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Biomedical subjects

S Teitelbaum

Publications and source records attributed to S Teitelbaum.

At least 19 recordsLinked to original sources
PubMed1999

Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.

beta3 integrins have been implicated in a wide variety of functions, including platelet aggregation and thrombosis (alphaIIbbeta3) and implantation, placentation, angiogenesis, bone remodeling, and tumor progression (alphavbeta3). The human bleeding disorder Glanzmann thrombasthenia (GT) can result from defects in the genes for either the alphaIIb or the beta3 subunit. In order to develop a mouse model of this disease and to further studies of hemostasis, thrombosis, and other suggested roles of beta3 integrins, we have generated a strain of beta3-null mice. The mice are viable and fertile, and show all the cardinal features of GT (defects in platelet aggregation and clot retraction, prolonged bleeding times, and cutaneous and gastrointestinal bleeding). Implantation appears to be unaffected, but placental defects do occur and lead to fetal mortality. Postnatal hemorrhage leads to anemia and reduced survival. These mice will allow analyses of the other suggested functions of beta3 integrins and we report that postnatal neovascularization of the retina appears to be beta3-integrin-independent, contrary to expectations from inhibition experiments.

Animals↗
PubMed1996

Deriving respiration from pulse wave: a new signal-processing technique.

Investigations of autonomic nervous system activity using spectral analysis of heart rate (HR) and blood pressure (BP) variability is very popular in many scientific disciplines, and yet only half of all studies involving spectral analysis control for respiration. Because respiration modulates HR and BP variability, knowledge of the respiratory rate is necessary for the proper interpretation of HR and BP power spectra. We devised and validated a new signal-processing technique to derive respiration from the blood pressure wave. This technique is based on the relationship between oscillations in the area under the dicrotic notch of the pulse wave and respiration. The results of our view signal-processing technique yielded significant correlations between protocols of the actual number of respiratory cycles and our blood pressure-derived respiratory cycles and their respective spectra for a number of standard autonomic tests (P < 0.05). Our method will allow retrospective extraction of the respiratory wave and as such afford a more precise interpretation of HR and BP spectra.

Adult↗
PubMed1993

1 alpha,25-dihydroxyvitamin D3 up-regulates expression of the osteoclast integrin alpha v beta 3.

Osteoclast precursors selectively attach to bone and differentiate into multinucleated cells that function to remodel and resorb it. We have shown previously that attachment of osteoclasts to bone and subsequent resorption are mediated by the integrin alpha v beta 3. 1 alpha,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) enhances osteoclast precursor differentiation in vivo by mechanisms that are still not clearly understood but entail enhanced attachment of cells to bone. This observation raises the possibility that at least one component of vitamin D-induced osteoclast precursor differentiation involves modulation of integrin expression. To test if the steroid modulates the osteoclast integrin alpha v beta 3 (the vitronectin receptor), we examined the effects of 1,25-(OH)2D3 on transcription of the alpha v gene as well as surface expression and function of alpha v beta 3, in chicken osteoclast precursors. Treatment of the cells with 1,25-(OH)2D3 led to a progressive dose-dependent increase in steady state alpha v mRNA levels with enhanced expression evident within 24 h. The effect was receptor-mediated as indicated by the effects of other vitamin D analogs. The increase in alpha v mRNA levels did not reflect decreased message degradation but, as demonstrated by nuclear run-on experiments, was due to accelerated rates of transcription. Most importantly, induction of alpha v mRNA by 1,25-(OH)2D3 was mirrored by higher levels of expression of alpha v beta 3 on the cell surface, as well enhanced attachment to its substrate, vitronectin.

Animals↗
PubMed1991

Histopathology of bacillary angiomatosis of lymph node.

Bacillary angiomatosis, a recently characterized pseudoneoplastic vascular proliferation caused by a bacterium identical or related to the cat-scratch disease bacillus, usually presents as cutaneous lesions. We report the histologic findings of this disease involving the lymph nodes of two immunocompromised patients. The lymph nodes showed patchy involvement by coalescent nodules of proliferated blood vessels lined by plump endothelial cells with pale cytoplasm. There were foci exhibiting mild to moderate nuclear atypia. Although neutrophil infiltration was prominent in one case, it was minimal in the other. The interstitium was formed by pink-staining material in hematoxylin-eosin-stained sections, and this proved to be aggregated bacilli on Warthin-Starry stain. Recognition of this potentially fatal disease is important because it is curable with antibiotics.

