Evaluation of RET polymorphisms in a six-generation family with G533C RET mutation: specific RET variants may modulate age at onset and clinical presentation

P>Context We previously described a six-generation family with G533C RET mutation and medullary thyroid carcinoma, in the largest family reported do date. Of particular interest, phenotype variability regarding the age of onset and clinical presentation of the disease, was observed. Objective We evaluate whether single SNPs within RET oncogene or haplotype comprising the RET variants (defined by Haploview) could predispose to early development of MTC in this family and influence the clinical manifestation. Design Eight SNPs were selected based on their previous association with the clinical course of hereditary or sporadic MTC, in particular promoting an early onset of disease. The variants were initially tested in 77 G533C-carriers and 100 controls using either PCR-direct sequencing or PCR-RFLP. Association between a SNP or haplotype and age at diagnosis or presence of lymph node metastasis was tested in 34 G533C-carries with MTC. Different bioinformatic tools were used to evaluate the potential effects on RNA splicing. Results An association was found between IVS1-126G > T and age at diagnosis. The variant [IVS8 +82A > G; 85-86 insC] was associated with the presence of lymph node metastases at diagnosis. In silico analysis suggested that this variant may induce abnormal splicing. This in silico analysis predicted that the [IVS8 +82A > G; 85-86 insC] could alter the splicing by disrupting and/or creating exonic splicing enhancer motifs. Conclusions We here identified two RET variants that were associated with phenotype variability in G533C-carriers, which highlights the fact that the modifier effect of a variant might depend on the type of mutation.

Orbitofrontal cortex gray matter volumes in bipolar disorder patients: a region-of-interest MRI study

Objectives: Functional and postmortem studies suggest that the orbitofrontal cortex (OFC) is involved in the pathophysiology of bipolar disorder (BD). This anatomical magnetic resonance imaging (MRI) study examined whether BD patients have smaller OFC gray matter volumes compared to healthy comparison subjects (HC). Methods: Twenty-eight BD patients were compared to 28 age- and gender-matched HC. Subjects underwent a 1.5T MRI with 3D spoiled gradient recalled acquisition. Total OFC and medial and lateral subdivisions were manually traced by a blinded examiner. Images were segmented and gray matter volumes were calculated using an automated method. Results: Analysis of covariance, with intracranial volume as covariate, showed that BD patients and HC did not differ in gray matter volumes of total OFC or its subdivisions. However, total OFC gray matter volume was significantly smaller in depressed patients (n = 10) compared to euthymic patients (n = 18). Moreover, total OFC gray matter volumes were inversely correlated with depressive symptom intensity, as assessed by the Hamilton Depression Rating Scale. OFC gray matter volumes were not related to lithium treatment, age at disease onset, number of episodes, or family history of mood disorders. Conclusions: Our results suggest that abnormal OFC gray matter volumes are not a pervasive characteristic of BD, but may be associated with specific clinical features of the disorder.

Conclusion

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Detection of Auditory Cortex Activity by fMRI Using a Dependent Component Analysis

Functional MRI (fMRI) data often have low signal-to-noise-ratio (SNR) and are contaminated by strong interference from other physiological sources. A promising tool for extracting signals, even under low SNR conditions, is blind source separation (BSS), or independent component analysis (ICA). BSS is based on the assumption that the detected signals are a mixture of a number of independent source signals that are linearly combined via an unknown mixing matrix. BSS seeks to determine the mixing matrix to recover the source signals based on principles of statistical independence. In most cases, extraction of all sources is unnecessary; instead, a priori information can be applied to extract only the signal of interest. Herein we propose an algorithm based on a variation of ICA, called Dependent Component Analysis (DCA), where the signal of interest is extracted using a time delay obtained from an autocorrelation analysis. We applied such method to inspect functional Magnetic Resonance Imaging (fMRI) data, aiming to find the hemodynamic response that follows neuronal activation from an auditory stimulation, in human subjects. The method localized a significant signal modulation in cortical regions corresponding to the primary auditory cortex. The results obtained by DCA were also compared to those of the General Linear Model (GLM), which is the most widely used method to analyze fMRI datasets.

Evaluation of short dietary questions from the 1995 National Nutrition Survey

Six of the short dietary questions used in the 1995 National Nutrition Survey (see box below) were evaluated for relative validity both directly and indirectly and for consistency, by documenting the differences in mean intakes of foods and nutrients as measured on the 24-hour recall, between groups with different responses to the short questions. 1. Including snacks, how many times do you usually have something to eat in a day including evenings? 2. How many days per week do you usually have something to eat for breakfast? 3. In the last 12 months, were there any times that you ran out of food and couldn’t afford to buy more? 4. What type of milk do you usually consume? 5. How many serves of vegetables do you usually eat each day? (a serve = 1/2 cup cooked vegetables or 1 cup of salad vegetables) 6. How many serves of fruit do you usually eat each day? (a serve = 1 medium piece or 2 small pieces of fruit or 1 cup of diced pieces) These comparisons were made for males and females overall and for population sub-groups of interest including: age, socio-economic disadvantage, region of residence, country of birth, and BMI category. Several limitations to this evaluation of the short questions, as discussed in the report, need to be kept in mind including: · The method for comparison available (24-hour recall) was not ideal (gold standard); as it measures yesterday’s intake. This limitation was overcome by examining only mean differences between groups of respondents, since mean intake for a group can provide a reasonable approximation for ‘usual’ intake. · The need to define and identify, post-hoc, from the 24-hour recall the number of eating occasions, and occasions identified by the respondents as breakfast. · Predetermined response categories for some of the questions effectively limited the number of categories available for evaluation. · Other foods and nutrients, not selected for this evaluation, may have an indirect relationship with the question, and might have shown stronger and more consistent responses. · The number of responses in some categories of the short questions eg for food security may have been too small to detect significant differences between population sub-groups. · No information was available to examine the validity of these questions for detecting differences over time (establishing trends) in food habits and indicators of selected nutrient intakes. By contrast, the strength of this evaluation was its very large sample size, (atypical of most validation studies of dietary assessment) and thus, the opportunity to investigate question performance in a range of broad population sub-groups compared with a well-conducted, quantified survey of intakes. The results of the evaluation are summarised below for each of the questions and specific recommendations for future testing, modifications and use provided for each question. The report concludes with some general recommendations for the further development and evaluation of short dietary questions.