pyrophosphate and Inflammation

Alkaline phosphatases (APs) remove the phosphate (dephosphorylation) needed in multiple metabolic processes (from many molecules such as proteins, nucleotides, or pyrophosphate). Therefore, APs are important for bone mineralization but paradoxically they can also be deleterious for other processes, such as vascular calcification and the increasingly known cross-talk between bone and vessels. A proper balance between beneficial and harmful activities is further complicated in the context of chronic kidney disease (CKD). In this narrative review, we will briefly update the complexity of the enzyme, including its different isoforms such as the bone-specific alkaline phosphatase or the most recently discovered B1x. We will also analyze the correlations and potential discrepancies with parathyroid hormone and bone turnover and, most importantly, the valuable recent associations of AP's with cardiovascular disease and/or vascular calcification, and survival. Finally, a basic knowledge of the synthetic and degradation pathways of APs promises to open new therapeutic strategies for the treatment of the CKD-Mineral and Bone Disorder (CKD-MBD) in the near future, as well as for other processes such as sepsis, acute kidney injury, inflammation, endothelial dysfunction, metabolic syndrome or, in diabetes, cardiovascular complications. However, no studies have been done using APs as a primary therapeutic target for clinical outcomes, and therefore, AP's levels cannot yet be used alone as an isolated primary target in the treatment of CKD-MBD. Nonetheless, its diagnostic and prognostic potential should be underlined.

Topics: Alkaline Phosphatase; Animals; Bone Remodeling; Chronic Kidney Disease-Mineral and Bone Disorder; Diphosphates; Humans; Inflammation; Isoenzymes; Parathyroid Glands; Parathyroid Hormone; Phosphates; Phosphorus; Proportional Hazards Models; Treatment Outcome; Vascular Calcification

Patients with chronic kidney disease have increased cardiovascular mortality from a combination of increased atherosclerotic disease, left ventricular hypertrophy and increased prevalence of vascular calcification (VC). Previously VC was thought to be a passive process which involved the deposition of calcium and phosphate into the vessel wall. However, recent studies have shown that VC is a highly regulated, cell-mediated process similar to bone formation, in that it is associated with expression of bone-related proteins, such as type I collagen and alkaline phosphatase. Animal and in vitro models of VC have shown that a multitude of factors including phosphate, matrix gla protein (MGP) and fetuin are involved in regulating VC. Certain factors induce calcification whereas others inhibit the process. Despite these insights, it is still not fully known how VC is regulated and a treatment for VC remains elusive. Ongoing research will hopefully elucidate these mechanisms and thereby produce targets for future therapeutic intervention. This review will highlight some of the scientific models of VC and how they have increased the understanding of this complex process.

Topics: Alkaline Phosphatase; alpha-Fetoproteins; Animals; Apoptosis; Atherosclerosis; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Collagen Type I; Diphosphates; Disease Models, Animal; Extracellular Matrix Proteins; Humans; Hypertrophy, Left Ventricular; Inflammation; Kidney Failure, Chronic; Matrix Gla Protein; Mice; Osteopontin; Phosphorus; Prevalence; Risk Factors; Vascular Diseases; Vitamin D; Vitamins

Calcium pyrophosphate and apatite crystals are common in osteoarthritic knee effusions. One or the other crystal was found in 60 percent or more of cases. These crystals offer the potential for mechanical effects in cartilage but are also often phagocytized by synovial cells. A low-grade inflammation with release of proteases and other mediators of inflammation may be an important factor in the pain and joint damage of osteoarthritis. Crystal-associated changes may merit specific attention in any future approach to therapy.

Topics: Apatites; Calcium Pyrophosphate; Crystallization; Diphosphates; Humans; Inflammation; Knee Joint; Microscopy, Electron; Osteoarthritis; Phagocytosis; Synovial Fluid; Synovial Membrane

Varying combinations of acute inflammatory and/or chronic degenerative arthritis have been found to be associated with crystals of calcium pyrophosphate dihydrate (CPPD) and/or basic calcium phosphates (BCPs). Since the arthropathies associated with CPPDs and/or BCPs occur in older individuals, while diagnosis and treatment for monosodium urate monohydrate crystal deposition disease (gout) have become extremely precise and effective, joint problems associated with calcium crystals have become more common than those associated with monosodium urate monohydrate crystals. The classification, pathogenesis, clinical manifestations, and treatment of CPPD and BCP crystal deposition are discussed.

