Κυριακή, 24 Απριλίου 2016

Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof-of-concept examples

Whole exome sequencing (WES) is a powerful tool to identify clinically undefined forms of intellectual disability/developmental delay (ID/DD), especially in consanguineous families. Here we report the genetic definition of two sporadic cases, with syndromic ID/DD for whom array—Comparative Genomic Hybridization (aCGH) identified a de novo copy number variant (CNV) of uncertain significance. The phenotypes included microcephaly with brachycephaly and a distinctive facies in one proband, and hypotonia in the legs and mild ataxia in the other. WES allowed identification of a functionally relevant homozygous variant affecting a known disease gene for rare syndromic ID/DD in each proband, that is, c.1423C>T (p.Arg377*) in the Trafficking Protein Particle Complex 9 (TRAPPC9), and c.154T>C (p.Cys52Arg) in the Very Low Density Lipoprotein Receptor (VLDLR). Four mutations affecting TRAPPC9 have been previously reported, and the present finding further depicts this syndromic form of ID, which includes microcephaly with brachycephaly, corpus callosum hypoplasia, facial dysmorphism, and overweight. VLDLR-associated cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia and moderate-to-profound intellectual disability. The c.154T>C (p.Cys52Arg) mutation was associated with a very mild form of ataxia, mild intellectual disability, and cerebellar hypoplasia without cortical gyri simplification. In conclusion, we report two novel cases with rare causes of autosomal recessive ID, which document how interpreting de novo array-CGH variants represents a challenge in consanguineous families; as such, clinical WES should be considered in diagnostic testing. © 2016 Wiley Periodicals, Inc.



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A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum

We report on a sib pair of Indian origin presenting with intellectual disability, dysmorphism, and macrocephaly. Exome sequencing revealed a homozygous splice site HERC1 mutation in both probands. Functional analysis revealed use of an alternate splice site resulting in formation of a downstream stop codon and nonsense mediated decay. In the light of recent reports of HERC1 mutations in two families with a similar phenotypic presentation, this report reiterates the pathogenic nature and clinical consequences of HERC1 disruption. © 2016 Wiley Periodicals, Inc.



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Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.



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Maternal somatic mosaicism of FOXF1 mutation causes recurrent alveolar capillary dysplasia with misalignment of pulmonary veins in siblings



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Impaired context processing during irony comprehension in schizotypy: An ERPs study

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Publication date: Available online 23 April 2016
Source:International Journal of Psychophysiology
Author(s): Sarah Del Goleto, Milena Kostova, Alain Blanchet
Mentalizing deficits are a core manifestation of schizophrenia spectrum disorders. They contribute to the social handicap associated with the pathology, leading to disruption in autonomy, professional achievement, and interpersonal relationships. However, the underlying mechanisms of these deficits remain poorly understood. The aim of the present study was to test the hypothesis that context processing deficits would be responsible for mentalizing difficulties in schizotypy (personality traits considered as attenuated manifestations of schizophrenic symptoms) by using an irony comprehension task. Irony processing is a mentalizing exercise that requires the ability to take into account the semantic context to understand the literal meaning of the utterance, and to integrate the pragmatic context to infer the speaker's intention. These two steps of processing can be indexed by the N400 and P600 components, respectively, of event-related brain potentials (ERPs). Forty participants were assigned to high or low schizotypy groups according to their Schizotypal Personality Questionnaire (SPQ) score, and ERPs were recorded while they read short stories ending with a literal, ironic, or incompatible statement. In the low-SPQ group, there was a significant N400 semantic context effect (literal targets elicited less negative N400 amplitudes compared to incompatible targets) followed by a P600 pragmatic context effect (ironic targets evoked greater positive P600 amplitudes than literal targets). In contrast, there was neither a N400 nor P600 effect in the high-SPQ group. These abnormalities were associated with high interpersonal SPQ factor scores. These results show a strong association between context processing, mentalizing abilities, and interpersonal functioning in schizophrenia spectrum.



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GI stem cells – new insights into roles in physiology and pathophysiology

Abstract

This overview gives a brief historical summary of key discoveries regarding stem cells of the small intestine. The current concept is that there are two pools of intestinal stem cells (ISCs): an actively cycling pool that is marked by Lgr5, is relatively homogeneous and is responsible for daily turnover of the epithelium; and a slowly cycling or quiescent pool that functions as reserve ISCs. The latter pool appears to be quite heterogeneous and may include partially differentiated epithelial lineages that can reacquire stem cell characteristics following injury to the intestine. Markers and methods of isolation for active and quiescent ISC populations are described as well as the numerous important advances that have been made in approaches to the in vitro culture of ISCs and crypts. Factors regulating ISC biology are briefly summarized and both known and unknown aspects of the ISC niche are discussed. Although most of our current knowledge regarding ISC physiology and pathophysiology has come from studies with mice, recent work with human tissue highlights the potential translational applications arising from this field of research. Many of these topics are further elaborated in the following articles.



