The global epidemic of overweight and obesity threatens gynecological and reproductive health, necessitating effective therapeutic strategies to improve maternal and fetal long-term health outcomes. This review provides an overview of weight loss interventions and discusses their use in the context of gestation, such as surgical interventions and anti-obesity medications. As the interest in incretin-based therapies has risen substantially, we discuss how incretin-based therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists and GLP-1 receptor agonists and glucose-dependent insulinotropic polypeptide (GIP) dual agonists, might improve reproductive function and could interact with the physiological metabolic changes ensuring a healthy pregnancy. These metabolic adaptations during pregnancy arise from the integration of insulin signaling, lipid metabolism, placental endocrine function, mitochondrial remodeling and inflammatory regulation. Furthermore, we consider not only short-term consequences of maternal overweight and obesity but also focus on fetal long-term health trajectories following pregnancy-related metabolic disorders, as maternal obesity and gestational weight gain are considered risk factors for childhood obesity and overweight.
Neuroimmunological diseases arise from a complex interplay of genetic susceptibility, environmental exposures, and immune-mediated mechanisms. In this context, modifiable lifestyle and environmental factors may contribute to disease risk and disease course, at least in a subset of patients. Accordingly, while disease-modifying immunotherapy remains the cornerstone of treatment, lifestyle-related factors are increasingly recognized as relevant targets for prevention and supportive disease management. This review summarizes current evidence on physical activity, nutrition, substance use, sleep, stress, rehabilitation, and digital health interventions across all levels of prevention—primary to quaternary. Physical activity exerts immunomodulatory and potential neuroprotective effects through pathways involving cytokines, growth factors, cerebral perfusion, and immune cell redistribution, and is associated with improvements in symptoms, function, and quality of life. Nutritional factors, including obesity and vitamin D deficiency, may be associated with MS risk and disease progression, whereas evidence for specific diets or supplements remains limited. Smoking represents a well-established modifiable risk factor for both MS disease development and progression, while findings regarding alcohol consumption are inconsistent. Sleep disturbances and chronic stress could influence immune regulation and symptom burden and may act as both risk and disease-modifying factors. Rehabilitation constitutes a cornerstone of tertiary prevention, and emerging digital technologies, including tele-exercise and virtual reality, may offer promising low-threshold strategies to support long-term self-management. Overall, lifestyle and behavioral interventions represent powerful, supportive and complementary tools in neuroimmunology, that may enhance overall health and disease management. High-quality interventional studies are required to define the optimal role of preventive strategies alongside immunotherapy.
Somatic KRAS (KRAS G12V ) mutation in endothelial cells (EC) induces brain arteriovenous malformation (bAVM) that could lead to vascular instability and ultimately bleeding. However, the causes of bAVM instability remain unclear. Here we demonstrate that KRAS G12V expressing cultured ECs (KRAS-G12V-EC) have increased expression of pro-inflammatory mediators and reduced expression of blood-brain-barrier (BBB) junction constituents. The conditioned medium from KRAS-G12V-EC can activate BV2-microglia (BV2-MG) and conditioned media from this primed BV2-MG can compromise the expression of EC-junction constituents when added to wild-type ECs. In an in vitro BBB model, KRAS-G12V-EC form a dysfunctional EC barrier that is further disrupted, leading to lower transendothelial electrical resistance and increased FITC-dextran leakage when blood-derived macrophages (Mφ) are included. KRAS-G12V-EC potently stimulates BV2-MG chemotaxis. In vitro BBB leakage and BV2-MG chemotaxis were inhibited by treatment with the anti-inflammatory drug minocycline in the KRAS-G12V-EC. In our bAVM mouse model that uses AAV-BR1-KRAS G12V injection to produce EC expression of KRAS G12V in the brain, minocycline injection reduced production of inflammatory cytokines by bAVM nidus, reduced leakage of BSA-647, and restored VE-cadherin expression on malformed vessels. Our findings suggest that KRAS-G12V-EC can activate local MG/Mφ that causes vascular inflammation and instability of malformed vessels in bAVM.
