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PubMed1991

Familial chondrocalcinosis due to calcium pyrophosphate dihydrate crystal deposition in English families.

Familial predisposition to chondrocalcinosis (CC) due to calcium pyrophosphate dihydrate (CPPD) crystal deposition is described in five English kindreds. Two families were characterized by premature-onset polyarticular CC with little associated structural arthropathy. In one of these families, recurrent childhood fits were strongly associated with subsequent development of CC. Affected members of the other three families resembled sporadic disease in showing predominantly late-onset, oligoarticular CC with mild arthritis and destructive change in only one case. Knee synovial fluid levels of inorganic pyrophosphate (PPi) and nucleoside triphosphate pyrophosphate (NTPP) did not differ from those of 59 sporadic cases of CC due to CPPD, although PPi and NTPP levels in both groups were higher than in normal knee synovial fluid (P less than 0.0001). Urinary PPi levels were not different from normal controls. Screening for other metabolic abnormality was negative in all cases. This is the first report of familial CC in the UK, and the first to associate this condition with childhood fits. Absence of overt primary abnormality of PPi metabolism suggests that other factors relating to crystal nucleation/growth may be more relevant to predisposition in these cases.

Calcium Pyrophosphate↗

PubMed2000

Formation of calcium pyrophosphate crystals: biologic implications.

The formation of calcium pyrophosphate dihydrate (CPPD) crystals in articular cartilage marks the earliest known phase of CPPD deposition disease. Although the exact mechanisms through which these crystals form remains unknown, work over the last year has added useful details to our current paradigms of crystal nucleation and growth. Key advances include (1) progress in understanding pyrophosphate elaboration and its modifiers, (2) further characterization of the enzymes responsible for pyrophosphate elaboration, and (3) the discovery of an association between two seemingly unrelated metabolic risk factors for CPPD deposition disease.

Arthritis, Rheumatoid↗

PubMed2004

Modulation of chondrocyte production of extracellular inorganic pyrophosphate.

PURPOSE OF REVIEW: Extracellular inorganic pyrophosphate (ePPi) both inhibits and promotes different forms of pathologic mineralization. Basic calcium phosphate (BCP) deposition results from depressed levels of ePPi while excess levels of ePPi leads to calcium pyrophosphate dihydrate crystal deposition (CPPD) disease. These crystals are also often identified in patients with osteoarthritis, the most prevalent form of arthritis causing significant morbidity. RECENT STUDIES: The two primary hypotheses for generation of ePPi, export of inorganic pyrophosphate through the multipass transmembrane protein ANK and generation of ePPi by ectoenzyme activity, continue to be supported and better understood through animal models and study of families with CPPD deposition disease. SUMMARY: As the pathophysiology of crystal formation in both articular cartilage and synovial fluid is better understood, the opportunity for prevention and treatment of pathologic mineralization increases. In particular, a more complex understanding of the ank gene, ectoenzyme PC-1, and the transglutaminase enzyme family may eventually translate into therapeutic application for both BCP deposition and CPPD deposition disease.

Calcium Phosphates↗

PubMed2004

Differential effect of calcium phosphate and calcium pyrophosphate on binding of matrix metalloproteinases to fibrin: comparison to a fibrin-binding protease from inflammatory joint fluids.

The ability of calcium phosphate (CaP) and calcium pyrophosphate (CaPPi) to mediate matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) binding to fibrin was evaluated. Substrate gel electrophoresis (gelatin zymography) revealed that CaP bound MMP-2 and MMP-9, forming a high molecular weight aggregate with lowered electrophoretic mobility. Formation of the CaP : MMP aggregate was necessary for fibrin binding. In contrast, CaPPi did not aggregate MMPs and did not promote uptake of MMPs into fibrin. Scatchard analysis (Ca/P ratio) revealed that CaPPi (1.96) was chemically similar to calcium pyrophosphate dihydrate (2.00) compared to amorphous CaP (1.50) or crystalline CaP, hydroxyapatite (1.66). MMP : CaP interaction appeared to be electrostatic in nature as high salt concentration (NaCl > 150 mm) reduced binding. In contrast, two non-ionic detergents (Brij-35 and Tween-20) did not prevent MMP : CaP binding. MMP : CaP interaction did not involve the C-terminal MMP region because the specific tissue inhibitor of metalloproteinases (TIMPs) also did not block MMP : CaP interaction and fibrin binding. Although MMP : CaP binding could be decreased with albumin, this effect appeared non-specific due to the high albumin concentration required. High albumin concentration could also partially dissociate preformed MMP : CaP complexes. Interestingly, type I and type IV collagen substantially increased MMP : fibrin-binding activity, whereas denatured collagen, gelatin, did not. Inflammatory joint fluid from five patients also demonstrated similar MMP fibrin-binding activity consistent with CaP mediation. The relevance of these findings to CaP and CaPPi in the pathogenesis of crystal arthropathies such as basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate crystal disease (CPPD) is discussed.

