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Acute uptake and chronic retention of infarct avid myocardial-seeking agents: 99Tcm-pyrophosphate and 125I-phenylphosphate.

The concentration of 125I-phenylphosphate (I phi PA), a long-lived bone-seeking radio-pharmaceutical (T1/2 biol = 962 days) that localizes in acute infarction (MI), was studied in 30 rats after ligation of the anterior descending coronary artery. At 23 h postMI, I phi PA was given intravenously to all animals, and five of this group received 99Tcm-pyrophosphate (99Tcm-pyro) intravenously. These five rats were sacrificed 2 h later and the content of I phi PA and 99Tcm-pyro activities was determined for normal and infarcted (INF) heart segments. There is a zone of INF that contains residual I phi PA which also concentrates 99Tcm-pyro consistently after MI. This zone may represent jeopardized myocardium which has not undergone complete necrosis.

Animals↗

Incidence, severity and clinical course of right ventricular involvement after acute inferior myocardial infarction; assessment by sequential 99Tcm-pyrophosphate scan and gated blood pool scan.

To evaluate the incidence, severity and clinical course of right ventricular (RV) involvement after acute inferior myocardial infarction (IMI), 78 patients (pts) with IMI were investigated by both 99Tcm-pyrophosphate (PYP) scan and gated blood pool scan (GBPS). GBPS was performed at admission and 10 days, whereas 99Tcm-PYP scan was performed at 3 to 6 days. RV uptake of PYP was demonstrated in 25 (32%) pts on 99Tcm-PYP scan and RV akinesis or moderate hypokinesis by GBPS was observed in 39 (50%) pts on the acute scan; 25 pts (Group A) with positive RV uptake and 14 pts (Group B) with no RV uptake. In the remaining 39 pts (Group C) had normal RV wall motion. Severely depressed RVEF improved nearly 10 points on the tenth day in Group A (from 30.8 +/- 12.3 to 40.9 +/- 6.7%, p less than 0.01) and Group B (from 35.6 +/- 8.2 to 44.5 +/- 10.5%, p less than 0.01), respectively. Group C showed normal RVEF (from 47.4 +/- 7.6 to 50.1 +/- 10.2%). Fourteen pts of 39 (Groups A and B) who had developed shock or hypotension improved strikingly after appropriate therapy except for one death during their hospital course. Our data demonstrated: some patients with RV dysfunction in IMI do not have severe necrosis as judged by PYP scanning, those with positive RV uptake and depressed RV function show a lower degree of recovery than those with no RV uptake, but start from a lower initial value of RV function, and the combination of 99Tcm-PYP scan and GBPS offers prognostic information in IMI with RV dysfunction.

Adult↗

Quantitation of skeletal muscle necrosis using 99Tcm-pyrophosphate with SPECT in a canine model.

Patients with acute arterial occlusion may suffer from significant muscle necrosis. It is important to determine the amount of regional muscle necrosis for prognostic purposes and evaluation of therapy. We have used technetium-99m-pyrophosphate (PPi) with single photon emission computed tomography (SPECT) to quantitate muscle necrosis. A canine gracilis muscle ischaemia model was used. PPi was injected 1.5 h before the muscle preparation was removed from the dog. SPECT was performed on the muscle preparations. An automatic edge detection program using the threshold technique determined the number of pixels with significant PPi activity in each transaxial section. Volume was calculated by summing the number of pixels with significant PPi activity and multiplying by the voxel size. The results were compared with quantitation using computerized planimetry with nitroblue tetrazolium staining (correlation coefficient = 0.93). PPi with SPECT is an accurate method for quantiating muscle necrosis.

Animals↗

Acute myocardial infarction delineated by noninvasive thallium-201/technetium-99m pyrophosphate tomography.

