Large Cohort Of Individuals Research Articles

Segmenting and validating brain tissue definitions in the presence of varying tissue contrast

We propose a method for segmenting brain tissue as either gray matter or white matter in the presence of varying tissue contrast, which can derive from either differential changes in tissue water content or increasing myelin content of white matter. Our method models the spatial distribution of intensities as a Markov Random Field (MRF) and estimates the parameters for the MRF model using a maximum likelihood approach. Although previously described methods have used similar models to segment brain tissue, accurate model of the conditional probabilities of tissue intensities and adaptive estimates of tissue properties to local intensities generates tissue definitions that are accurate and robust to variations in tissue contrast with age and across illnesses. Robustness to variations in tissue contrast is important to understand normal brain development and to identify the brain bases of neurological and psychiatric illnesses. We used simulated brains of varying tissue contrast to compare both visually and quantitatively the performance of our method with the performance of prior methods. We assessed validity of the cortical definitions by associating cortical thickness with various demographic features, clinical measures, and medication use in our three large cohorts of participants who were either healthy or who had Bipolar Disorder (BD), Autism Spectrum Disorder (ASD), or familial risk for Major Depressive Disorder (MDD).We assessed validity of the tissue definitions using synthetic brains and data for three large cohort of individuals with various neuropsychiatric disorders. Visual inspection and quantitative analyses showed that our method accurately and robustly defined the cortical mantle in brain images with varying contrast. Furthermore, associating the thickness with various demographic and clinical measures generated findings that were novel and supported by histological analyses or were supported by previous MRI studies, thereby validating the cortical definitions generated by the proposed method: (1) Although cortical thickness decreased with age in adolescents, in adults cortical thickness did not correlate significantly with age. Our synthetic data showed that the previously reported thinning of cortex in adults is likely due to decease in tissue contrast, thereby suggesting that the method generated cortical definitions in adults that were invariant to tissue contrast. In adolescents, cortical thinning with age was preserved likely due to widespread dendritic and synaptic pruning, even though the effects of decreasing tissue contrast were minimized. (3) The method generated novel finding of both localized increases and decreases in thickness of males compared to females after controlling for the differing brain sizes, which are supported by the histological analyses of brain tissue in males and females. (4) The proposed method, unlike prior methods, defined thicker cortex in BD individuals using lithium. The novel finding is supported by the studies that showed lithium treatment increased dendritic arborization and neurogenesis, thereby leading to thickening of cortex. (5) In both BD and ASD participants, associations of more severe symptoms with thinner cortex showed that correcting for the effects of tissue contrast preserved the biological consequences of illnesses. Therefore, consistency of the findings across the three large cohorts of participants, in images acquired on either 1.5T or 3T MRI scanners, and with findings from prior histological analyses provides strong evidence that the proposed method generated valid and accurate definitions of the cortex while controlling for the effects of tissue contrast.

Exploring the bacterial assemblages along the human nasal passage.

The human nasal passage, from the anterior nares through the nasal vestibule to the nasal cavities, is an important habitat for opportunistic pathogens and commensals alike. This work sampled four different anatomical regions within the human nasal passage across a large cohort of individuals (n = 79) comprising individuals suffering from chronic nasal inflammation clinically known as chronic rhinosinusitis (CRS) and individuals not suffering from inflammation (CRS-free). While individuals had their own unique bacterial fingerprint that was consistent across the anatomical regions, these bacterial fingerprints formed into distinct delineated groups comprising core bacterial members, which were consistent across all four swabbed anatomical regions irrespective of health status. The most significant observed pattern was the difference between the global bacterial profiles of swabbed and tissue biopsy samples from the same individuals, being also consistent across different anatomical regions. Importantly, no statistically significant differences could be observed concerning the global bacterial communities, any of the bacterial species or the range of diversity indices used to compare between CRS and CRS-free individuals, and between two CRS phenotypes (without nasal polyps and with nasal polyps). Thus, the role of bacteria in the pathogenesis of sinusitis remains uncertain.