Adult↗

PubMed1991

Calcium pyrophosphate dihydrate deposition disease: morphological and microanalytical features.

The light microscopic and polarization appearances of calcium pyrophosphate dihydrate crystal deposits in tissues are reviewed. In routine sections haematoxylinophilic crystalline deposits with a feathery or brush-like pattern are typical of calcium pyrophosphate dihydrate. Short rhomboidal crystals showing positive birefringence are seen on polarization; X-ray microanalytical and infrared spectroscopic data support the specificity of these appearances. The appearances of the crystal deposits in decalcified specimens are also described. We include six cases of calcium pyrophosphate dihydrate deposition within periarticular bone; to the best of our knowledge this has not previously been described.

Aged↗

PubMed1984

Non-invasive assessment of the presence and severity of cardiac amyloidosis. A study in familial amyloidosis with polyneuropathy by cross sectional echocardiography and technetium-99m pyrophosphate scintigraphy.

Twelve patients with familial amyloidosis with polyneuropathy were examined both by cross sectional echocardiography and by technetium-99m pyrophosphate scintigraphy to assess involvement of the heart non-invasively. All 12 patients had echocardiographic abnormalities. The most prominent findings were highly refractile myocardial echoes, thickened heart valves, and increased thickness of the heart walls. Four patients had abnormal myocardial uptake of technetium-99m pyrophosphate. The remaining eight had equivocal or no myocardial uptake and were considered to have normal scintigrams. A certain amount of amyloid is probably required to produce an abnormal scintigram, although lesions with less amyloid can evidently be identified by echocardiography. Neither the duration of polyneuropathy nor its severity showed any relation to the echocardiographic or scintigraphic findings. It is concluded that cross sectional echocardiography is superior to technetium-99m pyrophosphate scintigraphy in detecting cardiac involvement in familial amyloidosis with polyneuropathy and that these results may also be applicable to other forms of amyloidosis.

Adult↗

PubMed1977

Clinical, radiographic and pathologic abnormalities in calcium pyrophosphate dihydrate deposition disease (CPPD): pseudogout.

Clinical, radiographic and pathologic abnormalities in calcium pyrophosphate dihydrate deposition disease (CPPD) (pseudogout) are outlined in an investigation of 85 patients with definite or probable disease and available cadaveric and human surgical material. Pyrophosphate arthropathy produced distinctive roentgenographic abnormalities with were most frequent in the knee, wrist and metacarpophalangeal joints. Although the alterations superficially resembled osteoarthritis, they were frequently more severe and progressive with extensive fragmentation of bone, causing intra-articular osseous bodies. Pyrophosphate arthropathy occurred in unusual locations, such as the radiocarpal compartment of the wrist, elbow, and patellofemoral compartment of the knee. These characteristics allow the radiologist to suggest a probable diagnosis of CPPD even in the absence of articular calcification.

Aged↗

PubMed1995

Tumoral calcium pyrophosphate dihydrate deposition disease mimicking a cervical spine neoplasm: case report.

A case of tumoral calcium pyrophosphate dihydrate crystal deposition disease involving the upper cervical spine is reported. It presented clinically, radiographically, and by preliminary intraoperative pathological evaluation as a possible malignant soft tissue tumor. An aggressive resection of the lesion was performed. This case differs from previous reports of calcium pyrophosphate dihydrate crystal deposition disease of the cervical spine by the size, location, and radiographic appearance of the lesion. We suggest that radical surgical procedures should not be performed without consideration of this diagnosis in lesions with similar presentations. A brief review of spinal and tumoral calcium pyrophosphate dihydrate crystal deposition is presented.

