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Biomedical subjects

L M Adams

Publications and source records attributed to L M Adams.

At least 37 records · Page 2Linked to original sources
PubMed1995

Naturally occurring protein kinase C inhibitors; II. Isolation of oligomeric stilbenes from Caragana sinica.

The oligomeric stilbenes (+)-alpha-viniferin (1), miyabenol C (2), and kobophenol A (3) have been isolated from Caragana sinica (Buchoz) Rehd (Leguminosae). (+)-alpha-Viniferin (1) and miyabenol C (2) exhibited protein kinase C inhibitory activity at low micromolar concentrations. (+)-alpha-Viniferin inhibited keratinocyte proliferation (0.4 microM) and free radical release in whole blood (47 microM), in vitro, and may be useful in treating hyperproliferative or inflammatory skin diseases.

Cells, Cultured↗
PubMed1995

Human lumbar apophyseal joint damage and intervertebral disc degeneration.

OBJECTIVES: To record the extent and location of lumbar apophyseal cartilage damage, and to ascertain if the extent of damage is correlated with the grade of disc degeneration, age, or both. METHODS: The extent and location of fibrillated areas of the apophyseal cartilage of the joint surfaces of 29 lumbar motion segments were examined using computer aided image processing of Indian ink stained areas, and degeneration of the associated intervertebral discs graded using the method of Nachemson. RESULTS: It was found that these joints showed a greater extent and prevalence of cartilage fibrillation than the knee, hip or ankle, with significant damage in specimens younger than 30 years. Damage was predominantly located peripherally, superiorly, and posteriorly in the concave superior apophyseal surfaces, and was predominantly peripheral and posterior in the inferior surfaces, with a tendency to be located inferiorly. There was a weak correlation between apophyseal joint damage and the intervertebral disc degenerative grade, but this was inconclusive, as both increased with age. CONCLUSIONS: The pattern of damage exhibited by superior joint surfaces is most probably caused by tension on collagenous joint capsule fibres which insert into the surfaces posteriorly, so producing an area of fibrocartilage unsuited to loadbearing. Tension on such fibres would be greatest during spinal flexion. The pattern of damage of the inferior surfaces lends some support to the hypothesis that their apices impact the laminae of the lumbar vertebra inferior to them, consequent upon the degeneration and narrowing of the associated intervertebral disc. The predominantly peripheral location of fibrillation of both superior and inferior surfaces may be associated with inadequate mechanical conditioning of marginal joint areas. Disc degeneration cannot be the initial cause of apophyseal fibrillation in most specimens. The study indicates a need for regular spinal exercise, starting at a young age.

Adolescent↗
PubMed1994

Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus.

OBJECTIVE: To evaluate the effects of oral rapamycin (RAPA), a macrolide immunosuppressant that has been shown to interfere with T cell activation events, on the course of spontaneous disease progression in the MRL/MpJ/lpr/lpr (MRL/l) mouse model of lupus. METHODS: RAPA treatment (6, 12, or 25 mg/kg 3 times per week) was evaluated by monitoring survival rates, autoantibody levels, and urinary albumin levels. Additionally, concanavalin A responsiveness, interleukin-2 (IL-2) production, lymphoid organ size, and histopathology were evaluated ex vivo. RESULTS: RAPA prevented the typical rise in anti-double-stranded DNA antibody and urinary albumin levels and prolonged survival. Spleen and lymph node sizes were significantly decreased, inflammatory changes in the lung, liver, kidney, spleen, lymph node, and thymus were significantly reduced, and T cell mitogen-stimulated splenocyte proliferation and IL-2 production were restored. CONCLUSION: Data from 3 independent experiments demonstrated that RAPA significantly reduced or prevented many pathologic features of lupus normally seen in the MRL/l mouse, and suggest that RAPA may be useful as a therapeutic agent in SLE in humans.

Administration, Oral↗
PubMed1994

SPC-100270, a protein kinase C inhibitor, reduced hypoxic injury due to reperfusion following orthotopic liver transplantation in the rat.

