PubMed Health⌕ Search

Biomedical subjects

R S Weinstein

Publications and source records attributed to R S Weinstein.

At least 73 records · Page 4Linked to original sources
PubMed1996

Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial.

PURPOSE: The potent bisphosphonates offer great promise in the management of Paget's disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Paget's disease in preliminary studies. METHODS: We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Paget's disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS: N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION: Oral alendronate appears to be a safe and effective therapy for Paget's disease and results in healing of lytic bone lesions.

Administration, Oral↗
PubMed1996

Experience-related differences in diagnosis from medical images displayed on monitors.

OBJECTIVE: To compare diagnostic accuracy using conventional versus monitor-displayed medical images in order to determine if years of experience as a board-certified clinician influences diagnostic performance in either modality. MATERIALS AND METHODS: In separate observer performance studies, six radiologists and six pathologists differing in years of experience viewed clinical images, once in the conventional modality (X-ray film or light microscopy) and once using a monitor display. Readers also were surveyed regarding their experience with digital/video display systems. RESULTS: In both studies, performance was similar for conventional and monitor modalities. For the conventional displays, there was a positive correlation between years of clinical experience and performance. For the monitor displays, however, there was a strong negative correlation between years of clinical experience and performance. Performance using the monitor displays correlated highly with experience using digital/video systems in general. CONCLUSION: More exposure to and use of monitor displays, such as recreational video games and computers, may influence positively the clinician-monitor display system interaction and improve diagnostic performance.

Data Display↗
PubMed1996

Comparison of 22-oxacalcitriol and 1,25(OH)2D3 on bone metabolism in young X-linked hypophosphatemic male mice.

Using a mouse model (Hyp) of human hypophosphatemic vitamin D-resistant rickets [X-linked hypophosphatemia (XLH)], we compared the effects of 22-oxa-1,25-dihydroxyvitamin D3 (OCT) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on restoring defects in mineral and skeletal metabolism. Hyp/Y mice received OCT or 1,25(OH)2D3 at doses of 0.05-0.25 micron.kg-1.day-1 for 4 wk. OCT normalized serum calcium levels, whereas 1,25(OH)2D3 produced hypercalcemia in Hyp/Y. OCT and 1,25(OH)2D3 also normalized serum phosphate levels and increased urinary calcium levels. Additionally, OCT and 1,25(OH)2D3 reduced elevated urinary pyridinoline levels and suppressed urinary adenosine 3',5'-cyclic monophosphate levels to normal. Bone ash content was low in Hyp/Y, and OCT was more effective than 1,25(OH)2D3 in reversing this defect. Histomorphometric analysis of bone turnover, mineralization rate, and osteoid content demonstrated comparable responses with OCT and 1,25(OH)2D3, although the highest dose of 1,25(OH)2D3 resulted in increased osteoid content and delayed mineralization. OCT appears to be more effective and definitely less toxic than 1,25(OH)2D3 in reversing skeletal lesions in Hyp/Y mice and may prove to be the drug of choice in the treatment of childhood XLH.

Animals↗
PubMed1996

Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone.

Alendronate, an aminobisphosphonate, is much more potent than etidronate, an older bisphosphonate, in inhibiting osteoclast-mediated bone resorption, and unlike etidronate, therapeutic doses of alendronate are not associated with abnormal mineralization. In the present study, we compared the effectiveness, safety, and tolerability of 6 months of daily oral administration of alendronate (40 mg) with those of etidronate (400 mg) in 89 patients with clinically active Paget's disease. The primary efficacy end point was the percent change in serum alkaline phosphatase. Other end points included changes in urinary deoxypyridinoline excretion, pain, functional impairment scores, and radiological osteolysis. Tetracycline-labeled bone biopsies were obtained for histomorphometric analysis from a subset of 43 patients at the 6-month visit. The alendronate-treated group had significantly greater decreases in both serum alkaline phosphatase (79% vs. 44%) and urinary deoxypyridinoline (75% vs. 51%) than the etidronate-treated group (P < 0.001 in both cases). Normalization of serum alkaline phosphatase was much more frequent in alendronate-treated patients (63.4% vs. 17.0%; P < 0.001). Alendronate was well tolerated and had a safety profile similar to that of etidronate. Histomorphometry revealed decreased bone turnover and no qualitative abnormalities, including no direct negative effects on bone mineralization, with alendronate treatment. One patient receiving etidronate developed frank osteomalacia. Alendronate appears to be a highly effective treatment for Paget's disease of bone that offers an important therapeutic advance over etidronate.

Administration, Oral↗
PubMed1995

Panic disorder.

