Alzheimer's disease mutant mice exhibit reduced brain tissue stiffness compared to wild-type mice in both normoxia and following intermittent hypoxia mimicking sleep apnea

Background: Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD) and that AD is associated with reduced brain tissue stiffness.Aim: To investigate whether intermittent hypoxia (IH) alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA.Methods: Six-eight month old (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J) AD mutant mice and wild-type (WT) littermates were subjected to IH (21% O-2 40 s to 5% O-2 20 s; 6 h/day) or normoxia for 8 weeks. After euthanasia, the stiffness (E) of 200-mu m brain cortex slices was measured by atomic force microscopy.Results: Two-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT), but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice.Conclusion: AD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD

A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls

STUDY QUESTION Is there any difference in the clinical performance of the 3-year one-rod etonogestrel (ENG)- and the 5-year two-rod levonorgestrel (LNG)-releasing contraceptive implants during 3 years of insertion, and between implant and intrauterine device (IUD) contraception, in particular complaints possibly related to hormonal contraceptives? SUMMARY ANSWER The cumulative contraceptive effectiveness after 3 years and method continuation through 2.5 years were not significantly different between ENG and LNG implants, but both outcomes were significantly worse in the non-randomized age-matched group of IUD users than in the combined implant group. WHAT IS KNOWN ALREADY ENG- and LNG-releasing implants are safe and highly efficacious contraceptives with pregnancy rates reported to be 0.0-0.5 per 100 women-years (W-Y). No head-to-head comparative study of the two implants has been undertaken, and little information is available on comparisons of complaints of side effects of implant and copper IUD users. STUDY DESIGN, SIZE, DURATION This was an open parallel group RCT with 1:1 allocation ratio of the ENG and the LNG implants with non-randomized control group of women choosing TCu380A IUD to address lack of reliable data on common side effects typically attributed to the use of progestogen-only contraceptives. After device(s) placement, follow-ups were at 2 weeks, 3 and 6 months, and semi-annually thereafter for 3 years or until pregnancy, removal or expulsion of the implant/IUD occurred. PARTICIPANTS, SETTING, METHODS The study took place in family planning clinics in Brazil, Chile, Dominican Republic, Hungary, Thailand, Turkey and Zimbabwe. Women seeking long-term contraception were enlisted after an eligibility check and informed consent, and 2982 women were enrolled: 1003, 1005 and 974 in the ENG-implant, LNG-implant and IUD groups, respectively; 995, 997 and 971, respectively, were included in the per protocol analysis reported here. MAIN RESULTS AND THE ROLE OF CHANCE ENG and LNG implants each had the same 3-year cumulative pregnancy rate of 0.4 per 100 W-Y [95% confidence interval (CI) 0.1-1.4]. A weight of ≥70 kg at admission was unrelated to pregnancy. Method continuation rates for ENG and LNG implants at 2.5 years were 69.8 (95% CI 66.8-72.6) and 71.8 per 100 W-Y (68.8-74.5), and at 3 years 12.1 (95% CI 5.2-22.0) and 52.0 per 100 W-Y (95% CI 41.8-61.2), respectively. Bleeding disturbances, the most frequent reason for method discontinuation, were significantly more common in the ENG group [16.7 (95% CI 14.4-19.3)] than in the LNG group [12.5 (95% CI 10.5-14.9)] (P 0.019). The 3-year cumulative loss to follow-up was lower in the ENG- than in the LNG-implant group, 8.1 (95% CI 6.4-10.2) and 14.4 per 100 W-Y (95% CI 12.1-17.1), respectively. The median duration of implant removal was 50 s shorter among women with ENG than among women with LNG implant (P < 0.0001). In the observational comparison between IUD and implant users, the 3-year relative risk for pregnancy in IUD group compared with the combined implant group was 5.7 per 100 W-Y (95% CI 4.4-7.3) (P = 0.0003). The 3-year expulsion rate of the IUD was 17.8 per 100 W-Y (95% CI 14.5-21.9), while the discontinuation rate for bleeding disturbances was 8.5 (95% CI 6.7-10.9). Frequency of complaints of headache and dizziness was not significantly different between implant and IUD users (P = 0.16 and 0.77, respectively), acne and bleeding irregularities were more frequent among implant users (P < 0.0001), while heavy bleeding and lower abdominal pain occurred more often among IUD than implant users (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION Few women were ≤19 years old or nulligravida, the proportion of implant users ≥70 kg was <20% and <8% were obese. WIDER IMPLICATIONS OF THE FINDINGS Findings of the study can inform policy makers and clinicians about choice of implant, but also about TCu380A IUD in relation to implants. STUDY FUNDING/COMPETING INTEREST(S) UNDP/UNFPA/WHO/UNICEF/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization (WHO). This report contains the views of an international expert group and does not necessarily represent the decisions or the stated policy of the WHO. TRIAL REGISTRATION ISRCTN33378571 registered on 22 March 2004. The first participant was enrolled on 12 May 200

