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Biomedical subjects

R Ziegler

Publications and source records attributed to R Ziegler.

At least 145 records · Page 8Linked to original sources
PubMed1997

Endothelin-1 is a potent regulator of human bone cell metabolism in vitro.

Endothelial cell products may affect bone cell function, since trabecular and cortical bone are in close proximity to vascular endothelial cells. Incubation of cultured human osteoblastic cells with the endothelial cell polypeptide endothelin-1 (ET-1) resulted in a time- and dose-dependent stimulation of cell proliferation. Furthermore, markers of differentiated osteoblastic function, i.e., alkaline phosphatase and type-I collagen, were dose-dependently increased in response to ET-1. The effects of ET-1 on cell growth and function reached a maximum at higher ET-1 concentrations, and osteoblastic cells bound ET-1 specifically with a KD of 35 pM, corresponding to the biologic effects of ET-1 on bone cells. Under baseline conditions osteoblastic cells expressed 16,800 binding sites per cell. The effect of ET-1 was dependent on its binding to the endothelin-1 receptor A (ETRA), since an inhibitor of ET-1 binding blocked the biologic effects of ET-1. Northern blot analyses revealed that cultured human osteoblastic cells possess the transcript for the ETRA. Expression of ETRA mRNA was under control of 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3]. Incubation of osteoblastic cells with 1,25(OH)2D3 increased ETRA mRNA levels, corresponding to an increased effect of ET-1 on osteoblastic proliferation and function. Thus, a concerted action of the endothelial cell polypeptide ET-1 and 1,25(OH)2D3 may mediate an osteoanabolic effect of the vascular and endocrine vitamin D system.

Adult↗
PubMed1997

Skeletal site-dependent expression of the androgen receptor in human osteoblastic cell populations.

There are obvious sexual differences in adult skeletal morphology which for the most part are related to differences in size. Higher androgen serum levels in males exert potent osteoanabolic effects and therefore may contribute to this sexual dimorphism of the skeleton. The presence of androgen receptors (AR) in bone cells is a prerequisite for a direct osteoanabolic action of androgens. To investigate the possibility that, in addition to gender-related differences in androgen serum levels, there are also gender-related differences in the osteoblastic expression pattern of the androgen receptor, we examined AR mRNA expression, androgen binding sites, and mitogenic responses to the androgen dihydrotestosterone (DHT) in human osteoblastic cell (HOC) populations. HOCs were isolated from bone biopsy specimens derived from different skeletal sites of healthy adult males and females (2-69 years old). We found that male and female HOCs of all examined ages express similar AR mRNA levels and similar numbers of androgen binding sites. Using whole-cell-binding assays, we observed 3129-8417 androgen binding sites per femoral HOC with apparent KDs of 1.45-2.83 nM depending on the age of the investigated HOC population. Mandibular and cortical HOC of both sexes expressed higher AR mRNA levels, significantly more androgen binding sites per cell, and exhibited significantly greater mitogenic responses to DHT than iliac crest-derived and trabecular HOC of the same skeletal system and the same skeletal-site, respectively. In early adulthood, HOCs of both sexes appear to express somewhat higher AR mRNA levels and to possess more androgen binding sites than prepubertal and senescent HOC. Because sex hormone serum levels rise in puberty, we investigated the regulation of the AR mRNA expression by various steroids. We found that dexamethasone (dexa) and in some experiments also 17beta-estradiol (E2) and 1,25-dihydroxyvitamin D3 (D3) increased AR mRNA levels and androgen binding in HOC cultures. A pretreatment with dexa, E2, and D3 significantly increased the mitogenic response of HOCs to DHT. We conclude that (1) higher androgen serum levels in males together with a higher AR expression at certain skeletal sites may contribute to the development of sex-related differences in skeletal morphology, (2) glucocorticoids induce AR gene expression in HOC cultures, and (3) glucocorticoids, E2, and D3 enhance the mitogenic action of DHT.

Adolescent↗
PubMed1997

Tissue factor antigen is elevated in patients with microvascular complications of diabetes mellitus.

