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Biomedical subjects

J A Gasser

Publications and source records attributed to J A Gasser.

10 recordsLinked to original sources
PubMed2001

Bone tissue and its mineralization in aged estrogen-depleted rats after long-term intermittent treatment with parathyroid hormone (PTH) analog SDZ PTS 893 or human PTH(1-34).

Intermittently administered parathyroid hormone (PTH) is a potent bone anabolic agent. We aimed to determine the impact of long-term treatment with PTH on bone structure, dynamics, and mineralization. We ovariectomized (ovx) 1-year-old rats with the exception of a baseline and a sham-operated group. Twelve weeks later, a 36 week treatment with PTH analog SDZ PTS 893 (12.5, 25, 50, 100 microg/kg), human PTH(1-34) (25, 50, 100 microg/kg), or vehicle (ovx, sham) was initiated. Bone dynamics, structure, and mineralization were evaluated in the lumbar spine and in the femoral diaphysis. Cancellous bone turnover was elevated 12 weeks postovariectomy in estrogen-deficient, vehicle-treated animals, but returned to the level of the sham group by 48 weeks. The animals experienced substantial cancellous bone loss associated with a reduction of trabecular number and presented with a partly rod-like trabecular network. After 36 weeks of treatment with SDZ PTS 893 or human PTH(1-34), cancellous bone formation rates and turnover were raised in all treated groups compared with age-matched controls. The mineral apposition rate was increasing with dose. This amplified matrix synthesis led to trabecular thickening, but not to an increase in trabecular number, resulting in a crude, plate-like cancellous network with a high bone volume fraction. Fluorochrome label-based cortical bone dynamics demonstrated that a thick ring of new bone was formed at the endocortex by activation of modeling drifts during treatment. Treatment-induced cortical bone formation was increased with dose at the subperiosteal and endocortical envelopes, but substantially higher at the latter. Intracortical bone turnover was elevated near the endocortex. Bone mineralization was undisturbed in all compartments. The average degree of mineralization was lowered slightly, reflecting the increased portion of new bone formed during treatment. In summary, the main anabolic effect was mediated for both peptides by an increase in bone apposition with dose, persisting throughout treatment that lasted more than one third of the lifespan of the rats, and direct activation of bone-forming surfaces. As a result, a substantial amount of new bone, maintained at elevated turnover and adequate mineralization levels, formed predominantly at compartments exposed to bone marrow.

Aging↗
PubMed2000

Systemic administration of a novel octapeptide, amylin-(1---8), increases bone volume in male mice.

Amylin increases bone mass when administered systemically to mice. However, because of its size, the full peptide is not an ideal candidate for the therapy of osteoporosis. The fragment, amylin-(1---8), stimulates osteoblast proliferation in vitro, although it is without effect on carbohydrate metabolism. The present study assessed the effects of daily administration of this peptide on sexually mature male mice for 4 wk. Amylin-(1---8) almost doubled histomorphometric indices of osteoblast activity but did not change measures of bone resorption. Trabecular bone volume increased by 36% as a result of increases in both trabecular number and trabecular thickness, and tibial cortical width increased by 8%. On three-point bending tests of bone strength, displacement to fracture was increased by amylin-(1---8), from 0.302 +/- 0.013 to 0.351 +/- 0. 017 mm (P = 0.02). In a separate experiment using dynamic histomorphometry with bone-seeking fluorochrome labels, amylin-(1---8) was administered by local injection over the calvariae of female mice. Amylin-(1---8) (40 nM) increased the double-labeled surface threefold. The effect was dose dependent from 0.4 to 40 nM and was greater than that of an equimolar dose of human parathyroid hormone-(1---34) [hPTH-(1---34)]. Mineral apposition rate was increased by 40 nM amylin-(1---8) but not by hPTH-(1---34). Amylin-(1---8) thus has significant anabolic effects in vivo, suggesting that this peptide or analogs of it should be further evaluated as potential therapies for osteoporosis.

Amyloid↗
PubMed1999

Long-term therapy of ovariectomy-induced osteopenia with parathyroid hormone analog SDZ PTS 893 and bone maintenance in retired breeder rats.

