Efectos sobre los procesos cognitivos del entrenamiento basado en doble tarea en personas con enfermedad de Parkinson: una revisión sistemática / Effects on cognitive processes of dual-task training in people with Parkinson’s disease: a systematic review

Introducción: La doble tarea es una intervención no farmacológica en personas con condiciones neurodegenerativas, utilizada en la enfermedad de Parkinson (EP), principalmente para favorecer el desempeño motor. El objetivo de esta revisión es reunir la evidencia actual sobre cómo el entrenamiento de doble tarea afecta a los procesos cognitivos en personas que presenten EP. Material y métodos. Se desarrolló una revisión sistemática, aplicando las directrices de PRISMA, incluyendo artículos obtenidos en las bases de datos de PubMed, Web of Science, Science Direct y Springer Link. La calidad metodológica se evaluó mediante PEDro y ROBINS-I. Resultados: Doce artículos cumplieron con los criterios de inclusión y exclusión: nueve de ellos corresponden a ensayos controlados aleatorizados y los tres restantes fueron estudios no aleatorizados. Se identificaron mejoras en la atención y las funciones ejecutivas, aunque la diversidad en enfoques y duración dificulta llegar a conclusiones definitivas. Conclusiones: Es crucial expandir la investigación, estandarizando los programas de intervención. Del mismo modo, es importante llevar a cabo estudios longitudinales y controlados aleatorizados en muestras representativas que permitan llegar a conclusiones aplicables a otros contextos.(AU)

Introduction: Dual-tasking is a non-pharmacological intervention in people with neurodegenerative conditions, and is used in Parkinson’s disease (PD), primarily to enhance motor performance. The aim of this review is to compile the current evidence on how dual-task training affects cognitive processes in people with PD. Material and methods: A systematic review was undertaken, applying PRISMA guidelines, which included articles obtained from the PubMed, Web of Science, Science Direct and Springer Link databases. Methodological quality was assessed using PEDro and ROBINS-I. Results: Twelve articles met the inclusion and exclusion criteria: nine of them were randomized controlled trials, and the remaining three were non-randomized studies. Improvements in attention and executive functions were identified, although the diversity of approaches and duration means that reaching definitive conclusions is difficult. Conclusions: Increased research and standardized intervention programmes are essential. Longitudinal and randomized controlled studies in representative samples which provide conclusions that are applicable to other contexts are also important.(AU)

Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents.

Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in several neurological and neuropsychiatric disorders, including Parkinson´s disease, dystonia, tremor, and obsessive-compulsive disorder (OCD) for which DBS is already applied to alleviate severely afflicted individuals of symptoms. Tourette syndrome and drug addiction are two additional disorders for which DBS is in trial or proposed as treatment. However, some major remaining obstacles prevent this intervention from reaching its full therapeutic potential. Side-effects have been reported, and not all DBS-treated individuals are relieved of their symptoms. One major target area for DBS electrodes is the subthalamic nucleus (STN) which plays important roles in motor, affective and associative functions, with impact on for example movement, motivation, impulsivity, compulsivity, as well as both reward and aversion. The multifunctionality of the STN is complex. Decoding the anatomical-functional organization of the STN could enhance strategic targeting in human patients. The STN is located in close proximity to zona incerta (ZI) and the para-subthalamic nucleus (pSTN). Together, the STN, pSTN and ZI form a highly heterogeneous and clinically important brain area. Rodent-based experimental studies, including opto- and chemogenetics as well as viral-genetic tract tracings, provide unique insight into complex neuronal circuitries and their impact on behavior with high spatial and temporal precision. This research field has advanced tremendously over the past few years. Here, we provide an inclusive review of current literature in the pre-clinical research fields centered around STN, pSTN and ZI in laboratory mice and rats; the three highly heterogeneous and enigmatic structures brought together in the context of relevance for treatment strategies. Specific emphasis is placed on methods of manipulation and behavioral impact.

Cognitive dysfunction characteristics of multiple sclerosis with aging.

