Loss of bone morphogenetic protein signaling in fibroblasts results in CXCL12-driven serrated polyp development

Journal of Gastroenterology - Mutations in Bone Morphogenetic Protein (BMP) Receptor (BMPR)1A and SMAD4 are detected in 50% of juvenile polyposis syndrome (JPS) patients, who...     

Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology

Tau pathology is encountered in many neurodegenerative disorders known as tauopathies, including Alzheimer's disease. Physical activity is a lifestyle factor affecting processes crucial for memory and synaptic plasticity. Whether long-term voluntary exercise has an impact on Tau pathology and its pathophysiological consequences is currently unknown. To address this question, we investigated the effects of long-term voluntary exercise in the THY-Tau22 transgenic model of Alzheimer's disease-like Tau pathology, characterized by the progressive development of Tau pathology, cholinergic alterations and subsequent memory impairments. Three-month-old THY-Tau22 mice and wild-type littermates were assigned to standard housing or housing supplemented with a running wheel. After 9 months of exercise, mice were evaluated for memory performance and examined for hippocampal Tau pathology, cholinergic defects, inflammation and genes related to cholesterol metabolism. Exercise prevented memory alterations in THY-Tau22 mice. This was accompanied by a decrease in hippocampal Tau pathology and a prevention of the loss of expression of choline acetyltransferase within the medial septum. Whereas the expression of most cholesterol-related genes remained unchanged in the hippocampus of running THY-Tau22 mice, we observed a significant upregulation in mRNA levels of NPC1 and NPC2, genes involved in cholesterol trafficking from the lysosomes. Our data support the view that long-term voluntary physical exercise is an effective strategy capable of mitigating Tau pathology and its pathophysiological consequences.     

Bilateral leg symptoms – The T10 syndrome?

Prior studies have investigated the role of the sympathetic nervous system and the thoracic spine related to the upper extremities (known as the T4 syndrome). However, there is only little known about the role of the thoracic spine related to the lower extremities. In this case report, a patient with a heavy, tired feeling in both legs and hypomobile thoracic segments was treated with passive mobilisations of the thoracic spine.     

Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial

OBJECTIVE: To investigate the effect of melatonin treatment on health status and sleep in children with idiopathic sleep-onset insomnia. METHOD: A randomized, double-blind, placebo-controlled trial was conducted in a Dutch sleep center, involving 62 children, 6 to 12 years of age, who suffered more than 1 year from idiopathic chronic sleep-onset insomnia. Patients received either 5 mg melatonin or placebo at 7 pm. The study consisted of a 1-week baseline period, followed by a 4-week treatment. Health status was measured with the RAND General Health Rating Index (RAND-GHRI) and Functional Status II (FS-II) questionnaires. Lights-off time, sleep onset, and wake-up time were recorded in a diary, and endogenous dim light melatonin onset was measured in saliva. RESULTS: The total scores of the RAND-GHRI and FS-II improved significantly more during melatonin treatment compared to placebo. The magnitude of change was much higher in the melatonin group than in the placebo group, with standardized response means for the RAND-GHRI of 0.69 versus 0.07 and for the FS-II of 1.61 versus 0.64. Melatonin treatment also significantly advanced sleep onset by 57 minutes, sleep offset by 9 minutes, and melatonin onset by 82 minutes, and decreased sleep latency by 17 minutes. Lights-off time and total sleep time did not change. CONCLUSIONS: Melatonin improves health status and advances the sleep-wake rhythm in children with idiopathic chronic sleep-onset insomnia.     

Characterisation of solitary pulmonary lesions combining visual perfusion and quantitative diffusion MR imaging

Objective

To evaluate the diagnostic accuracy of dynamic contrast-enhanced (DCE) magnetic resonance (MR) and diffusion-weighted imaging (DWI) sequences for defining benignity or malignancy of solitary pulmonary lesions (SPL).

Methods

First, 54 consecutive patients with SPL, clinically staged (CT and PET or integrated PET-CT) as N0M0, were included in this prospective study. An additional 3-Tesla MR examination including DCE and DWI was performed 1 day before the surgical procedure. Histopathology of the surgical specimen served as the standard of reference. Subsequently, this functional method of SPL characterisation was validated with a second cohort of 54 patients.

Results

In the feasibility group, 11 benign and 43 malignant SPL were included. Using the combination of conventional MR sequences with visual interpretation of DCE-MR curves resulted in a sensitivity, specificity and accuracy of 100 %, 55 % and 91 %, respectively. These results can be improved by DWI (with a cut-off value of 1.52?×?10^?3 mm²/s for ADC_high) leading to a sensitivity, specificity and accuracy of 98 %, 82 % and 94 %, respectively. In the validation group these results were confirmed.

Conclusion

Visual DCE-MR-based curve interpretation can be used for initial differentiation of benign from malignant SPL, while additional quantitative DWI-based interpretation can further improve the specificity.

Key Points

? Magnetic resonance imaging is increasingly being used to help differentiate lung lesions. ? Solitary pulmonary lesions (SPL) are accurately characterised by combining DCE-MRI and DWI. ? Visual DCE-MRI assessment facilitates the diagnostic throughput in patients with SPL. ? DWI provides additional information in inconclusive DCE-MRI (type B pattern).     

