Styrene-maleic acid copolymers (SMA) have been gaining interest in the field of membrane research due to their ability to solubilize membranes into nanodics. The SMA molecules act as an amphipathic ...belt that surrounds the nanodiscs, whereby the hydrophobic styrene moieties can insert in between the lipid acyl chains. Here we used SMA variants with different styrene-to-maleic acid ratio (i.e. 2:1, 3:1 and 4:1) to investigate how lipid packing in the nanodiscs is affected by the presence of the polymers and how it depends on polymer composition. This was done by analyzing the thermotropic properties of a series of saturated phosphatidylcholines in nanodiscs using laurdan fluorescence and differential scanning calorimetry. In all cases it was found that the temperature of the main phase transition (Tm) of the lipids in the nanodiscs is downshifted and that its cooperativity is strongly reduced as compared to the situation in vesicles. These effects were least pronounced for lipids in nanodiscs bounded by SMA 2:1. Unexpected trends were observed for the calorimetric enthalpy of the transition, suggesting that the polymer itself contributes, possibly by rearranging around the nanodiscs when the lipids adopt the fluid phase. Finally, distinct differences in morphology were observed for nanodiscs at relatively high polymer concentrations, depending on the SMA variant used. Overall, the results suggest that the extent of preservation of native thermodynamic properties of the lipids as well as the stability of the nanodiscs at high polymer concentrations is better for SMA 2:1 than for the other SMA variants.
Background: Sleep disorders can cause tiredness. The relationship between sleep disorders and fatigue in patients with multiple sclerosis (MS) has not yet been investigated systematically.
Objective: ...To investigate the relationship between fatigue and sleep disorders in patients with MS.
Methods: Some 66 MS patients 20 to 66 years old were studied by overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the entire cohort was stratified into a fatigued MS subgroup (n = 26) and a non-fatigued MS subgroup (n = 40).
Results: Of the fatigued MS patients, 96% (n = 25) were suffering from a relevant sleep disorder, along with 60% of the non-fatigued MS patients (n = 24) (p = 0.001). Sleep-related breathing disorders were more frequent in the fatigued MS patients (27%) than in the non-fatigued MS patients (2.5%). Significantly higher MFIS values were detected in all (fatigued and non-fatigued) patients with relevant sleep disorders (mean MFIS 42.8; SD 18.3) than in patients without relevant sleep disorders (mean MFIS 20.5; SD 17.0) (p < 0.001). Suffering from a sleep disorder was associated with an increased risk of fatigue in MS (odds ratio: 18.5; 95% CI 1.6–208; p = 0.018).
Conclusion: Our results demonstrate a clear and significant relationship between fatigue and sleep disorders.
Cognitive impairment is increasingly recognized as relevant clinical feature in multiple sclerosis (MS). We applied the Paced Auditory Serial Addition Test (PASAT), a recommended screening tool for ...cognitive dysfunction in MS, to investigate the relationship between cognitive performance and the presence of gadolinium (Gd)-enhancing lesions on brain MRI.
In this longitudinal correlational research study, 75 patients with relapsing-remitting MS (48 women and 27 men, mean age 36 years, mean disease duration 5 years, mean Expanded Disability Status Scale EDSS 1.7) without clinical signs of a relapse underwent 2 MRI measurements (number and volume of T1 contrast-enhancing lesions and of T2 lesions) and clinical examinations (EDSS and Multiple Sclerosis Functional Composite MSFC) with a mean interscan interval of 10 weeks. Patients were divided into 3 groups: A (n = 38), Gd on 1 scan; B (n = 12), Gd on both scans; and C (n = 25), Gd on neither scan.
In group A, PASAT was better at the Gd-negative time point (p = 0.002), whereas the other MSFC subscores remained unchanged. Subgroup analysis confirmed the finding in patients with a Gd-positive scan first, whereas this was not the case for patients with a Gd-negative scan first, presumably owing to the small sample size of this subgroup. In groups B and C, there was no difference between both time points regarding MSFC and its subscores. EDSS remained stable in all groups during the investigation.