Panic disorder is a chronic illness that affects at least 3 percent of the population. Panic disorder is associated with significant morbidity and an increased risk of suicide. Patients generally present with multiple somatic and psychologic complaints, including heart palpitations, chest pain, tremor, shortness of breath, choking, nausea or abdominal distress, dizziness, derealization, fear of losing control or going crazy, fear of dying, paresthesias, chills or hot flushes, headache, diarrhea, insomnia, chronic fatigue, anxiety and depression. To make the correct diagnosis, these symptoms must be evaluated carefully since they also occur with serious cardiovascular, pulmonary, endocrinologic and neurologic disorders. Many effective treatments are available, including tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, benzodiazepines such as alprazolam and clonazepam, and psychotherapy.

Antidepressive Agents↗
PubMed1995

Case triage model for the practice of telepathology.

OBJECTIVE: To implement and evaluate a practice model for telepathology. METHODS: A case triage practice model was devised in which general pathologists review all cases and refer them to subspecialists only when necessary. In 1993, the Arizona-International Telemedicine Network (AITN), a high-resolution static imaging telepathology diagnostic network, linking six sites to the University of Arizona in Tucson, began testing the model. Work flow through the network was analyzed, and diagnostic concordance was assessed in 150 surgical cases by comparing the diagnoses of the referring (transmitting) pathologists with diagnoses of the consulting (receiving) telepathologists as well as by comparing the referring pathologists' diagnoses with the consensus diagnoses reached by an independent review panel. Data analysis was controlled for subspecialty case type. Telepathologists had access to the referring pathologists' preliminary diagnoses, and the review panel had access to the original glass slides and the surgical pathology reports prior to rendering their respective diagnoses. RESULTS: The triage pathologist completed the telepathology consultation without the assistance of a subspecialty pathologist in 66% of the cases. The review panel examined the original glass slides from 134 cases by light microscopy. Concordance rates of the telepathologists' or review panel's diagnoses with the referring pathologists' diagnoses were not statistically different (93.1% v 83.6%, respectively; P > 0.05). CONCLUSION: The case triage model is suitable for the practice of telepathology. It significantly reduces the need for subspecialty pathologists. Static imaging telepathology is useful and reasonably efficient for rendering diagnostic opinions in the majority of referred cases. Tissue sampling limitations imposed by static imaging occasionally resulted in diagnostic errors.

Adult↗
PubMed1995

Cardiotoxicity in the SCID mouse following administration of doxorubicin and cyclosporin A.

Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. Relapsing disease commonly heralds an increase in the incidence of drug resistance which is often mediated by the product of the MDR-1 gene, P-glycoprotein (Pgp). One approach to modulating drug resistance due to Pgp overexpression has involved the use of agents known as chemomodulators which inhibit its function. We have developed a human xenograft model of multiple myeloma using the SCID mouse to evaluate the efficacy and toxicities of new MDR-1 chemomodulators. Cyclosporin A (CsA) is a widely used immunosuppressant which has been demonstrated to be a potent inhibitor of Pgp in vitro at concentrations which are clinically achievable. Preliminary studies revealed an acute toxicity in our SCID model which was associated with the combination of CsA and doxorubicin, and which was not observed with either drug alone, nor with cremaphor, the vehicle for CsA. In the current study, non-tumor bearing SCID mice were dosed with doxorubicin or the combination of doxorubicin with cremaphor, verapamil or CsA. Animals were sacrificed and tissues harvested for morphologic examination and for HPLC analysis of doxorubicin levels. In all tissues examined, there was a marked increase in tissue levels of doxorubicin when combined with CsA. Results also revealed a higher incidence and severity of myocardial damage in those animals receiving the combination of doxorubicin and CsA than in those receiving other combinations. The elevations in tissue levels observed with doxorubicin and CsA may contribute to the acute toxicities observed in the SCID mouse model.

Animals↗
PubMed1995

Pathology consultation services via the Arizona-International Telemedicine Network.

The Arizona-International Telemedicine Network (AITN) links 4 cities in Arizona and two international sites in China and Mexico, into a telepathology diagnostic network. Established in 1993, the Network provides second opinions on surgical pathology and cytopathology cases. Workstations are 486 PC-based computers. Static images (1024 x 774 x 8 pixels) are grabbed with a variable resolution video camera and sent by 14,400 bit per second modems over ordinary telephone lines. Second opinions are either rendered directly by a general telepathologist or triaged to a specialist. Experience with the first 37 cases indicates a high level of success in providing useful information to referring pathologists over the Network.

Computer Communication Networks↗
PubMed1995

Severe combined immunodeficiency (SCID) mouse modeling of P-glycoprotein chemosensitization in multidrug-resistant human myeloma xenografts.

