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Introduction: Master athletes are examples of successful aging. It is not clear whether it is the competitive-oriented training or just the amount of total regular exercise that reduces the age-related decline in physiological functions. We aimed to compare health-related parameters in competitive (C) and physically active older adults (A) that performed the same weekly physical activity (PA) amount. Methods: Seventeen C and 17 A were matched for age (8 and 9 male participants under and over 70 years old respectively, for both groups) and weekly PA amount (GPAQ). Body composition, leg and arm maximal strength, balance and reaction time were measured; moreover, leg and arm exercise efficiency, estimated VO2max, and VO2/HR relationships were evaluated. Perception of life and sleep quality was also assessed through specific questionnaires (SF-36 and PSQI). The effect of group (C vs. A), age (U70 vs. O70) and their interaction was examined through a Two-Way ANOVA test. Results: C dedicated more time to vigorous PA compared to A (p = 0.03), while less to moderate daily work (p < 0.01) and active commuting (p = 0.06). C exhibited better body composition (all p < 0.05), higher leg maximal strength (p < 0.05) and a trend for elevated arm strength (p = 0.06). Reaction time, leg and arm cycling efficiency were similar in the two groups (all p > 0.05), while balance reduced in A O70. Estimated VO2max was higher for C in leg cycling (p = 0.05) and remained constant across ages (all p > 0.05). VO2/HR relationship, life and sleep quality did not differ for groups and ages. Conclusions: Regular physical exercise of about 6,000 METs/week seems to have a beneficial effect on health-related parameters, both in non-structured and competitive PA, when compared to sedentary behaviour. However, the older adults engaged in competitive training exhibit further advantages: better body composition, higher arm and leg muscle strength, and higher leg VO2max. This study highlights the importance of encouraging active lifestyles for maintaining long-term health, high levels of life quality perception and reducing age-related decline. However, vigorous training suitability needs to be verified by a team of PA specialists. [ABSTRACT FROM AUTHOR]

Background Neutralising antibodies (NAb) to interferon beta (IFNβ) are associated with a reduced bioactivity and efficacy of IFNβ in multiple sclerosis (MS). Unclear is how to apply IFNβ bioactivity measurements (quantification of Myxovirus resistance protein A (MxA) mRNA) in clinical practice. Objectives To evaluate value and feasibility of IFNβ bioactivity measurement with a single MxA mRNA measurement for screening and a second measurement before and after IFNβ administration for definite confirmation of IFNβ bioactivity status. Methods In 79 MS patients MxA mRNA expression was determined 4 hours after IFNβ administration. If inadequate, MxA mRNA expression testing was repeated 3 months afterwards, comparing post- and pre injection samples to determine whether IFNb bioactivity was persistently lacking. MxA mRNA expression was compared to NAβ titres, determined by the cytopathic effect assay (CPE). Results NAb titres correlated significantly with MxA mRNA expression and MxA mRNA induction. Of all screened patients, only one patient had adequate MxA mRNA expression and high NAb titres simultaneously. Of the biological non-responders at second measurement (21/55), 17 (81%) were high-titre NAb positive, 1 (5%) was low-titre NAb positive and 3 (14%) were NAb negative. Without considering the pre-injection measurement, two more NAb negative patients would have tested negative for IFNβ bioactivity, emphasizing the need of a pre-injection sample. Conclusions Our data suggest that for IFNβ bioactivity screening a single post-injection measurement seems reasonable. However, MxA induction measurement based on both pre- and post-IFNβ injection samples at second measurement is somewhat more precise in determining ultimate IFNβ bioactivity status. [ABSTRACT FROM AUTHOR]