Short-term low-severity spring grassland fire impacts on soil extractable elements and soil ratios in Lithuania.

Spring grassland fires are common in boreal areas as a consequence of slash and burn agriculture used to remove dry grass to increase soil nutrient properties and crop production. However, fewworks have investigated fire impacts on these grassland ecosystems, especially in the immediate period after the fire. The objective of this work was to study the short-termimpacts of a spring grassland fire in Lithuania. Four days after the firewe established a 400 m2 sampling grid within the burned area and in an adjacent unburned area with the same topographical, hydrological and pedological characteristics. Wecollected topsoil samples immediately after the fire (0 months), 2, 5, 7 and 9 months after the fire. We analysed soil pH, electrical conductivity (EC), major nutrients including calcium(Ca), magnesium(Mg), sodium(Na), and potassium(K), and theminor elements aluminium(Al), manganese (Mn), iron (Fe) and zinc (Zn). We also calculated the soil Na and K adsorption ratio (SPAR), Ca:Mg and Ca:Al. The results showed that this low-severity grassland fire significantly decreased soil pH, Al, and Mn but increased EC, Ca,Mg, and K,. There was no effect on Na, Fe, and Zn. Therewas a decrease of EC, Ca,Mg, and Na from 0months after the fire until 7 months after the fire,with an increase during the last sampling period. Fire did not significantly affect SPAR. Ca:Mg decreased significantly immediately after the fire, but not to critical levels. Ca:Al increased after the fire, reducing the potential effects of Al on plants. Overall, fire impactsweremainly limited to the immediate period after the fire

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

11 páginas, 4 figuras, 2 tablas. Datasets en su material suplementario. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2302720120/-/DCSupplemental.Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix.Peer reviewe

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Alzheimer's disease mutant mice exhibit reduced brain tissue stiffness compared to wild-type mice in both normoxia and following intermittent hypoxia mimicking sleep apnea

Background: Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD) and that AD is associated with reduced brain tissue stiffness.Aim: To investigate whether intermittent hypoxia (IH) alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA.Methods: Six-eight month old (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J) AD mutant mice and wild-type (WT) littermates were subjected to IH (21% O-2 40 s to 5% O-2 20 s; 6 h/day) or normoxia for 8 weeks. After euthanasia, the stiffness (E) of 200-mu m brain cortex slices was measured by atomic force microscopy.Results: Two-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT), but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice.Conclusion: AD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD

Alzheimer's disease mutant mice exhibit reduced brain tissue stiffness compared to wild-type mice in both normoxia and following intermittent hypoxia mimicking sleep apnea

Background: Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD) and that AD is associated with reduced brain tissue stiffness.Aim: To investigate whether intermittent hypoxia (IH) alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA.Methods: Six-eight month old (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J) AD mutant mice and wild-type (WT) littermates were subjected to IH (21% O-2 40 s to 5% O-2 20 s; 6 h/day) or normoxia for 8 weeks. After euthanasia, the stiffness (E) of 200-mu m brain cortex slices was measured by atomic force microscopy.Results: Two-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT), but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice.Conclusion: AD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD