Diverse molecules induce general anesthesia with potency strongly correlated with both their hydrophobicity and their effects on certain ion channels. We recently observed that several n-alcohol ...anesthetics inhibit heterogeneity in plasma-membrane-derived vesicles by lowering the critical temperature (Tc) for phase separation. Here, we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n-alcohols and effects on Tc. First, we show that hexadecanol acts oppositely to n-alcohol anesthetics on membrane mixing and antagonizes ethanol-induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described “intoxication reversers” raise Tc and counter ethanol’s effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that elevated hydrostatic pressure, long known to reverse anesthesia, also raises Tc in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that ΔTc predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia.
Abstract Preeclampsia remains a leading cause of maternal and fetal morbidity and mortality and has an unknown etiology. The limited progress made regarding new treatments to reduce the incidence and ...severity of preeclampsia has been attributed to the difficulties faced in the development of suitable animal models for the mechanistic research of this disease. In addition, animal models need hypotheses on which to be based and the slow development of testable hypotheses has also contributed to this poor progress. The past decade has seen significant advances in our understanding of preeclampsia and the development of viable reproducible animal models has contributed significantly to these advances. Although many of these models have features of preeclampsia, they are still poor overall models of the human disease and limited due to lack of reproducibility and because they do not include the complete spectrum of pathophysiological changes associated with preeclampsia. This review aims to provide a succinct and comprehensive assessment of current animal models of preeclampsia, their uses and limitations with particular attention paid to the best validated and most comprehensive models, in addition to those models which have been utilized to investigate potential therapeutic interventions for the treatment or prevention of preeclampsia.
Lipid bicontinuous cubic phases have attracted enormous interest as bio-compatible scaffolds for use in a wide range of applications including membrane protein crystallisation, drug delivery and ...biosensing. One of the major bottlenecks that has hindered exploitation of these structures is an inability to create targeted highly swollen bicontinuous cubic structures with large and tunable pore sizes. In contrast, cubic structures found in vivo have periodicities approaching the micron scale. We have been able to engineer and control highly swollen bicontinuous cubic phases of spacegroup Im3m containing only lipids by (a) increasing the bilayer stiffness by adding cholesterol and (b) inducing electrostatic repulsion across the water channels by addition of anionic lipids to monoolein. By controlling the composition of the ternary mixtures we have been able to achieve lattice parameters up to 470 Å, which is 5 times that observed in pure monoolein and nearly twice the size of any lipidic cubic phase reported previously. These lattice parameters significantly exceed the predicted maximum swelling for bicontinuous cubic lipid structures, which suggest that thermal fluctuations should destroy such phases for lattice parameters larger than 300 Å.
Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests ...that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.
•Pain and fatigue are prevalent among adult survivors of childhood cancer.•Survivors often have unmet needs for information about managing pain and fatigue.•Unmet needs are related to fear of cancer ...recurrence.
Pain and fatigue are under-researched late effects of childhood cancer and its treatment, and may be interpreted by survivors as indicating cancer recurrence. Moreover, unmet information needs for managing pain and fatigue may be related to fear of cancer recurrence. We investigated the complex relationships between perceived cancer-related pain and fatigue, unmet information needs for managing pain and fatigue, and fear of cancer recurrence.
We surveyed 404 adult survivors of any form of childhood cancer (M = 16.82 years since treatment completion).
Many survivors reported perceived cancer-related pain (28.7%) and fatigue (40.3%), and anticipated future pain (19.3%) and fatigue (26.2%). These symptomologies were all related to unmet information needs for managing pain (18.8%) and fatigue (32.2%; all p’s<.001). Survivors reporting unmet information needs for managing pain (B = .48, 95% CI = 0.19-0.76, p = .001) and fatigue (B = .32, 95% CI = 0.06-0.52, p = .015) reported higher fear of cancer recurrence than survivors reporting no information needs.
Survivors often have unmet information needs for managing pain and fatigue, and these unmet needs are related to fear of cancer recurrence.
Long-term follow-up clinics should assess pain and fatigue. Information provision about pain and fatigue may be an important tool to help manage fear of cancer recurrence.
To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: ...type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.
Objective
To examine the association between preeclampsia and attention‐deficit hyperactivity disorder (ADHD), using a large Swedish‐based registry cohort.
