PubMed Health⌕ Search

Biomedical subjects

S H Doppelt

Publications and source records attributed to S H Doppelt.

At least 19 recordsLinked to original sources
PubMed1996

Analysis of the lipids of normal and Gaucher bone marrow.

Quantitative chemical shift magnetic resonance imaging (QCSI) is currently being utilized for measuring the extent of bone marrow involvement and its response to enzyme replacement therapy in patients with Gaucher's disease. Quantitation of the major lipid species in human bone marrow is required to accurately interpret QCSI data on bone marrow composition. The major lipid species in bone marrow specimens from normal individuals and from patients with type 1 Gaucher's disease were analyzed by thin-layer and high-pressure liquid chromatography. In normal marrow (N = 5), triglycerides were by far the most abundant lipid (278 +/- 70 mg/gm wet wt), with other non-polar lipids and phospholipids totaling less than 20 mg/gm wet weight. The concentration of glucocerebroside in normal marrow was 0.061 +/- 0.06 mg/gm wet weight. Gaucher marrow (N = 9) had dramatically lower triglyceride levels (51 +/- 53 mg/gm wet wt), and as expected, it had markedly elevated levels of glucocerebroside (7.1 +/- 3.4 mg/gm wet wt). The other major non-polar lipids and phospholipids were measured in selected specimens, but none were found that differed so profoundly between normal and Gaucher's disease. These data support a model of bone marrow alteration in Gaucher's disease in which triglyceride-rich adipocytes are progressively replaced by storage cells, leading to an overall reduction in total lipid content. This phenomenon provides an explanation for the changes in proton signal intensity observed in QCSI studies of Gaucher bone marrow.

Adult↗
PubMed1995

Enzyme replacement therapy for Gaucher disease: skeletal responses to macrophage-targeted glucocerebrosidase.

OBJECTIVES: Reversal of the hematologic and visceral abnormalities characteristic of Gaucher disease, the most common lipid storage disorder, with biweekly infusions of macrophage-targeted glucocerebrosidase (glucosylceramidase) is well documented. The extent to which the skeleton responds to enzyme replacement therapy has not been systematically investigated. METHODS: To assess the skeletal response to enzyme replacement therapy, we treated 12 patients with type 1 Gaucher disease, who had intact spleens, with macrophage-targeted glucocerebrosidase. The initial dose of enzyme was 60 U/kg body weight every 2 weeks for 24 months, followed by reduction in dosage to 30 and then 15 U/kg body weight every 2 weeks, each for 9 months. RESULTS: The lipid composition of bone marrow, determined by direct chemical analysis, began to improve after 6 months of treatment at a time when noninvasive imaging studies showed no significant changes. By 42 months, improvement in marrow composition was demonstrable on all noninvasive, quantitative imaging modalities (magnetic resonance score, quantitative xenon scintigraphy, and quantitative chemical shift imaging) used in this study. Quantitative chemical shift imaging, the most sensitive technique, demonstrated a dramatic normalization of the marrow fat content in all patients. Net increases in either cortical or trabecular bone mass, as assessed by combined cortical thickness measurements and dual-energy quantitative computed tomography, respectively, occurred in 10 patients. CONCLUSIONS: Prolonged treatment over 3 1/2 years with macrophage-targeted glucocerebrosidase produces objective reversal of disease in both the axial and appendicular skeleton in patients with Gaucher disease. Marked improvement occurs in marrow composition and bone mass in both children and adults.

Adolescent↗
PubMed1993

Radiopharmacology of inhaled 133Xe in skeletal sites containing deposits of Gaucher cells.

