ABSTRACT
Over the past 25 years, hematopoietic stem cell transplantation (HSCT) has been evolving as specific treatment for patients with severe and refractory systemic autoimmune diseases, where mechanistic studies have provided evidence for a profound immune renewal facilitating the observed beneficial responses. In addition to autoimmune neurologic diseases, such as multiple sclerosis (MS) or neuromyelitis optica (NMO), rheumatic diseases with central or peripheral nervous system involvement and insufficient response to conventional immunosuppressive or biologic therapies represent a growing indication for autologous HSCT. They most commonly include connective tissue diseases, such as systemic lupus erythematosus (SLE), vasculitides, or rarer diseases from the autoinflammatory spectrum, such as Behçet's disease, where neurologic manifestations may represent the greatest disease burden. Neurologic manifestations may resemble those of MS, including myelitis optic neuropathy, stroke, or seizures. Outcomes of such manifestations are variable after autologous HSCT but most frequently improve or even resolve with the underlying disease, especially in SLE. This article will provide the current evidence and summarize the outcomes of HSCT for rheumatic autoimmune diseases with neurologic manifestations.
Subject(s)
Autoimmune Diseases , Hematopoietic Stem Cell Transplantation , Humans , Hematopoietic Stem Cell Transplantation/methods , Autoimmune Diseases/therapy , Nervous System Diseases/therapy , Nervous System Diseases/etiologyABSTRACT
Electroconvulsive therapy (ECT) demonstrates favorable outcomes in the management of severe depressive disorders. ECT has been consistently associated with volumetric increases in the amygdala and hippocampus. However, the underlying mechanisms of these structural changes and their association to clinical improvement remains unclear. In this cross-sectional structural MRI study, we assessed the difference in amygdala subnuclei and hippocampus subfields in n = 37 patients with either unipolar or bipolar disorder immediately after eighth ECT sessions compared to (n = 40) demographically matched patients in partial remission who did not receive ECT (NoECT group). Relative to NoECT, the ECT group showed significantly larger bilateral amygdala volumes post-treatment, with the effect originating from the lateral, basal, and paralaminar nuclei and the left corticoamydaloid transition area. No significant group differences were observed for the hippocampal or cortical volumes. ECT was associated with a significant decrease in depressive symptoms. However, there were no significant correlations between amygdala subnuclei volumes and symptom improvement. Our study corroborates previous reports on increased amygdalae volumes following ECT and further identifies the subnuclei driving this effect. However, the therapeutic effect of ECT does not seem to be directly related to structural changes in the amygdala.
ABSTRACT
INTRODUCTION: The role of uric acid (UA) on bone metabolism is controversially discussed. Higher UA levels have been associated with higher T-scores and a reduced incidence of fractures in postmenopausal women. However, in the context of rheumatoid arthritis (RA), the role of UA remains unclear. This pilot study aimed to investigate the association of UA levels with bone mineral density in RA female and male patients. METHODS: This pilot study analyzed patients with RA to explore preliminary associations. We utilized data from the Rh-GIOP cohort, a prospective monocentric observational study focusing on bone health in chronic rheumatic diseases. To assess the association between UA levels and the lowest T-scores measured at the lumbar spine, hip, or femur, we used linear regression with adjustment for various confounders. An interaction term was included to evaluate differential associations in pre- and postmenopausal women. RESULTS: Data on dual X-ray absorptiometry (DXA) measurements and serum UA levels were analyzed in a total of 206 patients. Among the 167 women 16 were premenopausal (age 40 ± 8 years) and 149 postmenopausal (age 65 ± 10 years). As expected, postmenopausal had lower T-scores than premenopausal patients (-1.53 ± 1.01 versus - 0.41 ± 1.29, respectively). No association of UA levels with T-scores was found when analyzing the whole cohort (Slope ß: -0.04; p = 0.45). However, a significant negative correlation of UA with T-scores in premenopausal (Slope ß: -0.98; p = 0.014), but not postmenopausal (Slope ß: -0.04; p > 0.05) women was found. CONCLUSION: Uric acid appears to be negatively associated with bone mineral density in premenopausal but not in postmenopausal women with RA. Thus, the impact of UA on bone health seems to depend on the hormonal status of women. Further investigations are required to validate these results in a larger cohort of patients and to investigate the underlying mechanisms.
