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Sclerochoroidal calcification associated with Gitelman syndrome and calcium pyrophosphate dihydrate deposition.

Sclerochoroidal calcification is an uncommon condition. Metabolic evaluation and clinical examination are important to exclude associated systemic conditions such as the Bartter and Gitelman syndromes. It has been suggested that the lesions seen in sclerochoroidal calcification are calcium pyrophosphate dihydrate crystals. This report describes the first documented case in the UK of sclerochoroidal calcification associated with Gitelman syndrome and calcium pyrophosphate dihydrate deposition.

Calcinosis↗

Gated blood pool imaging following 99mTc stannous pyrophosphate imaging.

Cardiac patients who have undergone 99mTc-stannous pyrophosphate (99mTc-PYP) myocardial imaging can be injected 24 hours later with 99mTc-pertechnetate (99mTc04) to assess left ventricular function. Reduction of 99mTc04 by tin remaining in the blood following the stannous pyrophosphate injection causes labeling of the red cells by 99mTc04 and the creation of a vascular tracer suitable for electrocardiographically gated imaging.

Animals↗

99mTc-pyrophosphate imaging in acute pericarditis: a clinical and experimental study.

Fifteen patients with clinical and electrocardiographic features of acute pericarditis underwent myocardial scintigraphy using 99mTc-pyrophosphate. All had normal images. In 5 additional patients with acute pericarditis and evidence of ischemic heart disease, 99mTc-pyrophosphate images showed focal abnormalities in 2 patients and equivocal findings in 2. Serial myocardial radionuclide images were obtained 2 to 18 days after induction of pericarditis in 8 dogs; all images were normal. No stainable tissue calcium was demonstrated histochemically in the pericardium or myocardium of these dogs. Our results suggest that 99mTc-PYP myocardial radionuclide images are normal in acute pericarditis in the absence of ischemic heart disease.

Acute Disease↗

99mTc-pyrophosphate bone imaging in osteopoikilosis, osteopathia striata, and melorheostosis.

Technetium-99m pyrophosphate bone images were contrasted with radiographic findings in two patients with osteopoikilosis, one with osteopathia striata, and one with melorheostosis. Despite the striking radiographic findings, scans were normal in osteopoikilosis and osteopathia striata. In melorheostosis, focal increased radiopharmaceutical accumulation appeared in each radiographically abnormal area. Technetium-99m pyrophosphate bone images should prove helpful when superimposed osseous disease must be differentiated from osteopoikilosis, osteopathia striata, or melorheostosis.

Adult↗

99mTc-pyrophosphate imaging in experimental mesenteric infarction: relationship of tracer uptake to the degree of ischemic injury.

Four-hour balloon occlusion of the cranial mesenteric artery in 13 dogs produced a spectrum of widespread ischemic injury to the small bowel ranging from superficial mucosal infarction to transmural infarction. Twenty-four hours after the beginning of balloon occlusion, 15 mCl of 99mTc-pyrophosphate was injected into the cranial mesenteric artery in 8 dogs and into a peripheral vein in 5. Gamma camera imaging of the abdomen followed three hours later. Four of 8 dogs injected intra-arterially showed positive images with full-thickness mucosal or transmural infarction. The 4 intravenously injected dogs with positive images had transmural infarction. Only minimal ischemic injury with superficial mucosal infarction was found in the 5 dogs with negative images. Tracer uptake per gram infarcted tissue was highest after intra-arterial injection. It was concluded that 99mTc-pyrophosphate allows external imaging of extensive intestinal infarctions after both intra-arterial and intravenous injection.

Animals↗

Scintigraphic visualization of myocardial infarcts in baboons using thallium-201 and technetium-99m pyrophosphate.