Characterization of limb differences in children with Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is a well-described multisystem developmental disorder characterized by dysmorphic facial features, growth and behavioral deficits, and cardiac, gastrointestinal, and limb anomalies. The limb defects seen in CdLS can be mild, with small feet or hands only, or can be severe, with variable deficiency defects involving primarily the ulnar structures and ranging from mild hypoplasia of the fifth digit to complete absence of the forearm. Interestingly, the upper limbs are typically much more involved than the lower extremities that generally manifest with small feet and 2-3 syndactyly of the toes and shortened fourth metatarsal. The upper limbs often manifest asymmetric involvement. The limb findings in our cohort of 378 individuals with CdLS demonstrate a consistent pattern of laterality and symmetry involvement (with increased severity of right-sided limb in individuals with asymmetric limb defects) and a correlation of more significant limb defects with an increased risk of other structural anomalies, and more severe behavioral outcomes. Additionally, we found that individuals with mutations in NIPBL were most likely to have limb defects compared to mutations in other genes with nonsense, exonic deletion, and frameshift mutations being most prevalent in those with limb defects. Characterization of the limb differences in children with CdLS may provide a tool to assist in genetic counseling and determining prognosis. This paper will review the limb involvement in a large cohort of individuals with CdLS assessing the correlation with molecular etiologies, symmetry, additional structural birth defects, and cognitive outcomes. © 2016 Wiley Periodicals, Inc.

LAYER SPECIFIC LEFT VENTRICULAR STRAIN MECHANICS WITH 2-DIMENSIONAL SPECKLE TRACKING ECHOCARDIOGRAPHY: A REFERENCE IN PATIENTS WITH NO STRUCTURAL HEART DISEASE

Advances in software have enabled LV myocardial layer-specific analysis. However reference ranges within these layers in a large cohort of individuals with no structural heart disease have not been established and was the subject of this study. 397 subjects (mean age 57.6 (range 16-91) years; 194 (

Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort

ObjectivesImmunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a...

Factors Associated with Mobility Outcomes in a National Spina Bifida Patient Registry.

To provide descriptive data on ambulatory ability and muscle strength in a large cohort of individuals with spina bifida enrolled in a National Spina Bifida Patient Registry and to investigate factors associated with ambulatory status. Cross-sectional analysis of data from a multisite patient registry. Descriptive analysis of mobility variables for 2604 individuals with spina bifida aged 5 and older are presented from 19 sites in the United States. Analysis of a subset of National Spina Bifida Patient Registry data from 380 individuals from 3 sites accompanied by data from a specialized spina bifida electronic medical record revealed that those with no history of a shunt, lower motor level, and no history of hip or knee contracture release surgery were more likely to be ambulatory at the community level than at the household or wheelchair level. This study is the first to examine factors associated with ambulatory status in a large sample of individuals with myelomeningocele and nonmyelomeningocele subtypes of spina bifida. Results of this study delineate the breadth of strength and functional abilities within the different age groups and subtypes of spina bifida. The results may inform physicians of the characteristics of those with varying ambulatory abilities.

Annotation of pseudogenic gene segments by massively parallel sequencing of rearranged lymphocyte receptor loci.

