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Biomedical subjects

A J Yates

Publications and source records attributed to A J Yates.

At least 109 records · Page 6Linked to original sources
PubMed1990

In vivo effects of human recombinant transforming growth factor beta on bone turnover in normal mice.

Reports of the effects of TGF-beta on bone cells are conflicting and controversial. Different cell culture and organ culture models for both osteoblasts and osteoclasts have given different responses. In some the effects are dependent on prostaglandin synthesis, and in others they are prostaglandin independent. To determine the effects of TGF-beta on osteoblasts and osteoclasts in vivo and the role of prostaglandins in mediating these effects, we injected 2.5-5 micrograms TGF-beta into the subcutaneous tissue overlying the calvariae of normal mice for 2-5 days anc compared the morphologic responses in underlying calvarial bone with those in mice injected caused a marked increase in periosteal thickness (fivefold) and cellularity, morphologic changes in osteoblasts, and new mineralized bone formation. These effects were localized to the site of injection and were partially inhibited by concomitant indomethacin treatment. There was a parallel increase in osteoclast numbers in adjacent marrow spaces, and the osteoclasts formed were unusually large. In contrast, no increase in the numbers of osteoclasts was seen in indomethacin-treat animals. These data show that TGF-beta has powerful effects on local bone cell function in vivo and that these effects may be mediated, in part, by prostaglandin generation.

Animals↗
PubMed1990

Effect of crush lesion on ganglioside radiolabelling patterns in rat sciatic nerve.

Left sciatic nerves in rats were crushed and allowed to regenerate for variable periods of time up to 14 days; uncrushed right nerves from the same animals were used as controls. Two days before killing the rats, both L-5 dorsal root ganglia (DRG) were injected with 100 microcuries [3H]glucosamine. Gangliosides were purified separately from sciatic nerve (SN) distal to the crush site, lumbosacral trunk (LST) proximal to the crush site, and the injected DRG. Changes in major glycoconjugate classes were previously reported; in this study total gangliosides were separated by high performance thin layer chromatography, located by autofluorography and radioactivity was measured by liquid scintillography. In control DRG, major radiolabelled gangliosides were GM3 and LM1; in control LST and SN, GD1b and GT1b were the major ones. During day two and four following crush, GM3 and LM1 decreased in DRG, but at one and two weeks were at normal and elevated levels, respectively; there were inverse changes in GD3, GT1b and GQ1b. GD1b, GT1b and GQ1b were lower in crushed than in control LST and SN between days zero and four. In LST, GM3 and LM1 remained constant for four days, but were elevated at one and two weeks, whereas GD1a was elevated at all times. Indeed, GD1a is the major recently synthesized ganglioside that is transported into LST and SN two to four days after trauma, suggesting that it may play an important role in regeneration. Indices of oligosaccharide complexity and degree of sialylation indicated that between two and four days following crush, gangliosides in DRG had more complex oligosaccharides and more sialic acid residues than in either controls or in DRG of crushed nerves at one and two weeks post-crush. The degrees of ganglioside sialylation and oligosaccharide complexity in crushed LST and SN were lower than in control specimens between one and seven days after crush. Changes in the ganglioside composition of peripheral nerve following trauma may be important for axonal regeneration.

Animals↗
PubMed1990

Boron neutron capture therapy of a rat glioma.

The purpose of the present study was to utilize a well-established rat glioma to evaluate boron neutron capture therapy for the treatment of malignant brain tumors. Boron-10 (10B) is a stable isotope which, when irradiated with thermal neutrons, produces a capture reaction yielding high linear energy transfer particles (10B + 1nth----[11B]----4He(alpha) + 7Li + 2.79 MeV). The F98 tumor is an anaplastic glioma of CD Fischer rat origin with an aggressive biological behavior similar to that of human glioblastoma multiforme. F98 cells were implanted intracerebrally into the caudate nuclei of Fischer rats. Seven to 12 days later the boron-10-enriched polyhedral borane, Na2B12H11SH, was administered intravenously at a dose of 50 mg/kg body weight at varying time intervals ranging from 3 to 23.5 hours before neutron irradiation. Pharmacokinetic studies revealed blood 10B values ranging from 0.33 to 10.5 micrograms/ml depending upon the time after administration, a T1/2 of 6.2 hours, normal brain 10B concentrations of 0.5 microgram/g, and tumor values ranging from 1.1 to 12.8 micrograms/g. No therapeutic gain was seen if the capture agent was given at 3 or 6 hours before irradiation with 4 x 10(12) n/cm2 (10 MW-min; 429 cGy). A 13.5-hour preirradiation interval resulted in a mean survival of 37.8 days (P less than 0.01), compared to 30.5 days (P less than 0.03) for irradiated controls and 22.1 days for untreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Hypoxia-induced neurotransmitter deficits in neonatal rats are partially corrected by exogenous GM1 ganglioside.