We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficiency (SCID) mouse using both the drug-sensitive 8226/S human myeloma cell line and the P-glycoprotein-expressing multidrug-resistant 8226/C1N subline. As demonstrated previously, the SCID mouse is well suited as a model for myeloma because: (a) human SCID xenografts are readily attained; (b) human myeloma xenografts are readily detected by their immunoglobulin secretion; and (c) differential therapy effects in drug-sensitive versus drug-resistant cell lines are readily demonstrable by monitoring mouse urinary human immunoglobulin output. In the current study, we have utilized this model to evaluate the in vivo efficacy of chemomodulators of P-glycoprotein-related multidrug resistance. In our initial experiments, doxorubicin alone was effective in treating the 8226/S human myeloma xenografts but had no effect on the drug-resistant 8226/C1N xenografts, in the absence of the chemosensitizing agent verapamil. In subsequent experiments, the combination of verapamil and doxorubicin resulted in both a decrease in human lambda light chain urinary excretion and an increase in survival of those animals bearing the 8226/C1N tumor. The median survival time of animals injected with 8226/C1N cells and subsequently treated with doxorubicin was 48.6 +/- 7 days, which compared to a survival of 89.6 +/- 18 days in animals receiving the 8226/S cell line and treated with doxorubicin alone (P < 0.001). When verapamil was added to the treatment regimen of those animals bearing the 8226/C1N xenografts, there was a 179% increase in their life span (P < 0.001), which corresponded with the observed decreased light chain in the urine. In animals receiving multiple courses of chemotherapy, an attenuated response to verapamil and doxorubicin was observed, in a manner analogous to the clinical setting of human drug-resistant myeloma escape from chemosensitivity. The SCID human myeloma xenograft model thus offers a means of evaluating the in vivo efficacy and potential toxicities of new therapeutic approaches directed against P-glycoprotein in multidrug-resistant human myeloma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Fractal geometry and vertebral compression fractures.

Cancellous bone in postmenopausal osteoporosis is characterized by widely spaced and disconnected trabeculae. These architectural changes may disproportionately increase bone fragility compared with the decrease in bone mass alone. To determine whether there is an independent architectural contribution to fracture risk, we applied fractal geometry to the cancellous bone in osteoporosis. Fractal objects have recurrent, branching patterns that are quantified by a fractal dimension D, that describes how the object fills space. Photomicrographs of transiliac bone biopsy specimens were digitized, and D was calculated from the negative of the straight portion of the slope of the log of the number of pixels containing boundary points versus the log of the pixel size over a range of pixel sizes. The results were compared with the cancellous bone histomorphometry in 31 individuals, aged 19-80 years, who were healthy before sudden death. D was inversely related to age (r = -0.72, p < 0.0001) and trabecular spacing (r = -0.87; p < 0.0001) and directly related to bone area (r = 0.86, p < 0.0001) and trabecular number (r = 0.83, p < 0.0001). We then examined 12 healthy volunteers and 12 patients with vertebral compression fractures as a result of osteoporosis who were matched for age and cancellous bone area. The patients with fractures had a 7.9% lower mean value for D (1.224 +/- 0.085 SD versus 1.329 +/- 0.125, p < 0.026). Other markers of the cancellous architecture, such as trabecular width, separation, and number, were not different between the matched groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy.

Multidrug-resistant (MDR) myeloma patients failing chemotherapy may express P-glycoprotein (PGP), which serves as an efflux pump protecting the neoplastic cells. Unknown is whether PGP expression might relate to prior cytotoxic drug exposure. To address this question, we studied 106 consecutive bone marrow samples from 104 myeloma patients with samples studied either before or after therapy and at the time of relapse. We performed an established immunocytochemical assay of PGP using an MDR-1-specific monoclonal antibody and correlated PGP status with prior chemotherapy dosage. Myeloma patients with no prior therapy had a low incidence of PGP expression (6%, 3/47), whereas those receiving chemotherapy had a significantly higher incidence (43%, 21/49) (P < .0001). A substantially higher incidence of PGP expression (50%, 83%, respectively) occurred when the total vincristine dose exceeded 20 mg and when doxorubicin exceeded 340 mg. In the 11 patients who received both high vincristine and doxorubicin dosages (> 20 mg, > 340 mg total dose) there was 100% incidence of PGP expression in the tumor cells. These data provided the basis for a predictive mathematical model from which dose-related PGP expression normograms were generated. Time with myeloma for PGP-negative patients (mean 33 months) had overlapping confidence limits with PGP-positive patients (mean 42 months), suggesting that disease duration was not a significant variable. PGP expression did not correlate with other clinical factors or immunophenotypic factors. Our findings indicate a strong correlation between PGP expression in myeloma and past chemotherapy in myeloma, in particular, related to prior exposure to the natural product agents vincristine and doxorubicin. Additionally, the proportion of PGP-positive plasma cells was significantly higher in the doxorubicin-treated patients than the nondoxorubicin-treated patients (87.7% v 65.17%; P = .013). Combined high vincristine and doxorubicin total dosage appear highly predictive of PGP expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Case report: hypercalcemia in acute myeloblastic leukemia is caused by osteoclast activation.