BACKGROUND: We aimed to investigate the characteristics of cognitive impairment in older people with multiple sclerosis (MS). METHODS: Cross-sectional study that included participants that were examined with a common and comprehensive neuropsychological protocol. The subjects were matched by sociodemographic variables and the following groups were generated for comparisons: young MS versus healthy controls (HC) (n = 246), old MS versus HC (n = 198), young MS vs old MS (n = 226), MS vs Alzheimer's disease (AD)(n = 70), and MS vs Parkinson's disease (PD) (n = 62). The ICCoDiMS criteria were used to define cognitive impairment in MS. RESULTS: Cognitive impairment was more frequent in young than old patients (70.8 % vs 52.2 %). Attention and speed processing is the most frequent cognitive domain impaired in MS (54.9 % of young MS vs 32.7 % of old MS). The frequency of impairment in attention/processing speed (54.9 % vs 32.7 %) and episodic memory (27.9 % vs 14.3) was higher in the young group than in the old group. There were no statistically significant differences in the distribution of impairment in executive function (46.0 % vs 35.3 %), visuospatial (17.9 % vs 9.5 %), and language (12.4 % vs 17.7 %). In those patients meeting the criteria for cognitive impairment, young MS patients showed lower performance in attention/processing speed tests. Conversely, old MS patients showed lower performance in episodic memory, verbal fluency, and planning. There were no differences in the correlations between SDMT and other neuropsychological tests in young and old patients, which suggests similar cognitive processes underlying SDMT performance in both groups. There were differences between old MS and prodromal AD, especially in episodic memory, while the cognitive profile of old MS was largely shared with PD. CONCLUSIONS: Our study found that the cognitive profile of MS is defined by a characteristic impairment in attention and processing speed, which is present during the lifespan. The impairment in processing speed is less prominent in old age, whereas the impairment of other cognitive functions becomes more relevant. These findings suggest potential differences in the pathophysiological processes associated with cognitive impairment between young and old ages that warrant further investigation.

Effects of physiotherapy and home-based training in parkinsonian syndromes: protocol for a randomised controlled trial (MobilityAPP).

INTRODUCTION: Gait and mobility impairment are pivotal signs of parkinsonism, and they are particularly severe in atypical parkinsonian disorders including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A pilot study demonstrated a significant improvement of gait in patients with MSA of parkinsonian type (MSA-P) after physiotherapy and matching home-based exercise, as reflected by sensor-based gait parameters. In this study, we aim to investigate whether a gait-focused physiotherapy (GPT) and matching home-based exercise lead to a greater improvement of gait performance compared with a standard physiotherapy/home-based exercise programme (standard physiotherapy, SPT). METHODS AND ANALYSIS: This protocol was deployed to evaluate the effects of a GPT versus an active control undergoing SPT and matching home-based exercise with regard to laboratory gait parameters, physical activity measures and clinical scales in patients with Parkinson's disease (PD), MSA-P and PSP. The primary outcomes of the trial are sensor-based laboratory gait parameters, while the secondary outcome measures comprise real-world derived parameters, clinical rating scales and patient questionnaires. We aim to enrol 48 patients per disease group into this double-blind, randomised-controlled trial. The study starts with a 1 week wearable sensor-based monitoring of physical activity. After randomisation, patients undergo a 2 week daily inpatient physiotherapy, followed by 5 week matching unsupervised home-based training. A 1 week physical activity monitoring is repeated during the last week of intervention. ETHICS AND DISSEMINATION: This study, registered as 'Mobility in Atypical Parkinsonism: a Trial of Physiotherapy (Mobility_APP)' at clinicaltrials.gov (NCT04608604), received ethics approval by local committees of the involved centres. The patient's recruitment takes place at the Movement Disorders Units of Innsbruck (Austria), Erlangen (Germany), Lausanne (Switzerland), Luxembourg (Luxembourg) and Bolzano (Italy). The data resulting from this project will be submitted to peer-reviewed journals, presented at international congresses and made publicly available at the end of the trial. TRIAL REGISTRATION NUMBER: NCT04608604.

Five-year outcomes of different techniques for minimally invasive mitral valve repair in barlow's disease.

