Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Fiber digestibility and protein value of pulp silage for lactating dairy cows: Effects of wet fractionation by screw pressing of perennial ryegrass.

The aim of the study was to investigate the effects of substituting silage of chopped grass with pulp silage of grass fractionated once or twice in a biorefinery using a screw press on fiber kinetics, protein value, and production of CH4 in dairy cows. Six lactating multiparous Holstein cows in mid-lactation (176 ± 93 d in milk), cannulated in the rumen, duodenum, and ileum, were used in an incomplete 6 × 4 Latin square design with a 2 × 3 factorial arrangement of treatments. Perennial ryegrass was harvested in third regrowth from the same field at early and late developmental stage (35 and 44 d of regrowth, respectively) and subjected to 1 of 3 types of processing within each developmental stage. Grass was either harvested for normal silage making (mowed, wilted, chopped, and ensiled), or harvested fresh and fractionated using a screw press. Half of the pulp from the first fractionation was ensiled, whereas the other half of the pulp was rehydrated, fractionated a second time, and pulp hereof was ensiled. The grass and pulp silages were used with concentrates (65:35 forage to concentrate ratio) to make total mixed rations (TMR) based on either silage of chopped grass (GS), pulp silage of grass fractionated once (1×P), or pulp silage of grass fractionated twice (2×P), harvested either at early (E) or late (L) developmental stage resulting in 6 different TMR treatments (EGS, E1×P, E2×P, LGS, L1×P, L2×P). The TMR were fed for ad libitum intake and samples of intestinal digesta and feces were collected for determination of digestibility. The effect of processing on ash-free neutral detergent fiber (aNDFom) concentration in silages depended on developmental stage, but showed that within each developmental stage, pulp silage of grass fractionated twice had higher aNDFom concentration than pulp silage of grass fractionated once and silage of chopped grass. The 2×P resulted in lower (14.9 ± 0.55 vs. 17.5 ± 0.54 kg/d) dry matter intake (DMI) compared with GS. The effects of processing and developmental stage interacted such that apparent total-tract aNDFom digestibility was higher (784 ± 13 vs. 715 ± 13 g/kg) for L2×P compared with LGS, whereas no difference was found between E2×P and EGS. Moreover, the protein value was higher (106 ± 5 vs. 92 ± 5 g AA digested in the small intestine/kg of DMI) for 2×P compared with GS. Unexpectedly, processing had no effect on fractional rate of digestion of digestible aNDFom or CH4 yield (L/kg of DMI), whereas feeding forages harvested at early compared with late developmental stage resulted in lower CH4 yield. Feeding pulp silage of grass fractionated once generally yielded results intermediate to cows fed silage of chopped grass and pulp silage of grass fractionated twice. This study showed that pulp silage of fractionated grass could serve as feed for dairy cows because the fiber digestibility and protein value improved, but further research investigating effects of physical processing of forage on fiber kinetics is required.

Effects on feed intake, milk production, and methane emission in dairy cows fed silage or fresh grass with concentrate or fresh grass harvested at early or late maturity stage without concentrate.