Background: MxA gene expression is one of the most appropriate markers of biological activity of exogenous interferon (IFN) beta. Methods: We quantified MxA mRNA for five consecutive days in 62 patients treated with IFN beta (16, Avonex; 10, Betaferon; 24, Rebif 22; 12, Rebif 44), by quantitative-competitive polymerase chain reaction. Every three months, IFN beta induced neutralising antibodies (NAbs) were evaluated in sera using a cytopathic effect assay. Results: Two categories of patients were identified: one group (49/62) hada sharp post-injection increase in MxA expression (defined as "IFN beta biological responder"), whereas the other group (13/62) had no MxA induction after IFN beta administrations (defined as "IFN beta biological non-responder"). In 11 / 13 biological non-responders, the persistent presence of NAbs correlated with abolished biological activity, independently of treatment regimen. The two remain in- IFN beta biological non-responders were NAb-. Among the 49 IFN beta biological responders, biological activity was comparable between the four preparations on day 2 and 3 (+12 and +36 hours post-injection), but it was greater in Betaferon and both Rebif preparations on day 1,4, and 5. In biological responders treated three times a week, only 82% (59/72) of injections were considered effective, compared with 100% (13/13) of Avonex injections. Conclusion: Our results suggest that an optimal IFN beta regimen is not yet available: Avonex, given once a week, shows lower cumulative biological activity. On the other hand, both Betaferon and Rebif, given three times a week, show 18% biologically ineffective injections and higher risk of developing NAbs, which abolish biological activity. [ABSTRACT FROM AUTHOR]

Background and Objectives: Multiple sclerosis (MS) is a heterogeneous disease, and its course is difficult to predict. Prediction models can be established by measuring intrathecally synthesized proteins involved in inflammation, glial activation, and CNS injury., Methods: To determine how these intrathecal proteins relate to the short-term, i.e., 12 months, disease activity in relapsing-remitting MS (RRMS), we measured the intrathecal synthesis of 46 inflammatory mediators and 14 CNS injury or glial activation markers in matched serum and CSF samples from 47 patients with MS (pwMS), i.e., 23 RRMS and 24 clinically isolated syndrome (CIS), undergoing diagnostic lumbar puncture. Subsequently, all pwMS were followed for ≥12 months in a retrospective follow-up study and ultimately classified into "active", i.e., developing clinical and/or radiologic disease activity, n = 18) or "nonactive", i.e., not having disease activity, n = 29. Disease activity in patients with CIS corresponded to conversion to RRMS. Thus, patients with CIS were subclassified as "converters" or "nonconverters" based on their conversion status at the end of a 12-month follow-up. Twenty-seven patients with noninflammatory neurologic diseases were included as negative controls. Data were subjected to differential expression analysis and modeling techniques to define the connectivity arrangement (network) between neuroinflammation and CNS injury relevant to short-term disease activity in RRMS., Results: Lower age and/or higher CXCL13 levels positively distinguished active/converting vs nonactive/nonconverting patients. Network analysis significantly improved the prediction of short-term disease activity because active/converting patients featured a stronger positive connection between IgG1 and CXCL10. Accordingly, analysis of disease activity-free survival demonstrated that pwMS, both RRMS and CIS, with a lower or negative IgG1-CXCL10 correlation, have a higher probability of activity-free survival than the patients with a significant correlation ( p < 0.0001, HR ≥ 2.87)., Discussion: Findings indicate that a significant IgG1-CXCL10 positive correlation predicts the risk of short-term disease activity in patients with RRMS and CIS. Thus, the present results can be used to develop a predictive model for MS activity and conversion to RRMS.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the United States. Decades before motor symptoms manifest, non-motor symptoms such as hyposmia and rapid eye movement (REM) sleep behavior disorder are highly predictive of PD. Previous immune profiling studies have identified alterations to the proportions of immune cells in the blood of clinically defined PD patients. However, it remains unclear if these phenotypes manifest before the clinical diagnosis of PD. We utilized longitudinal DNA methylation (DNAm) microarray data from the Parkinson's Progression Marker's Initiative (PPMI) to perform immune profiling in clinically defined PD and prodromal PD patients (Prod). We identified previously reported changes in neutrophil, monocyte, and T cell numbers in PD patients. Additionally, we noted previously unrecognized decreases in the naive B cell compartment in the defined PD and Prod patient group. Over time, we observed the proportion of innate immune cells in PD blood increased, but the proportion of adaptive immune cells decreased. We identified decreases in T and B cell subsets associated with REM sleep disturbances and early cognitive decline. Lastly, we identified increases in B memory cells associated with both genetic (LRRK2 genotype) and infectious (cytomegalovirus seropositivity) risk factors of PD. Our analysis shows that the peripheral immune system is dynamic as the disease progresses. The study provides a platform to understand how and when peripheral immune alterations occur in PD and whether intervention at particular stages may be therapeutically advantageous., (© 2024. The Author(s).)