Topics: Aged; Anti-Inflammatory Agents; Arthritis; Calcium Phosphates; Calcium Pyrophosphate; Colchicine; Crystallization; Diphosphates; Female; Humans; Hyperplasia; Inflammation; Joint Diseases; Methods; Peptide Hydrolases; Radiography; Shoulder Joint; Syndrome; Synovial Membrane

Iron deficiency (ID) and malaria co-exist in tropical regions and both contribute to high rates of anaemia in young children. It is unclear whether iron fortification combined with intermittent preventive treatment (IPT) of malaria would be an efficacious strategy for reducing anaemia in young children.. A 9-month cluster-randomised, single-blinded, placebo-controlled intervention trial was carried out in children aged 12-36 months in south-central Côte d'Ivoire, an area of intense and perennial malaria transmission. The study groups were: group 1: normal diet and IPT-placebo (n = 125); group 2: consumption of porridge, an iron-fortified complementary food (CF) with optimised composition providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferrous fumarate 6 days per week (CF-FeFum) and IPT-placebo (n = 126); group 3: IPT of malaria at 3-month intervals, using sulfadoxine-pyrimethamine and amodiaquine and no dietary intervention (n = 127); group 4: both CF-FeFum and IPT (n = 124); and group 5: consumption of porridge, an iron-fortified CF with the composition currently on the Ivorian market providing 2 mg iron as NaFeEDTA and 3.8 mg iron as ferric pyrophosphate 6 days per week (CF-FePP) and IPT-placebo (n = 127). The primary outcome was haemoglobin (Hb) concentration. Linear and logistic regression mixed-effect models were used for the comparison of the five study groups, and a 2 × 2 factorial analysis was used to assess treatment interactions of CF-FeFum and IPT (study groups 1-4).. After 9 months, the Hb concentration increased in all groups to a similar extent with no statistically significant difference between groups. In the 2 × 2 factorial analysis after 9 months, no treatment interaction was found on Hb (P = 0.89). The adjusted differences in Hb were 0.24 g/dl (95 % CI -0.10 to 0.59; P = 0.16) in children receiving IPT and -0.08 g/dl (95 % CI -0.42 to 0.26; P = 0.65) in children receiving CF-FeFum. At baseline, anaemia (Hb <11.0 g/dl) was 82.1 %. After 9 months, IPT decreased the odds of anaemia (odds ratio [OR], 0.46 [95 % CI 0.23-0.91]; P = 0.023), whereas iron-fortified CF did not (OR, 0.85 [95 % CI 0.43-1.68]; P = 0.68), although ID (plasma ferritin <30 μg/l) was decreased markedly in children receiving iron fortified CF (OR, 0.19 [95 % CI 0.09-0.40]; P < 0.001).. IPT alone only modestly decreased anaemia, but neither IPT nor iron fortified CF significantly improved Hb concentration after 9 months. Additionally, IPT did not augment the effect of the iron fortified CF. CF fortified with highly bioavailable iron improved iron status but not Hb concentration, despite three-monthly IPT of malaria. Thus, further research is necessary to develop effective combination strategies to prevent and treat anaemia in malaria endemic regions.. http://www.clinicaltrials.gov ; identifier NCT01634945; registered on July 3, 2012.