Adult↗
PubMed1988

Ca2+ priming during vitamin D-induced monocytic differentiation of a human leukemia cell line.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) induces monocytic differentiation of the human promyelocytic leukemia line, HL-60, and enhances Ca2+ transport in target cells of the mineral metabolism system. Hence, we determined whether the steroid's maturational effect on HL-60 involves alterations of intracellular calcium [( Ca2+]i). We found that, as detected by indo-1 fluorescence, [Ca2+]i increases in a slow tonic manner from 99 +/- 11 nM in virgin HL-60 to 182 +/- 19 nM (p less than 0.001) in those treated with 1,25-(OH)2D3 for 24 h. The first apparent rise in [Ca2+]i occurs at between 6 and 12 h and parallels expression of alpha-thrombin and N-formyl-methionyl-leucyl-phenylalanine (fMLP) receptors. This increase in [Ca2+]i is derived from extracellular calcium as its reduction abolishes the effect. The increase in [Ca2+]i is associated with an increase in inositol trisphosphate-stimulated Ca2+ flux from intracellular stores. Interestingly, 1,25-(OH)2D3-mediated HL-60 differentiation as manifest by expression of the macrophage-specific antigen, 63D3, is not blocked by low extracellular calcium. In contrast, the fMLP-induced superoxide ion generation is diminished if the increase in [Ca2+]i is prevented. Furthermore, fMLP-stimulated signal transduction is also reduced by limiting the stimulation of [Ca2+]i during 1,25-(OH)2D3 treatment. Thus, although differentiation of HL-60 to the monocytic phenotype by 1,25-(OH)2D3 is Ca2+-independent, expression of response to regulatory stimuli requires priming of cellular Ca2+ stores. The latter appears to be induced by 1,25-(OH)2D3 via stimulated Ca2+ entry through the plasma membrane.

Biological Transport↗
PubMed1987

Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis.

Osteoporosis is a state of reduced skeletal mass characterized by various rates of bone remodeling. Multiple locally elaborated factors have been identified that appear to influence the cellular events in bone remodeling. The possible role(s) of these factors in the pathogenesis of osteoporosis is unknown. One such factor, interleukin 1 (IL-1), is of particular interest, as this protein is known to stimulate bone resorption and perhaps formation. Consequently, we have measured the spontaneous secretion of IL-1 activity by cultured peripheral blood monocytes obtained from 22 osteoporotic patients and 14 age-matched control subjects. Monocytes from osteoporotic patients produced more IL-1 than did monocytes from control subjects. When patients were grouped according to monocyte-produced IL-1 activity, dynamic parameters of bone formation, as judged by quantitative histomorphometric analysis of iliac crest bone biopsies and by circulating levels of bone 4-carboxyglutamic acid protein (BGP)--a marker of bone formation--were higher in subjects with elevated IL-1 activity; whereas, indices of bone resorption and static indices of bone formation were similar in subjects with either high or normal IL-1 activity. IL-1 activity released by peripheral blood monocytes appears to reflect bone formation rate in osteoporotic patients and may be of pathogenetic significance in a subset of individuals with osteoporosis.

Adult↗
PubMed1987

Biological effects of aluminum on normal dogs: studies on the isolated perfused bone.