The aim of the study was to assess the long-term anabolic effect of the parathyroid hormone (PTH) analog SDZ PTS 893 in a dose-response manner, and to determine the ability of the antiresorptive agents estradiol and alendronate to maintain bone mass after withdrawal of SDZ PTS 893. One hundred thirty retired breeder Wistar rats were distributed into 13 groups with 10 rats in each group: 1 baseline group, 2 sham groups, and 10 ovariectomized groups. Treatment was initiated 12 weeks after ovariectomy. SDZ PTS 893 treatment was administered daily subcutaneously (Monday to Friday) for 36 weeks. Treatment regimens were as follows: (1) baseline (-12 weeks); (2) ovariectomy (ovx) (0 weeks); (3) sham (36 weeks); (4) ovx (36 weeks); (5) SDZ PTS 893 12.5 microg/kg/day (36 weeks); (6) SDZ PTS 893 25 microg/kg/day (36 weeks); (7) SDZ PTS 893 50 microg/kg/day (36 weeks); (8) SDZ PTS 893 100 microg/kg/day (36 weeks); for the maintenance part of the study: (9) sham (48 weeks); ovx animals treated with SDZ PTS 893, 50 microg/kg/day for 36 weeks followed by 12 weeks of treatment regimens: (10) placebo; (11) SDZ PTS 893 50 microg/kg/day; (12) estradiol 10 microg/kg/day; or (13) alendronate 28 microg/kg (2 injections/week). The effects of ovx, SDZ PTS 893 treatment, and maintenance regimens were measured at four skeletal sites: lumbar vertebra; femoral diaphysis; distal femoral metaphysis; and proximal femoral metaphysis (femoral neck). At these sites, bone density and bone strength were measured as treatment endpoints. Furthermore, bone dimensions were measured at the midpoint of the femur. The results showed that SDZ PTS 893 increased bone strength in a dose-dependent manner at all skeletal sites tested. At the vertebral body and distal femoral metaphysis, apparent ash density increased in a similar way. There was a slight decrease in cortical density at the mid-diaphyseal site. Static histomorphometry showed increased bone area due to a decreased marrow area (endosteal net bone gain) but also due to increased tissue area (periosteal net bone gain). For maintenance, continuous SDZ PTS 893 therapy was most efficient, followed by alendronate and estradiol treatment with regard to preservation of bone mass and strength. It is concluded that the new PTH analog SDZ PTS 893 has a highly anabolic, dose- and time-dependent effect on all skeletal sites tested. Bone formation is induced at both endosteal and periosteal surfaces.

Aging↗
PubMed1995

Assessing bone quantity by pQCT.

We have tested the ability of the XCT960A to detect bone loss in OVX-rats, as well as bone gain in the proximal tibial metaphysis of healthy rats treated with hPTH(1-34). The results demonstrated that high precision can be achieved, with CV's for most measurement parameters in the range of 1.6 to 5.9% being obtained in vivo with repositioning of animals. Significant changes in bone parameters in the tibia were observed already at 2 weeks following OVX or PTH-therapy, while whole bone mass measured in the tibia by DEXA ex vivo did not change significantly for up to 24 weeks. For the proximal rat tibia at location 5mm distal to the knee joint was identified as an optimal site. At this location, cortices are fairly parallel thus reducing the partial volume effect, the area is relatively rich in cancellous bone increasing the magnitude of bone gain or loss, and the site (2mm below the growth plate) is relevant for comparisons with histomorphometric measurements. The results demonstrate that pQCT can be adapted for use in small animals such as rats, and that it is a sensitive, reproducible, non-invasive method available to monitor changes in bone mass, bone density, and geometric properties. Future studies should help to establish whether the moment of inertia, moment of resistance and the newly added bone strength index provided by the machine are predictive in any way for bone strength as obtained from biomechanical testing procedures. Peripheral QCT in small animals is an important addition for drug evaluation because it is more sensitive than DEXA and allows for shorter duration of experiments. This non-invasive method can reliably measure changes in cancellous and cortical bone mass over time following ovariectomy or administration of the bone anabolic hormone hPTH(1-34). pQCT should be viewed as a complimentary technique to static and dynamic histomorphometry, which does not replace either of these methods. Its value in the field of basic research should be evaluated.

Analysis of Variance↗
PubMed1993

Altered cellular signalling and decreased platelet sensitivity to adenosine in insulin-dependent diabetic patients with proliferative retinopathy.

Platelets from patients with insulin-dependent diabetes with proliferative retinopathy showed the same reactivity to ADP as those from control subjects. Responsiveness of platelets to the aggregation inhibitor adenosine and to the analogue N-ethylcarboxamidoadenosine was decreased in diabetes. In contrast, responsiveness to the anti-aggregatory effects of prostaglandin I2 was not significantly altered in diabetes. Platelets from diabetic patients exhibited decreased formation of cyclic AMP in response to N-ethylcarboxamidoadenosine compared with those from control subjects. In contrast, when adenylyl cyclase was stimulated by prostaglandin I2 or by forskolin, no differences in cyclic AMP formation were observed between control and diabetic platelets. Diabetes was associated with an apparent loss of high-affinity binding of [3H]N-ethylcarboxamidoadenosine to platelet membranes. Possible mechanisms that could contribute to this diabetes-induced change in signalling through the platelet A2 adenosine receptor are discussed.