Patients with late diabetic complications have increased levels of parameters indicating activation of coagulation (Takakashi et al., 1989; Ceriello, 1993; Murakami et al., 1993; Kario et al., 1995; Shimizu et al., 1995; Yokoyama et al., 1996), endothelial cell damage (Jensen, 1989; Iwashima et al., 1990; Sernau et al., 1995; Gabath et al., 1996). TF is believed to activate the coagulation mechanism in patients with late complications of diabetes. We studied the TF antigen plasma levels in 72 patients with diabetes mellitus (36 type I, 36 type II) with respect to its relevance as a marker of microvascular diabetic complications. TF levels did not correlate with macrovascular disease, diabetes type or age. Sixty patients with decreased renal function not due to diabetes were studied for evaluation of the contribution of renal failure to TF antigen plasma levels. We did not find a significant correlation of TF with s-creatinine in non diabetic patients (r = 0.27, p > 0.05). However, TF levels were elevated in diabetic patients with microvascular disease. Patients with retinopathy had higher TF levels than without (0.30 ng/ml vs 0.11 ng/ml, p < 0.007). When patients were divided into subgroups according to the urine albumin concentration, TF antigen of patients without albuminuria (0.019 ng/ml, n = 25) did not differ from patients with microalbuminuria (0.095 ng/ml, n = 19 p > 0.05). However, TF levels were significantly higher in patients with macroalbuminuria (n = 28; 0.215 ng/ml, p < 0.005). Thus activation of coagulation in patients with microvascular complications of diabetes may be triggered by tissue factor.

Adult↗
PubMed1997

Current therapy of hypoparathyroidism--a survey of German endocrinology centers.

Hypoparathyroidism is a rare disease with hypocalcemia as the leading symptom. In adults, hypocalcemia is mainly due to postoperative hypoparathyroidism. Hypoparathyroidism requires lifelong therapy with vitamin D or metabolites. Genuine vitamin D3 (Vigantol) is the most economic treatment of hypoparathyroidism; however, vitamin D3 has a very long biologic half life with the subsequent danger of chronic vitamin D intoxication. Dihydrotachysterol (A.T.10), an analogue of vitamin D, acts similarly and can be used alternatively. 1,25-dihydroxyvitamin D3 (Rocaltrol), the biologically active metabolite of vitamin D3, is very potent, but bears the danger of causing acute intoxication; it has a short half life and is more expensive than vitamin D3. A further metabolite, 1-hydroxy-vitamin D3 (alfacalcidol, Doss, EinsAlpha) is available for therapeutic use. Clinical intervention trials concerning the best therapy and management of hypoparathyroidism are lacking. We therefore surveyed German physicians treating hypoparathyroidism. Furthermore, we carried out a retrospective study of 45 patients treated in our endocrinology department during the last 8 years and examined whether measurement of 25(OH)-vitamin D3 is helpful in managing hypoparathyroidism. The data from 59 children and 270 adults could be completed in the survey. 1,25-dihydroxyvitamin D3 was the only vitamin D agent that was administered in the treatment of children, whereas in adults 52% were treated with dihydrotachysterol, 28% with genuine vitamin D3, and 20% with 1,25-dihydroxyvitamin D3. There was a positive correlation between serum 25(OH)-vitamin D3 levels and administered vitamin D3 doses. In patients treated with vitamin D3, serum calcium levels correlated significantly with serum 25(OH)-vitamin D3 levels whereas they did not correlate with administered calcium doses. Thus: (1) in Germany dihydrotachysterol is preferred for therapy of hypoparathyroidism in adults and (2) measurement of serum 25(OH)-vitamin D3 may be helpful in assessing efficacy of therapy and compliance in patients treated with vitamin D3.

Adult↗
PubMed1997

The antioxidant properties of thioctic acid: characterization by cyclic voltammetry.

Thioctic acid (TA) level and its antioxidant capacity were monitored by cyclic voltammetry (CV), in solution and in human plasma. A linear correlation between the anodic wave current Ia at 900 mV and [TA] was obtained. This indicates that TA, commonly found in human plasma, is an antioxidant component characterized by a potential E1/2 = 900 mV and constitute, at least in part, the second anodic wave of the CV tracing. When plasma from diabetic patients was analyzed by CV, those patients under treatment with TA showed higher Ia than others not taking the drug. When the patients under treatment with TA were divided into groups according to the severity of their nephropathy, or according to the severity of their total complication count, Ia levels representing TA were significantly higher in those patients with more severe complications.