Although it is well known that aluminum (Al) plays a role in the development of osteomalacia in patients with chronic renal failure, the mechanisms are not fully understood. Since the osteoblasts are the cells responsible for the formation of osteoid tissue, which is greatly affected in patients with Al-induced osteomalacia, it is possible that Al could affect the number of osteoblasts or interfere with their function. To further characterize this potential mechanism, we performed studies in isolated perfused tibiae from normal and Al-treated dogs. In this system, when PTH is added to the perfusate, cAMP, a major marker of osteoblasts, is released. The dogs were divided into two groups: control, and Al-treated (0.75 mg/kg, iv, 5 days a week for 3 months). Thereafter, the dogs were killed, and the tibiae were perfused in vitro. PTH-(1-34) (3-4 ng/ml) and 3-isobutyl-1-methylxanthine (an inhibitor of phosphodiesterase) were added to the perfusate. Basal cAMP secretion was the same in both groups of dogs. After PTH was added to the perfusate, cAMP increased to a peak of 188.2 +/- 30.6 pmol/min in the normal dogs vs. 113 +/- 8.15 in Al-treated dogs (P less than 0.05). Cumulative cAMP secretion over a 30-min period was 766 +/- 127.9 pmol in the normal dogs vs. 455.6 +/- 38.2 pmol in the experimental animals (P less than 0.05). The histological appearance of bone biopsies taken before and after Al administration are consistent with a suppressive effect of the cation on osteoblast function. In particular, the number of osteoblasts had decreased 8-fold (P less than 0.01) under the influence of Al, and tetracycline-based measurements of mineralization kinetics show that osteoblast-mediated calcification was dysfunctional (P less than 0.01-0.025). On the other hand, the histological features of the post Al treatment biopsies suggest that at some time during its administration, the cation stimulates osteoblastic activity. For example, new (woven) bone formation was present in two dogs, and in another, lamellar bone, deposited under the influence of Al, covered the entire trabecular surface. Moreover, Al-associated osteoid was deposited independent of prior resorptive activity, indicating that the cation promotes bone formation in the absence of prior resorption. In keeping with its trophic effect on matrix deposition, Al also led to extensive marrow fibrosis in five dogs, indicating that Al also stimulates the activity of fibroblasts, cells closely related to osteoblasts.(ABSTRACT TRUNCATED AT 400 WORDS)

Aluminum↗
PubMed1986

Observations of end-user online searching behavior over eleven years.

End-user searching of National Library of Medicine (NLM) online data bases during eleven years has been investigated through transaction logs, questionnaires, and follow-up interviews. From 1976 through 1984, pathologists and pharmacists performed 8,313 searches. Highlights of our studies are compared with a review of other end-user research. Volume of searching is directly related to the convenient placement of the terminal in the work place. Slightly fewer than half of all potential searchers actually search for themselves. Practices of pharmacists and pathologists do not differ in important ways. Nonmediated searchers feel they need answers more promptly than do those who obtain mediated searches. End-users perform very simple searches, mostly using only the AND operator. Problems with techniques are fewer and more easily solved than those with the vocabulary and content of the system. The major problems, with the most powerful capabilities of MEDLINE--subheadings and explosions--sometimes cause substantial loss of references, but in relatively few searches. One-on-one teaching is most popular, with trial-and-error the most frequent procedure used in actual learning.

Data Collection↗
PubMed1986

Regional cerebral cortical deficits in the immune-deficient nude mouse: a preliminary study.

This report examines the morphology of the cerebral cortex in the nude mouse (nu/nu) compared with the BALB/c(+/+). Our experiments indicated that the thickness of the lateral frontal lobe was significantly reduced (8%; P less than 0.005) in the 4-month-old, female nude mouse compared with a BALB/c mouse of like sex and age. In addition, the left hemisphere was, in general, thinner in the nude than in the BALB/c, with area 18 being significantly thinner (2%; P less than 0.005). Oligodendrocytes were less in area 18 in the nude by 25% (P less than 0.02) in contrast to the BALB/c. In some respects these results extend the work of others. In previously published experiments, we showed that the thickness of the frontal cortex from enriched and impoverished female rats (from 60 to 116 days of age) differed by 2 to 3% (P less than 0.001) and in male rats by 3 to 4% (P less than 0.001). The oligodendrocytes in area 18 in the male differed by 20% (P less than 0.02) in rats exposed to their respective enriched or impoverished environments from 25 to 105 days of age. Thus, we have shown that the frontal cortical morphology as well as the occipital cortical oligodendrocytes were altered in both immune-deficient animals and environmentally stimulated or impoverished animals. Based on these separate sets of data, we will be interested to learn if our environmental conditions can alter the immune system and if so by what mechanism.

Animals↗
PubMed1986

The effects of discontinuation of aluminum exposure on aluminum-induced osteomalacia.