4 baboons with myocardial infarcts were evaluated using thallium-201 for myocardial imaging and 99Tcm pyrophosphate for infarct visualization. Scintiphotographic findings were compared with the size of myocardial infarcts calculated from measurements of the activity of MB isoenzymes of creatine kinase (CK-MB) in serum and in the myocardium at autopsy, as described by Sobel's method. Lack of thallium-201 accumulation was noted in left ventricular infarcts of 3 of the 4 baboons. These same areas localized 99Tcm pyrophosphate administered 24--30 h after infarction.

Animals↗

The prognostic implications of acute myocardial infarct scintigraphy with 99mTc-pyrophosphate.

The predictive value of the myocardial scintigraphy with 99mTc-pyrophosphate was studied in 100 patients admitted to the coronary care unit with suspected acute myocardial infarction. None of the 21 patients with normal scintigrams had acute myocardial infraction by other criteria. Fifty-five percent of patients with diffuse uptake (pattern B), 73% of patients with focal uptake (pattern C) and all patients with intense focal uptake (pattern D) and massive uptake (pattern E) had acute infarction. The complication rate in the hospital and after discharge (mean followup: 6.1 months) for patients with pattern E was 88% compared to 42% for D, 30% for C, 36% for B and 10% for patients with normal scintigrams (A). For patients with acute infarction with patterns C, D and E, the complication rate rose with increasing size of the myocardial uptake of 99mTc-pyrophosphate. In addition to its diagnostic potential, scintigraphy provides prognostic information which is useful for patient triage and for therapeutic decisions early in the evolution of the infarct.

Angina Pectoris↗

Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone.

An isotope dilution method, using (32)P-labeled pyrophosphate, has been developed for the measurement of inorganic pyrophosphate (PP(1)) in human plasma. The specificity of the method was better than 90% as assessed by elution patterns during ion-exchange chromatography, by paper chromatography, and by incubation with inorganic pyrophosphatase. The 99% confidence limits for a single estimation of plasma PP(1) was +/-13%. There were no differences in plasma PP(1) between men and women, but the values in young people (0-15 yr) were slightly higher than in older people. The mean concentration (+/-SE) of PP(1) in the plasma of 73 men and women was 3.50 +/-0.11 mumoles/liter (0.217 +/-0.007 mug P/ml) and the normal range (99% limits) was 1.19-5.65 mumoles/liter (0.074-0.350 mug P/ml). It has been suggested that PP(1) may be important in calcium metabolism because PP(1) can prevent the precipitation of calcium phosphates in vitro and in vivo, and can slow the rates at which hydroxyapatite crystals grow and dissolve. Plasma PP(1) was therefore measured in several disorders of bone. Normal values were found in osteogenesis imperfecta, osteopetrosis, "acute" osteoporosis, and primary hyperparathyroidism. Plasma PP(1) was invariably raised in hypophosphatasia. The excess of PP(1) in plasma might be the cause of the defective mineralization in hypophosphatasia and the function of alkaline phosphatase in bone may be to act as a pyrophosphatase at sites of calcium deposition.

Adenine Nucleotides↗

Inorganic pyrophosphate pool size and turnover rate in arthritic joints.