Introduction: Gross Motor Coordination (GMC) is crucial for the adequate development of motor competence. Our purpose in this semi-longitudinal study was to evaluate the influence of BMI on GMC in children and pre-adolescents of both sexes, across school years (classes)., Methods: We evaluated 117 subjects (aged 8-13 years) belonging to three different cohorts for 4 consecutive years, providing data over 6 years (classes). GMC was assessed through the Körperkoordinationstest für Kinder (KTK) test. Class and weight status effects were then evaluated by dividing the subjects into a normal weight group and an overweight group based on their weight status., Results: A significant increase across classes was found for BMI ( p  < 0.001) and KTK raw score ( p  < 0.001) and a decrease was found for KTK normalized score (MQ) ( p  = 0.043). Significantly lower MQ values were found for girls. Absolute GMC increased across the years and there was no difference between boys and girls. Correlations between GMC scores and BMI were negative and significant in 5 of 6 classes. It was confirmed that overweight subjects had lower MQ and RAW values than normal-weight subjects, with no class-by-weight status interaction., Discussion: The level of competence and its development are strictly dependent on weight status during childhood and pre-adolescence. The present investigation suggests that the adequate development of GMC requires not only targeted physical education programs but also the promotion of healthy habits aimed at maintaining a normal weight status during childhood and pre-adolescence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Biino, Pellegrini, Zoppirolli, Lanza, Gilli, Giuriato and Schena.)

Background: There is a lack of understanding of the mechanisms by which the CNS is injured in multiple sclerosis (MS). Since Theiler's murine encephalomyelitis virus (TMEV) infection in SJL/J mice is an established model of progressive disability in MS, and CNS atrophy correlates with progressive disability in MS, we used in vivo MRI to quantify total ventricular volume in TMEV infection. We then sought to identify immunological and virological biomarkers that correlated with increased ventricular size., Methods: Mice, both infected and control, were followed for 6 months. Cerebral ventricular volumes were determined by MRI, and disability was assessed by Rotarod. A range of immunological and virological measures was obtained using standard techniques., Results: Disability was present in infected mice with enlarged ventricles, while infected mice without enlarged ventricles had Rotarod performance similar to sham mice. Ventricular enlargement was detected as soon as 1 month after infection. None of the immunological and virological measures correlated with the development of ventricular enlargement., Conclusions: These results support TMEV infection with brain MRI monitoring as a useful model for exploring the biology of disability progression in MS, but they did not identify an immunological or virological correlate with ventricular enlargement., (© 2023. The Author(s).)

Given that multiple sclerosis (MS) is a complex disease with an unclear etiology, a single animal model is unlikely to accurately represent all aspects of pathology and clinical features of the human condition. However, the availability of three major types of murine models of MS, that is, experimental autoimmune encephalomyelitis (EAE), viral models, and toxic models, enables studies of several relevant features of this debilitating disease. Researchers have recently begun to combine magnetic resonance imaging (MRI) technologies with other experimental strategies to acquire complementary information, for example, anatomical and functional, and study the effect of experimental manipulations longitudinally in a noninvasive way. This review summarizes the latest MRI studies investigating critical aspects of MS, such as atrophy, demyelination, neuroaxonal damage, and neuroinflammation, in mouse models of MS. Advanced techniques will be briefly discussed, providing references to specialized literature for the readers. Thus, this review aims to describe different imaging protocols used to study critical aspects of MS in a research laboratory, discussing the main related findings in the most significant murine models of the disease., (© 2023 Wiley Periodicals LLC.)

