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Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.
Methods:
The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.
Results:
The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.
Conclusion:
Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
We undertook a quality improvement project to address challenges with pulmonary artery catheter (PAC) line maintenance in a setting of low-baseline central-line infection rates. We observed a subsequent reduction in Staphylococcal PAC line infections and a trend toward a reduction in overall PAC infection rates over 1 year.
Background: Axial myopathy is a rare neuromuscular disorder of variable etiology characterised by preferential involvement of the paraspinal muscles. We reviewed clinical features of patients with axial myopathies and the diagnostic yield of myositis-associated antibodies and targeted next generation sequencing panels. Methods: We performed a retrospective review of patients presenting with axial myopathy at the Montreal Neurological Hospital from 2011-2018. Data collection included clinical presentation, disease course, results of electromyography, imaging, laboratory and genetic testing, and histopathology on muscle biopsy. Results: Twenty-five patients were identified. Initial manifestation of axial weakness was head drop (15), camptocormia (8), and rigid spine (2). Autoimmune myositis was diagnosed in 9 patients, seropositive in 7 out of 7 tested for myositis-associated antibodies. Genetic testing was consistent with oculopharyngeal muscular dystrophy in one patient and RYR-1 (ryanodine receptor 1) related core myopathy in another. Local radiotherapy or spine surgery preceded the onset of axial weakness in 1 and 6 patients, respectively. Muscle biopsies were available in 17 patients and revealed myopathic changes (16), inflammatory changes (6), and myopathy with vacuoles (3). Conclusions: Recent advancements in genetic and antibody testing, combined with paraspinal muscle biopsy, allow for more precise classification and identification of potentially treatable axial myopathies.
The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled ‘Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies’. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation–health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation–health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.
As essay after essay in this series has reminded us, the term “neomedievalism” is too multivalent and maddeningly complex to define with any satisfaction: any attempt to create a definition invariably oversimplifies the concept or distorts it to fit current needs. In the case of neomedievalism, rather than attempt another iteration of an Ur-definition, Carol R. Robinson and Pamela Clements have done invaluable work in creating a field guide to understanding the characteristics of neomedievalism. In brief, we can call a text neomedieval when it does one or more of the following:
It is playful or ironic in nature.
It calls attention to its own construction, often as a work of bricolage.
It deliberately shatters any possibility for a “sealed world” of the text.
It refuses the nostalgic fantasy of being able to retrieve the medieval past.
Its task is to create a conscious vision of an alternative universe.
This last item holds the most promise as a way of reading George R. R. Martin's multi-volume A Song of Ice and Fire as a text concerned with particular ethical issues surrounding disability: the damage ableist discourses and narratives inflict on the disabled.
In the landmark case Arline vs. Nassau County, Justice William J. Brennan, Jr., summarizing the need for an inclusive definition of disability, noted the problems that narratives of disability posed for the disabled: “society's accumulated myths and fears about disability and disease are as handicapping as are the physical limitations that flow from actual impairment.”
To describe a relatively unknown clinical entity – inflammatory cast of the tympanic membrane after acute otitis media – and its simple out-patient treatment.
Study design:
Retrospective review of case series.
Setting:
Subspecialty practice at a tertiary hospital.
Patients:
Seven patients diagnosed previously with acute otitis media with perforation or otitis externa, and with persistent ear discomfort.
Methods:
Retrospective chart review.
Results:
The patients presented with weeks to months of persistent hearing loss after acute otitis media with perforation or acute otitis externa. Visits to their primary care physicians had been uninformative. After comparison of the affected and unaffected tympanic membranes, a thin, hard cast was identified and removed from the affected tympanic membrane. Improvement in hearing was documented in the three patients who underwent audiometric testing; the remainder had subjective improvement without audiometric evaluation.
Conclusion:
Otolaryngologists should be aware of the possibility of an inflammatory cast of the tympanic membrane following acute otitis media with perforation or otitis externa, and should carefully compare the unaffected and affected ears in such cases. Treatment – removal of the rigid cast – is both simple and effective.
Neutralization tests for poliovirus antibodies were carried out on 74 patients in an adult mental deficiency hospital: 37 patients with Down's syndrome and 37 non- Down's mental defectives. The distribution of antibody titres to poliovirus types 1, 2 and 3 did not differ significantly between the two groups. Most patients had antibody to at least one poliovirus typebut less than a third had antibodies at a titre of 1/8 or greater to all three types. The low level of poliovirus immunity in this population may be of epidemiological importance.