Recent studies have shown elevated inorganic pyrophosphate (PPi) levels in most knee joint fluid supernates from patients with pseudogout (PG) or osteoarthritis (OA) and more modestly elevated levels in some supernates from patients with gout or rheumatoid arthritis (RA) relative to PPi levels found in the venous blood plasma of normal or arthritic subjects. We measured the intraarticular PPi pool and its rate of turnover to better understand the significance of the joint fluid-plasma PPi gradient. Preliminary studies in rabbits showed that (32-P)PPi passed from joint space to blood and vice versa without detectable hydrolysis. Incubation of natural or synthetic calcium pyrophosphate dihydrate (CPPD) microcrystals with synovial fluid in vitro in the presence of (32P)PPi tracer showed no change in PPi specific activity in the supernate over a 19-h period so that exchange of PPi in solution with that in CPPD microcrystals could be ignored. Clearance rates of (32P)PPi and of (33P)Pi, as determined by serially sampling the catheterized knee joints of volunteers with various types of arthritis over a 3-h period, were nearly identical. The (32P)PPi/(32P)Pi was determined in each sample. A mixture of a large excess of cold PPi did not influence the clearance rate of either nuclide. The quantity of PPi turned over per hous was calculated from the pool size as determined by isotope dilution and the turnover rate. The residual joint fluid nuclide was shown to be (32P)PPi. The PPi pool was generally smaller and the rate of turnover was greater in clinically inflamed joints. The mean plus or minus SEM pool size (mu-moles) and turnover rate (percent/hour) in PG knees was 0.23 plus or minus 0.07 and 117 plus or minus 11.9, hydrolysis rate (%/h) to Pi was 27.7 plus or minus 13.2; in OA knees: 0.45 plus or minus 0.26 and 72 plus or minus 9.2, hydrolysis 6.9 plus or minus 0.9; in gouty knees: 0.8 plus or minus 0.41 and 50 plus or minus 11.6, hydrolysis 9.8 plus or minus 2.8; and in RA knees: 0.14 plus or minus 0.14 and 114 plus or minus 35.8, hydrolysis 236 plus or minus 116. PPi turnover (mumoles/hour) correlated with the degree of OA change present in the joint as graded by radiologic criteria irrespective of the clinical diagnosis. Mean PPi turnover in joints with advanced OA was greater than in those with mild or moderate changes (P smaller than 0.001), but the mild and moderate groups showed no significant difference. We conclude that synovial PPi turnover and elevated PPi fluid concentrations are not specific for PG patients, and that these factors alone cannot be the only determinants of CPPD crystal deposition.

Adult↗

Extrusion of pyrophosphate into extracellular media by osteoarthritic cartilage incubates.

The distribution of calcium pyrophosphate mineral phase, almost exclusively confined to articular cartilage in chondrocalcinosis, and the high level of pyrophosphate (PPi) ion relative to serum in synovial fluid in patients with either chondrocalcinosis or advanced osteoarthritis led to an investigation of whether cartilage cells elaborate PPi ions. Incubates of articular cartilage from young rabbits but not from mature rabbits, as well as growth plates cartilage, released PPi into incubation media during a 4h period. Control rabbit ear cartilage and synovial membrane elaborated negligible amounts of PPi. The PPi was shown to be undialyzable but could be dissociated from the alkaline phosphatase by ultracentrifugation. In 16 patients with osteoarthritis, a substantial output of PPi by samples of articular cartilage from the knee was demonstrated. It is postulated that either rapid cell division and matrix synthesis found in the base of ulcerating osteoarthritic cartilage or remodeling calcified sites are the source of the PPi in such osteoarthritic cartilage. It is further hypothesized that this PPi output accounts at least in part for the elevated PPi levels found in synovial fluid of patients with osteoarthritis.

Alkaline Phosphatase↗

Factors affecting the solubility of calcium pyrophosphate dihydrate crystals.

The solubility of triclinic calcium pyrophosphate dihydrate (CPPD) crystals was measured under varying conditions using 45Ca-labeled crystals, expressing solubility as micromoles per liter of 45Ca in solution. In a 0.1-M Tris-HC1 buffer pH 7.4, the solubility of accurately sized CPPD crystals (37-20mum) was 60muM with maximal solubility being attained after about 8 h incubation at 37degreeC. Reduction in crystal size, decrease in pH, increase in ionic strength, Mg++, citrate, and albumin all increased solubility. The most marked effects on solubility occurred when changing the calcium concentration or by enzymatic hydrolysis of inoganic pyrophosphate to orthophosphate. It was found that decreasing the ionized calcium level below 5 mg/100 ml resulted in a progressive enhancement of solubility. The observed solubility-enhancing effects of albumin could be explained solely on its calcium-binding ability and thereby, altered ionized calcium level. Diffusible calcium in synovial fluid was only 40% of the total calcium concentration, which means most joint fluids are normally near the critical concentration of 5 mg/100 ml of ionized calcium, below which solubility is enhanced. During surgery, especially parathyroidectomy, calcium levels fall, favoring dissolution of CPPD crystals. We speculate that the slight decrease in crystal size during dissolution frees them from their cartilaginous mold, resulting in a dose-dependent inflammatory reaction as they are "shed" into the joint space. Crystal shedding may be reinforced by the modest fall in joint fluid pH accompanying the inflammatory response.

