Objective:
To determine the prevalence and the prognostic value of exercise‐induced ventricular arrhythmia (EIVA) in chronic Chagas’ heart disease.
Study Design and Setting:
An open prospective ...cohort of 130 clinically stable patients at a University Hospital outpatient unit in Rio de Janeiro, Brazil, was followed up at scheduled clinical visits from 1990 through 2007. The endpoint was total cardiovascular mortality. Survival curves (Kaplan‐Meier) and a multivariate Cox proportional hazard model were adjusted to determine the association between EIVA and mortality.
Results:
The median duration of follow‐up was 9.9 years (range, 132 days to 17 years). EIVA prevalence was 43.1% (95% CI: 34.5–51.7). Thirty‐three cardiovascular deaths (25.4%) occurred. The hazard ratio of EIVA for cardiovascular death, after adjustment for age, was 1.84 (P = 0.09). An interaction was found between EIVA and cardiomegaly on x‐ray. In the group with cardiomegaly, the hazard of dying was four times greater in the presence of EIVA (P for interaction = 0.05).
Conclusion:
In clinically stable chagasic subjects with cardiomegaly, EIVA is a clinically significant marker of total cardiovascular mortality and may be a useful risk stratification tool in this population. (PACE 2011; 34:1492–1497)
The aim of this study was to investigate the involvement of oxidative stress and apoptosis in an animal model of Menière’s disease. Endolymphatic hydrops (ELH) is generally accepted as the decisive ...histological characteristic of Menière’s disease.
Closure of the endolymphatic duct (Kimura’s method) was used to induce endolymphatic hydrops in guinea pigs. Sham-operated animals served as controls. After 4 weeks the animals operated showed a significant elevation of the hearing thresholds as measured by audiometric brainstem responses (ABR) pre- and postoperatively. Immediately after the second ABR measurement, the animals were sacrificed for further immunohistological examinations of the inner ear with specific antibodies to active caspase-3 (cas-3) as a marker for apoptosis and antibodies to 8-isoprostane (8-iso) and nitrotyrosine (NT) as indicators of oxidative stress.
Compared with the sham-operated controls, hydropic cochleae showed strong immunostaining for both oxidative stress markers in spiral ganglion cells, in the blood-vessels and fibrocytes of the lateral wall, as well as in supporting cells of the organ of Corti. Activation of cas-3 in spiral ganglion cells and the lateral wall was found exclusively in hydropic cochleae.
Our findings suggest that oxidative stress is involved in the development of endolymphatic hydrops and may lead to cellular damage which induces apoptosis by activation of cas-3. Apoptotic cell death might contribute to the sensorineural hearing loss found in later stages of Menière’s disease.
Objective. To analyze changes in functional status and the factors contributing to disability in a national inception cohort of 257 patients with polymyositis/dermatomyositis (PM/DM).
Methods. Data ...were gathered from patients' self‐reports on questionnaires: one concerning disease‐ and treatment‐related complications, and the other concerning disability, as reflected by a disability index (DI) derived from the Health Assessment Questionnaire (HAQ).
Results. Based on certain characteristics that differentiated disability patterns, 3 groups of patients were identified. Group 1 patients (n = 153) were ≥60 years old and never had avascular necrosis (AVN) or a vertebral compression fracture (CF), Group 2 patients were >60 and never had AVN or a vertebral CF, and Group 3 patients reported AVN or a vertebral CF irrespective of age. As measured by the HAQ DI, disability increased very gradually over time in Group 1 patients and more rapidly in Group 2 and Group 3 patients. The increase in disability in patients experiencing AVN was greater than that in patients with similar pre‐AVN disease characteristics who did not develop AVN (P = 0.003).
Conclusion. In this prospective study of disease course and iatrogenic factors related to functional disability in PM/DM, the HAQ DI increased with disease duration. Corticosteroid‐related morbidity, as reflected by the development of AVN or CF, significantly contributed to patient‐reported functional disability.
Vaccine Therapies in Malignant Glioma Oh, Taemin; Sayegh, Eli T.; Fakurnejad, Shayan ...
Current neurology and neuroscience reports,
01/2015, Volume:
15, Issue:
1
Journal Article
Peer reviewed
Open access
Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal, and even when tumors undergo ...gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered.
Abstract
Background
Understanding the diversity, breadth, magnitude, and functional profile of the T cell response against SARS-CoV-2 in recovered COVID-19 individuals is critical to evaluate the ...contribution of T cells to produce a potentially protective immune response.
Methods
We used a multiplexed peptide-MHC tetramer approach to screen a total of 408 SARS-CoV-2 candidate peptide epitopes for CD8+ T cell recognition in a cohort of 30 individuals recovered from COVID-19. The peptides spanned the whole viral genome and were restricted to six prevalent HLA alleles; T cells were simultaneously characterized by a 28-marker phenotypic panel. The evolution of the SARS-CoV-2 T cell responses was then statistically modeled against time from diagnosis, and in relation to humoral and inflammatory response.