BackgroundThe adaptive immune system generates a remarkable range of antigen-specific T-cell receptors (TCRs), allowing the recognition of a diverse set of antigens. Most of this diversity is encoded in the complementarity determining region 3 (CDR3) of the β chain of the αβ TCR, which is generated by somatic recombination of noncontiguous variable (V), diversity (D), and joining (J) gene segments. Deletion and non-templated insertion of nucleotides at the D-J and V-DJ junctions further increases diversity. Many of these gene segments are annotated as non-functional owing to defects in their primary sequence, the absence of motifs necessary for rearrangement, or chromosomal locations outside the TCR locus.MethodsWe sought to utilize a novel method, based on high-throughput sequencing of rearranged TCR genes in a large cohort of individuals, to evaluate the use of functional and non-functional alleles. We amplified and sequenced genomic DNA from the peripheral blood of 587 healthy volunteers using a multiplexed polymerase chain reaction assay that targets the variable region of the rearranged TCRβ locus, and we determined the presence and the proportion of productive rearrangements for each TCRβ V gene segment in each individual. We then used this information to annotate the functional status of TCRβ V gene segments in this cohort.ResultsFor most TCRβ V gene segments, our method agrees with previously reported functional annotations. However, we identified novel non-functional alleles for several gene segments, some of which were used exclusively in our cohort to the detriment of reported functional alleles. We also saw that some gene segments reported to have both functional and non-functional alleles consistently behaved in our cohort as either functional or non-functional, suggesting that some reported alleles were not present in the population studied.ConclusionsIn this proof-of-principle study, we used high-throughput sequencing of the TCRβ locus of a large cohort of healthy volunteers to evaluate the use of functional and non-functional alleles of individual TCRβ V gene segments. With some modifications, our method has the potential to be extended to gene segments in the α, γ, and δ TCR loci, as well as the genes encoding for B-cell receptor chains.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0238-z) contains supplementary material, which is available to authorized users.

Abstract 1575: Serum circulating miR–Test application: Standardized protocol for miR–Test clinical application

Abstract Lung cancer is leading cause of cancer death worldwide. Being lung cancer asymptomatic in its early stages, the majority of patients are diagnosed with advanced disease. Therefore, it is vital that screening programs and novel diagnostic tools are developed to increase lung cancer early detection. The development of a minimally invasive blood-based diagnostic tool would be ideal as a first-line screening procedure. An increasing number of studies are demonstrating that fluctuations of circulating miRNAs are associated to lung cancer. Recently, we described a serum circulating miRNA signature (miR-Test) diagnostic for asymptomatic, early stage, lung cancer, that was validated in a large cohort of individuals (N = 1115) enrolled in the lung cancer screening program COSMOS (Continuous Observation of SMOking Subjects). However, the transfer to the clinic of a blood test based on circ-miRNAs requires the establishment of standardized operating procedures (SOPs), working instructions and guidelines for all pre-analytical and analytical procedures. We identified possible sources of variability affecting circulating miRNAs, analyzed their impact on the miR-Test performance, and defined a standardized protocol to optimize miR-Test application. Analysis of all possible technical and biological variation affecting circ-miRNAs level, revealed two main sources of variability: one related to analytical procedures for miRNAs extraction and quantification, and the other due to pre-analytical conditions, on how samples are prepared. The extraction causes the main source of analytical imprecision. In conclusion, we identified an optimal protocol for the application of miR-Test for lung cancer early diagnosis. Citation Format: Francesca Montani, Matteo Marzi, Fabio Dezi, Elisa Dama, Rose Mary Carletti, Giulia Veronesi, Francesco Nicassio, Pier Paolo Di Fiore, Fabrizio Bianchi. Serum circulating miR–Test application: Standardized protocol for miR–Test clinical application. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1575. doi:10.1158/1538-7445.AM2015-1575

Abstract 5575: Obesity and genomic changes in patients with myelodysplastic syndromes