The objective of the study was to quantify the effects on dry matter intake (DMI), nutrient digestibility, gas exchange, milk production, and milk quality in dairy cows fed fresh grass harvested at different maturity stages. Sixteen Danish Holstein cows in mid-lactation were divided into 4 blocks and used in 4 incomplete 4 × 2 Latin squares with 2 periods of 21 d. The cows received 1 of 4 treatments in each period, resulting in 8 cows per treatment, as follows: grass-clover silage supplemented with 6 kg/d concentrate pellets (SILc), fresh grass harvested at late maturity stage supplemented with 6 kg/d concentrate pellets (LATc), fresh grass harvested at late maturity stage (LAT), and fresh grass harvested at early maturity stage (ERL). The cows were housed in tiestalls and milked twice daily. The cows had ad libitum access to the forage, and concentrate pellets were divided into equal amounts and fed separately in the morning and afternoon. Fecal samples were collected to determine apparent total-tract digestibility, and samples of rumen fluid were collected for determination of short chain fatty acid composition. Halters were used for measuring eating and rumination time. Gas exchange was measured in open-circuit respiration chambers. Total DMI was higher in LATc and ERL (16.9 ± 0.45 and 15.5 ± 0.39 kg/d, respectively) compared with LAT (14.1 ± 0.42 kg/d). Relative to SILc, cows fed fresh grass experienced a convex pattern in DMI during the experiment. The changes in DMI were related to changes in leaf to stem ratio, fiber concentration, and organic matter digestibility determined in vitro in samples of the fresh grass harvested throughout the experiment. The apparent total-tract digestibility of organic matter was higher in SILc and LAT compared with LATc. Methane yield was lower for LATc compared with LAT (19.5 ± 0.61 vs. 22.6 ± 0.55 g of CH4/kg of DMI), and was not different between LAT and ERL. Compared with LAT, milk yield was higher for ERL (21.1 ± 1.14 vs. 23.4 ± 1.11 kg/d) and energy-corrected milk (ECM) yield was higher for LATc (21.5 ± 0.99 vs. 25.3 ± 1.03 kg/d). We detected no differences in milk or ECM yield between SILc and LATc. Milk protein yield was higher and milk fat concentration was lower in LATc compared with LAT. The fatty acid percentages of ∑C4-C14:1 and ∑C16 in milk were higher for SILc compared with LATc, signifying pronounced de novo synthesis. The n-6:n-3 ratio in milk fatty acids was lower for SILc and LAT compared with LATc, indicating improved nutritional quality for SILc and LAT. However, retinol concentration in milk was lower in SILc compared with all other treatments. The study implies that feeding silage instead of fresh grass has no effect on DMI, ECM yield, or CH4 yield, and that concentrate supplementation can increase milk production, affects milk quality, and reduces the effect on climate, whereas feeding less mature grass increases DMI and milk yield, but has no effect on CH4 yield.

Evaluation of APOE ɛ2/ɛ3/ɛ4 Alleles in a Cohort of Individuals Affected by Developmental Topographical Disorientation.

The three common alleles of the APOE gene, ɛ2/ɛ3/ɛ4, have been linked to human spatial orientation. We investigated the genetic role of APOE in developmental topographical disorientation (DTD), a lifelong condition that results in topographical disorientation. We genotyped the APOE ɛ2/ɛ3/ɛ4 alleles in a cohort of 20 unrelated DTD probands, and found allele frequencies not statistically different from the those seen in the population as a whole. Therefore, we found no evidence that DTD occurs preferentially on a genetic background containing any particular APOE allele, making it unlikely that these APOE alleles are contributing to the development of DTD.

Fava beans can substitute soybean meal and rapeseed meal as protein source in diets for lactating dairy cows.

The effect of replacing mixtures of wheat and soybean meal and wheat and rapeseed meal by toasted fava beans, and the effect of toasting fava beans on feed intake, milk yield, and composition of milk and feces were investigated using 40 Holstein cows in each of two 4 × 4 Latin square design trials conducted simultaneously. In trial 1, the 4 treatment concentrates were untreated fava beans, toasted fava beans, 42% soybean meal + 58% rolled wheat, and a 21, 29, and 50% mix of soybean meal, rolled wheat, and toasted fava beans, respectively [on dry matter (DM) basis]. In trial 2, the 4 experimental treatments were untreated fava beans, toasted fava beans, 64% rapeseed meal + 36% rolled wheat, and a 32, 18, and 50% mix of rapeseed meal, rolled wheat, and toasted fava beans, respectively (on DM basis). In each trial, 16 primiparous and 24 multiparous cows were fed the treatment concentrates as part of a partial mixed ration, of which the forage consisted of 50% corn silage and 50% grass-clover silage. Substitution of soybean meal and wheat or rapeseed meal and wheat with toasted fava beans did not affect total DM intake, and no linear effects were observed on milk yield or energy-corrected milk (ECM) yield. However, in trial 2, a quadratic effect was observed on milk yield when substituting rapeseed meal and wheat with toasted fava beans. In both trials, substitution of soybean meal and wheat or rapeseed meal and wheat with toasted fava beans increased milk lactose concentration and decreased milk protein yield and concentration of protein in milk. In both trials, fecal concentration of starch increased linearly when substituting soybean meal and wheat or rapeseed meal and wheat with toasted fava beans. In trial 2, fecal concentration of P decreased when substituting rapeseed meal and wheat with toasted fava beans. In situ investigations showed increased rumen undegradable protein concentration and thereby increased estimated metabolizable protein supply when toasting fava beans. However, in both trials, milk protein yield and concentration decreased when cows were fed toasted compared with untreated fava beans. Furthermore, when cows were fed toasted compared with untreated fava beans in trial 1, milk yield, ECM yield, and nitrogen efficiency decreased. We conclude that toasted fava beans could substitute soybean meal and wheat or rapeseed meal and wheat with regard to ECM yield. However, milk protein yield decreased when substituting soybean meal and wheat or rapeseed meal and wheat with toasted fava beans. Compared with untreated fava beans, toasting had no positive effect on milk production and nitrogen efficiency.

