ABSTRACT
CONTEXT.: Fondaparinux monitoring is not required among noncritically ill patients due to a predictable dose-response effect. However, this is debatable among critically ill patients, because fondaparinux bioavailability can be influenced by complicated medical conditions. OBJECTIVE.: To investigate fondaparinux monitoring among the critically ill. DESIGN.: Retrospective analysis of patients admitted in intensive care unit from February 2021 to December 2021, who received prophylactic fondaparinux and had anti-Xa activity tests. RESULTS.: Of 156 anti-Xa values, 86 (55.1%) were within 0.10-0.50 µg/mL (the recommended prophylactic range), 38 (24.4%) were less than 0.10 µg/mL, 32 (20.5%) were greater than 0.50 µg/mL, demonstrating an unpredictable dose-response effect. Among 70 patients, thrombotic tendency was controlled in 32 (45.7%), thrombosis progressed in 22 (31.4%), bleeding events occurred in 16 (22.9%). Patients with progressed thrombosis had 17 of 54 (31.5%) anti-Xa less than 0.10 µg/mL, even though this proportion was greater than that of patients with controlled thrombotic tendency (11 of 72, 15.3%), it was similar to that of patients with bleeding (10 of 30, 33.3%), indicating a weak practicability of anti-Xa for monitoring fondaparinux efficacy. Thrombin-antithrombin complex showed a gradual decline among patients with controlled thrombotic tendency, but a bounce-back effect among patients with progressed thrombosis. Thrombelastography R value above the upper reference value occurred more frequently among patients with bleeding (4 of 6, 66.7%) compared to patients without bleeding (4 of 22, 18.2%) (P = .01). CONCLUSIONS.: The fondaparinux dose-response effect was unpredictable among the critically ill; anti-Xa activity combined with thrombin-antithrombin complex and thrombelastography can be helpful to guide a precise fondaparinux therapy in this population.
ABSTRACT
BACKGROUND: Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood. METHODS: A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice. RESULTS: Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression. CONCLUSIONS: Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.
Subject(s)
Ferroptosis , Hematopoietic Stem Cells , Insulin-Like Growth Factor I , Megakaryocytes , Regeneration , Animals , Hematopoietic Stem Cells/metabolism , Megakaryocytes/metabolism , Megakaryocytes/radiation effects , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/genetics , Ferroptosis/genetics , Mice , Mice, Inbred C57BL , Radiation Injuries/metabolism , Radiation Injuries/pathology , Radiation Injuries/genetics , Signal Transduction/radiation effectsABSTRACT
Despite breakthroughs in modern medical care, the incidence of cardiovascular disease (CVD) is even more prevalent globally. Increasing epidemiologic evidence indicates that emerging cardiovascular risk factors arising from the modern lifestyle, including psychosocial stress, sleep problems, unhealthy diet patterns, physical inactivity/sedentary behavior, alcohol consumption, and tobacco smoking, contribute significantly to this worldwide epidemic, while its underpinning mechanisms are enigmatic. Hematological and immune systems were recently demonstrated to play integrative roles in linking lifestyle to cardiovascular health. In particular, alterations in hematopoietic stem cell (HSC) homeostasis, which is usually characterized by proliferation, expansion, mobilization, megakaryocyte/myeloid-biased differentiation, and/or the pro-inflammatory priming of HSCs, have been shown to be involved in the persistent overproduction of pro-inflammatory myeloid leukocytes and platelets, the cellular protagonists of cardiovascular inflammation and thrombosis, respectively. Furthermore, certain lifestyle factors, such as a healthy diet pattern and physical exercise, have been documented to exert cardiovascular protective effects through promoting quiescence, bone marrow retention, balanced differentiation, and/or the anti-inflammatory priming of HSCs. Here, we review the current understanding of and progression in research on the mechanistic interrelationships among lifestyle, HSC homeostasis, and cardiovascular health. Given that adhering to a healthy lifestyle has become a mainstream primary preventative approach to lowering the cardiovascular burden, unmasking the causal links between lifestyle and cardiovascular health from the perspective of hematopoiesis would open new opportunities to prevent and treat CVD in the present age.
Subject(s)
Cardiovascular Diseases , Hematopoietic Stem Cells , Life Style , Humans , Hematopoietic Stem Cells/metabolismABSTRACT
Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8â118.2) and 88.4 (77.7â102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status.