Adult↗
PubMed1997

Tumor necrosis factor increases serum leptin levels in humans.

Leptin is a pleiotropic hormone believed to regulate body weight. Its function in wasting during inflammatory disease in humans is unknown. We studied the effect of repeated tumor necrosis factor (TNF) infusion on serum leptin levels in six patients with solid tumors. TNF infusion on day 1 resulted in an increase in serum leptin levels from 3.1 (SEM +/- 0.28) ng/mL to 5.2 (SEM +/- 0.6) ng/mL after 12 h (P < 0.001). The serum levels returned to baseline within 24 h. Similar results were obtained when TNF was infused on subsequent days. The study shows that leptin serum levels are under control of TNF.

Aged↗
PubMed1997

Gonadal and adrenal androgens are potent regulators of human bone cell metabolism in vitro.

Androgens stimulate bone formation and play an important role in the maintenance of bone mass. Clinical observations suggest that both gonadal and adrenal androgens contribute to the positive impact of androgenic steroids on bone metabolism. We investigated the mechanism of action of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfated compound dehydroepiandrosterone sulfate (DHEAS) on human osteoblastic cells (HOCs) in vitro. The DHEA- and DHEAS-induced effects were analyzed in parallel with the actions elicited by the gonadal androgen dihydrotestosterone (DHT). There was no qualitative difference between the effects of gonadal and adrenal androgens on HOC metabolism in vitro. Both were stimulatory as regards cell proliferation and differentiated functions, but the gonadal androgen DHT was significantly more potent than DHEA. The actions of DHT and DHEA on HOC proliferation and alkaline phosphatase (ALP) production could be prevented by the androgen receptor antagonist hydroxyflutamide and inhibitory transforming growth factor beta antibodies (TGF-beta ab), respectively, but were not affected by the presence of the 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) and 5-alpha-reductase (5-AR) inhibitor 17 beta-N,N-diethylcarbamoyl-4-methyl- 4aza-5 alpha-androstan-3-one (4-MA). This indicates that DHT and DHEA (1) exert their mitogenic effects by androgen receptor-mediated mechanisms, (2) stimulate ALP production by increased TGF-beta expression, (3) that the action of DHT is not affected by the presence of 4-MA, and that (4) DHEA does not need to be metabolized by 3 beta HSD or 5-AR first to exert its effects on HOCs in vitro.

Adolescent↗
PubMed1997

Clinical grading of spinal osteoporosis: quality of life components and spinal deformity in women with chronic low back pain and women with vertebral osteoporosis.