Process and Outcome Evaluation of a Mindfulness-Based Cognitive Therapy Intervention for Cisgender and Transgender African American Women Living with HIV/AIDS.

There is a need for evidence-based contextualized mental health interventions for persons living with HIV/AIDS. In the current study, the primary researcher conducted open trials with African American women living with HIV/AIDS (AAWLWHA) to examine the acceptability and feasibility of Project UPLIFT, a mindfulness-based cognitive therapy intervention that has demonstrated effectiveness in persons living with epilepsy. Women were recruited for a tele-delivered phone intervention group separated by gender identity, as well as participated in pre- and post-test assessments. Additionally, data on acceptability was collected. Both cis- and transgender women were highly satisfied with the intervention and demonstrated improvement in depressive and stress symptoms. The intervention seemed to be particularly feasible for cisgender women, though more qualitative mental health research may be warranted with transgender women. The current research has implications for the utility of mindfulness-based interventions such as UPLIFT, with AAWLWHA.

Transgenic Expression of Cacna1f Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A).

Purpose: Congenital stationary night blindness 2A (CSNB2A) is a genetic retinal disorder characterized by poor visual acuity, nystagmus, strabismus, and other signs of retinal dysfunction resulting from mutations in Cacna1f-the gene coding for the pore-forming subunit of the calcium channel CaV1.4. Mouse models of CSNB2A have shown that mutations causing the disease deleteriously affect photoreceptors and their synapses with second-order neurons. This study was undertaken to evaluate whether transgenic expression of Cacna1f could rescue morphology and visual function in a Cacna1f-KO model of CSNB2A. Methods: Strategic creation, breeding and use of transgenic mouse lines allowed for Cre-driven retina-specific expression of Cacna1f in a CSNB2A model. Transgene expression and retinal morphology were investigated with immunohistochemistry in retinal wholemounts or cross-sections. Visual function was assessed by optokinetic response (OKR) analysis and electroretinography (ERG). Results: Mosaic, prenatal expression of Cacna1f in the otherwise Cacna1f-KO retina was sufficient to rescue some visual function. Immunohistochemical analyses demonstrated wild-type-like photoreceptor and synaptic morphology in sections with transgenic expression of Cacna1f. Conclusions: This report describes a novel system for Cre-inducible expression of Cacna1f in a Cacna1f-KO mouse model of CSNB2A and provides preclinical evidence for the potential use of gene therapy in the treatment of CSNB2A. Translational Relevance: These data have relevance in the treatment of CSNB2A and in understanding how photoreceptor integration might be achieved in retinas in which photoreceptors have been lost, such as retinitis pigmentosa, age-related macular degeneration, and other degenerative conditions.

Molecular-Weight Growth in Ozone-Initiated Low-Temperature Oxidation of Methyl Crotonate.

We report experiments of ozone-initiated low-temperature oxidation of methyl crotonate (MC, CH3-CH═CH-C(O)OCH3) from 420 to 660 K in a near-atmospheric-pressure jet-stirred reactor using photoionization molecular-beam mass spectrometry as a sampling technique. In this temperature regime, no typical low-temperature combustion (LTC) reactions have been observed for MC when oxygen (O2) is used as the oxidizer. Upon ozone addition, significant oxidation of methyl crotonate is found. On the basis of experimentally observed energy-dependent mass peaks in combination with temperature-dependent mole fraction profiles and photoionization efficiency curves, we provide new insights into the methyl crotonate ozonolysis reaction network. The observed MC + O3 products, C5H8O5, are found to be related to the keto-hydroperoxides resulting from the isomerization of the primary ozonide. Evidence is also provided that molecular growth mainly results from cycloaddition reactions of the Criegee intermediate into aldehydes and alkenes as well as addition reactions of the Criegee intermediates to the double bond of methyl crotonate and sequential decomposition into ketones. Furthermore, species that contribute in large amounts to the low-temperature oxidation of methyl crotonate, like H2O2, CH3OOH, CH3OH, and HC(O)OH, are identified, and their mole fractions are reported. Additionally, preliminary modeling is performed which qualitatively captures the observed NTC behavior and reveals future research opportunities.