Recently, we reported that SPC-100270, a sphingosine derivative and inhibitor of protein kinase C (50-90 microM) in mixed micelle assays, reduced reperfusion injury resulting from hypoxia in a low-flow, reflow model of liver perfusion. Here we report that SPC-100270 has similar beneficial effects following liver transplantation in vivo. Rat liver transplantation was performed using nonarterial and rearterial techniques. Livers from syngenic rats were harvested surgically, prepared with vascular cuffs and a splint, and stored for 24 or 48 h in University of Wisconsin (UW) cold storage solution. Just prior to completion of vascular reconstruction, the organ was rinsed with 3 or 10 ml of Ringer's solution, vehicle, or a solution containing SPC-100270 (up to 500 microM). Following implantation surgery, low doses of SPC-100270 were ineffective at reducing both parenchymal and nonparenchymal cell death, yet significant (P < 0.05) reductions were observed with 500 microM. Further, nonparechnymal cell viability was improved nearly four fold by the drug. SPC-100270 (500 microM) tended to increase survival following 48 h cold storage in UW solution, but the improvement was not statistically significant. SPC-100270 also did not diminish carbon-centered free radical formation in transplanted livers from alcohol-treated rats. Collectively, these data support the hypothesis that pretreatment of donor livers with an inhibitor of protein kinase C is effective in vivo at reducing reperfusion injury, particularly to nonparenchymal cells, following orthotopic liver transplantation in the rat.

Adenosine↗
PubMed1994

Adherence characteristics of attaching and effacing strains of Escherichia coli from rabbits.

Twelve strains of Escherichia coli previously reported to cause diarrhea in rabbits were examined for properties associated with virulence. Ten strains met the criteria for classification as enteropathogenic E. coli in that they were diarrheagenic strains that evoked attaching-effacing lesions in the small intestine and did not produce detectable enterotoxins or cytotoxins. These bacteria exhibited a variety of patterns when investigated for adherence to HEp-2 epithelial cells. Although several strains displayed localized and/or diffuse adherence to epithelial cells, they did not hybridize with DNA probes that recognize the genes responsible for these phenotypes in diarrheagenic E. coli from humans. The bacteria also varied in their ability to bind to erythrocytes and intestinal brush borders from various animal species. Six strains adhered to rabbit brush borders; two of these also adhered to brush borders from other animals. Two strains that did not adhere to rabbit brush borders adhered to those from guinea pigs or sheep. Only one of the strains investigated carried AF/R1 fimbriae, which are believed to govern the host specificity of this category of diarrheagenic E. coli. This strain was E. coli RDEC-1, which remains the only E. coli strain to date that is known to carry fimbriae of this type. The results indicate that although diarrheagenic E. coli strains from rabbits may have common properties associated with the ability to produce attaching-effacing lesions, they differ from each other and from enteropathogenic E. coli of humans in terms of some of the adhesins that mediate binding to eukaryotic cells.

Animals↗
PubMed1994

Host specificity of enteropathogenic Escherichia coli from rabbits: lack of correlation between adherence in vitro and pathogenicity for laboratory animals.

The pathogenicity of four attaching and effacing strains of enteropathogenic Escherichia coli originally isolated from diarrheic rabbits was investigated by inoculating them perorally into rabbits, guinea pigs, and mice. The ability of the four strains to adhere to cultured epithelial cells, erythrocytes, and intestinal brush borders from various animal species, including rabbits, guinea pigs, and mice, varied considerably. Only one strain carried AF/R1 fimbriae, which are believed to determine the host specificity of these bacteria. Despite these differences, the pattern of behavior of the four strains in experimentally infected animals was similar. Each strain caused fatal diarrhea in rabbits (although the virulence of individual strains for rabbits differed significantly), and none was virulent for guinea pigs or mice. None of the strains colonized the intestinal tract of guinea pigs, but all were able to cause attaching-effacing lesions in ligated loops of guinea pig small intestine. By contrast, all four strains colonized mice, in particular the distal intestine, but none induced attaching-effacing lesions in mouse intestinal loops. These findings suggest that there may be previously unrecognized host-restricted adhesins in enteropathogenic E. coli and indicate that adherence to erythrocytes or intestinal brush borders in vitro does not necessarily reflect colonizing ability or pathogenicity in vivo.