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Expression of genes involved in lipid droplet formation ( BSCL2 , SNAP23 and COPA ) during porcine in vitro adipogenesis

Abstract

Adipogenesis is a complex process of fat cells development driven by the expression of numerous genes. Differentiation of progenitor cells into mature adipocytes is accompanied by changes in cell shape, as a result of lipid accumulation. In the present study, expression of three genes involved in lipid droplet formation (SNAP23, BSCL2 and COPA) was evaluated during porcine adipogenesis. It was found that mRNA levels of BSCL2 and SNAP23, but not COPA, increased during differentiation. Redistribution of SNAP23 protein to different cellular compartments was observed when comparing undifferentiated mesenchymal stem cells and differentiated adipocytes. The BSCL2 protein was found to be highly specific to cells with accumulated lipids, while COPA protein coated the lipid droplets. Obtained results indicated that the studied genes may be considered as candidates for fatness traits in pigs. Moreover, this study has shown that the porcine in vitro adipogenesis system provides a useful tool for the characterisation of novel genes involved in adipose tissue accumulation.



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Considering causal genes in the genetic dissection of kernel traits in common wheat

Abstract

Genetic factors controlling thousand-kernel weight (TKW) were characterized for their association with other seed traits, including kernel width, kernel length, ratio of kernel width to kernel length (KW/KL), kernel area, and spike number per m2 (SN). For this purpose, a genetic map was established utilizing a doubled haploid population derived from a cross between German winter wheat cultivars Pamier and Format. Association studies in a diversity panel of elite cultivars supplemented genetic analysis of kernel traits. In both populations, genomic signatures of 13 candidate genes for TKW and kernel size were analyzed. Major quantitative trait loci (QTL) for TKW were identified on chromosomes 1B, 2A, 2D, and 4D, and their locations coincided with major QTL for kernel size traits, supporting the common belief that TKW is a function of other kernel traits. The QTL on chromosome 2A was associated with TKW candidate gene TaCwi-A1 and the QTL on chromosome 4D was associated with dwarfing gene Rht-D1. A minor QTL for TKW on chromosome 6B coincided with TaGW2-6B. The QTL for kernel dimensions that did not affect TKW were detected on eight chromosomes. A major QTL for KW/KL located at the distal tip of chromosome arm 5AS is being reported for the first time. TaSus1-7A and TaSAP-A1, closely linked to each other on chromosome 7A, could be related to a minor QTL for KW/KL. Genetic analysis of SN confirmed its negative correlation with TKW in this cross. In the diversity panel, TaSus1-7A was associated with TKW. Compared to the Pamier/Format bi-parental population where TaCwi-A1a was associated with higher TKW, the same allele reduced grain yield in the diversity panel, suggesting opposite effects of TaCwi-A1 on these two traits.



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Effect of prefrontal and parietal tDCS on learning and recognition of verbal and non-verbal material

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Publication date: Available online 23 April 2016
Source:Clinical Neurophysiology
Author(s): Aurélie L. Manuel, Armin Schnider
ObjectiveInformation learned in a spaced way is usually better recognized than information learned in a massed way. The brain mechanisms underlying this spacing effect remain unclear.MethodsWe applied anodal transcranial direct current stimulation (tDCS) to the left and right prefrontal (PFC) or posterior parietal (PPC) cortices to study how stimulation influences learning and retrieval of information, as evidenced by item recognition and the spacing effect, and whether the effects are lateralized according to stimulus material and site of stimulation. We devised a continuous recognition task with verbal and non-verbal stimuli repeated either immediately or after a delay. Stimulus recognition was tested 30minutes later.ResultsThere was a spacing effect for both materials, which, however, was not modulated by tDCS. Nonetheless, tDCS differentially impacted memory retrieval regardless of repetition mode during learning: tDCS over the PPC during learning enhanced recognition of non-verbal material regardless of side of stimulation, while tDCS over the left PFC decreased recognition regardless of material.ConclusionsThe PPC seems to be involved specifically in the mnesic treatment of non-verbal material whereas the left PFC specifically influences learning irrespective of stimulus material.SignificancePrefrontal and posterior parietal cortices follow different lateralization rules in recognition memory.



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Frequent Flyers: Navigating 'land mines' on calls

See all of Lenwood Brown's comics.



