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JAMA Cardiology Oct 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy...
IMPORTANCE
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP.
OBJECTIVE
To derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF.
DESIGN, SETTING, AND PARTICIPANTS
Retrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation.
MAIN OUTCOMES AND MEASURES
Performance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials.
RESULTS
Participant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range -1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P < .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow χ2 = 2.8; P = .84; Hosmer-Lemeshow χ2 = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score.
CONCLUSIONS AND RELEVANCE
A simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community. Further validation in larger and more diverse populations is needed.
Topics: Amyloidosis; Cardiomyopathies; Female; Heart Failure; Humans; Male; Prealbumin; Radiopharmaceuticals; Retrospective Studies; Stroke Volume; Technetium Tc 99m Pyrophosphate
PubMed: 36069809
DOI: 10.1001/jamacardio.2022.1781 -
Dental Materials Journal Oct 2022The relative dentin abrasivity-profilometry equivalent values were compared using non-contact profilometry with three subtypes of regular toothpaste and two subtypes of...
The relative dentin abrasivity-profilometry equivalent values were compared using non-contact profilometry with three subtypes of regular toothpaste and two subtypes of whitening toothpaste containing sodium bicarbonate and 35% hydrogen peroxide. Bovine dentin specimens were assigned to six groups: regular toothpaste (R): R1 (BAMBOO SALT GUM OINTMENT); R2 (MEDIAN TARTAR ORIGINAL); R3 (PERIOE Alpha), Reference slurry: RS (calcium pyrophosphate), whitening toothpaste (W): W1 (NET. WT); W2 (Vussen 28 WHITENING). Relative dentin abrasion-profilometry equivalent (RDA-PE) was determined by brushing 10,000 times (n=8). The pH of the toothpaste was measured (n=5) and the abrasive constituents of the toothpaste was analyzed by FE-SEM and EDS. The RDA-PE values ranged from 26 to 166, and the pH level ranges were 4.928-9.153. The RDA-PE value of the whitening toothpaste containing hydrogen peroxide was not high compared with that of the regular toothpaste. The RDA-PE values of whitening toothpaste could vary depending on the mechanism and ingredients of the whitening agents.
Topics: Animals; Bleaching Agents; Calcium Pyrophosphate; Cattle; Dentin; Hydrogen; Materials Testing; Ointments; Sodium Bicarbonate; Tooth Abrasion; Toothbrushing; Toothpastes
PubMed: 35793939
DOI: 10.4012/dmj.2021-303 -
Radiologic Clinics of North America Jul 2022Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints that lead to joint destruction and soft tissue masses. Clinical... (Review)
Review
Imaging of Crystal Disorders:: Calcium Pyrophosphate Dihydrate Crystal Deposition Disease, Calcium Hydroxyapatite Crystal Deposition Disease and Gout Pathophysiology, Imaging, and Diagnosis.
Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints that lead to joint destruction and soft tissue masses. Clinical presentation is variable and diagnosis might be challenging. In this article the pathophysiology is addressed, the preferred deposition of crystal arthropathies and imaging findings. Case studies of calcium pyrophosphate dihydrate crystal deposition disease, hydroxyapatite crystal deposition disease, and gout are shown. Guidelines for the use of dual-energy computed tomography are given to enable the diagnosis and follow-up of gout.
Topics: Calcium Pyrophosphate; Chondrocalcinosis; Crystal Arthropathies; Durapatite; Gout; Humans
PubMed: 35672096
DOI: 10.1016/j.rcl.2022.03.007 -
Annals of the Rheumatic Diseases Oct 2023Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic...
OBJECTIVE
Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease.
METHODS
Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort.
RESULTS
Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers).
CONCLUSION
The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.