Methods
This study comprised 2 047 619 ...children, with 114 934 (5.6%) cases of ADHD. Preeclampsia was based on two alternate definitions: (i) preeclampsia (using ICD‐9/ICD‐10) and (ii) preeclampsia and small for gestational age (SGA) combined. ADHD was determined in one of two ways: (i) if a diagnosis of ADHD was present in the National Patient Register or (ii) if an individual was in receipt of ADHD medication in the Prescribed Drug Register. Multivariate Cox proportional hazards regression analysis allowed adjustment for several perinatal/sociodemographic factors. Sibling‐matched analysis further controlled for shared genetic and familial confounding.
Results
In the adjusted Cox model, preeclampsia was associated with an increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling‐matched analysis did not materially change these associations (HR: 1.13, 95% CI: 1.05, 1.22) and 1.55 (95% CI: 1.28, 1.88).
Conclusions
Exposure to preeclampsia or preeclampsia/SGA was associated with ADHD, independent of genetic/familial factors shared by siblings. However, it is important to note that sibling‐matched analysis can only adjust for factors that are constant between pregnancies; therefore, residual confounding cannot be ruled out. Further research is needed to explore modifiable risk factors and identify those most‐at‐risk babies following delivery.
Recurrence rates remain high after surgical treatment of diffuse-type Tenosynovial Giant Cell Tumour (TGCT). Imatinib Mesylate (IM) blocks Colony Stimulating Factor1 Receptor (CSF1R), the driver ...mechanism in TGCT. The aim of this study was to determine if IM reduces the tumour metabolic activity evaluated by PET-CT and to compare this response with the response seen on MR imaging.
25 Consecutive patients treated with IM (off label use) for locally advanced (N = 12) or recurrent (N = 13) diffuse-type TGCT were included, 15 male and median age at diagnosis 39 (IQR 31–47) years. The knee was most frequently affected (n = 16; 64%). The effect of IM was assessed pre- and post-IM treatment by comparing MR scans and PET-CT. MR scans were assessed by Tumour Volume Score (TVS), an estimation of the tumour volume as a percentage of the total synovial cavity. PET-CT scans were evaluated based on maximum standardized uptake value (SUV-max). Partial response was defined as more than 50% tumour reduction with TVS and a decrease of at least 30% on SUV-max.
Median duration of IM treatment was 7.0 (IQR 4.2–11.5) months. Twenty patients (80%) discontinued IM treatment for poor response or intended surgery. Twenty patients experienced an adverse event grade 1–2, three patients grade 3 (creatinine increment, neutropenic sepsis, liver dysfunction). MR assessment of all joints showed 32% (6/19) partial response and 63% (12/19) stable disease, with a mean difference of 12% (P = 0.467; CI -22.4-46.0) TVS between pre- and post-IM and a significant mean difference of 23% (P = 0.021; CI 4.2–21.6) in all knee lesions. PET-CT, all joints, showed a significantly decreased mean difference of 5.3 (P = 0.004; CI 1.9–8.7) SUV-max between pre- and post-IM treatment (58% (11/19) partial response, 37% (7/19) stable disease). No correlation between MR imaging and PET-CT could be appreciated in 15 patients with complete radiological data.
This study confirms the moderate radiological response of IM in diffuse-type TGCT. PET-CT is a valuable additional diagnostic tool to quantify response to tyrosine kinase inhibitor treatment. Its value should be assessed further to validate its efficacy in the objective measurement of biological response in targeted systemic treatment of TGCT.
•Tenosynovial Giant Cell Tumour (TGCT), is a rare mono-articular tumour affecting the synovium, bursae and tendon sheath.•Diagnosing and staging the extension of TGCT is assessed on MR imaging and can be quantified by the Tumour Volume Score (TVS).•PET-CT provides understanding of the metabolic activity of TGCT, expressed as maximum Standardized Uptake Values (SUV-max).•As treatment in diffuse-type TGCT, Imatinib Mesylate, a tyrosine kinase inhibitor, can be provided.•PET-CT is a valuable additional diagnostic tool to quantify response to tyrosine kinase inhibitor treatment in TGCT.
We have imaged the formation of membrane microdomains immediately after their induction using a novel technology platform coupling high hydrostatic pressure to fluorescence microscopy. After ...formation, the ordered domains are small and highly dynamic. This will enhance links between model lipid assemblies and dynamic processes in cellular membranes.
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