ABSTRACT
Background: Over the last 3 decades, hematopoietic stem cell transplantation (HSCT) has been successfully used to treat severe and refractory autoimmune diseases (AIDs). A multidisciplinary appraisal of potential benefits and risks by disease and transplant specialists is essential to determine individual suitability for HSCT. Objective: Our aim was to observe that patient-reported outcomes (PROs) and health-related quality of life instruments can capture the unique patient perspective on disease burden and impact of treatment. Methods: Herein, we describe the basis and complexity of end points measuring patient-reported perceptions of efficacy and tolerability used in clinical practice and trials for patients with AIDs undergoing autologous HSCT. Results: PRO measures and patient-reported experience measures are key tools to evaluate the impact and extent of disease burden for patients affected by AIDs. For formal scientific assessment, it is essential that validated general instruments are used, whereas adaptations have resulted in disease-specific instruments that may help guide tailored interventions. An additional approach relates to qualitative evaluations, from carefully structured qualitative research to informal narratives, as patient stories. The patients' subjectively reported responses to HSCT may be influenced by their preprocedure expectations and investment in the HSCT journey. Conclusions: The complexity of AIDs advocates for individualized and multidisciplinary approach to positively affect the patient journey. PROs and health-related quality of life need to be collected using validated instruments in clinical practice and trials to enable robustness of data and to ensure the impact of the intervention is comprehensively assessed, addressing the main questions and needs of the involved stakeholders.
ABSTRACT
Despite the use of 'high efficacy' disease-modifying therapies, disease activity and clinical progression of different immune-mediated neurological diseases continue for some patients, resulting in accumulating disability, deteriorating social and mental health, and high economic cost to patients and society. Although autologous hematopoietic stem cell transplant is an effective treatment modality, it is an intensive chemotherapy-based therapy with a range of short- and long-term side-effects. Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of B-cell and other hematological malignancies, conferring long-term remission for otherwise refractory diseases. However, the toxicity of this treatment, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and the complexity of production necessitate the need for a high level of specialization at treating centers. Early-phase trials of CAR-T therapies in immune-mediated B cell driven conditions, such as systemic lupus erythematosus, neuromyelitis optica spectrum disorder and myasthenia gravis, have shown dramatic clinical response with few adverse events. Based on the common physiopathology, CAR-T therapy in other immune-mediated neurological disease, including multiple sclerosis, chronic inflammatory polyradiculopathy, autoimmune encephalitis, and stiff person syndrome, might be an effective option for patients, avoiding the need for long-term immunosuppressant medications. It may prove to be a more selective immunoablative approach than autologous hematopoietic stem cell transplant, with potentially increased efficacy and lower adverse events. In this review, we present the state of the art and future directions of the use of CAR-T in such conditions. ANN NEUROL 2024;96:441-452.
Subject(s)
Immunotherapy, Adoptive , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/immunology , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/adverse effects , Nervous System Diseases/therapy , Nervous System Diseases/immunologyABSTRACT
Complexes of ERLIN1 and ERLIN2 (ER lipid raft-associated 1 and 2) form large ring-like cup-shaped structures on the endoplasmic reticulum (ER) membrane and serve as platforms to bind cholesterol and E3 ubiquitin ligases, potentially defining functional nanodomains. Here, we show that ERLIN scaffolds mediate the interaction between the full-length isoform of TMUB1 (transmembrane and ubiquitin-like domain-containing 1) and RNF170 (RING finger protein 170). We identify a luminal N-terminal conserved region in TMUB1 and RNF170, which is required for this interaction. Three-dimensional modelling shows that this conserved motif binds the stomatin/prohibitin/flotillin/HflKC domain of two adjacent ERLIN subunits at different interfaces. Protein variants that preclude these interactions have been previously linked to hereditary spastic paraplegia. Using omics-based approaches in combination with phenotypic characterization of HeLa cells lacking both ERLINs, we demonstrate a role of ERLIN scaffolds in limiting cholesterol esterification, thereby favouring cholesterol transport from the ER to the Golgi apparatus and regulating Golgi morphology and the secretory pathway.
