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G Acs

Publications and source records attributed to G Acs.

At least 37 records · Page 2Linked to original sources
PubMed1996

Distinct structure-activity relations for stimulation of 45Ca uptake and for high affinity binding in cultured rat dorsal root ganglion neurons and dorsal root ganglion membranes.

The [3H]resiniferatoxin (RTX) binding assay using membrane preparations has been used to identify and characterize the vanilloid receptors in the central and peripheral nervous system of different species. In the present study, using cultured adult rat dorsal root ganglion neurons either in suspension or attached to the tissue culture plates, we developed an assay to measure specific [3H]RTX binding by the intact cells. We were able to characterize the vanilloid binding characteristics of the neurons and compared those to the properties of vanilloid binding sites present in rat dorsal root ganglia membrane preparations. We found that [3H]RTX bound with similar affinity and positive cooperativity to attached neurons (cultured for 5 days before being assayed), neurons in suspension (using a filtration assay) and dorsal root ganglion membrane preparations. Dissociation constants obtained in the three assays were 47.6 +/- 3.5 pM, 38.4 +/- 3.1 pM and 42.6 +/- 3.1 pM, respectively. The cooperativity indexes determined by fitting the data to the Hill equation were 1.73 +/- 0.11, 1.78 +/- 0.12 and 1.78 +/- 0.09, respectively. The maximal binding capacity was 0.218 +/- 0.026 fmol/10(3) cells and 0.196 +/- 0.021 fmol/10(3) cells in the case of the attached cells and cells in suspension, respectively. Nonradioactive RTX, capsaicin, capsazepine and resiniferonol 20-homovanillylamide fully displaced specifically bound [3H]RTX from cells in suspension with Ki and Hill coefficient values of 42.5 +/- 5.3 pM, 2.06 +/- 0.16 microM, 3.16 +/- 0.21 microM and 32.4 +/- 4.1 nM and 1.79 +/- 0.17, 1.68 +/- 0.06, 1.72 +/- 0.11 and 1.81 +/- 0.12, respectively. Structure-activity analysis of different vanilloid derivatives revealed that the various compounds have distinct potencies for receptor binding and inducing 45Ca uptake in rat dorsal root ganglion neurons. Affinities for receptor binding and stimulation of 45Ca uptake of RTX, resiniferonol 20-homovanillylamide, RTX-thiourea, tinyatoxin, phorbol 12,13-dibenzoate 20-homovanillylamide and capsaicin were 38.5 +/- 2.9 pM, 25.7 +/- 3.0 nM, 68.5 +/- 3.8 nM, 173 +/- 25 pM, 7.98 +/- 0.83 microM and 4.93 +/- 0.35 microM as compared to 0.94 +/- 0.12 nM, 26.5 +/- 3.5 nM, 149 +/- 30 nM, 1.46 +/- 0.25 nM, 1.41 +/- 0.48 microM and 340 +/- 57 nM. Computer fitting of the data yielded Hill coefficient values indicating positive cooperativity of receptor binding; however, stimulation of 45Ca uptake appeared to follow a non-cooperative mechanism of action. The competitive capsaicin antagonist capsazepine inhibited specific binding of [3H]RTX by rat dorsal root ganglion membrane preparations with Ki and Hill coefficient values of 3.89 +/- 0.38 microM and 1.74 +/- 0.11. On the other hand it inhibited the induction of 45Ca uptake into the cells induced by capsaicin and RTX in a non-cooperative fashion with Ki values of 271 +/- 29 nM and 325 +/- 47 nM. Our results show that the membrane binding assay relates to the reality of receptor function in the intact, cultured neurons, both in terms of affinity and positive cooperativity. However the different vanilloid derivatives displayed markedly distinct structure-activity relations for high affinity receptor binding and stimulation of 45Ca uptake into rat dorsal root ganglion neurons. Among various explanations for this discrepancy, we favor the possibility that the two assays detect distinct classes of the vanilloid (capsaicin) receptor present in primary sensory neurons.

Animals↗
PubMed1996

Specific binding of [3H]resiniferatoxin by human and rat preoptic area, locus ceruleus, medial hypothalamus, reticular formation and ventral thalamus membrane preparations.

Specific [3H]resiniferatoxin (RTX) binding detects the vanilloid (capsaicin) receptors and provides a biochemical means for exploring their pharmacology. In the present study we demonstrate specific vanilloid (RTX) binding sites in various brain areas not known to be innervated by primary afferent neurons. Specific high-affinity binding of [3H]RTX could be detected in membrane preparations of the posterior ("hypothalamic") and anterior ("septal") parts of the preoptic area, locus ceruleus, medial hypothalamus, brainstem reticular formation and ventral thalamic nuclei from naive rats. The determined levels of binding at 4 nM [3H]RTX were 23.0 +/- 4.5, 7.1 +/- 1.6, 29.9 +/- 2.3, 23.5 +/- 2.4, 9.9 +/- 2.2 and 8.1 +/- 1.9 fmol/mg, respectively; unfortunately, the high levels of non-specific binding (higher than 80%) in the present experiments made it impossible for us to characterize fully the binding properties of the receptors. However, no detectable specific [3H]RTX binding was present in membranes of brain nuclei from rats pretreated with 300 mg/kg capsaicin, a treatment which causes loss of response to capsaicin. Significant specific [3H]RTX binding was also absent in membrane preparations of the midbrain central gray matter, somatosensory cortex and cerebellum either from naive or capsaicin treated rats. In human brain specific [3H]RTX binding measured at 4 nM [3H]RTX showed a pattern of distribution similar to that in the rat brain. The corresponding levels of specific [3H]RTX binding in the preoptic area, locus ceruleus, medial hypothalamus, reticular formation and ventral thalamus were 44.9 +/- 2.4, 50.6 +/- 3.0, 36.1 +/- 2.9, 9.4 +/- 2.8 and 8.4 +/- 2.4 fmol/mg, respectively. Our findings corroborate previous biological evidence that vanilloid receptors are present in brain as well as in sensory afferent neurons.

Animals↗
PubMed1996

The stimulation of capsaicin-sensitive neurones in a vanilloid receptor-mediated fashion by pungent terpenoids possessing an unsaturated 1,4-dialdehyde moiety.

1. The irritant fungal terpenoid isovelleral caused protective eye-wiping movements in the rat upon intraocular instillation and showed cross-tachyphylaxis with capsaicin, the pungent principle in hot pepper. 2. Isovelleral induced a dose-dependent calcium uptake by rat dorsal root ganglion neurones cultured in vitro with an EC50 of 95 nM, which was fully inhibited by the competitive vanilloid receptor antagonist capsazepine. 3. Isovelleral inhibited specific binding of [3H]-resiniferatoxin (RTX), an ultrapotent capsaicin analogue, to rat trigeminal ganglion or spinal cord preparations with an IC50 of 5.2 microM; in experiments in which the concentration of [3H]-RTX was varied, isovelleral changed both the apparent affinity (from 16 pM to 37 pM) and the co-operativity index (from 2.1 to 1.5), but not the Bmax. 4. The affinity of isovelleral for inducing calcium uptake or inhibiting RTX binding was in very good agreement with the threshold dose (2.2. nmol) at which it provoked pungency on the human tongue. 5. For a series of 14 terpenoids with an unsaturated 1,4-dialdehyde, a good correlation was found between pungency on the human tongue and affinity for vanilloid receptors on the rat spinal cord. 6. The results suggest that isovelleral-like compounds produce their irritant effect by interacting with vanilloid receptors on capsaicin-sensitive sensory neurones. Since these pungent diterpenes are structurally distinct from the known classes of vanilloids, these data provide new insights into structure-activity relations and may afford new opportunities for the development of drugs targeting capsaicin-sensitive pathways.

Aldehydes↗
PubMed1996

Self-insured employer health plans: prevalence, profile, provisions, and premiums.

Data from three recent surveys indicate that about 40 percent of workers with employment-based health insurance are enrolled in plans that their employers self-insure. Despite the considerable differences between federal regulation of these self-insured plans and state regulation of employer plans purchased from an insurance company, we find striking similarities in the populations they serve, the benefits they offer, and their premium costs. Implications for health policy are discussed.

Adult↗
PubMed1995

Protein kinase C in cell signaling: strategies for the development of selective inhibitors.

Protein kinase C plays a central role in the cellular signaling pathway for the lipophilic second messenger sn-1,2-diacylglycerol, which is involved in many biological responses, including tumor promotion and inflammation. A major effort has been directed at understanding diversity within this system in order to develop strategies for selective inhibition. Two classes of ligands for the regulatory domain of protein kinase C have been identified which, although they function in vitro as activators of the enzyme, paradoxically behave in vivo as partial antagonists. Identification of targets for the phorbol esters distinct from protein kinase C argues that antagonists acting on the regulatory and catalytic domains of protein kinase C will have different spectra of action.

Animals↗
PubMed1995

A comparison between radiographic and sonically produced cephalometric values.