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The Rapid Aspiration Screening in Suspected Stroke Part 1: Development and Validation

Publication date: Available online 23 April 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Stephanie K. Daniels, Shweta Pathak, John C. Rosenbek, Robert O. Morgan, Jane A. Anderson
ObjectivesTo develop and validate a nurse-administered screening tool to identify aspiration risk in patients with suspected stroke.DesignValidity study comparing evidence-based swallowing screening items with videofluoroscopic swallowing study (VFSS).SettingsThe study was completed in a certified primary stroke center in a major metropolitan medical facility.ParticipantsConsecutive patients (N=250) admitted with suspected stroke.InterventionsPatients were administered evidence-based swallowing screening items by nurses. A VFSS was completed within 2 hours of swallowing screening.Main Outcome MeasureValidity relative to identifying VFSS determined aspiration for each screening item and for various combinations of items.ResultsAspiration was identified in 29 of the 250 participants. Logistic regression revealed age (p=0.012), dysarthria (p=0.001), abnormal volitional cough (p=0.030), and signs related to trial water swallow (p=0.021) to be significantly associated with aspiration. Validity was then determined based on the best combination of significant items for predicting aspiration. Results revealed that age >70, or dysarthria, or signs related to trial water swallow (i.e., cough, throat clear, wet vocal quality, and inability to continuously swallow 90ml water) yielded 93% sensitivity and 98% negative predictive value.ConclusionsThe final validated tool, Rapid Aspiration Screening for Suspected Stroke (RAS3), is a valid nurse-administered tool to detect risk of aspiration in patients presenting with suspected stroke.



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Matching task-difficulty to patient-ability during task practice improves upper extremity motor skill after stroke: a proof of concept study

Publication date: Available online 23 April 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Michelle L. Woodbury, Kelly Anderson, Christian Finetto, Andrew Fortune, Blair Dellenbach, Emily Grattan, Scott Hutchison
ObjectiveTo test the feasibility of the Fugl-Meyer Upper Extremity Assessment (FMA-UE) "keyform," derived from Rasch Analysis, as a method for systematically planning and progressing rehabilitation.DesignFeasibility study, single group design.SettingUniversity rehabilitation research laboratory.ParticipantsSubjects with ischemic or hemorrhagic stroke >3 mo. prior, voluntarily shoulder flexion ≥30° and simultaneous elbow extension ≥20°.Intervention: The keyform method defined initial rehabilitation targets (goals) and progressed the rehabilitation program after every 3rd session. Targets were repetitively practiced within the context of client-selected functional tasks not in isolation.Main outcome measuresFeasibility was defined by subject pain/fatigue, upper extremity (UE) motor function (Wolf Motor Function Test, WMFT) and movement patterns (kinematics). Assessments were administered pre- and post-treatment and compared with paired t-tests. Task-difficulty and patient-ability measures were calculated with Rasch analysis and compared with paired t-tests (p<0.05).ResultsTen subjects (59.70±9.96 yrs., 24.1±30.54 mo. post-stroke) participated in 9 sessions, 200 movement repetitions/session in <2 hrs without pain or fatigue. Subjects gained UE motor function (WMFT: Pre 22.23±24.26 seconds, Post 15.46±22.12 seconds, p=0.01), improved shoulder-elbow coordination (index of curvature: Pre 1.30±0.15, Post 1.21±0.11, p=0.01) and exhibited reduced trunk compensatory movement (trunk displacement: Pre 133.97±74.15 mm, Post 108.08±64.73 mm, p=0.02). Task-difficulty and patient-ability measures were not statistically different throughout the program (Person-ability measures of 1.01±0.05, 1.64±0.45 and 2.22±0.65 logits and item difficulty measures of 0.93±0.37, 1.70±0.20, and 2.06±0.24 logits at the 3 testing time points respectively, p>0.05).ConclusionThe FMA-UE keyform is a feasible method to assure that the difficulty of tasks practiced were well matched to initial and evolving levels of UE motor ability.