Topics: Amodiaquine; Anemia; Antimalarials; Child, Preschool; Cote d'Ivoire; Diphosphates; Drug Combinations; Edetic Acid; Ferric Compounds; Food, Fortified; Hemoglobins; Humans; Infant; Inflammation; Iron; Iron Deficiencies; Malaria; Male; Prevalence; Pyrimethamine; Sulfadoxine

Anemia is a common complication in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Anemia is principally the result of erythropoietin deficiency, inflammation, and iron deficiency. High molecular weight iron oxide nanoparticles (IONP) are routinely administered intravenously to replace iron losses and, although effective, there are lingering concerns about possible safety issues. Ferric pyrophosphate citrate (FPC, Triferic, Triferic AVNU [Triferic and Triferic AVNU are the proprietary name for ferric pyrophosphate citrate. Triferic and Triferic AVNU are registered trademarks of Rockwell medical Inc.]) is a complex iron salt that donates iron directly to plasma transferrin. FPC is devoid of any carbohydrate moiety and is administered

Topics: Anemia; Anemia, Iron-Deficiency; Citrates; Dialysis Solutions; Diphosphates; Ferric Compounds; Hemoglobins; Humans; Inflammation; Iron; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

The study included 15 patients (median age - 61 [47; 73] years) with aortic dilatation more than 45 mm and thoracic aortic aneurysm who were candidates for surgical treatment. All patients underwent a chest scintigraphy with. According to the results of this novel scintigraphic technique, artifacts from the radioactivity of the vascular blood pool were eliminated and pathological RP uptake was identified in 5 (33.3±1.5%) out of 15 examined patients. The "focus/vessel lumen" ratio averaged at 1.47 [1.30; 1.48]. Histological examination of resected aorta samples confirmed the presence of chronic inflammation in 4 (26.7±1.3%) out of 15 patients. Parameters of diagnostic efficiency were: sensitivity - 100%, specificity - 91%, diagnostic accuracy - 93%.. The method of scintigraphic diagnostics of inflammatory processes in the aorta using

Topics: Aorta; Diphosphates; Humans; Inflammation; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals

It is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components. The aim of this work is to provide evidence that similar inflammatory mechanisms exist in synovial membrane (n = 24) obtained from three pathologies presenting altogether an inflammatory gradient: OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA). Synovial biopsies were first characterized by a histological score based on synovial hyperplasia and infiltration of lymphocytes, plasma cells, polymorphonuclear and macrophages. All biopsies were also analyzed by 2D-nano-UPLC-ESI-Q-Orbitrap for protein identification and quantification. Protein levels were correlated with the histological score. Histological score was in the range of 3 to 8 for OA, 5 to 13 for CPPA and 12 to 17 for RA. Of the 4,336 proteins identified by mass spectrometry, 51 proteins were selected for their strong correlation (p < 0.001) with the histological score of which 11 proteins (DNAJB11, CALR, ERP29, GANAB, HSP90B1, HSPA1A, HSPA5, HYOU1, LMAN1, PDIA4, and TXNDC5) were involved in the endoplasmic reticulum (ER) stress. Protein levels of S100A8 and S100A9 were significantly higher in RA compared to OA (for both) or to CPPA (for S100A8 only) and also significantly correlated with the histological score. Eighteen complement component proteins were identified, but only C1QB and C1QBP were weakly correlated with the histological score. This study highlights the inflammatory gradient existing between OA, CPPA and RA synovitis either at the protein level or at the histological level. Inflamed synovitis was characterized by the overexpression of ER stress proteins.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Biomarkers; Chondrocalcinosis; Diphosphates; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Female; Humans; Inflammation; Inflammation Mediators; Male; Middle Aged; Osteoarthritis; Proteins; Proteome; Retrospective Studies; Synovitis

The current study aimed to investigate the association of calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals in synovial fluid (SF) of patients with osteoarthritis (OA) with disease severity, clinical symptoms, and synovial inflammation. One-hundred-and-ten patients with knee OA completed the Western Ontario and McMaster Universities Arthritis Index (WOMAC) self-assessment questionnaire, the Lequesne algofunctional index survey, and the visual analogic scale forms; they also underwent power Doppler ultrasonography (PDUS) to assess synovial inflammation. Scanning electron microscopy (SEM) was used to detect SF crystals. SEM analyses uncovered CPP crystals in 26 patients (23.6%), BCP crystals in 24 patients (21.8%), and both types of crystals in 7 patients (6.3%). Categorizing patients according to SF crystal type, a strong association between BCP crystal presence, and higher WOMAC and Lequesne index scores has been uncovered. Classifying our patients according the severity Kellgre-Lawrence score, we found that the prevalence of CPP alone (27.8%) or in combination with BCP (11.1%) was higher in the late stage group with respect to the early one (CPP 21.6% and CPP + BCP 4.1%, respectively). The prevalence of BCP crystals alone was, instead, higher in the early (23%) with respect to the late group (19.4%). No association between the presence of crystals and the radiographic scores has been observed. Considering the growing evidence supporting a role of low-grade inflammation in OA pathogenesis, the results of this study suggest a role for calcium crystals in the development of the disease.

