"Worn out": Coping strategies for managing antiretroviral treatment fatigue among urban people of color living with HIV who were recently disengaged from outpatient HIV care.

Antiretroviral-related treatment fatigue is inconsistently defined in the literature on barriers to ART adherence. Research suggests that treatment fatigue is a salient challenge for people struggling with antiretroviral therapy adherence, but little is known about how people living with HIV attempt to manage this fatigue. Twenty-seven semi-structured interviews were conducted with low-income people of color living with HIV in NYC that were currently, or recently, disengaged from HIV care. The findings from this exploratory study suggest that treatment fatigue was common and that participants devised personal strategies to overcome it. These strategies included using reminder programs, requesting weekly rather than monthly pill quantities, and taking "pill holidays". The varied nature- and varying levels of effectiveness- of these strategies highlight the need for specific programming to provide tailored support. Future research should examine treatment fatigue as a specific subtype of adherence challenge, and aim to define pill fatigue clearly.

Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo.

Two diphosphonates containing the P-C-P bond, CH(3)C(OH)(PO(3)HNa)(2) and H(2)C(PO(3)HNa)(2), inhibit the crystallization of calcium phosphate in vitro and prevent aortic calcification of rats given large amounts of vitamin D(3). The diphosphonates therefore have effects similar to those described for compounds containing the P-O-P bond but are active when administered orally.

Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo.

Two diphosphonates containing the P-C-P bond, Cl(2)C(PO(3)HNa)(2), and H(2)C(PO(3)HNa)(2) retard the rate of dissolution of apatite crystals in vitro. They inhibit bone resorption induced by parathyroid extract in mouse calvaria in tissue culture and in thyroparathyroidectomized rats in vivo.

Sites and mechanisms of localization of technetium-99m phosphorus radiopharmaceuticals in acute myocardial infarcts and other tissues.

This study was performed to elucidate the localization at the cellular level of technetium-99m phosphorus ((99m)Tc-P) radiopharmaceuticals in acute myocardial infarcts and the mechanisms responsible for (99m)Tc-P uptake in acute myocardial infarcts and other tissues. In 20 dogs with proximal left anterior descending coronary arterial ligation for 1-3 days, elevated calcium levels were measured at all sites of increased (99m)Tc-P uptake (acute myocardial infarcts, necrotic thoracotomy muscle, lactating breast, and normal bone); however, a consistent linear relationship between (99m)Tc-P and calcium levels was not observed. A strong correlation (r = 0.95 and 0.99, n = 2 dogs) was demonstrated between levels of (3)H-diphosphonate and (99m)Tc-P in infarcted myocardium. Autoradiographic studies with (3)H-diphosphonate revealed extensive labeling in the infarct periphery which contained necrotic muscle cells with features of severe calcium overloading, including widespread hypercontraction as well as more selective formation of mitochondrial calcific deposits. Autoradiography also demonstrated labeling of a small population of damaged border zone muscle cells which exhibited prominent accumulation of lipid droplets and focal, early mitochondrial calcification. Cell fractionation studies revealed major localization of both (99m)Tc-P and calcium in the soluble supernate and membrane-debris fractions of infarcted myocardium and less than 2% of total (99m)Tc-P and calcium in the mitochondrial fractions; however, electron microscopic examination showed that mitochondria with calcific deposits were not preserved in the mitochondrial fractions. In vitro studies evaluating the role of serum protein binding on tissue uptake of (99m)Tc-P agents demonstrated that, in spite of significant complexing with serum proteins, serum (99m)Tc-P activity retained the ability to adsorp to calcium hydroxyapatite and amorphous calcium phosphate. In vivo studies showed that concentration of human serum albumin (labeled with iodine-131) in infarcted myocardium reached a maximum of only 3.8 times normal after a circulation time of 96 h, whereas (99m)Tc-P uptake was at least 10 times normal after a circulation time as short as 1 h. It is concluded that: (a) (99m)Tc-P uptake in acutely infarcted myocardium, and possibly other types of soft tissue damage, is limited to necrotic and severely injured cells; (b) concentration of (99m)Tc-P results from selective adsorption of (99m)Tc-P with various forms of tissue calcium stores, including amorphous calcium phosphate, crystalline hydroxyapatite, and calcium complexed with myofibrils and other macromolecules, possibly supplemented by calcium-independent complexing with organic macromolecules; and (c) lack of a linear relationship between (99m)Tc-P and tissue calcium levels mainly results from local differences in composition and physicochemical properties of tissue calcium stores and from local variations in levels of blood flow for delivery of (99m)Tc-P agents.