Subject(s)
Dipterocarpaceae , Genomics , Rainforest , Genome , PhylogenyABSTRACT
A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease (NAFLD), coupled with hepatitis and insulin resistance. Yet the details of the underlying mechanisms are not fully understood. Here, we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD. Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation (FAO), and induced insulin resistance. Conversely, hepatic Zbtb18 overexpression alleviated hepato-steatosis, insulin resistance, and hyperglycemia in mice fed on a high-fat diet (HFD) or in diabetic mice. Notably, in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor (FXR) mediated FAO and Clathrin Heavy Chain (CLTC) protein hinders NLRP3 inflammasome activity. This key mechanism by which hepatocyte's Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR's deletion and forced expression in mice and cultured mouse primary hepatocytes (MPHs). Moreover, CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages. Altogether, Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression, which inhibits NLRP3 inflammasome's activity alleviating inflammatory stress and insulin resistance, representing an attractive remedy for hepatic steatosis and fibrosis.
Subject(s)
BTB-POZ Domain , Diabetes Mellitus, Experimental , Insulin Resistance , Non-alcoholic Fatty Liver Disease , Animals , Humans , Mice , Fatty Acids , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Zinc FingersABSTRACT
AIM: To assess temporal trends of chronic kidney disease (CKD) attributable to type 2 diabetes (T2D) globally and in five sociodemographic index (SDI) regions. MATERIALS AND METHODS: We extracted the population data and CKD burden attributable to T2D from the Global Burden of Disease Study 2019. We evaluated the trends of disability-adjusted life years (DALYs), mortality, prevalence and incidence through age-period-cohort modelling, and calculated net drifts (overall annual percentage changes), local drifts (annual percentage changes in each age group), longitudinal age curves (fitted longitudinal age-specific rates), period relative risks (RRs) and cohort RRs. RESULTS: From 1990 to 2019, the global burden of CKD attributable to T2D showed increasing trends in general. The burden of CKD attributable to T2D was highest in the middle SDI region and lowest in the low SDI region. Age effects increased with age, and peaked at the ages of 75-79 and 80-84 years for incidence and prevalence, respectively. Period RRs in the burden of CKD attributable to T2D increased, with the high SDI being the most remarkable in DALYs and mortality, and the middle SDI being the most notable in incidence. Cohort RRs showed unfavourable trends in incidence and prevalence among recent cohorts. CONCLUSIONS: After a lengthy period of multi-initiative diabetes management, the high-middle SDI region exhibited improvement. However, unresolved issues and improvement gaps were still remarkable. Future efforts to reduce the burden of CKD attributable to T2D in the population should prioritize addressing the unfavourable patterns identified.
Subject(s)
Diabetes Mellitus, Type 2 , Renal Insufficiency, Chronic , Humans , Quality-Adjusted Life Years , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Global Burden of Disease , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/etiology , Cohort StudiesABSTRACT
BACKGROUND: The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. METHODS: A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. RESULTS: In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-ß (IFN-ß) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. CONCLUSIONS: Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-ß-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.
Subject(s)
Radiation Injuries , Thrombocytopenia , Thrombosis , Humans , Animals , Mice , Megakaryocytes/metabolism , Megakaryocytes/pathology , Thrombocytopenia/etiology , Apoptosis , Nucleotidyltransferases/metabolism , Thrombosis/metabolismABSTRACT
Although DNA mutation drives stem cell aging, how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood. Here, using a mouse model of irradiation-induced premature aging and middle-aged mice, we show that DNA mutation accumulation in hematopoietic stem cells (HSCs) during aging upregulates their surface expression of major histocompatibility complex class II (MHCII). MHCII upregulation increases the chance for recognition by bone marrow (BM)-resident regulatory T cells (Tregs), resulting in their clonal expansion and accumulation in the HSC niche. On the basis of the establishment of connexin 43 (Cx43)-mediated gap junctions, BM Tregs transfer cyclic adenosine monophosphate (cAMP) to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A (PKA) signaling. Importantly, targeting the HSC-Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs. These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.