Abstract Background As improvements in anti-cancer treatments have extended survival, patients with advanced cancer and their family caregivers face existential tension between engaging in life and coping with uncertainty about illness trajectory and the course of treatment. For a subgroup, this tension is associated with overwhelming fear and existential distress. Such adjustment difficulties may increase the risk of mental disorders, poor quality of life, and suicidality, and impair prognostic awareness and patient-clinician communication. Despite growing interest in open conversations about end-of-life issues, systematic evidence on effective psychotherapies to best support psychological adaptation in patients with high levels of existential distress is still scarce. We aim to evaluate the effectiveness of a short-term psychodynamic therapy (ORPHYS) to mitigate existential distress compared to usual psycho-oncological treatment (TAU). Methods We conduct a two-arm parallel randomized controlled trial with an active control group. ORPHYS is a manualized individual face-to-face psychotherapy focusing on emotional and relational conflicts specific to cancer patients’ illness situation. Treatment lasts between 5 and 11 months with 15 to 31 weekly sessions (50 min). TAU includes at least one individual session provided by physicians or psychologists with experience in psycho-oncological care. Patients will be assessed pre-intervention and 3, 6, 9, and 12 months after baseline. Target sample size is 160 randomized participants. We recruit patients with stage III/IV solid tumors or advanced hematological cancer and clinically significant existential distress from psycho-oncology clinics and referring oncologists at Hamburg, Düsseldorf, and Würzburg Comprehensive Cancer Centers, Germany. The primary outcome is demoralization (Demoralization Scale-II). Secondary outcomes include diagnoses of affective, anxiety and stress-related disorders, death anxiety, dignity-related distress, and quality of life. Outcome assessments are conducted via self-report questionnaires and diagnostic interviews. Linear mixed models examine outcome differences between trial arms. A confirmatory test of the group contrast at 6-month follow-up after baseline is conducted. Discussion Due to an aging population and prolonged survival, there is a growing demand to help patients deal with existential challenges undergoing palliative cancer care. The study will contribute to knowledge about how clinicians can best help patients with advanced cancer who substantially struggle with uncertainty at the end of life. Trial registration German Clinical Trials Registry, DRKS00038173. Registered October 20th, 2025, https://drks.de/search/en/trial/DRKS00038173 . ClinicalTrials.gov, NCT07312760. Registered December 30, 2025, https://clinicaltrials.gov/study/NCT07312760 .
Impaired cerebellar influence on motor cortical excitability and plasticity has been reported in cervical dystonia (CD) patients, accompanied by the absence of cerebellar brain inhibition (CBI). Polarity-specific modulation of CBI in healthy individuals using cerebellar transcranial direct current stimulation (ctDCS) suggested that ctDCS could normalize abnormal cerebellar output and improve clinical symptom severity in CD. The objective of this study was to determine whether anodal or cathodal ctDCS can modulate neurophysiological parameters of cortico-cortical, cerebello-cortical or afferent inhibition and improve motor symptom severity in CD patients. Fifteen patients with isolated CD participated in a randomized, double-blinded crossover study consisting of three sessions of anodal, cathodal, or sham ctDCS. Before and after each intervention, motor symptom severity and inhibitory circuits of the sensorimotor network were investigated using transcranial magnetic stimulation (TMS), including short-interval intracortical inhibition (SICI), short-latency afferent inhibition (SAI) and CBI. Baseline TMS measurements showed inhibitory influence of SICI (p < 0.001) and SAI (p < 0.001) in CD patients, whereas CBI had no inhibitory effect (p = 0.281). The different ctDCS interventions caused no significant modulation in any of the inhibitory TMS paradigms investigated. Similarly, motor symptom severity remained unchanged after the ctDCS interventions. A single session of ctDCS was not effective to modulate inhibitory circuits of the sensorimotor network in isolated CD patients. Future studies focusing on repetitive ctDCS interventions or multifocal stimulation protocols are needed to assess the influence on network excitability and connectivity as well as on motor symptoms.