Health care quality in the 21st century.

The concepts of healthcare quality have evolved over the years. Many stakeholders have become quite engaged in the movement towards improvement in healthcare quality and safety. The standardization and national endorsement of performance measures, the assessment of outcomes, and the reporting for accountability are now being coupled with more transparency, and technological innovation. As the quality landscape changes to evaluation of episodes of care and performance at the individual clinician level measures (primary and specialty care), collaboration is critical among consumers, purchasers, measure developers, implementers of measures to identify and adopt national standards to tell a clear story of healthcare quality.

Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases.

Bisphosphonates (formerly termed diphosphonates) were first synthesized in the late 1800s; however, their clinical use has been relatively recent. The bisphosphonates' affinity for hydroxyapatite crystal surface led Procter and Gamble to test these compounds in dental, then medical applications. With key input from university researchers, this led to the medical use of the first bisphosphonate, etidronate disodium in 1968 to treat a young patient with myositis ossificans progressiva. Further clinical research led to widespread medical application for the bisphosphonate class including use as a diagnostic in radionuclide bone imaging agents, treatment of osteoporosis, Paget's disease of bone, hypercalcemia of malignancy and metastatic bone disease. The historical development of bisphosphonates provides an excellent example of how observations and knowledge obtained at the basic science level were applied and successfully tested in the clinic. The end result of these efforts has provided health care professionals with diagnostic and therapeutic tools to improve the lives of patients.

Multiple human progesterone receptor messenger ribonucleic acids and their autoregulation by progestin agonists and antagonists in breast cancer cells.

We have used AB-52, a monoclonal antibody which recognizes both the A (94,000 daltons) and B (120,000 daltons) proteins of human progesterone receptors (hPR), and hPR-50, a PR complementary DNA probe isolated from a T47D-pcD library, to study the structure and hormonal regulation of the hPR mRNAs and proteins in human breast cancer cells. RNA blot hybridization analysis of poly(A+) RNA shows that T47DCO, an estrogen resistant human breast tumor cell line in which PR are constitutively expressed, contain at least six PR mRNAs ranging in size from 2.5 to 11.4 kilobases. All six are mature cytoplasmic messages that are also present in normal human endometrium and in PR-positive MCF-7 breast cancer cells, but not in PR-negative cells. Using hPR-50 RNA synthesized in vitro as a 1.3 kilobase standard, we calculate that MCF-7 cells contain approximately 16 message molecules per cell which are increased to approximately 45 by estradiol treatment; T47DCO cells contain approximately 90 message molecules per cell constitutively expressed. Treatment of T47DCO cells with progesterone leads to down-regulation of immunoreactive A- and B-receptors in the first 8-12 h, followed by their replenishment during the next 48 h. In parallel, hPR message levels initially decrease and then return to pretreatment levels. The synthetic progestin R5020 chronically down-regulates A- and B-receptors; the proteins are profoundly suppressed for at least 48 h, while PR mRNAs fall to less than 15% of control. However, with both hormones, parallel changes in protein and message levels are observed, suggesting that progestational agonists autoregulate the levels of their own receptors by inhibiting transcription of the PR gene. Antagonists appear to have different effects. With the antiprogestin RU 486 there is discordance between hPR protein and message levels which may be due to an ineffective inhibitory interaction between the antagonist-occupied receptors and PR genes, thereby disrupting the negative feedback loop.

Retention of etidronate in human, dog, and rat.

