Russell E. Dill

Platelet-derived growth factor levels in wounds of diabetic rats

Delayed wound healing is a troublesome complication of Diabetes. Results from recent investigations concerning the potential cellular and molecular mechanisms responsible for diabetic wound healing deficiency are preliminary in nature. Some studies have demonstrated that direct application of certain growth factors/cytokines can facilitate wound healing in diabetic models. It is possible that refractory diabetic wounds are the result of deficiencies in growth factors/cytokines important for the normal wound healing process. Platelet-Derived Growth Factor (PDGF) levels were examined by radioimmunoassay in wound tissue of normal and diabetic rats (streptozotocin-induced diabetes). Immunohistochemical analysis was utilized to localize and characterize PDGF immunopositive cells at the wound site of normal and diabetic animals. At the wound site, normal animals demonstrated significantly elevated PDGF levels compared to diabetic animals at 5 days post-wounding (no differences were observed in the spleen or contralateral control tissue). There appeared to be a visible increase in PDGF immunopositive cells at the wound site in both experimental and control groups. By day 10 post-wounding, PDGF levels at the wound site in normal animals were reduced becoming similar to PDGF levels in diabetic animals. This corresponded to an apparent reduction of PDGF immunopositive cells in both groups (similar to baseline levels). PDGF levels in both groups remained stable until day 20 post-wounding when a significant elevation of wound site PDGF levels occurred in the diabetic group. The findings suggest that absence of an initial increase in PDGF may play an important role in poor wound healing observed in diabetic animals. The reduction in PDGF may be related to decreased cellular PDGF production rather than a lack of PDGF-producing cells. Perhaps the diabetic state inhibits cellular PDGF gene expression signaled by wounding or interferes with normal PDGF expression at the wound site.

Potentiation of haloperidol-induced catalepsy by ascorbic acid in rats and nonhuman primates.

Ascorbic acid was examined for potentiative effects on the catalepsy induced by haloperidol in rats and squirrel monkeys. In both animal species pretreatment with ascorbic acid (1000 mg/kg) markedly potentiated catalepsy induced by haloperidol. It is suggested that vitamin binds to, and inactivates, some brain dopamine receptors and in so doing potentiates an otherwise minimally cataleptogenic dose of haloperidol.

Comparison of behavioral effects of systemic L-DOPA and intracranial dopamine in mesolimbic forebrain of nonhuman primates

The systemic administration of L-DOPA and carbidopa to six rhesus and four squirrel monkeys produced an initial period of depressed activity followed by increased locomotion, hypervigilance, involuntary oral-facial movements and a gnawing syndrome. The squirrel monkey exhibited a depressed phase, locomotor stimulation, searching behavior, stereotypic grooming and gnawing syndrome. Most of these activities were prevented by pretreatment with 0.1 mg/kg haloperidol. Bilateral injection of 100 microgram dopamine into the mesolimbic forebrain of four squirrel monkeys also produced an initial depression followed by hyperactivity similar to that produced by L-DOPA, but without gnawing. A stereotyped submissive or juvenile posturing occurred in three animals. These DA-induced activities were blocked by 0.1 mg/kg haloperidol. Similar injection of 100 microgram L-norepinephrine produced a profound depression followed by moderate activity coupled with loss of extensor muscle strength in the legs. Bilateral injection of 300 microgram dopamine into the nucleus accumbens of a rhesus monkey produced stereotypic pacing. These data confirm in primates the importance of dopaminergic mechanisms of the mesolimbic forebrain in locomotor activity and behavior.

Biphasic locomotor response to intra-accumbens dopamine in a nonhuman primate

Locomotor activity of ten squirrel monkeys, Saimiri sciureus, was evaluated by means of a photocell activity cage following intracranial application of dopamine (DA). A biphasic response consisting of an initial quiet period followed by increased locomotor activity was seen following intra-accumbens DA, 12.5--100 micrograms bilaterally. Both the length of the quiet phase and intensity of locomotor activity were positively related to DA dose. Intra-caudate DA (50 micrograms) was significantly less effective in producing locomotor effects. The specificity of the DA response was substantiated by dose-related inhibition with both systemic (0.1 or 0.05 mg/kg) and intra-accumbens (2--10 micrograms) administration of the DA antagonist haloperidol. Additionally, the intra-accumbens application of haloperidol was found to be ineffective in inducing catalepsy, a state readily produced by systemically administered haloperidol.