Subject(s)
Cholesterol , Endoplasmic Reticulum , Golgi Apparatus , Membrane Proteins , Secretory Pathway , Ubiquitin-Protein Ligases , Humans , Membrane Proteins/metabolism , Cholesterol/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Endoplasmic Reticulum/metabolism , HeLa Cells , Golgi Apparatus/metabolism , Protein Binding , Nerve Tissue ProteinsABSTRACT
OBJECTIVE: To assess the effect of proton pump inhibitor (PPI) use on bone mineral density (BMD) and bone microarchitecture as measured by the trabecular bone score (TBS) in patients with inflammatory rheumatic and musculoskeletal diseases (iRMDs). METHODS: Cross-sectional data from a prospective single-center cohort (2015 to 2022) of patients with iRMDs were used to evaluate 3 co-primary outcomes: BMD of the left femoral neck and the lumbar spine (as T-scores) and the TBS. Inverse probability weighting adjusted for numerous confounders including age, sex, body mass index, current and cumulative glucocorticoid (GC) dose, C-reactive protein levels, disability, and others. Analyses were based on general linear models, following a prespecified statistical analysis plan. RESULTS: The study included 1495 patients (75% women; mean age, 62.6±13.1 years; 49% and 63% with regular PPI and GC use, respectively). The PPI users had lower BMD at both spine (adjusted contrast -0.25; 95% CI, -0.47 to -0.04; P=.02) and femoral neck (-0.17 [-0.35 to 0.01]; P=.07). Differences between PPI users and nonusers were statistically significant only in patients concurrently using GCs at more than 7.5 mg/d prednisone equivalent. The TBS was similar in PPI users and nonusers (adjusted contrast, 0.00 [-0.04 to 0.04]; P=.97). CONCLUSION: Our results suggest that PPIs lead to a loss of BMD rather than an impairment of bone microarchitecture in patients with iRMDs. The negative association between PPI use and BMD appears to be dependent on concurrent GC use. Clinicians should carefully review the indication for PPI use in patients with iRMDs, especially in those receiving higher dose GCs.
Subject(s)
Bone Density , Proton Pump Inhibitors , Rheumatic Diseases , Humans , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/administration & dosage , Female , Male , Cross-Sectional Studies , Middle Aged , Bone Density/drug effects , Rheumatic Diseases/drug therapy , Rheumatic Diseases/complications , Prospective Studies , Aged , Glucocorticoids/adverse effects , Glucocorticoids/administration & dosage , Femur Neck/diagnostic imaging , Lumbar Vertebrae/drug effects , Lumbar Vertebrae/diagnostic imagingABSTRACT
Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is a common gynecologic tumor and patients with advanced and recurrent disease usually have a poor clinical outcome. Angiogenesis is involved in the biological processes of tumors and can promote tumor growth and invasion. In this paper, we created a signature for predicting prognosis based on angiogenesis-related lncRNAs (ARLs). This provides a prospective direction for enhancing the efficacy of immunotherapy in CESC patients. We screened seven OS-related ARLs by univariate and multivariate regression analyses and Lasso analysis and developed a prognostic signature at the same time. Then, we performed an internal validation in the TCGA-CESC cohort to increase the precision of the study. In addition, we performed a series of analyses based on ARLs, including immune cell infiltration, immune function, immune checkpoint, tumor mutation load, and drug sensitivity analysis. Our created signature based on ARLs can effectively predict the prognosis of CESC patients. To strengthen the prediction accuracy of the signature, we built a nomogram by combining signature and clinical features.