The retention of radioactivity in human, rat, and dog following a single injected dose of radiolabeled etidronate disodium (EHDP) is shown to follow power-law decay curves with similar slopes for times up to 4, 60, and 80 days, respectively. During this period retention declines with time according to a weak inverse power of the time since dosing, with an exponent ranging from -0.05 (dog) to -0.09 (human and rat). Direct analyses of dog bones either 90 days after a single dose or 365 days after cessation of chronic dosing indicate a more rapid bone clearance of EHDP than predicted by the initial power law. Direct skeletal analysis also shows a more rapid loss of radioactivity in the rat between 60 and 365 days, indicative of either a second power law or a terminal exponential phase in the retention function occurring after 60 days. These data are used to estimate the minimum and maximum amounts of drug that would remain in the body following long-term treatment in humans. For the intermittent cyclic EHDP treatment (ICT) regimen for osteoporosis (repeated cycles of 14 daily doses of 400 mg orally followed by 76 days drug free), the projected retention of EHDP after 3 years of treatment is 25-50 times the daily absorbed dose. Thus, for a 60 kg woman with a daily absorbed dose of 12 mg, the retained mass of EHDP would be about 300-600 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Theoretical physical chemical studies of the cause of fluoride-induced osteomalacia.

In this study we investigated the possibility of the formation of a calcium fluoride surface film on the new bone matrix in patients undergoing fluoride treatment for osteoporosis. This calcium fluoride film could interfere with the normal mineralization process and lead to hyperosteoidosis (osteomalacia), a well-documented complication seen in fluoride-treated patients. During treatment, fluoride circulating in the blood and extracellular fluid of patients, could interact with the components of the serum, but particularly calcium and magnesium ions. The interrelationships among serum components in the presence of fluoride ion may result, at thermodynamic equilibrium, in deposition on the apatitic bone surface of phases such as calcium fluoride, fluorapatite, or fluorhydroxyapatite. Differences in the phase deposited among patients could result in differences in response to fluoride treatment. A computer program based on equilibrium thermodynamic data was utilized to study the physicochemical calcium, fluoride, and phosphate interrelationships in serum. In all the computer calculations, fluorhydroxyapatite (FHAP), alone or in combination with hydroxyapatite (HAP), was determined to be the thermodynamically stable precipitating surface phase. These data strongly suggest that calcium fluoride surface film is not the reason for the delay of mineralization of fluoride-stimulated new bone. Based on these calculations, we now advance the hypothesis that the effect of fluoride to cause osteomalacia is due to an effect on osteoblasts and also on osteocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro stabilization of a low-tin bone-imaging agent (99mTc-Sn-HEDP) by ascorbic acid.

The presence of oxidants in the 99mTc-pertechnetate and of oxygen in diagnostic kits containing low concentrations of Sn(II) has a detrimental effect upon in vitro and in vivo stability. Maintaining a nitrogen atmosphere or increasing the Sn(II) concentration inhibits the formation of 99mTcO4-. However, the latter remedy is likely to cause uptake in the reticuloendothelial system and has been associated with false positive or negative brain scans. We used ascorbic acid (an antioxidant) to ensure the in vitro stability with the low-Sn(II) bone agent disodium etidronate. In vitro stability studies by instant thin-layer chromatography, using high-acitivity generators and "instant pertechnetate," yielded less than 2% free pertechnetate at 24 hr after preparation. Distribution studies in guinea pigs show neither altered distribution of the bone agent nor abnormal distribution of ascorbic acid, suggesting its sole function as a noncomplexing stabilizer.

Correlation of neoplasms with incidence and localization of skeletal metastases: An analysis of 1,355 diphosphonate bone scans.

A total of 1,355 patients from clinical trails with the 99mTc-labeled bone agent, Osteoscan (99mTc-Sn -EHDP), has shown a higher incidence of skeletal abnormalities than previously reported. Overall in this study, 60% of bone scans were abnormal in patients with nonosseous neoplasms. Carcinoma of breast, lung, and prostate yielded 67%, 64%, and 62% skeletal involvement, respectively. Over 50% of all the skeletal abnormalities for the neoplastic indications were detected in the thorax and vertebra while the skull, pelvis, and extremities accounted for 22%, 38%, and 34%, respectively.