Cephalometric radiography has become a standard and invaluable means of obtaining diagnostic information for the management of malocclusion and skeletal disharmony. However, concerns over radiographic exposure, particularly in growing individuals, may limit its use, especially in longitudinal analyses. Less invasive means of obtaining vital information would be desirable. A recently introduced system (Digigraph, Dolphin Imaging Systems; Valencia, Calif) provides sonically produced representations of cranial landmarks and has been introduced by its manufacturer as an alternative to standard cephalometric radiography. The purpose of the study was to compare the validity and reproducibility of cephalometric values generated sonically on a digital image analyzer (Digigraph) with those obtained from standard cephalometric radiographs for 43 different measurements. Although 58.1% of the sonically produced measurements showed significant correlation with radiographically produced measurements, there were no trends observed for correlation, either in dental or skeletal structure classifications. Additionally, this study found the data generated from the digital image analyzer to be markedly variable, while the radiographically obtained data were reproducible.

Adult↗
PubMed1995

Resiniferatoxin-amide and analogues as ligands for protein kinase C and vanilloid receptors and determination of their biological activities as vanilloids.

The naturally occurring diterpene resiniferatoxin (RTX) is an ultrapotent analogue of capsaicin. Acting on polymodal afferent neurons, RTX induces a generally similar pattern of responses as does capsaicin. However, the two compounds, as well as other vanilloid derivatives, display different relative potencies for different responses. In the present study, we examined the vanilloid-like activities of two new derivatives, the amide analogue of RTX and phorbol 12,13-dibenzoate 20-homovanillylamide. Structurally, RTX-amide resembles capsaicin more closely than does RTX, and after cleavage of the amide bond the resulting amine would be predicted to not bind to protein kinase C in contrast to resiniferonol 9,13,14-orthophenylacetate, the parent diterpene of RTX. In contrast to our expectations the binding potency of the RTX-amide for the vanilloid receptor present in rat spinal cord was 450-fold lower than that of RTX (Ki values for the RTX-amide and RTX were 10.4 +/- 0.7 nM and 23.1 +/- 3.2 pM, respectively). In the case of phorbol 12,13-dibenzoate 20-homovanillylamide, there was a further loss of affinity for the vanilloid receptor compared with RTX; nonetheless, the Ki (8.56 +/- 0.61 microM) was comparable with that of capsaicin (5.31 +/- 0.37 microM). Computer fitting of the binding data yielded Hill coefficient values of 2.25 +/- 0.03, 2.33 +/- 0.03, and 1.84 +/- 0.05 for RTX, RTX-amide, and phorbol 12,13-dibenzoate 20-homovanillylamide, respectively, indicating that both new compounds induced apparent positive cooperativity among vanilloid binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Trifluoperazine modulates [3H]resiniferatoxin binding by human and rat vanilloid (capsaicin) receptors and affects 45Ca uptake by adult rat dorsal root ganglion neurones.

Optimum treatment of neuropathic pain includes the use of adjuvant analgesics such as antipsychotic drugs and tricyclic antidepressants. Although the mechanism of their analgesic action is not known, it is possible that such agents act directly on pain pathways. The ability of capsaicin and its analogs to selectively deactivate primary afferent neurons provides a basis for their use in human therapy to relieve a number of chronic pain conditions. We examined whether the phenothiazine antipsychotic drug trifluoperazine (TFP) as well as other neuroleptics and tricyclic antidepressants have an effect on the agonist binding properties and the activation of the human and rat vanilloid receptors. Binding of [3H]resiniferatoxin (RTX) to membrane preparations of human dorsal horn and rat whole spinal cord was affected by TFP in a biphasic fashion, with an initial 25 and 65% enhancement of [3H]RTX binding, respectively, preceding inhibition. The apparent Ki values for inhibition were 3.93 +/- 0.13 microM for human dorsal horn and 7.91 +/- 0.62 microM for rat spinal cord. Scatchard analyses revealed that TFP affected both the affinity and the cooperativity of [3H]RTX binding by the receptors, leaving the receptor density unaltered. Similar effects on [3H]RTX binding to rat spinal cord membranes were also induced by other antipsychotic phenothiazines and other types of antipsychotics, by phenothiazines without antipsychotic actions, as well as by tricyclic antidepressants. In cultures of dorsal root ganglion neurones, TFP at concentrations that increased [3H]RTX binding (1-3 microM) also induced an increase in 45Ca uptake; this increase was absent in cultures prepared from capsaicin desensitized animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Explaining trends in health insurance coverage between 1988 and 1991.

This paper uses regression-based decompositions to examine the downward trend in insurance coverage between 1988 and 1991. I find that falling family incomes account for much of the decline in overall insurance coverage, while a secular decline in insurance coverage across all industries, firm sizes, employment statuses, income levels, and demographic groups accounts for most of the decline in employer-sponsored insurance among workers. Rising unemployment and changing patterns of industrial employment explain little of the decline in coverage across the entire population. Taken together, these results suggest that fewer employers are offering health coverage, workers are finding it difficult to pay their share of the premiums, and those without access to employer-sponsored plans are finding it harder to purchase nongroup insurance. Thus, it appears that the rising cost of health insurance coupled with falling incomes and profits during the recession account for the fall in health insurance coverage between 1988 and 1991.

Family↗
PubMed1994

Comparison of [3H]resiniferatoxin binding by the vanilloid (capsaicin) receptor in dorsal root ganglia, spinal cord, dorsal vagal complex, sciatic and vagal nerve and urinary bladder of the rat.

In the present report we compared the properties of [3H]resiniferatoxin (RTX) binding by the vanilloid receptors present at different parts of the primary afferent neurons of the rat. We found no major differences in either the affinity or the cooperativity of [3H]RTX binding by vanilloid receptors on the cell body, central terminals, peripheral terminals or axons. Specific binding of [3H]RTX to dorsal root ganglia, whole spinal cord, dorsal vagal complex, urinary bladder, and sciatic and vagal nerves all followed sigmoidal saturation kinetics indicating positive cooperativity among the binding sites. The cooperativity indexes determined by fitting the data to the Hill equation were 1.82 +/- 0.11, 2.21 +/- 0.04, 2.55 +/- 0.01, 1.91 +/- 0.11, 2.03 +/- 0.09 and 2.27 +/- 0.04, respectively. The dissociation constants in dorsal root ganglia, spinal cord, dorsal vagal complex, urinary bladder, and sciatic and vagal nerve membranes were 46.5 +/- 2.7, 29.3 +/- 5.1, 28.2 +/- 1.2, 60.8 +/- 4.4, 59.9 +/- 1.9 and 45.2 +/- 0.7 pM; the receptor densities were 219 +/- 14, 48 +/- 5, 67 +/- 1, 32 +/- 7, 61 +/- 9, and 100 +/- 20 fmol/mg protein, respectively. We could not show any major differences in the affinities of capsaicin and capsazepine in inhibition of [3H]RTX binding by the different membrane preparations either. In all cases the initial enhancement of [3H]RTX binding by nonradioactive RTX, capsaicin, and capsazepine confirmed the existence of positive cooperativity among the binding sites. We were unable to detect specific [3H]RTX binding sites in membrane preparations of the preoptic area, locus ceruleus, substantia nigra, striatum and paraventricular nuclei of the rat brain under our present conditions. Our results suggest the uniformity of the vanilloid receptors present at different parts of the primary afferent neuron.

Animals↗
PubMed1994

[3H]resiniferatoxin binding to pig dorsal horn membranes displays positive cooperativity.

In the present report we have reevaluated specific [3H]resiniferatoxin (RTX) binding, thought to represent the vanilloid (capsaicin) receptor, to whole spinal cord and dorsal horn membranes of the pig using a modified [3H]RTX binding assay. The high nonspecific [3H]RTX binding of the original protocol was reduced by the addition of alpha 1-acid glycoprotein (AGP), a plasma protein that binds RTX, to the assay mixture after the binding reaction had been terminated. Specific [3H]RTX binding to pig whole spinal cord and dorsal horn membranes followed sigmoidal saturation kinetics indicating apparent positive cooperativity. The cooperativity index determined by fitting the data to the Hill equation was 2.31 +/- 0.24 in the spinal cord and 2.27 +/- 0.13 in the dorsal horn. The apparent dissociation constants in spinal cord and dorsal horn membranes were 87.8 +/- 2.7 and 103.9 +/- 1.9 pM; the receptor densities were 23 +/- 3 and 203 +/- 5 fmol/mg protein, respectively. In parallel experiments, rat spinal cord membranes bound [3H]RTX with 2 - 3 fold higher affinity, equal positive cooperativity, and a 49 +/- 6 fmol/mg receptor density. As predicted by the modified Hill equation, at low receptor occupancy nonradioactive RTX produced biphasic competition curves. Capsaicin and the competitive antagonist capsazepine also fully displaced specifically bound [3H]RTX from pig dorsal horn membranes with Ki values of 9.7 +/- 1.7 microM and 6.8 +/- 0.7 microM, respectively; the corresponding Hill coefficients were 1.81 +/- 0.17 and 2.32 +/- 0.11. [3H]RTX binding was not inhibited by resiniferonol 9, 13, 14-orthophenylacetate, the biologically inactive parent diterpene of RTX. These findings suggest that the vanilloid receptor present in the dorsal horn of the pig, like those present in human and in the rat, is a receptor cluster in which the subunits cooperate.