Abstract Obesity is rapidly overtaking smoking as the leading preventable cause of cancer, particularly in cancers of the breast and colon. In a large cohort of individuals participating in the National Institutes of Health-AARP Diet and Health Study, a higher incidence of MDS and an increased mortality was observed in individuals with body mass index (BMI) >30 compared to those with BMI <25 (HR 2.18 (95% CI: 1.51, 3.17; P < 0.001). The biology underlying these findings in MDS patients (pts) is not established. We hypothesized that genomic patterns may distinguish obese from non-obese pts with MDS and that these genomic changes may be associated with disease characteristics. We performed genomic analyses by using next-generation targeted deep sequencing (NGS) and whole exome sequencing (WES) of 62 significantly affected genes that play an important role in MDS pathogenesis. Mutations were considered individually and grouped into several functional pathways. Overweight (BMI 25-29) and obese (BMI >30) were combined in one group (BMI-H). Of 205 pts with MDS treated at our institution between 1/2000 - 1/2013, 146 (71%) were BMI-H. Interestingly, only 2 patients had BMI <18.5 (underweight) and were combined with normal BMI group (BMI-N). BMI-H pts presented with lower white blood count (median 3.6 vs. 4.4, p = .03), but other clinical characteristics were similar. With median follow up of 33.6 months (mo) (range 0.4-128.5), a trend toward inferior survival was observed in BMI-H group compared to BMI-N (32.9 mo vs. 34.8 mo, p = .07). Furthermore, higher rates of progression to acute myeloid leukemia (AML) were seen in the BMI-H as compared to BMI-N pts (23% vs. 19%, p = .02). Overall, 74% of pts had at least one of the 62 screened mutations, the most common being: SF3B1 (17%), TET2 (17%), ASXL1 (14%), STAG2 (12%), DNMT3A (9%), U2AF1/2 (8%), GPR98 (8%), and RUNX1(7%). Mutations in IDH1/2 (5% vs. 0%), DNMT3A (11% vs. 5%), TET2 (18% vs. 14%) occurred more frequently in BMI-H, where SF3B1 (25% vs. 13%), and NRAS (7% vs. 2%) mutations were more common in BMI-N. Within functional groups, mutations in splicing machinery genes were less common in BMI-H compared to BMI-N (32% vs. 41%, p = .05) and mutations in DNA methylation genes were more common in BMI-H (20% vs. 34%, p = .02). Clonal architecture analysis points to the presence of different dominant clones between the two groups. In the dominant MDS clones, mutations in TET2 and DNMT3A were observed more frequently in pts with BMI-H, whereas mutations in SF3B1 were more frequently observed in BMI-N pts. In conclusion, overweight and obese pts with MDS have a trend for inferior survival and higher rate of progression to AML as compared to MDS pts with normal weight. Genomic differences in clonal architecture and distribution of somatic mutations were observed in the BMI-H group. Further exploration including germline mutations and previously described familial obesity genes is needed to expound on the interaction between the biology of obesity and leukemogenesis of MDS. Citation Format: Aziz Nazha, David Seastone, Hideki Makishima, Matt Kalaycio, Hetty E. Carraway, Anjali S. Advani, Ahamd Zarzour, Jennifer Carew, Aaron T. Gerds, Sudipto Mukherjee, Jaroslaw P. Maciejewski, Mikkael A. Sekeres. Obesity and genomic changes in patients with myelodysplastic syndromes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5575. doi:10.1158/1538-7445.AM2015-5575

V41. Static sway patterns of individuals with increased risk for, and converters to Parkinson’s disease. Analysis of 700 participants of the TREND-study

Background and aim Quantitative assessment of prodromal presentations (e.g. motor signs, hyposmia, depression, REM sleep behavior disorder) of Parkinson’s disease (PD) may be the key to eventually enable earlier diagnosis of this disease. Recent observations indicate that subtle balance deficits belong to these prodromal presentations. Moreover, the higher the number of risk markers and prodromal presentations an individual combines, the more likely is it that this person gets PD. We therefore hypothesized that individuals with a high number of risk factors for PD, as well as individuals with PD who were assessed two and four years before diagnosis (already) show altered static sway characteristics in this risk and prodromal phase of PD. Methods In the first wave of the longitudinal TREND ( Tu binger evaluation of R isk factors for E arly detection of N euro D egeneration)-study ( www.trend-studie.de ), 657 older individuals with and without risk factors for PD (0 risk factors, N = 315; 1 risk factor, N = 240; 2 risk factors, N = 90; 3 risk factors, N = 12) as well as 35 PD patients without clinical evidence for a balance deficit were investigated. Seven individuals out of the 645 developed PD during the subsequent observation period of four years (PD converters). From these individuals, quantitative sway parameters data of the first as well as of the second wave were included in the analysis. Quantitative balance assessment was performed with the McRoberts Dynaport® sensor at the lower back. Participants were asked to stand for 30 s on foam in semitandem stance (i) with eyes closed and (ii) with eyes open. Parameters of area of sway, velocity, acceleration, JERK and mean power frequency (MPF) of sway were analyzed. Results Under eyes-closed conditions, PD patients had a larger area and a lower MPF of sway, compared to the 0, 1 and 2 risk factor(s) cohorts ( p -values. Conclusion To the best of our knowledge, this is the first study reporting about quantitative cross-sectional balance assessment in a large cohort of individuals at risk for PD, as well as about longitudinal balance assessment in PD converters during their prodromal phase over observation periods of up to four years. Our findings confirm previous results from a smaller study which demonstrated static balance differences between high risk individuals for PD and PD patients which were only visible under most challenging conditions. Moreover, results obtained from the PD converters argue for the potential of quantitative balance parameters as trait and state markers in the prodromal phase of PD. Further implications and potential clinical impact of this will be discussed.

