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INTRODUCTION: Atypical Parkinsonian Syndromes(APS) are challenging neurodegenerative disorders due to their heterogeneous phenotypic overlaps.So far,there are no validated biomarkers that can accurately predict disease progression,and survival studies were highly different and contradictory. AIM: To investigate clinical and molecular survival factors among Tunisian APS patients. METHODS: A retrospective study included Tunisian APS-patients.Using clinical and molecular parameters,survival was explored by Kaplan-Meier analysis. RESULTS: We included 409-APS patients divided into 166-DLB,112-PSP,81-MSA and 50-CBS.Survival rate was similar in synucleinopathies, while it differed in tauopathies,being shorter in PSP compared to CBS.Median survival in DLB was different according to gender(p = 0.0048),early parkinsonism and cognitive disorders. Among MSA, prognosis was worse in MSA-C-patients(p = 0.012) and those with stridor(p = 0.0049),oculomotor and neuropsychiatric disorders. For tauopathies, survival was shorter in PSP-RS(p = 0.027),cerebellar phenotype, those with tremor and swallowing problems at onset, early parkinsonism and memory impairment. For CBS,prognosis was worse in patients with tremor,swallowing and cognitive problems.Significant differences were noted in terms of survival across APS non-carriers of APOE-ε4(p < 0.001) as well APS patients carriers of MAPT-H1.PSP patients had lower survival rate according to MAPT haplotype carriage. Moreover, the number of copies had an influence as patients with H1/H2-MAPT profile had better prognosis than those with H1/H1. CONCLUSION: This study determined survival rates in APS subgroups,which were comparable across synucleinopathies but shorter in PSP and longer in CBS.It also characterized demographic,phenotypic,and genetic profiles identifying more aggressive forms within APS subgroups.These findings address clinical gaps,aiding counseling for patients and families and guiding clinical management.Furthermore,they could facilitate patient stratification in clinical trials where mortality is an outcome measure.
Subject(s)
Parkinsonian Disorders , Tertiary Care Centers , Humans , Male , Female , Parkinsonian Disorders/genetics , Parkinsonian Disorders/mortality , Parkinsonian Disorders/diagnosis , Middle Aged , Retrospective Studies , Aged , Tunisia/epidemiology , Prognosis , North African PeopleABSTRACT
Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition. Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing. Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.
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Background: Parkinson disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorders characterized by the accumulation of alpha-synuclein. Distinguishing between these conditions remains a significant challenge. This study thus employed quantitative susceptibility mapping (QSM) to evaluate subcortical iron deposition and its clinical implications in patients with PD or MSA and a group of healthy controls (HCs). Methods: The study included 26 patients with MSA, 40 patients with PD, and 35 HCs. We used magnetic resonance imaging (MRI)-based QSM to measure iron accumulation in the substantia nigra pars compacta (SNc), substantia nigra pars reticulata (SNr), and globus pallidus internus (GPi). We assessed differences between groups, examined correlations with clinical scores, and conducted receiver operating characteristic (ROC) curve analysis. Results: Compared to those with PD, patients with MSA showed more severe motor and nonmotor impairment. QSM analysis indicated a significant increase in iron levels in the SNc, SNr, and GPi regions in patient groups compared to HCs. In patients with MSA, a notable positive correlation was found between SNc QSM values and Non-Motor Symptoms Scale scores (r=0.4; P=0.043). In patients with PD, a positive association was observed between iron levels in the SNc and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) (r=0.395; P=0.012) and Hamilton Depression Rating Scale scores (r=0.313; P=0.049). Furthermore, iron content in the GPi inversely correlated with rapid-eye movement sleep behavior disorder questionnaire-Hong Kong scores (r=-0.342; P=0.031). The SNr region demonstrated the best ability to discriminate between MSA and PD with an area under the curve (AUC) of 0.67, followed by the GPi (AUC =0.64) and SNc (AUC =0.57). Conclusions: QSM effectively quantified subcortical iron deposition in the PD, MSA, and HC groups. The correlations found between iron levels and clinical manifestations provide insights into the pathophysiological processes of these disorders, highlighting the potential of QSM as a diagnostic tool for differentiation.