Topics: Aged; Aged, 80 and over; Calcium Phosphates; Diphosphates; Disease Progression; Female; Humans; Inflammation; Male; Microscopy, Electron, Scanning; Middle Aged; Osteoarthritis, Knee; Severity of Illness Index; Surveys and Questionnaires; Synovial Fluid; Ultrasonography, Doppler

Sucrosomial

Topics: Anemia, Iron-Deficiency; Animals; Diphosphates; Disease Models, Animal; Female; Ferric Compounds; Ferrous Compounds; Hep G2 Cells; Hepcidins; Humans; Inflammation; Intestinal Absorption; Intestines; Iron; Iron Deficiencies; Mice, Inbred BALB C

Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.

Topics: Animals; Antigen-Presenting Cells; Antigens, Neoplasm; Biocompatible Materials; Bone Marrow Cells; Cancer Vaccines; CpG Islands; Dendritic Cells; Diphosphates; DNA; Humans; Immunotherapy; Inflammation; Lysosomes; Macrophages; Magnesium Compounds; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Nanoparticles; Oligonucleotides; RAW 264.7 Cells; Spleen; Toll-Like Receptor 9

Purinergic signaling cascade includes the release of endogenous ATP and other agonists by chemical and mechanical stimuli, modulation of diverse cellular functions and subsequent ectoenzymatic inactivation. Basal release of extracellular purines and its physiological relevance remain controversial. Here we employed a combination of enzyme-coupled approaches for simultaneous bioluminescent (ATP, ADP, PP(i)) and fluorometric (AMP), adenosine, inosine, hypoxanthine) measurements of ATP and its metabolites without additional manipulations or derivatization of sampled biological fluids. By using these sensing techniques, extracellular purines were determined in various cells and tissues both at resting and pro-inflammatory conditions. The results obtained revealed the ability of endothelial, lymphoid and tumor cells to maintain extracellular ATP, ADP and adenosine at certain characteristic nanomolar levels. By quantifying the amounts of endogenously released and/or exogenously applied purines and their metabolites, these sensing techniques may be applied for evaluating purine-converting pathways on the cell surfaces and also for ex vivo analysis of purine homeostasis in the intact tissues. Furthermore, we provide novel insight into the mechanisms underlying tumorigenic effects of ATP by demonstrating the ability of metastatic prostate carcinoma PC3 and breast cancer MDA-MB-231 cells to maintain PP(i), which derives from extracellular ATP in the course of nucleotide pyrophosphatase/phosphodiesterase reaction. Collectively, the results imply a complex pattern of nucleotide turnover where extracellular ATP, ADP and adenosine are maintained at steady-state levels via conunterbalanced release and inactivation of ATP and other purines, and further suggest the importance of basal agonist release for continuous activation and/or desensitization of purinergic receptors.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Cell Line, Tumor; Chromatography, Thin Layer; Diphosphates; Enzyme Assays; Extracellular Fluid; Fluorometry; Homeostasis; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Inosine; Luminescent Measurements; Lymphocytes; Neoplasm Metastasis; Nucleosides; Nucleotides; Pyrophosphatases