Functionality of dengue virus specific memory T cell responses in individuals who were hospitalized or who had mild or subclinical dengue infection.

BackgroundAlthough antibody responses to dengue virus (DENV) in naturally infected individuals have been extensively studied, the functionality of DENV specific memory T cell responses in relation to clinical disease severity is incompletely understood.Methodology/Principal findingsUsing ex vivo IFNγ ELISpot assays, and by determining cytokines produced in ELISpot supernatants, we investigated the functionality of DENV-specific memory T cell responses in a large cohort of individuals from Sri Lanka (n=338), who were naturally infected and were either hospitalized due to dengue or had mild or sub clinical dengue infection. We found that T cells of individuals with both past mild or sub clinical dengue infection and who were hospitalized produced multiple cytokines when stimulated with DENV-NS3 peptides. However, while DENV-NS3 specific T cells of those with mild/sub clinical dengue infection were more likely to produce only granzyme B (p=0.02), those who were hospitalized were more likely to produce both TNFα and IFNγ (p=0.03) or TNFα alone.We have also investigated the usefulness of a novel T cell based assay, which can be used to determine the past infecting DENV serotype. 92.4% of DENV seropositive individuals responded to at least one DENV serotype of this assay and none of the seronegatives responded. Individuals who were seronegative, but had received the Japanese encephalitis vaccine too made no responses, suggesting that the peptides used in this assay did not cross react with the Japanese encephalitis virus.Conclusions/significanceThe types of cytokines produced by DENV-specific memory T cells appear to influence the outcome of clinical disease severity. The novel T cell based assay, is likely to be useful in determining the past infecting DENV serotype in immune-epidemiological studies and also in dengue vaccine trials.

Desire for hastened death: exploring the emotions and the ethics.

As we approach the end of our lives, many of us will have a desire for hastened death (DHD). Fortunately, our ability to respond to suffering at the end of life is improving. At the same time, in many jurisdictions, changes are underway to legislate physician-assisted death. This compels us as clinicians to explore DHD in a compassionate way - to reduce suffering and reduce premature death. This challenge is becoming more compelling as a large cohort of individuals, who value autonomy and control, age and experience illness. Studies confirm that DHD is not always a request to die. Clarifying the intention behind the desire and exploring the individual factors and underlying reasons behind the wish have been described. Another theme questions our basic assumptions about these statements - a normal part of a human experience or an indicator of disease. This tension is also manifested in the appropriate balance between patient autonomy and preventing harm. We have a professional responsibility to mindfully explore with the patient the suffering that can be relieved and the suffering that remains.