The purpose of this study was to validate different scintigraphic approaches for assessing acute myocardial infarctions. 201Tl, 99Tcm pyrophosphate (PPi) and combined 201Tl/99Tcm PPi tomograms were evaluated in 115 consecutive patients, in 85 of whom clinical examination revealed acute myocardial infarction. The overall sensitivity and specificity for infarct detection was 80% versus 56% for 201Tl alone, 61% versus 97% for 99Tcm PPi alone, and 100% each for the combined 201Tl/99Tcm PPi imaging. The sensitivity for nontransmural infarcts was 57% for 201Tl, 37% for 99Tcm PPi and 100% for combined imaging. The overlay of 201Tl and 99Tcm PPi images increases the observer's confidence in the diagnosis and provides better localization of the infarction. 201Tl alone could localize the infarction in 80%, 99Tcm PPi alone in 49% and 201Tl/99Tcm PPi in 100% of the cases. ECG and 201Tl/99Tcm PPi tomography concurred upon infarct localization in 98% of the patients. Based on the 201Tl/99Tcm accumulation pattern, 94% of the Q-wave infarctions were judged to be transmural and 83% of the non-Q-wave infarctions were judged to be nontransmural. It is concluded that combined 201Tl/99Tcm PPi tomography is highly accurate for determining the presence and location of acute myocardial infarction. This technique appears to be superior to studies where only one radioisotope is used.

Adult↗

Quantification of skeletal muscle necrosis in the lower extremities using 99Tcm pyrophosphate with single photon emission computed tomography.

No non-invasive quantitative method is currently available for measuring the amount of regional skeletal muscle necrosis in humans. A threshold method using 99Tcm pyrophosphate (PPi) with single photon emission computed tomography (SPECT) has been reported to quantify muscle necrosis successfully in a canine model. This method has been modified to measure muscle necrosis in the lower extremities of human patients. Modifications include adding background subtraction and using the contralateral unaffected lower extremity as background region. A region of interest was also manually drawn around the affected lower extremity muscle to exclude the tibia. In order to identify the group of patients with no significant necrosis and with diffuse hyperaemia, nine control subjects were studied. The variance of the counts within the pixels of the lower extremities was 132 (S.D. = 27). A variance of greater than 159 was considered as being significant for necrosis. Thirteen patients were studied. Six patients had significant muscle necrosis (462 ml, S.D. = 280 ml). All except one patient (who had a small amount of muscle necrosis) developed foot drop. Seven patients had no significant necrosis. All patients had normal ankle dorsiflexion. It is possible to quantify regional muscle necrosis using PPi with SPECT. Volume of necrosis determined by this method can also predict clinical outcome.

Aged↗

Efficacy of technetium Tc 99m pyrophosphate imaging in patients with equivocal myocardial infarction.

We studied the efficacy of technetium Tc 99m pyrophosphate imaging in patients with equivocal evidence of acute myocardial infarction. Only patients with positive enzyme findings (regardless of ECG findings) had scans with greater than or equal to 2+ focal uptake. None of 26 patients with negative or equivocal enzyme findings (regardless of ECG findings) had greater than 2+ diffuse uptake. These results support the contention that infarct-avid imaging has little clinical utility in patients with equivocal evidence of myocardial infarction.

Clinical Enzyme Tests↗

Genetic regulation mediated by thiamin pyrophosphate-binding motif in Saccharomyces cerevisiae.

The expression of genes of Saccharomyces cerevisiae encoding the enzymes involved in the metabolism of thiamin (THI genes) is co-ordinately repressed by exogenous thiamin and induced in the absence of thiamin. In this yeast THI regulatory system acts mainly at the transcriptional level, thiamin pyrophosphate (TDP) seems to serve as a corepressor, and genetic studies have identified three positive regulatory factors (Thi2p, Thi3p and Pdc2p). We found in a DNA microarray analysis that the expression of THI genes increased 10- to 90-fold in response to thiamin deprivation, and likewise, the expression of THI2 and THI3 increased 17-fold and threefold, respectively. After transfer from repressing to inducing medium, the promoter activity of both THI2 and THI3 increased in parallel with that of PHO3, one of THI genes. The stimulation of THI3 promoter activity was diminished by deletion of THI3, indicative of the autoregulation of THI3. The THI genes were not induced when THI2 was expressed from the yeast GAL1 promoter in a thi3Delta strain or when THI3 was expressed in a thi2Delta strain, suggesting that Thi2p and Thi3p participate simultaneously in the induction. When mutant Thi3p proteins lacking TDP-binding activity were produced in the thi3Delta strain, THI genes were expressed even under thiamin-replete conditions. This result supports the hypothesis that Thi3p senses the intracellular signal of the THI regulatory system to exert transcriptional control. Furthermore, Thi2p and Thi3p were demonstrated to bind each other and this interaction was partially diminished by exogenous thiamin, suggesting that Thi2p and Thi3p stimulate the expression as a complex whose function is disturbed by TDP bound to Thi3p. We discuss the possibility that the induction of THI genes is triggered by the activation of the complex attributed to decrease in intracellular TDP and the elevated complex in the autoregulatory fashion further upregulates THI genes. This is the first report of the involvement of the TDP-binding motif in genetic regulation.