Pyrimidine nucleotides are signaling molecules, which activate G protein-coupled membrane receptors of the P2Y family. P2Y(2) and P2Y(4) receptors are part of the P2Y family, which is composed of 8 subtypes that have been cloned and functionally defined. We have previously found that uridine-5'-triphosphate (UTP) reduces infarct size and improves cardiac function following myocardial infarct (MI). The aim of the present study was to determine the role of P2Y(2) receptor in cardiac protection following MI using knockout (KO) mice, in vivo and wild type (WT) for controls. In both experimental groups used (WT and P2Y(2)(-/-) receptor KO mice) there were 3 subgroups: sham, MI, and MI+UTP. 24h post MI we performed echocardiography and measured infarct size using triphenyl tetrazolium chloride (TTC) staining on all mice. Fractional shortening (FS) was higher in WT UTP-treated mice than the MI group (44.7±4.08% vs. 33.5±2.7% respectively, p<0.001). However, the FS of P2Y(2)(-/-) receptor KO mice were not affected by UTP treatment (34.7±5.3% vs. 35.9±2.9%). Similar results were obtained with TTC and hematoxylin and eosin stainings. Moreover, troponin T measurements demonstrated reduced myocardial damage in WT mice pretreated with UTP vs. untreated mice (8.8±4.6 vs. 12±3.1 p<0.05). In contrast, P2Y(2)(-/-) receptor KO mice pretreated with UTP did not demonstrate reduced myocardial damage. These results indicate that the P2Y(2) receptor mediates UTP cardioprotection, in vivo.

Topics: Animals; Diphosphates; Genotype; Inflammation; L-Lactate Dehydrogenase; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; Receptors, Purinergic P2Y2; Troponin T; Uridine Triphosphate; Ventricular Remodeling

Vgamma9/Vdelta2 T cells are a minor subset of T cells in human blood and differ from other T cells by their immediate responsiveness to microbes. We previously demonstrated that the primary target for Vgamma9/Vdelta2 T cells is (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), an essential metabolite produced by a large range of pathogens. Here we wished to study the consequence of this unique responsiveness in microbial infection. The majority of peripheral Vgamma9/Vdelta2 T cells shares migration properties with circulating monocytes, which explains the presence of these two distinct blood cell types in the inflammatory infiltrate at sites of infection and suggests that they synergize in anti-microbial immune responses. Our present findings demonstrate a rapid and HMB-PP-dependent crosstalk between Vgamma9/Vdelta2 T cells and autologous monocytes that results in the immediate production of inflammatory mediators including the cytokines interleukin (IL)-6, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and oncostatin M (OSM); the chemokines CCL2, CXCL8, and CXCL10; and TNF-related apoptosis-inducing ligand (TRAIL). Moreover, under these co-culture conditions monocytes differentiate within 18 hours into inflammatory dendritic cells (DCs) with antigen-presenting functions. Addition of further microbial stimuli (lipopolysaccharide, peptidoglycan) induces CCR7 and enables these inflammatory DCs to trigger the generation of CD4(+) effector alphabeta T cells expressing IFN-gamma and/or IL-17. Importantly, our in vitro model replicates the responsiveness to microbes of effluent cells from peritoneal dialysis (PD) patients and translates directly to episodes of acute PD-associated bacterial peritonitis, where Vgamma9/Vdelta2 T cell numbers and soluble inflammatory mediators are elevated in patients infected with HMB-PP-producing pathogens. Collectively, these findings suggest a direct link between invading pathogens, microbe-responsive gammadelta T cells, and monocytes in the inflammatory infiltrate, which plays a crucial role in the early response and the generation of microbe-specific immunity.

Topics: Antigen-Presenting Cells; Bacterial Infections; Cell Communication; Cell Differentiation; Cell Survival; Cells, Cultured; Cytokines; Data Interpretation, Statistical; Diphosphates; Humans; Inflammation; Monocytes; Peritoneal Cavity; Peritoneal Dialysis; Peritonitis; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocyte Subsets