Animals↗
PubMed1993

A prospective controlled investigation of the cognitive effects of amateur boxing.

Eighty six amateur boxers underwent a series of neuropsychological assessments on three occasions--pre bout, immediate post bout and follow up within two years; 31 water polo players and 47 rugby union players acted as controls. The neuropsychological tests were selected as being sensitive to subtle cognitive dysfunction and formed part of a battery of other neurological and ophthalmic assessments. No evidence of neuropsychological dysfunction due to boxing was found, either following a bout or a series of bouts at follow up. None of a range of parameters including number of previous contests, recovery from an earlier bout, number of head blows received during a bout and number of bouts between initial assessment and follow up, were found to be related to changes in cognitive functioning.

Adolescent↗
PubMed1993

Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia-ischemia.

Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspartate receptor and protects the hippocampal slice from hypoxic damage, shows remarkably low toxicity in animals and in humans. Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5% O2 for 1 hour. Brain temperature was unaffected by surgery, hypoxia, or felbamate. Neuroprotection was greatest at 300 mg/kg, less effective at 200 and 400 mg/kg, and ineffective at 100 mg/kg. Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67% +/- 7% of neocortex in unmedicated rats to 32% +/- 8%, 51% +/- 12%, 38% +/- 19%, and 53% +/- 10% when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively. By 6 hours, post hoc protection was no longer significant. Delayed neuronal necrosis in hippocampal granule cells was reduced from 156 +/- 33 neurons to 12 +/- 7 (0 hours, p < 0.01) and 37 +/- 17 (1 hour, p < 0.05). These effects were obtained at plasma concentrations (60 to 120 mg/ml) that have occasionally been reached without serious toxicity in human anticonvulsant trials. These data suggest that, in this animal model, felbamate given after a hypoxic-ischemic insult is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis, but that the window of opportunity for post hoc treatment is only 1 to 4 hours.

Animals↗
PubMed1992

Felbamate reduces hypoxic-ischemic brain damage in vivo.

The neuroprotective effects of felbamate were tested in a model of incomplete cerebral ischemia and hypoxia in 7-day-old rat pups. Felbamate pretreatment (300 mg/kg) reduced the surface of infarcted cortex following bilateral carotid ligation, by 42-49% compared to saline and dimethylsulfoxide (DMSO) controls, respectively. The number of necrotic neurons in the dentate gyrus was reduced by 77% over both DMSO controls and saline controls. These results suggest that felbamate deserves further evaluation for its therapeutic potential in hypoxia-ischemia.

Animals↗
PubMed1992

A modification of the in vivo mixed lymphocyte reaction and rapamycin's effect in this model.

Rapamycin, a novel macrocyclic immunosuppressive agent, suppresses murine T cell activation in vitro by mechanisms distinct from cyclosporin A (CsA). This study was designed to examine rapamycin and CsA in the host vs graft popliteal lymph node (PLN) model, an in vivo system of T cell-dependent lymphocyte activation. The PLN procedure was modified by using irradiated CTLL-2 cells of C57BL/6 origin, instead of primary mouse splenocytes, as the allogeneic stimulus in C3H/HeN recipient mice. PLN cell proliferation was determined by [3H]-thymidine uptake. We found that the host lymphocyte proliferative response to CTLL-2 cells (H-2b) is greater than the response to mouse Balb/c splenocytes (H-2d). Rapamycin (ip or po) produced a dose-related inhibition of the in vivo mixed lymphocyte reaction. By contrast, the effects of CsA and FK-506 were not dose related within the same dose range (0.006-12 mg/kg). These data indicate that rapamycin is an effective immunosuppressive agent and confirm its ability to affect the allogeneic T cell response in vivo. Furthermore, the pharmacological data suggest that this PLN model utilizing irradiated CTLL-2 cells as an allogeneic stimulus provides a reproducible system to examine mixed lymphocyte reactions in vivo.