Multiple sclerosis (MS) is a clinically heterogenous disease. Currently, we cannot identify patients with more active disease who may potentially benefit from earlier interventions. Previous data from our lab identified the CXCL13 index (I CXCL13 ), a measure of intrathecal production of CXCL13, as a potential biomarker to predict future disease activity in MS patients two years after diagnosis. Patients with clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS) underwent a lumbar puncture and blood draw, and the I CXCL13 was determined. They were then followed for at least 5 years for MS activity. Patients with high I CXCL13 were more likely to convert to clinically definite MS (82.4%) compared to those with low I CXCL13 (10.0%). The data presented below demonstrate that this predictive ability holds true in CIS and RIS patients, and for at least five years compared to our initial two-year follow-up study. These data support the concept that I CXCL13 has the potential to be used to guide immunomodulatory therapy in MS.

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease of unknown etiology. However, several studies suggest that infectious agents, e.g., Human Herpes Viruses (HHV), may be involved in triggering the disease. Molecular mimicry, bystander effect, and epitope spreading are three mechanisms that can initiate immunoreactivity leading to CNS autoimmunity in MS. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is a pre-clinical model of MS in which intracerebral inoculation of TMEV results in a CNS autoimmune disease that causes demyelination, neuroaxonal damage, and progressive clinical disability. Given the spectra of different murine models used to study MS, this review highlights why TMEV-IDD represents a valuable tool for testing the viral hypotheses of MS. We initially describe how the main mechanisms of CNS autoimmunity have been identified across both MS and TMEV-IDD etiology. Next, we discuss how adaptive, innate, and CNS resident immune cells contribute to TMEV-IDD immunopathology and how this relates to MS. Lastly, we highlight the sexual dimorphism observed in TMEV-IDD and MS and how this may be tied to sexually dimorphic responses to viral infections. In summary, TMEV-IDD is an underutilized murine model that recapitulates many unique aspects of MS; as we learn more about the nature of viral infections in MS, TMEV-IDD will be critical in testing the future therapeutics that aim to intervene with disease onset and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pike, Welsh, Linzey and Gilli.)

Multiple sclerosis (MS) is a neurological disease featuring neuroinflammation and neurodegeneration in young adults. So far, most research has focused on the peripheral immune system, which appears to be the driver of acute relapses. Concurrently, the mechanisms underlying neurodegeneration in the progressive forms of the disease remain unclear. The complement system, a molecular component of the innate immunity, has been recently implicated in several neurological disorders, including MS. However, it is still unknown if the complement proteins detected in the central nervous system (CNS) are actively involved in perpetuating chronic inflammation and neurodegeneration. To address this knowledge gap, we compared two clinically distinct mouse models of MS: 1) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (rEAE) resembling a relapsing-remitting disease course, and 2) Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) resembling a progressive disease. Real-time PCR was performed in the spinal cord of rEAE mice, TMEV-IDD mice and age-matched sham controls to quantify gene expression for a broad range of complement components. In both experimental models, we found significantly increased expression of complement factors, such as C1q, C3, CfB, and C3aR. We showed that the complement system, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of C1q, C3 and C3aR1 were all significantly correlated to a worse disease outcome (all P ≤0.0168). In line with this finding, C1q and C3 deposition was observed in the spinal cord of TMEV-IDD mice. Furthermore, C1q deposition was detected in spinal cord regions characterized by inflammation, demyelination, and axonal damage. Conversely, activation of the classical complement cascade seemed to result in protection from rEAE (C1q: P =0.0307). Interestingly, the alternative pathway related to a worse disease outcome in rEAE (CFb: P =0.0006). Overall, these results indicate potential divergent roles for the complement system in MS. The chronic-progressive disease form is more reliant on the activation of the classic complement pathway, while protecting from acute relapses. Conversely, relapsing MS appears more likely affected by the alternative pathway. Understanding the functions of the complement system in MS is critical and can lead to better, more targeted therapies in the future., Competing Interests: FG and ARP have received research support from Biogen Idec, Sanofi Genzyme, and Serono. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Linzey, DiSano, Welsh, Pachner and Gilli.)