Leveraging Lymphoblastoid Cell Lines for Drug Response Modeling

Lymphoblastoid cell lines (LCL) are becoming popular tools for modeling drug response. LCLs, and other in vitro assays, offer the ability to test many drugs, doses, and biological samples relatively quickly and inexpensively. In addition, a unique advantage to LCLs is that they are available from a large cohort of individuals, providing the capability to test for genetic variability on a scale not readily available in other in vitro systems. Since oftentimes the genotype data is publically available, the experimental costs can be limited to the cost of the drug response phenotyping. Here we describe several advantages and limitations of LCLs. In addition we review several important aspects of LCL experimental design and statistical analysis. Lastly, we present an example of LCLs being successfully used to identify candidate single nucleotide polymorphisms and genes for variability in response to a chemotherapeutic used to treat chronic myeloid leukemia.

Inflammation, obesity, and metabolic syndrome in depression: analysis of the 2009-2010 National Health and Nutrition Examination Survey (NHANES).

To describe the rates of elevated inflammation, obesity, and metabolic syndrome (MetS) within a large cohort of individuals with depression and to examine the interrelationships of inflammation and MetS in depressed individuals. Analyses were conducted on study participants from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) with Patient Health Questionnaire (PHQ-9) depression scores ≥ 10 to (1) examine the relationship of inflammation (C-reactive protein; CRP) with demographic and clinical characteristics and (2) examine the prevalence of MetS criteria within CRP groups. 5,579 participants provided PHQ-9 data; of those, 606 had PHQ-9 scores ≥ 10 and were included in further analysis. Of the 606 depressed participants, 585 participants had valid CRP data; 275 participants (47.01%) had CRP levels ≥ 3.0 mg/L, while 170 (29.06%) had CRP levels ≥ 5.0 mg/L. Elevated inflammation was significantly correlated with body weight, waist circumference, body mass index, insulin, 2-hour glucose tolerance, and self-report general health (P values < .05). 112 subjects (41.18%) met American Heart Association/National Heart, Lung, and Blood Institute criteria for MetS. Those with elevated CRP were more likely to meet criteria for MetS (odds ratios of 2.81 for those with CRP levels ≥ 3.0 mg/L and 1.94 for those with CRP levels ≥ 5.0 mg/L). Over 29% of depressed individuals had elevated levels of CRP, and 41% met criteria for MetS. Individuals with elevated inflammation are more likely to be obese and meet criteria for MetS. These results highlight the significant inflammatory and metabolic burden of individuals with depression.

Prevalence of detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes.

It is generally accepted that complete β-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown. The frequency of residual insulin secretion was determined by measurement of nonfasting serum C-peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control. The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time from diagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with ≤18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing. The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 or more years from type 1 diabetes diagnosis. The frequency of residual C-peptide decreases with time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide.

A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria.

Symptoms of attention deficit-hyperactivity disorder (ADHD), particularly inattention, and impairments in executive functioning have been reported in early and continuously treated children, adolescents, and adults with phenylketonuria (PKU). In addition, higher blood phenylalanine (Phe) levels have been correlated with the presence of ADHD symptoms and executive functioning impairment. The placebo-controlled PKU ASCEND study evaluated the effects of sapropterin therapy on PKU-associated symptoms of ADHD and executive and global functioning in individuals who had a therapeutic blood Phe response to sapropterin therapy. The presence of ADHD inattentive symptoms and executive functioning deficits was confirmed in this large cohort of 206 children and adults with PKU, of whom 118 responded to sapropterin therapy. In the 38 individuals with sapropterin-responsive PKU and ADHD symptoms at baseline, sapropterin therapy resulted in a significant improvement in ADHD inattentive symptoms in the first 4 weeks of treatment, and improvements were maintained throughout the 26 weeks of treatment. Sapropterin was well-tolerated with a favorable safety profile. The improvements in ADHD inattentive symptoms and aspects of executive functioning in response to sapropterin therapy noted in a large cohort of individuals with PKU indicate that these symptoms are potentially reversible when blood Phe levels are reduced.

Damage to the immature optic radiation causes severe reduction of the retinal nerve fiber layer, resulting in predictable visual field defects.