Adult↗

PubMed1991

The scoring system for early technetium-99m pyrophosphate scintigraphy as a method of evaluation of limiting the myocardial infarct size by thrombolysis.

The usefulness of a scoring system with early technetium-99m pyrophosphate scintigraphy as a method for evaluating the efficacy of myocardial preservation after thrombolysis was studied. The mean time from the onset of acute myocardial infarction to injection of the tracer was 5.6 +/- 1.5 h (range 2.8 to 11.9 h). All 36 patients underwent successful recanalization. Patients with strongly positive technetium-99m pyrophosphate uptake in anterior acute myocardial infarction had a significantly lower regional ejection fraction and a significantly larger thallium-201 defect score than those with 2+ positive results in chronic stage. Similarly, in inferior acute myocardial infarction, the thallium-201 defect score was significantly larger in patients with strongly positive uptake than in those with 2+ and negative uptake scores. In conclusion, strongly positive results in early technetium-99m pyrophosphate scintigraphy within 12h after the onset of acute myocardial infarction may indicate failure in limiting the infarct size by coronary thrombolysis.

Aged↗

PubMed1996

Different extent of inhibition of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase both containing endogenous thiamine pyrophosphate, by some anticoenzyme analogues.

Inhibitory effects of 4'-oxythiamine pyrophosphate (OTPP) and tetrahydrothiamine pyrophosphate (ThTPP) on the purified bison heart pyruvate dehydrogenase complex (PDC) semisaturated with endogenous thiamine pyrophosphate (TPP) and 2-oxoglutarate dehydrogenase complex (OGDC) saturated about 85% with endogenous TPP, were studied. It has been established that the thiamine derivatives strongly inhibit not only the PDC apoenzyme moiety, but also the PDC holoenzyme moiety. The apparent I50 values for the holoenzyme were 0.006 microM and 0.046 microM for OTPP and ThTPP, respectively. The inhibition of the PDC is reversible. After removal of the anticoenzyme analogues by gel filtration the endogenous TPP within the PDC is retained as it is evidenced by complete recovery of the enzyme activity without added TPP. In contrast with the PDC, OGDC holoenzyme form is weakly inhibited by the anticoenzyme analogues.

Animals↗

PubMedDate not supplied

[Radiochemical purity and stability of Tc-99m-pyrophosphate].

INTRODUCTION: In vitro stability of 99mTc-radiopharmaceuticals is an important parameter of quality. In the paper the shelf-life of the bone-seeking radiopharmaceutical 99mTc(Sn)-pyrophosphate was examined under different experimental conditions. MATERIAL AND METHODS: The solution of pyrophosphate was prepared and dispensed into 2-ml fractions which were kept at-20 degrees C. In different time intervals the samples were thawed and labeled. The in vitro stability of labeled preparation was examined on the unprotected and the samples protected by nitrogen purge or by addition of solutions of ascorbic or genetisic acid of known concentrations. The content of 99mTc-pertechnetate was determined by paper chromatography. RESULTS AND DISCUSSION: In comparison with unprotected, samples protected by nitrogen purge exhibit better, but not satisfactory stability. Best results are obtained by using chemical stabilizers. The presence of 50-60 micrograms/ml of ascorbic acid keeps the content of 99mTc-pertechnetate below 5% during six hours even in solutions of high initial radioactive concentrations (up to about 814 MBq/ml). With this concentration of ascorbic acid, good results are obtained also by labeling inactive solutions kept at low temperatures during seven days. Genetisic acid is also efficient but its concentration should be about ten times higher. CONCLUSION: The in vitro stability of 99mTc(Sn)-pyrophosphate depends on the initial radioactive concentration of 99mTc and time after labeling. Best results were obtained when the preparation contained ascorbic acid as a chemical stabilizer. Its concentration in the range of 50-60 micrograms/ml is sufficient to keep the content of 99mTc-pertechnetate below 5% during six hours, both in freshly prepared samples and those kept at low temperatures for seven days.

Drug Stability↗

PubMed1975

Conformation of complexes of thiamin pyrophosphate with divalent cations as studied by nuclear magnetic resonance spectroscopy.

