Diagnostic criteria for Susac syndrome Kleffner, Ilka; Dörr, Jan; Ringelstein, Marius ...
Journal of neurology, neurosurgery and psychiatry,
12/2016, Letnik:
87, Številka:
12
Journal Article
Recenzirano
Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often ...delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome.
The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012.
Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup.
We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.
Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches ...carry the risk of Fcγ receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-Aβ monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fcγ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of Aβ, protected against Aβ1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic Aβ oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP((V717I))/PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to Aβ, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNFα. We propose that a humanized IgG4 anti-Aβ antibody that takes advantage of a unique Aβ binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers.
We describe the rehabilitation management during a 12-month period of a 14-year-old female with Friedreich ataxia. Interventions included task-oriented bimanual reaching activities, functional ...strengthening, and gait training using a walker featuring tension-controlled wheels and a reverse-braking system. Her physical status was assessed with the Nine-Hole Peg Test, single limb stance time, manual muscle testing, self-reported falls, isometric force control testing, and 3-dimensional gait analysis in a motion-capture laboratory. Although measures of the patient’s Nine-Hole Peg Test, single limb stance time, and manual muscle testing reflected minimal changes, her gait speed decreased by 69.4%. However, the force-control targeting of her dominant knee extensors showed a 43.7% increase in force variability that was concomitant with her decline in gait performance. The decrement of her initial gait speed was reduced to 42.9% on replacing the wheeled walker with the U-Step Walking Stabilizer at the end of the intervention period. Although the patient’s gait remained significantly impaired, extended use of the U-Step Walking Stabilizer modestly improved her gait performance, and her rate of falls decreased from 10 to 3 per month. Our observations suggest that use of force-control testing as proxy measures of ataxia and tension-controlled gait aids show promise in the management of Friedreich ataxia and merit further investigation.
Bilayers of 2D materials offer opportunities for creating devices with tunable electronic, optical, and mechanical properties. In van der Waals heterostructures (vdWHs) where the constituent ...monolayers have different lattice constants, a moiré superlattice forms with a length scale larger than the lattice constant of either constituent material regardless of twist angle. Here, we report the appearance of moiré Raman modes from nearly aligned WSe2–WS2 vdWHs in the range of 240–260 cm–1, which are absent in both monolayers and homobilayers of WSe2 and WS2 and in largely misaligned WSe2–WS2 vdWHs. Using first-principles calculations and geometric arguments, we show that these moiré Raman modes are a consequence of the large moiré length scale, which results in zone-folded phonon modes that are Raman active. These modes are sensitive to changes in twist angle, but notably, they occur at identical frequencies for a given small twist angle away from either the 0-degree or 60-degree aligned heterostructure. Our measurements also show a strong Raman intensity modulation in the frequency range of interest, with near 0 and near 60-degree vdWHs exhibiting a markedly different dependence on excitation energy. In near 0-degree aligned WSe2–WS2 vdWHs, a nearly complete suppression of both the moiré Raman modes and the WSe2 A1g Raman mode (∼250 cm–1) is observed when exciting with a 532 nm CW laser at room temperature. Temperature-dependent reflectance contrast measurements demonstrate the significant Raman intensity modulation arises from resonant Raman effects.
Results are presented from the multi‐institution partnership to develop a real‐time and retrospective North American Land Data Assimilation System (NLDAS). NLDAS consists of (1) four land models ...executing in parallel in uncoupled mode, (2) common hourly surface forcing, and (3) common streamflow routing: all using a 1/8° grid over the continental United States. The initiative is largely sponsored by the Global Energy and Water Cycle Experiment (GEWEX) Continental‐Scale International Project (GCIP). As the overview for nine NLDAS papers, this paper describes and evaluates the 3‐year NLDAS execution of 1 October 1996 to 30 September 1999, a period rich in observations for validation. The validation emphasizes (1) the land states, fluxes, and input forcing of four land models, (2) the application of new GCIP‐sponsored products, and (3) a multiscale approach. The validation includes (1) mesoscale observing networks of land surface forcing, fluxes, and states, (2) regional snowpack measurements, (3) daily streamflow measurements, and (4) satellite‐based retrievals of snow cover, land surface skin temperature (LST), and surface insolation. The results show substantial intermodel differences in surface evaporation and runoff (especially over nonsparse vegetation), soil moisture storage, snowpack, and LST. Owing to surprisingly large intermodel differences in aerodynamic conductance, intermodel differences in midday summer LST were unlike those expected from the intermodel differences in Bowen ratio. Last, anticipating future assimilation of LST, an NLDAS effort unique to this overview paper assesses geostationary‐satellite‐derived LST, determines the latter to be of good quality, and applies the latter to validate modeled LST.