Animals↗
PubMed1992

Rapamycin prevents the onset of insulin-dependent diabetes mellitus (IDDM) in NOD mice.

The effect of the immunosuppressive agent rapamycin (RAPA) was assessed in the non-obese diabetic (NOD) mouse which is an autoimmune model of IDDM. RAPA was prepared in a vehicle of 8% cremophor EL/2% ethanol and investigated in two studies. NOD/MrK female mice (six per group, study no. 1; 10 per group, study no. 2) were dosed three times per week p.o. by gavage from 56 to 170 days of age (study no. 1) or from 64 to 176 days of age (study no. 2). Mice treated with RAPA at 0.6 mg/kg, 6 mg/kg, or 12 mg/kg maintained normal plasma glucose through 170 or 176 days of age with 10%, 0%, and 0% incidence of diabetes respectively. In contrast, naive, vehicle-treated, or RAPA 0.06 mg/kg-treated mice exhibited elevated plasma glucose and disease incidence typical for female NOD mice. Mice which became diabetic had elevated levels of beta-hydroxybutyrate, triglycerides and cholesterol. These plasma lipid concentrations were positively correlated with the duration of hyperglycaemia (r = 0.85, 0.87 and 0.84 respectively). Outside of its ability to prevent diabetes, RAPA itself did not affect the lipid profile of the mice. Intervention therapy with RAPA was ineffective at reversing the course of disease after IDDM onset under these experimental conditions. Finally, we report here that prophylactic treatment with RAPA was able to protect against IDDM development in some RAPA-treated mice 41 weeks after cessation of treatment. These data show that orally administered RAPA is effective in preventing onset of disease in the NOD mouse, a relevant model of autoimmune type I diabetes in man.

Animals↗
PubMed1991

Inhibition of interleukin-1 (IL-1) induced neutral proteases from rabbit articular chondrocytes by WY-46,135 and WY-48,989.

The effects of potential anti-osteoarthritic compounds both on the direct inhibition of collagenase and neutral protease activities and on IL-1 induced release of neutral proteases from rabbit articular chondrocytes were investigated. WY-46,135 ((+)-N-[[[(5-chloro-2-benzothiazolyl)thio]phenyl]acetyl]-L- cysteine) directly inhibited collagenase activity (IC50 = 15.4 microM). This inhibition was reversible upon dialysis. WY-46,135 also directly inhibited neutral protease activity (IC50 = 16.8 microM) but did not significantly block bacterial collagenase activity at a concentration of 80 microM. In contrast, WY-48,989 (4-[[2-(7-chloro-2-phenyl-2H-pyrazolo[4,3-c]quinolin-4- yl)ethyl]amino]benzonitrile) did not directly inhibit either collagenase (10 microM) or neutral protease (100 microM) activity. Both WY-48,989 and WY-46,135 inhibited IL-1 stimulated release of neutral proteases (IC50 = 3 microM). The activities of these compounds represents two potential approaches for the treatment of osteoarthritis. WY-46,135 combines direct metalloprotease inhibitory activity with the inhibition of IL-1 stimulated neutral protease release from articular chondrocytes while WY-48,989 selectively inhibits the IL-1 induced release of metalloproteases.

Acetylcysteine↗
PubMed1991

Electrophysiological evidence for the involvement of the locus coeruleus in alerting, orienting, and attending.

In this chapter, we describe recent observations from our laboratory which support the thesis that the locus coeruleus (LC), via its massively divergent efferent projections, participates in generating a generalized brain state that can be characterized as "alertness." The first of these observations suggests that LC activation can convert the electroencephalographic (EEG) activity of the forebrain from patterns characteristic of a non-alert state to those characteristic of an alert state. The second observation indicates that LC activation alters sensory responses of individual neocortical neurons in a way that is compatible with the general thesis presented here, suggesting that LC-induced alterations in cortical neuronal activity may be an integral component of a hypothesized participation of the LC in cortically mediated attentional processes. The third observation indicates that LC may modulate forebrain components of orienting responses that are indexed by event-related potentials (ERPs). Thus, the experiments described below involve electrophysiological assessment of forebrain information processing at three different levels of organization: activity of individual neurons in the millisecond range, neuronal ensemble activity persisting for 10-200 msec as indexed by ERPs, and ensemble/regional activity sustained for seconds to minutes as indicated by EEG measures. These observations suggest that alterations induced in forebrain function by manipulations of LC activity are evident at all three of these levels.