Gaucher's disease is a lysosomal storage disease in which cells of the reticuloendothelial system accumulate the lipid glucocerebroside. It is characterized by slowly progressive visceral and osseous involvement. One of the latter manifestations includes lipid infiltration of bone marrow. We monitored the rate of inhaled 133Xe uptake and wash-out over diseased and normal metaphyseal and epiphyseal areas of the knee. Twenty-two patients (15 adults, 7 children) with various degrees of previously diagnosed Gaucher's disease were positioned supine under a gamma-camera interfaced to a computer system. All patients rebreathed 133Xe gas from a closed system for 10 min followed by 14 min of wash-out. Digitized images of the lung, liver, spleen, bony sites and soft tissue were obtained at 1 min intervals during the wash-in and wash-out phases. Counts for each ROI were normalized per 100 pixels and plotted as a function (time). Maximum uptake was also calculated by relating the counts/ROI/100 pixels to the 10 min integrated lung count during equilibrium (the administered "dose"). There was essentially no 133Xe uptake in liver and spleen involved with Gaucher's disease. Monophasic uptake and biphasic wash-out curves were observed in the limited investigative population. Skeletal Gaucher deposits released the 133Xe at a greater rate relative to soft tissue.

Administration, Inhalation↗
PubMed1992

Quantitative chemical shift imaging of vertebral bone marrow in patients with Gaucher disease.

To evaluate extent of bone marrow involvement and disease severity in Gaucher patients, results of modified Dixon quantitative chemical shift imaging (QCSI) of the lumbar spine were correlated with quantitative analysis of marrow triglycerides and glucocerebrosides and with quantitative determination of splenic volume at magnetic resonance (MR) imaging. High-field-strength MR spectra of surgical marrow specimens were dominated by a single fat and a water peak, validating use of QCSI. QCSI showed average vertebral marrow fat fractions of 10% +/- 8 in Gaucher patients (normal adult averages, 29% +/- 6). Relaxation times for lipid and water approximated normal averages; bulk T1 values were significantly longer, reflecting decreased marrow fat. Glucocerebroside concentrations were higher in Gaucher marrow and inversely correlated with triglyceride concentrations. Extent of marrow infiltration determined by fat fraction measurements correlated with disease severity measured by splenic enlargement. These results show that as Gaucher cells infiltrate bone marrow and displace normal marrow adipocytes, bulk T1 increases due to the higher T1 of water compared with that of fat. QCSI provides a sensitive, noninvasive technique for evaluating bone marrow involvement in Gaucher disease.

Body Water↗
PubMed1992

Quantitative imaging of Gaucher disease.

Twenty-three patients with type 1 Gaucher disease were evaluated with a battery of quantitative imaging techniques. Plain radiographs were used to measure cortical thickness and Erlenmeyer flask deformity. Xenon-133 uptake was measured in scans of the lower extremities. Dual-energy quantitative computed tomography was used for calculation of trabecular bone and bone marrow fat content in the spine and long bones. Magnetic resonance (MR) imaging was performed to evaluate disease extent and three-dimensional splenic volume. MR images were also used to provide quantitative measurements of each vertebral fat fraction. Each imaging modality was correlated with the others as well as with the clinical history of skeletal complications and the hematocrit and acid phosphatase activity. There was a strong relationship between splenic volume and disease severity as measured clinically and with laboratory testing. The spinal fat fraction also correlated with these measures of disease severity and with the femoral fat fraction and xenon uptake. No measurement allowed discrimination of patients with from those without skeletal complications.

Adolescent↗
PubMed1991

Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

BACKGROUND AND METHODS: Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. RESULTS: The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. CONCLUSIONS: Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.

Acid Phosphatase↗
PubMed1991

Neurologic complications of nonneuronopathic Gaucher's disease.

We describe eight patients with type 1 Gaucher's disease who developed neurologic complications that were secondary to systemic features of the illness. Four patients experienced neurologic difficulties because of coagulopathy, and the other four patients had involvement of the nervous system secondary to skeletal disease. Early recognition of these complications in patients with type 1 Gaucher's disease may lead to improved neurologic outcome.

Aged↗
PubMed1989

Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism.

