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Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed 'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) Aqp4 gene deletion did not impair transport of fluorescent solutes from sub-arachnoid space to brain in mice or rats. Our results do not support the proposed glymphatic mechanism of convective solute transport in brain parenchyma.

Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement 'bystander mechanism' to account for early oligodendrocyte injury in NMO in which activated, soluble complement proteins following AQP4-IgG binding to astrocyte AQP4 result in deposition of the complement membrane attack complex (MAC) on nearby oligodendrocytes. Primary cocultures of rat astrocytes and mature oligodendrocytes exposed to AQP4-IgG and complement showed early death of oligodendrocytes in close contact with astrocytes, which was not seen in pure oligodendrocyte cultures, in cocultures exposed to AQP4-IgG and C6-depleted serum, or when astrocytes were damaged by a complement-independent mechanism. Astrocyte-oligodendrocyte cocultures exposed to AQP4-IgG and complement showed prominent MAC deposition on oligodendrocytes in contact with astrocytes, whereas C1q, the initiating protein in the classical complement pathway, and C3d, a component of the alternative complement pathway, were deposited only on astrocytes. Early oligodendrocyte injury with MAC deposition was also found in rat brain following intracerebral injection of AQP4-IgG, complement and a fixable dead-cell stain. These results support a novel complement bystander mechanism for early oligodendrocyte injury and demyelination in NMO.

BackgroundKnowledge about expected recovery after hip fracture is essential to help patients and families set realistic expectations and plan for the future.ObjectivesTo determine rates of functional recovery in older adults who sustained a hip fracture based on one's previous function.DesignObservational study.ParticipantsWe identified subjects who sustained a hip fracture while enrolled in the nationally representative Health and Retirement Study (HRS) using linked Medicare claims. HRS interviews subjects every 2 years. Using information from interviews collected during the interview preceding the fracture and the first interview 6 or more months after the fracture, we determined the proportion of subjects who returned to pre-fracture function.Main measuresFunctional outcomes of interest were: (1) ADL dependency, (2) mobility, and (3) stair-climbing ability. We examined baseline characteristics associated with a return to: (1) ADL independence, (2) walking one block, and (3) climbing a flight of stairs.Key resultsA total of 733 HRS subjects ≥65 years of age sustained a hip fracture (mean age 84 ± 7 years, 77 % female). Thirty-one percent returned to pre-fracture ADL function, 34 % to pre-fracture mobility function, and 41 % to pre-fracture climbing function. Among those who were ADL independent prior to fracture, 36 % returned to independence, 27 % survived but needed ADL assistance, and 37 % died. Return to ADL independence was less likely for those ≥85 years old (26 % vs. 44 %), with dementia (8 % vs. 39 %), and with a Charlson comorbidity score >2 (23 % vs. 44 %). Results were similar for those able to walk a block and for those able to climb a flight of stairs prior to fracture.ConclusionsRecovery rates are low, even among those with higher levels of pre-fracture functional status, and are worse for patients who are older, cognitively impaired, and who have multiple comorbidities.

A "glymphatic system," which involves convective fluid transport from para-arterial to paravenous cerebrospinal fluid through brain extracellular space (ECS), has been proposed to account for solute clearance in brain, and aquaporin-4 water channels in astrocyte endfeet may have a role in this process. Here, we investigate the major predictions of the glymphatic mechanism by modeling diffusive and convective transport in brain ECS and by solving the Navier-Stokes and convection-diffusion equations, using realistic ECS geometry for short-range transport between para-arterial and paravenous spaces. Major model parameters include para-arterial and paravenous pressures, ECS volume fraction, solute diffusion coefficient, and astrocyte foot-process water permeability. The model predicts solute accumulation and clearance from the ECS after a step change in solute concentration in para-arterial fluid. The principal and robust conclusions of the model are as follows: (a) significant convective transport requires a sustained pressure difference of several mmHg between the para-arterial and paravenous fluid and is not affected by pulsatile pressure fluctuations; (b) astrocyte endfoot water permeability does not substantially alter the rate of convective transport in ECS as the resistance to flow across endfeet is far greater than in the gaps surrounding them; and (c) diffusion (without convection) in the ECS is adequate to account for experimental transport studies in brain parenchyma. Therefore, our modeling results do not support a physiologically important role for local parenchymal convective flow in solute transport through brain ECS.