Paced Auditory Serial Addition Test performance is affected by the appearance of Gd enhancement as surrogate marker of inflammatory activity in otherwise physically stable patients with multiple sclerosis, which may indicate that Gd enhancement causes a diffuse impairment of cerebral connectivity with a negative impact on cognitive functioning.
A brief review of Susac syndrome Kleffner, I; Duning, T; Lohmann, H ...
Journal of the neurological sciences,
11/2012, Letnik:
322, Številka:
1
Journal Article
Recenzirano
Abstract Susac syndrome was named after J.O. Susac who first described the syndrome in 1979. It is characterized by the clinical triad of encephalopathy, branch retinal artery occlusion, and ...sensorineural hearing loss. It mainly occurs in young women. This underdiagnosed disease needs to be considered in the differential diagnosis of a broad variety of disorders. In Susac syndrome, autoimmune processes leading to damage and inflammation-related occlusion of the microvessels in brain, retina, and inner ear are thought to play a causal role. The diagnosis is based primarily on the clinical presentation, the documentation of branch retinal artery occlusion by fluorescence angiography, and characteristic findings on cerebral MRI, that help in distinguishing Susac syndrome from other inflammatory entities, like multiple sclerosis. Antiendothelial cell antibodies could be detected in some patients. Patients are successfully treated with immunosuppression, however, the best regimen still needs to be defined. As a result of the rarity of the disease, controlled therapeutic trials are missing so far. In this review, we want to demonstrate the clinical features, natural history, treatment, and clinical course of Susac syndrome, illustrated by a typical case history.
Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk ...stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677G>T, 3435C>T and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2% of patients) was 37.7% lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P < 0.05, 14.8% of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2–/– animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2–/– mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n = 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate overall 121 of 155 patients (78.1%) increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function ABCB1/ABCG2-H 15/24 (62.5%) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6%), ABCB1/ABCG2-L 28/33 (84.8%), exact Cochran-Armitage test P = 0.039. The odds ratio for response was 1.9 (95% CI 1.0–3.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to –I-, and –I to –L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m2 MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation.
The volume, extent and age of Arctic sea ice is in decline, yet winter sea ice production appears to have been increasing, despite Arctic warming being most intense during winter. Previous work ...suggests that further warming will at some point lead to a decline in ice production, however a consistent explanation of both rise and fall is hitherto missing. Here, we investigate these driving factors through a simple linear model for ice production. We focus on the Kara and Laptev seas-sometimes referred to as Arctic "ice factories" for their outsized role in ice production, and train the model on internal variability across the Community Earth System Model's Large Ensemble (CESM-LE). The linear model is highly skilful at explaining internal variability and can also explain the forced rise-then-fall of ice production, providing insight into the competing drivers of change. We apply our linear model to the same climate variables from observation-based data; the resulting estimate of ice production over recent decades suggests that, just as in CESM-LE, we are currently passing the peak of ice production in the Kara and Laptev seas.
The aims of this study were: to determine the incidence of concurrent infections on a serovar level; to determine the incidence of multiple anatomical infected sites on a detection and genotyping ...level and analyse site-specific serovar distribution; to identify tissue tropism in urogenital versus rectal specimens.
Chlamydia trachomatis-infected patients in two populations were analysed: 75 visiting the outpatient department of obstetrics and gynaecology of the MC Haaglanden, and 358 visiting the outpatient sexually transmitted disease clinic, The Hague, The Netherlands. The PACE 2 assay (Gen-Probe) was used to detect C trachomatis from urethral, cervical, vaginal, oropharyngeal and anorectal swabs. C trachomatis genotyping was performed on all C trachomatis positive samples, using the CT-DT genotyping assay.
Samples from 433 patients (256 female and 177 male) with confirmed C trachomatis infection were analysed. In 11 patients (2.6%), concurrent serovars in one anatomical sample site were present. In 62 (34.1%) female and four (9.3%) male patients, multiple sample site infections were found. A substantial percentage of women tested at the cervical/vaginal and rectal site were found to be positive at both sites (36.1%, 22/61). In men, D/Da and G/Ga serovars were more prevalent in rectal than urogenital specimens (p=0.0081 and p=0.0033, respectively), while serovar E was more prevalent in urogenital specimens (p=0.0012).
