Selective age-related changes in orientation perception

Orientation perception is a fundamental property of the visual system and an important basic processing stage for visual scene perception. Neurophysiological studies have found broader tuning curves and increased noise in orientation-selective neurons of senescent monkeys and cats, results that suggest an age-related decline in orientation perception. However, behavioral studies in humans have found no evidence for such decline, with performance being comparable for younger and older participants in orientation detection and discrimination tasks. Crucially, previous behavioral studies assessed performance for cardinal orientation only, and it is well known that the human visual system prefers cardinal over oblique orientations, a phenomenon called the oblique effect. We hypothesized that age-related changes depend on the orientation tested. In two experiments, we investigated orientation discrimination and reproduction for a large range of cardinal and oblique orientations in younger and older adults. We found substantial age-related decline for oblique but not for cardinal orientations, thus demonstrating that orientation perception selectively declines for oblique orientations. Taken together, our results serve as the missing link between previous neurophysiological and human behavioral studies on orientation perception in healthy aging.     

ESAT and M-CHAT as screening instruments for autism spectrum disorders at 18 months in the general population: issues of overlap and association with clinical referrals

The Modified Checklist for Autism in Toddlers (M-CHAT) and the Early Screening of Autistic Traits (ESAT) were designed to screen for autism spectrum disorders in very young children. The aim of this study was to explore proportions of children that screened positive on the ESAT or the M-CHAT and to investigate if screening positive on the ESAT and M-CHAT is associated with clinical referral by 18 months and other aspects of children’s development, health, and behavior. In this study, the mothers of 12,948 18-month-old children returned a questionnaire consisting of items from the ESAT and M-CHAT, plus questions about clinical and developmental characteristics. The M-CHAT identified more screen-positive children than the ESAT, but the ESAT was associated with more clinical referrals and tended to identify more children with medical, language, and behavioral problems. A post hoc analysis of combining the two instruments found this to be more effective than the individual instruments alone in identifying children referred to clinical services at 18 months. Further analysis at the level of single items is warranted to improve these screening instruments.     

An inactive lifestyle and low physical fitness are associated with functional somatic symptoms in adolescents. The TRAILS study

Objective

An inactive lifestyle has been associated with functional somatic symptoms (FSS), but findings are contradictory. Moreover, mediating factors in this relationship are unclear. We examined whether low physical activity was related to FSS in adolescents, and whether this association was mediated by low physical fitness.

Methods

This study was part of the Dutch longitudinal cohort study TRAILS, in which 1816 adolescents (mean age 16.3 years, SD 0.7) participated during the third (T3) and 1881 (mean age 19.1 years, SD 0.6) during the fourth (T4) assessment waves. Adolescents' exercise and sedentary behavior levels and the number of FSS were assessed by questionnaires at T3 and T4. Physical fitness (VO₂Max) was determined for 687 adolescents by a shuttle run test at T3. The association between physical activity and FSS was examined with bootstrapped linear regression analyses, adjusted for smoking and gender. In addition, bootstrapped mediation analyses were performed.

Results

A lack of exercise (b = 0.05, bootstrap 95%-CI: 0.01 to 0.09) and high sedentary behavior (b = 0.10, bootstrap 95%-CI: 0.06 to 0.14) at T3 were positively associated with FSS at T3. Since no longitudinal effects were found, shared associations were tested instead of mediation. The associations between a lack of exercise and FSS, and sedentary behavior and FSS were shared with physical fitness (b = 0.01, bootstrap 95%-CI: 0.010.02. and b = 0.03, bootstrap 95%-CI: 0.010.05).

Conclusion

An inactive lifestyle is associated with increased FSS in adolescents. Only part of this association is shared with low physical fitness.     

Myotonia in DNM2-related centronuclear myopathy

Centronuclear myopathy (CNM) is a rare hereditary myopathy characterized by centrally located muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are characteristic of certain neuromuscular disorders. Such activity has been reported in only one CNM case without a known genetic cause. We sequenced the DNM2 gene and the genes associated with myotonia (CLCN1, SCN4A, DMPK and ZNF9) in a sporadic adult patient with CNM and myotonic discharges. Sequencing the entire coding region and exon–intron boundaries revealed a heterozygous c.1106g-a substitution in exon 8, resulting in a R369Q change in the DNM2. Sequencing the CLCN1, SCN4A, DMPK and ZNF9 genes ruled out mutations in these genes. This is the first report of DNM2-related CNM presenting with myotonia. The diagnosis of CNM should be considered in patients with myotonic discharges of an unknown cause.     

