Spoken words are processed during dexmedetomidine-induced unresponsiveness

Background: Studying the effects of anaesthetic drugs on the processing of semantic stimuli could yield insights into how brain functions change in the transition from wakefulness to unresponsiveness. Here, we explored the N400 event-related potential during dexmedetomidine- and propofol-induced unresponsiveness. Methods: Forty-seven healthy subjects were randomised to receive either dexmedetomidine (n = 23) or propofol (n = 24) in this open-label parallel-group study. Loss of responsiveness was achieved by stepwise increments of pseudo-steady-state plasma concentrations, and presumed loss of consciousness was induced using 1.5 times the concentration required for loss of responsiveness. Pre-recorded spoken sentences ending either with an expected (congruous) or an unexpected (incongruous) word were presented during unresponsiveness. The resulting electroencephalogram data were analysed for the presence of the N400 component, and for the N400 effect defined as the difference between the N400 components elicited by congruous and incongruous stimuli, in the time window 300-600 ms post-stimulus. Recognition of the presented stimuli was tested after recovery of responsiveness. Results: The N400 effect was not observed during dexmedetomidine- or propofol-induced unresponsiveness. The N400 component, however, persisted during dexmedetomidine administration. The N400 component elicited by congruous stimuli during unresponsiveness in the dexmedetomidine group resembled the large component evoked by incongruous stimuli at the awake baseline. After recovery, no recognition of the stimuli heard during unresponsiveness occurred. Conclusions: Dexmedetomidine and propofol disrupt the discrimination of congruous and incongruous spoken sentences, and recognition memory at loss of responsiveness. However, the processing of words is partially preserved during dexmedetomidine-induced unresponsiveness.</p

Single-subject analysis of N400 event-related potential component with five different methods

There are several different approaches to analyze event-related potentials (ERPs) at single-subject level, and the aim of the current study is to provide information for choosing a method based on its ability to detect ERP effects and factors influencing the results. We used data from 79 healthy participants with EEG referenced to mastoid average and investigated the detection rate of auditory N400 effect in single-subject analysis using five methods: visual inspection of participant-wise averaged ERPs, analysis of variance (ANOVA) for amplitude averages in a time window, cluster-based non-parametric testing, a novel Bayesian approach and Studentized continuous wavelet transform (t-CWT). Visual inspection by three independent raters yielded N400 effect detection in 85% of the participants in at least one paradigm (active responding or passive listening), whereas ANOVA identified the effect in 68%, the cluster-method in 59%, the Bayesian method in 89%, and different versions of t-CWT in 22–59% of the participants. Thus, the Bayesian method was the most liberal and also showed the greatest concordance between the experimental paradigms (active/passive). ANOVA detected significant effect only in cases with converging evidence from other methods. The t-CWT and cluster-based method were the most conservative methods. As we show in the current study, different analysis methods provide results that do not completely overlap. The method of choice for determining the presence of an ERP component at single-subject level thus remains unresolved. Relying on a single statistical method may not be sufficient for drawing conclusions on single-subject ERPs.</p

Haploinsufficiency of the NF1 gene is associated with protection against diabetes

Abstract Background The hereditary predisposition to diabetes is only partially explained by genes identified so far. Neurofibromatosis type 1 (NF1) is a rare monogenic dominant syndrome caused by aberrations of the NF1 gene. Here, we used a cohort of 1410 patients with NF1 to study the association of the NF1 gene with type 1 (T1D) and type 2 diabetes (T2D). Methods A total of 1410 patients were confirmed to fulfil the National Institutes of Health diagnostic criteria for NF1 by individually reviewing their medical records. The patients with NF1 were compared with 14 017 controls matched for age, sex and area of residence as well as 1881 non-­NF1 siblings of the patients with NF1. Register-based information on purchases of antidiabetic medication and hospital encounters related to diabetes were retrieved. The Cox proportional hazards model was used to calculate the relative risk for diabetes in NF1. Results Patients with NF1 showed a lower rate of T2D when compared with a 10-fold control cohort (HR 0.27, 95% CI 0.17 to 0.43) or with their siblings without NF1 (HR 0.28, 95% CI 0.16 to 0.47). The estimates remained practically unchanged after adjusting the analyses for history of obesity and dyslipidaemias. The rate of T1D in NF1 was decreased although statistically nonsignificantly (HR 0.58, 95% CI 0.27 to 1.25). Conclusion Haploinsufficiency of the NF1 gene may protect against T2D and probably T1D. Since NF1 negatively regulates the Ras signalling pathway, the results suggest that the Ras pathway may be involved in the pathogenesis of diabetes.</p

An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

PurposeAdvanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.MethodsCollective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.ResultsType 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.ConclusionsThe relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.Peer reviewe

Dreaming and awareness during dexmedetomidine- and propofol-induced unresponsiveness