Purpose: There are limited data on SARS-CoV-2 (COVID-19) infection in children with cancer or after haematopoietic stem cell transplant (HSCT). We describe the severity and outcomes of SARS-COV-2 in these patients and identify factors associated with severe disease., Methods: This was a multinational, observational study of children (aged <19 years) with cancer or HSCT and SARS-CoV-2 confirmed by polymerase chain reaction. COVID-19 was classified as asymptomatic, mild, moderate, severe or critical (≥1 organ support). Exact polytomous regression was used to determine the relationship between clinical variables and disease severity., Results: One hundred and thirty-one patients with COVID-19 across 10 countries were identified (median age 8 years). Seventy-eight (60%) had leukaemia/lymphoma, 48 (37%) had solid tumour and five had primary immunodeficiency and HSCT. Fever (71%), cough (47%) and coryza (29%) were the most frequent symptoms. The median duration of detectable virus was 16 days (range, 1-79 days). Forty-nine patients (37%) were hospitalised for COVID-19 symptoms, and 15 (11%) required intensive care unit-level care. Chemotherapy was delayed/modified in 35% of patients. COVID-19 was asymptomatic in 32% of patients, mild in 47%, moderate in 8%, severe in 4% and critical in 9%. In 124 patients (95%), a full recovery was documented, and four (3%) died due to COVID-19. Any comorbidity (odds ratio, 2.94; 95% confidence interval [CI], 1.81-5.21), any coinfection (1.74; 95% CI 1.03-3.03) and severe baseline neutropenia (1.82; 95% CI 1.13-3.09) were independently and significantly associated with increasing disease severity., Conclusion: Although most children with cancer had asymptomatic/mild disease, 13% had severe COVID-19 and 3% died. Comorbidity, coinfection and neutropenia may increase the risk of severe disease. Our data may help management decisions in this vulnerable population., Competing Interests: Conflict of interest statement A.H.G. has research support from Gilead Sciences, Merck Sharp and Dohme and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer; and served at the speakers' bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer. A.A. is a consultant for Jazz Pharmaceuticals, Amgen, Novartis, Gilead Sciences and MSD/Merck and served at the speakers' bureau of Jazz Pharmaceuticals, Amgen and Novartis. T.L. has an unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas and Roche; and serves at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer and GlaxoSmithKline. All the other authors do not have to declare a conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Once thought to be primarily driven by T cells, B cells are emerging as central players in MS immunopathogenesis. Interest in multiple B cell phenotypes in MS expanded following the efficacy of B cell-depleting agents targeting CD20 in relapsing-remitting MS and inflammatory primary progressive MS patients. Interestingly, these therapies primarily target non-antibody secreting cells. Emerging studies seek to explore B cell functions beyond antibody-mediated roles, including cytokine production, antigen presentation, and ectopic follicle-like aggregate formation. Importantly, memory B cells (Bmem) are rising as a key B cell phenotype to investigate in MS due to their antigen-experience, increased lifespan, and rapid response to stimulation. Bmem display diverse effector functions including cytokine production, antigen presentation, and serving as antigen-experienced precursors to antibody-secreting cells. In this review, we explore the cellular and molecular processes involved in Bmem development, Bmem phenotypes, and effector functions. We then examine how these concepts may be applied to the potential role(s) of Bmem in MS pathogenesis. We investigate Bmem both within the periphery and inside the CNS compartment, focusing on Bmem phenotypes and proposed functions in MS and its animal models. Finally, we review how current immunomodulatory therapies, including B cell-directed therapies and other immunomodulatory therapies, modify Bmem and how this knowledge may be harnessed to direct therapeutic strategies in MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 DiSano, Gilli and Pachner.)