Decomposing neural responses to melodic surprise in musicians and non-musicians: Evidence for a hierarchy of predictions in the auditory system.

Neural responses to auditory surprise are typically studied with highly unexpected, disruptive sounds. Consequently, little is known about auditory prediction in everyday contexts that are characterized by fine-grained, non-disruptive fluctuations of auditory surprise. To address this issue, we used IDyOM, a computational model of auditory expectation, to obtain continuous surprise estimates for a set of newly composed melodies. Our main goal was to assess whether the neural correlates of non-disruptive surprising sounds in a musical context are affected by musical expertise. Using magnetoencephalography (MEG), auditory responses were recorded from musicians and non-musicians while they listened to the melodies. Consistent with a previous study, the amplitude of the N1m component increased with higher levels of computationally estimated surprise. This effect, however, was not different between the two groups. Further analyses offered an explanation for this finding: Pitch interval size itself, rather than probabilistic prediction, was responsible for the modulation of the N1m, thus pointing to low-level sensory adaptation as the underlying mechanism. In turn, the formation of auditory regularities and proper probabilistic prediction were reflected in later components: The mismatch negativity (MMNm) and the P3am, respectively. Overall, our findings reveal a hierarchy of expectations in the auditory system and highlight the need to properly account for sensory adaptation in research addressing statistical learning.

Diagonal Acceleration for Covariance Matrix Adaptation Evolution Strategies.

We introduce an acceleration for covariance matrix adaptation evolution strategies (CMA-ES) by means of adaptive diagonal decoding (dd-CMA). This diagonal acceleration endows the default CMA-ES with the advantages of separable CMA-ES without inheriting its drawbacks. Technically, we introduce a diagonal matrix D that expresses coordinate-wise variances of the sampling distribution in DCD form. The diagonal matrix can learn a rescaling of the problem in the coordinates within a linear number of function evaluations. Diagonal decoding can also exploit separability of the problem, but, crucially, does not compromise the performance on nonseparable problems. The latter is accomplished by modulating the learning rate for the diagonal matrix based on the condition number of the underlying correlation matrix. dd-CMA-ES not only combines the advantages of default and separable CMA-ES, but may achieve overadditive speedup: it improves the performance, and even the scaling, of the better of default and separable CMA-ES on classes of nonseparable test functions that reflect, arguably, a landscape feature commonly observed in practice. The article makes two further secondary contributions: we introduce two different approaches to guarantee positive definiteness of the covariance matrix with active CMA, which is valuable in particular with large population size; we revise the default parameter setting in CMA-ES, proposing accelerated settings in particular for large dimension. All our contributions can be viewed as independent improvements of CMA-ES, yet they are also complementary and can be seamlessly combined. In numerical experiments with dd-CMA-ES up to dimension 5120, we observe remarkable improvements over the original covariance matrix adaptation on functions with coordinate-wise ill-conditioning. The improvement is observed also for large population sizes up to about dimension squared.

Avian Adeno-Associated Viral Transduction of the Postembryonic Chicken Retina.

PURPOSE: The posthatching chicken is a valuable animal model for research, but molecular tools needed for altering its gene expression are not yet available. Our purpose here was to adapt the adeno-associated viral (AAV) vector method, used widely in mammalian studies, for use in investigations of the chicken retina. We hypothesized that the recently characterized avian AAV (A3V) vector could effectively transduce chick retinal cells for manipulation of gene expression, after intravitreal or subretinal injection. METHODS: A3V encoding enhanced green fluorescent protein (EGFP) was injected intravitreally or subretinally into P1-3 chick eye and left for 7 to 10 days. Retinas were then sectioned or flat-mounted and visualized via laser-scanning confocal microscopy for analysis of expression and imaging of retinal cells. RESULTS: Intravitreal A3V-EGFP injection resulted in EGFP expression in a small percent of retinal cells, primarily those with processes and/or cell bodies near the vitreal surface. In contrast, subretinal injection of A3V-EGFP within confined retinal "blebs" produced high rates of transduction of rods and all types of cones. Some examples of all other major retinal cell types, including horizontal, amacrine, bipolar, ganglion, and Müller cells, were also transduced, although with much lower frequency than photoreceptors. CONCLUSIONS: A3V is a promising tool for investigating chick retinal cells and circuitry in situ. This novel vector can be used for studies in which local photoreceptor transduction is sufficient for meaningful observations. TRANSLATIONAL RELEVANCE: With this vector, the postembryonic chick retina can now be used for preclinical trials of gene therapy for prevention and treatment of human retinal disease.