OBJECTIVES: Barlow's disease is a specific sub-form of mitral valve (MV) disease, characterized by diffuse excessive tissue and multi segment prolapse. The anterolateral mini-thoracotomy represents the standard access for MV regurgitation in many centers. It still remains unclear which surgical technique provides the best results. Therefore, the aim of this study was to compare operative safety and mid-term outcomes after (a) isolated annuloplasty, (b) use of additional artificial chordae or (c) leaflet resection in patients suffering from Barlow's disease undergoing minimally invasive mitral valve repair. METHODS: A consecutive series of patients suffering from Barlow`s disease undergoing minimally invasive mitral valve surgery (MIMVS) between 2001-2020 were analyzed (n = 246). Patients were grouped and analyzed according to the used surgical technique. The primary outcome was a modified Mitral Valve Academic Research Consortium combined end-point of mortality, reoperation due to repair failure or reoccurrence of severe mitral regurgitation within 5 years. The secondary outcome included operative success and safety up to 30 days. RESULTS: No significant difference was found between the three surgical techniques in regard to the operative safety (p-value = 0.774). The primary outcome did not differ between groups (p-value = 0.244). Operative success was achieved in 93.5% and was lowest in the isolated annuloplasty group (77.1%). Conversion to mitral valve replacement was increased in patients undergoing isolated annuloplasty (p-value < 0.001). CONCLUSIONS: Isolated annuloplasty, use of additional artificial chordae and leaflet resection represent feasible techniques in Barlow patients undergoing MIMVS with comparable five-year results. In view of the increased conversion rate in the annuloplasty group, the pathology should not be oversimplified.

SEX-RELATED DIFFERENCES IN THE PHENOTYPE AND COURSE OF INFLAMMATORY BOWEL DISEASE: SEXEII STUDY OF ENEIDA.

BACKGROUND AND AIMS: The impact of patient sex on the presentation of inflammatory bowel disease (IBD) has been poorly evaluated. Our aims were to assess potential disparities in IBD phenotype and progression between sexes. METHODS: Observational multicentre study that included patients with Crohn's disease (CD) or ulcerative colitis (UC) from the Spanish ENEIDA registry. Data extraction was conducted in July 2021. RESULTS: 51,595 patients with IBD were included, 52% were males and 25,947 had CD. The median follow-up after diagnosis was 9 years in males and 10 in females. In CD, female sex was an independent risk factor for medium disease onset (17-40 years) (RRR 1.45, 95% CI 1.31-1.62), later disease onset (>40 years) (RRR 1.55, 95% CI: 1.38-1.73), exclusive colonic involvement (OR 1.24, 95%CI 1.14-1.34), inflammatory behaviour (OR 1.14, 95%CI 1.07-1.21) and extraintestinal manifestations (OR 1.48, 95%CI 1.38-1.59). However, female sex was a protective factor for upper gastrointestinal involvement (OR 0.84, 95%CI 0.79-0.90), penetrating behaviour (OR 0.76, 95%CI 0.70-0.82), perianal disease (OR 0.77, 95CI% 0.71-0.82) and complications (OR 0.73, 95%CI 0.66-0.80). In UC, female sex was an independent risk factor for extraintestinal manifestations (OR 1.48, 95%CI 1.26-1.61). However, female sex was an independent protective factor for disease onset from age 40 onward (RRR 0.76, IC 95%: 0.66-0.87), left sided colonic involvement (RRR 0.72, 95% CI 0.67-0.78), extensive colonic involvement (RRR 0.59, 95%CI 0.55-0.64) and abdominal surgery (OR 0.78, 95%CI 0.69-0.88). CONCLUSIONS: There is sexual dimorphism in IBD. The patient's sex should be taken into account in the clinical management of the disease.

Alterations in Gut Microbiota as Early Biomarkers for Predicting Inflammatory Bowel Disease Onset and Progression: A Systematic Review.

Inflammatory bowel disease (IBD) is a chronic ailment impacting the digestive system, triggered by an unusual reaction of the immune system. It includes two types of diseases: ulcerative colitis and Crohn's disease. Nonetheless, the diagnosis and evaluation of disease progression in IBD are difficult due to the absence of distinct indicators. While conventional biomarkers from blood plasma and feces, such as C-reactive protein, fecal calprotectin, and S100A12, can be employed to gauge inflammation, they are not exclusive to IBD. There is a broad consensus that intestinal microorganisms significantly contribute to the onset of intestinal imbalance, a condition intimately linked with the cause and development of IBD. Numerous studies have indicated that the makeup of intestinal microorganisms varies between individuals with IBD and those who are healthy, particularly concerning the diversity of microbes and the proportional prevalence of certain bacteria. A total of 1475 records underwent examination. Following the eligibility assessment, 17 reports were considered. The final review encompassed 12 studies, as five articles were excluded due to insufficient details regarding cases, controls, and comparability. This article suggests that gut microbiota has potential biomarkers for the noninvasive evaluation of IBD activity. Recognizing the microbiome linked with disease activity paves the way for the development of a group of microbiota-derived indicators to evaluate the initiation and advancement of IBD. This article discusses whether changes in gut microbial composition can serve as early indicators of IBD onset and progression.