Clinical consequences of osteoporotic vertebral fractures, such as back pain, functional limitations, and impairment of mood, are often cited as justification for prevention and therapy. But these symptoms are poorly characterized, and a clinical grading system is not available. The aim of this study was to compare clinical measures for spinal deformation and quality of life components between patients with osteoporosis and patients with chronic low back pain (CLBP) and to determine the relationship between spinal deformation and quality of life components. A total of 130 female patients (63 osteoporotic patients, 65 +/- 7.9 years, and 77 CLBP patients, 56 +/- 6.5 years) had a standardized interview on quality of life components (pain, activities of daily life, mood) and clinical measures of spinal deformation (height reduction [HR], distance from occiput to wall [DOW], and distance from iliac crest to ribs [DIR]). Spinal X-rays were reviewed in all patients for the evidence of vertebral fractures. In osteoporotic patients, vertebral deformity was quantified by the spine deformity index (SDI) on X-rays. It was assessed whether subgroups could be identified by a combination of indices for spinal deformation (SDI, HR, DOW) using a cluster analysis. Back pain was a major complaint in both groups, without differences in pain intensity and frequency. Impairment of general well being and mood was found in about one-third of the patients in both groups. Independent of age, the disability score was significantly higher in patients with osteoporosis than in patients with CLBP. Both groups differed with respect to clinical measures of spinal deformity (HR, DOW, DIR). Among osteoporotic patients, parameters of quality of life were not linearly related to the degree of radiologically assessed vertebral deformity, but osteoporotic patients with two or more vertebral fractures tended to have more functional limitations than those with only one fracture. There was, however, a significant linear relationship between components of quality of life (disability score, pain) and clinical measures of spinal deformation (HR, DOW, DIR). The osteoporotic patients were subdivided into three clusters. The first group was characterized by low spinal deformation (decreases SDI, decreases HR, decreases DOW) and little impairment of quality of life. The second group had significantly greater spinal deformation (increases SDI, increases HR, increases DOW) and significantly more pain and functional limitations. The third group was characterized by increased kyphosis, mainly caused by nonskeletal dysfunction (decreases SDI, decreases HR, increases DOW), but pain and functional limitations were impaired to the same degree as in the second group with severe skeletal spinal deformation. We conclude that with respect to quality of life components, functional limitation is the most specific to spinal osteoporosis and is related to clinical measures of spinal deformation. Furthermore, spinal deformation and the clinical course of osteoporosis appears to be insufficiently reflected by radiological indices of vertebral deformity (such as SDI) alone. For grading the disease and for therapeutical concepts, radiological measures and clinical evaluation should be considered in combination.

Aged↗
PubMed1997

Suppression of serum thyrotropin with thyroxine in patients with Graves' disease: effects on recurrence of hyperthyroidism and thyroid volume.

Based on findings that thyroxine may have a beneficial effect on the recurrence of Graves' hyperthyroidism, we prospectively studied the effects of a TSH suppressive treatment with thyroxine on the course of Graves' disease in fifty patients with recent onset of hyperthyroidism. After the normalization of serum tri-iodothyronine (T3) and thyroxine (T4) concentrations, one group of patients was randomly assigned to a combined treatment with carbimazole and a TSH suppressive dose of T4 for 12 months, followed by another 12 months of TSH suppressive therapy alone. The other group of patients also received carbimazole for one year, but T4 was only added as indicated to normalize elevated TSH serum concentrations, and patients received no therapy during the second year. By the end of the second year, a relapse of hyperthyroidism had occurred in 43% of the patients with and in 45% of the patients without suppressive T4 treatment. In those patients without a relapse of hyperthyroidism, initial thyroid size significantly (P = 0.01) decreased with time in both treatment groups. However, patients on suppressive T4 treatment tended to have a greater reduction in thyroid volume than patients with normal TSH serum concentrations (P = 0.05). In conclusion, we were unable to detect a preventive effect of exogenous TSH suppression on the recurrence of hyperthyroidism. However, our data suggest that TSH suppressive treatment may have a beneficial effect on thyroid enlargement in Graves' disease.

Adrenergic beta-Antagonists↗
PubMed1997

Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells.

Depletion of cellular antioxidant defense mechanisms and the generation of oxygen free radicals by advanced glycation end products (AGEs) have been proposed to play a major role in the pathogenesis of diabetic vascular complications. Here we demonstrate that incubation of cultured bovine aortic endothelial cells (BAECs) with AGE albumin (500 nmol/l) resulted in the impairment of reduced glutathione (GSH) and ascorbic acid levels. As a consequence, increased cellular oxidative stress led to the activation of the transcription factor NF-kappaB and thus promoted the upregulation of various NF-kappaB-controlled genes, including endothelial tissue factor. Supplementation of the cellular antioxidative defense with the natural occurring antioxidant alpha-lipoic acid before AGE albumin induction completely prevented the AGE albumin-dependent depletion of reduced glutathione and ascorbic acid. Electrophoretic mobility shift assays (EMSAs) revealed that AGE albumin-mediated NF-kappaB activation was also reduced in a time- and dose-dependent manner as long as alpha-lipoic acid was added at least 30 min before AGE albumin stimulation. Inhibition was not due to physical interactions with protein DNA binding, since alpha-lipoic acid, directly included into the binding reaction, did not prevent binding activity of recombinant NF-kappaB. Western blots further demonstrated that alpha-lipoic acid inhibited the release and translocation of NF-kappaB from the cytoplasm into the nucleus. As a consequence, alpha-lipoic acid reduced AGE albumin-induced NF-kappaB mediated transcription and expression of endothelial genes relevant in diabetes, such as tissue factor and endothelin-1. Thus, supplementation of cellular antioxidative defense mechanisms by extracellularly administered alpha-lipoic acid reduces AGE albumin-induced endothelial dysfunction in vitro.

