103 research outputs found
In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection
An overt pro-inflammatory immune response is a key factor contributing to lethal pneumococcal infection in an influenza pre-infected host and represents a potential target for therapeutic intervention. However, there is a paucity of knowledge about the level of contribution of individual cytokines. Based on the predictions of our previous mathematical modeling approach, the potential benefit of IFN-Îł- and/or IL-6-specific antibody-mediated cytokine neutralization was explored in C57BL/6 mice infected with the influenza A/PR/8/34 strain, which were subsequently infected with the Streptococcus pneumoniae strain TIGR4 on day 7 post influenza. While single IL-6 neutralization had no effect on respiratory bacterial clearance, single IFN-Îł neutralization enhanced local bacterial clearance in the lungs. Concomitant neutralization of IFN-Îł and IL-6 significantly reduced the degree of pneumonia as well as bacteremia compared to the control group, indicating a positive effect for the host during secondary bacterial infection. The results of our model-driven experimental study reveal that the predicted therapeutic value of IFN-Îł and IL-6 neutralization in secondary pneumococcal infection following influenza infection is tightly dependent on the experimental protocol while at the same time paving the way toward the development of effective immune therapies
Modulation of Allergic Sensitization and Allergic Inflammation by Staphylococcus aureus Enterotoxin B in an Ovalbumin Mouse Model
The superantigen Staphylococcus aureus (S. aureus) enterotoxin B (SEB) has been proposed a central player in the associations between S. aureus nasal colonization and the development of allergic asthma. Previously, SEB has been shown to aggravate allergic sensitization and allergic airway inflammation (AAI) in experimental mouse models. Aiming at understanding the underlying immunological mechanisms, we tested the hypothesis that intranasal (i.n.) SEB-treatment divergently modulates AAI depending on the timing and intensity of the SEB-encounter. In an ovalbumin-mediated mouse model of AAI, we treated mice i.n. with 50 ng or 500 ng SEB either together with the allergic challenge or prior to the peripheral sensitization. We observed SEB to affect different hallmark parameters of AAI depending on the timing and the dose of treatment. SEB administered i.n. together with the allergic challenge significantly modulated respiratory leukocyte accumulation, intensified lymphocyte activation and, at the higher dose, induced a strong type-1 and pro-inflammatory cytokine response and alleviated airway hyperreactivity in AAI. SEB administered i.n. prior to the allergic sensitization at the lower dose significantly boosted the specific IgE response while administration of the higher dose led to a significantly reduced recruitment of immune cells, including eosinophils, to the respiratory tract and to a significantly dampened Th-2 cytokine response without inducing a Th-1 or pro-inflammatory response. We show a remarkably versatile potential for SEB to either aggravate or alleviate different parameters of allergic sensitization and AAI. Our study thereby not only highlights the complexity of the associations between S. aureus and allergic asthma but possibly even points at prophylactic and therapeutic pathways
Comparative cost of illness analysis and assessment of health care burden of Duchenne and Becker muscular dystrophies in Germany.
Our study aimed to determine the burden of illness in dystrophinopathy type Duchenne (DMD) and Becker (BMD), both leading to progressive disability, reduced working capacity and high health care utilization
Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9
Objective
The Global FKRP Registry is a database for individuals with conditions caused by mutations in the FukutinâRelated Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, MuscleâEyeâBrain Disease and WalkerâWarburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRPârelated conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities.
Methods
Registration is patientâinitiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain.
Results
Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchairâdependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129).
Interpretation
The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trialâready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.publishedVersio
Treatment expectations and perception of therapy in adult patients with spinal muscular atrophy receiving nusinersen
Background and purpose: This was an investigation of treatment expectations and of the perception of therapy in adult patients with 5q-associated spinal muscular atrophy (5q-SMA) receiving nusinersen.
Methods: A prospective, non-interventional observational study of nusinersen treatment in adult 5q-SMA patients was conducted at nine SMA centers in Germany. The functional status, treatment expectations and perceived outcomes were assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-extended (ALS-FRS-ex), the Measure Yourself Medical Outcome Profile (MYMOP2), the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the Net Promoter Score (NPS).
Results: In all, 151 patients were included with a median age of 36 years (15-69 years). SMA type 3 (n = 90, 59.6%) prevailed, followed by type 2 (33.8%) and type 1 (6.6%). In SMA types 1-3, median ALS-FRS-ex scores were 25, 33 and 46 (of 60 scale points), respectively. MYMOP2 identified distinct treatment expectations: head verticalization (n = 13), bulbar function (n = 16), arm function (n = 65), respiration (n = 15), trunk function (n = 34), leg function (n = 76) and generalized symptoms (n = 77). Median symptom severity decreased during nusinersen treatment (median observational period 6.1 months, 0.5-16 months) from 3.7 to 3.3 MYMOP2 score points (p < 0.001). The convenience of drug administration was critical (49.7 of 100 TSQM-9 points, SD 22); however, the overall treatment satisfaction was high (74.3, SD 18) and the recommendation rating very positive (NPS +66).
Conclusions: Nusinersen was administered across a broad range of ages, disease durations and motor function deficits. Treatment expectations were highly differentiated and related to SMA type and functional status. Patient-reported outcomes demonstrated a positive perception of nusinersen therapy in adult patients with 5q-SMA
Spectroscopic time series performance of the Mid-Infrared Instrument on the JWST
We present here the first ever mid-infrared spectroscopic time series
observation of the transiting exoplanet \object{L 168-9 b} with the
Mid-Infrared Instrument (MIRI) on the James Webb Space Telescope. The data were
obtained as part of the MIRI commissioning activities, to characterize the
performance of the Low Resolution Spectroscopy (LRS) mode for these challenging
observations. To assess the MIRI LRS performance, we performed two independent
analyses of the data. We find that with a single transit observation we reached
a spectro-photometric precision of 50 ppm in the 7-8 \micron range at
R=50, consistent with 25 ppm systematic noise. The derived band averaged
transit depth is 524 15 ppm and 547 13 ppm for the two applied
analysis methods, respectively, recovering the known transit depth to within 1
. The measured noise in the planet's transmission spectrum is
approximately 15-20 \% higher than random noise simulations over wavelengths
m. \added{We observed an larger excess
noise at the shortest wavelengths of up to a factor of two, for which possible
causes are discussed.} This performance was achieved with limited in-flight
calibration data, demonstrating the future potential of MIRI for the
characterization of exoplanet atmospheres.Comment: Accepted for publishing in PASP, 21 pages, 10 figure
Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregiversâ Lives
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patientsâ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregiversâ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patientsâ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patientsâ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the Kingâs Stages for ALS. The caregiversâ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregiversâ burden was high (mean ZBI = 26/88, 0 = no burden, â„24 = highly burdened) and correlated with patientsâ functional status (rp = â0.555, p < 0.001, n = 242). It was influenced by the CGsâ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patientsâ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGsâ depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = â0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patientsâ impairment in daily routine (rs = â0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGsâ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGsâ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required
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The Clinical Outcome Study for dysferlinopathy: An international multicenter study
Objective: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.
Methods: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.
Results: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.
Conclusions: These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design
Force-Velocity Measurements of a Few Growing Actin Filaments
The authors propose a new mechanism for actin-based force generation based on results using chains of actin-grafted magnetic colloids
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