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Deutsche Medizinische Wochenschrift... Jul 2024Immune thrombocytopenia (ITP) is due to autoantibodies against platelet surface antigens. ITP is considered as either primary, with no clear etiology, or as secondary... (Review)
Review
Immune thrombocytopenia (ITP) is due to autoantibodies against platelet surface antigens. ITP is considered as either primary, with no clear etiology, or as secondary ITP (drug-induced; underlying diseases). Autoantibodies lead both to loss of platelets in the spleen and/or liver but simultaneously reduce their production. Contrary to other disorders with thrombocytopenia, ITP has reduced levels of thrombopoetin. ITP remains a diagnosis of exclusion. A single defining laboratory test does not exist. Glycoprotein-specific antibodies can be detected in only about 50% of cases. Ruling out EDTA-induced pseudo thrombocytopenia is of particular relevance. Secondary causes of thrombocytopenia should be excluded through medical history (especially medication history), physical examination and possibly bone-marrow puncture.
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Autoantibodies; Diagnosis, Differential; Blood Platelets; Platelet Count
PubMed: 38950548
DOI: 10.1055/a-2317-3073 -
Clinical and Translational Science Jul 2024Physiological determinants of drug dosing (PDODD) are a promising approach for precision dosing. This study investigates the alterations of PDODD in diseases and...
Physiological determinants of drug dosing (PDODD) are a promising approach for precision dosing. This study investigates the alterations of PDODD in diseases and evaluates a variational autoencoder (VAE) artificial intelligence model for PDODD. The PDODD panel contained 20 biomarkers, and 13 renal, hepatic, diabetes, and cardiac disease status variables. Demographic characteristics, anthropometric measurements (body weight, body surface area, waist circumference), blood (plasma volume, albumin), renal (creatinine, glomerular filtration rate, urine flow, and urine albumin to creatinine ratio), and hepatic (R-value, hepatic steatosis index, drug-induced liver injury index), blood cell (systemic inflammation index, red cell, lymphocyte, neutrophils, and platelet counts) biomarkers, and medical questionnaire responses from the National Health and Nutrition Examination Survey (NHANES) were included. The tabular VAE (TVAE) generative model was implemented with the Synthetic Data Vault Python library. The joint distributions of the generated data vs. test data were compared using graphical univariate, bivariate, and multidimensional projection methods and distribution proximity measures. The PDODD biomarkers related to disease progression were altered as expected in renal, hepatic, diabetes, and cardiac diseases. The continuous PDODD panel variables generated by the TVAE satisfactorily approximated the distribution in the test data. The TVAE-generated distributions of some discrete variables deviated from the test data distribution. The age distribution of TVAE-generated continuous variables was similar to the test data. The TVAE algorithm demonstrated potential as an AI model for continuous PDODD and could be useful for generating virtual populations for clinical trial simulations.