ABSTRACT
Autoimmune diseases (ADs) represent a heterogeneous group of conditions affecting 5-10% of the global population. In recent decades, hematopoietic stem cell transplant (HSCT), mainly autologous, has been successfully adopted to treat patients affected by severe/refractory ADs. In this context malnutrition has a detrimental impact on relapse, mortality, infection rate, engraftment, long-term survival, and prolongation of hospitalization. However, in this population, the management of nutrition should be improved since nutritional assessment is partially performed in routine clinical practice. A panel of nurses and physicians from the European Society for Blood and Marrow Transplantation (EBMT) reviewed all available evidence based on current literature and expert practices from centers with extensive experience in HSCT for ADs, on the nutritional management of ADs patients during HSCT procedure. In this context, adequate nutritional status predicts a better response to treatment and improves quality of life. Herein, a systematic and comprehensive monitoring of nutritional status before, during and after HSCT, with adequate nutritional support in the case of ADs patients, in addition to assessing the dietary requirements associated with HSCT has been covered. Moreover, given the singularity of each AD, the underlying disease should be considered for an appropriate approach. The management and evaluation of nutritional status must be carried out by a multidisciplinary team to assess the needs, monitor the effectiveness of each intervention, and prevent complications, especially in complex situations as patients affected by ADs.
ABSTRACT
In the National database (NDB) of the German regional collaborative arthritis centres, annual data on the rheumatological care of patients with inflammatory rheumatic diseases have been collected since 1993. This first annual report presents current cross-sectional data on medication and patient-reported outcomes gathered in 2022.
ABSTRACT
Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors originating from perivascular epithelioid cells. In gynecological system, the uterus is one of the most common sites affected by PEComas. Most PEComas are benign, and patients usually have a good prognosis. However, malignant uterus PEComa is rare, and better comprehensive epidemiological investigations are needed. To date, there are a few reported cases of uterus PEComa. We herein report a rare case of malignant PEComa occurred in the uterine corpus and cervix, possibly accompanied by pulmonary lymphangioleiomyomatosis (PLAM). In addition, 55 cases of malignant uterus PEComa were picked out and collected in the data base of PubMed and Medline. On the one hand, the age of onset, population distribution, clinical manifestations, metastatic sites and routes of metastasis were analysed. On the other hand, a summary of the epidemiology, pathogenesis, diagnosis, and treatments of uterus PEComa was given.
ABSTRACT
BACKGROUND: Pediatric generalized anxiety disorder (GAD) is debilitating and increasingly prevalent, yet its etiology remains unclear. Some believe the disorder to be propagated by chronic dysregulation of the limbic-hypothalamic-pituitary-adrenal (L-HPA) axis, but morphometric studies of implicated subcortical areas have been largely inconclusive. Recognizing that certain subcortical subdivisions are more directly involved in L-HPA axis functioning, this study aims to detect specific abnormalities in these critical areas. METHODS: Thirty-eight MRI scans of preschool children with (n = 15) and without (n = 23) GAD underwent segmentation and between-group volumetric comparisons of the basolateral amygdala (BLA), ventral hippocampal subiculum (vSC), and mediodorsal medial magnocellular (MDm) area of the thalamus. RESULTS: Children with GAD displayed significantly larger vSC compared to healthy peers, F(1, 31) = 6.50, pFDR = .048. On average, children with GAD presented with larger BLA and MDm, Fs(1, 31) ≥ 4.86, psFDR ≤ .054. Exploratory analyses revealed right-hemispheric lateralization of all measures, most notably the MDm, F(1, 31) = 8.13, pFDR = .024, the size of which scaled with symptom severity, r = .83, pFDR = .033. CONCLUSION: The BLA, vSC, and MDm are believed to be involved in the regulation of anxiety and stress, both individually and collectively through the excitation and inhibition of the L-HPA axis. All were found to be enlarged in children with GAD, perhaps reflecting hypertrophy related to hyperexcitability, or early neuronal overgrowth. Longitudinal studies should investigate the relationship between these early morphological differences and the long-term subcortical atrophy previously observed.