Exposure of 7-day-old rats to 7% oxygen/balance nitrogen for 2 h results in selective changes of cholinergic, serotonergic, and dopaminergic neuronal markers in the frontal cortex, hippocampus, and striatum when evaluated 3 weeks after the insult. There is also about a 15% deficiency in brain weight. Treatment with GM1 ganglioside, 50 mg/kg i.p., for 2 days before and for 3 weeks after the hypoxic insult partially corrects the neurodevelopmental abnormalities including the deficiency in brain weight. We conclude that GM1 ganglioside might have therapeutic potential for treating suspected neonatal hypoxia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

A noncyclical analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT) retains full potency without inducing anorexia in rats.

A new analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT; RG-12851; here termed CTR), which lacks the ring structure of native calcitonin, was tested for biological activity in several in vitro and in vivo assay systems. The analog (CTR) and salmon calcitonin (sCT) stimulated kidney cell adenylate cyclase activity and inhibited bone resorption in organ cultures of fetal rat long bones with similar potencies and efficacies. Furthermore, CTR and sCT, at similar doses, induced comparable hypocalcemic responses in mice following sc injection or infusions. However, unlike sCT, CTR did not induce anorexia and weight loss in rats following sc injection. These data suggest that the ring structure of sCT may be important for the anorexigenic effect but is not required for effect on bone resorption or calcium homeostasis. Clinical studies appear warranted as, potentially, CTR might induce fewer side effects than does sCT.

Adenylyl Cyclases↗
PubMed1990

Increased production of tumor necrosis factor by normal immune cells in a model of the humoral hypercalcemia of malignancy.

The rat Leydig cell tumor is a well characterized model of the humoral hypercalcemia of malignancy. The studies reported here were provoked by the observation that tumor-bearing rats become extremely cachectic and develop hypertriglyceridemia as they become hypercalcemic. Since the bone resorbing cytokine tumor necrosis factor (TNF)/cachectin is associated with cachexia and hypertriglyceridemia, we examined hypercalcemic tumor-bearing rats for evidence of increased TNF production using a TNF radioimmunoassay. We found that immunoreactive TNF was increased in the plasma of tumor-bearing rats. The increase in plasma TNF was comparable to that previously shown in hypercalcemic nude mice bearing Chinese hamster ovarian cell tumors transfected with the human TNF gene. There was no detectable TNF activity in tumor culture media which suggested that the tumor itself was not the source of excess TNF production. However, we found that tumor cell conditioned media enhanced the production of TNF activity by normal macrophages in vitro, indicating that increased TNF production in vivo may result from a tumor factor(s) which stimulates TNF production by normal immune cells. When TNF was added together with tumor products to organ cultures of fetal rat long bones, osteoclastic bone resorption was potentiated. These data are consistent with the concept that in this model of the humoral hypercalcemia of malignancy, increased TNF production by normal immune cells is increased, has systemic effects as suggested by cachexia and hypertriglyceridemia, and may work in concert with factors produced directly by tumor cells to overwhelm normal calcium homeostasis.

Animals↗
PubMed1989

Ganglioside synthesis and transport in regenerating sensory neurons of the rat sciatic nerve.

The sciatic nerves of rats were crushed with fine forceps and allowed to survive for 3 or 7 days, at which time the 5th lumbar dorsal root ganglion was injected with [3H]glucosamine. Animals were killed 18 h later and the nerves proximal and distal to the crush site were cut into 3 mm segments. Gangliosides were purified from these segments, and radioactivity was separately measured in gangliosides, neutral glycolipids and glycoproteins. For all 3 fractions, radioactivity was distributed similarly between the crush site and point of maximum axonal elongation. A second smaller peak of ganglioside radioactivity was seen to span a few segments immediately distal to the point of maximum axonal elongation. We propose two possible explanations for this: (1) it represents ganglioside synthesis by Schwann cells (from blood-borne [3H]glucosamine) as part of the mitogenic response of these cells to the reappearance of axons; or (2) recently synthesized, transported gangliosides are released from the growth cone and taken up by adjacent mitogenic Schwann cells.