Topics: Humans; Male; Female; Middle Aged; Heart Diseases; Kidney Diseases; Biomarkers; Adult; Liver Diseases; Aged; Metabolic Diseases; Artificial Intelligence; Nutrition Surveys; Drug Dosage Calculations; Models, Biological
PubMed: 38949489
DOI: 10.1111/cts.13872 -
Pharmacotherapy Jul 2024Platelet glycoprotein (GP) IIb/IIIa antagonists have been employed in selective patients after endovascular therapy (EVT) for acute ischemic stroke (AIS), yet... (Review)
Review
Platelet glycoprotein (GP) IIb/IIIa antagonists have been employed in selective patients after endovascular therapy (EVT) for acute ischemic stroke (AIS), yet application in patients without EVT is debated. This meta-analysis of randomized controlled studies on AIS patients without EVT assessed the effectiveness and safety of platelet GP IIb/IIIa antagonists compared with traditional antiplatelet or thrombolysis therapy. Articles were retrieved from databases, including PubMed, Web of Science, EMBASE, and Cochrane. The risk of bias and certainty level of evidence were assessed. Fifteen studies were included. GP IIb/IIIa antagonists increased the proportion of patients with modified Rankin Scale (mRS) 0-1 (odd ratio [OR] 1.37, 95% confidence interval [CI] 1.04-1.81, p = 0.03), mRS 0-2 (OR 1.27, 95% CI 1.12-1.46, p = 0.0004), and Barthel Index (BI) 95-100 (OR 1.25, p = 0.005); decreased the proportion of stroke progression within 5 days (OR 0.66, p = 0.006); and lowered the mean mRS score at 90 days (mean difference [MD] -0.43, p = 0.002) and the National Institute of Health stroke scale score at 7 days (MD -1.64, p < 0.00001) compared with conventional treatment. Proportions of stroke recurrence within 90 days (OR 1.20, p = 0.60), any intracranial hemorrhage (aICH) (OR 1.20, p = 0.12), symptomatic intracranial hemorrhage (sICH) (OR 0.91, p = 0.88), and death (OR 0.87, p = 0.25) had no statistical difference between both groups. This meta-analysis finds that compared with traditional antiplatelet or thrombolysis therapy, GP IIb/IIIa antagonists administered within 24-96 h of ischemic stroke onset significantly improve functional prognosis of patients with AIS not receiving EVT, as indicated by mRS and BI at 90 days, and do not increase the incidence of aICH, sICH, and death.
PubMed: 38949433
DOI: 10.1002/phar.2949 -
ACS Applied Materials & Interfaces Jul 2024Trauma is the leading cause of death for adults under the age of 44. Internal bleeding remains a significant challenge in medical emergencies, necessitating the...
Trauma is the leading cause of death for adults under the age of 44. Internal bleeding remains a significant challenge in medical emergencies, necessitating the development of effective hemostatic materials that could be administered by paramedics before a patient is in the hospital and treated by surgeons. In this study, we introduce a graphene oxide (GO)-based PEGylated synthetic hemostatic nanomaterial with an average size of 211 ± 83 nm designed to target internal bleeding by mimicking the role of fibrinogen. Functionalization of GO--PEG with peptides derived from the α-chain of fibrinogen, such as GRGDS, or the γ-chain of fibrinogen, such as HHLGGAKQAGDV:H12, was achieved with peptide loadings of 72 ± 6 and 68 ± 15 μM, respectively. studies with platelet-rich plasma (PRP) under confinement demonstrated aggregation enhancement of 39 and 24% for GO--PEG-GRGDS and GO--PEG-H12, respectively, compared to buffer, while adenosine diphosphate (ADP) alone induced a 5% aggregation. Compared to the same materials in the absence of ADP, GO--PEG-GRGDS achieved a 47% aggregation enhancement, while GO--PEG-H12 a 25% enhancement. This is particularly important for injectable hemostats and highlights the fact that our nanographene-based materials can only act as hemostats in the presence of agonists, reducing the possibility of unwanted clotting during circulation. Further studies on collagen-coated wells under dynamic flow revealed statistically significant augmentation of PRP fluorescence signal using GRGDS- or H12-coated GO--PEG compared to controls. Hemolysis studies showed <1% lysis of red blood cells (RBCs) at the highest PEGylated nanographene concentration. Finally, whole human blood coagulation studies reveal faster and more pronounced clotting using our nanohemostats PBS control from 3 min and below (blood is clotted with 10% CaCl within 4-5 min), with the biggest differences to be shown at 2 and 1 min. At 1 min, the clot weight was found to be ∼45% of that between 4 and 5 min, while no clot was formed in PBS-treated blood. Reduction of CaCl to 5 and 3%, or utilization of prostaglandin E1, an anticoagulant, still leads to clots but of smaller weight. The findings highlight the potential of our fibrinogen-mimic PEGylated nanographene as a promising non-hemolytic injectable scaffold for targeting internal bleeding, offering insights into its platelet aggregation capabilities under confinement and under dynamic flow as well as its pronounced coagulation abilities.
PubMed: 38949260
DOI: 10.1021/acsami.4c09828 -
EFORT Open Reviews Jul 2024The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic...