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STING agonists are potent enhancers of a pro-inflammatory response and, thus, potentially useful therapeutics. Unfortunately, many agonists developed to date require complex drug delivery formulations and often have poor water solubility, limiting their use for systemic administration. Here, we report the discovery and chemical characterization of lactones of MSA-2 as new STING prodrugs with enhanced properties. We show that these prodrugs form efficient inclusion complexes with tumor myeloid cell targeting cyclodextrin nanoparticles and propose a new mechanism of formation and hydrolysis.
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Aim and Objective: To assess the dentist perception of efficiency, treatment outcome, and stability of the tooth movement treated with mysmartalign clear aligner therapy (MSA CAT). Materials and Method: A cross-sectional web-based questionnaire survey was carried out to evaluate the dentist perception of MYSMARTALIGN (MSA). To determine the sample size, a pilot study has been carried out and the final sample arrived was 4990 subjects. The current study's inclusion criteria took into account those who had finished their BDS and MDS as well as dentists and orthodontists who had been using the MSA CAT system on their patients for the previous 7 years. Results: The result of the study showed that most research participants (3650) used MSA to treat mild to moderate malocclusion, and 3996 participants said that initial digital treatment plans have been authorised with no revisions. In view of efficiency, 3894 doctors were satisfied with the final outcome. Conclusions: Finally concluded that recent survey showed that dentists were very satisfied with the effectiveness and treatment results of the MSA clear aligner procedure.
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The stimulator of interferon genes (STING) connects the innate and adaptive immune system and plays a significant role in antitumor immunity. Over the past decades, endogenous and CDN-derived STING agonists have been a hot topic in the research of cancer immunotherapies. However, these STING agonists are either in infancy with limited biological effects or have failed in clinical trials. In 2020, a non-nucleotide STING agonist MSA-2 was identified, which exhibited satisfactory antitumor effects in animal studies and is amenable to oral administration. Due to its distinctive binding mode and enhanced bioavailability, there have been accumulating interests and an array of studies on MSA-2 and its derivatives, spanning its structure-activity relationship, delivery systems, applications in combination therapies, etc. Here, we provide a comprehensive review of MSA-2 and interventional strategies based on this family of STING agonists to help more researchers extend the investigation on MSA-2 in the future.
Subject(s)
Membrane Proteins , Humans , Membrane Proteins/agonists , Animals , Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic useABSTRACT
The aggregated alpha-synuclein (αsyn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that αsyn accumulates not only in neurons but also in OLGs long after the administration of αsyn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial αsyn aggregates was technically difficult due to the background neuronal αsyn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of αsyn aggregates in OLGs and the comparable analysis of the cellular tropism of αsyn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human αsyn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of αsyn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial αsyn aggregates than neuronal αsyn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of αsyn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of αsyn aggregates in OLGs and could contribute to the development of therapeutics targeting αsyn aggregates in OLGs.
Subject(s)
Inclusion Bodies , Multiple System Atrophy , Oligodendroglia , Protein Aggregates , alpha-Synuclein , Animals , Humans , Mice , alpha-Synuclein/metabolism , Brain/pathology , Brain/metabolism , Cytoplasm/metabolism , Disease Models, Animal , Green Fluorescent Proteins/metabolism , Inclusion Bodies/metabolism , Inclusion Bodies/pathology , Mice, Transgenic , Multiple System Atrophy/pathology , Multiple System Atrophy/metabolism , Oligodendroglia/metabolism , Oligodendroglia/pathology , Protein Aggregation, Pathological/metabolismABSTRACT
Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.
Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Multiple System Atrophy , Multiple System Atrophy/genetics , Humans , Genetic Predisposition to Disease/genetics , Female , Male , Aged , Quantitative Trait Loci/genetics , Middle Aged , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Therapeutic education programs are effective in several chronic conditions. However, evidence is lacking in multiple system atrophy (MSA). We aimed to assess efficacy and safety of a comprehensive therapeutic education program in people with MSA (PwMSA) and their caregivers. METHODS: In this prospective longitudinal study we included 16 PwMSA and their main caregivers in 4 groups of 4 dyads each. The program consisted of eight 60-min interdisciplinary sessions: introduction, orthostatic hypotension, speech therapy, gait and respiratory physiotherapy, psychological support, urinary dysfunction, occupational therapy/social work. UMSARS, NMSS, PDQ39, EQ5 and Zarit scales were administered at baseline and 6 months later. After each session participants filled-out a modified EduPark satisfaction questionnaire and a Likert scale. Educational material was generated for each session after suggestions by participants. RESULTS: At baseline PwMSA and caregivers were comparable in age and sex, with significant correlation between UMSARS-IV (disability) and PDQ39 (quality of life). Adherence to sessions was of 94,92 %. Total modified EduPark scores and Likert scales did not differ in PwMSA vs. caregivers, mild-moderate vs. severe-advanced cases or between genders. The significant difference in satisfaction across sessions (p = 0.03) was driven by higher scores in speech, respiratory and occupational therapy sessions. Longitudinally there was no significant worsening in any scale, nor a significant increase post-vs. pre-program in the number of consultations. CONCLUSIONS: The healthcare education program in MSA was feasible, satisfactory, and safe for patients and caregivers. The educational material of the program is being forwarded to incident MSA cases attending our clinic.
Subject(s)
Caregivers , Multiple System Atrophy , Quality of Life , Registries , Humans , Male , Female , Multiple System Atrophy/therapy , Multiple System Atrophy/rehabilitation , Middle Aged , Longitudinal Studies , Aged , Caregivers/psychology , Caregivers/education , Pilot Projects , Patient Education as Topic , Patient Satisfaction , Prospective StudiesABSTRACT
Cadmium (Cd) contamination in cropland poses a significant threat to the quality of agricultural products, but even though in-situ remediation has been extensively applied, non-selective immobilization remains an issue. In order to develop a material that specifically immobilizes Cd in soil, a layered double hydroxide, intercalated with mercaptosuccinic acid (MSA-CFA), was synthesized through co-precipitation. In this case, the MSA-CFA's maximum adsorption capacity was increased from the 513.8 mg·g-1 for unintercalated hydrotalcite CFA to 692.6 mg·g-1. Besides, MSA-CFA efficiently removed 99.25 % of Cd from soil water-extract solution and immobilized up to 70.03 % of bio-available Cd. However, interestingly, its immobilization effects on beneficial metal elements Fe, Mn and Zn were milder, being equivalent to 2/7, 5/7 and 1/2 that of lime, respectively. Moreover, XRD and XPS techniques revealed isomorphous substitution with calcium and sulfhydryl complexation during the Cd adsorption by MSA-CFA. Compared with CFA, the increased adsorption capacity of MSA-CFA for Cd was due to intercalated MSA acting as a new adsorption site, while the enhanced selectivity was contributed by sulfhydryl's affinity for Cd. Altogether, MSA-CFA showed great promise as a competitive and highly efficient candidate amendment in Cd-contaminated soil remediation.
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This study employs ab initio calculations based on density functional theory (DFT) to investigate the structural properties, 1H-NMR spectra, and vibrational spectra of methane sulfonic acid (MSA) at low degree of hydration. The findings reveal that energetically stable structures are formed by small clusters consisting of one or two MSA molecules (m = 1 and 2) and one or two water molecules in (MSA)m·(H2O)n (m = 1-2 and n = 1-5).These stable structures arise from the formation of strong cyclic hydrogen bonds between the proton of the hydroxyl (OH) group in MSA and the water molecules. However, clusters containing three or more water molecules (n > 2) exhibit proton transfer from MSA to water, resulting in the formation of ion-pairs composed of CH3SO3- and H3O+species. The measured 1H-NMR spectra demonstrate the presence of hydrogen-bonded interactions between MSA and water, with a single MSA molecule interacting with water molecules. This interaction model accurately represents the hydrogen bonding network, as supported by the agreement between the experimental and calculated NMR chemical shift results.