To assess the effects of gonadal steroid replacement on bone density in men with osteoporosis due to severe hypogonadism, we measured cortical bone density in the distal radius by 125I photon absorptiometry and trabecular bone density in the lumbar spine by quantitative computed tomography in 21 men with isolated GnRH deficiency while serum testosterone levels were maintained in the normal adult male range for 12-31 months (mean +/- SE, 23.7 +/- 1.1). In men who initially had fused epiphyses (n = 15), cortical bone density increased from 0.71 +/- 0.02 to 0.74 +/- 0.01 g/cm2 (P less than 0.01), while trabecular bone density did not change (116 +/- 9 compared with 119 +/- 7 mg/cm3). In men who initially had open epiphyses (n = 6), cortical bone density increased from 0.62 +/- 0.01 to 0.70 +/- 0.03 g/cm2 (P less than 0.01), while trabecular bone density increased from 96 +/- 13 to 109 +/- 12 mg/cm3 (P less than 0.01). Cortical bone density increased 0.03 +/- 0.01 g/cm2 in men with fused epiphyses and 0.08 +/- 0.02 g/cm2 in men with open epiphyses (P less than 0.05). Despite these increases, neither cortical nor trabecular bone density returned to normal levels. Histomorphometric analyses of iliac crest bone biopsies demonstrated that most of the men had low turnover osteoporosis, although some men had normal to high turnover osteoporosis. We conclude that bone density increases during gonadal steroid replacement of GnRH-deficient men, particularly in men who are skeletally immature.

Adult↗
PubMed1987

Methods of banking bone and cartilage for allograft transplantation.

Storage of bone for use as allograft has become an important endeavor because banked bone is becoming increasingly useful and popular as a substitute for, or as a supplement to, autograft bone. Methods have been developed for safe and reliable bone banking, including standard criteria for acceptable donors, proven techniques of retrieval of tissue, and appropriate storage facilities and conditions. In contrast, cartilage banking is still an investigative procedure, but current research may provide more effective approaches to maintaining viable cells during freezer storage of osteochondral allografts.

Animals↗
PubMed1986

Restoration of spinal bone in osteoporotic men by treatment with human parathyroid hormone (1-34) and 1,25-dihydroxyvitamin D.

Daily subcutaneous injection of a synthetic human parathyroid hormone fragment, combined with daily ingestion of 1,25(OH)2 vitamin D, significantly increased trabecular bone density in the spine (p less than .01), and improved intestinal calcium and phosphorus absorption and total body retention of dietary calcium and phosphorus in middle-aged men with idiopathic osteoporosis. The increases in spinal bone mineral were marked and progressive during a year of treatment. These results indicate that increasing intestinal absorption of dietary calcium while simultaneously stimulating new bone formation with small doses of parathyroid hormone can restore spinal bone in osteoporotic men.

Adult↗
PubMed1986

Inhibition of the in vivo parathyroid hormone-mediated calcemic response in rats by a synthetic hormone antagonist.

The parathyroid hormone (PTH) analog, [Tyr34]bovine PTH-(7-34)-amide, can inhibit the PTH-mediated elevation of plasma calcium in thyroparathyroidectomized rats in vivo. The analog is devoid of PTH-like agonist activity in this system. Repeated doses of analog inhibit the animal's calcemic response to PTH. The elevation in serum calcium levels mediated by PTH in this assay reflects PTH action (calcium mobilization) on bone. Earlier studies demonstrated antagonist properties of the analog in a renal-based assay; PTH-stimulated increases in urinary phosphate and cyclic AMP excretion were completely inhibited by the synthetic analog. Along with previous studies, this report indicates that [Tyr34]bovine PTH-(7-34)-amide is an effective in vivo antagonist for several major parameters of PTH action in both kidney and bone.

Animals↗
PubMed1986

Osteomyelitis in Gaucher disease.