Subject(s)
Hematopoietic Stem Cells , T-Lymphocytes, Regulatory , Bone Marrow , Cellular Senescence , DNA/metabolismABSTRACT
Science educators report that students struggle with understanding, using, and evaluating the evidence underpinning scientific knowledge. However, there are not many studies focused on helping instructors address those difficulties. Here, we report on a laboratory instructor's scaffolding of students' evidentiary reasoning with and about evidence for evolutionary trees with guidance from the Conceptual Analysis of Disciplinary Evidence (CADE) framework, which links biological knowledge with epistemic considerations. To consider both domain-general and discipline-specific aspects of evidence, CADE was implemented to inform scaffolds in two ways: (1) generic evidence scaffolds (GES) reminded students of general epistemic considerations; (2) disciplinary evidence scaffolds (DES) explicitly reminded students of the disciplinary knowledge of relevance for considering biological evidence. An instructor's lab discussions were compared before and after they had a workshop with CADE. CADE helped the lab instructor facilitate students' evidentiary reasoning about evolutionary trees. In comparison to baseline, both GES and DES discussions covered more aspects and relationships among types of evidence for evolutionary tree-thinking and the instructor prompted more kinds of general epistemic considerations and biological knowledge. DES discussions emphasized the importance of disciplinary knowledge for research design. The CADE framework guided planning and implementation of intentional scaffolding aimed at guiding evidentiary reasoning. Supplementary Information: The online version contains supplementary material available at 10.1007/s11191-023-00435-6.
ABSTRACT
There is growing appreciation that hematopoietic alterations underpin the ubiquitous detrimental effects of metabolic disorders. The susceptibility of bone marrow (BM) hematopoiesis to perturbations of cholesterol metabolism is well documented, while the underlying cellular and molecular mechanisms remain poorly understood. Here we reveal a distinct and heterogeneous cholesterol metabolic signature within BM hematopoietic stem cells (HSCs). We further show that cholesterol directly regulates maintenance and lineage differentiation of long-term HSCs (LT-HSCs), with high levels of intracellular cholesterol favoring maintenance and myeloid bias of LT-HSCs. During irradiation-induced myelosuppression, cholesterol also safeguards LT-HSC maintenance and myeloid regeneration. Mechanistically, we unravel that cholesterol directly and distinctively enhances ferroptosis resistance and boosts myeloid but dampens lymphoid lineage differentiation of LT-HSCs. Molecularly, we identify that SLC38A9-mTOR axis mediates cholesterol sensing and signal transduction to instruct lineage differentiation of LT-HSCs as well as to dictate ferroptosis sensitivity of LT-HSCs through orchestrating SLC7A11/GPX4 expression and ferritinophagy. Consequently, myeloid-biased HSCs are endowed with a survival advantage under both hypercholesterolemia and irradiation conditions. Importantly, a mTOR inhibitor rapamycin and a ferroptosis inducer imidazole ketone erastin prevent excess cholesterol-induced HSC expansion and myeloid bias. These findings unveil an unrecognized fundamental role of cholesterol metabolism in HSC survival and fate decisions with valuable clinical implications.
Subject(s)
Ferroptosis , Hematopoietic Stem Cells/metabolism , Bone Marrow , Cell Differentiation/physiology , TOR Serine-Threonine Kinases/metabolism , Cholesterol/metabolismABSTRACT
Birds infected by Reticuloendotheliosis virus (REV) are vulnerable to other microorganisms. This immunosuppression is related to the immune organs (thymus, bursa of Fabricius, and spleen) damaged by REV. The regulation of IFN-ß greatly depends on pattern recognition receptor TLR-3 and nuclear factors IRF-7, NF-κB. To address if and how the TLR-3/IFN-ß pathway is disturbed by REV, 60 one-day-old specific-pathogen-free chickens were intraperitoneally injected with RE virus dilution (n = 30) or stroke-physiological saline solution (n = 30). At 1, 3, 7, 21, and 28 days post-infection, after collecting thymuses, bursas, and spleens, we monitor the kinetics of TLR-3, IFN-ß, NF-κB p65, and IRF-7 at transcriptional and translational levels using qPCR, Western blotting, and ELISA separately. As a result, compared with control chickens, the mRNA levels of TLR-3, IRF-7, and NF-κB p65 showed increasingly differences in the early period of REV infection. Synchronal changes occurred at translation levels. In the latter infection period, a decrease of NF-κB p65 was contemporaneous with a fall in IFN-ß at both transcriptional and translational levels in the thymuses and bursas. These data suggest that the changes of IFN-ß content are closely related to NF-κB p65 when REV invades chicken central immune organs. That reveals new insights into the immunosuppression mechanism of REV in avian.