Effects of sputtered metal oxide films on the ceramic-to-metal bond

The application of a thin oxide film is seen as a method of improving the ceramic-to-metal bond. Using sputter coating to form oxide films allows control of its thickness. The thickness of the oxide layer can also be controlled by sputter coating. Films produced by sputtering, in themselves, have superior bond strengths in that the high-energy levels that are used in the technique drive the coating material into the atomic lattice of the substrate material (dental gold). Remaining to be determined are optimum film thickness and the oxide to be used. However, the present study opens a field of study showing promise of improving porcelain-to-metal bonding in dental restoration.

The role of GABA in dyskinesias induced by chemical stimulation of the striatum.

Abstract The gamma aminobutyric acid (GABA) antagonists picrotoxin and bicuculline were injected into the striatum of rats via chronic cannulae. Dyskinesias were produced by these drugs which could be blocked by their injection combined with GABA. The intrastriatal (i.s.) injection of a cholinergic drug, carbachol, also produced dyskinesias which were blocked by GABA. The use of i.s. injection of GABA antagonists to produce an animal model of Huntingtons chorea is discussed.

A pharmacologic model of Huntington's chorea.

of the (+)and (-)-enantiomen of butaclamol on the increase in cyclic AMP elicited by 5 p~ noradrenaline (approximate Ka value). As shown in Table 2, (+)-butaclamol inhibits the increase in cyclic AMP in a dose-dependent manner, having an IC50 of approximately 0.5 p ~ . (-)-Butaclamol was found to be a weak inhibitor of the noradrenaline stimulated rise in cyclic AMP, having an IC50 > >10 p ~ . Neither (+)nor (-)-butaclamol, in concentrations from 0 1 to 5 0 p ~ , changed the basal concentration of the nucleotide. The present results indicate that the blocking effect of butaclamol on the specific noradrenergic cyclic AMP generating system in slices of the limbic forebrain also resides in the (+)-enantiomer thus also demonstrating sterospecificity for central noradrenaline receptor blockade. The availabilty of a stereochemically specific antagonist of a central noradrenaline adenylate cyclase receptor should provide an important tool to further elucidate this system. Although the stereospecific blockade by butaclamol of limbic dopamine receptors is quantitatively more pronounced (Lippmann & others, 1975), the present results do nevertheless further support the view that blockade of noradrenergic receptors in the limbic system may also contribute to the pharmacologic and perhaps therapeutic action of antipsychotic drugs. We are grateful to Dr D. J. Marshall of Ayerst Research Laboratories Montreal, Canada for the generous supply of the (+)and (-)-enantiomers of butaclamol. The research was supported by USPHS Grants MH-11468 and 5-TOl-GM0058. February 2, 1976

Synthesis of platelet-derived growth factor by cells of splenic red pulp in normal rats

A population of cells in the spleens of normal rats was found to contain platelet-derived growth factor (PDGF) B chain mRNA. These cells were found predominantly in the red pulp and nuclear morphology of some was consistent with that of macrophages. Similar cells were also shown by immunocytochemical staining to contain PDGF-AB/BB. These PDGF-positive cells were also found almost exclusively in the red pulp. It has been suggested by others that PDGF plays an important role in the function of the lymphohemopoietic microenvironment.

Importance of O-methylation in dopamine-induced motor and behavioral phenomena.

There is currently considerable interest in motor and behavioral phenomena attributed to excessive activity of dopamine (DA) in the striatum 7,1°-12. In most of the non-clinical investigations, the animals were pretreated with a monoamine oxidase inhibitor in order to elevate the striatal level of DA 1,4,5,1s. However, little consideration has been given to the possibility that some of these effects could be due to increased brain levels of the DA metabolite, 3-methoxytyramine (3-MT). It would seem that 3-MT must be given some consideration in this regard since it has been shown to produce motor effects when injected intrastriatally (i.s.) in rats and squirrel monkeys 8,13.

Analgesic effects of 3-methoxybenzamide in rats.

Abstract— The i.p. injection of 3‐methoxybenzamide (3‐MBA) in rats produces a dose‐related elevation of the threshold for response to a painful stimulus. Metoclopramide, also a substituted benza‐mide, has analgesic activity that is attenuated by bromocriptine, a dopamine receptor agonist, and by the narcotic antagonist, naloxone, suggesting involvement of dopamine and opiate receptors in the action of this drug. The involvement of these receptors in the analgesic action of 3‐MBA has been examined using L ‐dopa and naloxone. Neither significantly altered the analgesic action. Although the results are preliminary, the analgesic action of 3‐MBA would not seem to occur via opiate or dopamine receptors.