Subject(s)
Amygdala , Anxiety Disorders , Hippocampus , Hypothalamo-Hypophyseal System , Magnetic Resonance Imaging , Thalamus , Humans , Male , Female , Anxiety Disorders/diagnostic imaging , Anxiety Disorders/pathology , Anxiety Disorders/physiopathology , Amygdala/pathology , Amygdala/diagnostic imaging , Amygdala/physiopathology , Child , Hippocampus/pathology , Hippocampus/diagnostic imaging , Thalamus/diagnostic imaging , Thalamus/pathology , Thalamus/physiopathology , Hypothalamo-Hypophyseal System/physiopathology , Hypothalamo-Hypophyseal System/pathology , Hypothalamo-Hypophyseal System/metabolism , Child, Preschool , Pituitary-Adrenal System/physiopathology , Pituitary-Adrenal System/pathologyABSTRACT
INTRODUCTION: The progressive nature of Parkinson's disease (PD) affords emphasis on accurate early-stage individual-level assessment of risk and intervention appropriateness. In PD, cognitive impairment (CI) may follow or precede motor symptoms but are generally underdetected. In addition to impeding daily functioning and quality of life, CIs increase the risk for later conversion to dementia, providing a pressing need to develop novel tools to detect and interpret them. Connectome-based predictive modelling (CPM) is an emerging machine-learning approach to individual prediction that holds translational promise due to its noninvasiveness and simple implementation. The aim of this study was to investigate CPM's potential to predict and understand CIs in PD. METHODS: Resting-state functional connectivity from 58 patients with PD of varying cognitive status was used to train a CPM-model to predict a global cognitive composite (GCC) score. The model was validated using cross-validation, permutation testing, and internal stability analyses. The combined predictive strength of two brain connectivity networks, positive and negative, directly and inversely correlated with GCC, respectively, was assessed. RESULTS: The model significantly predicted individual GCC scores, râ¯=â¯0.63, pperm < .05. Separately, the positive and negative networks were similar in performance, rsâ¯≥â¯.58, psâ¯<â¯.05, but varied in anatomical distribution. CONCLUSIONS: This study identified a connectome predictive of cognitive scores in PD, with features overlapping with established and emerging evidence on aberrant connectivity in PD-related CIs. Overall, CPM appears promising for clinical translation in this population, but longitudinal studies with out-of-sample validation are needed.
Subject(s)
Cognitive Dysfunction , Connectome , Magnetic Resonance Imaging , Parkinson Disease , Humans , Parkinson Disease/physiopathology , Parkinson Disease/complications , Parkinson Disease/diagnostic imaging , Male , Female , Aged , Middle Aged , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/diagnostic imaging , Machine Learning , Nerve Net/diagnostic imaging , Nerve Net/physiopathology , Brain/diagnostic imaging , Brain/physiopathologyABSTRACT
Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated.
ABSTRACT
Primary small bowel adenocarcinoma (SBA) is a rare gastrointestinal cancer with a low incidence of ovarian metastasis. Differential diagnosis of metastatic and primary ovarian cancer is often challenging. The present study reported the case of a 45-year-old woman with jejunal adenocarcinoma who presented with right ovarian, left ovarian, abdominopelvic implant and local recurrent bowel wall metastases successively after primary tumor resection. The ovarian masses of the patient originated from SBA, which was confirmed by immunohistochemical results. Following four comprehensive evaluations by an experienced multidisciplinary team (MDT) during the disease period, the patient underwent four operations, 28 cycles of chemotherapy, 24 cycles of targeted therapy and maintenance therapy for 8 months. As of February 2023, the patient has survived for 73 months and has a high quality of life. It is suggested that when a patient with SBA presents with an ovarian mass, the differential diagnosis between metastatic ovarian cancer and primary ovarian cancer mainly relies on immunohistochemistry. After a comprehensive evaluation by an experienced MDT, surgical resection is the primary treatment for advanced SBA, thus demonstrating some benefits for patients.