The presence of matrix metalloproteinase-2 and -9 (MMP-2, MMP-9), gelatinase A and B, in synovial fluid is typical in inflammatory connective tissue diseases especially rheumatoid arthritis (RA). Because MMPs are synthesized as latent proforms, a pathophysiologic understanding of MMP regulation has focused on mechanisms of activation that remain to date largely unresolved.. Synovial fluid was collected by aseptic aspiration from RA patients and incubated with and without physiologic levels of calcium and other modifiers (pyrophosphate, bisphosphonates, and the tissue inhibitors of MMPs (TIMPs), under conditions that activate MMPs. MMP-2 and -9 were then characterized by substrate gel electrophoresis (gelatin zymography) to resolve both latent and activated 'partially proteolyzed' forms.. Gelatin zymography revealed that RA synovial fluid contained latent neutrophil MMP-9 (92, 130, 225 kDa) and fibroblast MMP-2 (72 kDa). A small amount of activated MMP-2 (64 kDa) was also noted. Incubation of synovial fluid without calcium resulted in MMP-9 activation to 87, 116, and 209 kDa forms. MMP-9 activation was, however, substantially delayed in the presence of physiologic calcium (2.5 mmol/l). MMP-2 did not demonstrate any appreciable activation with or without physiologic calcium. MMP-9 activation likely occurred via an autoactivation mechanism since it was susceptible to inhibition by the tissue inhibitor of MMP-9 (TIMP-1). Pyrophosphate and bisphosphonates (alendronate and risedronate) were ineffective in blocking synovial fluid MMP-9 autoactivation. Some early MMP-9 activation was noted with alendronate despite the presence of physiologic calcium.. Although RA synovial fluid contained abundant MMP-2 and MMP-9, only MMP-9 underwent autoactivation to lower molecular weight forms. MMP-9 was transiently stable in the presence of physiologic calcium concentration, whereas autoactivation was more pronounced without exogenous calcium. The apparent lack of MMP-2 autoactivation with or without calcium, likely resulted from the coexistence of its bound endogenous inhibitor, TIMP-2. The role of differential autoactivation of MMPs activity in inflammatory arthritic disease is discussed.

Topics: Aged; Arthritis, Rheumatoid; Calcium; Diphosphates; Diphosphonates; Enzyme Activation; Female; Humans; Inflammation; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Molecular Structure; Synovial Fluid

Electron microscopy was used to investigate the characteristics of calcium pyrophosphate dihydrate (CPPD) crystals in chondrocalcinosis (pseudogout syndrome). Crystals in midzone cartilage were frequently seen adjacent to chondrocytes. Great variation in crystal size and shape was observed. Most of the pyrophosphate crystals that had been phagocytosed by polymorphonuclear leukocytes of synovial fluid from patients with acute pseudogout were small (less than or equal to 1 micron), indicating that small crystals can cause intense inflammation. Large numbers of polymorphonuclear leukocytes became attached to the eroded articular surface and phagocytosed microcrystals. Interaction of polymorphonuclear leukocytes with CPPD crystals in the superficial region of articular cartilage may stimulate the release of inflammatory mediators.

Topics: Aged; Calcium Pyrophosphate; Cartilage; Chondrocalcinosis; Crystallography; Diphosphates; Humans; Inflammation; Microscopy, Electron; Middle Aged; Neutrophils

Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals initiated acute inflammatory reactions characterized by increased plasma extravasation and polymorphonuclear leukocyte (PMNL) accumulation in the rat subcutaneous air-pouch. Pretreatment of rats with colchicine (1 mg kg-1, s.c.) inhibited PMNL accumulation induced by either crystal type but had a greater inhibitory effect on MSU-induced plasma extravasation compared with that induced by CPPD crystals. Colchicine (1 mg kg-1, s.c.) did not reduce histamine-induced plasma extravasation in the air-pouch. The lipoxygenase product of arachidonic acid metabolism, leukotriene B4 (LTB4), was detected in MSU-induced exudates but not in CPPD-induced exudates. Pretreatment of rats with colchicine (1 mg kg-1, s.c.) inhibited LTB4 production in MSU-induced exudates.