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Background and objectives: The differentiation of spinocerebellar ataxia type II (SCA 2) from idiopathic multiple systemic atrophy of the cerebellar type (MSA-C) is often difficult in patients with cerebellar ataxia when molecular testing is not available. Besides genetic testing, magnetic resonance imagining (MRI) and magnetic resonance spectroscopy (MRS) prove to be beneficial. Nevertheless, the characteristics observed through radiology change as the disease advances. Different radiological criteria may be needed across different stages of the disease. This study aimed to assess the radiological characteristics of MSA-C or SCA 2 patients across various stages of the disease and to identify potential distinguishing factors. Methods: Between January 2000 and January 2020, a total of 390 patients, diagnosed with probable MSA-C according to the second consensus on MSA (317 cases) or with molecularly confirmed SCA 2 (73 cases), who had undergone at least one brain MRI and MRS targeting the cerebellar hemispheres, were enrolled in the study. The clinical parameters and neuroimaging features between these two diseases were compared and analyzed. Results: A greater occurrence of a pontine hot cross bun sign (HCBS), higher scores on the scale for the assessment and rating of ataxia, and reduced levels of cerebellar N-acetyl aspartate (NAA)/creatine (Cr), and cerebellar choline (Cho)/Cr were found in MSA-C patients as compared with SCA 2 patients at similar disease durations. For the patients with an HCBS, a cerebellar Cho/Cr level of <0.53 was indicative of the potential presence of MSA-C, with significant level of specificity (85.96%). Discussion: Discerning SCA2 from MSA-C using MRI and MRS appears to be plausible at various disease stages.
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Methane is both a significant and short-lived greenhouse gas compared to CO2, and reducing methane emissions from natural gas distribution systems may offer cost-effective reduction opportunities. We report substantial new direct leak rate measurements from customer meter set assemblies (MSAs) in Southern California. In a novel way, emission factors are defined in terms of aboveground Hazardous and Nonhazardous leak categories, which take direct advantage of readily available industry leak data. We also studied leaks that were not detected as part of normal leak survey procedures. As a result, this yields company-specific emission factors that can be used to track progress in reducing methane emissions. This approach also has the advantage of explicitly accounting for the skewed or fat-tail distribution of leak rates by treating high flow rate MSA leaks separately from low flow rate MSA leaks. The Southern California Gas (SoCalGas) methane emission factors, based on 485 leak rate measurements by direct enclosure, were 4.55 (95% confidence interval: 2.32 to 7.14) kg/day for Hazardous leaks, 0.149 (0.119 to 0.183) kg/day for Nonhazardous leaks, and 0.0039 (0.0003 to 0.0198) kg/day for Non-Detected leaks. The percentage of surveyed meters with nondetected leaks was 29.1% (24.3 to 34.6%). Based on a robust Monte Carlo analysis, total leak emissions from MSAs for the SoCalGas system were reduced by 35% based on data from 2015 to 2022. These reductions were attributed to surveying a larger number of MSAs and accelerated leak repair rates. In traditional population-based emission inventories, an individual emission factor for a given asset category is multiplied by the total population of MSAs within the category. This approach simply cannot capture the reduction in leak numbers and methane emissions resulting from leak mitigation and prevention programs.
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Glioblastoma (GBM) is an aggressive brain tumor, with a highly immunosuppressive tumor immune microenvironment (TIME). In this work, we investigated the use of the STimulator of INterferon Genes (STING) pathway as an effective means to remodel the GBM TIME through the recruitment of both innate and adaptive immune cell populations. Using hyaluronic acid (HA), we developed a novel polymer-drug conjugate of a non-nucleotide STING agonist (MSA2), called HA-MSA2 for the in situ treatment of GBM. In JAWSII cells, HA-MSA2 exerted a greater increase of STING signaling and upregulation of STING-related downstream cyto-/chemokines in immune cells than the free drug. HA-MSA2 also elicited cancer cell-intrinsic immunostimulatory gene expression and promoted immunogenic cell death of GBM cells. In the SB28 GBM model, local delivery of HA-MSA2 induced a delay in tumor growth and a significant extension of survival. The analysis of the TIME showed a profound shift in the GBM immune landscape after HA-MSA2 treatment, with higher infiltration by innate and adaptive immune cells including dendritic, natural killer (NK) and CD8 T cell populations. The therapeutic potential of this novel polymer conjugate warrants further investigation, particularly with other chemo-immunotherapeutics or cancer vaccines as a promising combinatorial therapeutic approach.