An unusual case of adult-onset still's disease complicated with anti-complement factor H antibodies associated atypical haemolytic uraemic syndrome.

BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. CASE PRESENTATION: A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). CONCLUSION: Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.

Body map stories from Colombia: experiences of people affected by leprosy and the influence of peers during diagnosis and treatment.

INTRODUCTION: Almost one third of people affected by leprosy in Colombia suffer from disability, which often results from delayed diagnosis and treatment. We aimed to explore the experience of people affected by leprosy during the process of diagnosis and treatment and if and how this experience was influenced by peers. METHODS: A qualitative study using body map stories was conducted from October 2019 to February 2020 in Colombia. Adult people affected by leprosy were recruited through patient associations in different cities. We conducted three sessions with an average duration of 2-3 h per participant, during which the participants created a painted map of their body and chose symbols to represent their experience, while being engaged in an informal interview. The sessions were audio recorded, transcribed verbatim and analyzed thematically by an interdisciplinary team, consisting of physicians, social workers and a person affected by leprosy. RESULTS: The 17 study participants (11 female) were aged 20 to 70 years. Leprosy-related manifestations ranged from no to advanced disability. Some participants were active members of associations for people affected by leprosy. Three main themes were identified during analysis: (1) A long pathway to diagnosis, (2) Therapy as a double-edged sword and (3) The influence of other people affected by leprosy. The participants described an often years-long process until being diagnosed, which was marked by insecurities, repeated misdiagnosis, and worsening mental and physical health. Delayed diagnosis was related to late health care seeking, but also to inadequate health communication, lack of leprosy-related knowledge and negligence among health care workers. A high desire to cure motivated the participants to take their medication rigorously, despite the high treatment burden. Support from peers, either within the own social environment or provided from associations, contributed to a faster diagnosis and increased therapy adherence. Peers helped to recognize the symptoms, urged patients to seek care, recommended physicians with leprosy-related knowledge and provided a realistic example of both disease severity and curability. CONCLUSION: People affected by leprosy experience a significant burden during the process of diagnosis and treatment. Involving well-trained peers could foster early diagnosis, treatment compliance and prevention of disability.

Loss of glycine receptors in the nucleus accumbens and ethanol reward in an Alzheimer´s Disease mouse model.

Alterations in cognitive and non-cognitive cerebral functions characterize Alzheimer's disease (AD). Cortical and hippocampal impairments related to extracellular accumulation of Aß in AD animal models have been extensively investigated. However, recent reports have also implicated intracellular Aß in limbic regions, such as the nucleus accumbens (nAc). Accumbal neurons express high levels of inhibitory glycine receptors (GlyRs) that are allosterically modulated by ethanol and have a role in controlling its intake. In the present study, we investigated how GlyRs in the 2xTg mice (AD model) affect nAc functions and ethanol intake behavior. Using transgenic and control aged-matched litter mates, we found that the GlyRα2 subunit was significantly decreased in AD mice (6-month-old). We also examined intracellular calcium dynamics using the fluorescent calcium protein reporter GCaMP in slice photometry. We also found that the calcium signal mediated by GlyRs, but not GABAAR, was also reduced in AD neurons. Additionally, ethanol potentiation was significantly decreased in accumbal neurons in the AD mice. Finally, we performed drinking in the dark (DID) experiments and found that 2xTg mice consumed less ethanol on the last day of DID, in agreement with a lower blood ethanol concentration. 2xTg mice also showed lower sucrose consumption, indicating that overall food reward was altered. In conclusion, the data support the role of GlyRs in nAc neuron excitability and a decreased glycinergic activity in the 2xTg mice that might lead to impairment in reward processing at an early stage of the disease.