PURPOSE
The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic reviews have validated their combined efficacy. In this study, we investigated the effects of the combination of pharmacological agents and exercise on knee osteoarthritis.
METHODS
Randomized controlled trials that investigated the efficacy of pharmacological agents combined with exercise for knee osteoarthritis were searched in PubMed, Embase, and Cochrane Library up to February 2024. The network meta-analysis was performed within the frequentist framework. Standardized mean difference (SMD) with 95% CI was estimated for pain and function. Grading of recommendations, assessment, development, and evaluations were used to evaluate the certainty of evidence.
RESULTS
In total, 71 studies were included. The combination therapy outperformed pharmacological or exercise therapy alone. Among the various pharmacological agents combined with exercise, mesenchymal stem cell injection was ranked the best for short-term pain reduction (SMD: -1.53, 95% CI: -1.92 to -1.13, high certainty), followed by botulinum toxin A, dextrose, and platelet-rich plasma. For long-term pain relief, dextrose prolotherapy was the optimal (SMD: -1.76, 95% CI: -2.65 to -0.88, moderate certainty), followed by mesenchymal stem cells, platelet rich in growth factor, and platelet-rich plasma.
CONCLUSION
Exercise programs should be incorporated into clinical practice and trial design. For patients undergoing exercise therapies, mesenchymal stem cell, dextrose, platelet-rich plasma, platelet rich in growth factor, and botulinum toxin A may be the optimal agents.
PubMed: 38949167
DOI: 10.1530/EOR-23-0136 -
JPMA. the Journal of the Pakistan... Jun 2024Liquid biopsy has multiple benefits and is used extensively in other fields of oncology, but its role in neuro-oncology has been limited so far. Multiple tumour-derived... (Review)
Review
Liquid biopsy has multiple benefits and is used extensively in other fields of oncology, but its role in neuro-oncology has been limited so far. Multiple tumour-derived materials like circulating tumour cells (CTCs), tumour-educated platelets (TEPs), cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), and miRNA are studied in CSF, blood (plasma, serum) or urine. Large and complex amounts of data from liquid biopsy can be simplified by machine learning using various algorithms. By using this technique, we can diagnose brain tumours and differentiate low versus highgrade glioma and true progression from pseudo-progression. The potential of liquid biopsy in brain tumours has not been extensively studied, but it has a bright future in the coming years. Here, we present a literature review on the role of machine learning in liquid biopsy of brain tumours.
Topics: Humans; Liquid Biopsy; Machine Learning; Brain Neoplasms; Neoplastic Cells, Circulating; Circulating Tumor DNA; Glioma; Biomarkers, Tumor; MicroRNAs
PubMed: 38949002
DOI: 10.47391/JPMA.24-46 -
BioRxiv : the Preprint Server For... Jun 2024Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if...
OBJECTIVE
Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline.
METHODS
We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity.
RESULTS
Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism.
CONCLUSION
This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.
PubMed: 38948810
DOI: 10.1101/2024.06.17.599436 -
BioRxiv : the Preprint Server For... Jun 2024Oxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial...
BACKGROUND
Oxidative stress is implicated in the pathogenesis and progression of abdominal aortic aneurysm (AAA). Antioxidant delivery as a therapeutic for AAA is of substantial interest although clinical translation of antioxidant therapy has met with significant challenges due to limitations in achieving sufficient antioxidant levels at the site of AAA. We posit that nanoparticle-based approaches hold promise to overcome challenges associated with systemic administration of antioxidants.
METHODS
We employed a peptide-based nanoplatform to overexpress a key modulator of oxidative stress, superoxide dismutase 2 (SOD2). The efficacy of systemic delivery of SOD2 mRNA as a nanotherapeutic agent was studied in two different murine AAA models. Unbiased mass spectrometry-enabled proteomics and high-dimensional bioinformatics were used to examine pathways modulated by SOD2 overexpression.