Background: Clinicians caring for patients with Multiple Sclerosis (MS) need improved biomarkers to aid them in disease management., Objective: We assessed the predictive value of the candidate biomarker CXCL13 index in comparison to oligoclonal bands (OCBs) and CSF neurofilament light (NfL) concentration, examining the ability of each biomarker to predict future disease activity in clinically and radiologically isolated syndromes, relapsing-remitting MS, and progressive MS., Methods: Matched serum and CSF samples were obtained from 67 non-inflammatory neurologic disease patients and 67 MS patients. CSF and serum CXCL13 and CSF NfL were analyzed by Luminex and ELISA, respectively. CXCL13 data were also analyzed as CSF/serum ratios and indices. Electronic medical records were accessed to determine diagnosis, CSF profiles, and disease activity after the lumbar puncture., Results: Among CXCL13 measures, CXCL13 index was the best predictor of future disease activity in MS patients (AUC = 0.82; CI = 0.69-0.95; p = 0.0002). CXCL13 index values were significantly elevated in activity-positive MS patients compared to activity-negative patients (p < 0.0001). As a single predictor, CXCL13 index outperformed both OCBs and CSF NfL in sensitivity, specificity, and positive and negative predictive value, for future disease activity in MS patients. Moreover, combining CXCL13 index and CSF NfL status improved sensitivity and predictive values for disease activity in MS patients., Conclusions: The CXCL13 index is an excellent candidate prognostic biomarker for disease activity in patients with MS., (© The Author(s) 2020.)

Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). An interesting feature that this debilitating disease shares with many other inflammatory disorders is that susceptibility is higher in females than in males, with the risk of MS being three times higher in women compared to men. Nonetheless, while men have a decreased risk of developing MS, many studies suggest that males have a worse clinical outcome. MS exhibits an apparent sexual dimorphism in both the immune response and the pathophysiology of the CNS damage, ultimately affecting disease susceptibility and progression differently. Overall, women are predisposed to higher rates of inflammatory relapses than men, but men are more likely to manifest signs of disease progression and worse CNS damage. The observed sexual dimorphism in MS may be due to sex hormones and sex chromosomes, acting in parallel or combination. In this review, we outline current knowledge on the sexual dimorphism in MS and discuss the interplay of sex chromosomes, sex hormones, and the immune system in driving MS disease susceptibility and progression., (Copyright © 2020 Gilli, DiSano and Pachner.)

The central nervous system (CNS) is comprised of the brain and spinal cord and is enveloped by the meninges, membranous layers serving as a barrier between the periphery and the CNS. The CNS is an immunologically specialized site, and in steady state conditions, immune privilege is most evident in the CNS parenchyma. In contrast, the meninges harbor a diverse array of resident cells, including innate and adaptive immune cells. During inflammatory conditions triggered by CNS injury, autoimmunity, infection, or even neurodegeneration, peripherally derived immune cells may enter the parenchyma and take up residence within the meninges. These cells are thought to perform both beneficial and detrimental actions during CNS disease pathogenesis. Despite this knowledge, the meninges are often overlooked when analyzing the CNS compartment, because conventional CNS tissue extraction methods omit the meningeal layers. This protocol presents two distinct methods for the rapid isolation of murine CNS tissues (i.e., brain, spinal cord, and meninges) that are suitable for downstream analysis via single-cell techniques, immunohistochemistry, and in situ hybridization methods. The described methods provide a comprehensive analysis of CNS tissues, ideal for assessing the phenotype, function, and localization of cells occupying the CNS compartment under homeostatic conditions and during disease pathogenesis.

