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α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about the effects of LB pathology in preclinical (presymptomatic) individuals, either as isolated pathology or coexisting with Alzheimer’s disease (AD) pathology (β-amyloid (Aβ) and tau). We examined the effects of LB pathology using a cerebrospinal fluid α-synuclein-seed amplification assay in 1,182 cognitively and neurologically unimpaired participants from the BioFINDER study: 8% were LB positive, 26% Aβ positive (13% of those were LB positive) and 16% tau positive. LB positivity occurred more often in the presence of Aβ positivity but not tau positivity. LB pathology had independently negative effects on cross-sectional and longitudinal global cognition and memory and on longitudinal attention/executive function. Tau had cognitive effects of a similar magnitude, but these were less pronounced for Aβ. Participants with both LB and AD (Aβ and tau) pathology exhibited faster cognitive decline than those with only LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell. Only LB-positive participants progressed to clinical LB disease over 10 years. These results are important for individualized prognosis, recruitment and choice of outcome measures in preclinical LB disease trials, but also for the design of early AD trials because >10% of individuals with preclinical AD have coexisting LB pathology. A longitudinal study of clinically unimpaired individuals reveals that Lewy body pathology measured in vivo is associated with worse smell and cognitive functions and predicted subsequent cognitive decline and progression to Parkinson’s disease or dementia with Lewy bodies.

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration. The transitional link from robust clearance of intravenously injected nanoparticles by strategically placed macrophages in systemic circulation to adverse haemodynamic reactions can be overcome by changing nanoparticle geometry or by prior nanoparticle attachment to erythrocytes

BackgroundThe 10-m walk test (10MWT) is a widely used measure of gait speed in Parkinson’s disease (PD). However, it is unclear if different standardizations of its conduct impact test results.Aim of the studyWe examined the clinical significance of two aspects of the standardization of the 10MWT in mild PD: static vs. dynamic start, and a single vs. repeated trials. Implications for fall prediction were also explored.Methods151 people with PD (mean age and PD duration, 68 and 4 years, respectively) completed the 10MWT in comfortable gait speed with static and dynamic start (two trials each), and gait speed (m/s) was recorded. Participants then registered all prospective falls for 6 months.ResultsAbsolute mean differences between outcomes from the various test conditions ranged between 0.016 and 0.040 m/s (effect sizes, 0.06–0.14) with high levels of agreement (intra-class correlation coefficients, 0.932–0.987) and small standard errors of measurement (0.032–0.076 m/s). Receiver operating characteristic curves showed similar discriminate abilities for prediction of future falls across conditions (areas under curves, 0.70–0.73). Cut-off points were estimated at 1.1–1.2 m/s.ConclusionsDifferent 10MWT standardizations yield very similar results, suggesting that there is no practical need for an acceleration distance or repeated trials when conducting this test in mild PD.

To determine factors associated with future falls and/or near falls in people with mild PD. The study included 141 participants with PD. Mean (SD) age and PD-duration were 68 (9.7) and 4 years (3.9), respectively. Their median (q1-q3) UPDRS III score was 13 (8-18). Those >80 years of age, requiring support in standing or unable to understand instructions were excluded. Self-administered questionnaires targeted freezing of gait, turning hesitations, walking difficulties in daily life, fatigue, fear of falling, independence in activities of daily living, dyskinesia, demographics, falls/near falls history, balance problems while dual tasking and pain. Clinical assessments addressed functional balance performance, retropulsion, comfortable gait speed, motor symptoms and cognition. All falls and near falls were subsequently registered in a diary during a six-month period. Risk factors for prospective falls and/or near falls were determined using logistic regression. Sixty-three participants (45%) experienced ≥ 1 fall and/or near fall. Three factors were independent predictors of falls and/or near falls: fear of falling (OR = 1.032, p<0.001) history of near falls (OR = 3.475, p = 0.009) and retropulsion (OR = 2.813, p = 0.035). The strongest contributing factor was fear of falling, followed by a history of near falls and retropulsion. Fear of falling seems to be an important issue to address already in mild PD as well as asking about prior near falls.

