Skeletal Uptake Research Articles

Prolonged suppression of glucose metabolism causes insulin resistance in rat skeletal muscle.

To determine whether an impairment of intracellular glucose metabolism causes insulin resistance, we examined the effects of suppression of glycolysis or glycogen synthesis on whole body and skeletal muscle insulin-stimulated glucose uptake during 450-min hyperinsulinemic euglycemic clamps in conscious rats. After the initial 150 min to attain steady-state insulin action, animals received an additional infusion of saline, Intralipid and heparin (to suppress glycolysis), or amylin (to suppress glycogen synthesis) for up to 300 min. Insulin-stimulated whole body glucose fluxes were constant with saline infusion (n = 7). In contrast, Intralipid infusion (n = 7) suppressed glycolysis by approximately 32%, and amylin infusion (n = 7) suppressed glycogen synthesis by approximately 45% within 30 min after the start of the infusions (P < 0.05). The suppression of metabolic fluxes increased muscle glucose 6-phosphate levels (P < 0.05), but this did not immediately affect insulin-stimulated glucose uptake due to compensatory increases in other metabolic fluxes. Insulin-stimulated whole body glucose uptake started to decrease at approximately 60 min and was significantly decreased by approximately 30% at the end of clamps (P < 0.05). Similar patterns of changes in insulin-stimulated glucose fluxes were observed in individual skeletal muscles. Thus the suppression of intracellular glucose metabolism caused decreases in insulin-stimulated glucose uptake through a cellular adaptive mechanism in response to a prolonged elevation of glucose 6-phosphate rather than the classic mechanism involving glucose 6-phosphate inhibition of hexokinase.

Tissue distribution of transplanted fetal liver cells in the human fetal recipient

OBJECTIVE: Our purpose was to study the tissue distribution and concentrations of transplanted fetal liver cells in the human fetus. STUDY DESIGN: Radiolabeled indium 111 fetal liver cells were injected in vivo under ultrasonographic guidance into 10 normal fetuses (13 to 17 weeks of gestation) before a prostaglandin abortion. Six fetuses were injected intraperitoneally and four intracardially. Another two fetuses serving as controls were injected with indium-labeled maternal plasma. The fetuses were all alive, at least until 6 hours before expulsion. After expulsion the fetuses were dissected, and radioactivity was measured in various fetal tissues. Results for each tissue were expressed as percentages of the total injected dose. RESULTS: Significantly greater uptake of fetal liver cells in the liver, spleen, thymus, kidney, lung, and placenta was obtained with intracardiac than with intraperitoneal injection. Skeletal uptake did not differ in relation to mode of administration. With intracardiac injection uptake was greater in such parenchymal organs as the liver, spleen, and thymus (4.9%, 4.0%, and 3.9%, respectively). Uptake in the rib, clavicle, humerus, and sternum was 2.7%, 1.8%, 2.1%, and 1.1%, respectively. Placental uptake was 0.1%. The intracardiac route yielded a higher concentration of cells in different fetal organs than did injection of only radiolabeled maternal plasma, suggesting an active uptake of cells in different fetal hematopoietic organs. CONCLUSION: The mode of administration of fetal liver cells seems to be a major determinant of donor cell concentration in the transplanted human fetus and may be a significant determinant of the rate of successful engraftment. (Am J Obstet Gynecol 1997;176:49-53.)

Crosstalk of the Heart and Periphery: Skeletal and Cardiac Muscle as Therapeutic Targets in Heart Failure