Topics: Humans; United States; Chondrocalcinosis; Rheumatology; Calcium Pyrophosphate; Calcinosis; Syndrome
PubMed: 37495237
DOI: 10.1136/ard-2023-224575 -
Molecules (Basel, Switzerland) Aug 2022Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents.... (Review)
Review
Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents. Additionally, they are also valuable for tumor immunotherapy. Thus, studies on the functions and biosynthetic pathways of rhamnose-containing compounds are in progress. In this paper, studies on the biosynthetic pathways of three rhamnose donors, i.e., deoxythymidinediphosphate-L-rhamnose (dTDP-Rha), uridine diphosphate-rhamnose (UDP-Rha), and guanosine diphosphate rhamnose (GDP-Rha), are firstly reviewed, together with the functions and crystal structures of those associated enzymes. Among them, dTDP-Rha is the most common rhamnose donor, and four enzymes, including glucose-1-phosphate thymidylyltransferase RmlA, dTDP-Glc-4,6-dehydratase RmlB, dTDP-4-keto-6-deoxy-Glc-3,5-epimerase RmlC, and dTDP-4-keto-Rha reductase RmlD, are involved in its biosynthesis. Secondly, several known rhamnosyltransferases from , , , , and are discussed. In these studies, however, the functions of rhamnosyltransferases were verified by employing gene knockout and radiolabeled substrates, which were almost impossible to obtain and characterize the products of enzymatic reactions. Finally, the application of rhamnose-containing compounds in disease treatments is briefly described.
Topics: Biosynthetic Pathways; Racemases and Epimerases; Rhamnose; Thymine Nucleotides; Uridine Diphosphate
PubMed: 36014553
DOI: 10.3390/molecules27165315 -
Current Opinion in Rheumatology Nov 2022The aim of this study was to provide updated information on the prevalence, pathogenesis, diagnostics and therapeutics of calcinosis cutis associated with systemic... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to provide updated information on the prevalence, pathogenesis, diagnostics and therapeutics of calcinosis cutis associated with systemic sclerosis (SSc).
RECENT FINDINGS
Observational studies show ethnic and geographical differences in the prevalence of calcinosis. In addition to clinical and serological associations, biochemical studies and in-vivo models have attempted to explain theories behind its pathogenesis, including prolonged state of inflammation, mechanical stress, hypoxia and dysregulation in bone and phosphate metabolism. Long-term use of proton pump inhibitors may increase the risk for calcinosis in SSc. Few single-centre observational studies have shown mild benefit with minocycline and topical sodium thiosulfate.
SUMMARY
Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It affects up to 40% of SSc patients and causes significant morbidity. Long disease duration, features of vascular dysfunction and osteoporosis have been associated with calcinosis. Altered levels of inorganic pyrophosphate and fibroblast growth factor-23 have been implicated in dysregulated phosphate metabolism that may lead to calcinosis in SSc. Plain radiography can help with diagnosis and quantifying the calcinosis burden. Surgical treatment remains the most effective therapy when feasible. At present, no medical therapies have proven efficacy in large randomized controlled trials.
Topics: Calcinosis; Calcium; Diphosphates; Humans; Minocycline; Proton Pump Inhibitors; Scleroderma, Systemic
PubMed: 35993867
DOI: 10.1097/BOR.0000000000000896 -
Nature Aug 2022Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance. Teixobactin represents a new class of antibiotics with a unique chemical scaffold...
Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance. Teixobactin represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.