Morphological and physiological properties of enhanced green fluorescent protein (EGFP)‐expressing wide‐field amacrine cells in the ChAT‐EGFP mouse line

Mammalian retinas comprise a variety of interneurons, among which amacrine cells represent the largest group, with more than 30 different cell types each exhibiting a rather distinctive morphology and carrying out a unique function in retinal processing. However, many amacrine types have not been studied systematically because, in particular, amacrine cells with large dendritic fields, i.e. wide‐field amacrine cells, have a low abundance and are therefore difficult to target. Here, we used a transgenic mouse line expressing the coding sequence of enhanced green fluorescent protein under the promoter for choline acetyltransferase (ChAT‐EGFP mouse) and characterized a single wide‐field amacrine cell population monostratifying in layer 2/3 of the inner plexiform layer (WA‐S2/3 cell). Somata of WA‐S2/3 cells are located either in the inner nuclear layer or are displaced to the ganglion cell layer and exhibit a low cell density. Using immunohistochemistry, we show that WA‐S2/3 cells are presumably GABAergic but may also release acetylcholine as their somata are weakly positive for ChAT. Two‐photon‐guided patch‐clamp recordings from intact retinas revealed WA‐S2/3 cells to be ON‐OFF cells with a homogenous receptive field even larger than the dendritic field. The large spatial extent of the receptive field is most likely due to the extensive homologous and heterologous coupling among WA‐S2/3 cells and to other amacrine cells, respectively, as indicated by tracer injections. In summary, we have characterized a novel type of GABAergic ON‐OFF wide‐field amacrine cell which is ideally suited to providing long‐range inhibition to ganglion cells due to its strong coupling.     

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%–5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.     

The Target for Statins,HMG-CoA Reductase,Is Expressed in Ductal Carcinoma-In Situ and May Predict Patient Response to Radiotherapy

Background

Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benefit from radiotherapy is warranted. Statins have been suggested to exert radio-sensitizing effects. The target for cholesterol-lowering statins is HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. The aim of this study was to examine HMGCR expression in DCIS and study its treatment predictive value.

Methods

A population-based cohort including 458 women diagnosed with primary DCIS between 1986 and 2004 were followed until November 2011 to study long-term survival. Tumor tissue microarrays were constructed, and immunohistochemical analyses were performed to detect cytoplasmic protein expression of HMGCR. The association between DCIS HMGCR expression and invasive breast cancer recurrence-free survival (RFS_inv) and overall survival (OS) was analyzed by Kaplan–Meier curves, log rank test, and Cox proportional hazard analysis.

Results

HMGCR was strongly expressed in 24 % of the assessed DCIS samples, moderately expressed in 46 %, and weakly expressed in 23 %; no expression was detected in 7 % of the samples. During the follow-up time (median 13.8 years), 61 patients were diagnosed with an invasive breast cancer recurrence, and 80 patients died. A crude analysis showed no survival benefit from radiotherapy. However, patients with strong HMGCR expression showed an improved RFS_inv (log rank, p = 0.03) and OS (log rank, p = 0.04) after radiotherapy. No statistically significant interaction was observed for HMGCR and radiotherapy (RFS_inv p = 0.69 and OS p = 0.29).

Conclusions

This study demonstrates HMGCR expression in DCIS and suggests HMGCR as a predictive marker of response to postoperative radiotherapy in DCIS, although the test for interaction was nonsignificant. Future DCIS studies addressing the potential of statin treatment targeting HMGCR are warranted.     

Is there a need for orthodontic plaque indices?—diagnostic accuracy of four plaque indices

Objectives

The aim of this study was to assess the diagnostic performance and accuracy of four plaque indices for orthodontic patients.

Materials and methods

The plaque accumulation of 140 maxillary incisors with bonded brackets was recorded using intra-oral photographs and assessed using four different plaque indices: the orthodontic plaque (OP) index, the modified orthodontic plaque (MOP) index, the Quigley and Hein (QHP) index and the modified Navy plaque (MNP) index. The assessment was performed twice within a time interval of 4 weeks by four different examiner groups: orthodontists, dentists, students and orthodontic assistants.

Results

No significant differences were detected for the OP and MOP indices among the examiner groups. A significant difference was found for the QHP and MNP indices. The inter- and intra-examiner reliability of the OP and MOP indices was good. In contrast, the reliability for the QHP and MNP indices was moderate to poor with few exceptions. The discrimination performance of the OP and MOP indices was excellent. The sum of the sensitivity and specificity was generally lower for the QHP and MNP indices compared with the OP and MOP indices.

Conclusion

OP and MOP indices showed good performance. The QHP and MNP indices are not appropriate for orthodontic purposes.

Clinical relevance

Traditional plaque indices reflect the typical pattern of plaque accumulation for patients without multi-bracket appliances. The performance of these indices for orthodontic patients has never been investigated. Orthodontic plaque indices that focus on the surface along the gingival margin and areas around the bracket exhibit higher diagnostic performance and accuracy compared with traditional indices.