Studies in patients on dialysis have shown that aluminum (Al) accumulation in bone plays a major role in the pathogenesis of osteomalacia. It has been suggested that deferoxamine (DFO) may be beneficial in the treatment of aluminum-induced osteomalacia. The present studies were performed in four groups of uremic rats to determine if DFO and/or discontinuation of Al administration have an effect on bone histomorphometry and blood chemistries. The groups were: 1) uremic control 2) aluminum (0.75 to 1.0 mg/rat i.p., five times a week for twelve weeks): 3) aluminum + DFO, after twelve weeks Al was discontinued and the rats received DFO (75 mg/rat two times a week for nine weeks); 4) aluminum + time, after twelve weeks Al was discontinued and the rats were sacrificed after nine weeks. High levels of Al in serum and bone and low levels of PTH were seen in rats receiving Al. Bone histology revealed Al at the mineralization front, abnormal tetracycline uptake, and an increase in osteoid. DFO treatment did not significantly change the level of Al in bone, however both DFO treatment and discontinuation of Al reversed towards normal the above described lesions. In conclusion, these studies suggest that DFO and/or discontinuation of Al administration to rats with approximately 30% of renal function greatly improve aluminum-induced osteomalacia.

Aluminum↗
PubMed1984

Effect of 24,25(OH)2D3 on PTH levels and bone histology in dogs with chronic uremia.

Controversy exists as to whether 24,25(OH)2D3 has a direct inhibitory effect on parathyroid hormone (PTH) secretion. Therefore, the present investigation examined the effect of long-term administration of 24,25(OH)2D3 on immunoassayable PTH levels (iPTH) and bone histology in dogs with chronic renal failure. Chronic renal failure was produced in 16 dogs, half of which served as controls whereas the other half received 2.5 micrograms/day of 24,25(OH)2D3, orally. Serum iPTH, serum total, ionized calcium, serum phosphorus, and creatinine were followed at weekly or biweekly intervals in both groups. Also, creatinine clearances, serum levels of 25(OH)D3, 24,25(OH)2D3, and 1,25(OD)2D3 and the intestinal absorption of calcium were measured. After 1 year of chronic renal failure the dogs were sacrificed and rib biopsy specimens were obtained for histological examination and measurement of mineral content. Serum iPTH increased equally in the two dog groups with no effect at any time of 24,25(OH)2D3 treatment, despite a significant increase in the serum levels of 24,25(OH)2D3 and a concomitant decrease of the 1,25(OH)2D3 levels. There was no difference in the levels of serum calcium or in the calcium content of bone. Furthermore, after 8 months of uremia three control dogs were switched to the group treated with 24,25(OH)2D3 and followed for another 7 months. No suppressive effect of administering 24,25(OH)2D3 on the iPTH levels could be demonstrated in these three dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

24,25-Dihydroxyvitamin D 3↗
PubMed1983

Altered adenosine 3',5'-monophosphate release in response to parathyroid hormone by isolated perfused bone from glucocorticoid-treated dogs.

The interaction between glucocorticoids (GC) and PTH has been suggested to play a role in the pathogenesis of GC-induced osteopenia. The present studies were designed to examine the effect of acute (5-h) or chronic (4-week) GC administration in vivo on 1) cAMP release by the isolated perfused dog tibia before (basal) and after the addition of synthetic bovine PTH-(1-34) [syn bPTH-(1-34)] (stimulated) to the perfusate in vitro, in the presence or absence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX; 1 mM), and 2) the percent arteriovenous difference of immunoreactive PTH across bone. Acute administration of 6 mg/kg methylprednisolone (MP) did not affect the basal release of cAMP from bone (6.9 +/- 1.6 pmol/min in control vs. 6.1 +/- 1.2 pmol/min in MP-treated animals); however, syn bPTH-(1-34) stimulated release of cAMP was higher in the MP-treated animals (45 +/- 8.1 pmol/min) than in controls (26.8 +/- 3.0 pmol/min). When IBMX was added to the perfusate, basal cAMP release was not different in control and MP-treated bone (17.2 +/- 2.1 pmol/min in control vs. 19.1 +/- 1.9 pmol/min in MP-treated bone), and syn bPTH-(1-34)-stimulated release of cAMP was equivalent in both groups. In contrast, chronic prednisone therapy lead to a decrease in both basal and PTH-stimulated release of cAMP from bone (3.1 +/- 0.4 and 6.9 +/- 1.6 pmol/min for basal, and 13.1 +/- 1.7 and 26.8 +/- 3.0 pmol/min for stimulated values, respectively). However, the percent changes from the basal levels were not different in the two groups. These results were correlated with histological studies of rib biopsies obtained from these animals, which showed evidence of osteopenia and decreased bone turnover. Neither acute nor chronic GC administration had any effect on arterio-venous differences for PTH across the bone. Thus, these studies demonstrate that 1) acute administration of MP enhances the response of bone to PTH, an effect that is not apparent in the presence of the phosphodiesterase inhibitor IBMX; and 2) chronic prednisone therapy decreased basal and PTH-stimulated cAMP release, an effect that correlated with histological evidence of decreased bone turnover.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Absence of metabolic bone disease in adult patients with the nephrotic syndrome and normal renal function.