Heart failure syndrome is initiated as the body's metabolic needs temporarily exceed the pumping capacity of the heart. In most cases, this phenomenon tends to occur during physical exercise. Although not always subjectively recognized, limited exercise capacity remains the clinical hallmark of congestive heart failure. It can be measured objectively as reduced skeletal muscle performance and maximal whole-body oxygen uptake, which are not necessarily explained by central haemodynamic abnormalities. In fact, the initial cardiac condition sets forth a series of peripheral adaptations that are potentially life-saving during acute decompensation but become disadvantageous and symptom-generating in stable heart failure. Inodilator drugs were theoretically ideal to revert the adverse haemodynamic crosstalk between the heart and periphery. However, these drugs failed to improve prognosis in congestive heart failure, whereas drugs that did so showed typically unimpressive haemodynamic effects. Exercise therapy has recently emerged as a safe and effective way to enhance physical performance and subjective well-being in congestive heart failure. A dual therapeutic approach is suggested, consisting of exercise training to improve the periphery and the use of cardioprotective drugs to limit cardiac cellular damage from neurohormonal activation.

Effects of continuous percutaneous estradiol administration on skeletal turnover in postmenopausal women: a 1-year prospective controlled study

The aim of this study was to investigate the short and long term effects of continuous percutaneous administration of estradiol (E2) cream on skeletal turnover in women in surgical postmenopause. Forty women were randomly divided into two groups, one treated with a single daily application of 3 mg/day E2 cream continuously for 12 months, the other receiving placebo cream. Forearm densitometry was performed before and at the end of treatment. Serum E2, osteocalcin (BGP), alkaline posphatase (AP) and urinary N-telopeptide of type I collagen (NTX) were also measured at baseline, month 4 and 12 of the protocol. At month 4, bone turnover was also assessed by evaluating 99mtechnetium-methylene diphosphonate ( 99mTc-MDP) skeletal uptake. Changes in E2, BGP, AP and NTX as well as 99mTc-MDP skeletal uptake in hormone group vs. placebo were significant after 4 months of treatment. At month 12, proximal site densitometry showed no variation in either group whereas the percentage of variation in distal site measurements resulted significantly different with an increase in the hormone group and a reduction in the placebo group. In conclusion continuous percutaneous administration of E2 cream was effective in rapidly reducing bone turnover in postmenopausal women and in counteracting the accelerated postmenopausal bone loss.

Age-related changes in the global skeletal uptake of technetium-99m methylene diphosphonate in healthy women.

A short-term evaluation of global skeletal uptake (GSU) of technetium-99m methylene diphosphonate (MDP) was performed in 40 healthy female subjects with a wide age range in order to investigate the clinical performance of the technique and to detect the age-related changes in bone turnover. The results obtained were compared with measurements of the main biochemical markers of skeletal metabolism. We found that GSU increases progressively with age, independently of concomitant changes in renal function; significant correlations with biochemical markers of bone formation were also found. Therefore, the method appears to provide useful information concerning the bone turnover rate, and is also applicable to elderly people owing to its simplicity.

Accumulation of 99mTc-MIBI in bone marrow.

99mTc-MIBI (Sestamibi) was originally developed for myocardial perfusion studies. The agent also may be used for the depiction and characterization of tumors. Performing such examinations has shown uptake in skeletal structures in several patients suggesting bone engagement of the disease which later was excluded. Retrospective evaluation of 44 examinations with 99mTc-MIBI performed in order to localize diseased parathyroid in patients with suspected hyperparathyroidism showed skeletal activity in 21 (48%) patients. Although these patients represent a selected group, the observation indicates a mechanism for skeletal accumulation of this radiopharmaceutical. Evaluation of another 13 normocalcemic patients undergoing whole-body registration for malignancy staging or to assess lower extremity ischemia with 99mTc-MIBI showed skeletal activity in 6 (46%) patients. Complementary mouse experiments confirmed skeletal uptake of 99mTc-MIBI, where most of the activity is taken up by the red bone marrow. It is concluded that homogeneous, diffuse weak skeletal activity at examination with 99mTc-MIBI is a normal finding and does not indicate malignancy.

Metformin in noninsulin-dependent diabetes mellitus.