Objective: The transversus abdominis plane (TAP) block and local anaesthetic infiltration (LAI) of port sites provide adequate analgesia after laparoscopic cholecystectomy (LC). Little is known if the two techniques affect the day-case (DC) rate of LC. We tested the appropriateness of the research design in view of a larger randomised controlled trial (RCT) – laparoscopic-assisted right subcostal TAP block plus local anaesthetic wound infiltration (STALA) versus LAI. Subjects and Methods: Sixty patients having DC LC were randomised into STALA and LAI. Participants received bupivacaine 0.5% 30 mL. Pain scores were evaluated with the Visual Analogue Scale (VAS) score, at 1 h post-surgery and at discharge. Need of postoperative intravenous (IV) opioids, DC rate, and Quality of Recovery-15 questionnaires were compared between groups and were considered as measures of efficacy of the interventions and follow-up in a definitive trial. Results: Twenty-nine participants were randomised to STALA, and 31 to LAI. Subjects in LAI group were all women (p = 0.0007) and younger (43.8 vs. 37.7 years, p = 0.023). Median VAS scores were 0 versus 1 at 1 h (p = 0.60), 0 versus 1.5 at discharge (p = 0.55). The need of IV opioids was 15/29 (51.7%) versus 13/31 (41.9%; p = 0.60). The DC rate was 93.1% versus 93.5% (p = 0.39). Fifty (83.3%) participants responded the questionnaires. Conclusions: The laparoscopically guided right subcostal TAP block provided no additional benefit to LAI on pain control after LC and DC rate. Despite the appropriate design, our findings do not support a larger RCT. [ABSTRACT FROM AUTHOR]

Hurricane Fiona made landfall as an extra-tropical storm along the north shore of Prince Edward Island (PEI), Canada, in October 2022. The state of the beach and dune immediately before and after the storm was captured through the Coastie citizen science beach and dune photo monitoring initiative, as part of the global CoastSnap Community Beach Monitoring program. Coastie monitoring sites within Prince Edward Island National Park (PEINP) revealed extensive dune scarping, capturing a 12–17 m retreat of the foredune at Brackley and Cavendish Beaches. Using foredune scarp and post-storm shoreline positions, volumetric losses between 28 and 76 m3 m−1 are estimated from profiles located within the first 150 m of the stations. The average horizontal position of the projected foredune scarp position was within 2.8 m of the position identified from high accuracy unoccupied aerial system (UAS) surveys, corresponding to a mean absolute difference of 15.3 m3 m−1 or 45.3% for dune volume changes estimated from the images. Continued monitoring will yield further improvements to the volume loss estimation methodology, and insight on the timing and mechanisms of beach and dune recovery. [ABSTRACT FROM AUTHOR]