The prevalence of multiple serovar infections is relatively low. Significant differences in serovar distribution are found in rectal specimens from men, with serovar G/Ga being the most prominent, suggesting tissue tropism.
BackgroundChimeric antigen receptor (CAR) T cell therapy has transformed the landscape of hematologic malignancy treatment. However, its successful translation to solid cancer treatment remains ...challenging, primarily due to the immunosuppressive tumor microenvironment (TME). Prostaglandin E2 (PGE2) has emerged as a pivotal player in TME immunosuppression, whereby its impact on T cell function has been recognized as a novel immune checkpoint. This study focuses on enhancing CAR T cell efficacy against solid tumors by disrupting PGE2 signaling through the targeted knockout of its receptors, EP2 and EP4.Materials and MethodsUtilizing CRISPR/Cas9 technology, we generated double knockout CAR T cells deficient in EP2 and EP4. In vitro analyses assessed the impact of PGE2 on CAR T cell functions, including proliferation, activation, and cytotoxicity. To translate these findings to a human system, we conducted tumor growth and survival experiments using a xenograft mouse model. Additionally, T cell tracking was performed to elucidate the fate of EP2-/-EP4-/- CAR T cells in vivo.ResultsWe could successfully generate murine as well as human EP2 and EP4 single and double knockout CAR T cells, which showed complete abrogation of PGE2 signaling, as indicated by suppressed cAMP production and CREB phosphorylation. While wild type CAR T cells were suppressed in their proliferative abilities by PGE2, their capacity to become activated remained unaffected. PGE2-induced reduction in CAR T cell numbers ultimately compromised their anti-tumor activity both in vitro and in vivo. This effect was rescued by the EP2 and EP4 double knockout, leading to increased EP2-/-EP4-/- T cell accumulation within tumors. As a consequence, bettered therapeutic efficacy and prolonged survival were achieved in a xenograft mouse model.ConclusionsOur findings underscore the detrimental impact of PGE2-mediated suppression on CAR T cell efficacy in the TME, highlighting the potential to rescue therapeutic cells through EP2 and EP4 knockout. Notably, single knockouts of either receptor proved insufficient to shield CAR T cells from PGE2. Genetic ablation of EP2 and EP4 presents a promising strategy to shield CAR T cells from PGE2 without disrupting healthy PGE2 signaling and encourages further exploration and development of this novel therapeutic strategy. J. Dörr: None. L. Gregor: None. S.B. Lacher: None. A. Öner: None. S. Lesch: None. S. Michaelides: None. L. Majed: None. L. Fertig: None. E. Carlini: None. D. Andreu Sanz: None. D. Briukhovetska: None. S. Stock: None. A. Gottschlich: None. J.P. Böttcher: None. S. Kobold: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; TCR2 Inc, Catalym, Plectonic, Arcus Biosciences, Tabby Therapeutics. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Significant; GSK, BMS, Novartis, Miltenyi Biotherapeutics, TCR2 Inc. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; TCR2 Inc, Carina Biotech.
BACKGROUND: A multicentre randomized controlled trial with or without hysterosalpingography (HSG) was conducted to assess the usefulness of HSG as a routine investigation in the fertility workup ...prior to laparoscopy and dye. METHODS: From 1 April 1997 to 1 April 2002, subfertile women were allocated by a computer–based 1 : 1 ratio randomization procedure, either for an HSG followed by laparoscopy and dye (the intervention group) of for laparoscopy and dye only (the control group) as a part of their fertility workup. Cumulative pregnancy rate (CPR) within 18 months after randomization was the primary outcome of interest. RESULTS: 344 women were randomized to the intervention group (n = 169) and the control group (n = 175). There was no significant difference in CPR at 18 months in the intervention group (49.1%) 95% confidence interval (CI) 41.6 to 56.6 and the control group (50.3%) (95% CI 42.8 to 57.8), a difference of –1.2% (95% CI –11.8% to 9.5%). CONCLUSION: The routine use of HSG at an early stage in the fertility workup prior to laparoscopy and dye does not influence CPR, compared with the routine use of laparoscopy and dye without HSG.
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