Arthritis, Rheumatoid↗

Purification and characterization of mouse mevalonate pyrophosphate decarboxylase.

Mevalonate pyrophosphate decarboxylase (MPD) in mouse liver was purified by affinity chromatography. The purified enzyme was a homodimer of 46-kDa subunits and had an isoelectric point of 5.0. Kinetic analysis revealed an apparent Km value of 10 microm for mevalonate pyrophosphate. The enzyme required ATP as a phosphate acceptor and Mg as a divalent cation, which could be substituted with Mn or Co. Its optimum pH was 4.0-7.0. A comparison with MPD from various other sources revealed the mouse MPD to have essentially the same properties as rat MPD, expect for the optimum pH range. An excess of rabbit anti-rat MPD antibody deleted approximately 80% of the MPD activity in the crude extract of mouse liver. These results suggested that the homodimer of 46-kDa subunits represents the major active form of MPD in mice.

Animals↗

A very rare benign tumour in the parotid region: calcium pyrophosphate dihydrate crystal deposition disease.

Calcium pyrophosphate dihydrate crystal deposition disease, exhibits several clinical manifestations, from absence of symptoms to severely destructive arthropathy or conditions simulating neoplasm, which is frequently related to the temporomandibular joint. Fifteen of the 31 reported cases of tophaceous pseudogout were found in the head and neck region. A patient presented with a parotid swelling, which initially was suspected to be malignant because of the following findings: radiodensity, progression into the joint, osseous destruction of the major ala of the sphenoid and a fine needle aspirate with crystals, osteoblasts, megakaryocytes and irregular cells of varying size. At surgery there was found a tumour consisting of a white, firm gritty material. It progressed to the skull base where material had to be left, because of the presence of the nerves and vessels. A frozen specimen was reported to be benign. Histological examination showed inflammatory cells, macrophages, a chondroid material with embedded metaplastic chondroid cells and giant cells of foreign body type. Crystal examination of X-ray diffraction revealed calcium pyrophosphate dihydrate.

Chondrocalcinosis↗

A computer assisted comparison of 99Tcm-methylene-diphosphonate and 99Tcm-pyrophosphate bone imaging.

A total of 350 patient studies were carried out using clinical trials' batches of the Technetium (MDP) agent for bone scintigraphy (The Radiochemical Centre), and a commercially available Technetium pyrophosphate agent (CIS). The bone seeking properties of 99Tcm Sn-methylene-diphosphonate (MDP) and 99Tcm Sn-pyrophosphate (PYP) were evaluated by their comparative uptake in compact bone, cancellous bone and soft tissue using a region-of-interest technique. From these data uptake ratios were computed in order to correlate the values with (a) the amount of 99Tcm-MDP injected, (b) the time after injection and (c) the age of patients examined. All ratios derived with 99Tcm-MDP were superior to those using 99Tcm-PYP and were not dependent on the amount of 99Tcm-MDP injected. Uptake ratios determined for 99Tcm-MDP (1.5 h to 2.5 h after injection) were found to be higher than those for 99Tcm-PYP 2.5 to 3.5 h after injection. Soft tissue accumulation of 99Tcm-MDP, visible on scintiphotos, occurred only in 26% of cases but with 99Tcm-PYP, in 75% out of all cases studied. A decrease of cancellous bone/compact bone ratios with increasing age of the patients was found with both radiopharmaceuticals. This is most probably correlated with a diminished mass and/or surface of the cancellous bone in the elderly patient.

Adult↗

Detection of unstable angina by 99m technetium pyrophosphate myocardial scintigraphy.