Integrated bioinformatics analysis for exploring potential biomarkers related to Parkinson's disease progression.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease with increasing prevalence. Effective diagnostic markers and therapeutic methods are still lacking. Exploring key molecular markers and mechanisms for PD can help with early diagnosis and treatment improvement. METHODS: Three datasets GSE174052, GSE77668, and GSE168496 were obtained from the GEO database to search differentially expressed circRNA (DECs), miRNAs (DEMis), and mRNAs (DEMs). GO and KEGG enrichment analyses, and protein-protein interaction (PPI) network construction were implemented to explore possible actions of DEMs. Hub genes were selected to establish circRNA-related competing endogenous RNA (ceRNA) networks. RESULTS: There were 1005 downregulated DECs, 21 upregulated and 21 downregulated DEMis, and 266 upregulated and 234 downregulated DEMs identified. The DEMs were significantly enriched in various PD-associated functions and pathways such as extracellular matrix organization, dopamine synthesis, PI3K-Akt, and calcium signaling pathways. Twenty-one hub genes were screened out, and a PD-related ceRNA regulatory network was constructed containing 31 circRNAs, one miRNA (miR-371a-3p), and one hub gene (KCNJ6). CONCLUSION: We identified PD-related molecular markers and ceRNA regulatory networks, providing new directions for PD diagnosis and treatment.

Sublingual apomorphine in the treatment of Parkinson's disease.

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials.

Role of virtual reality in examining the effect of fear of falling (FOF) on postural stability in individuals without and with Parkinson's disease in Egypt: a mixed-methods feasibility study protocol.

BACKGROUND: Falls are common in older people and individuals with neurological conditions. Parkinson's disease (PD) is known for postural instability causing mobility disabilities, falls and reduced quality of life. The fear of falling (FOF), a natural response to unstable balance, can worsen postural control problems. Evaluating FOF relies largely on affected persons' subjective accounts due to limited objective assessment methods available. The aim of this mixed-methods feasibility study is to develop an assessment method for FOF while in motion and walking within virtual environments. This study will assess a range of FOF-related responses, including cognitive factors, neuromuscular response and postural stability. METHODS AND ANALYSIS: This feasibility study will consist of four phases: the first two phases will include people without PD, while the other two will include people diagnosed with PD. Participants will be assessed for direct and indirect responses to real life, as well as virtual environment walking scenarios that may induce FOF. Data from questionnaires, different neurophysiological assessments, movement and gait parameters, alongside evaluations of usability and acceptability, will be collected. Semistructured interviews involving both participants and research assistants shall take place to elicit their experiences throughout different phases of the assessments undertaken. Demographic data, the scores of assessment scales, as well as feasibility, usability and acceptability of the measurement methods, will be illustrated via descriptive statistics. Movement and gait outcomes, together with neurophysiological data, will be extracted and calculated. Exploring relationships between different factors in the study will be achieved using a regression model. Thematic analysis will be the approach used to manage qualitative data. ETHICS AND DISSEMINATION: This feasibility study was approved by the Ethics Committee of the Faculty of Physical Therapy, Kafr El Sheikh University, Egypt (number: P.T/NEUR/3/2023/46). The results of this study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05931692).

[The most frequent febrile syndromes and autoinflammatory diseases in adulthood]. / Die häufigsten Fiebersyndrome und autoinflammatorischen Erkrankungen im Erwachsenenalter.

Autoinflammatory diseases are characterized by inflammatory manifestations in various organ systems, whereby recurrent febrile episodes, musculoskeletal complaints, gastrointestinal and cutaneous symptoms frequently occur accompanied by serological signs of inflammation. Autoinflammatory diseases include rare monogenic entities and multifactorial or polygenic diseases, which can manifest as a variety of symptoms in the course of time. Examples of monogenic autoinflammatory diseases are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and the recently described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory and somatic) syndrome. For non-monogenically determined autoinflammatory diseases, the most important representatives in adulthood are adult-onset Still's disease (AOSD) and the Schnitzler syndrome, in which a polygenic susceptibility and epigenetic factors are more likely to play a role.

Efficacy and safety of acupuncture therapy for Parkinson's disease with neuropsychiatric symptoms: protocol for a systematic review and meta-analysis.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are common non-motor symptoms among patients with Parkinson's disease (PD) and significantly impact their overall quality of life detrimentally. Several studies have reported the clinical effect of acupuncture therapy in treating NPS in PD. Therefore, the objective of this systematic review is to evaluate the potential inclusion of acupuncture therapy as an integral component of complementary treatment for PD with NPS. METHODS AND ANALYSIS: From their inception until 1 December 2023, we will search eight databases, including PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, China Science Periodical Database, Chinese Citation Database and China Biology Medicine disc for randomised controlled trials examining the effectiveness of acupuncture for PD with NPS. Literature screening and data extraction will be carried out independently by the authors. RevMan V.5.3 software will be used for meta-analysis, while the Cochrane risk-of-bias tool will assess the potential for bias. ETHICS AND DISSEMINATION: This systematic review protocol does not require ethical approval because it does not include private information or data of participants. This article will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022324494.