Background: Experiences during anaesthetic-induced unresponsiveness have previously been investigated by interviews after recovery. To explore whether experiences occur during drug administration, we interviewed participants during target-controlled infusion (TCI) of dexmedetomidine or propofol and after recovery.Methods: Healthy participants received dexmedetomidine (n = 23) or propofol (n = 24) in stepwise increments until loss of responsiveness (LOR1). During TCI we attempted to arouse them for interview (return of responsiveness, ROR1). After the interview, if unresponsiveness ensued with the same dose (LOR2), the procedure was repeated (ROR2). Finally, the concentration was increased 1.5-fold to achieve presumable loss of consciousness (LOC), infusion terminated, and the participants interviewed upon recovery (ROR3). An emotional sound stimulus was presented during LORs and LOC, and memory for stimuli was assessed with recognition task after recovery. Interview transcripts were content analysed.Results: Of participants receiving dexmedetomidine, 18/23 were arousable from LOR1 and LOR2. Of participants receiving propofol, 10/24 were arousable from LOR1 and two of four were arousable from LOR2. Of 93 interviews performed, 84% included experiences from periods of unresponsiveness (dexmedetomidine 90%, propofol 74%). Internally generated experiences (dreaming) were present in 86% of reports from unresponsive periods, while externally generated experiences (awareness) were rare and linked to brief arousals. No within drug differences in the prevalence or content of experiences during infusion vs after recovery were observed, but participants receiving dexmedetomidine reported dreaming and awareness more often. Participants receiving dexmedetomidine recognised the emotional sounds better than participants receiving propofol (42% vs 15%), but none reported references to sounds spontaneously.Conclusion: Anaesthetic-induced unresponsiveness does not induce unconsciousness or necessarily even disconnectedness.</p

Cargo-specific recruitment in clathrin and dynamin-independent endocytosis

Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis, and cancer invasion and is often hijacked by viral infections. Unlike clathrin-mediated endocytosis, which exploits cargo-specific adaptors for selective protein internalization, the clathrin and dynamin-independent endocytic pathway (CLIC-GEEC, CG-pathway) has until now been considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. Although the core molecular players of CG endocytosis have been recently defined, no cargo-specific adaptors are known and evidence of selective protein uptake into the pathway is lacking. Here, we identify the first cargo-specific adaptor for CG-endocytosis and demonstrate its clinical relevance in breast cancer progression. By combining unbiased molecular characterization and super-resolution imaging, we identified the actin-binding protein swiprosin-1 (EFHD2) as a cargo-specific adaptor regulating integrin internalization via the CG-pathway. Swiprosin-1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery, IRSp53 and actin. Swiprosin-1 is critical for integrin endocytosis, but not for other CG-cargo and supports integrin-dependent cancer cell migration and invasion, with clinically relevant implications for breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG-pathway and opens the possibility to discover more adaptors regulating it

Comparative effects of dexmedetomidine, propofol, sevoflurane, and S-ketamine on regional cerebral glucose metabolism in humans: a positron emission tomography study

Introduction: The highly selective alpha(2)-agonist dexmedetomidine has become a popular sedative for neurointensive care patients. However, earlier studies have raised concern that dexmedetomidine might reduce cerebral blood flow without a concomitant decrease in metabolism. Here, we compared the effects of dexmedetomidine on the regional cerebral metabolic rate of glucose (CMRglu) with three commonly used anaesthetic drugs at equi-sedative doses.Methods: One hundred and sixty healthy male subjects were randomised to EC50 for verbal command of dexmedetomidine (1.5 ng ml (1); n=40), propofol (1.7 mu g ml (1); n=40), sevoflurane (0.9% end-tidal; n=40) or S-ketamine (0.75 mu g ml (1); n=20) or placebo (n=20). Anaesthetics were administered using target-controlled infusion or vapouriser with end-tidal monitoring. F-18-labelled fluorodeoxyglucose was administered 20 min after commencement of anaesthetic administration, and high-resolution positron emission tomography with arterial blood activity samples was used to quantify absolute CMRglu for whole brain and 15 brain regions.Results: At the time of [F-18]fluorodeoxyglucose injection, 55% of dexmedetomidine, 45% of propofol, 85% of sevoflurane, 45% of S-ketamine, and 0% of placebo subjects were unresponsive. Whole brain CMRglu was 63%, 71%, 71%, and 96% of placebo in the dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively (PConclusions: At equi-sedative doses in humans, potency in reducing CMRglu was dexmedetomidine>propofol>ketamine=placebo. These findings alleviate concerns for dexmedetomidine-induced vasoconstriction and cerebral ischaemia.</p

Breast cancer in neurofibromatosis type 1 : overrepresentation of unfavourable prognostic factors

Background: An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers. Methods: The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls. Results: A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P = 0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population. Conclusions: These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1.Peer reviewe

An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

PurposeAdvanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed ‘Type 1’), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.MethodsCollective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.ResultsType 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49–53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.ConclusionsThe relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.</p