Animals↗
PubMed1988

Effects of locally infused pharmacological agents on spontaneous and sensory-evoked activity of locus coeruleus neurons.

Electrophysiological activity of individual locus coeruleus (LC) neurons was recorded in halothane-anesthetized rats before, during, and after the infusion of adrenergic, cholinergic, or peptidergic compounds about 400 micron lateral to LC. The alpha-adrenergic agonist clonidine (CLON), in concentrations ranging from 5-20 microM (67-270 pg/50 nl injection), reversibly suppressed activity with latencies to onset of 5-15 min and durations of 20-120 min. During the onset of suppressed firing, responses to sensory stimuli (footshock) were relatively preserved, but at later times the reliability of footshock responses was greatly reduced. The alpha-adrenergic antagonist piperoxane (PIP) rapidly reversed the inhibitory effects of CLON. Infusion of 0.1 microliter of 0.02 M acetylcholine (ACh) produced a 3-4 min period of increased LC firing, with a 1 min latency to onset. Larger volumes (0.15 microliter) produced greater increases in firing rate lasting 10-12 min. ACh effects were readily reversed with equimolar doses of scopolamine (SCOP). The effects of 0.02 M ACh were also rapidly reversed by equal volumes of 0.001 M CLON, SCOP and CLON reduced basal firing rates without blocking responses to sensory stimuli. Infusion of the cholinergic agonist carbamyl-beta-choline (carbachol) produced robust, reliable activation of LC neurons at doses of 25-1,000 ng per 100 nl injection. The electrophysiological effects of 3 adrenocorticotropin hormone (ACTH) fragments [1-24], [4-10], and [1-10] were also evaluated. ACTH[1-10] and ACTH[4-10] decreased LC activity for up to 2 hr. ACTH[1-24] exhibited more complex effects, with an increase in discharge rate being accompanied by a decrease in action potential amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

Interaction of neutrophils with vascular smooth muscle: identification of a neutrophil-derived relaxing factor.

Experiments were designed to study the interaction of rat peritoneal neutrophils with the vascular smooth muscle of the rat aorta. Rings of aorta, suspended in 10-ml organ chambers containing a physiologic salt solution, were precontracted with phenylephrine. Neutrophils (1 X 10(5) -4 X 10(7) cells/organ chamber) caused a cell number-dependent relaxation of the rat aorta that was augmented by superoxide dismutase (100 U/ml) or changing the oxygen content from 95 to 21%. The neutrophil-induced smooth muscle relaxation occurred in rings with and without endothelium and in rings precontracted with increasing concentrations of phenylephrine, prostaglandin F2 alpha or KCI. Catalase (1000 U/ml) and mannitol (1 X 10(-3) M) did not block the neutrophil-induced relaxation, whereas phenazine methosulfate (1 X 10(-5) M), hydroquinone (3 X 10(-5) M) and methylene blue (1 X 10(-5) M) reversed the neutrophil-induced relaxation. Pre-exposure of endothelium-rubbed rings to neutrophils (2 X 10(7) cells/organ chamber; 15 min) depressed the subsequent concentration-response curve to phenylephrine but augmented the relaxation induced by the phosphodiesterase inhibitor zaprinast (1 X 10(-5) M). The effluent from a column restraining the neutrophils induced a relaxation of endothelium-rubbed aortic rings that was prevented by methylene blue (1 X 10(-5) M). These results demonstrate that rat neutrophils release a factor that has a pharmacologic profile similar to that previously reported for the relaxing factor released from the vascular endothelium.

Animals↗