Patients with the nephrotic syndrome and normal renal function have low levels of 25(OH)D in serum presumably due to the loss of this metabolite in the urine. Osteomalacia and hyperparathyroidism have been recently reported to occur as a consequence of those low levels of 25-hydroxyvitamin D (25OHD). We studied six patients (aged 26-52 yr) with the nephrotic syndrome (mean duration, 6.7 yr; range, 2-12 yr) and normal renal function, and evaluated their calcium, phosphorus, PTH, and vitamin D metabolite levels. Bone biopsies were obtained in all patients. The creatinine clearance ranged from 83-134 ml/min . 1.73 m2 of body surface, serum albumin was 2.65 +/- 0.42 (+/- SD) g/100 ml, and proteinuria ranged from 3.5-13.2 g/24 h. All patients had normal serum magnesium, phosphorus, ionized calcium, and alkaline phosphatase (total and bone fraction), and normal roentgenographic metabolic bone survey. Serum PTH, measured by the carboxy-terminal RIA, was 5.1 +/- 2.3 mu leq/ml (normal, 2-10), serum 250HD was 8.8 +/- 4.0 ng/ml (normal, 15-30), and 1,25-dihydroxyvitamin D3 was 38 +/- 25 pg/ml (normal, 17-58). Serum vitamin D-binding protein was 420 +/- 42 micrograms/ml (normal, 400-800). The histological appearance of bone biopsies obtained in these patients was not different from that in a group of sex- and age-matched controls. Specifically, there was no increase in the volume of osteoid (unmineralized bone), the percentage of trabecular surface covered by osteoid, or the number of osteoclasts. The cellular rate of mineralization was normal in all six patients. Thus, these data indicate that low serum levels of 250HD in patients with the nephrotic syndrome and normal renal function do not necessarily result in the development of osteomalacia and/or hyperparathyroidism.

Adult↗
PubMed1979

Serum concentrations of 25-hydroxyvitamin D in rickets of extremely premature infants.

Nine premature infants developed radiographic and biochemical rickets at a mean +/- SD of 12.6 +/- 2.8 weeks of age. Serum 25-hydroxyvitamin D concentrations were all low, with a mean of less than 3.6 +/- 2.1 ng/ml. The mean average daily intake of vitamin D since birth had been 300 +/- 181 IU, and the mean average daily intake during the week of diagnosis was 587 +/- 313 IU. All of the infants were extremely premature (mean weight 948 +/- 153 gm, mean gestation 27.7 +/- 1.1 weeks), and were being fed either a low-calcium "human milk-like" formula or a soy formula. It is postulated that low-calcium intake may have increased 25-OHD utilization in the face of a decreased ability of the extremely premature infant to produce 25-OHD. Because of multiple factors leading to both decreased production and possible increased utilization of 25-OHD, such infants have an increased requirement for vitamin D to maintain normal serum 25-OHD concentrations, and daily intakes of at least 400 IU vitamin D orally must be assured. Serum 25-OHD measurements and radiographs may be important in following infants at risk.

Humans↗
PubMed1979

Evidence for skeletal resistance to parathyroid hormone in magnesium deficiency. Studies in isolated perfused bone.

Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83+/-0.1 mg/100 ml) and experimental dogs (serum Mg 1.34+/-0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5+/-3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1+/-1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8+/-0.2 to 17.5+/-0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5+/-0.1 pmol/min, and increased to only 7.1+/-0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency.

Animals↗