[Picosecond infrared laser fiber-assisted sclerostomy (PIRL-FAST) : A first proof of principle analysis]. / Pikosekundenlaser-Faser-assistierte Sklerostomie (PIRL-FAST) : Ein erster Machbarkeitsnachweis.

INTRODUCTION: The aim of this study was an analysis of the feasibility of a picosecond infrared laser fiber-assisted sclerostomy (PIRL-FAST) using a novel sapphire fiber and different energy levels of the picosecond laser. METHOD: The laser-assisted sclerostomy was carried out with a newly generated sapphire fiber of the PIRL-HP2-1064 OPA-3000 (Attodyne, Canada). Immediately after the intervention, the eyes were fixed in phosphate-buffered 3.5% formaldehyde. For subsequent histological analysis the eyes were cut into 4 µm thick sections and stained with hematoxylin and eosin (H&E, Merck, Darmstadt, Germany). All preparations were then scanned and digitalized using the MIRAX SCAN (Carl Zeiss Microimaging GmbH, Jena, Germany). RESULTS: The pulse energies 150 µJ (N = 4), 175 µJ (N = 6), 200 µJ (N = 7) and 250 µJ (N = 6) were selected. Within the framework of this first feasibility analysis 400 µm (10 sequential sections) of the sclerotomies were evaluated. The mean area of PIRL-FAST showed a dependency on the pulse energy applied. The diameter of the collateral damage zone (CDZ) depended on the pulse energy used. The largest CDZ could be measured using the highest pulse energy in this experiment (250 µJ). The environmental scanning electron microscope (ESEM) results revealed circular smooth sclerostomy wall with only minimal change of tissue ultrastructure. CONCLUSION: The PIRL-FAST using sapphire fibers is a new minimally invasive instrument to provide robust stenting from the anterior chamber to the subconjunctival space. Since the PIRL has proven to work efficiently in sectioning several tissues with minimal collateral damage these first proof of principle experiments might pave the way for a new minimally invasive glaucoma surgery strategy. We have already initiated experiments to analyze the wound healing and scar formation in vivo.

Detection of Aliphatically Bridged Multi-Core Polycyclic Aromatic Hydrocarbons in Sooting Flames with Atmospheric-Sampling High-Resolution Tandem Mass Spectrometry.

This paper provides experimental evidence for the chemical structures of aliphatically substituted and bridged polycyclic aromatic hydrocarbon (PAH) species in gas-physe combustion environments. The identification of these single- and multicore aromatic species, which have been hypothesized to be important in PAH growth and soot nucleation, was made possible through a combination of sampling gaseous constituents from an atmospheric pressure inverse coflow diffusion flame of ethylene and high-resolution tandem mass spectrometry (MS-MS). In these experiments, the flame-sampled components were ionized using a continuous VUV lamp at 10.0 eV and the ions were subsequently fragmented through collisions with Ar atoms in a collision-induced dissociation (CID) process. The resulting fragment ions, which were separated using a reflectron time-of-flight mass spectrometer, were used to extract structural information about the sampled aromatic compounds. The high-resolution mass spectra revealed the presence of alkylated single-core aromatic compounds and the fragment ions that were observed correspond to the loss of saturated and unsaturated units containing up to a total of 6 carbon atoms. Furthermore, the aromatic structures that form the foundational building blocks of the larger PAHs were identified to be smaller single-ring and pericondensed aromatic species with repetitive structural features. For demonstrative purposes, details are provided for the CID of molecular ions at masses 202 and 434. Insights into the role of the aliphatically substituted and bridged aromatics in the reaction network of PAH growth chemistry were obtained from spatially resolved measurements of the flame. The experimental results are consistent with a growth mechanism in which alkylated aromatics are oxidized to form pericondensed ring structures or react and recombine with other aromatics to form larger, potentially three-dimensional, aliphatically bridged multicore aromatic hydrocarbons.

ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison.

BACKGROUND: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a very rare and potentially fatal pediatric disorder, the cause of which is presently unknown. ROHHAD is often compared to Prader-Willi syndrome (PWS) because both share childhood obesity as one of their most prominent and recognizable signs, and because other symptoms such as hypoventilation and autonomic dysfunction are seen in both. These phenotypic similarities suggest they might be etiologically related conditions. We performed an in-depth clinical comparison of the phenotypes of ROHHAD and PWS and used NGS and Sanger sequencing to analyze the coding regions of genes in the PWS region among seven ROHHAD probands. RESULTS: Detailed clinical comparison of ROHHAD and PWS patients revealed many important differences between the phenotypes. In particular, we highlight the fact that the areas of apparent overlap (childhood-onset obesity, hypoventilation, autonomic dysfunction) actually differ in fundamental ways, including different forms and severity of hypoventilation, different rates of obesity onset, and different manifestations of autonomic dysfunction. We did not detect any disease-causing mutations within PWS candidate genes in ROHHAD probands. CONCLUSIONS: ROHHAD and PWS are clinically distinct conditions, and do not share a genetic etiology. Our detailed clinical comparison and genetic analyses should assist physicians in timely distinction between the two disorders in obese children. Of particular importance, ROHHAD patients will have had a normal and healthy first year of life; something that is never seen in infants with PWS.

Channeling Vision: CaV1.4-A Critical Link in Retinal Signal Transmission.

Voltage-gated calcium channels (VGCC) are key to many biological functions. Entry of Ca2+ into cells is essential for initiating or modulating important processes such as secretion, cell motility, and gene transcription. In the retina and other neural tissues, one of the major roles of Ca2+-entry is to stimulate or regulate exocytosis of synaptic vesicles, without which synaptic transmission is impaired. This review will address the special properties of one L-type VGCC, CaV1.4, with particular emphasis on its role in transmission of visual signals from rod and cone photoreceptors (hereafter called "photoreceptors," to the exclusion of intrinsically photoreceptive retinal ganglion cells) to the second-order retinal neurons, and the pathological effects of mutations in the CACNA1F gene which codes for the pore-forming α1F subunit of CaV1.4.

Effect of hyoscine butylbromide on prostate multiparametric MRI anatomical and functional image quality.

AIM: To evaluate the effect of the spasmolytic agent hyoscine butylbromide (HBB) on the quality of anatomical and functional imaging of the prostate. MATERIALS AND METHODS: One hundred and seventy-three patients were included in this retrospective study. Eighty-seven patients received intravenous HBB prior to scanning (HBB group) and 86 patients did not (non-HBB group). Multiparametric (mp) 3 T magnetic resonance imaging (MRI) was performed using a 32-channel body coil. Two radiologists independently evaluated the image quality of T2-weighted imaging (WI), diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps, using a five-point Likert scale. DWI was further assessed for distortion and artefact (four-point Likert scale), and T2WI for the presence of motion artefact or blurring. Dynamic contrast-enhanced (DCE) image quality was assessed by recording the number of corrupt contrast curve data points. RESULTS: T2W image quality in the HBB group was significantly higher than in the non-HBB group (3.63±1.11 versus 2.84±0.899); p<0.001. The HBB group also showed significantly less T2W motion and T2W blur than the non-HBB group (23% and 51.7% versus 53.5% and 83.7%, respectively; p<0.001); however, there was no significant improvement in DWI or ADC image quality, or DWI degree of distortion or artefact. There was a trend towards a lower number of corrupted data points from the contrast curve (2.47±2.44 versus 3.68±2.64), but this did not reach significance (p=0.052). CONCLUSION: Administration of HBB significantly improves the image quality of T2WI images. These results provide evidence for the use of HBB in routine patient preparation prior to prostate mpMRI.

Neuroanatomic, epigenetic and genetic differences in monozygotic twins discordant for attention deficit hyperactivity disorder.