This review aimed to systematically compare microbial profiles of peri-implantitis to those of periodontitis and healthy implants. Therefore, an electronic search in five databases was conducted. For inclusion, studies assessing the microbiome of peri-implantitis in otherwise healthy patients were considered. Literature was assessed for consistent evidence of exclusive or predominant peri-implantitis microbiota. Of 158 potentially eligible articles, data of 64 studies on 3730 samples from peri-implant sites were included in this study. Different assessment methods were described in the studies, namely bacterial culture, PCR-based assessment, hybridization techniques, pyrosequencing, and transcriptomic analyses. After analysis of 13 selected culture-dependent studies, no microbial species were found to be specific for peri-implantitis. After assessment of 28 studies using PCR-based methods and a meta-analysis on 19 studies, a higher prevalence of Aggregatibacter actinomycetemcomitans and Prevotella intermedia (log-odds ratio 4.04 and 2.28, respectively) was detected in peri-implantitis biofilms compared with healthy implants. Actinomyces spp., Porphyromonas spp. and Rothia spp. were found in all five pyrosequencing studies in healthy-, periodontitis-, and peri-implantitis samples. In conclusion, the body of evidence does not show a consistent specific profile. Future studies should focus on the assessment of sites with different diagnosis for the same patient, and investigate the complex host-biofilm interaction.

Cerebrospinal fluid (CSF), a fluid found in the brain and the spinal cord, is of great importance to both basic and clinical science. The analysis of the CSF protein composition delivers crucial information in basic neuroscience research as well as neurological diseases. One caveat is that proteins measured in CSF may derive from both intrathecal synthesis and transudation from serum, and protein analysis of CSF can only determine the sum of these two components. To discriminate between protein transudation from the blood and intrathecally produced proteins in animal models as well as in humans, CSF protein profiling measurements using conventional protein analysis tools must include the calculation of the albumin CSF/serum quotient (Qalbumin), a marker of the integrity of the blood-brain interface (BBI), and the protein index (Qprotein/Qalbumin), an estimate of intrathecal protein synthesis. This protocol illustrates the entire procedure, from CSF and blood collection to quotients and indices calculations, for the quantitative measurement of intrathecal protein synthesis and BBI impairment in mouse models of neurological disorders.

Persistent central nervous system (CNS) inflammation, as seen in chronic infections or inflammatory demyelinating diseases such as Multiple Sclerosis (MS), results in the accumulation of various B cell subsets in the CNS, including naïve, activated, memory B cells (Bmem), and antibody secreting cells (ASC). However, factors driving heterogeneous B cell subset accumulation and antibody (Ab) production in the CNS compartment, including the contribution of ectopic lymphoid follicles (ELF), during chronic CNS inflammation remain unclear and is a major gap in our understanding of neuroinflammation. We sought to address this gap using the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model of progressive MS. In this model, injection of the virus into susceptible mouse strains results in a persistent infection associated with demyelination and progressive disability. During chronic infection, the predominant B cell phenotypes accumulating in the CNS were isotype-switched B cells, including Bmem and ASC with naïve/early activated and transitional B cells present at low frequencies. B cell accumulation in the CNS during chronic TMEV-IDD coincided with intrathecal Ab synthesis in the cerebrospinal fluid (CSF). Mature and isotype-switched B cells predominately localized to the meninges and perivascular space, with IgG isotype-switched B cells frequently accumulating in the parenchymal space. Both mature and isotype-switched B cells and T cells occupied meningeal and perivascular spaces, with minimal evidence for spatial organization typical of ELF mimicking secondary lymphoid organs (SLO). Moreover, immunohistological analysis of immune cell aggregates revealed a lack of SLO-like ELF features, such as cell proliferation, cell death, and germinal center B cell markers. Nonetheless, flow cytometric assessment of B cells within the CNS showed enhanced expression of activation markers, including moderate upregulation of GL7 and expression of the costimulatory molecule CD80. B cell-related chemokines and trophic factors, including APRIL, BAFF, CXCL9, CXCL10, CCL19, and CXCL13, were elevated in the CNS. These results indicate that localization of heterogeneous B cell populations, including activated and isotype-switched B cell phenotypes, to the CNS and intrathecal Ab (ItAb) synthesis can occur independently of SLO-like follicles during chronic inflammatory demyelinating disease.