Cell Nucleus↗

Enhancement of intracellular 5-phosphoribosyl 1-pyrophosphate levels as a major factor in the 6-azauridine-induced stimulation of carbamoyl phosphate synthesis in mouse spleen slices.

Brief exposure to 6-azauridine stimulates the production of carbamoyl phosphate for de novo pyrimidine biosynthesis in vitro in slices of haematopoietic spleen from anaemic mice (preceding paper). In studies of the underlying mechanism for this response we turned our attention to changes in the level of substrates and effectors for carbamoyl-phosphate synthetase II. Intermediates of the orotic acid pathway and 6-azauridine had little effect on the synthetase activity in vitro. 6-Azauridine 5'-monophosphate (6-AzaUMP) stimulated synthetase II, possibly in an allosteric manner. However, in view of the potency as an activator and the tissue levels, 6-azaUMP may be only partially responsible for the stimulation. Adenine nucleotide levels in the tissue showed only minor changes after brief exposure (15 min) to 6-azauridine. The level of UTP and UDP, potent inhibitors for synthetase II, showed no significant change. The level of 5-phosphoribosyl 1-pyrophosphate (PPRibP), a potent positive effector for the synthetase II, showed a more than 1.5-fold increase after 15 min. The relative importance of these factors was evaluated by assay of the synthetase, partially purified from mouse spleen, under simulated conditions in vitro. The results indicated that the enhanced level of PPRibP played a major role in increasing the production of carbamoyl phosphate. In Ehrlich ascites cells in vitro, where 6-azauridine did not increase carbamoyl phosphate production, the basal PPRibP level was high (range over 0.1 mM) and the changes in the level, brought about by the analogue, were relatively small.

Animals↗

A case of the calcium pyrophosphate dihydrate (CPPD) deposition disease without condylar destruction of the temporomandibular joint.

The case of calcium pyrophosphate dihydrate (CPPD) deposition disease, which occurred at a rare site in the temporomandibular joint (TMJ), is presented. A 48-year-old woman noted swelling in the preauricular area of her left cheek, which restricted her mouth opening. Radiological examination revealed a radiopaque lesion in the posterior and medial area of the left space of the TMJ. During the operation, the superior joint space was entirely filled with a solid and whitish-gray mass of chalky appearance. The lesion was partly attached to the retrodiscal tissue without any destructive change around the condyle and mandibular fossa. Histological examination revealed the foci of amorphous crystalline material to contain rhomboidal, rod and needle shaped crystals, which had cartilaginous tissue in the dense fibrous background admixed with chronic inflammatory cells and foreign body-type giant cells. The crystals were positive for von Kossa's stain and spectral peaks for phosphorus and calcium were evident by electron probe microanalysis, thus suggesting the presence of CPPD.

Calcium Pyrophosphate↗

Mutation thi81 causing a deficiency in the signal transduction of thiamine pyrophosphate in Saccharomyces cerevisiae.