RESULTS
The murine SOD2 mRNA sequence was mixed with p5RHH, an amphipathic peptide capable of delivering nucleic acids to form self-assembled nanoparticles of ∼55 nm in diameter. We further demonstrated that the nanoparticle was stable and functional up to four weeks following self-assembly when coated with hyaluronic acid. Delivery of SOD2 mRNA mitigated the expansion of small AAA and largely prevented rupture. Mitigation of AAA was accompanied by enhanced SOD2 protein expression in aortic wall tissue. Concomitant suppression of nitric oxide, inducible nitric oxide synthase expression, and cell death was observed. Proteomic profiling of AAA tissues suggests that SOD2 overexpression augments levels of microRNAs that regulate vascular inflammation and cell apoptosis, inhibits platelet activation/aggregation, and downregulates mitogen-activated protein kinase signaling. Gene set enrichment analysis shows that SOD2 mRNA delivery is associated with activation of oxidative phosphorylation, lipid metabolism, respiratory electron transportation, and tricarboxylic acid cycle pathways.
CONCLUSIONS
These results confirm that SOD2 is key modulator of oxidative stress in AAA. This nanotherapeutic mRNA delivery approach may find translational application in the medical management of small AAA and the prevention of AAA rupture.
PubMed: 38948794
DOI: 10.1101/2024.06.17.599454 -
BioRxiv : the Preprint Server For... Jun 2024Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoter to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms...
BACKGROUND
Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoter to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream-gene regulation in megakaryocytes and platelets are unknown.
OBJECTIVES
To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms.
METHODS
We performed studies on RUNX1 isoforms in megakaryocytic HEL cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD).
RESULTS
In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes ( and others) differentially in HEL cells. In platelets RUNX1B transcripts (by RNAseq) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with , and others, and negatively with . In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets and associated with acute events.
CONCLUSIONS
RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner and this associates with acute events in CVD.
SCIENTIFIC CATEGORY
Platelets.
ESSENTIALS
RUNX1 is expressed from 2 promoters (P1 and P2) to yield isoforms RUNX1C and RUNX1B.RUNX1B and RUNX1C regulate RUNX1 and target genes differentially in megakaryocytes/platelets.In platelets RUNX1B and RUNX1C expression is inversely related and ticagrelor increases RUNX1C RUNX1 target gene ( ) expression in blood is associated with death or MI in cardiac disease.
PubMed: 38948740
DOI: 10.1101/2024.06.18.599563 -
Turkish Journal of Physical Medicine... Jun 2024This study aims to compare the efficacy of intra-articular platelet-rich plasma (PRP) injections over a saline placebo in terms of reduction of pain and impact on...
OBJECTIVES
This study aims to compare the efficacy of intra-articular platelet-rich plasma (PRP) injections over a saline placebo in terms of reduction of pain and impact on quality of life among patients with hip osteoarthritis.
PATIENTS AND METHODS
A total of 60 patients (29 males, 31 females, mean age: 57.9±7.3 years; range, 47 to 69 years) with known hip osteoarthritis of Kellgren-Lawrance (KL) Grades 2/3 were randomized into placebo (n=30) and PRP groups (n=30) between June 2014 and June 2015. Both groups received intra-articular injections into the hip joint under ultrasound guidance for three consecutive weeks. The patients were followed for six months, and pain reduction was assessed using the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire, and Short Form Health Survey-36 (SF-36).
RESULTS
Intra-articular PRP treatment showed no advantage over a saline placebo in terms of VAS scores during activity. Both groups showed a significant improvement in VAS activity scores at one and six months. The placebo group showed improvements in VAS resting scores, whereas the PRP group did not. Both groups showed no improvement in WOMAC-total scores. Both groups showed no significant improvement across most SF-36 domains with the exception of improved physical role functioning at one month and general health at one and six months in the placebo group.
CONCLUSION
Intra-articular injections of PRP show no significant difference compared to a saline placebo over a period of six months on pain, function, and quality of life scores in patients with hip osteoarthritis.
PubMed: 38948640
DOI: 10.5606/tftrd.2024.13855