Functional anatomy of the gibbon forelimb: adaptations to a brachiating lifestyle

It has been shown that gibbons are able to brachiate with very low mechanical costs. The conversion of muscle activity into smooth, purposeful movement of the limb depends on the morphometry of muscles and their mechanical action on the skeleton. Despite the gibbon's reputation for excellence in brachiation, little information is available regarding either its gross musculoskeletal anatomy or its more detailed muscle–tendon architecture. We provide quantitative anatomical data on the muscle–tendon architecture (muscle mass, physiological cross-sectional area, fascicle length and tendon length) of the forelimb of four gibbon species, collected by detailed dissections of unfixed cadavers. Data are compared between different gibbon species and with similar published data of non-brachiating primates such as macaques, chimpanzees and humans. No quantitative differences are found between the studied gibbon species. Both their forelimb anatomy and muscle dimensions are comparable when normalized to the same body mass. Gibbons have shoulder flexors, extensors, rotator muscles and elbow flexors with a high power or work-generating capacity and their wrist flexors have a high force-generating capacity. Compared with other primates, the elbow flexors of gibbons are particularly powerful, suggesting that these muscles are particularly important for a brachiating lifestyle. Based on this anatomical study, the shoulder flexors, extensors, rotator muscles, elbow flexors and wrist flexors are expected to contribute the most to brachiation.     

Object form discontinuity facilitates displacement discrimination across saccades

Stimulus displacements coinciding with a saccadic eye movement are poorly detected by human observers. In recent years, converging evidence has shown that this phenomenon does not result from poor transsaccadic retention of presaccadic stimulus position information, but from the visual system's efforts to spatially align presaccadic and postsaccadic perception on the basis of visual landmarks. It is known that this process can be disrupted, and transsaccadic displacement detection performance can be improved, by briefly blanking the stimulus display during and immediately after the saccade. In the present study, we investigated whether this improvement could also follow from a discontinuity in the task-irrelevant form of the displaced stimulus. We observed this to be the case: Subjects more accurately identified the direction of intrasaccadic displacements when the displaced stimulus simultaneously changed form, compared to conditions without a form change. However, larger improvements were still observed under blanking conditions. In a second experiment, we show that facilitation induced by form changes and blanks can combine. We conclude that a strong assumption of visual stability underlies the suppression of transsaccadic change detection performance, the rejection of which generalizes from stimulus form to stimulus position.     

Radiobiologic parameters and local effect model predictions for head-and-neck squamous cell carcinomas exposed to high linear energy transfer ions

PURPOSE: To establish the radiobiologic parameters of head-and-neck squamous cell carcinomas (HNSCC) in response to ion irradiation with various linear energy transfer (LET) values and to evaluate the relevance of the local effect model (LEM) in HNSCC. METHODS AND MATERIALS: Cell survival curves were established in radiosensitive SCC61 and radioresistant SQ20B cell lines irradiated with [33.6 and 184 keV/n] carbon, [302 keV/n] argon, and X-rays. The results of ion experiments were confronted to LEM predictions. RESULTS: The relative biologic efficiency ranged from 1.5 to 4.2 for SCC61 and 2.1 to 2.8 for SQ20B cells. Fixing an arbitrary D(0) parameter, which characterized survival to X-ray at high doses (>10 Gy), gave unsatisfying LEM predictions for both cell lines. For D(0) = 10 Gy, the error on survival fraction at 2 Gy amounted to a factor of 10 for [184 keV/n] carbon in SCC61 cells. We showed that the slope (s(max)) of the survival curve at high doses was much more reliable than D(0). Fitting s(max) to 2.5 Gy(-1) gave better predictions for both cell lines. Nevertheless, LEM could not predict the responses to fast and slow ions with the same accuracy. CONCLUSIONS: The LEM could predict the main trends of these experimental data with correct orders of magnitude while s(max) was optimized. Thus the efficiency of carbon ions cannot be simply extracted from the clinical response of a patient to X-rays. LEM should help to optimize planning for hadrontherapy if a set of experimental data is available for high-LET radiations in various types of tumors.     

Subject-specific muscle properties from diffusion tensor imaging significantly improve the accuracy of musculoskeletal models

Musculoskeletal modelling is an important platform on which to study the biomechanics of morphological structures in vertebrates and is widely used in clinical, zoological and palaeontological fields. The popularity of this approach stems from the potential to non-invasively quantify biologically important but difficult-to-measure functional parameters. However, while it is known that model predictions are highly sensitive to input values, it is standard practice to build models by combining musculoskeletal data from different sources resulting in ‘generic’ models for a given species. At present, there are little quantitative data on how merging disparate anatomical data in models impacts the accuracy of these functional predictions. This issue is addressed herein by quantifying the accuracy of both subject-specific human limb models containing individualised muscle force-generating properties and models built using generic properties from both elderly and young individuals, relative to experimental muscle torques obtained from an isokinetic dynamometer. The results show that subject-specific models predict isokinetic muscle torques to a greater degree of accuracy than generic models at the ankle (root-mean-squared error – 7.9% vs. 49.3% in elderly anatomy-based models), knee (13.2% vs. 57.3%) and hip (21.9% vs. 32.8%). These results have important implications for the choice of musculoskeletal properties in future modelling studies, and the relatively high level of accuracy achieved in the subject-specific models suggests that such models can potentially address questions about inter-subject variations of muscle functions. However, despite relatively high levels of overall accuracy, models built using averaged generic muscle architecture data from young, healthy individuals may lack the resolution and accuracy required to study such differences between individuals, at least in certain circumstances. The results do not wholly discourage the continued use of averaged generic data in musculoskeletal modelling studies but do emphasise the need for to maximise the accuracy of input values if studying intra-species form–function relationships in the musculoskeletal system.     

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.