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Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases ( n  = 74), including non-demented cases ( n  = 15), early-onset (EO)AD ( n  = 38), and late-onset (LO)AD cases ( n  = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrP C ), Aβ isoform composition (Aβ 40 , Aβ 42 , Aβ N3pE , pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ 40 . Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ 40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

Objective Elevated levels of anti‐amyloid‐β (anti‐Aβ) autoantibodies in cerebrospinal fluid (CSF) have been proposed as a diagnostic biomarker for cerebral amyloid angiopathy‐related inflammation (CAA‐RI). We aimed to independently validate the immunoassay for quantifying these antibodies and evaluate its diagnostic value for CAA‐RI. Methods We replicated the immunoassay to detect CSF anti‐Aβ autoantibodies using CSF from CAA‐RI patients and non‐CAA controls with unrelated disorders and further characterized its performance. Moreover, we conducted a literature review of CAA‐RI case reports to investigate neuropathological and CSF evidence of the nature of the inflammatory reaction in CAA‐RI. Results The assay demonstrated a high background signal in CSF, which increased and corresponded with higher total immunoglobulin G (IgG) concentration in CSF (rsp = 0.51, p = 0.02). Assay levels were not elevated in CAA‐RI patients (n = 6) compared to non‐CAA controls (n = 20; p = 0.64). Literature review indicated only occasional presence of B‐lymphocytes and plasma cells (i.e., antibody‐producing cells), alongside the abundant presence of activated microglial cells, T‐cells, and other monocyte lineage cells. CSF analysis did not convincingly indicate intrathecal IgG production. Interpretation We were unable to reproduce the reported elevation of anti‐Aβ autoantibody concentration in CSF of CAA‐RI patients. Our findings instead support nonspecific detection of IgG levels in CSF by the assay. Reviewed CAA‐RI case reports suggested a widespread cerebral inflammatory reaction. In conclusion, our findings do not support anti‐Aβ autoantibodies as a diagnostic biomarker for CAA‐RI.

Purpose>The purpose of this paper is to identify sensing, seizing and reconfiguring routines of dynamic capabilities that enable digital transformation in firms.Design/methodology/approach>A qualitative approach is used. Representatives from a firm going through digital transformations are interviewed, and focus groups have been carried out with a consultancy firm experienced in giving advice to firms going through digital transformation.Findings>Six routines identified as relevant specifically for digital transformation are identified. These are cross-industrial digital sensing, inside-out digital infrastructure sensing, digital strategy development, determination of enterprise boundaries, decomposition of digital transformation into specified projects and creation of a unified digital infrastructure.Practical implications>The authors provide direction for managers on how to approach digital transformation. In relation to previous research, the authors provide more specific guidance regarding how to reconfigure the organization in digital transformation.Originality/value>The paper uses a novel context for digital transformation and complements the very few studies available using dynamic capabilities to understand digital transformation.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid β (Aβ) protein in the cerebral vasculature and poses a major risk factor for the development of intracerebral haemorrhages (ICH). However, only a minority of patients with CAA develops ICH (CAA-ICH), and to date it is unclear which mechanisms determine why some patients with CAA are more susceptible to haemorrhage than others. We hypothesized that an imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to vessel wall weakening. MMP9 plays a role in the degradation of various components of the extracellular matrix as well as of Aβ and increased MMP9 expression has been previously associated with CAA. TIMP3 is an inhibitor of MMP9 and increased TIMP3 expression in cerebral vessels has also been associated with CAA. In this study, we investigated the expression of MMP9 and TIMP3 in occipital brain tissue of CAA-ICH cases ( n  = 11) by immunohistochemistry and compared this to the expression in brain tissue of CAA cases without ICH (CAA-non-haemorrhagic, CAA-NH, n  = 18). We showed that MMP9 expression is increased in CAA-ICH cases compared to CAA-NH cases. Furthermore, we showed that TIMP3 expression is increased in CAA cases compared to controls without CAA, and that TIMP3 expression is reduced in a subset of CAA-ICH cases compared to CAA-NH cases. In conclusion, in patients with CAA, a disbalance in cerebrovascular MMP9 and TIMP3 expression is associated with CAA-related ICH.