Determinations have been made, by neutron activation analysis, of the concentrations of tantalum in the tissues of some common crustaceans, molluscs, echinoderms and tunicates of coastal waters of southern England. The concentrations ranged from less than 0·01 ppm dry weight in the muscle of Mytilus edulis to 2 ppm dry weight in Neomysis integer. Two ascidian species showed concentrations of about 0·2 ppm dry weight in the whole organism. The measurements support the generalised concentration factors which have previously been assumed in assessing the radiobiological significance of discharges of radioactive tantalum to the marine environment.
The Arcetri/Bologna H2O maser group has been monitoring the 1.3-cm water maser emission from a sample of 43 star-forming regions (SFRs) and 22 late-type stars for about 20 years at a sampling rate of 4-5 observations each year, using the 32-m Medicina Radio Telescope (HPBW 1.′9 at 22 GHz). For the late-type stars we observe representative samples of OH/IR-stars, Mira's, semi-regular variables, and supergiants. The SFR-sample spans a large interval in FIR luminosity of the associated Young Stellar Object (YSO), from 20 L⊙ to 1.5 × 106 L⊙, and offers a unique data base for the study of the long-term (years) variability of the maser emission in regions of star formation.
This presentation concerns only the masers in SFRs. The information obtained from single-dish monitoring is complementary to what is extracted from higher-resolution (VLA and VLBI) observations, and can better explore the velocity domain and the long-term variability therein.
We characterize the variability of the sources in various ways and we study how it depends on the luminosity and other properties of the associated YSO and its environment.
Various physical processes are believed to trigger star formation on the borders of Galactic HII regions. Among these, the collect & collapse process is particularly attractive as it allows the formation of massive objects (single stars or clusters). In order to identify specific cases of this way of triggering star formation we are carrying out a multi-wavelength study of Galactic HII regions that exhibit signposts of massive-star formation at their borders. Hereby, we present two typical examples of such sources and discuss the results in the framework of the collect and collapse process, which seems to be at work as the major triggering agent in these two cases.
Psychiatric consultation and supportive psychotherapy provide many benefits for women with breast cancer including an opportunity to address existential, physical, emotional, social, psychosexual and relationship (family and others) concerns. The psychiatrist is a source of meaningful information and helps the patient challenge pessimistic thoughts and consider life, health, family and career priorities. The management of psychiatric symptoms and the treatment of side effects helps promote adherence to cancer treatment.
A detailed transmission electron microscopy study is performed on the
pyramidal inversion domains that appear in highly Mg-doped GaN grown by
metalorganics vapor phase epitaxy or by the high-pressure, high-temperature
method. From a comparison between high resolution images of the inversion
domain boundaries and simulations using different atomic models, we conclude
that both basal and inclined domain boundaries are likely formed of a
monomolecular layer of the definite compound Mg3N2. We show that,
due to their high concentration, the formation of these defects may account
for auto-compensation in Mg-doped GaN. We also show that the local band
bending induced by the polarity inversion due to these defects can be at the
origin of the blue luminescence of highly Mg-doped GaN, always observed when
nanometric pyramidal inversion domains are also present.
We present here the results of a search for new microquasars at low galactic latitudes, based on a cross-identification between the ROSAT all sky Bright Source Catalog (RBSC) and the NRAO VLA Sky Survey (NVSS) and follow-up observations. The results obtained up to now suggest that persistent/silent microquasars such as LS 5039 are rare objects in our Galaxy, and indicate that future deeper surveys, and harder than the RBSC in X-rays, will play a fundamental role in order to discover them.
Alkylresorcinols (AR) are amphiphilic 1,3-dihydroxy-5-alkyl phenolic lipids. AR in food are only found in the outer layers of wheat and rye grains, and in whole grains are present at concentrations of 500–1000 μg/g. In wheat and rye, there are five main homologues, differing in the length of the odd-numbered alkyl chain (from seventeen to twenty-five C atoms long). Because AR may be bioactive, and might serve as biomarkers for these cereals, their absorption was investigated in model experiments with pigs and rats. Pigs with a cannula in the terminal ileum were fed four diets containing rye fractions with different levels of AR and the ileal effluents were analysed. The ileal recovery of AR was found to vary between 21 and 40 %, with no major difference between different chain-length homologues. The absorption of AR by rats was investigated by feeding 14C-labelled heneicosylresorcinol (C21:0). Of the total activity, about 34% was recovered in the urine, showing that the labelled AR was absorbed and metabolised by rats. AR were mostly cleared from rats by 60h. It is concluded that AR are absorbed in the small intestine of single-stomached animals and excreted in metabolised form in the urine, and might contribute to the nutritional qualities of wholegrain wheat and rye diets.