A comparison of skeletal uptakes of three diphosphonates by whole-body retention: concise communication.

Twenty normal volunteers had measurements of 24-hr whole-body retention (WBR) of three structurally related Tc-99m-labeled phosphonate skeletal imaging agents: (1-hydroxyethylidene) diphosphonate (HEDP), methylene diphosphonate (MDP), and hydroxymethylene diphosphonate (HMDP). The average WBR values, reflecting skeletal uptake, were 18.4, 30.3, and 36.6%, respectively. These results clearly illustrate that slight alterations in diphosphonate molecular structure have a significant effect upon specificity for osseous tissue, and thus may affect skeletal image quality and the usefulness of the WBR technique in diagnosing metabolic bone disease.

Distribution of 99mTc-Sn diphosphonate and free 99mTc-pertechnetate in selected soft and hard tissues.

Because increased uptake of 99mTc-diphosphonate (ethane-hydroxy-1, 1-diphosphonate) occasionally occurs in the anterior neck region, the possible increased affinity of the diphosphonate bone-scanning agent for cartilage was investigated. In vivo scintigraphic studies and organ analyses from rats and rabbits injected with this bone scintigraphic agent were performed. Trachea-to-muscle uptake ratios were a high 45:1 in adult Sprague-Dawley rats and approached the femur-to-muscle ratio of 93:1. Technetium-99m-diphosphonate uptake was also increased, but to a lesser extent, in xiphoid cartilage, tendon, and ear cartilage; this was proportional to the calcium content of the organ. The thyroid showed a high affinity for free pertechnetate but not 99mTc-diphosphonate, providing further evidence that the increased neck uptake of this 99mTc-diphosphonate is due to tracheal, not thyroid activity. In addition, premedication of three patients with 200 mg of potassium-perchlorate did not block this neck uptake. Interpretation of scintigraphs performed with 99mTc-diphosphonate that show lesions in the cervical spine should take into account the potential for false-positive readings caused by this increased tracheal uptake.

Comparative evaluation of three diphosphonates: in vitro adsorption (C- 14 labeled) and in vivo osteogenic uptake (Tc-99m complexed).

We have investigated the in vitro adsorption of three C-14-labeled diphosphonates on calcium phosphate. The three are 1-hydroxy[1-14C]ethylidene diphosphonate (C-14 HEDP), [14C]methylenediphosphonate (C-14 MDP), and hydroxy[14C]methylenediphosphonate (C-14 HMDP). All three adsorbed significantly more, per mole of calcium, on amorphous calcium phosphate than on crystalline hydroxyapatite. Among the three diphosphonates, C-14 HMDP adsorbed--on both amorphous and crystalline calcium phosphate--to a greater degree than did the other two bone-seeking agents. Moreover, when HMDP was complexed with Sn(II) and Tc-99m, it produced a significantly higher uptake of Tc-99m, per mg of calcium, in an isolated in vivo site of osteogenesis. The mechanisms of adsorption are discussed relative to the hydroxyl group on the diphosphonate, to the solubility of the calcium salts to the diphosphonates, and to the form of the calcium phosphate. These studies form a working rationale for the clinically observed high contrast obtained with Tc-99m HMDP between normal bone and soft tissue, and between normal and abnormal bone.

Tc-99m HMDP (hydroxymethylene diphosphonate): a radiopharmaceutical for skeletal and acute myocardial infarct imaging. I. Synthesis and distribution in animals.

Technetium-99m hydroxymethylene diphosphonate (Tc-99M HMDP) is a new diphosphonate skeletal imaging agent. Animal studies show that Tc-99m HMDP has a higher uptake on bone and a more rapid clearance from the blood than any of the three technetium-labeled bone imaging agents in current use: Tc-99m methylene diphosphonate (DMP), Tc-99 (1-hydroxyethylidene) diphosphonate (HEDP), and Tc-99m pyrophosphate (PPi). On the basis of these animal studies, Tc-99m HMDP is a highly promising candidate for skeletal imaging.