ABSTRACT
BACKGROUND: Electroconvulsive therapy (ECT) is an efficient and rapid-acting treatment indicated for severe depressive disorders. While ECT is commonly accompanied by transient memory decline, the brain mechanisms underlying these side effects remain unclear. AIMS: In this exploratory functional magnetic resonance (fMRI) study, we aimed to compare effects of ECT versus pharmacological treatment on neural response during episodic memory encoding in patients with affective disorders. METHODS: This study included 32 ECT-treated patients (major depressive disorder (MDD), n = 23; bipolar depression, n = 9) and 40 partially remitted patients in pharmacological treatment (MDD, n = 24; bipolar disorder, n = 16). Participants underwent neuropsychological assessment, a strategic picture encoding fMRI scan paradigm, and mood rating. The ECT group was assessed before ECT (pre-ECT) and 3 days after their eighth ECT session (post-ECT). RESULTS: Groups were comparable on age, gender, and educational years (ps ⩾ 0.05). Within-group analyses revealed a selective reduction in verbal learning and episodic memory pre- to post-ECT (p = 0.012) but no decline in global cognitive performance (p = 0.3). Functional magnetic resonance imaging analyses adjusted for mood symptoms revealed greater activity in ECT-treated patients than pharmacologically treated No-ECT patients across left precentral gyrus (PCG), right dorsomedial prefrontal cortex (dmPFC), and left middle frontal gyrus (MFG). In ECT-treated patients, greater decline in verbal learning and memory performance from pre- to post-ECT correlated with higher PCG response (r = -0.46, p = 0.008), but not with dmPFC or MFG activity (ps ⩾ 0.1), post-ECT. CONCLUSIONS: Episodic memory decline was related to greater neural activity in the left PCG, but unrelated to increased dmPFC and MFG activity, immediately after ECT.
Subject(s)
Depressive Disorder, Major , Electroconvulsive Therapy , Memory, Episodic , Humans , Electroconvulsive Therapy/adverse effects , Electroconvulsive Therapy/methods , Depressive Disorder, Major/diagnostic imaging , Depressive Disorder, Major/therapy , Brain/diagnostic imaging , Magnetic Resonance Imaging , Treatment OutcomeABSTRACT
BACKGROUND: Patients with bipolar disorder (BD) who are presenting with cognitive impairment and associated structural brain abnormalities have generally a poorer clinical outcome. This study aims to map the early longitudinal trajectories in brain structure and cognition in patients with recently diagnosed BD. METHODS: Fully or partially remitted patients with a recent diagnosis of BD and matched healthy controls (HC) underwent structural MRI and neuropsychological testing at baseline (BD n = 97; HC n = 66) and again following an average of 16 (range 6-27) months (BD n = 50; HC n = 38). We investigated the differential trajectories in BD vs. HC in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning using linear mixed models. Within patients, we further investigated whether brain structural abnormalities detected at baseline were associated with subsequent mood episodes. RESULTS: Compared to HC, patients showed a decline in total white matter volume over time and they had a larger amygdala volume, both at baseline and at follow-up time. Patients further showed lower cognitive performance at both times of investigation with no significant change over time. There were no differences between patients and HC in cortical gray matter volume or thickness, hippocampal volume, or brain-aging patterns. CONCLUSIONS: Cognitive impairment and amygdala enlargement may represent stable markers of BD early in the course of illness, whereas subtle white matter decline may result from illness progression.