To investigate age-related default mode network (DMN) connectivity in a large cognitively normal elderly cohort and in patients with Alzheimer disease (AD) compared with age-, gender-, and ...education-matched controls.
We analyzed task-free-fMRI data with both independent component analysis and seed-based analysis to identify anterior and posterior DMNs. We investigated age-related changes in connectivity in a sample of 341 cognitively normal subjects. We then compared 28 patients with AD with 56 cognitively normal noncarriers of the APOE ε4 allele matched for age, education, and gender.
The anterior DMN shows age-associated increases and decreases in fontal lobe connectivity, whereas the posterior DMN shows mainly age-associated declines in connectivity throughout. Relative to matched cognitively normal controls, subjects with AD display an accelerated pattern of the age-associated changes described above, except that the declines in frontal lobe connectivity did not reach statistical significance. These changes survive atrophy correction and are correlated with cognitive performance.
The results of this study indicate that the DMN abnormalities observed in patients with AD represent an accelerated aging pattern of connectivity compared with matched controls.
The LHCb simulation application, Gauss, is based on the Gaudi framework and on experiment basic components such as the Event Model and Detector Description. Gauss also depends on external libraries ...for the generation of the primary events (PYTHIA 6, EvtGen, etc.) and on GEANT4 for particle transport in the experimental setup. The application supports the production of different types of events from minimum bias to B physics signals and particle guns. It is used for purely generator-level studies as well as full simulations. Gauss is used both directly by users and in massive central productions on the grid. The design and implementation of the application and its evolution due to evolving requirements will be described as in the case of the recently adopted Python-based configuration or the possibility of taking into account detectors conditions via a Simulation Conditions database. The challenge of supporting at the same time the flexibililty needed for the different tasks for which it is used, from evaluation of physics reach to background modeling, together with the stability and reliabilty of the code will also be described.
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic ...drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
•NTRK gene fusions are oncogenic drivers in a variety of tumor types including adult and pediatric sarcomas.•TRK inhibitors provide effective treatment options for patients with sarcomas harboring NTRK gene fusions.•Integrating NTRK testing into the management of patients with sarcoma is challenging due to the rarity of this biomarker.•Massive parallel RNA sequencing provides the optimal NTRK fusion test and immunohistochemistry is a valuable screening tool.•We propose a diagnostic strategy that considers histologic and molecular subtypes to facilitate routine NTRK fusion testing.
To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine.
Randomized, double-blind, ...parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses.
Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose.
The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.
Mortality in Cushing's disease is double that of the general population, but for patients in remission mortality to date is not increased.
Context:
Pituitary ACTH-dependent Cushing's disease (CD) is ...uncommon, and there are very limited data on long-term mortality.
Objective:
The aim was to summarize what is known about mortality in ACTH-dependent CD, to report on our own data, and to provide a meta-analysis of six other reports that addressed mortality of CD.
Design and Methods:
Vital status of 60 CD patients was recorded as of December 31, 2009, and the standardized mortality ratio (SMR) was calculated and compared with the general population of England and Wales, United Kingdom. A meta-analysis of SMRs from seven studies (including ours) was performed for overall mortality in CD. Where reported (four studies), a similar meta-analysis was performed for those patients whose hypercortisolism was in remission after treatment compared to those patients from the same center with persistent disease.
Results:
1. From Stoke-on-Trent, 51 of 60 patients were female, median age at diagnosis was in the range of 36–46 yr, and median follow-up was 15 yr. There were 13 deaths, nine due to cardiovascular disease. Overall SMR for the whole cohort was 4.8 (95% confidence interval, 2.8–8.3) (P < 0001). SMR for vascular disease was 13.8 (7.2–36.5) (P < 0001). For persistent disease (n = 6), SMR was 16 (6.7–38.4) vs. remission (n = 54) SMR of 3.3 (1.7–6.7); after adjustment for age and sex, relative risk of death for persistent disease was 10.7 (2.3–48.6) (P = 0.002). Hypertension and diabetes mellitus were associated with significantly worse survival. 2. Using a random effects model meta-analysis revealed an overall (remission plus persistent disease) SMR of 2.2 (1.45–3.41) (P < 0.001). Pooled SMR was 1.2 (0.45–3.2) (P = not significant) for patients in remission and 5.5 (2.7–11.3) (P = 0.001) for patients with persistent disease. Persistence of disease, older age at diagnosis, and presence of hypertension and diabetes are the main determinants of mortality.
Conclusions:
Overall mortality in CD is double that of the general population. However, patients with CD in remission fare much better than those with persistence of hypercortisolism, and they appear not to have an increased mortality rate. Hypertension and diabetes mellitus are risk factors for worse outcome. Because diagnosis and treatment of patients are at a young age, much longer follow-up of patients in remission is required before one can be confident that their mortality outcome is no different from that of the general population, especially because cardiovascular risk factors may persist after successful biochemical control of the disease.
Abstract Although much progress has been made in determining the cognitive profile of strengths and weaknesses that characterise individuals with autism spectrum disorders (ASDs), there remain a ...number of outstanding questions. These include how universal strengths and deficits are; whether cognitive subgroups exist; and how cognition is associated with core autistic behaviours, as well as associated psychopathology. Several methodological factors have contributed to these limitations in our knowledge, including: small sample sizes, a focus on single domains of cognition, and an absence of comprehensive behavioural phenotypic information. To attempt to overcome some of these limitations, we assessed a wide range of cognitive domains in a large sample ( N = 100) of 14- to 16-year-old adolescents with ASDs who had been rigorously behaviourally characterised. In this review, we will use examples of some initial findings in the domains of perceptual processing, emotion processing and memory, both to outline different approaches we have taken to data analysis and to highlight the considerable challenges to better defining the cognitive phenotype(s) of ASDs. Enhanced knowledge of the cognitive phenotype may contribute to our understanding of the complex links between genes, brain and behaviour, as well as inform approaches to remediation.