Tc-99m HMDP (hydroxymethylene diphosphonate): a radiopharmaceutical for skeletal and acute myocardial infarct imaging. II. Comparison of Tc-99m hydroxymethylene diphosphonate (HMDP) with other technetium-labeled bone-imaging agents in a canine model.

Technetium-99m hydroxymethylene diphosphate (Tc-HMDP) was compared with the two other diphosphonates (Tc-MDP and Tc-HEDP) and Tc-99m pyrophosphate (Tc-PPi) in a canine model of acute myocardial infarction. The TC-HMDP showed higher uptake in infarcted myocardium than the other two diphosphonates, and uptake equivalent to that of Tc-PPi.

Gentisic acid: a new stabilizer for low tin skeletal imaging agents: concise communication.

In vitro stabilization of low-tin bone-imaging agents has previously been achieved with ascorbic acid. In this study gentisic acid is shown to be an equally effective antioxidant for the (1-hydroxyethylidene) diphosphonate (HEDP) and hydroxymethylenediphosphonate (HMDP) skeletal agents. In vitro studies show less than 2% free sodium [99mTc] pertechnetate at 24 hr with the gentisic acid stabilizer. Studies in guinea pigs at 3 and 24 hr--whether with C-14 or H-3-labeled gentisic acid as stabilizer--show no alteration in the biodistribution of either skeletal imaging agent by the addition of the gentisic acid. Gentisic acid is a safe and effective stabilizer, and clinical studies have shown bioequivalency with ascorbic acid.

Preparation and biological distribution of technetium diphosphonate radiotracers synthesized without stannous ion.

Two HEDP complexes of technetium (either Tc-99 or a mixture of Tc-99 and Tc-99m) have been prepared without the use of stannous ion. The first, Tc(NaBH4)-HEDP, is synthesized by reduction of TcO4- with NaBH4 in the presence of excess HEDP; this is analogous to the preparation of Tc(Sn)-HEDP in commercial kits wherein SN(II) functions as the reductant. The second, Tc-HEDP, is prepared by substitution of HEDP onto the pre-formed, pre-reduced, technetium center TcBr62-. The HEDP-to-Tc ratio in Tc-HEDP was found to be 1.0 by double-labeling procedures (Tc-99 and [3H]HEDP), implying that in solution this material is polymeric or at least dimeric. Preparations of Tc(NaBH4)-HEDP and Tc-HEDP with Tc-99m are excellent bone-imaging agents in both rats and dogs. Tissue distribution studies in rats show that uptake of Tc(NaBH4)-HEDP and Tc-HEDP by the bone is at least equivalent to that achieved by Tc(Sn)-HEDP prepared in commercial kits with Sn(II) as the reductant. Tin is therefore not necessary for the bone-seeking properties of Tc(Sn)-HEDP, and the in vivo distribution of a given HEDP radiotracer seems to depend primarily on the presence of the HEDP ligand and not on the exact nature of the technetium complex itself. Synthesis of technetium radiotracers by a substitution route, rather than by redox, is practicable; this route has the potential of introducing hitherto unattainable flexibility and subtlety into the preparation of technetium radiotracers.

[32P] diphosphonate dose determination in patients with bone metastases from prostatic carcinoma.

In an initial safety study, phosphorus-32 (as diphosphonate) was administered intravenously to five patients with painful bone metastases from prostatic carcinoma; two patients received 9 mCi and three were given 3 mCi. Hematological, biochemical, ECG, x-ray, bone-scan data, and clinical observation, were followed for 2 mo. At both dose levels, bone-marrow depression was noted. One of the patients, who received 9 mCi, had only a slight dip in the levels of circulating white blood cells and platelets. The other 9-mCi patient was the only one with discrete metastases by bone scan; he had bone-marrow depression, from which he recovered, and was the only one of the five who had relief of bone pain.

Bone scanning: radionuclidic reaction mechanisms.

One of the major successes of nuclear medicine in recent years has been the clinical utility of the 99mTc-labeled bone-imaging agents. This article is concerned with the evidence available for the mechanisms by which these and other such radiopharmaceuticals localize at sites in the skeleton.