Osteoporotic fractures are a major global health burden. To uncover potential targets for fracture prevention, we use a proteome-wide Mendelian randomization (MR) approach combined with colocalization. Here we show that nine circulating proteins associate with forearm fracture risk, including sclerostin and osteoprotegerin targeted by existing osteoporosis treatments, and three other known bone-related proteins, providing proof of concept for our MRpipeline. Notably, we identify ephrin-A1 as a novel protective factor against fractures, a membrane-linked protein partly released into circulation that binds its high-affinity receptor EphA2 on osteoblasts. Experimental models and genetic analyses indicate that ephrin-A1 increases bone mineral density, supporting a mechanism by which this pathway may mediate fracture protection. Spatial expression analysis with the innovative 3D DeepBone technique suggests ephrin-A1 on endothelial cells interacts with EphA2 on adjacent osteoblasts at the bone surface. These findings position ephrin-A1–EphA2 signalling as a therapeutic target to strengthen bone and reduce fracture risk. Osteoporotic fractures are a major global health burden. Here the authors show, using proteome wide Mendelian randomization, that nine circulating proteins influence forearm fracture risk and identify a novel protective role for ephrin A1

Treatment for follicular lymphoma (FL) improved with rituximab. In Sweden, first-line rituximab was gradually introduced between 2003 and 2007, with regional differences. The first national guidelines for FL were published in November 2007, recommending rituximab in first-line therapy. Using the population-based Swedish Lymphoma Registry, 2641 patients diagnosed with FL from 2000 to 2010 were identified and characterized by year and region of diagnosis, age (median, 65 years), gender (50% men), first-line therapy and clinical risk factors. Overall and relative survivals were estimated by calendar periods (2000–2002, 2003–2007 and 2008–2010) and region of diagnosis. With each period, first-line rituximab use and survival increased. Survival was superior in regions where rituximab was quickly adopted and inferior where slowly adopted. These differences were independent in multivariable analyses. Ten-year relative survival for patients diagnosed 2003–2010 was 92%, 83%, 78% and 64% in the age groups 18–49, 50–59, 60–69 and ⩾70, respectively. With increasing rituximab use, male sex emerged as an adverse factor. Survival improved in all patient categories, particularly in elderly women. The introduction and the establishment of rituximab have led to a nationwide improvement in FL survival. However, rituximab might be inadequately dosed in younger women and men of all ages.

BackgroundThe complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. Complement analysis requires accurate and standardized sampling and assay procedures, which has proven to be challenging.ObjectiveWe performed a systematic analysis of the current methods used to assess complement components and reviewed whether the identified studies performed their complement measurements according to the recommended practice regarding pre-analytical sample handling and assay technique. Results are supplemented with own data regarding the assessment of key complement biomarkers to illustrate the importance of accurate sampling and measuring of complement components.MethodsA literature search using the Pubmed/MEDLINE database was performed focusing on studies measuring the key complement components C3, C5 and/or their split products and/or the soluble variant of the terminal C5b-9 complement complex (sTCC) in human blood samples that were published between February 2017 and February 2022. The identified studies were reviewed whether they had used the correct sample type and techniques for their analyses.ResultsA total of 92 out of 376 studies were selected for full-text analysis. Forty-five studies (49%) were identified as using the correct sample type and techniques for their complement analyses, while 25 studies (27%) did not use the correct sample type or technique. For 22 studies (24%), it was not specified which sample type was used.ConclusionA substantial part of the reviewed studies did not use the appropriate sample type for assessing complement activation or did not mention which sample type was used. This deviation from the standardized procedure can lead to misinterpretation of complement biomarker levels and hampers proper comparison of complement measurements between studies. Therefore, this study underlines the necessity of general guidelines for accurate and standardized complement analysis