Subject(s)
Poultry Diseases , Reticuloendotheliosis virus , Animals , Chickens/metabolism , NF-kappa B/metabolism , Reticuloendotheliosis virus/metabolism , Thymus Gland/metabolism , Toll-Like Receptor 3 , Interferon-beta/metabolismABSTRACT
Platelets are increasingly recognized as key regulators of inflammatory and immune responses, through their interaction with endothelium and immune cells. Therefore they might have a role in transfusion-related acute lung injury (TRALI), in which endothelial cells and neutrophils are the key players. In this study, by a classic TRALI animal model, combining a custom-designed system for intravital confocal microscopy of pulmonary microvasculature and a platelet tracking technique, we found that thrombin-activated platelets transfusion aggravated TRALI while resting platelets transfusion alleviated TRALI. Promoting endogenous platelets activation also aggravated TRALI while inhibiting endogenous platelets activation alleviated TRALI. Activated platelets interfered with the stability of endothelial barrier function while resting platelets modulated the activation of neutrophils. Anti-thrombin could alleviate TRALI, which was not reproduced upon anti-GPIIbIIIa or anti-P-selectin In conclusion, platelets might play a dual role (protective and pathogenic) in TRALI, the balance between the two roles is highly dependent on whether platelets are activated by thrombin or not. This might explain the conflicting results of previous researches studying the contribution of platelets in TRALI by platelet depletion technology, in which the induction of TRALI and the condition of animals were different, hence the state of platelets during TRALI was different. Moreover, anti-platelet-activation (such as anti-thrombin) might be a better approach than anti-activated-platelets (such as anti-P-selectin) to search for potential therapies in TRALI. Considering the involvement of thrombin-activated platelets in TRALI, anti-thrombin might be needed when blood component transfusion is performed.
Subject(s)
Transfusion-Related Acute Lung Injury , Animals , Transfusion-Related Acute Lung Injury/pathology , Endothelial Cells , Blood Platelets , Lung/pathology , SelectinsABSTRACT
BACKGROUND: Thrombosis and hemorrhage as two opposite pathologies are prevalent within the chronic kidney disease (CKD) population. Platelet homeostasis, which positions centrally in their pathogenesis, varies among the CKD population, while the underlying mechanism is poorly understood. OBJECTIVE: To investigate the change character and mechanism of platelet homeostasis in CKD and its association with renal Klotho deficiency. METHODS: The change character of platelet homeostasis and its association with renal Klotho deficiency were determined based on a cohort study as well as CKD mice and Klotho-deficient mice with CKD. The effects on thrombopoiesis and platelet lifespan were examined by flow cytometry and platelet transfer. The underlying mechanism was explored by proteomics, flow cytometry, western blot, and immunoprecipitation. RESULTS: We show that platelet count declines both in patient and mouse models with advanced CKD (Adv-CKD) and is positively associated with circulating Klotho levels. Mechanistically, we identify that ubiquitin ligase UBE2O governs Bcl-xL ubiquitination and degradation in platelets, whereas Adv-CKD-induced oxidative stress in platelets stimulates p38MAPK to promote Bcl-xL phosphorylation, which facilitates UBE2O binding to Bcl-xL and subsequent Bcl-xL degradation. Consequently, platelet lifespan is shortened in Adv-CKD, culminating in platelet count decline. However, kidney-secreted soluble Klotho protein restricts oxidative stress in platelets, thereby preserving Bcl-xL expression and platelet lifespan. CONCLUSIONS: Our findings uncover the mechanism of platelet count decline in Adv-CKD and identify renal Klotho as a long-range regulator of platelet lifespan, which not only provide a molecular mechanism underlying CKD-associated thrombocytopenia and hemorrhage but also offer a promising therapy choice.
Subject(s)
Longevity , Renal Insufficiency, Chronic , Mice , Animals , Cohort Studies , Kidney , UbiquitinationABSTRACT
Myelosuppression is a common and intractable side effect of cancer therapies including radiotherapy and chemotherapy, while the underlying mechanism remains incompletely understood. Here, using a mouse model of radiotherapy-induced myelosuppression, we show that inorganic phosphate (Pi) metabolism is acutely inhibited in hematopoietic stem cells (HSCs) during irradiation-induced myelosuppression, and closely correlated with the severity and prognosis of myelosuppression. Mechanistically, the acute Pi metabolic inhibition in HSCs results from extrinsic Pi loss in the bone marrow niche and the intrinsic transcriptional suppression of soluble carrier family 20 member 1 (SLC20A1)-mediated Pi uptake by p53. Meanwhile, Pi metabolic inhibition blunts irradiation-induced Akt hyperactivation in HSCs, thereby weakening its ability to counteract p53-mediated Pi metabolic inhibition and the apoptosis of HSCs and consequently contributing to myelosuppression progression. Conversely, the modulation of the Pi metabolism in HSCs via a high Pi diet or renal Klotho deficiency protects against irradiation-induced myelosuppression. These findings reveal that Pi metabolism and HSC survival are causally linked by the Akt/p53-SLC20A1 axis during myelosuppression and provide valuable insights into the pathogenesis and management of myelosuppression.