Metformin is an oral antihyperglycemic agent that is approved by the Food and Drug Administration for the treatment of noninsulin-dependent diabetes mellitus. It differs from the sulfonylureas in that it is does not enhance insulin secretion and normally does not produce hypoglycemia. Metformin acts to decrease preprandial and postprandial blood glucose concentrations by increasing skeletal muscle uptake of glucose, decreasing gluconeogenesis, and decreasing absorption of glucose. The addition of metformin to maximum dosages of a sulfonylurea may synergistically improve glucose control. The drug may offer other potential benefits, such as weight loss or minimal weight gain, improved blood flow in patients with peripheral vascular disease, reduction of tissue plasminogen activator inhibitor, and improved lipid profiles. It is relatively safe if taken appropriately. Its most common side effects are gastrointestinal (nausea, diarrhea, anorexia), metallic taste, and vitamin B12 malabsorption. Lactic acidosis may also occur, but it is rare if metformin is avoided in patients with contraindications to its use. With careful monitoring, the agent may be considered for the initial treatment of obese patients who fail dietary measures, and those whose disease is refractory to maximum dosages of sulfonylureas or who do not tolerate them.

Applications of XRF, NAA and low-kV radiographic techniques in the study of body composition and diseased tissue

Members of this group have responded to a number of challenging health issues by attempting to devise sensitive XRF, NAA and low-kV radiographic measurement systems foboth in vivo and in vitro applications. These studies are generally either of toxicological importance, examine potential for diagnosing the presence of disease, or offer effective means for monitoring potentially harmful side-effects of therapy. Particular examples include the in vivo XRF investigation of human skeletal uptake of Pb in working and living environments, in vivo XRF monitoring of elevated levels of Fe in skin (indicating the presence of an undesirable side-effect of the treatment of thalassaemia), in vivo NAA monitoring of elevated levels of Al in bone (indicating an undesirable side-effect of the treatment of chronic renal failure) and in vitro characterization, by means of low-kV imaging, of a range of calcification parameters in healthy and diseased breast tissue. The latter investigation has been conducted in association with an in vitro NAA study of concentrations of trace elements in the same types of tissue. Figures of merit for the various measurement systems have been obtained in terms of minimum detectable levels and concentrations (MDL's and MDC's) and where applicable, image related parameters.

Kit preparation of153Sm-EDTMP and factors affecting radiochemical purity and stability

A fast kit method was developed for the production of153Sm-EDTMP in two steps avoiding the use of nitric acid, evaporation and sterilization of the final solution by autoclave. Methods of analysis for the determination of chemical and radiochemical purity in the radiopharmaceutical solution were established. Factors affecting radiochemical purity and stability of the complex as the molar ratio of EDTMP/Sm, concentration of phosphate buffer and neutralization of EDTMP prior kit preparation were also analyzed. The use of this radiopharmaceutical in rabbits and patients showed selective skeletal uptake.

Case report: Ossifying metastases from carcinoma of the large bowel demonstrated by bone scintigraphy

A 65-year-old man was admitted with abdominal pain. He had a history of resection of a carcinoma of the sigrnoid colon two years previously, after which he had two laparotomies for episodes of intestinal obstruction, secondary to peritoneal and omental metastases. On this admission an abdominal film showed no evidence of intestinal obstruction but several amorphous clusters of calcific density were noted in the lower abdomen (Fig. 1) which had not been present on previous abdominal films. The patient was also complaining of back pain and a bone scan was performed to exclude bone metastases. This showed no abnormal skeletal uptake but very high uptake of tracer in the dense soft tissue opacities (Fig. 2). A limited CT scan was undertaken to establish the site of these lesions, demonstrating most to be in the anterior abdominal wall and left psoas (Fig. 3). The anterior abdominal wall lesions were palpable, lying within taparotomy scars, and one of these was biopsied two days later. Histologically, the fragments consisted of connective tissue which was quite densely infiltrated by metastatic adenocarcinoma. The tttmour was forming occasional glands and there was also abundant metaplastic bone formation. The bony trabeculae appeared orderly, and there was also a little osteoid. Clusters of tumour cells and also extracellular mucin were both associated with bone formation. It was concluded that this showed metastastic adenocarcinoma with metaplastic bone formation. Figure 4 shows a representative sample of the specimen. Review of the report on the microscopy of the primary tumour, excised two years previously, revealed that this too had shown adenocarcinoma 'with a few areas of mucin secretion, and in much of the tumour there is striking metaplasfic ossification'.

