GM-CSF Production Allows the Identification of Immunoprevalent Antigens Recognized by Human CD4+ T Cells Following Smallpox Vaccination

The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-α is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a “T cell–driven” methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens

Telerehabilitation in response to constrained physical distance: an opportunity to rethink neurorehabilitative routines

Ensuring proper dosage of treatment and repetition over time is a major challenge in neurorehabilitation. However, a requirement of physical distancing to date compromises their achievement. While mostly associated to COVID-19, physical distancing is not only required in a pandemic scenario, but also advised for several clinical conditions (e.g. immunocompromised individuals) or forced for specific social contexts (e.g. people living in remote areas worldwide). All these contexts advocate for the implementation of alternative healthcare models. The objective of this perspective is to highlight the benefits of remote administration of rehabilitative treatment, namely telerehabilitation, in counteracting physical distancing barriers in neurorehabilitation. Sustaining boosters of treatment outcome, such as compliance, sustainability, as well as motivation, telerehabilitation may adapt to multiple neurological conditions, with the further advantage of a high potential for individualization to patient’s or pathology’s specificities. The effectiveness of telerehabilitation can be potentiated by several technologies available to date: virtual reality can recreate realistic environments in which patients may bodily operate, wearable sensors allow to quantitatively monitor the patient’s performance, and signal processing may contribute to the prediction of long-term dynamics of patient recovery. Telerehabilitation might spark its advantages far beyond the mere limitation of physical distancing effects, mitigating criticalities of daily neurorehabilitative practice, and thus paving the way to the envision of mixed models of care, where hospital-based procedures are complementarily integrated with telerehabilitative ones

Return to physical activity and change in body mass index after hypoallergenic medial mobile-bearing unicompartmental knee arthroplasty

Background: The primary purpose of the present prospective study was to consecutively analyse the outcomes of the return to sports activity of patients with positive patch tests undergoing a medial mobile-bearing titanium niobium nitride (TiNbN) unicompartmental knee arthroplasty (UKA). The secondary purpose was to ascertain if a higher grade of physical activity leads to a reduction in the body mass index (BMI) of the patients. Material and methods: Forty-one patients with positive skin patch tests were included in this prospective study. The clinical evaluation consisted of the University of California, Los Angeles (UCLA) activity scale and the High-Activity Arthroplasty Score (HAAS). Each patient was evaluated the day before surgery (T0), after 12.37 ± 0.70 months (T1), and on the day of the final follow-up, after 67.03 ± 18.2 months (T2). Furthermore, the BMI of each patient was analysed before surgery and during the final follow-up. Results: The UCLA and HAAS mean preoperative values ranged from 3.68 ± 1.1.7 and 6.15 ± 0.76 to 6.1 ± 0.76 and 10.34 ± 1.3, respectively, at T1 (p < 0.0001) and to the final values of 6.34 ± 0.62 and 11.0 ± 8.9, respectively, at T2 (UCLA: T2 versus T1: p = 0.132; T2 versus T0: p < 0.0001; HAAS: T2 versus T1: p = 0.0027; T2 versus T0: p < 0.001). BMI ranged from a preoperative value of 27.97 ± 3.63 to a final value of 26.84 ± 3.11 (p < 0.0001). The only differences within the subgroups concerned patients with BMI ≥ 28, showing a superior HAAS at each follow-up (p < 0.05). A positive correlation was found between BMI and HAAS at T0 and T2 (p < 0.05). Conclusions: This is the first study to evaluate the rate of the return to sports activities and change in BMI following hypoallergenic UKA. The majority of patients reduced their weight following UKA and improved their physical activity, showing outcomes that were comparable to the standard cobalt–chrome (CoCr) prostheses, regardless of gender, age, BMI and implant size. Level of evidence: IV – Prospective Cohort Study. Trial registration researchregistry5978—Research Registry www.researchregistry.com © 2021, The Author(s)

Spatio-temporal dynamics of interictal activity in musicogenic epilepsy: Two case reports and a systematic review of the literature

Objective: To explore neurophysiological features of musicogenic epilepsy (ME), discussing experimental findings in the framework of a systematic review on ME. Methods: Two patients with ME underwent high-density-electroencephalography (hd-EEG) while listening to ictogenic songs. In one case, musicogenic seizures were elicited. Independent component analysis (ICA) was applied to hd-EEG, and components hosting interictal and ictal elements were identified and localized. Finally, the temporal dynamics of spike-density was studied relative to seizures. All findings were compared against the results of a systematic review on ME, collecting 131 cases. Results: Interictal spikes appeared isolated in specific fronto-temporal independent components, whose cortical generators were located in the anterior temporal and inferior frontal lobe. In the patient undergoing seizure, ictal discharge relied in the same component, with the interictal spike-density decreasing before the seizure onset. Conclusion: Our study shows how ICA can isolate neurophysiological features of ictal and interictal discharges in ME, highlighting a fronto-temporal localization and a suppression of spike-density preceding the seizure onset. Significance: While the localization of ME activity could indicate which aspect within the musical stimulus might trigger musicogenic seizures for each patient, the study of ME dynamics could contribute to the development of models for seizure-prediction and their validation

Structure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ-binding protein

Ectromelia virus (ECTV) encodes an IFN-γ-binding protein (IFN-γBPECTV) that disrupts IFN-γ signaling and its ability to induce an antiviral state within cells. IFN-γBPECTV is an important virulence factor that is highly conserved (>90%) in all orthopoxviruses, including variola virus, the causative agent of smallpox. The 2.2-Å crystal structure of the IFN-γBPECTV/IFN-γ complex reveals IFN-γBPECTV consists of an IFN-γR1 ligand-binding domain and a 57-aa helix-turn-helix (HTH) motif that is structurally related to the transcription factor TFIIA. The HTH motif forms a tetramerization domain that results in an IFN-γBPECTV/IFN-γ complex containing four IFN-γBPECTV chains and two IFN-γ dimers. The structure, combined with biochemical and cell-based assays, demonstrates that IFN-γBPECTV tetramers are required for efficient IFN-γ antagonism