Subject(s)
Phosphates , Tumor Suppressor Protein p53 , Bone Marrow/metabolism , Hematopoietic Stem Cells/metabolism , Phosphates/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
ß-Thalassemia (ß-thal) is caused by mutations on the ß-globin genes, causing reduced (ß+) or absent (ß0) synthesis of the ß chains of hemoglobin (Hb). In this report, a 28-year-old male patient with anemia and jaundice, was diagnosed with triple-heterozygous ß-thal [an IVS-II-654 (C>T) mutation, a Hb Zürich-Langstrasse (HBB: c.151A>T) mutation and a Hb G-Siriraj (HBB: c.22G>A) mutation] by gene sequencing. However, his electrophoresis pattern was unusual: 90.8% Hb G-Siriraj, 5.9% Hb A2, 3.3% Hb F, no Hb A, no Hb Zürich-Langstrasse. His mother carried a ß-thal trait (ßA/ßIVS-II-654) having mild anemia, with a classical electrophoresis pattern (95.1% Hb A, 4.4% Hb A2, 0.5% Hb F). His father was heterozygous for Hb G-Siriraj (ßA/ßG-Siriraj) but asymptomatic, with a corresponding electrophoresis pattern (63.9% Hb A, 3.5% Hb A2, 32.6% Hb G-Siriraj). In view of the family study results, the Hb Zürich-Langstrasse mutation in the proband was considered a de novo mutation occurring on the ßIVS-II-654 allele that he inherited from his mother, resulting in a ßIVS-II-654/Hb Zürich-Langstrasse genotype, which should be interpreted as a novel ß0 mutation. This report illustrates that mutations in cis can confound genotype-phenotype correlations, therefore, just as DNA testing and Hb analysis, family study is also indispensable to the accurate identification of ß-thal mutations.
Subject(s)
beta-Thalassemia , Male , Humans , beta-Thalassemia/diagnosis , beta-Thalassemia/genetics , beta-Globins/genetics , Hemoglobin A2/genetics , Mutation , Genotype , ElectrophoresisABSTRACT
AIMS/INTRODUCTION: The optimal therapy for latent autoimmune diabetes in adults (LADA) remains undefined. Increasing evidence has shown that sitagliptin and insulin treatment can benefit patients with LADA, but the efficacy still lacks systematic evaluation. We carried out this systematic review and meta-analysis to summarize the current data on the efficacy and safety of sitagliptin combined with insulin on LADA, providing a reliable reference for the effective therapeutic treatment of LADA patients. MATERIALS AND METHODS: We retrieved the literature in PubMed, Cochrane Library, Embase, Web of Science and CNKI from inception to August 2021. Randomized controlled trials comparing the effects of sitagliptin plus insulin with insulin alone in LADA patients were identified. The outcome measures included parameters of glycemic control, ß-cell function, body mass index and adverse events. The Review Manager 5.2 and Stata 14.0 were utilized for data analysis. RESULTS: Eight randomized controlled trials involving 295 participants were identified. Sitagliptin and insulin treatment lowered hemoglobin A1c (weighted mean difference -0.36, 95% confidence interval -0.61 to -0.10, I2 = 91.6%), increased fasting C-peptide (weighted mean difference 0.08, 95% confidence interval -0.02 to 0.17, I2 = 88.8%) and had fewer adverse events compared with insulin alone. The inter-study heterogeneity, potential publication bias and other factors might interpret asymmetrical presentation of funnel plots. There was no significant association between sitagliptin plus insulin treatment and levels of hemoglobin A1c or fasting C-peptide, regardless of the duration of intervention and sample size. CONCLUSIONS: Sitagliptin combined with insulin can achieve better glycemic control and improve islet ß-cell function with lower incidence of hypoglycemia compared with insulin alone, which provides an effective and tolerated therapeutic regimen for LADA patients. However, further well-designed and rigorous randomized controlled trials are required to validate this benefit due to the limited methodology quality of included trials.
Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Latent Autoimmune Diabetes in Adults , Adult , C-Peptide , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glycated Hemoglobin , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Latent Autoimmune Diabetes in Adults/drug therapy , Randomized Controlled Trials as Topic , Sitagliptin Phosphate/therapeutic useABSTRACT
CONTEXT.: A prolonged activated partial thromboplastin time (APTT), a vital screening test for coagulation, can be due to deficiencies in coagulation factors and the existence of factor inhibitors or antiphospholipid antibodies. APTT mixing studies are being optimized to help find the cause. OBJECTIVE.: To optimize APTT mixing studies, we evaluated existing standards and explored when and how to combine 1:1 and 4:1 mixing. DESIGN.: Patients with a prolonged APTT but otherwise normal prothrombin time and thrombin time were enrolled in our hospital from January 1, 2018, to December 31, 2019. All samples were subjected to 1:1 mixing studies, while 134 were subjected to 4:1. RESULTS.: A total of 251 samples were involved, including 116 with factor deficiencies, 75 with FVIII inhibitors, and 60 with antiphospholipid antibodies. A Rosner index less than 11% or an extended incubation time of more than 3 seconds was better than other existing standards in differentiating factor deficiencies from inhibitors and in differentiating time-dependent inhibitors from time-independent inhibitors, but the approach presented here improves upon those. For the best diagnostic accuracy, samples with a Rosner index between 5.0% and 9.1% need a 4:1 mixing study, while others need 1:1. A combination of Rosner index and percent-extended incubation time-P seemed to offer objective and effective criteria for interpreting the results. CONCLUSIONS.: APTT mixing studies had overall good sensitivity and specificity in differentiating factor deficiencies from inhibitors, or time-dependent from time-independent inhibitors. The combination of 1:1 and 4:1 mixing studies can improve the diagnostic ability compared with 1:1 alone.
Subject(s)
Blood Coagulation Disorders , Thrombosis , Humans , Partial Thromboplastin Time , Blood Coagulation Tests/methods , Prothrombin Time , Blood Coagulation Factors , Antibodies, AntiphospholipidABSTRACT
OBJECTIVES: The endpoint for all lupus anticoagulant (LA) assays is a clotting time in seconds. This study aimed to clarify the use of normalizing clotting time to ratio and how the use of different denominators is relevant. METHODS: Whether normalization could reduce reagent variability and possess better diagnostic performances was assessed; denominators included reference interval (RI) mean, local-obtained pooled plasma clotting time, standard plasma clotting time, and control plasma clotting time (CNPPct). Moreover, whether day-to-day variation in CNPPct would impact its application was studied. RESULTS: If not normalized, significant difference existed among different reagent batches; if normalized (against any denominators), no statistically significant difference existed anymore. The validation of in-house RIs achieved a 100% success rate. Normalization against different denominators had different RIs, but the same diagnostic efficacies (when a prolonged LA1 is used to suggest further LA-related testings, normalized LA1 demonstrated a better sensitivity: 1.0 vs. 0.95). Normalization against a "daily" CNPPct (obtained alongside test plasmas day to day) demonstrated low inter-day variations (LA1: ~1%, LA2: ~1%), and it could employ the RI for normalization against a "fixed" CNPPct (obtained alongside normal plasmas when the RI was established). CONCLUSIONS: Normalizing clotting time reduces reagent-batch variability and promotes the adoption of common RIs, and therefore reduces the necessity of establishing RI for new reagent batches. Normalized LA1 is more sensitive when used to suggest further LA-related testings, and therefore reduces the rate of missed LA diagnosis. All denominators are of the same application value. Day-to-day variation in CNPPct did not impact its application as a reliable denominator.
Subject(s)
Blood Coagulation , Lupus Coagulation Inhibitor , Blood Coagulation Tests , Humans , Partial Thromboplastin Time , Plasma , Reference ValuesABSTRACT
The composition and origin of extrinsic cues required for hematopoietic stem cell (HSC) maintenance are incompletely understood. Here we identify renal Klotho and inorganic phosphate (Pi) as extrinsic factors that antagonistically regulate HSC maintenance in the bone marrow (BM). Disruption of the Klotho-Pi axis by renal Klotho deficiency or Pi excess causes Pi overload in the BM niche and Pi retention in HSCs, leading to alteration of HSC maintenance. Mechanistically, Pi retention is mediated by soluble carrier family 20 member 1 (SLC20A1) and sensed by diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) to enhance Akt activation, which then upregulates SLC20A1 to aggravate Pi retention and augments GATA2 activity to drive the expansion and megakaryocyte/myeloid-biased differentiation of HSCs. However, kidney-secreted soluble Klotho directly maintains HSC pool size and differentiation by restraining SLC20A1-mediated Pi absorption of HSCs. These findings uncover a regulatory role of the Klotho-Pi axis orchestrated by the kidneys in BM HSC maintenance.