99mTechnetium stannous pyrophosphate has been shown to accumulate in acutely infarcted myocardium. To determine if the isotope is also taken up by severely ischemic, but not necrotic myocardium, we performed myocardial scintigraphic studies in 17 patients with chest pains. Seven of the patients satisfied conventional clinical, electrographic, and laboratory criteria for the diagnosis of unstable angina and showed no electrocardiographic or enzymatic evidence of myocardial necrosis. Five of these seven patients with unstable angina demonstrated abnormal localized patterns, and one showed a borderline picture. Myocardial scintiscans were normal in all of a control group of ten patients with stable angina. Thus, scanning with 99mtechnetium stannous pyrophosphate is shown to be of value in the objective demonstration of myocardial abnormality in unstable angina.

Angina Pectoris↗

The effect of soluble pyrophosphates on dental calculus in adults.

A sodium fluoride dentifrice, containing a mixture of soluble pyrophosphates, was used ad libitum in an adult population for 6 months after receiving a dental prophylaxis. In comparison with the control group, who used the sodium fluoride formula without the pyrophosphates, the test group had significantly less calculus by occurrence and severity. Thus, a significant reduction in newly forming calculus was obtained with the experimental dentifrice when used as an adjunct to regular professional care and personal oral hygiene procedures.

Adolescent↗

Synergistic effect of pyrophosphate and sodium dodecyl sulfate on periodontal pathogens.

Our previous studies have shown that pyrophosphate (PPi), the anticalculus component of tartar-control dentifrices, inhibits the growth of organisms associated with coronal and root surface caries. The purposes of this investigation were to: 1) determine if periodontal pathogens are similarly susceptible to the growth-inhibitory properties of PPi; and 2) determine if combinations of pyrophosphate-sodium dodecyl sulfate (PPi-SDS) inhibit growth synergistically. Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, Eikenella corrodens, and Campylobacter rectus (formerly Wolinella recta) were cultured in appropriate enriched media under anaerobic conditions. Inhibition assays were performed in tubes containing media supplemented with PPi and/or SDS. A range of concentrations of PPi and SDS in 2-fold increments was employed, with each concentration assayed in triplicate. Minimal inhibitory concentration (MIC) analyses revealed all of the bacteria were susceptible to PPi and SDS, with MICs of 0.67% (25 mM) and 0.01% w/v respectively. Combination studies with PPi-SDS showed much greater growth inhibition against P. gingivalis and A. actinomycetemcomitans than achieved with the agents individually. Determination of fractional inhibitory concentration indices indicated a synergistic growth-inhibitory effect. Under the constraints of the conditions employed, these studies demonstrate the efficacy of PPi-SDS combinations in inhibiting the growth of periodontal pathogens. It is conceivable that these compounds may have clinical benefit as a subgingival irrigant.

Aggregatibacter actinomycetemcomitans↗

The dynamics of calcium phosphate precipitation studied with a new polyacrylamide steady state matrix-model: influence of pyrophosphate collagen and chondroitin sulfate.

A novel steady-state gel-matrix model system is described which facilitates the quantitative kinetic study of the influence of media and matrix composition on a precipitation process. The potentialities of the system are illustrated in experiments in which the precipitation of calcium phosphate in a polyacrylamide film is studied as a function of the calcium and phosphate concentration in the solutions flowing along opposite sides of the film. Addition of pyrophosphate to the reactant solutions was found to diminish the (calcium) x (phosphate) millimolar product at which precipitation starts, indicating a positive effect on nucleation. The slope of the curve was found to decrease, which points to a negative influence of pyrophosphate on the crystal growth process. Incorporation of collagen in the matrix did not change the curve, but incorporation of chondroitin sulfate decreased the formation product since the intercept of the curve was reduced. The usefulness of the system compared with test-tube and non-steady state gel experiments for calcium phosphate precipitation studies and its significance for the study of in vitro and in vivo precipitation processes in general, are discussed.

Acrylic Resins↗