Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination

: The introduction of anti-SARS-CoV-2 vaccines in late 2020 substantially changed the pandemic picture, inducing effective protection in the population. However, individual variability was observed with different levels of cellular response and neutralizing antibodies. We report data on the impact of age, gender, and 16 single nucleotide polymorphisms (SNPs) of cytokine genes on the anti-SARS-CoV-2 IgG titers measured 31 and 105 days after administration of the second dose of BNT162b2 vaccine to 122 healthy subjects from the health care staff of the Palermo University Hospital, Italy. The higher titers at 31 days were measured in the younger subjects and in subjects bearing T-positive genotypes of IL-1R1 rs2234650 or the GG homozygous genotype of IL-6 rs1800795 SNP. T-positive genotypes are also significantly more common in subjects with higher titers at day 105. In addition, in this group of subjects, the frequency of the CT genotype of IL-4 rs2243250 is higher among those vaccinated with higher titers. Moreover, these SNPs and TNFA rs1800629 are differently distributed in a group of subjects that were found infected by SARS-CoV-2 at day 105 of evaluation. Finally, subjects that were found to be infected by SARS-CoV-2 at day 105 were significantly older than the uninfected subjects. Taken together, these data seem to suggest that age and polymorphisms of key cytokines, which regulate inflammation and humoral immune response, might influence the magnitude of the antibody response to vaccination with BNT162B2, prompting speculation about the possible benefit of a genetic background-based assessment of a personalized approach to the anti-COVID vaccination schedule

Redox Modulations, Antioxidants, and Neuropsychiatric Disorders

Although antioxidants, redox modulations, and neuropsychiatric disorders have been widely studied for many years, the field would benefit from an integrative and corroborative review. Our primary objective is to delineate the biological significance of compounds that modulate our redox status (i.e., reactive species and antioxidants) as well as outline their current role in brain health and the impact of redox modulations on the severity of illnesses. Therefore, this review will not enter into the debate regarding the perceived medical legitimacy of antioxidants but rather seek to clarify their abilities and limitations. With this in mind, antioxidants may be interpreted as natural products with significant pharmacological actions in the body. A renewed understanding of these often overlooked compounds will allow us to critically appraise the current literature and provide an informed, novel perspective on an important healthcare issue. In this review, we will introduce the complex topics of redox modulations and their role in the development of select neuropsychiatric disorders

Molecular characterisation of congenital myasthenic syndromes in Southern Brazil

Objective To perform genetic testing of patients with congenital myasthenic syndromes (CMS) from the Southern Brazilian state of Parana. Patients and methods Twenty-five CMS patients from 18 independent families were included in the study. Known CMS genes were sequenced and restriction digest for the mutation RAPSN p.N88K was performed in all patients. Results We identified recessive mutations of CHRNE in ten families, mutations in DOK7 in three families and mutations in COLQ, CHRNA1 and CHRNB1 in one family each. The mutation CHRNE c. 70insG was found in six families. We have repeatedly identified this mutation in patients from Spain and Portugal and haplotype studies indicate that CHRNE c. 70insG derives from a common ancestor. Conclusions Recessive mutations in CHRNE are the major cause of CMS in Southern Brazil with a common mutation introduced by Hispanic settlers. The second most common cause is mutations in DOK7. The minimum prevalence of CMS in Parana is 0.18/100 000

Comparison of intrascalar location of straight vs perimodiolar electrode array by flat-panel computerized tomography

Introduction, One of the fields of technological advancement in cochlear implants (CI) pursued by all manufacturers is the development of less traumatic electrodes that can conform to the anatomy of the cochlea, and possibly enhance the outcomes. Recently, a slim precurved perimodiolar electrode with an insertion guidance sleeve has been designed in order to facilitate the insertion and to avoid the inter-scalar dislodgement that frequently occurs at the first basal turn. Aim of this study was to evaluate the intracochlear position of different Nucleus electrode arrays in aduld and pediatric CI recipients by means of flat-panel volume computerized tomography (FPCT). Methods, Fifty-six CI recipients (37 females, 19 males), 1 to 80 years of age, operated by the same surgeon with the same technique, were included. All underwent FPCT with a C-arm angiographic system including a digital flat panel detector 30 x 40 cm, with a source-to-image-receptor distance of 120cm. The imaging assessment was performed the day after surgery in all cases. Sequential and simultaneous CI were included and a total of 68 ears have been analyzed. The primary objective was to identify the scalar location of the array (completely in scala tympani vs. partially dislodged in scala vestibuli) and the site of dislocation. Secondarily, we measured the medial-lateral position within the scala, the insertion depth (mm and angles). The FPCT findings were also contrasted with the type of cochleostomy (round window (RW), extended RW, promontorial) and with the residual hearing preservation. Results, Fifty-nine ears were implanted with a perimodiolar electrode, either Nucleus CI532 (n=45) or a CI412 / CI512 Contour Advance (n=14), while 9 received a straight one (Nucleus CI422/CI522). A RW approach was performed more frequently (41 out of 45 = 91.1 %) with CI532 than with the other arrays (10 out of 23 = 43.5%). Inferior and/or anterior cochleostomy were never performed. The CI532 showed the most consistent and reliable intrascalar position, close to the modiolus and in the scala tympani. Scala vestibuli dislodgement was observed in (14.3%) of the Contour Advance electrodes and in (6.7%) of the CI532. Pre-operative residual hearing was preserved within 10 dB HL in 62% of the cases. Conclusions: the CI532 electrode array achieved the most consistent and reliable perimodiolar location by FPCT; in our small series it appeared to be dislodged in the scala tympani in the minority of cases

