focused attention. We did not find associations between the 7-repeat allele or the T.7 haplotype and the early ERP responses suggesting that DRD4 polymorphisms did not affect the detection of novelty. However, the same polymorphisms affected the late negative components (LN1 and LN2). Late negativities elicited by deviant and novel sounds have been regarded as reflecting reorientation after distraction or additional processing of new information. Children carrying the T.7 haplotype had significantly smaller LN1 and LN2 amplitudes. The presence of the T.7 haplotype also significantly enhanced behavioral resistance to distraction. We suggest that less distraction in T.7 carriers led to less reorienting activity (reflected by the LN components). We also speculate that activation of less sensitive and fewer D4 receptors (as with the T.7 haplotype) is less effective in modulating GABAergic inhibitory signaling, which in turn is reflected in smaller LN amplitudes.