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The Rapid Aspiration Screening in Suspected Stroke Part 2: Initial and Sustained Nurse Accuracy and Reliability

Publication date: Available online 24 April 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Jane A. Anderson, Shweta Pathak, John C. Rosenbek, Robert O. Morgan, Stephanie K. Daniels
ObjectivesThe aim of this study was to determine registered nurses' (RNs) ability to obtain and maintain accurate procedural skills and reliable interpretation of the Rapid Aspiration Screening for Suspected Stroke (RAS3).DesignProspective, observation studySettingA certified primary stroke center in a major metropolitan facilityParticipantsA total of 15 RNs were recruited and trained in the administration and interpretation of the screening items under study to develop the RAS3.InterventionsRNs completed a total of 239 screenings of patients admitted with suspected stroke over a 2 year period. RNs administered the swallowing screening items (SSI) and interpreted the patient's response for each item. Independent to the RN, a speech-language pathologist simultaneously interpreted the stroke participant's response to each SSI.Main Outcome MeasuresReliability of interpretation and accuracy of administering SSIsResultsAverage accuracy rate for administration of the RAS3 was 98.33% with the overall accuracy rate for each procedural task ranging from 95.42% to 100%. For the specific SSIs that formed the RAS3, dysarthria and a positive sign after water swallow, reliability was very high (k=0.817). Accuracy rate for administration and reliability in interpretation of the SSIs improved as the RNs gained experience, and both were maximized at 20 screening opportunities.ConclusionsRNs demonstrate both excellent accuracy in procedural administration and reliability in item interpretation of the RAS3. With feedback and repeated opportunities to practice, maintenance of skills is achievable.



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Communication partner training in aphasia: An updated systematic review

Publication date: Available online 23 April 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Nina Simmons-Mackie, Anastasia Raymer, Leora R. Cherney
ObjectivesThis systematic review updates an earlier review1 describing the impact of communication partner training on individuals with aphasia and their communication partners. Three clinical questions addressing effects of partner training on language, communication and participation, psychosocial adjustment, and quality of life for adults with aphasia and their communication partners were addressed.Data SourcesTwelve electronic databases were searched using 23 search terms. References from relevant articles were hand-searched.Study SelectionThree reviewers independently reviewed abstracts excluding those that failed to meet inclusion criteria. Thirty-two full text articles were reviewed by 2 independent reviewers. Articles not meeting inclusion criteria were eliminated resulting in a corpus of 25 articles for full review.Data ExtractionFor the 25 articles, one reviewer extracted descriptive data regarding participants, intervention, outcome measures and results. A second reviewer verified the accuracy of the extracted data.Data SynthesisThe 3-member review team classified studies using the American Academy of Neurology (AAN) levels of evidence2. Two independent reviewers evaluated each article using design specific tools to assess research quality.ConclusionsAll 25 of the current review articles reported positive changes from partner training. Therefore, to date, 56 studies across two systematic reviews have reported positive outcomes from communication partner training in aphasia. The results of the current review are consistent with the earlier review1 and necessitate no change to the earlier recommendations, suggesting that communication partner training should be conducted to improve partner skill in facilitating the communication of people with chronic aphasia. Additional high quality research is needed to strengthen the original 2010 recommendations and expand recommendations to individuals with acute aphasia. High quality clinical trials are also needed to demonstrate implementation of CPT in complex environments such as health care.



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Transfer technique is associated with shoulder pain and pathology in people with spinal cord injury: A cross-sectional investigation

Publication date: Available online 23 April 2016
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Nathan S. Hogaboom, Lynn A. Worobey, Michael L. Boninger
ObjectivesTo evaluate how transfer technique and subject characteristics relate to ultrasound measures of shoulder soft tissue pathology, and self-reported shoulder pain during transfers in a sample of wheelchair users with spinal cord injury (SCI).DesignCross-sectional observational study.SettingResearch laboratory, national and local veterans' wheelchair sporting events.ParticipantsA convenience sample of 76 wheelchair users with non-progressive SCI. Participants were over 18 years old, greater than one year post-injury, and could complete repeated independent wheelchair transfers without the use of their leg muscles.InterventionsN/AMain OutcomesTransfer pain items from the Wheelchair User's Shoulder Pain Index; Transfer technique assessed using the Transfer Assessment Instrument (TAI); shoulder pathology markers examined using the Ultrasound Shoulder Pathology Rating Scale (USPRS).ResultsBetter transfer technique (higher TAI) correlated with less injury (lower USPRS) (partial-η2=.062, p<.05) and less pain during transfers (partial-η2=.049, p<.10). Greater age was the strongest predictor of greater pathology (USPRS total: partial-η2=.225, supraspinatus grade: partial-η2=.174, p<.01). An interaction between technique and weight was found (p<.10): participants with lower bodyweights showed a decrease in pathology markers with better transfer technique (low-weight: R2=0.422, p<.05; middle-weight: R2=0.200, p<.01), while those with higher weight showed little change with technique (R2=0.018, p>.05).ConclusionsParticipants with better transfer technique exhibited less shoulder pathology and reported less pain during transfers. The relationship between technique and pathology was strongest in lower-weight participants. While causation cannot be proven due to study design, it is possible that using a better transfer technique and optimizing bodyweight could reduce the incidence of shoulder pathology and pain.



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