Background: The mechanisms driving multiple sclerosis (MS), the most common cause of non-traumatic disability in young adults, remain unknown despite extensive research. Especially puzzling are the underlying molecular processes behind the two major disease patterns of MS: relapsing-remitting and progressive. The relapsing-remitting course is exemplified by acute inflammatory attacks, whereas progressive MS is characterized by neurodegeneration on a background of mild-moderate inflammation. The molecular and cellular features differentiating the two patterns are still unclear, and the role of inflammation during progressive disease is a subject of active debate., Methods: We performed a comprehensive analysis of the intrathecal inflammation in two clinically distinct mouse models of MS: the PLP 139-151 -induced relapsing experimental autoimmune encephalomyelitis (R-EAE) and the chronic progressive, Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Microarray technology was first used to examine global gene expression changes in the spinal cord. Inflammation in the spinal cord was further assessed by immunohistochemical image analysis and flow cytometry. Levels of serum and cerebrospinal fluid (CSF) immunoglobulin (Ig) isotypes and chemokines were quantitated using Luminex Multiplex technology, whereas a capture ELISA was used to measure serum and CSF albumin levels. Finally, an intrathecal Ig synthesis index was established with the ratio of CSF and serum test results corrected as a ratio of their albumin concentrations., Results: Microarray analysis identified an enrichment of B cell- and Ig-related genes upregulated in TMEV-IDD mice. We also demonstrated an increased level of intrathecal Ig synthesis as well as a marked infiltration of late differentiated B cells, including antibody secreting cells (ASC), in the spinal cord of TMEV-IDD, but not R-EAE mice. An intact blood-brain barrier in TMEV-IDD mice along with higher CSF levels of CXCL13, CXCL12, and CCL19 provides evidence for an intrathecal synthesis of chemokines mediating B cell localization to the central nervous system (CNS)., Conclusions: Overall, these findings, showing increased concentrations of intrathecally produced Igs, substantial infiltration of ASC, and the presence of B cell supporting chemokines in the CNS of TMEV-IDD mice, but not R-EAE mice, suggest a potentially important role for Igs and ASC in the chronic progressive phase of demyelinating diseases.

Objective: The aim of this study was to assess the short-term effectiveness of an intensive inpatient multidimensional rehabilitation program (MRP), including diet, exercise, and behavioral therapy, in elderly patients with severe obesity., Methods: Forty-four elderly patients (old; age 69.3 ± 3.5 years, BMI 41.9 ± 14.9) were analyzed against 215 younger patients (young; age 48.2 ± 18.5 years, BMI 43.9 ± 9.4), who were used as controls. All patients underwent MRP, based on group therapy guided by a multidisciplinary team (physicians, dietitians, exercise trainers, psychologists). We evaluated changes in anthropometry, cardiovascular risk factors, physical fitness, quality of life, and eating behavior., Results: After 3 weeks of MRP, we observed a reduction in body weight (old -3.8%, young -4.3%), BMI (old -3.9%, young -4.4%), waist circumference (old -3.4%, young -4.1%), total cholesterol (old -14.0%, young -15.0%), and fasting glucose (old -8.3%, young -8.1%), as well as improved performance in the Six-Minute-Walk Test (old +28.7%, young +15.3%), chair-stand test (old +24.8%, young +26.9%), and arm-curl test (old +15.2%, young +27.3%). Significant improvement was registered in all other analyzed domains., Conclusion: Our 3-week MRP provided significant clinical and functional improvement, which was similar between elderly and younger patients with severe obesity. In the long-term, this may be translated into better quality of life, through better management of obesity-associated morbidities and reduced frailty., (© 2019 The Author(s) Published by S. Karger AG, Basel.)