Workflow for Study. A multiplexed peptide-MHC tetramer approach was used to screen SARS-CoV-2 candidate peptide epitopes in a cohort of 30 COVID-19 recovered patients across 6 prevalent HLA alleles, and T cells profiled with a 28-marker phenotypic panel.
Multiplex tetramer screen. One representative COVID-19 recovered patient and one healthy donor were screened for HLA- relevant SARS-CoV-2 epitopes, as well as epitopes for CMV, EBV, Influenza, Adenovirus and MART-1. Shown are the frequencies of tetramer-positive CD8 T cells from 2 technical replicates per subject.
Results
Almost all individuals screened showed a T cell response against SARS-CoV-2 (29/30): 132 SARS-CoV-2-specific CD8+ T cells hits were detected, corresponding to 52 unique reactive epitopes. Twelve of the 52 unique SARS-CoV-2-specific epitopes were recognized by more than 40% of the individuals screened, indicating high prevalence in the subjects. Importantly, these CD8+ T cell responses were directed against both structural and non-structural viral proteins, with the highest magnitude against nucleocapsid derived peptides, but without any antigen-driven bias in the phenotype of specific T cells. Overall, SARS-CoV-2 T cells showed specific states of differentiation (stem-cell memory and transitional memory), which differed from those of MART-1, influenza, CMV and EBV-specific T cells.
UMAP visualization revealed a phenotypic profile of SARS-CoV-2-specific CD8 T cells in COVID-19 convalescent donors that is distinct from other viral specificities, such as influenza, CMV, EBV and Adenovirus.
SARS-CoV-2 epitope screening revealed CD8+ T cell responses directed against both structural and non-structural viral proteins, with the highest magnitude response against nucleocapsid derived peptides
Conclusion
The kinetics modeling demonstrates a dynamic, evolving immune response characterized by a time-dependent decrease in overall inflammation, increase in neutralizing antibody titer, and progressive differentiation of a broad SARS-CoV-2 CD8 T cell response. It could be desirable to aim at recapitulating the hallmarks of this robust CD8 T cell response in the design of protective COVID-19 vaccines.
Disclosures
Hassen Kared, PhD, ImmunoScape (Shareholder) Alessandra Nardin, DvM, ImmunoScape (Shareholder) Hermi Sumatoh, BSc, Dip MTech, ImmunoScape (Shareholder) Faris Kairi, BSc, ImmunoScape (Shareholder) Daniel Carbajo, PhD, ImmunoScape (Shareholder) Brian Abel, PhD, MBA, ImmunoScape (Shareholder) Evan Newell, PhD, ImmunoScape (Shareholder)
Two ways of introducing spatial information in Dempster–Shafer evidence theory are examined: in the definition of the monosource mass functions, and, during data fusion. In the latter case, a ...“neighborhood” mass function is derived from the label image and combined with the “radiometric” masses, according to the Dempster orthogonal sum. The main advantage of such a combination law is to adapt the importance of neighborhood information to the level of radiometric missing information. The importance of introducing neighborhood information has been illustrated through the following application: forest area detection using radar and optical images showing a partial cloud cover.
The near-field interaction of an atom with a dielectric surface is inversely proportional to the cube to the distance to the surface, and its coupling strength depends on a dielectric image ...coefficient. This coefficient, simply given in a pure electrostatic approach by (ε−1)/(ε+1) with ε the permittivity, is specific to the frequency of each of the various relevant atomic transitions: it depends on the bulk material properties in a complex manner, and can exhibit resonances connected to the surface-polariton modes. We list here the surface resonances for about a hundred of optical windows whose bulk properties are currently tabulated. The study concentrates on the infrared domain because it is the most relevant for atom–surface interaction. Aside from this tabulation, we discuss simple hints to estimate the position of surface resonances, and how uncertainties in the bulk data for the material dramatically affect the predictions for the image coefficient. We also evaluate the contribution of UV resonances of the material to the non-resonant part of the image coefficient.
Plant α‐amylase inhibitors show great potential as tools to engineer resistance of crop plants against pests. Their possible use is, however, complicated by observed variations in specificity of ...enzyme inhibition, even within closely related families of inhibitors. Five α‐amylase inhibitors of the structural 0.19 family were isolated from wheat kernels, and assayed against three insect α‐amylases and porcine pancreatic α‐amylase, revealing several intriguing differences in inhibition profiles, even between proteins sharing sequence identity of up to 98%. Inhibition of the enzyme from a commercially important pest, the bean weevil Acanthoscelides obtectus, is observed for the first time. Using the crystal structure of an insect α‐amylase in complex with a structurally related inhibitor, models were constructed and refined of insect and human α‐amylases bound to 0.19 inhibitor. Four key questions posed by the differences in biochemical behaviour between the five inhibitors were successfully explained using these models. Residue size and charge, loop lengths, and the conformational effects of a Cys to Pro mutation, were among the factors responsible for observed differences in specificity. The improved structural understanding of the bases for the 0.19 structural family inhibitor specificity reported here may prove useful in the future for the rational design of inhibitors possessing altered inhibition characteristics.
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