Pathological implications of Th1/Th2 cytokine genetic variants in Beh\ue7et's disease: Data from a pilot study in a Sicilian population

Cytokines act as pleiotropic polypeptides able to regulate inflammatory/immune responses and to provide important signals in physiological and pathological processes. Several cytokines (Th1, Th2, and Th17) seem to be involved in the pathophysiology of Beh\ue7et's disease, a chronic immune-mediated disease characterized by oral and genital lesions and ocular inflammation. Its individual susceptibility seems to be modulated by genetic variants in genes codifying these cytokines. Th1 and Th17 seem to be involved in the disease's active phases, and Th2 seems to affect the development or severity of the disease; however, contrasting data are reported. In this study, some genetic variants of the Th1/Th2 cytokine genes were investigated in Sicilian patients and age- and gender-matched controls. Three very significant associations with Beh\ue7et's disease were detected, and combined genotypes associated with increased disease risk were identified. Results obtained point to the key role of Th1/Th2 cytokine genetic variants in disease susceptibility

Robust Local Stabilization of Discrete-Time Systems with Time-Varying State Delay and Saturating Actuators

The robust local stabilization of uncertain discrete-time systems with time-varying state delayed and subject to saturating actuators is investigated in this work. A convex optimization method is proposed to compute robust state feedback control law such that the uncertain closed-loop is locally asymptotically stable if the initial condition belongs to an estimate of the region of attraction for the origin. The proposed procedure allows computing estimates of the region of attraction through the intersection of ellipsoidal sets in an augmented space, reducing the conservatism of the estimates found in the literature. Also, the conditions can handle the amount of delay variation between two consecutive samples, which is new in the literature for the discrete-time case. Although the given synthesis conditions are delay dependent, the proposed control law is delay independent, yielding to easier real time implementations. A convex procedure is proposed to maximize the size of the set of safe initial conditions. Numerical examples are provided to illustrate the effectiveness of our approach and also to compare it with other conditions in the literature.Fil: Silva, J. V. V.. Centro Federal de Educação Tecnológica de Minas Gerais; BrasilFil: Silva, L. F. P.. Centro Federal de Educação Tecnológica de Minas Gerais; BrasilFil: Rubio Scola, Ignacio Eduardo Jesus. Cefetmg/ufjs;Fil: Leite, V. J. S.. Cefetmg/ufjs

Polymorphisms of pro-inflammatory IL-6 and IL-1\u3b2 cytokines in ascending aortic aneurysms as genetic modifiers and predictive and prognostic biomarkers

Background: Previous studies have demonstrated that polymorphisms involved in immune genes can affect the risk, pathogenesis, and outcome of thoracic ascending aortic aneurysms (TAAA). Here, we explored the potential associations of five functional promoter polymorphisms in interleukin-6 (IL-6), IL-1B, IL-1A, IL-18, and Tumor necrosis factor (TNF)A genes with TAAA. Methods: 144 TAAA patients and 150 age/gender matched controls were typed using KASPar assays. Effects on telomere length and levels of TAAA related histopathological and serological markers were analyzed. Results: Significant associations with TAAA risk were obtained for IL-6 rs1800795G>C and IL-1B rs16944C>T SNPs. In addition, the combined rs1800795C/rs16944T genotype showed a synergic effect on TAAA pathogenesis and outcome. The combined rs1800795C/rs16944T genotype was significantly associated with: (a) higher serum levels of both cytokines and MMP-9 and-2; (b) a significant CD3+CD4+CD8+ CD68+CD20+ cell infiltration in aorta aneurysm tissues; (c) a significant shorter telomere length and alterations in telomerase activity. Finally, it significantly correlated with TAAA aorta tissue alterations, including elastic fragmentation, medial cell apoptosis, cystic medial changes, and MMP-9 levels. Conclusions: the combined rs1800795C/rs16944T genotype appears to modulate TAAA risk, pathogenesis, and outcome, and consequently can represent a potential predictive and prognostic TAAA biomarker for individual management, implementation of innovative treatments, and selection of the more proper surgical timing and approaches

The signature of longevity in Sicily

Ageing is a natural and physiological condition that is the result of compromised stress response, homeostatic imbalance and increased risk of developing diseases. However, if aging with good health and functions (successful ageing) and aging with disease and disability (unsuccessful ageing) depends on a combination of “positive features”, including genetic, epigenetic and phenotypic characteristics in combination with favourable environment, economic status and social involvement. In our study, we summarize some key points for the identification of a longevity signature, with a particular focus on long-living Sicilian individuals and centenarians. Analysing three different Sicilian cohorts (young, people with no centenarian parents and long-living individuals (LLI) aged >90) we found APOE e3e3 in our LLIs and no presence of e4. Regarding FOXO rs2802292 G-allele (G>T) we did not observe an association with longevity, probably because of the small sample of centenarians studied. Regarding haematological and anthropometric results, it is still difficult to point specific longevity features and so far, we cannot specify a single one. On the other hand, we believe that the synergy among genetics and environment might create successful interaction to achieve and obtain effective longevity