The binding of Ni-2+ and Mn-2+ to thiamin phosphate and thiamin pyrophosphate (thiamin-PP) has been compared with the binding of these ions to oxythiamin phosphate and oxythiamin pyrophosphate, analogues of thiamin in which the C-4 amino group has been replaced by an -OH group. The replacement of the NH2 group results in reduced basicity of N-1 of the pyrimidine ring of oxythiamine derivatives. The effects of pD, ligand concentration, and temperature on the binding of metal ions to N-1 have been studied by observing the metal ion-induced shifting and broadening of the C-6-H signal of these compounds. The results indicate the following: (a) the metal ion is held near N-1, resulting in a "folded" conformation, because of a favorable bonding interaction between N-1 and the metal ion rather than for general conformational reasons alone; and (b) the amount of "folded" conformation present in the different pyrophosphate complexes at neutral pH follows the order: Ni-2+-thiamin-PP greater than Mn-2+-thiamin-PP greater than Mn-2+-oxythiamin-PP and Ni-2+-oxythiamin-PP It is concluded that the strength of the metal ion-pyrimidine interaction in the "folded" conformation depends strongly both on the coordination affinity of the metal ion and on the basicity of N-1. Since the interaction of the phosphate-bound metal ion with the pyrimidine ring in the Mg-2+-thiamin-PP complex is probably weaker than the corresponding interaction in the Mn-2+-thiamin-PP complex, these results predict that the Mg-2+-thiamin-PP complex in solution, at neutral pH, exists predominantly in an "unfolded" conformation.

Ligands↗

PubMedDate not supplied

[Use of 99mTc-pyrophosphate and coronarography in the diagnosis of simultaneous myocardial infarct of the right and left cardiac ventricles].

Myocardial scintigraphy was performed using 99m-Tc-pyrophosphate in 50 patients with suspected coexisting right ventricular and left inferior ventricular heart infarction and in 50 patients with left inferior ventricular infraction only. In all survived patients additional selective coronarography was performed and in all died patients autopsy was performed. The aim of the study was to evaluate reliability of myocardial scintigraphy using 99m-Tc-pyrophosphate in the diagnosis of coexisting infarction of both heart ventricles. In a group of patients with coexisting right and left ventricular infarction (45 proved by coronarography, and 5 by autopsy), scintigraphic finding was confirmed in 46 (93%) patients. In all 50 patients with left inferior ventricular infarction, scintigraphic finding was confirmed in 48 of them by coronarography and in 2 by autopsy (100%). Of 4 patients with false negative scintigraphic finding 2 were treated with fibrinolytic therapy immediately after admission and in 2 diffuse occlusive changes were found on all three blood vessels by coronarography. It has been concluded that myocardial scintigraphy using 99m-Tc-pyrophosphate is a very sensitive (92%), specific (100%), exact (96%), simple and safe diagnostical method in detecting coexisting acute infarction of both heart ventricles.

Coronary Angiography↗

PubMedDate not supplied

[Phosphoribosyl pyrophosphate and its metabolic enzymes in the erythrocytes in certain forms of anemia].

Content of phosphoribosyl pyrophosphate and the activity of ribose phosphate pyrophosphokinase and AMP-pyrophosphorylase were studied in erythrocytes of healthy persons and of patients with various types of anemia. Deficiency of phosphoribosyl pyrophosphate and a decrease in the activity of enzymes studied were observed in erythrocytes under microspherocytic and hypoplastic anemia. The alterations correlated with impairments in energy metabolism. At the same time an activation of phosphoribosyl pyrophosphate enzymatic system and an increase of its content in erythrocytes did not depend on energy metabolism in Marchiafava--Micheli disease.

Adenine Phosphoribosyltransferase↗

PubMed1991

Activation of Escherichia coli pyruvate oxidase enhances the oxidation of hydroxyethylthiamin pyrophosphate.