Anabolic effects of fluoride on bone

Fluoride exerts a biphasic action at the level of osteoblasts, on bone mineral, on bone structure and function, and in the treatment of osteoporosis. At low circulating concentrations, skeletal uptake of fluoride is limited and the effects are beneficial. At higher concentrations and greater skeletal uptake, fluoride may cause the formation of abnormally mineralized bone of impaired quality. A new treatment program entailing intermittent slow release sodium fluoride (SR-NaF) with continuous calcium citrate may capture desirable qualities of fluoride without toxic effects, and be therapeutically efficacious in postmenopausal osteoporosis.

Poor Renal Uptake of Tc-99m DMSA and Tc-99m MDP in a Patient With Fanconi Syndrome and Near Normal Glomerular Filtration Rate

The authors present a patient with Fanconi syndrome who demonstrated poor renal uptake of Tc-99m DMSA and high urinary concentration of the tracer. Tc-99m DTPA imaging was normal and the creatinine clearance was only minimally decreased. These findings suggest that Tc-99m DMSA may be accumulated in the kidney by glomerular filtration and subsequent tubular reabsorption. A Tc-99m MDP bone scan showed faint renal uptake, as well as diffuse high skeletal uptake, particularly in the spine, demonstrating that the metabolic bone disease associated with Fanconi syndrome can be one of the causes of poor renal visualization on a bone scan.

Intake and metabolism of fluoride.

The purpose of this paper is to discuss the major factors that determine the body burden of inorganic fluoride. Fluoride intake 25 or more years ago was determined mainly by measurement of the concentration of the ion in the drinking water supply. This is not necessarily true today because of ingestion from fluoride-containing dental products, the "halo effect", the consumption of bottled water, and the use of water purification systems in the home. Therefore, the concentration of fluoride in drinking water may not be a reliable indicator of previous intake. Under most conditions, fluoride is rapidly and extensively absorbed from the gastrointestinal tract. The rate of gastric absorption is inversely related to the pH of the gastric contents. Overall absorption is reduced by calcium and certain other cations and by elevated plasma fluoride levels. Fluoride removal from plasma occurs by calcified tissue uptake and urinary excretion. About 99% of the body burden of fluoride is associated with calcified tissues, and most of it is not exchangeable. In general, the clearance of fluoride from plasma by the skeleton is inversely related to the stage of skeletal development. Skeletal uptake, however, can be positive or negative, depending on the level of fluoride intake, hormonal status, and other factors. Dentin fluoride concentrations tend to increase throughout life and appear to be similar to those in bone. Research to determine whether dentin is a reliable biomarker for the body burden of fluoride is recommended. The renal clearance of fluoride is high compared with other halogens. It is directly related to urinary pH. Factors that acidify the urine increase the retention of fluoride and vice versa. The renal clearance of fluoride decreases and tissue levels increase when the glomerular filtration rate is depressed on a chronic basis.

99Tcm-MDP global skeletal uptake and markers of bone metabolism in patients with bone diseases.

99Tcm-methylene diphosphonate (MDP) global skeletal uptake (4 h GSU) was determined by quantitative measurement of activity on bone scan images 4 h after injection in whole skeleton regions of interest (ROI) in 16 normal subjects, in five patients with hypertrophic pulmonary osteoarthropathy (HPO) and in 12 with Paget's disease. Values were correlated with those of whole body retention (24 h WBR), and serum bone gla protein (BGP), i.e. osteocalcin, alkaline phosphatase (AP) and type 1 procollagen (P1CP). They were 40% higher in HPO than in the normal controls, while in Paget's disease they increased more in polyostotic than in monostotic patients. A statistically significant difference was noted between 4 h GSU and 24 h WBR values in the two groups of patients compared with the controls. Of the bone metabolism markers, serum AP and P1CP were higher in the patients and positively correlated with their enhanced 4 h GSU values, whereas BGP was always within the normal range. This method may thus be regarded as a useful way of simultaneously determining bone 99Tcm-MDP uptake and altered bone turnover sites, especially in patients with systemic bone disease.