Alzheimer's disease (AD) is characterized by amyloid-beta (A[beta]) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical A[beta] deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø [almost equal to] 80 [micro]m) deposit, characterized as having multiple cores and A[beta]-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of A[beta]-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE [epsilon]4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrP.sup.C), A[beta] isoform composition (A[beta].sub.40, A[beta].sub.42, A[beta].sub.N3pE, pSer8A[beta]), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of A[beta].sub.40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular A[beta].sub.40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent A[beta] plaque-type associated with EOAD. Differences in A[beta] processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other A[beta] deposits. Disentangling specific A[beta] deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

This doctoral dissertation examines literature’s relationship with the past, specifically the ways in which literature rewrites, and also fails to rewrite, multiple pasts. This project considers the narratives of immigrant Jewish-American authors from Eastern Europe who arrived in America during the third wave, namely between 1880 and 1924. The following four chapters focus upon seven literary works by five of these authors: Abraham Cahan’s Yekl (1896), Mary Antin’s From Plotzk to Boston (1899) and The Promised Land (1912), Rose Gollup Cohen’s Out of the Shadow: A Russian Jewish Girlhood on the Lower East Side (1918), Ludwig Lewisohn’s Up Stream (1922), and Anzia Yezierska’s All I Could Never Be (1932) and Red Ribbon on a White Horse (1950). The following pages explore different questions: how do these texts reinterpret the past? What remains of this past, if anything remains at all, in their American present? In order to do this, the methodological framework draws on both canonical and recent scholarly work from memory studies and literary studies. Recent work on memory and mobility, such as Andreas Kitzmann’s and Julia Creet’s Memory and Migration: Multidisciplinary Approaches to Memory Studies and Monika Palmberger’s and Jelena Tošić’s Memories on the Move: Experiencing Mobility, Rethinking the Past, form the foundations of this methodology. Other studies on culture, memory and the past, as well as secondary criticism on the selected authors, also inform this theoretical framework on its emphasis upon the intertwinement between memory and literature. Through these specific theories and close textual analysis, this dissertation posits a study of the intricacies that accompany and inform literary narratives of the past. The central thesis of this dissertation is that, in these seven texts, the past constitutes a malleable, rewritten narrative between interrupted temporalities in which routes only lead to other routes.

Abstract Aims Patients with Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) are a heterogenous group and previous studies indicate a decreased Health-related quality-of-life (HRQoL) compared with patients with myocardial infarction with obstructive coronary artery disease and healthy individuals. However, longitudinal data are scarce. Therefore, the aim was to explore HRQoL among patients with MINOCA during a one-year period after the acute event in comparison with a group of healthy individuals and to describe HRQoL in patients with Takotsubo Syndrome (TTS). Methods and results Patients with MINOCA were recruited from five hospitals in the Stockholm region (SMINC-2 study, clinical trials: NCT2318498). Patients responded to the HRQoL questionnaire RAND-36 between days 2–4, after 6 and 12 months respectively. A sample of population-based individuals was used as a comparison group. A total of 142 MINOCA patients, (70% women) mean age of 56 years, responded. A population-based sample of 317 volunteers (66% women) mean age of 57 years. Patients with MINOCA scored lower than the comparison group in the domains role functioning physical, social functioning, and role functioning emotional (P = 0.01–0.02) at 12 months. In these domains of HRQoL there was no improvement in MINOCA patients during 12 months follow-up. In the domains of energy/fatigue vitality and emotional well-being the scores improved and were similar to the comparison group at 12 months. Patients with TTS scored generally lower on RAND-36 than MINOCA patients without TTS. Conclusion Physical, social, and emotional functioning did not improve during the first year after MINOCA, indicating a need for increased follow-up including psychological support. Graphical Abstract Graphical Abstract