This study investigates the clustering and bias of Luminous Red Galaxies (LRG) in the BOSS-LOWZ, -CMASS, -COMB, and eBOSS samples, using two types of simulated lightcones: (i) high-fidelity lightcones from Uchuu N -body simulation, employing SHAM technique to assign LRG to (sub)haloes, and (ii) 16 000 covariance lightcones from GLAM-Uchuu N -body simulations, including LRG using HOD data from Uchuu. Our results indicate that Uchuu and glam lightcones closely replicate BOSS/eBOSS data, reproducing correlation function and power spectrum across scales from redshifts 0.2 to 1.0, from 2 to |$150 \,h^{-1}\,\mathrm{Mpc}$| in configuration space, from 0.005 to |$0.7\, h\,\mathrm{Mpc}^{-1}$| in Fourier space, and across different LRG stellar masses. Furthermore, comparing with existing MD-Patchy and EZmock BOSS/eBOSS lightcones based on approximate methods, our GLAM-Uchuu lightcones provide more precise clustering estimates. We identify significant deviations from observations within |$20 \,h^{-1}\,\mathrm{Mpc}$| scales in MD-Patchy and EZmock , with our covariance matrices indicating that these methods underestimate errors by between 10 per cent and 60 per cent. Lastly, we explore the impact of cosmology on galaxy clustering. Our findings suggest that, given the current level of uncertainties in BOSS/eBOSS data, distinguishing models with and without massive neutrino effects on large-scale structure (LSS) is challenging. This paper highlights the Uchuu and GLAM-Uchuu simulations' robustness in verifying the accuracy of Planck cosmological parameters, providing a strong foundation for enhancing lightcone construction in future LSS surveys. We also demonstrate that generating thousands of galaxy lightcones is feasible using N -body simulations with adequate mass and force resolution. [ABSTRACT FROM AUTHOR]

The purpose of the study is to ascertain how high-intensity exercise affects heart health. The study's foundation was an investigation of middle-aged persons' main data. These data were gathered using specific questions on high-intensity interval training. Studies on the effects of high-intensity interval training (HIIT) on older adults are necessary since exercise is a potent inducer of mitochondrial biogenesis. Examined and summarized using smart PLS software, the study measures the effect of HIIT on mitochondria and various cardio-metabolic health outcomes in older adults, both in good health and with co-occurring conditions. The results produced include descriptive statistics, correlation coefficients, and a smart PLS algorithm model between them. Electronic databases were searched for pertinent studies using variants of keywords related to the cardiac health, the HIIT, mitochondria, cell organelles, and cardio-metabolic health outcomes. This review contains twenty-one papers that satisfied the inclusion criteria. HIIT is an original treatment approach that helps maintain mitochondrial integrity as people age and is a good, safe, and effective substitute for exercise for older persons who are well or sick. Overall, the result found a direct and significant impact of high-intensity training on cardiac health in middle-aged adults. [ABSTRACT FROM AUTHOR]

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

The water channel aquaporin-4 (AQP4) forms supramolecular clusters whose size is determined by the ratio of M1- and M23-AQP4 isoforms. In cultured astrocytes, differences in the subcellular localization and macromolecular interactions of small and large AQP4 clusters results in distinct physiological roles for M1- and M23-AQP4. Here, we developed quantitative superresolution optical imaging methodology to measure AQP4 cluster size in antibody-stained paraffin sections of mouse cerebral cortex and spinal cord, human postmortem brain, and glioma biopsy specimens. This methodology was used to demonstrate that large AQP4 clusters are formed in AQP4(-/-) astrocytes transfected with only M23-AQP4, but not in those expressing only M1-AQP4, both in vitro and in vivo. Native AQP4 in mouse cortex, where both isoforms are expressed, was enriched in astrocyte foot-processes adjacent to microcapillaries; clusters in perivascular regions of the cortex were larger than in parenchymal regions, demonstrating size-dependent subcellular segregation of AQP4 clusters. Two-color superresolution imaging demonstrated colocalization of Kir4.1 with AQP4 clusters in perivascular areas but not in parenchyma. Surprisingly, the subcellular distribution of AQP4 clusters was different between gray and white matter astrocytes in spinal cord, demonstrating regional specificity in cluster polarization. Changes in AQP4 subcellular distribution are associated with several neurological diseases and we demonstrate that AQP4 clustering was preserved in a postmortem human cortical brain tissue specimen, but that AQP4 was not substantially clustered in a human glioblastoma specimen despite high-level expression. Our results demonstrate the utility of superresolution optical imaging for measuring the size of AQP4 supramolecular clusters in paraffin sections of brain tissue and support AQP4 cluster size as a primary determinant of its subcellular distribution.