The precise regulation of cerebral blood flow is critical for normal brain function, and its disruption underlies many neuropathologies. The extent to which smooth muscle-covered arterioles or ...pericyte-covered capillaries control vasomotion during neurovascular coupling remains controversial. We found that capillary pericytes in mice and humans do not express smooth muscle actin and are morphologically and functionally distinct from adjacent precapillary smooth muscle cells (SMCs). Using optical imaging we investigated blood flow regulation at various sites on the vascular tree in living mice. Optogenetic, whisker stimulation, or cortical spreading depolarization caused microvascular diameter or flow changes in SMC but not pericyte-covered microvessels. During early stages of brain ischemia, transient SMC but not pericyte constrictions were a major cause of hypoperfusion leading to thrombosis and distal microvascular occlusions. Thus, capillary pericytes are not contractile, and regulation of cerebral blood flow in physiological and pathological conditions is mediated by arteriolar SMCs.
•Pericytes are morphologically and functionally distinct from precapillary SMCs•Capillary pericytes lack smooth muscle actin and are not contractile in vivo•Neurovascular coupling is mediated by arteriolar smooth muscle contractility•Ischemia causes transient SMC constrictions that lead to capillary thrombosis
The extent to which arteriolar smooth muscle cell or capillary pericyte contractility regulates regional cerebral blood flow is debated. Hill et al. use optogenetic, whisker stimulation, spreading depolarization, and transient cerebral ischemia to demonstrate that capillary pericytes are not contractile in vivo and that arteriolar smooth muscle cells mediate physiological and pathological vasomotion.
Cardiovascular diseases are the leading cause of death worldwide. Overweight and obesity are strongly associated with comorbidities such as hypertension and insulin resistance, which collectively ...contribute to the development of cardiovascular diseases and resultant morbidity and mortality. Forty-two percent of adults in the United States are obese, and a total of 1.9 billion adults worldwide are overweight or obese. These alarming numbers, which continue to climb, represent a major health and economic burden. Adipose tissue is a highly dynamic organ that can be classified based on the cellular composition of different depots and their distinct anatomical localization. Massive expansion and remodeling of adipose tissue during obesity differentially affects specific adipose tissue depots and significantly contributes to vascular dysfunction and cardiovascular diseases. Visceral adipose tissue accumulation results in increased immune cell infiltration and secretion of vasoconstrictor mediators, whereas expansion of subcutaneous adipose tissue is less harmful. Therefore, fat distribution more than overall body weight is a key determinant of the risk for cardiovascular diseases. Thermogenic brown and beige adipose tissue, in contrast to white adipose tissue, is associated with beneficial effects on the vasculature. The relationship between the type of adipose tissue and its influence on vascular function becomes particularly evident in the context of the heterogenous phenotype of perivascular adipose tissue that is strongly location dependent. In this review, we address the abnormal remodeling of specific adipose tissue depots during obesity and how this critically contributes to the development of hypertension, endothelial dysfunction, and vascular stiffness. We also discuss the local and systemic roles of adipose tissue derived secreted factors and increased systemic inflammation during obesity and highlight their detrimental impact on cardiovascular health.