Topics: Animals; Anti-Inflammatory Agents; Calcium Pyrophosphate; Colchicine; Diphosphates; Disease Models, Animal; Inflammation; Leukotriene B4; Male; Neutrophils; Rats; Rats, Inbred Strains; Uric Acid

The authors have performed radioisotope examinations in 271 patients with various non-neoplastic bone diseases. According to their opinion, early diagnosis and follow-up of therapeutic results are the main characteristics which allow radioisotopes to play an important and irreplaceable role. They particularly emphasize the usefulness of radioisotope methods in femoral aseptic necrosis and Paget's disease.

Topics: Adolescent; Bone Diseases; Diphosphates; Epiphyses, Slipped; Female; Femur Head Necrosis; Follow-Up Studies; Hip Prosthesis; Humans; Inflammation; Osteitis Deformans; Postoperative Complications; Radionuclide Imaging; Technetium

Deposition of 67Ga in bone does not explicitly imply osteomyelitis. Osteomyelitis complicating insertion of orthopedic devices is manifested by lack of congruence in the distribution patterns of 99mTc-PP and 67Ga. Congruent patterns can reflect the increased bone reaction to implantation or loosening of the device, not necessarily osteomyelitis. Both (a) nonseptic synovitis secondary to reactive bursa formation and (b) cellulitis exhibit an affinity for 67Ga and virtually none for 99mTc-PP, whereas the reverse is true for heterotopic bone. Thus combined sequential 99mTc-PP/67Ga imaging is necessary for evaluation of complications associated with internal orthopedic devices.

Topics: Adult; Aged; Child; Diphosphates; Female; Follow-Up Studies; Gallium Radioisotopes; Humans; Inflammation; Joint Prosthesis; Male; Middle Aged; Orthopedic Fixation Devices; Radionuclide Imaging; Technetium

A gallium-67/technetium-99m subtraction technique was used with a variable weighting factor. That is, each image was separately set to 100%. Varying amounts of the Tc-99m images were subtracted from those of Ga-67. A total of 95 patients who had radiogallium scanning for suspected inflammatory disease were studied by the subtraction technique. Thirty of these patients had abnormal Tc-99m pyrophosphate bone scans, while 20 had abnormal radiogallium abdominal foci; 45 had defects in liver, spleen, or kidney images. The subtraction technique with variable weighting was highly successful in enhancing hot-spot visibility, and in providing information as to the anatomic location of the defect.

Topics: Abscess; Adult; Arthritis, Infectious; Citrates; Computers; Diphosphates; Female; Gallium Radioisotopes; Humans; Inflammation; Kidney Diseases; Liver Abscess; Male; Middle Aged; Osteomyelitis; Radionuclide Imaging; Splenic Diseases; Technetium

The pleural cavity of rats and guinea-pigs has been utilized to study the inflammatory response to immediate hypersensitivity, delayed hypersensitivity, calcium pyrophosphate and carrageenan. The mediators will be described and their possible interaction with cyclic AMP. Finally the effect of some anti-inflammatory agents on these models will be discussed.

Topics: Animals; Arthritis; Arthus Reaction; Carrageenan; Cyclic AMP; Diphosphates; Disease Models, Animal; Guinea Pigs; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Inflammation; Lung; Pleura; Rats; Synovial Fluid

The changes in leucocyte concentrations of cyclic AMP and cyclic GMP were monitored during pyrophosphate-induced pleurisy in rats. A classical 'Yin Yang' relationship was demonstrated.

Topics: Animals; Cyclic AMP; Cyclic GMP; Diphosphates; Inflammation; Male; Pleurisy; Rats; Time Factors

Colchicine, given locally, inhibits urate-crystal- and CaPPD-crystal-induced inflammation. Since this inflammation is known to be mediated in part by PGE1 these observations indicate colchicine acts as an anti-PG agent. Colchicine counteracts the phlogistic action of exogenous PGE1 in both urate- and CaPPD-crystal-induced inflammation. With use of large excesses of colchicine, its anti-inflammatory action appears limited to its anti-PGE1 activity. In turn, PGE1 counteracts the antiphlogistic action of colchicine. Colchicine is less effective in reducing swelling due to CaPPD-crystals than that due to urate-crystals, a finding similar to the clinical observations that colchicine is more effective therapy for gout than for pseudogout. Some relationships are reviewed to suggest that CaPPD-crystal inflammation is a more severe membrane disorder than is urate-crystal inflammation.