The catalytic efficiency (kcat/Km) of Escherichia coli flavin pyruvate oxidase can be stimulated 450-fold either by the addition of lipid activators or by limited proteolytic hydrolysis. Previous studies have shown that a functional lipid binding site is a mandatory prerequisite for the in vivo functioning of this enzyme (Grabau, C., and Cronan, J. E., Jr. (1986) Biochemistry 25, 3748-3751). The effect of activation on the transient state kinetics of partial reactions in the overall oxidative conversion of pyruvate to acetate and CO2 has now been examined. The rate of decarboxylation of pyruvate to form CO2 and hydroxyethylthiamin pyrophosphate for both activated and unactivated forms of the enzyme is identical within experimental error. The decarboxylation step was measured using substrate concentrations of the enzyme in the absence of an electron acceptor. The pseudo-first order rate constant for the decarboxylation step is 60-80 s-1. The rate of oxidation of hydroxyethylthiamin pyrophosphate and concomitant enzyme-bound flavin reduction was analyzed by stopped-flow methods utilizing synthetic hydroxyethylthiamin pyrophosphate. The pseudo-first order rate for this step with unactivated enzyme was 2.85 s-1 and increased 145-fold for lipid-activated enzyme to 413 s-1 and 61-fold for the proteolytically activated enzyme to 173 s-1. The analysis of a third reaction step, the reoxidation of enzyme-bound FADH, was also investigated by stopped-flow techniques utilizing ferricyanide as the electron acceptor. The rate of oxidation of enzyme.FADH is very fast for both unactivated (1041 s-1) and activated enzyme (645 s-1). The data indicate that the FAD reduction step is the rate-limiting step in the overall reaction for unactivated enzyme. Alternatively, the rate-limiting step in the overall reaction with the activated enzyme shifts to one of the partial steps in the decarboxylation reaction.

Binding Sites↗

PubMed1978

Calcium pyrophosphate dihydrate crystal formation in model hydrogels.

Using powder x-ray diffraction analysis, we studied calcium pyrophosphate crystal formation in silica and gelatin gels was well as in comparable aqueous solutions. We demonstrated that the physiological salts, monoclinic and triclinic calcium pyrophosphate dihydrate can be formed in gels and that gels do affect the type of crystals formed from ions in solution. These observations support our hypothesis that calcium pyrophosphate dihydrate crystal deposition in joints is regulated by the physical chemical gel state of the connective tissue matrix.

Calcium Pyrophosphate↗

PubMed1986

Quantitative analysis of acute myocardial infarction using single photon emission computed tomography using technetium-99m pyrophosphate.

The usefulness of single photon emission computed tomography (SPECT) using technetium-99m pyrophosphate (99mTc-PPi) was evaluated in 15 patients with acute myocardial infarction. SPECT was performed with a rotating gamma camera after conventional planar images were made. Infarct size was measured from transaxial images of myocardial pyrophosphate uptakes. In each slice, the boundary was defined by subtracting 70 percent of the maximal counts and the number of voxels automatically counted. This subtraction rate was determined by phantom study and by comparing SPECT using 99mTc-PPi with thallium-201-gated myocardial scintigraphy (201Tl gated SPECT). The planar images showed diffuse uptakes in two of the 15 patients, and in these cases it was difficult to detect the infarct site. In contrast, SPECT images clearly imaged the infarct site consistent with the electrocardiographic findings, and they were definitely separated from the uptakes in the bones in all cases. Infarct size, ranging from 3.4 ml to 78.3 ml, correlated well with cumulative creatine kinase release (r = 0.84, p less than 0.01, y = 772x + 13900). Correlation of infarct size with peak serum creatine kinase level was also significant (r = 0.66, p less than 0.01, y = 10.6x + 693). In conclusion, SPECT with 99mTc-PPi is a useful means of investigating the spatial distribution of pyrophosphate uptake and of evaluating the size of myocardial infarction.

Aged↗

PubMed1988

[Osteoscintigraphy and dynamic studies of the kidneys using 99mTc-pyrophosphate in tumors of the retroperitoneal space in children].

Osteoscintigraphy and dynamic scintigraphy of the kidneys with 99mTc-pyrophosphate were used for investigation of 24 pediatric patients with tumorous involvement of the retroperitoneal space. Bone metastases were detected by osteoscintigraphy in 8 patients, pathological changes of the kidneys and urinary tract in 9 patients. Dynamic investigation of the kidneys with 99mTc-pyrophosphate performed in the first 20 min. after the drug injection showed disorders of renal evacuatory function of a varied degree of expression in all 24 patients. Dynamic investigation of the kidneys with 99mTc-pyrophosphate was not accompanied by an increase in radiation exposures therefore it was recommended at the first stage of radionuclide investigation of children with tumorous involvement of the retroperitoneal space followed by osteoscintigraphy.

Adult↗