Animals↗
PubMed1989

Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics.

A 36-year-old man with myoclonic epilepsy and ragged-red fibers (MERRF) died after more than 18 years of follow-up study. He was 1 of 3 affected siblings and the offspring of an affected mother, suggesting maternal transmission. At autopsy, there was neuronal loss and gliosis in the dentate nucleus of the cerebellum and in the inferior olivary nucleus. Skeletal muscle showed ragged-red fibers, and paracrystalline inclusions in mitochondria by electron microscopy. Biochemical analysis showed a generalized partial defect of cytochrome c oxidase (COX) in mitochondria isolated from all tissues, including brain, heart, skeletal muscle, kidney, and liver. The Michaelis constant (Km) for cytochrome c was abnormally low, suggesting a defect of the mitochondrially encoded subunit II of COX. Immunological studies (enzyme-linked immunosorbent assay, dot-blot, Western blot, and immunohistochemistry) showed that the holoenzyme was decreased but subunit II was decreased more than the holocomplex or the nuclearly encoded subunit IV. However, Northern and Southern blots showed that the gene for subunit II, as well as the genes for subunits I, III, IV, and VIII, were of normal size and were normally transcribed. A point mutation or a small deletion of mitochondrial DNA, probably affecting the COX-II gene, may be responsible for the COX deficiency in this case of MERRF.

Adolescent↗
PubMed1989

Sensitivity of glioma and fetal brain cell lines to natural killer cytolysis in a monolayer assay.

We have developed an in vitro assay for Natural Killer (NK) cell cytolysis of and binding to substrate attached human glioma and fetal brain cells. The monolayer cells were labeled with [51Cr] and the effectors were directly sedimented onto these substrate attached target cells. Using this method we screened several glioma and fetal brain cell lines. The results indicate that the majority of gliomas are NK resistant, however two of the tested lines (U251MG and BN3) were relatively sensitive as were the fetal brain cell lines (CHI and CHII). We conclude that this monolayer assay for NK cytotoxicity and binding of glioma targets is a reproducible and valid method for assessing NK sensitivity, and should have applications in the study of other cultured solid tumors and substrate attached cells.

Brain↗
PubMed1989

The effects of rHuIFN-alpha A/D on brain lipids and behavior of neonatal ICR Swiss albino mice.

Systemic administration of interferon (IFN) can cause reversible neurologic side effects, but there is little information on its effect on the developing nervous system. We studied the effects of daily, subcutaneous injections of recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) (which has biological activity in mice) on brain development of neonatal ICR Swiss albino mice. Animals were treated daily between 8 and 20 days of age (doa) with 5 x 10(4) units (U) of rHuIFN-alpha A/D and sacrificed at 24, 62, and 111 doa following testing in an active avoidance paradigm. Results show that rHuIFN-alpha A/D causes transient decreases in body and brain weights. There were no changes in brain total lipid, ganglioside, phosphorus, or cholesterol content, but there was a transient decrease in neutral glycolipid content. In addition, treated animals exhibited decreased spontaneous activity levels and an impaired retention of a learned behavior. These results suggest that there are some long-term treatment effects on behavior following administration of rHuIFN-alpha A/D to mice during the neonatal period.

Animals↗
PubMed1989

Ganglioside modulation of cyclic AMP-dependent protein kinase and cyclic nucleotide phosphodiesterase in vitro.