Antioxidants↗
PubMed1997

Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM.

OBJECTIVE: While elevated blood levels of homocyst(e)ine represent an independent risk factor for macrovascular disease, we assessed the link between hyperhomocyst(e)inemia and diabetic microvascular diseases. RESEARCH DESIGN AND METHODS: Plasma levels of homocyst(e)ine and thrombomodulin (TM), markers of endothelial cell damage, were measured before and 3 h after oral methionine loading in 75 patients with IDDM and 40 healthy control subjects matched for sex and age. Exclusion criteria were hyperlipidemia, hypertension, smoking, or positive family history for cardiovascular disease. RESULTS: IDDM patients had higher pre- and postload plasma levels of homocyst(e)ine than did healthy control subjects (12.0 vs. 7.7 mumol/l and 27.6 vs. 16.0 mumol/l; P < 0.001). Of 75 IDDM patients, 26 had plasma homocyst(e)ine levels above the normal range (means +/- 2 SD of values obtained in the control group). These IDDM patients with hyperhomocyst(e)inemia had higher plasma TM levels (62.2 vs. 38.2 ng/ml, P < 0.001), higher albumin excretion rates (485 vs. 115 mg/l, P < 0.005), and a higher prevalence of late diabetic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs. 51%; neuropathy, 57 vs. 41%; and macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells showed an increased release of TM into the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might contribute to vascular complications in patients with diabetes. CONCLUSIONS: Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.

Administration, Oral↗
PubMed1997

Virtual reality in the operating room of the future.

In cooperation with the Max-Delbrück-Centrum/Robert-Rössle-Klinik (MDC/RRK) in Berlin, the Fraunhofer Institute for Computer Graphics is currently designing and developing a scenario for the operating room of the future. The goal of this project is to integrate new analysis, visualization and interaction tools in order to optimize and refine tumor diagnostics and therapy in combination with laser technology and remote stereoscopic video transfer. Hence, a human 3-D reference model is reconstructed using CT, MR, and anatomical cryosection images from the National Library of Medicine's Visible Human Project. Applying segmentation algorithms and surface-polygonization methods a 3-D representation is obtained. In addition, a "fly-through" the virtual patient is realized using 3-D input devices (data glove, tracking system, 6-DOF mouse). In this way, the surgeon can experience really new perspectives of the human anatomy. Moreover, using a virtual cutting plane any cut of the CT volume can be interactively placed and visualized in realtime. In conclusion, this project delivers visions for the application of effective visualization and VR systems. Commonly known as Virtual Prototyping and applied by the automotive industry long ago, this project shows, that the use of VR techniques can also prototype an operating room. After evaluating design and functionality of the virtual operating room, MDC plans to build real ORs in the near future. The use of VR techniques provides a more natural interface for the surgeon in the OR (e.g., controlling interactions by voice input). Besides preoperative planning future work will focus on supporting the surgeon in performing surgical interventions. An optimal synthesis of real and synthetic data, and the inclusion of visual, aural, and tactile senses in virtual environments can meet these requirements. This Augmented Reality could represent the environment for the surgeons of tomorrow.

Computer Simulation↗
PubMed1997

The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B.

The natural occurring pigment curcumin, a major component of the spice tumeric, has been described to have antioxidative, anti-tumorpromoting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibition of the transcription factors NF-kappa B and AP-1. This study investigates the effect of curcumin on the TNF alpha induced expression of endothelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-kappa B. When bovine aortic endothelial cells (BAEC) were preincubated in the presence of curcumin, TNF alpha induced TF gene transcription and expression were reduced. Transient transfection studies with TF-promoter plasmids revealed that both, NF-kappa B and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumin inhibited TNF alpha induced I kappa B alpha degradation and the nuclear import of NF-kappa B. In contrast, inhibition of AP-1 was due to a direct interaction of curcumin with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-kappa B and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro.