Observations and models agree that the Greenland Ice Sheet (GrIS)
surface mass balance (SMB) has decreased since the end of the 1990s due to
an increase in meltwater runoff and that this trend will ...accelerate in the
future. However, large uncertainties remain, partly due to different
approaches for modelling the GrIS SMB, which have to weigh physical
complexity or low computing time, different spatial and temporal
resolutions, different forcing fields, and different ice sheet
topographies and extents, which collectively make an inter-comparison
difficult. Our GrIS SMB model intercomparison project (GrSMBMIP) aims to
refine these uncertainties by intercomparing 13 models of four types which
were forced with the same ERA-Interim reanalysis forcing fields, except for
two global models. We interpolate all modelled SMB fields onto a common ice
sheet mask at 1 km horizontal resolution for the period 1980–2012 and score
the outputs against (1) SMB estimates from a combination of gravimetric
remote sensing data from GRACE and measured ice discharge; (2) ice cores,
snow pits and in situ SMB observations; and (3) remotely sensed bare ice extent
from MODerate-resolution Imaging Spectroradiometer (MODIS). Spatially, the
largest spread among models can be found around the margins of the ice
sheet, highlighting model deficiencies in an accurate representation of the
GrIS ablation zone extent and processes related to surface melt and runoff.
Overall, polar regional climate models (RCMs) perform the best compared to
observations, in particular for simulating precipitation patterns. However,
other simpler and faster models have biases of the same order as RCMs
compared with observations and therefore remain useful tools for long-term
simulations or coupling with ice sheet models. Finally, it is interesting to
note that the ensemble mean of the 13 models produces the best estimate of
the present-day SMB relative to observations, suggesting that biases are not
systematic among models and that this ensemble estimate can be used as a
reference for current climate when carrying out future model developments.
However, a higher density of in situ SMB observations is required,
especially in the south-east accumulation zone, where the model spread can
reach 2 m w.e. yr−1 due to large discrepancies in modelled snowfall accumulation.
Performance-based financing (PBF) is currently tested in many low- and middle-income countries as a health system strengthening strategy. One of the main mechanisms through which PBF is assumed to ...effect change is by motivating health workers to improve their service delivery performance. This article aims at a better understanding of such motivational effects of PBF. In particular, the study focused on organizational context factors and health workers' perceptions thereof as moderators of the motivational effects of PBF, which to date has been little explored.
We conducted a multiple case study in 2 district hospitals and 16 primary health facilities across three districts. Health facilities were purposely sampled according to pre-PBF performance levels. Within sampled facilities, 82 clinical skilled healthcare workers were in-depth interviewed one year after the start of the PBF intervention. Data were analyzed using a blended deductive and inductive process, using self-determination theory (SDT) as an analytical framework.
Results show that the extent to which PBF contributed to positive, sustainable forms of motivation depended on the "ground upon which PBF fell," beyond health workers' individual personalities and disposition. In particular, health workers described three aspects of the organizational context in which PBF was implemented: the extent to which existing hierarchies fostered as opposed to hindered participation and transparency; managers' handling of the increased performance feedback inherent in PBF; and facility's pre-PBF levels in regards to infrastructure, equipment, and human resources.
Our results underline the importance of leadership styles and pre-implementation performance levels in shaping health workers' motivational reactions to PBF. Ancillary interventions aimed at fostering participatory as opposed to directional leadership or start-up support to low-performing health facilities will likely boost PBF effects in regards to the development of valuable motivational capacities.
Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface ...wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class.
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