Hypercalcemia in adult T-cell leukemia has been attributed to increased levels of 1,25-dihydroxyvitamin D (1,25(OH)2D), whereas in other types of leukemia, hypercalcemia has been blamed on direct skeletal invasion by malignant cells, ectopic parathyroid hormone (PTH) production or bone-resorbing cytokines. A 51-year-old man was studied who presented with back pain, circulating myeloblasts, and hypercalcemia. The bone marrow revealed acute myeloblastic leukemia. While the ionized calcium concentration was 8.17 mg/dL (normal, 4.73 to 5.21 mg/dL), the levels of PTH, PTH-related peptide, vitamin D, and thyroxine were normal or subnormal. Bone histomorphometry showed a decreased cortical width with intracortical erosion cavities dissecting into the marrow space. In cancellous bone, the osteoid area, osteoblast perimeter, and tetracycline fluorescence were sparse, whereas the osteoclast perimeter was increased. Persistent marrow fat, the general absence of trabecular narrowing, and the prompt response to calcitonin suggest that the osteoclasts caused the hypercalcemia and lytic lesions, rather than pressure atrophy or osteolysis by leukemic infiltration. Osteoclast activation and subsequent hypercalcemia may have been due to a locally produced cytokine, such as interleukin-1 beta or tumor necrosis factor.

Biopsy↗
PubMed1993

An in vivo model of human multidrug-resistant multiple myeloma in SCID mice.

We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficient (SCID) mouse using both the RPMI 8226 human myeloma cell line and the P-glycoprotein-expressing multidrug-resistant 8226/C1N subline. SCID mice 5 to 8 weeks of age were injected intraperitoneally with either 8226 drug-sensitive or P-glycoprotein-expressing multidrug-resistant myeloma cells (8226/C1N). Tumors were detected within 5 days after injection by the presence of human lambda light chain excretion in the mouse urine. Growth of the tumor was observed primarily in the abdominal cavity with spread to the abdominal organs. The anti-neoplastic agent doxorubicin was effective in treating the drug-sensitive 8226 human-SCID xenografts but had no effect on the multi-drug-resistant 8226/C1N human-SCID xenografts. In the 8226-sensitive xenografts, treatment with doxorubicin resulted in a sharp decline in the concentration of human lambda light chain being excreted in the mouse urine. This correlated with an increased survival of the drug-treated animals. This mouse model offers an in vivo means of evaluating efficacy and toxicity of new therapeutic approaches, including development of chemosensitizers directed against P-glycoprotein in multidrug-resistant myelomas.

Animals↗
PubMed1992

Variable expression of P-glycoprotein in normal, inflamed, and dysplastic areas in ulcerative colitis.

Screening programs for the detection of cancer in ulcerative colitis are inexact and not always successful in finding early, curable cancers. P-glycoprotein is a membrane-based, energy-dependent protein found in varying degrees within normal human tissue. P-glycoprotein is overexpressed in malignant tumors, particularly colorectal cancer, and is known to convey resistance to certain anticancer drugs by acting as a membrane "pump." The purpose of this study was to determine the expression of this protein in inflamed and premalignant colonic epithelium, compare its expression with normal controls, and assess its potential use as a screening tool for high-risk patients with ulcerative colitis. Using immunohistochemical techniques, the colons of 21 patients (10 with dysplasia) with ulcerative colitis were stained with monoclonal antibody C-219 (MAbC219) specific for P-glycoprotein. P-glycoprotein was expressed in 38 percent of normal areas, 71 percent of inflamed areas (P = 0.0156), and 70 percent of dysplastic areas. Comparing the level of expression when progressing from normal to inflamed areas within a given patient, 11 patients (52 percent) showed increased expression, 8 (38 percent) showed equal expression, and only 2 (10 percent) showed decreased expression (P = 0.0225). Comparing expression when progressing from inflamed to dysplastic areas (10 patients), 7 showed equal expression and 3 showed increased expression (P = 0.25). Increasing duration of disease was associated with a significant increase in P-glycoprotein expression, but only in histologically normal areas. Duration of disease had no effect on P-glycoprotein expression in inflamed or dysplastic areas. Similarly, when surgery was performed for elective reasons, there was a significant overexpression of P-glycoprotein, but only in histologically normal areas. Our findings suggest that the increase in P-glycoprotein expression from normal to inflamed and dysplastic areas reflects the premalignant nature of ulcerative colitis and occurs early in the course of the disease. Further research needs to be done to determine its role in cancer surveillance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