Does decreased skeletal uptake of 99mTc-methylene bisphosphonate in irradiated bone indicate the absence of bone metastases?

Reduced uptake of 99mTc-methylene bisphosphonate ( 99mTc-MBP) was found in irradiated bone in all of 13 tumour-free patients who had undergone radiotherapy (30–40 Gy) due to seminoma 3–8 years prior to bone scintigraphy. Decreased uptake of 99mTc phosphate compounds can not per se be interpreted as a sign of absence of metastases or reduced tumour burden.

Skeletal Uptake and Lifetime Retention of 90 Sr and 226 Ra in Beagles

Skeletal uptake and retention of graded doses of ingested or injected 90Sr and injected 226Ra have been studied in 863 beagles; measurements of skeletal burden were made up to a maximum lifetime of 18.5 years. Doses ranged from 0 in 162 controls to levels that markedly reduced life span. Skeletal uptake of the administered doses averaged 2 to 2.3% for 90Sr fed to 388 beagles from midgestation to age 540 days, 33 to 35% for 45 dogs that were given single intravenous injections of 90Sr at age 540 days, and 37 to 45% for 226Ra given in eight fortnightly intravenous injections to 253 dogs from age 435 to 540 days. Skeletal retention was evaluated from the time when uptake ended until death, which occurred, on the average, at 14 to 14.5 years for the lower levels. Simple two-parameter power functions of the form SB(t) = at-b, with SB the skeletal burden, t the time after beginning of intake, and a and b fitted parameters, but corrected for radioactive decay, were used to describe the whole-skeleton retention of deposited 90Sr or 226Ra, as well as in 17 skeletal subgroups. The negative logarithmic slope, b, of these power functions for whole skeleton was about the same for both 90Sr and 226Ra, with an average value of 0.30 +/- 0.05 SD, indicating a common clearance mechanism. The lifetime average cumulative absorbed dose to irradiated skeleton varied from 0.38 to 107 Gy for beta rays in the 90Sr studies and from 0.94 to 167 Gy for alpha particles in the 226Ra studies. Daily dose rates to the skeleton for singly injected 90Sr fell rapidly after injection and declined to about 10% of the peak values late in life. Rates declined more slowly to 40-50% of peak values in other treatment groups. The time-weighted average dose rate for fed 90Sr and injected 226Ra was a robust measure that declined only about 20% late in life compared to peak values. The lifetime average dose rate varied from 0.08 to 133 mGy day-1 for the 90Sr studies and from 0.21 to 162 mGy day-1 for the 226Ra studies. Lifetime doses to mandible and cervical vertebrae for the intermediate dose levels of fed 90Sr were calculated to be about 40% higher than the skeletal average.

A Generic Age-Specific Biokinetic Model for Calcium-like Elements

Publication No. 56 of the International Commission on Radiological Protection (ICRP) introduces a generic model structure to address the age-specific biokinetics of "calcium-like" radionuclides, including Sr, Ba, and Ra, and less complete physiological analogues of Ca, such as Pb and U, in humans. This paper outlines the conceptual basis for the model, summarises the selection of parameter values for the alkaline earth elements, and describes special features of the model included for consideration of Pb. The model differs in form from the alkaline earth model for adult man described in Publication No. 20 of the ICRP but depicts similar processes of skeletal uptake and removal. In contrast to the earlier alkaline earth model, parameter values are age specific, redeposition of biologically removed activity is treated explicitly, diminution of activity in bone volume is assumed to be a first-order process, and soft tissues are addressed explicitly rather than as the whole body minus bone and blood.

Bisphosphonate space measurement in Paget's disease of bone treated with APD.