Topics: Anti-Bacterial Agents; Bacteria; Cell Membrane; Cell Wall; Depsipeptides; Diphosphates; Drug Resistance, Bacterial; Humans; Lipids; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Atomic Force; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Protein Structure, Secondary; Pyrrolidines; Sugars
PubMed: 35922513
DOI: 10.1038/s41586-022-05019-y -
International Journal of Molecular... Aug 2020The NME (Non-metastatic) family members, also known as NDPKs (nucleoside diphosphate kinases), were originally identified and studied for their nucleoside diphosphate... (Review)
Review
The NME (Non-metastatic) family members, also known as NDPKs (nucleoside diphosphate kinases), were originally identified and studied for their nucleoside diphosphate kinase activities. This family of kinases is extremely well conserved through evolution, being found in prokaryotes and eukaryotes, but also diverges enough to create a range of complexity, with homologous members having distinct functions in cells. In addition to nucleoside diphosphate kinase activity, some family members are reported to possess protein-histidine kinase activity, which, because of the lability of phosphohistidine, has been difficult to study due to the experimental challenges and lack of molecular tools. However, over the past few years, new methods to investigate this unstable modification and histidine kinase activity have been reported and scientific interest in this area is growing rapidly. This review presents a global overview of our current knowledge of the NME family and histidine phosphorylation, highlighting the underappreciated protein-histidine kinase activity of NME family members, specifically in human cells. In parallel, information about the structural and functional aspects of the NME family, and the knowns and unknowns of histidine kinase involvement in cell signaling are summarized.
Topics: Amino Acid Sequence; Animals; Biocatalysis; Histidine; Humans; NM23 Nucleoside Diphosphate Kinases; Phosphorylation; Structure-Activity Relationship
PubMed: 32823988
DOI: 10.3390/ijms21165848 -
Current Opinion in Chemical Biology Oct 2022Inositol pyrophosphates (PP-InsPs) constitute a group of highly charged messengers, which regulate central biological processes in health and disease, such as cellular... (Review)
Review
Inositol pyrophosphates (PP-InsPs) constitute a group of highly charged messengers, which regulate central biological processes in health and disease, such as cellular phosphate and general energy homeostasis. Deciphering the molecular mechanisms underlying PP-InsP-mediated signaling remains a challenge due to the unique properties of these molecules, the different modes of action they can access, and a somewhat limited chemical and analytical toolset. Herein, we summarize the most recent mechanistic insights into PP-InsP signaling, which illustrate our progress in connecting mechanism and function of PP-InsPs.
Topics: Biological Phenomena; Diphosphates; Inositol Phosphates; Phosphates; Signal Transduction
PubMed: 35780751
DOI: 10.1016/j.cbpa.2022.102177 -
The Journal of Histochemistry and... Jan 2021Hyaluronan (HA) is a linear glycosaminoglycan (GAG) of extracellular matrix (ECM) synthesized by three hyaluronan synthases (HASes) at the plasma membrane using uridine... (Review)
Review
Hyaluronan (HA) is a linear glycosaminoglycan (GAG) of extracellular matrix (ECM) synthesized by three hyaluronan synthases (HASes) at the plasma membrane using uridine diphosphate (UDP)-glucuronic acid (UDP-GlcUA) and UDP-acetylglucosamine (UDP-GlcNAc) as substrates. The production of HA is mainly regulated by hyaluronan synthase 2 (HAS2), that can be controlled at different levels, from epigenetics to transcriptional and post-translational modifications. HA biosynthesis is an energy-consuming process and, along with HA catabolism, is strongly connected to the maintenance of metabolic homeostasis. The cytoplasmic pool of UDP-sugars is critical for HA synthesis. UDP-GlcNAc is an important nutrient sensor and serves as donor substrate for the -GlcNAcylation of many cytosolic proteins, including HAS2. This post-translational modification stabilizes HAS2 in the membrane and increases HA production. Conversely, HAS2 can be phosphorylated by AMP activated protein kinase (AMPK), a master metabolic regulator activated by low ATP/AMP ratios, which inhibits HA secretion. Similarly, HAS2 expression and the deposition of HA within the pericellular coat are inhibited by sirtuin 1 (SIRT1), another important energetic sensor, confirming the tight connection between nutrients availability and HA metabolism.
Topics: Animals; Biosynthetic Pathways; Energy Metabolism; Humans; Hyaluronan Synthases; Hyaluronic Acid; Uridine Diphosphate Glucuronic Acid; Uridine Diphosphate N-Acetylglucosamine
PubMed: 32623953
DOI: 10.1369/0022155420929772