We isolated a strain carrying a recessive constitutive mutation (thi81) for the expression of thiamine metabolism in Saccharomyces cerevisiae. The thi81 mutant exhibits significant thiamine transport, thiamine-repressible acid phosphatase (T-rAPase) activities and significant activities of enzymes involved in thiamine biosynthesis which are repressed in the wild-type strain in medium supplemented with thiamine (2 x 10(-7) M). The thi81 mutant exhibited the same level of thiamine pyrophosphokinase activity and intracellular thiamine pyrophosphate concentration as the wild-type strain in medium supplemented with exogenous thiamine. The mutant strain constitutively produced PHO3 mRNA encoding T-rAPase in medium supplemented with thiamine. These results suggest that the thi81 mutant lacks a negative factor involved in the regulation of the genes encoding proteins involved in yeast thiamine metabolism.

Acid Phosphatase↗

Local articular amyloid deposition in pyrophosphate arthritis. Histological aspects.

A material of 15 cases of histologically examined pyrophosphate arthritis (hip-joint: 7 cases, knee joint: 8 cases) is presented. Amyloid deposits were found in 14 cases and chondromatosis in the subsynovial connective tissue of all the cases. The significance of this high, not previously reported, coincidence is discussed, together with various pathogenetic possibilities, as related to the theories of the genesis of amyloid substance.

Aged↗

Structure of the eukaryotic thiamine pyrophosphate riboswitch with its regulatory ligand.

Riboswitches are untranslated regions of messenger RNA, which adopt alternate structures depending on the binding of specific metabolites. Such conformational switching regulates the expression of proteins involved in the biosynthesis of riboswitch substrates. Here, we present the 2.9 angstrom-resolution crystal structure of the eukaryotic Arabidopsis thaliana thiamine pyrophosphate (TPP)-specific riboswitch in complex with its natural ligand. The riboswitch specifically recognizes the TPP via conserved residues located within two highly distorted parallel "sensor" helices. The structure provides the basis for understanding the reorganization of the riboswitch fold upon TPP binding and explains the mechanism of resistance to the antibiotic pyrithiamine.

3' Untranslated Regions↗

Pathway of thiamine pyrophosphate synthesis in Micrococcus denitrificans.

The pathway of thiamine pyrophosphate (TPP) biosynthesis, which is formed either from exogeneously added thiamine or from the pyrimidine and thiazole moieties of thiamine, in Micrococcus denitrificans was investigated. The following indirect evidence shows that thiamine pyrophosphokinase (EC 2.7.6.2) catalyzes the synthesis of TPP from thiamine: (i) [35S]thiamine incubated with cells of this microorganism was detected in the form of [35S]thiamine; (ii) thiamine gave a much faster rate of TPP synthesis than thiamine monophosphate (TMP) when determined with the extracts; and (iii) a partially purified preparation of the extracts can use thiamine, but not TMP, as the substrate. The activities of the four enzymes involved in TMP synthesis from pyrimidine and thiazole moieties of thiamine were detected in the extracts of M. denitrificans. The extracts contained a high activity of the phosphatase, probably specific for TMP. After M. denitrificans cells were grown on a minimal medium containing 3 mM adenosine, which causes derepression of de novo thiamine biosynthesis in Escherichia coli, the activities of the four enzymes involved with TMP synthesis, the TMP phosphatase, and the thiamine pyrophosphokinase were enhanced two- to threefold. These results indicate that TPP is synthesized directly from thiamine without forming TMP as an intermediate and that de novo synthesis of TPP from the pyrimidine and thiazole moieties involves the formation of TMP, followed by hydrolysis to thiamine, which is then converted to TPP directly. Thus, the pathway of TPP synthesis from TMP synthesized de novo in M. denitrificans is different from that found in E. coli, in which TMP synthesized de novo is converted directly to TPP without producing thiamine.

Adenosine↗

Thiamine pyrophosphate requirement for o-succinylbenzoic acid synthesis in Escherichia coli and evidence for an intermediate.