The aim of the present study was to seek evidence of a relationship between damage to the optic radiation (OR) in the immature brain and subsequent development of the retinal nerve fiber layer (RNFL) and associated visual manifestations. Seven cases (2 males and 5 females ranging in age from 18 to 35 years old) were selected from a large cohort of individuals with known white matter damage of immaturity (WMDI), who had presented with visual dysfunction. They underwent magnetic resonance imaging (MRI), including diffusion-weighted MRI. Visual function was evaluated by best-corrected visual acuity and visual field (VF) testing using Goldmann perimetry and Humphrey field analyzer (HFA). RNFL thickness was measured by optical coherence tomography. A homogeneous lesion pattern with bilateral WMDI predominantly in the superior posterior periventricular white matter was seen in all subjects. However, as shown by white matter fiber tractography, only cases with injuries to the superior portion of the OR had corresponding inferior VF defects. In the individuals showing structural abnormalities in the OR, a commensurate reduction in the peripapillary RNFL was seen. The RNFL loss was most pronounced in the subjects suffering from the more extensive lesions, and it followed the pattern of OR damage in the sense that damage in the superior portion of the OR gave a reduced RNFL thickness in the superior part of the peripapillary RNFL. Primary injuries in the immature OR are associated with reduced RNFL thickness, and examination of the RNFL may be a helpful predictor of VF defects.

Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series.

Epilepsy affects approximately 3% of the world's population, and sudden death is a significant cause of death in this population. Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of all these cases, which increases the rate of sudden death by 24-fold as compared to the general population. The underlying mechanisms are still not elucidated, but recent studies suggest the possibility that a common genetic channelopathy might contribute to both epilepsy and cardiac disease to increase the incidence of death via a lethal cardiac arrhythmia. We performed genetic testing in a large cohort of individuals with epilepsy and cardiac conduction disorders in order to identify genetic mutations that could play a role in the mechanism of sudden death. Putative pathogenic disease-causing mutations in genes encoding cardiac ion channel were detected in 24% of unrelated individuals with epilepsy. Segregation analysis through genetic screening of the available family members and functional studies are crucial tasks to understand and to prove the possible pathogenicity of the variant, but in our cohort, only two families were available. Despite further research should be performed to clarify the mechanism of coexistence of both clinical conditions, genetic analysis, applied also in post-mortem setting, could be very useful to identify genetic factors that predispose epileptic patients to sudden death, helping to prevent sudden death in patients with epilepsy.

Low levels of IgM antibodies against phosphorylcholine are associated with fast carotid intima media thickness progression and cardiovascular risk in men

ObjectiveLow levels of IgM anti-phosphorylcholine (anti-PC) increase the risk of cardiovascular events (CVE). Here we investigate the association of low anti-PC with the progression of carotid intima media thickness (C-IMT) and incidence of CVE in a large cohort of individuals at high risk of CVE, the IMPROVE, a prospective multicenter European study. Methods3711 subjects (54–79 years) with at least three established cardiovascular risk factors were enrolled. Baseline serum levels of IgM anti-PC were measured by ELISA. Carotid ultrasound investigations were performed at baseline and after 15 and 30 months of follow-up. The risk of C-IMT progression and ischemic CVE associated with low anti-PC levels was tested by logistic regression and Cox regression analysis, respectively. Risk estimates were adjusted by center and conventional cardiovascular risk factors. Results3670 study participants were included in the present analysis and 213 CVE were recorded during a 3 year follow up. Anti-PC levels (U/ml) were classified into quartiles [Q1≤ 40, Q2 >40-≤64, Q3 >64-≤102, Q4 >102]. In men, low levels of anti-PC (Q1) were associated with the highest (>90th) percentile of the fastest C-IMT progression, i.e. the segment showing the fastest progression over 30 months in the whole carotid tree, with an OR of 1.41 (95%CI, 1.02–1.9) and with an increased risk of CVE with a multivariable adjusted HR of 1.85 (95%CI, 1.1–3.1). No significant associations were found in women. ConclusionsLow anti-PC levels increase the risk of CVE in men. This effect may be partly mediated by a fast C-IMT progression.

Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association.