Topics: Animals; Anti-Inflammatory Agents; Colchicine; Diphosphates; Inflammation; Male; Prostaglandin Antagonists; Prostaglandins E; Rats; Time Factors; Uric Acid

A model is described of acute inflammation in the pleural cavity of rats using calcium pyrophosphate as the irritant. This model would seem to simulate the pseudogout syndrome. It has been shown to be acute in onset, dominated by polymorphonuclear cells, complement independent. The advantage of the model is that volume of exudate, numbers and types of cells may be quantitated. Prostaglandins and cyclic AMP have been measured in the migrating cells. The significance of these findings has been discussed.

Topics: Animals; Calcium Phosphates; Cyclic AMP; Diphosphates; Disease Models, Animal; Indomethacin; Inflammation; Male; Pleural Effusion; Pleurisy; Prostaglandins E; Prostaglandins F; Rats; Snake Venoms

Promotion of calcium pyrophosphate dihydrate (CaPPD) crystal-induced inflammation by prostaglandin (PG) E1 has been demonstrated by two new techniques: (1) Rats deficient in essential fatty acids, biological precursors of PG, developed less footpad swelling than did normal rats following injections of unheated CaPPD. Addition of one ng of PGE1 to these crystals resulted in normal swelling. (2) This phlogistic effect of PGE1 was also demonstrated in normal rats fed a normal dietwho received injections of CaPPD crystals heated to 200 degrees C for three hours. The heated crystals induced less footpad swelling than did unheated crystals. When one ng of PGE1 was added to the suspensions of heated crystals the resultant swelling approximated that obtained by unheated crystals. The possible role of PGE1 in mediating CaPPD crystal-induced inflammation is suggested. An analysis of urate and CaPPD crytal-induced inflammation is presented with comments setting forth the concept that these metabolic crystal disorders are membrane diseases.

Topics: Animals; Calcium Phosphates; Diphosphates; Fatty Acids, Essential; Inflammation; Male; Prostaglandins E; Rats

Topics: Acid Phosphatase; Chondrocalcinosis; Diphosphates; Female; Gout; Hemolysis; Humans; Inflammation; Leukocytes; Lysosomes; Male; Membranes; Phagocytosis; Sex Factors; Silicon Dioxide; Uric Acid

Topics: Aminocaproates; Animals; Aprotinin; Arthritis; Complement Inactivator Proteins; Crystallization; Diphosphates; Inflammation; Injections, Intra-Articular; Injections, Subcutaneous; Leukocytes; Lysosomes; Protease Inhibitors; Rabbits; Skin Diseases; Synovial Membrane; Trypsin Inhibitors; Venoms; Vinblastine

Topics: Antibodies, Antinuclear; Arthritis, Rheumatoid; Biopsy; Connective Tissue; Dermatomyositis; Diphosphates; Gout; Humans; Hyperparathyroidism; Inflammation; Joint Diseases; Lupus Erythematosus, Systemic; Neutrophils; Polyarteritis Nodosa; Psoriasis; Rheumatoid Factor; Salicylates; Sarcoidosis; Spondylitis, Ankylosing; Synovial Fluid; Synovial Membrane; Uric Acid

Topics: Adenosine Triphosphate; Animals; Anti-Inflammatory Agents; Cyclic AMP; Diphosphates; Histamine Release; Inflammation; Rats; Theophylline

Topics: Acute Disease; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cell Membrane Permeability; Cyclic AMP; Dermatitis; Diphosphates; Epinephrine; Female; Histamine; Histamine Release; Inflammation; Injections, Subcutaneous; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Rats; Rats, Inbred Strains; Skin; Xanthines

Topics: Animals; Calcium Phosphates; Carbon; Chemotaxis; Colchicine; Crystallography; Diphosphates; Dogs; Humans; In Vitro Techniques; Inflammation; Injections, Intra-Articular; Leukocytes; Phagocytosis; Uric Acid