The bisphosphonate space (BPS) is a quantitative measurement of skeletal uptake of 99mTc-HMDP. We measured BPS in 36 patients with Paget's disease of bone, both before and 6 months after treatment with intravenous APD (disodium pamidronate) infusions. BPS fell after treatment, but proportionally less than serum alkaline phosphatase (ALP) and fasting urinary hydroxyproline/creatinine (HYPRO). There was no dose-response relationship between the dose of APD given and the percentage reduction in ALP and HYPRO at 6 months. Log dose of APD/pretreatment BPS, however, predicted the percentage reduction in ALP and HYPRO very well, and from the respective regression equations it was possible to predict the dose of APD needed to achieve normal values of ALP and HYPRO. In the 10 patients who achieved a normal ALP and 9 patients a normal HYPRO after more than 6 months treatment with APD (range 7-18 months), the predicted dose of APD agreed closely with the actual dose. In conclusion, our data support the idea that log dose APD/pretreatment BPS is a valid predictor of biochemical response in Paget's disease.

A new method for assessing 99Tcm-MDP bone uptake from a bone scan image: quantitative measurement of radioactivity in global skeletal regions of interest.

Bone uptake of 99Tcm-MDP was evaluated 4 h after injection in 27 normal subjects aged 23-50 years by gamma camera measurement of the activity in whole skeleton regions of interest (ROIs) in anterior and posterior projection. The mean global skeletal uptake (GSU) (% of whole-body activity in both projections measured 30 s after injection) was 33.5 +/- 4%. The standard urinary excretion method (whole-body retention, WBR) gave a mean bone uptake value of 31.5 +/- 4%. A significant correlation (r = 0.570; P less than 0.002) was found between GSU and WBR. The mean bone-to-soft tissue ratio (B/S index) was 3.0 +/- 1.1. It is suggested that this direct, external counting method provides a way of obtaining both a qualitative and a semiquantitative evaluation of bone uptake with a single tracer administration in a routine bone scan. Investigation of its use in the assessment of bone involvement in low and high turnover bone diseases is now under way.

Skeletal Muscle Blood Flow and O2 Uptake During Intravenous Nicotine With and Without Hypertension

The mechanism by which nicotine causes peripheral vasoconstriction and its relationship to the increased risk of peripheral vascular disease in smokers are unknown. To study the peripheral vascular effects of nicotine, we measured hemodynamic responses and oxygen consumption of the in situ gracilis muscle during intravenous (i.v.) nicotine infusions in anesthetized dogs. Nicotine 36.0 micrograms/kg/min increased gracilis artery pressure (Pga) 91 +/- 17% and muscle vascular resistance (MVR) 96 +/- 18% whereas muscle blood flow (MBF) and oxygen consumption (MVO2) were unchanged from baseline. In dogs with extracorporeal-controlled normotension during nicotine infusion, however, Pga was held at baseline levels but similar increases in MVR were observed (95 +/- 11%) as flows decreased 52 +/- 9%. Oxygen consumption decreased in direct proportion (53 +/- 5%) to MBF, indicating complete impairment of oxygen extraction (A-VO2). Thus impaired oxygen extraction was masked in dogs in which Pga was allowed to increase because of sustained pressure-dependent flows. Phenoxybenzamine block of muscle alpha-adrenoceptors increased MBF and MVO2 in both normotensive and hypertensive dogs. Combined alpha- and beta-blockade effectively neutralized all sympathoadrenal responses in the muscle. All the above results occurred regardless of innervation. Plasma levels of norepinephrine (NE) and epinephrine (EPI) increased greater than 1,000% during nicotine infusion. Apparently, these levels were high enough to (a) override dilator effects of plasma EPI and (b) cause vasoconstriction in muscle independent of nerve supply. Infusion of nicotine in the gracilis artery had no effect on muscle hemodynamics. Nicotine-induced increase in plasma catecholamines resulted in a powerful constriction of both resistance and oxygen-exchange vessels of skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)