The study of monozygotic twins discordant for attention deficit hyperactivity disorder can elucidate mechanisms that contribute to the disorder, which affects ~7% of children. First, using in vivo neuroanatomic imaging on 14 pairs of monozygotic twins (mean age 9.7, s.d. 1.9 years), we found that discordance for the disorder is mirrored by differing dimensions of deep brain structures (the striatum and cerebellum), but not the cerebral cortex. Next, using whole-blood DNA from the same twins, we found a significant enrichment of epigenetic differences in genes expressed in these 'discordant' brain structures. Specifically, there is differential methylation of probes lying in the shore and shelf and enhancer regions of striatal and cerebellar genes. Notably, gene sets pertaining to the cerebral cortex (which did not differ in volume between affected and unaffected twins) were not enriched by differentially methylated probes. Genotypic differences between the twin pairs-such as copy number and rare, single-nucleotide variants-did not contribute to phenotypic discordance. Pathway analyses of the genes implicated by the most differentially methylated probes implicated γ-aminobutyric acid (GABA), dopamine and serotonin neurotransmitter systems. The study illustrates how neuroimaging can help guide the search for epigenomic mechanisms in neurodevelopmental disorders.

Survival of localized NSCLC patients without active treatment or treated with SBRT.

BACKGROUND: Little information on the natural history of patients with localized NSCLC is available since many of the studies covering the subject lack information on pathological confirmation, staging procedures and comorbidity. No randomized studies have compared SBRT with no treatment for patients with localized NSCLC. The purpose of this study was to evaluate whether SBRT has influence on overall survival for patients with localized NSCLC and investigate the effect of baseline ventilatory lung function on overall survival. MATERIAL AND METHODS: From 2007 to 2013, 136 patients treated with SBRT at Odense University Hospital were prospectively recorded. The thoracic SBRT consisted of three fractions of 15-22 Gy delivered in 9 days. For comparison, a national group of 73 untreated patients in the same time period was extracted from the Danish Lung Cancer Registry. All patients had histologically/cytologically proven NSCLC T1-2N0M0 with a tumour diameter ≤5 cm. RESULTS: The 5-year relative survival was 44% versus 7% for the SBRT and untreated groups, respectively. In a propensity score matched comparison the median overall survival was 47 months versus 11 months for the SBRT and untreated groups, respectively (p < .05). On multivariate analysis, SBRT was significantly associated with improved prognosis while ECOG performance status 2+ and tumour diameter ≥3 cm significantly predicted poorer prognosis. Severe to very severe reduction of forced expiratory volume in one second (FEV1) did not predict poorer survival for the SBRT treated patients with localized NSCLC. CONCLUSIONS: SBRT offers more favourable survival than no treatment for patients with localized NSCLC. Performance status of 0-1, tumour diameter less than 3 cm and SBRT predicted improved survival. SBRT should not be withheld for patients with localized NSCLC based on poor ventilatory lung function.

Cone dystrophy and ectopic synaptogenesis in a Cacna1f loss of function model of congenital stationary night blindness (CSNB2A).

Congenital stationary night blindness 2A (CSNB2A) is an X-linked retinal disorder, characterized by phenotypically variable signs and symptoms of impaired vision. CSNB2A is due to mutations in CACNA1F, which codes for the pore-forming α1F subunit of a L-type voltage-gated calcium channel, Cav1.4. Mouse models of CSNB2A, used for characterizing the effects of various Cacna1f mutations, have revealed greater severity of defects than in human CSNB2A. Specifically, Cacna1f-knockout mice show an apparent lack of visual function, gradual retinal degeneration, and disruption of photoreceptor synaptic terminals. Several reports have also noted cone-specific disruptions, including axonal abnormalities, dystrophy, and cell death. We have explored further the involvement of cones in our 'G305X' mouse model of CSNB2A, which has a premature truncation, loss-of-function mutation in Cacna1f. We show that the expression of genes for several phototransduction-related cone markers is down-regulated, while that of several cellular stress- and damage-related markers is up-regulated; and that cone photoreceptor structure and photopic visual function - measured by immunohistochemistry, optokinetic response and electroretinography - deteriorate progressively with age. We also find that dystrophic cone axons establish synapse-like contacts with rod bipolar cell dendrites, which they normally do not contact in wild-type retinas - ectopically, among rod cell bodies in the outer nuclear layer. These data support a role for Cav1.4 in cone synaptic development, cell viability, and synaptic transmission of cone-dependent visual signals. Although our novel finding of cone-to-rod-bipolar cell contacts in this mouse model of a retinal channelopathy may challenge current views of the role of Cav1.4 in photopic vision, it also suggests a potential new target for restorative therapy.