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Fungal polyketides are a large group of secondary metabolites, valuable due to their diverse spectrum of pharmacological activities. Polyketide biosynthesis in filamentous fungi presents some challenges: small yield and low-purity titers. To tackle these issues, we switched to the yeast Yarrowia lipolytica, an easily cultivable heterologous host. As an oleaginous yeast, Y. lipolytica displays a high flux of acetyl- and malonyl-CoA precursors used in lipid synthesis. Likewise, acetyl- and malonyl-CoA are the building blocks of many natural polyketides, and we explored the possibility of redirecting this flux toward polyketide production. Despite its promising prospect, Y. lipolytica has so far only been used for heterologous expression of simple type III polyketide synthases (PKSs) from plants. Therefore, we decided to evaluate the potential of Y. lipolytica by targeting the more complex fungal polyketides synthesized by type I PKSs. We employed a CRISPR-Cas9-mediated genome editing method to achieve markerless gene integration of the genes responsible for bostrycoidin biosynthesis in Fusarium solani (fsr1, fsr2, and fsr3) and 6-methylsalicylic acid (6-MSA) biosynthesis in Aspergillus hancockii (6MSAS). Moreover, we attempted titer optimization through metabolic engineering by overexpressing two enzymes, TGL4 and AOX2, involved in lipid ß-oxidation, but we did not observe an effect on polyketide production. With maximum titers of 403 mg/L 6-MSA and 35 mg/L bostrycoidin, the latter being substantially higher than our previous results in Saccharomyces cerevisiae (2.2 mg/L), this work demonstrates the potential of Y. lipolytica as a platform for heterologous production of complex fungal polyketides.
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Radish (Raphanus sativus L.), a root vegetable belonging to the Brassicaceae family, is considered one of the representative crops displaying sporophytic self-incompatibility (SSI). The utilization of a self-incompatibility system in F1 breeding can improve the efficiency of cross-combinations, leading to a reduction in breeding time and aiding in the development of novel F1 varieties. The successful implementation of this system necessitates the rapid and accurate identification of S haplotypes in parental lines. In this study, we identified a total of nine S haplotypes among 22 elite radish lines through Sanger sequencing. Subsequently, we obtained sequences for showing a 95% similarity to nine S haplotypes, along with sequences identified by other researchers using BLAST. Following this, multiple sequence alignment (MSA) was conducted to identify SRK and SLG sequence similarities, as well as polymorphisms within the class I and II groups. Subsequently, S haplotype-specific marker sets were developed, targeting polymorphic regions of SRK and SLG alleles. These markers successfully amplified each of the nine S haplotypes. These markers will play a crucial role in the rapid and precise identification of parental S haplotypes in the radish F1 breeding process, proving instrumental in the radish F1 purity test.
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PURPOSE: Magnetic Sphincter Augmentation (MSA) is an FDA-approved anti-reflux procedure with comparable outcomes to fundoplication. However, most data regarding its use are limited to single or small multicenter studies which may limit the generalizability of its efficacy. The purpose of this study is to evaluate the outcomes of patients undergoing MSA vs fundoplication in a national database. MATERIALS AND METHODS: The 2017-2020 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Registry was utilized to evaluate patients undergoing MSA or fundoplication. Patients requiring Collis gastroplasty, paraesophageal hernia repair, and emergency cases, were excluded. Patient outcomes included overall complication rates, readmissions, reoperations, and mortality. RESULTS: A total of 7,882 patients underwent MSA (n = 597) or fundoplication (n = 7285). MSA patients were younger (51 vs 57, p < 0.001), and more often male (49.6 vs 34.3%, p < 0.001). While patients undergoing MSA experienced similar rates of reoperation (1.0 vs 2.0%, p = 0.095), they experienced fewer readmissions (2.2 vs 4.7%, p = 0.005), complications (0.6 vs 4.0%, p < 0.001), shorter mean (SD) hospital length of stay(days) (0.4 ± 4.3 vs 1.8 ± 4.6, p < 0.001) and operative time(min) (80.8 ± 36.1 vs 118.7 ± 63.7, p < 0.001). Mortality was similar between groups (0 vs 0.3%, p = 0.175). On multivariable analysis, MSA was independently associated with reduced postoperative complications (OR 0.23, CI 0.08 to 0.61, p = 0.002), readmissions (OR 0.53, CI 0.30 to 0.94, p = 0.02), operative time (RC - 36.56, CI - 41.62 to - 31.49. p < 0.001) and length of stay (RC - 1.22, CI - 1.61 to - 0.84 p < 0.001). CONCLUSION: In this national database study, compared to fundoplication MSA was associated with reduced postoperative complications, fewer readmissions, and shorter operative time and hospital length of stay. While randomized trials are lacking between MSA and fundoplication, both institutional and national database studies continue to support the use of MSA as a safe anti-reflux operation.