The high power RF device performance decreases as operation
temperature increases (e.g. fall of electron mobility impacting the cut-off frequencies
and degradation of device reliability). Therefore the determination of device
temperature is a key issue for device topology optimisation. This work presents the
comparison between pulsed I-V at different temperature and DC measurements of
AlGaN/GaN HEMTs grown on two different substrates: sapphire and silicon. This
technique allows the determination of mean channel temperature and the device
thermal resistance. The thermal resistance is a classical way to define the average
channel temperature as a function of the dissipated power. In this work the thermal
resistance ratio of the HEMT grown on sapphire compared to the one grown on silicon
is found to be 1.7 instead of 3 as expected from straightforward thermal conductivity
ratio. This lower difference is clearly attributed to the contribution of the GaN buffer
layer.
In a recent paper [Phys. Rev. B 68, 153313 (2003)], we reported the first experimental observation of the strong coupling regime in a GaN-based microcavity. The λ/2 GaN optical cavity was grown by molecular beam epitaxy on a Si(111) substrate. The upper mirror is a SiO2/Si3N4 dielectric mirror and the silicon substrate acts as the bottom mirror. With such a relatively simple and low-finesse microcavity, a Rabi splitting of 31 meV was measured at 5K. On the basis of this very encouraging result, approaches to fabricate high-finesse GaN-based cavities exhibiting strong coupling with stable polaritons at room temperature are discussed.
In this paper we review studies aiming at elucidation of the mechanisms responsible for anomalously low pressure coefficients of the light emission energy, dEE/dP, observed in quantum structures of InGaN/GaN and GaN/AlGaN. We have established that in hexagonal InGaN/GaN and GaN/AlGaN structures the main mechanism involved is related to the pressure induced increase of the piezoelectric field which determines also the strong red shift of the emission energy with thickness of the quantum well. To reproduce the experimental findings in InGaN/GaN case, it is necessary to take into account the dependence of the piezoelectric constants on the volume-conserving strain. Whereas the experimental results on a decrease of dEE/dP in GaN/AlGaNstructures can be fully accounted for within the linear elasticity theory. In contrast to these findings, dEE/dP magnitude measured in cubic InGaN/GaN quantum structures shows value close to changes of the InGaN bangap with pressure obtained from first principle calculations. The latter result is consistent with the absence of the built-in electric fields in the cubic nitride structures.
We present the results of the high magnetic field studies of properties of two-dimensional electron gas (2DEG) in AlGaN/GaN heterostructures grown over high-pressure bulk GaN, sapphire, and insulating SiC substrates. The experimental results include the low field Hall measurements, cyclotron resonance measurements, and cryogenic temperature Quantum Hall Effect studies as well as room-temperature characteristics of High Electron Mobility Transistors fabricated on all these substrates. The room temperature high field measurements allow us to clearly separate the contributions of a parasitic parallel conduction from 2DEG conduction in all investigated heterostructures.
The magnetotransport measurements are performed in the magnetic fields up to 30 Tesla for temperatures between 50mK-300K. This high magnetic field in combination with very high mobilities (over 60.000 cm2/Vs) in the sample on the bulk GaN substrates allow us to observe features related both to cyclotron resonance and spin splitting. The temperature dependence of this splitting determines the spin and cyclotron resonance energy gaps and, in combination with cyclotron resonance and tilted field experiments, allows us to determine the complete energy structure of 2DEG conduction band. We also present the first experimental results showing so called “the exchange enhancement” of the energy gaps between spin Landau levels.
We present the results of the experimental and theoretical studies of the low field mobility of two-dimensional electrons in the homoepitaxial AlGaN/GaN heterostructures and in the AlGaN/GaN heterostructures grown on SiC. We show that, at cryogenic temperatures, the temperature dependence of the mobility is primarily determined by the deformation potential scattering and that most of other important scattering mechanisms are temperature independent. We show also that two-dimensional (2D) and three-dimensional (3D) mobility models yield very close results. The analysis of the mobility dependence on the electron sheet density ns shows two possible explanations of the non monotonic mobility versus carrier density dependence: i) the alloy/interface scattering and ii) transfer of the 2D electrons into 3D states in GaN. We present experimental data suggesting that for high 2D gas densities in the investigated structure grown on SiC the 2D-3D transition should take place and might be responsible for the mobility decrease at high electron sheet densities.