Nutritional excess is a major forerunner of type 2 diabetes. It enhances the secretion of insulin, but attenuates insulin's metabolic actions in the liver, skeletal muscle and adipose tissue. ...However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes, pointing to a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity seems to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletal muscle. These and other advances over the past 5 years offer exciting opportunities and daunting challenges for the development of new therapeutic strategies for the treatment of type 2 diabetes.
Age-Associated B Cells Cancro, Michael P
Annual review of immunology,
04/2020, Letnik:
38, Številka:
1
Journal Article
Recenzirano
The age-associated B cell subset has been the focus of increasing interest over the last decade. These cells have a unique cell surface phenotype and transcriptional signature, and they rely on TLR7 ...or TLR9 signals in the context of Th1 cytokines for their formation and activation. Most are antigen-experienced memory B cells that arise during responses to microbial infections and are key to pathogen clearance and control. Their increasing prevalence with age contributes to several well-established features of immunosenescence, including reduced B cell genesis and damped immune responses. In addition, they are elevated in autoimmune and autoinflammatory diseases, and in these settings they are enriched for characteristic autoantibody specificities. Together, these features identify age-associated B cells as a subset with pivotal roles in immunological health, disease, and aging. Accordingly, a detailed understanding of their origins, functions, and physiology should make them tractable translational targets in each of these settings.
Among adults with chronic illness, 30% to 50% of medications are not taken as prescribed. In the United States, it is estimated that medication nonadherence is associated with 125 000 deaths, 10% of ...hospitalizations, and $100 billion in health care services annually.
PubMed was searched from January 1, 2000, to September 6, 2018, for English-language randomized clinical trials of interventions to improve medication adherence. Trials of patients younger than 18 years, trials that used self-report as the primary adherence outcome, and trials with follow-up periods less than 6 months were excluded; 49 trials were included. The most common methods of identifying patients at risk for nonadherence were patient self-report, electronic drug monitors (pill bottles), or pharmacy claims data to measure gaps in supply. Patient self-report is the most practical method of identifying nonadherent patients in the context of clinical care but may overestimate adherence compared with objective methods such as electronic drug monitors and pharmacy claims data. Six categories of interventions, and characteristics of successful interventions within each category, were identified: patient education (eg, recurrent and personalized telephone counseling sessions with health educators); medication regimen management (using combination pills to reduce the number of pills patients take daily); clinical pharmacist consultation for chronic disease co-management (including education, increased frequency of disease monitoring via telephone or in-person follow-up visits, and refill reminders); cognitive behavioral therapies (such as motivational interviewing by trained counselors); medication-taking reminders (such as refill reminder calls or use of electronic drug monitors for real-time monitoring and reminding); and incentives to promote adherence (such as reducing co-payments and paying patients and clinicians for achieving disease management goals). The choice of intervention to promote adherence will depend on feasibility and availability within a practice or health system. Successful interventions that are also clinically practical include using combination pills to reduce daily pill burden, clinical pharmacist consultation for disease co-management, and medication-taking reminders such as telephone calls to prompt refills (maximum observed absolute improvements in adherence of 10%, 15%, and 33%, respectively).
Adherence can be assessed and improved within the context of usual clinical care, but more intensive and costly interventions that have demonstrated success will require additional investments by health systems.
Over the past three decades, a considerable body of evidence has highlighted T cells as pivotal culprits in the pathogenesis of psoriasis. This includes the association of psoriasis with certain MHC ...(HLA) alleles, oligoclonal expansion of T cells in some cases, therapeutic response to T cell-directed immunomodulation, the onset of psoriasis following bone marrow transplantation, or induction of psoriasis-like inflammation by T cells in experimental animals. There is accumulating clinical and experimental evidence suggesting that both autoimmune and autoinflammatory mechanisms lie at the core of the disease. Indeed, some studies suggested antigenic functions of structural proteins, and complexes of self-DNA with cathelicidin (LL37) or melanocytic ADAMTSL5 have been proposed more recently as actual auto-antigens in some cases of psoriasis. These findings are accompanied by various immunoregulatory mechanisms, which we increasingly understand and which connect innate and adaptive immunity. Specific adaptive autoimmune responses, together with our current view of psoriasis as a systemic inflammatory disorder, raise the question of whether psoriasis may have connections to autoimmune or autoinflammatory disorders elsewhere in the body. While such associations have been suspected for many years, compelling mechanistic evidence in support of this notion is still scant. This review sets into context the current knowledge about innate and adaptive immunological processes in psoriasis and other autoimmune or autoinflammatory diseases.
In Natural Rights and the New Republicanism, Michael Zuckert proposes a new view of the political philosophy that lay behind the founding of the United States. In a book that will interest political ...scientists, historians, and philosophers, Zuckert looks at the Whig or opposition tradition as it developed in England. He argues that there were, in fact, three opposition traditions: Protestant, Grotian, and Lockean. Before the English Civil War the opposition was inspired by the effort to find the "one true Protestant politics--an effort that was seen to be a failure by the end of the Interregnum period. The Restoration saw the emergence of the Whigs, who sought a way to ground politics free from the sectarian theological-scriptural conflicts of the previous period.