Estradiol (E2) affects both reproductive and non-reproductive tissues, and the sensitivity to different doses of E2 varies between tissues. Membrane estrogen receptor α (mERα)-initiated signaling plays a tissue-specific role in mediating E2 effects, however, it is unclear if mERα signaling modulates E2 sensitivity. To determine this, we treated ovariectomized C451A females, lacking mERα signaling, and wildtype (WT) littermates with physiological (0.05 μg/mouse/day (low); 0.6 μg/mouse/day (medium)) or supraphysiological (6 μg/mouse/day (high)) doses of E2 (17β-estradiol-3-benzoate) for three weeks. Low-dose treatment increased uterus weight in WT, but not C451A mice, while non-reproductive tissues (gonadal fat, thymus, trabecular and cortical bone) were unaffected in both genotypes. Medium-dose treatment increased uterus weight and bone mass and decreased thymus and gonadal fat weights in WT mice. Uterus weight was also increased in C451A mice, but the response was significantly attenuated (− 85%) compared to WT mice, and no effects were triggered in non-reproductive tissues. High-dose treatment effects in thymus and trabecular bone were significantly blunted (− 34% and − 64%, respectively) in C451A compared to WT mice, and responses in cortical bone and gonadal fat were similar between genotypes. Interestingly, the high dose effect in uterus was enhanced (+ 26%) in C451A compared to WT mice. In conclusion, loss of mERα signaling reduces the sensitivity to physiological E2 treatment in both non-reproductive tissues and uterus. Furthermore, the E2 effect after high-dose treatment in uterus is enhanced in the absence of mERα, suggesting a protective effect of mERα signaling in this tissue against supraphysiological E2 levels.

Mitochondrial morphology and function are coupled in healthy cells, during pathological conditions and (adaptation to) endogenous and exogenous stress. In this sense mitochondrial shape can range from small globular compartments to complex filamentous networks, even within the same cell. Understanding how mitochondrial morphological changes (i.e. \"mitochondrial dynamics\") are linked to cellular (patho) physiology is currently the subject of intense study and requires detailed quantitative information. During the last decade, various computational approaches have been developed for automated 2-dimensional (2D) analysis of mitochondrial morphology and number in microscopy images. Although these strategies are well suited for analysis of adhering cells with a flat morphology they are not applicable for thicker cells, which require a three-dimensional (3D) image acquisition and analysis procedure. Here we developed and validated an automated image analysis algorithm allowing simultaneous 3D quantification of mitochondrial morphology and network properties in human endothelial cells (HUVECs). Cells expressing a mitochondria-targeted green fluorescence protein (mitoGFP) were visualized by 3D confocal microscopy and mitochondrial morphology was quantified using both the established 2D method and the new 3D strategy. We demonstrate that both analyses can be used to characterize and discriminate between various mitochondrial morphologies and network properties. However, the results from 2D and 3D analysis were not equivalent when filamentous mitochondria in normal HUVECs were compared with circular/spherical mitochondria in metabolically stressed HUVECs treated with rotenone (ROT). 2D quantification suggested that metabolic stress induced mitochondrial fragmentation and loss of biomass. In contrast, 3D analysis revealed that the mitochondrial network structure was dissolved without affecting the amount and size of the organelles. Thus, our results demonstrate that 3D imaging and quantification are crucial for proper understanding of mitochondrial shape and topology in non-flat cells. In summary, we here present an integrative method for unbiased 3D quantification of mitochondrial shape and network properties in mammalian cells.

Background Fear of falling is common among persons with Parkinson’s disease and is negatively associated with quality of life. However a lack of in-depth understanding of fear of falling as a phenomenon persists. This qualitative study aimed to explore the experiences of fear of falling in persons with Parkinson’s disease. Methods Individual interviews were performed with twelve persons with Parkinson’s disease (median age 70 years, median Parkinson duration 9 years, 50% women). The interviews were semi-structured and followed a study-specific interview guide. The transcribed interviews were analyzed using qualitative content analysis. Results Fear of falling was experienced as a disturbing factor in everyday life. It generated a feeling of vulnerability and made daily activities and everyday environments seem potentially hazardous. Persons also missed performing previous activities. The fear of falling was a varying experience, fueled by an awareness of falls and near falls, Parkinson-related symptoms and disabilities, and by others in their environment. The persons adopted different strategies to handle their fear of falling. Activities were adapted, avoided, performed with help, or carried out despite their fear of falling. Conclusions The experiences of fear of falling were complex, multifaceted and varied over time and in relation to different activities and environments. This indicates that interventions targeting fear of falling need to be individually tailored for persons with Parkinson’s disease and should focus on several aspects, such as Parkinson-related symptoms and disabilities, activities and environmental factors. This study provides new information that increases the understanding of fear of falling, which has implications for researchers as well as clinicians working with persons with Parkinson’s disease and fear of falling.