Cell-free extracts of various strains of Escherichia coli synthesize the menaquinone biosynthetic intermediate o-succinylbenzoic acid (OSB) when supplied with chorismic acid, 2-ketoglutaric acid, and thiamine pyrophosphate (TPP). To assay for OSB synthesis, 2-[U-14C]ketoglutaric acid was used as substrate, and the synthesized OSB was examined by radiogas chromatography (as the dimethyl ester). [U-14C]Shikimic acid also gave rise to radioactive OSB if the cofactors necessary for enzymatic conversion to chorismic acid were added. Use of 2-[1-14C]ketoglutaric acid does not give rise to labeled OSB. In the absence of TPP during the incubations, OSB synthesis was much reduced; these observations are consistent with the proposed role for the succinic semialdehyde-TPP anion as the reagent adding to chorismic acid. Extracts of cells from menC and menD mutants did not form OSB separately, but did so in combination. There was evidence for formation of a product, X, by extracts of a menC mutant incubated with chorismic acid, TPP, and 2-ketoglutaric acid; X was converted to OSB by extracts of a menD mutant. It appears that the intermediate, X, is formed by one gene product and converted to OSB by the second gene product.

Chorismic Acid↗

Characterization of two kinases involved in thiamine pyrophosphate and pyridoxal phosphate biosynthesis in Bacillus subtilis: 4-amino-5-hydroxymethyl-2methylpyrimidine kinase and pyridoxal kinase.

Two Bacillus subtilis genes encoding two proteins (currently annotated ThiD and YjbV) were overexpressed and characterized. YjbV has 4-amino-5-hydroxymethyl-2-methylpyrimidine and 4-amino-5-hydroxymethyl-2-methylpyrimidine pyrophosphate kinase activity and should be reannotated ThiD, and B. subtilis ThiD has pyridoxine, pyridoxal, and pyridoxamine kinase activity and should be reannotated PdxK.

Bacillus subtilis↗

Diagnosis of calcium pyrophosphate dihydrate crystal deposition disease: ultrasonographic criteria proposed.

OBJECTIVE: To investigate by high frequency ultrasonography the appearance of calcium pyrophosphate dihydrate (CPPD) calcifications, in the most commonly affected sites in CPPD disease, and the relationship between ultrasonographic CPPD deposits and the presence of CPPD crystals in synovial fluid. METHODS: Three ultrasonographic patterns of CPPD calcification were identified and 11 patients enrolled. A control group comprised 13 patients with no evidence of CPPD deposits. Synovial fluid was aspirated from all patients and controls and examined for identification of crystals. All patients underwent a standard radiography examination at the same sites investigated by ultrasound. RESULTS: In all patients with ultrasonographically defined CPPD deposits, CPPD crystals were found in the synovial fluid. In two cases, standard radiographic examination did not show evidence of the calcific deposits that were identified by ultrasonography. CPPD crystals were not found in the synovial fluid of controls. In four control group patients, ultrasonography identified calcifications defined as deposits of another nature. CONCLUSIONS: The ultrasonographic pattern used in this study for the diagnosis of CPPD disease demonstrated a very high correlation with the presence of CPPD crystals in synovial fluid. Ultrasonography demonstrated a sensitivity and specificity at least equal to that of radiography in identifying CPPD crystal calcifications.

Aged↗

Synthesis and concentration of 5-phosphoribosyl-1-pyrophosphate in erythrocytes from patients with Down's syndrome.

Plasma urate levels and erythrocyte glucose-6-phosphate dehydrogenase activity were not significantly different in patients with Down's syndrome when compared with control subjects with mental retardation. No significant difference was found in 5-phosphoribosyl-1-pyrophosphate (PRPP) concentration and synthesis of PRPP in erythrocytes from glucose between subjects with Down's syndrome and controls. The purine metabolism of Down's syndrome is discussed.

Adolescent↗

Pyrophosphate arthropathy in hypophosphatasia.

The association of hypophosphatasia and pyrophosphate arthropathy in an adult patient has been described on 1 previous occasion. We report a further 2 patients with this disease combination. One patient suffers from the type of hypophosphatasia that presents in adult life, with fractures that are either spontaneous or the result of minimal trauma. The other patient suffered from the severe type of hypophosphatasia that presents in infancy but survived longer than is usual; the necropsy findings on this patient are reported.

Arthritis↗