A relatively common complication of Gaucher disease, the so-called crisis, frequently is difficult to differentiate from acute osteomyelitis. We reviewed the cases of forty-nine patients with Gaucher disease who were treated at the Massachusetts General Hospital and found that eleven patients had required admission to the hospital for an acute symptom complex that represented either a crisis or an infection. Five of the patients proved to have acute hematogenous osteomyelitis. The delayed diagnosis of the infection in three of the patients with osteomyelitis led to an unsatisfactory outcome.

Acute Disease↗
PubMed1984

Vitamin D, rickets, and osteomalacia.

Rickets and osteomalacia result from a variety of inherited and acquired conditions, but affected individuals present with striking stereotypical features. In most cases, the bone disease can be cured, or at least improved, with appropriate therapy for the specific metabolic abnormality. In this article, the author provides a discussion of vitamin D metabolism and a detailed description of the clinical presentation, diagnosis, evaluation, and treatment of rickets and osteomalacia. He stresses the importance of orthopedic surgeons' awareness of these metabolic problems so that they may play a more active role in the diagnosis of these disorders and the effective management of the skeletal complications.

Bone and Bones↗
PubMed1983

Hematoma-induced febrile response in the pediatric patient.

Frequently there is a temperature elevation in children following operative procedures or trauma involving the long bones. A combined clinical and laboratory study investigated the possibility that this was secondary to blood resorption. A clinical study was conducted by reviewing the records of all children admitted to the hospital over a 10-year period with closed femoral or tibial fractures. All these patients demonstrated a temperature elevation to at least 101 degrees F. In the laboratory study, rabbits of different ages were bled, and this blood was reinjected into their quadriceps muscle to create hematomas. Control rabbits were hemorrhaged and either were not reinjected with their blood or were injected intramuscularly with lactated Ringer's solution. Those rabbits that received the intramuscular blood injections developed significant temperature elevations, and the younger the rabbit the more pronounced the temperature rise.

Adolescent↗
PubMed1983

1983 bone bank procedures.

Bone banks large enough to support an allograft program require dedicated medical personnel to manage them. A large potential donor population, extensive financial resources, and modern storage facilities are necessary. Infected donors and contamination of procured bones during storage and retrieval must be avoided at all costs. Detailed record keeping is of vital importance to clinical investigations, especially for evaluating complications. These considerations must be taken into account before embarking on an institutional bone banking program, to provide safe and satisfactory allogeneic bone for clinical use.

Bone Transplantation↗
PubMed1982

Osteoarticular and intercalary allograft transplantation in the management of malignant tumors of bone.

Since 1971, the Orthopaedic Service at the Massachusetts General Hospital has treated 106 patients with malignant or aggressive bone tumors by wide resection and replacement with frozen cadaveric allograft. Sixty-one of these patients have been followed for over two years (mean, 4.5 years), allowing a comprehensive end-results analysis. In 45 patients, mostly with giant-cell tumors of chondrosarcomas, the resection involved the articular end of a long bone and the replacement not only included bone, but glycerolized (to prevent freezing injury) and articular cartilage. Ten of the segments were intercalary (bone alone) and six involved a combination of bone and metallic joint prosthesis. Patients were graded as excellent, good, fair, or failure, depending principally on functional capacity. End-results analysis in this group showed that five of the 61 patients had either a local recurrence (2) and/or distant metastases (3); in five additional patients the limb was amputated or the implant removed, primarily because of infection (total failure rate, 16.5%). Forty-five (73.8%) had successful transplants (graded excellent or good) and were able to live essentially normal lives. Six of the patients (10%) required a brace or cane but three of these patients were able to return to preoperative work activities. Although the operations were arduous and difficult, and despite a high infection rate (13%) and occasional pathologic fractures (10%), the results compare favorably with other techniques used to restore the skeleton following massive segmental resection. In long-term follow-up, the data suggest that if no complication ensue in the first two years, the results are generally quite good and the grafts show no evidence of progressive deterioration with time.

Adolescent↗