Physical Exercise-Induced Activation of NRF2 and BDNF as a Promising Strategy for Ferroptosis Regulation in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Ferroptosis, an iron-dependent form of regulated cell death, may contribute to the progression of PD owing to an unbalanced brain redox status. Physical exercise is a complementary therapy that can modulate ferroptosis in PD by regulating the redox system through the activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and brain-derived neurotrophic factor (BDNF) signaling. However, the precise effects of physical exercise on ferroptosis in PD remain unclear. In this review, we explored how physical exercise influences NRF2 and BDNF signaling and affects ferroptosis in PD. We further investigated relevant publications over the past two decades by searching the PubMed, Web of Science, and Google Scholar databases using keywords related to physical exercise, PD, ferroptosis, and neurotrophic factor antioxidant signaling. This review provides insights into current research gaps and demonstrates the necessity for future research to elucidate the specific mechanisms by which exercise regulates ferroptosis in PD, including the assessment of different exercise protocols and their long-term effects. Ultimately, exploring these aspects may lead to the development of improved exercise interventions for the better management of patients with PD.

The Impact of Microbiome Interventions on the Progression and Severity of Inflammatory Bowel Disease: A Systematic Review.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation. The dysbiotic gut microbiome likely contributes to IBD pathogenesis. Microbiome-directed therapies such as fecal microbiota transplantation (FMT), probiotics, and synbiotics may help induce and maintain remission. This systematic review aimed to determine the efficacy of microbiome interventions compared to standard therapy or placebo for IBD treatment. PubMed, EMBASE, Cochrane CENTRAL, and Web of Science were searched for randomized controlled trials on microbiome interventions in IBD from inception to October 2023. The risk of bias was assessed using Cochrane tools. Outcomes included disease activity, endoscopy, histology, quality of life, and adverse events. A total of 18 randomized controlled trials were included. Three trials found intensive (i.e., high frequency of administration and/or large volumes of fecal material) multi-donor FMT superior to autologous FMT or glucocorticoids for UC remission induction. Seven placebo-controlled trials demonstrated higher remission rates with FMT, especially intensive protocols, versus control for mild-to-moderate UC. However, a single FMT did not prevent relapses. Seven probiotic trials showed the potential to improve UC activity and maintain remission. One synbiotic trial reported reduced inflammation and symptoms versus placebo. Serious adverse events were rare. Small sample sizes and protocol heterogeneity limited the conclusions. Current evidence indicates the potential benefits of microbiome interventions, particularly intensive multi-donor FMT, for inducing and maintaining remission in UC. Probiotics may also improve outcomes. Adequately powered trials using standardized protocols are still needed to firmly establish efficacy and safety. Microbiome-directed therapies represent a promising approach for improving IBD outcomes.

Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity.

Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b+ cells and astrocytes in the α-synuclein overexpression mouse model of Parkinson´s disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b+ cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b+ cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.

The need for surgery in pediatric patients with inflammatory bowel disease treated with biologicals.

PURPOSE: Inflammatory bowel disease (IBD) in childhood often presents with a more extensive and more aggressive disease course than adult-onset disease. We aimed to evaluate if biological treatment started in childhood decreases the need for intestinal surgery over time. METHODS: This was a retrospective, single-center, cohort study. All pediatric patients with IBD initiated to biological therapy at the Children's Hospital, were included in the study and followed up to the first surgical procedure or re-operation in their adulthood or until 31.12.2021 when ≥ 18 of age. Data were collected from the pediatric registry of IBD patients with biologicals and medical charts. RESULTS: A total of 207 pediatric IBD patients were identified [150 with Crohn´s disease (CD), 31 with ulcerative colitis (UC), 26 with IBD unclassified (IBDU)] of which 32.9% (n = 68; CD 49, UC 13, IBDU 6) underwent intestinal surgery. At the end of a median follow-up of 9.0 years (range 2.0-25.9), patients reached a median age of 21.4 years (range 18-36). Patients who had intestinal surgery in childhood were more likely to have IBD-related surgery also in early adulthood. The duration of the disease at induction of the first biological treatment emerged as the only risk factor, with a longer duration in the surgical group than in patients with no surgery. CONCLUSION: Despite initiation of biological treatment, the risk of intestinal surgery remains high in pediatric IBD patients and often the need for surgery emerges after the transition to adult IBD clinics.