Purified cyclic AMP-dependent protein kinase (cAK) catalytic subunit phosphorylated 180-, 49-, 31-, 19-, and 14-kilodalton (kDa) proteins of rabbit sciatic nerve membranes. The ability of cAK to phosphorylate these membrane substrate proteins was inhibited by gangliosides GM1, GD1a, and GT1b with half-maximal inhibitory concentration (I50) = 7-25 microM. Neutral glycolipids and lysophosphatidylcholine were much less effective. Cyclic AMP (cAMP) kinase phosphorylation of histone IIA was inhibited by GM1, GD1a, and GT1b (I50 = 115 microM, 75 microM, and 75 microM, respectively). Inhibition by GM1 was competitive with respect to histone (Ki = 108 microM). Autophosphorylation of cAMP kinase was inhibited by GM1 (I50 = 15 microM). GT1b, GD1a, and GM1 half-maximally stimulated calmodulin-dependent cyclic nucleotide phosphodiesterase at 0.1 microM, 0.2 microM, and 0.3 microM, respectively. Although GT1b stimulated phosphodiesterase by increasing Vmax and decreasing Km (similar to calmodulin), GD1a and GM1 produced only an increase in Vmax. These results suggest that ganglioside can modulate the activity of cAMP kinase by both direct inhibition of the enzyme and indirect reduction of cAMP levels through activation of phosphodiesterase. Through these mechanisms, gangliosides may alter cAMP-dependent protein phosphorylation and cell function within the nervous system.

Animals↗
PubMed1989

Effects of interleukin-1 on bone turnover in normal mice.

Interleukin-1 (IL-1) is a potent stimulator of osteoclastic bone resorption in vitro and causes hypercalcemia and increased osteoclastic resorption when infused into normal mice for 72 h. However, its longer term or local effects on bone turnover in vivo are unknown. To study these, we injected IL-1 alpha once daily for 3 days into the sc tissue over the calvariae of normal mice and examined its effects on calvarial bone morphology during the subsequent 4 weeks using quantitative histomorphometry. Increased bone resorption inside the calvariae and elevated plasma calcium concentrations were present 24 h after the last IL-1 injection. These early systemic effects were not prevented by indomethacin. During the following 3-4 weeks most of the bone on the injected side of the calvariae was resorbed by osteoclasts and was subsequently replaced by increased amounts of new bone. These longer term local effects on bone turnover were prevented by indomethacin. However, indomethacin did not prevent the formation of new bone inside the calvariae at sites of resorption induced by IL-1 independent of prostaglandin production. These findings indicate that IL-1 stimulates bone turnover systemically, independent of prostaglandin production, and that it has profound long term local effects on bone turnover that are mediated through prostaglandins.

Animals↗
PubMed1989

Bolus injections of recombinant human interleukin-1 cause transient hypocalcemia in normal mice.

Single daily injections of recombinant human interleukin-1 alpha (IL-1 alpha) or interleukin-1 beta (IL-1 beta) were given for 1-3 days to normal mice, and blood ionized calcium concentrations were measured before and at various times after each injection. Mean blood calcium levels fell significantly in both groups of animals 3 h after the first IL-1 injections and returned to pretreatment values at 5 h. However, at 24 and 48 h mean values were significantly higher than those in saline-heated controls. Despite this progressive underlying increase in mean blood ionized calcium concentrations, blood calcium concentrations also fell significantly 3 h after the second and third IL-1 injections. The transient decrease in blood calcium was prevented by treatment with indomethacin and, thus, appears to be prostaglandin mediated. Hypocalcemia was not observed after single bolus injections of tumor necrosis factor-alpha or -beta (lymphotoxin). These findings suggest that IL-1 is a potential mediator of the hypocalcemia that occurs in up to 40% of patients with bacteremic sepsis and severe tissue injury and is associated with an increased mortality rate.

Animals↗
PubMed1988

Forskolin augments the effects of calcitonin on cytoplasmic spreading of isolated rat osteoclasts and plasma calcium levels in the rat.

Recently we have shown that forskolin acts synergistically with calcitonin on stimulation of cyclic AMP (cAMP) production in isolated rat osteoclasts and now show that forskolin also augments later physiological responses to calcitonin. The sensitivity of calcitonin inhibition of cytoplasmic spreading in isolated rat osteoclasts was increased 3.5-fold by simultaneous treatment with 10(-7) M forskolin, which alone had no effect on the response. In weanling rats the threshold of the hypocalcemic response to salmon calcitonin was reduced fivefold by simultaneous treatment with 200 micrograms/kg forskolin i.v., which alone did not influence the plasma calcium. These results provide further evidence that calcitonin-induced inhibition of osteoclast function is mediated by elevation of cAMP levels and suggest that forskolin could be used to augment the therapeutic effects of calcitonin.

Animals↗