Adenosine↗
PubMed1993

Decreased sensitivity to adenosine in platelets from patients with familial hypercholesterolaemia--a change reversed by cholestyramine treatment.

Platelet-rich plasma was obtained from patients with untreated heterozygous familial hypercholesterolaemia (FH), from FH patients treated with cholestyramine and from control subjects. Responsiveness of platelets to the aggregation inhibitors adenosine, its analogue N-ethylcarboxamidoadenosine (NECA) and prostaglandin I2 was decreased in FH. Patients on cholestyramine therapy showed normal responsiveness to adenosine and NECA. There were only minor changes in the binding of [3H]NECA to high-affinity binding sites on platelet membranes from untreated FH or cholestyramine-treated FH patients. The initial rate of cyclic AMP formation in response to a high concentration of NECA was severely decreased in platelets from FH patients. By contrast, the rate of cyclic AMP formation in response to forskolin or a high concentration of prostaglandin I2 was unchanged. These data point to a defect in the coupling of the platelet A2 adenosine receptor to adenylyl cyclase in untreated FH patients.

Adenosine↗
PubMed1991

Comparison of the effects of carvedilol, propranolol, and verapamil on in vitro platelet function in healthy volunteers.

The effects of the two beta-blockers carvedilol and propranolol and the calcium antagonist verapamil on platelet aggregation induced by ADP, epinephrine, or collagen was examined in the serum of eight healthy volunteers. The inhibitory potential of the three drugs on the arachidonic acid-prostaglandin pathway was measured by the assessment of the formation of the stable metabolite thromboxane B2. Furthermore, the influence of drugs on intracellular cAMP levels was measured in platelets aggregated with ADP, epinephrine, or collagen. All three drugs were able to inhibit platelet aggregation induced by a threshold concentration of ADP, epinephrine (10 microM), or collagen (1 micrograms/ml) in a concentration-dependent manner, preventing aggregation completely in the high micromolar range. Propranolol is 1.6 and 2.3 times more active than verapamil and carvedilol in inhibiting ADP-induced platelet aggregation. Although the two beta-blockers were marginally more potent than verapamil in inhibiting platelet aggregation induced by collagen, this was not statistically significant. Both propranolol and verapamil were slightly more active than carvedilol in inhibiting epinephrine-induced platelet aggregation, a trend consistent with the IC50 values. Intracellular cAMP levels decreased in platelets aggregated with ADP, epinephrine, and collagen. The inhibition of platelet aggregation with the three drugs resulted in a return of intracellular cAMP levels to basal values. Carvedilol and propranolol were of similar potency and around 1.5-3 times as potent as verapamil for all agonists. The formation of thromboxane B2, an end product of the arachidonic acid pathway, could be completely inhibited by the three drugs. Propranolol was 2.4 and 2.1 times more potent than carvedilol and verapamil when platelets were aggregated with ADP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1990

Lipids and thrombosis.

There is extensive evidence of important interactions between plasma lipoproteins and platelet function. Some population groups, particularly hypercholesterolaemic patients, have strong evidence of abnormal platelet function which is mediated by the binding of lipoproteins, especially oxidized LDL, to surface receptors. Additionally, abnormal plasma lipid levels precipitate membrane composition changes by increasing the cholesterol:phospholipid ratio. The resulting changes in microviscosity seem to affect transmembrane signalling and might in some cases influence receptor binding. This not only has important therapeutic implications with regard to lipid-lowering drug therapy but also with regard to the potential beneficial effects of dietary therapy.

Blood Platelets↗
PubMed1983

Comparison of the healing and revascularization of onlayed autologous and lyophilized allogeneic rib grafts to the edentulous maxilla.

The healing and revascularization of onlayed autologous and lyophilized allogeneic rib grafts to the edentulous maxilla in the Macaca fascicularis monkey were studied using clinical, histologic, and microangiographic methods at varying intervals of up to eight months. Results indicated that healing and revascularization were similar but resorption of the allografts occurred approximately three months later than resorption of the autografts. Both grafting systems appeared to have minimal osteogenic potential. Osteoinduction and the final bony augmentation obtained were less than were seen with comparable autologous and allogeneic interpositional grafts.

Alveolar Ridge Augmentation↗