Subject(s)
Gastroplasty , Laparoscopy , Humans , Male , Fundoplication/adverse effects , Fundoplication/methods , Esophageal Sphincter, Lower/surgery , Quality Improvement , Laparoscopy/methods , Treatment Outcome , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/surgery , Magnetic Phenomena , Quality of Life , Retrospective StudiesABSTRACT
OBJECTIVE: Fetal magnetic resonance imaging (MRI) is broadly used as a method for assessing prognosis in congenital diaphragmatic hernia (CDH). In addition to the extent of lung hypoplasia, determined by measuring the lung volume, cardiac impairment due to pulmonary hypertension and left cardiac hypoplasia is decisive for the prognosis. The percentage area of left ventricle (pALV) describes the percentage of the inner area of the left ventricle in relation to the total area, whereas the mediastinal shift angle (MSA) quantifies the extent of cardiac displacement. The prognostic value of pALV and MSA should be evaluated in terms of survival, the need for extracorporeal membrane oxygenation (ECMO) therapy, and the development of chronic lung disease (CLD). METHODS: In a total of 122 fetal MRIs, the MSA and pALV were measured retrospectively and complete outcome parameters were determined regarding survival for all 122 subjects, regarding ECMO therapy in 109 cases and about the development of CLD in 78 cases. The prognostic value regarding the endpoints was evaluated using logistic regression and ROC analysis. RESULTS: The MSA was significantly higher in children who received ECMO therapy (p = 0.0054), as well as in children who developed CLD (p = 0.0018). ROC analysis showed an AUC of 0.68 for ECMO requirement and 0.77 with respect to CLD development. The pALV showed a tendency towards higher levels in children who received ECMO therapy (p = 0.0824). The MSA and the pALV had no significant effect on survival (MSA: p = 0.4293, AUC = 0.56; pALV: p = 0.1134, AUC = 0.57). CONCLUSIONS: The MSA determined in fetal MRI is a suitable prognostic parameter for ECMO requirement and CLD development in CDH patients and can possibly be used as a supplement to the established parameters.
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PURPOSE: Multiple system atrophy (MSA) is a rare neurodegenerative disease, often presented with orthostatic hypotension (OH), which is a disabling symptom but has not been very explored. Here, we investigated MSA patients with OH by using positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) and 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) for in vivo evaluation of the glucose metabolism and dopaminergic function of the brain. METHODS: Totally, 51 patients with MSA and 20 healthy controls (HC) who underwent 18F-FDG PET/CT were retrospectively enrolled, among which 24 patients also underwent 11C-CFT PET/CT. All patients were divided into MSA-OH(+) and MSA-OH(-) groups. Then, statistical parametric mapping (SPM) method was used to reveal the regional metabolic and dopaminergic characteristics of MSA-OH(+) compared with MSA-OH(-). Moreover, the metabolic networks of MSA-OH(+), MSA-OH(-) and HC groups were also constructed and analyzed based on graph theory to find possible network-level changes in MSA patients with OH. RESULTS: The SPM results showed significant hypometabolism in the pons and right cerebellar tonsil, as well as hypermetabolism in the left parahippocampal gyrus and left superior temporal gyrus in MSA-OH(+) compared with MSA-OH(-). A reduced 11C-CFT uptake in the left caudate was also shown in MSA-OH(+) compared with MSA-OH(-). In the network analysis, significantly reduced local efficiency and clustering coefficient were shown in MSA-OH(+) compared with HC, and decreased nodal centrality in the frontal gyrus was found in MSA-OH(+) compared with MSA-OH(-). CONCLUSION: In this study, the changes in glucose metabolism in the pons, right cerebellar tonsil, left parahippocampal gyrus and left superior temporal gyrus were found closely related to OH in MSA patients. And the decreased presynaptic dopaminergic function in the left caudate may contribute to OH in MSA. Taken together, this study provided in vivo pathophysiologic information on MSA with OH from neuroimaging approach, which is essential for a better understanding of MSA with OH.