Research into the pathophysiology of psoriasis has shed light onto many fascinating immunological interactions and underlying genetic constellations. Most prominent among these is the crosstalk ...between components of the innate and the adaptive immune system and the crucial role of interleukins (IL)-23 and -17 within this network. While it is clear that IL-23 drives and maintains the differentiation of Th17 lymphocytes, many aspects of the regulation of IL-23 and IL-17 are not quite as straightforward and have been unraveled only recently. For example, we know now that Th17 cells are not the only source of IL-17 but that cells of the innate immune system also produce considerable amounts of this central effector cytokine. In addition, there is IL-23-independent production of IL-17. Besides other innate immune cells, neutrophilic granulocytes prominently contribute to IL-17-related immune regulations in psoriasis, and it appears that they employ several mechanisms including the formation of neutrophil extracellular traps. Here, we strive to put the central role of the IL-23/IL-17 axis into perspective within the crosstalk between components of the innate and the adaptive immune system. Our aim is to better understand the complex immune regulation in psoriasis, a disorder that has become a model disease for chronic inflammation.
The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from ...the organelle to the cytosol and nucleus. Superoxide (O2(*-)) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2(*-) production within the matrix of mammalian mitochondria. The flux of O2(*-) is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2(*-) production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Deltap (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Deltap and NADH/NAD+ ratio, the extent of O2(*-) production is far lower. The generation of O2(*-) within the mitochondrial matrix depends critically on Deltap, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2(*-) generation by mitochondria in vivo from O2(*-)-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2(*-) and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
As a consequence of the accumulation of insertion events over evolutionary time, mobile elements now comprise nearly half of the human genome. The Alu, L1, and SVA mobile element families are still ...duplicating, generating variation between individual genomes. Mobile element insertions (MEI) have been identified as causes for genetic diseases, including hemophilia, neurofibromatosis, and various cancers. Here we present a comprehensive map of 7,380 MEI polymorphisms from the 1000 Genomes Project whole-genome sequencing data of 185 samples in three major populations detected with two detection methods. This catalog enables us to systematically study mutation rates, population segregation, genomic distribution, and functional properties of MEI polymorphisms and to compare MEI to SNP variation from the same individuals. Population allele frequencies of MEI and SNPs are described, broadly, by the same neutral ancestral processes despite vastly different mutation mechanisms and rates, except in coding regions where MEI are virtually absent, presumably due to strong negative selection. A direct comparison of MEI and SNP diversity levels suggests a differential mobile element insertion rate among populations.
Hypophosphatasia is the inborn error of metabolism characterized by low serum alkaline phosphatase activity (hypophosphatasaemia). This biochemical hallmark reflects loss-of-function mutations within ...the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, extracellular accumulation of TNSALP natural substrates includes inorganic pyrophosphate, an inhibitor of mineralization, which explains the dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Severely affected infants sometimes also have hypercalcaemia and hyperphosphataemia due to the blocked entry of minerals into the skeleton, and pyridoxine-dependent seizures from insufficient extracellular hydrolysis of pyridoxal 5'-phosphate, the major circulating form of vitamin B6, required for neurotransmitter synthesis. Autosomal recessive or dominant inheritance from ~300 predominantly missense ALPL (also known as TNSALP) mutations largely accounts for the remarkably broad-ranging expressivity of hypophosphatasia. High serum concentrations of pyridoxal 5'-phosphate represent a sensitive and specific biochemical marker for hypophosphatasia. Also, phosphoethanolamine levels are usually elevated in serum and urine, though less reliably for diagnosis. TNSALP mutation detection is important for recurrence risk assessment and prenatal diagnosis. Diagnosing paediatric hypophosphatasia is aided by pathognomic radiographic changes when the skeletal disease is severe. Hypophosphatasia was the last type of rickets or osteomalacia to await a medical treatment. Now, significant successes for severely affected paediatric patients are recognized using asfotase alfa, a bone-targeted recombinant TNSALP.
Animal models of psoriasis—highlights and drawbacks Schön, Michael P.; Manzke, Veit; Erpenbeck, Luise
Journal of allergy and clinical immunology,
February 2021, 2021-Feb, 2021-02-00, 20210201, Letnik:
147, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Research into the pathophysiology of psoriasis remains challenging, because this disease does not occur naturally in laboratory animals. However, specific aspects of its complex immune-pathology can ...be illuminated through transgenic, knockout, xenotransplantation, immunological reconstitution, drug-induced, or spontaneous mutation models in rodents. Although some of these approaches have already been pursued for more than 5 decades and even more models have been described in recent times, they have surprisingly not yet been systematically validated. As a consequence, researchers regularly examine specific aspects that only partially reflect the complex overall picture of the human disease. Nonetheless, animal models are of great utility to investigate inflammatory mediators, the communication between cells of the innate and the adaptive immune systems, the role of resident cells as well as new therapies. Of note, various manipulations in experimental animals resulted in rather similar phenotypes. These were called “psoriasiform”, “psoriasis-like” or even “psoriasis” usually on the basis of some similarities with the human disorder. Xenotransplantation of human skin onto immunocompromised animals can overcome this limitation only in part. In this review, we elucidate approaches for the generation of animal models of psoriasis and assess their strengths and limitations with a certain focus on more recently developed models.
PDF