The remit of this review is to provide the non-specialist reader of Avian Pathology with an overview of research carried out on infectious bronchitis over the 40 years since the journal was first ...published. In order to do this, we felt it necessary to summarize the knowledge acquired previously, since the since the disease was first identified in the 1930s. Infectious bronchitis virus is a significant pathogen in the domestic chicken, affecting the respiratory and renal systems as well as the female reproductive tract. The virus exists in the form of many, ever changing, serotypic or genotypic variants, some of which have global distribution whilst others are found only in more local areas. This review mentions the major discoveries concerning both the virus itself and the types of disease it causes and considers recent changes in its pathogenesis. It also discusses the impact of developments in the field of molecular biology and highlights possible areas for future work.
Patients with Parkinson’s disease experience motor and perceptual timing difficulties, which are ameliorated by dopaminergic medication. We investigated the neural correlates of motor timing in ...Parkinson’s disease, including the effects of dopaminergic medication on patterns of brain activation. Eight patients with Parkinson’s disease and eight healthy controls were scanned with H152 positron emission tomography while engaged in three tasks: synchronization (right index finger tapping in synchrony with a tone presented at 1 Hz), continuation (tapping at 1 Hz in the absence of a tone), and a control simple reaction time task. During the first 6 scans, the patients were assessed after overnight withdrawal of medication. Scans 7–12 were completed with the patients in the ‘ON’ state, after injections of apomorphine, a dopamine receptor agonist. For the healthy controls, relative to the control reaction time task, motor timing (synchronization + continuation) was associated with significantly greater activation in left medial prefrontal cortex (Brodmann area 10, 32), right hippocampus, bilateral angular gyrus (Brodmann area 39), left posterior cingulate (Brodmann area 31) and left nucleus accumbens/caudate. This pattern of brain activation during motor timing was not observed for patients, who showed significantly greater activation in bilateral cerebellum, right thalamus and left midbrain/substantia nigra compared to the control participants. Relative to the externally-paced synchronization task, the internally controlled continuation task was associated with greater activation in the dorsolateral prefrontal cortex (Brodmann area 46/9) in both the control and Parkinson’s disease groups. Analysis of medication-related effects indicated that cortical activation was significantly more predominant during motor timing when the patients were ‘ON’ medication, whereas pallidal and cerebellar activations were evident ‘OFF’ medication. Effective connectivity analysis established that activity in the left caudate nucleus was associated with increased activity in the right lentiform nucleus and cerebellum ‘OFF’ medication, and with increased activity in the prefrontal cortex ‘ON’ medication. These results suggest that in Parkinson’s disease, in the ‘OFF’ medication state, excessive inhibitory pallidal outflow is associated with a lack of adequate frontal activation and reliance on the cerebellum for motor timing. In contrast, our results establish for the first time that administration of dopaminergic medication increases striatal-frontal connectivity between the caudate nucleus and prefrontal cortex during motor timing.
We find that clusters of β4 integrin, organized into distinct puncta, localize along vimentin filaments within lamellipodia at the cell edge of A549 cells, as assessed by interferometric ...photoactivated localization microscopy. Moreover, puncta and vimentin filaments exhibit a dynamic interplay in live cells, as viewed by structured-illumination microscopy, with β4 integrin puncta that associate with vimentin persisting for longer than those that do not. Interestingly, in A549 cells β4 integrin regulates vimentin cytoskeleton organization. When β4 integrin is knocked down there is a loss of vimentin filaments from lamellipodia. However, in these conditions, vimentin filaments instead concentrate around the nucleus. Although β4 integrin organization is unaffected in vimentin-deficient A549 cells, such cells move in a less-directed fashion and exhibit reduced Rac1 activity, mimicking the phenotype of β4 integrin-deficient A549 cells. Moreover, in vimentin-deficient cells, Rac1 fails to cluster at sites enriched in α6β4 integrin heterodimers. The aberrant motility of both β4 integrin and vimentin-deficient cells is rescued by expression of active Rac1, leading us to propose that complexes of β4 integrin and vimentin act as signaling hubs, regulating cell motility behavior.
By comparison of the methane mixing ratio and the carbon isotope ratio (δ13CCH4) in Arctic air with regional background, the incremental input of CH4 in an air parcel and the source δ13CCH4 signature ...can be determined. Using this technique the bulk Arctic CH4 source signature of air arriving at Spitsbergen in late summer 2008 and 2009 was found to be −68‰, indicative of the dominance of a biogenic CH4 source. This is close to the source signature of CH4 emissions from boreal wetlands. In spring, when wetland was frozen, the CH4 source signature was more enriched in 13C at −53 ± 6‰ with air mass back trajectories indicating a large influence from gas field emissions in the Ob River region. Emissions of CH4 to the water column from the seabed on the Spitsbergen continental slope are occurring but none has yet been detected reaching the atmosphere. The measurements illustrate the significance of wetland emissions. Potentially, these may respond quickly and powerfully to meteorological variations and to sustained climate warming.
Key Points
Isotopic measurements have been used to identify major sources of Arctic methane
In late summer biogenic methane sources dominate the bulk Arctic source mix
Seabed emissions near Spitsbergen have not been detected reaching the atmosphere
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