Animals↗
PubMed1997

[Impact of pretreatment variables on the outcome of standardized 131I therapy with 150 Gray in Graves' disease].

AIM: We examined the impact of several pretreatment variables on thyroid size and function in 61 patients with Graves' disease one year after a standardized [131]I treatment with 150 Gray. METHODS: FT3, FT4, and TSH serum concentrations were determined before and 1.5, 3, 6, and 12 months after therapy. Thyroid size was measured by ultrasound and scintigraphy before and one year after therapy. RESULTS: One year after therapy, 30% of the patients had latent or manifest hyperthyroidism, 24% were euthyroid, and 46% had developed latent or manifest hypothyroidism. Age and initial thyroid volume were major predictors of post-therapeutical thyroid function. Thus, persistent hyperthyroidism was observed in 70% of the patients age 50 years and older with a thyroid size of more than 50 ml. With few exception, thyroid size markedly decreased after therapy. Initial thyroid size and age were also major predictors of posttherapeutical thyroid volume. Thyroid size normalized in all patients younger than 50 years of age, independent from initial thyroid size. CONCLUSION: Radioiodine treatment with 150 Gray causes a considerable decrease in thyroid size in most patients with Graves' disease. Age and initial thyroid volume are important determinants of thyroid function and size after therapy and should be considered in dose calculation.

Adult↗
PubMed1997

Improved purification of human bone sialoprotein and development of a homologous radioimmunoassay.

Bone sialoprotein (BSP) is a phosphorylated skeletal glycoprotein. Here we describe a new procedure for the purification of BSP involving wide-pore reversed-phase HPLC, and the development of a homologous RIA for human BSP. The immunoassay showed linearity between 3 and 120 micrograms/L, a lower detection limit of 0.7 micrograms/L, and a mean recovery rate of 99.4%. Intraassay variation was 7.0% (mean = 10.9 micrograms/L) and 6.1% (mean = 38.8 micrograms/L), and interassay variation was 9.2% (mean = 11.1 micrograms/L) and 9.4% (mean = 39.0 micrograms/L). No cross-reactivity was detected with osteocalcin, osteonectin, or bone alkaline phosphatase. Preliminary clinical evaluation in healthy controls (n = 90) showed a mean serum BSP concentration on 12.1 +/- 5.0 micrograms/L (+/- SD). BSP was significantly increased in patients with Paget disease of bone, primary and secondary hyperparathyroidism, and also in subjects with renal failure without skeletal involvement. Impairment of hepatic function did not affect serum BSP concentrations.

Adult↗
PubMed1996

Intravenous somatic gene transfer with antisense tissue factor restores blood flow by reducing tumor necrosis factor-induced tissue factor expression and fibrin deposition in mouse meth-A sarcoma.

Fibrin is deposited on the endothelial cell surface in the vasculature of murine methylcholanthrene A-induced sarcomas after injection of tumor necrosis factor (TNF). Capillary endothelial cells of the tumor vascular bed become positive for tissue factor after TNF injection, based on immunocytochemistry and in situ hybridization. Intravascular clot formation was not dependent on tissue factor derived from tumor cells, since in vessels of tumors not expressing tissue factor, TNF also induced fibrin/fibrinogen deposition. However, the time course of fibrin/fibrinogen deposition after TNF differed in tumors expressing no, little, or greater amounts of tissue factor. Fibrin/fibrinogen deposition was more rapid in tumors in which the neoplastic cells expressed tissue factor than in tumors not expressing tissue factor. In the tumors not expressing tissue factor, activation of coagulation was dependent on TNF-induced synthesis of tissue factor by host cells, i.e., endothelium or monocytes/macrophages. Intravenous somatic gene transfer with tissue factor cDNA in the antisense orientation (but not sense or vector alone) reduced intravascular fibrin/fibrinogen deposition and restored blood flow to the tumor, showing that de novo tissue factor expression is central in TNF-induced activation of the coagulation mechanism.

Animals↗