The 2019 novel coronavirus (renamed SARS-CoV-2, and generally referred to as the COVID-19 virus) has spread to 184 countries with over 1.5 million confirmed cases. Such major viral outbreaks demand ...early elucidation of taxonomic classification and origin of the virus genomic sequence, for strategic planning, containment, and treatment. This paper identifies an intrinsic COVID-19 virus genomic signature and uses it together with a machine learning-based alignment-free approach for an ultra-fast, scalable, and highly accurate classification of whole COVID-19 virus genomes. The proposed method combines supervised machine learning with digital signal processing (MLDSP) for genome analyses, augmented by a decision tree approach to the machine learning component, and a Spearman's rank correlation coefficient analysis for result validation. These tools are used to analyze a large dataset of over 5000 unique viral genomic sequences, totalling 61.8 million bp, including the 29 COVID-19 virus sequences available on January 27, 2020. Our results support a hypothesis of a bat origin and classify the COVID-19 virus as Sarbecovirus, within Betacoronavirus. Our method achieves 100% accurate classification of the COVID-19 virus sequences, and discovers the most relevant relationships among over 5000 viral genomes within a few minutes, ab initio, using raw DNA sequence data alone, and without any specialized biological knowledge, training, gene or genome annotations. This suggests that, for novel viral and pathogen genome sequences, this alignment-free whole-genome machine-learning approach can provide a reliable real-time option for taxonomic classification.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autoimmune hemolytic anemia Hill, Anita; Hill, Quentin A
Hematology,
11/2018, Letnik:
2018, Številka:
1
Journal Article
Odprti dostop
The diagnosis of autoimmune hemolytic anemia (AIHA) can be made with a stepwise approach that aims to identify laboratory and clinical evidence of hemolysis and then determine the immune nature of ...hemolysis with the direct anti-globulin test. Once alternative causes for these findings have been excluded, AIHA is established, and the clinician must search for secondary causes, as well as identify the type of AIHA. Rituximab is now the preferred second-line treatment for primary warm AIHA and first-line treatment for primary cold agglutinin disease (CAD), either as monotherapy or combined with bendamustine. Complement inhibitors have shown utility in stabilizing AIHA patients with acute severe hemolysis. Future prospects are discussed and include the C1s inhibitor BIVV009 (sutimlimab) that is now entering phase 3 studies for CAD.
Axonal myelin increases neural processing speed and efficiency. It is unknown whether patterns of myelin distribution are fixed or whether myelinating oligodendrocytes are continually generated in ...adulthood and maintain the capacity for structural remodeling. Using high-resolution, intravital label-free and fluorescence optical imaging in mouse cortex, we demonstrate lifelong oligodendrocyte generation occurring in parallel with structural plasticity of individual myelin internodes. Continuous internode formation occurred on both partially myelinated and unmyelinated axons, and the total myelin coverage along individual axons progressed up to two years of age. After peak myelination, gradual oligodendrocyte death and myelin degeneration in aging were associated with pronounced internode loss and myelin debris accumulation within microglia. Thus, cortical myelin remodeling is protracted throughout life, potentially playing critical roles in neuronal network homeostasis. The gradual loss of internodes and myelin degeneration in aging could contribute significantly to brain pathogenesis.
The human intestine is colonized by an estimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple ...inflammatory diseases including IBD and asthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease. We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them. We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease. We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease.
Background
This is the fourth updated Enhanced Recovery After Surgery (ERAS
®
) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded ...recommendations for each ERAS item within the ERAS
®
protocol.
Methods
A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.
Results
All recommendations on ERAS
®
protocol items are based on best available evidence; good-quality trials; meta-analyses of good-quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly.
Conclusions
The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS
®
Society in this comprehensive consensus review.
Fibrosis is a consequence of the inflammatory response. When fibrotic tissue becomes excessive, it can have diverse pathophysiological effects on a number of organ systems. The mechanisms underlying ...fibrosis and approaches to therapy are reviewed.
Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminates in tissue fibrosis. Although this fibrogenic response may have adaptive features in the short term, when it progresses over a prolonged period of time, parenchymal scarring and ultimately cellular dysfunction and organ failure ensue (Figure 1).
We and others have proposed four major phases of the fibrogenic response (Figure 2). First is initiation of the response, driven by primary injury to the organ. The second phase is the activation of effector cells, and the third phase is the elaboration of extracellular matrix, both of . . .
Autoimmune hemolytic anemias (AIHAs) are rare and heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. There is currently no licensed treatment ...for AIHA. Due to the paucity of clinical trials, recommendations on diagnosis and therapy have often been based on expert opinions and some national guidelines. Here we report the recommendations of the First International Consensus Group, who met with the aim to review currently available data and to provide standardized diagnostic criteria and therapeutic approaches as well as an overview of novel therapies. Exact diagnostic workup is important because symptoms, course of disease, and therapeutic management relate to the type of antibody involved. Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup, and any causes of secondary AIHA have to be diagnosed. Corticosteroids remain first-line therapy for warm-AIHA, while the addition of rituximab should be considered early in severe cases and if no prompt response to steroids is achieved. Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy. We identified a need to establish an international AIHA network. Future recommendations should be based on prospective clinical trials whenever possible.
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