Animals↗
PubMed1994

Comparison of [3H]resiniferatoxin binding to spinal cord and dorsal root ganglia of newborn and adult rats.

Capsaicin is frequently used in neurobiological investigations to selectively inhibit response by the primary sensory afferent neurons. The effectiveness of treatment depends significantly on the age of the animals; newborns are both quantitatively and qualitatively more sensitive than adults. In the present study, we used the [3H]resiniferatoxin binding assay to determine whether this different susceptibility to capsaicin between newborns and adult animals may reflect differences either in receptor affinity or density. We report here that whole spinal cord membranes of neonates bound [3H]RTX with similar affinity and positive cooperativity as did the spinal cord membranes from adult animals (Kd values were 24.8 +/- 3.7 and 26.8 +/- 4.8 pM, respectively; Hill coefficients were 2.25 +/- 0.03 and 2.17 +/- 0.05, respectively). However, the receptor density was three-fold higher in the spinal cord membranes of neonates than of adult rats (Bmax values were 142 +/- 13 and 43 +/- 3 fmol/mg protein, respectively). We found no significant difference in the [3H]RTX binding properties of dorsal root ganglia membranes of newborn and adult animals. Our results suggest that a higher density of the vanilloid receptor in the spinal cord (but not in the dorsal root ganglia) of newborn animals may contribute to the quantitative differences between the sensitivity of adult animals and neonates.

Age Factors↗
PubMed1994

[3H]resiniferatoxin binding by the human vanilloid (capsaicin) receptor.

We report here that we were able to detect the human vanilloid receptor in all three major central endings of primary afferent neurons--in the dorsal horn of the spinal cord, in the cuneate and gracile nuclei and in the spinal nucleus of the trigeminal nerve--and to characterize the binding properties of the receptor in the dorsal horn. Specific [3H]resiniferatoxin (RTX) binding is thought to represent the vanilloid (capsaicin) receptor. [3H]RTX binding to membranes obtained from total human spinal cord and dorsal horn followed sigmoidal saturation kinetics indicating apparent positive cooperativity. The cooperativity index determined by fitting the data to the Hill equation was 1.37 +/- 0.02 in the total spinal cord and 1.77 +/- 0.16 in the dorsal horn. The apparent dissociation constants in whole spinal cord and dorsal horn membranes were 915 +/- 12 and 532 +/- 27 pM; the receptor densities were 140 +/- 6 and 227 +/- 15 fmol/mg protein, respectively. Membrane preparations from the spinal nucleus of the trigeminal nerve and the cuneate and gracile nuclei also bound [3H]RTX in a similar fashion. In parallel experiments, rat spinal cord membranes bound [3H]RTX with 20- to 40-fold higher affinity, somewhat greater positive cooperativity, but at a 3-fold lower receptor density. As predicted by the modified Hill equation, non-radioactive RTX at low receptor occupancy produced biphasic competition curves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

[Traumatic hip dislocation in childhood].

Authors describe the diagnostic and therapeutic problems of the traumatic dislocation of the hip in children and report on the experiences of their 8 cases. It is stressed that the condition of the good result in the early diagnosis and reduction. For the recognition and treatment of the late complications a 1.5-2 years follow-up of the patients is thought to be important.

Accidental Falls↗
PubMed1993

Pediatric infection with the human immunodeficiency virus.

While rates of infection with the HIV virus are decreasing, the number of children infected continues to increase. There are multiple implications for the practicing pediatric dentist. Many of these children will seek or be referred by other health care providers for treatment of resulting oral pathology. Dentists must be prepared to provide dental services to the HIV-infected child.

AIDS-Related Opportunistic Infections↗
PubMed1992

Productive nonlytic human immunodeficiency virus type 1 replication in a newly established human leukemia cell line.

We have isolated a lymphoid cell line, MDS, from the pleural exudate of a patient with chronic myelomonocytic leukemia. The cells are biphenotypic, containing various T-cell and myeloid markers, and are surface negative for CD4 and CD8 but have low CD4 mRNA. The cells grow in suspension with a doubling time of 15 hr, have been karyotyped as trisomy 21, are negative for human immunodeficiency virus type 1 (HIV-1), and are tumorigenic in the nude mouse. We have isolated two stable HIV-1-producing cell lines, MDS-T, by transfecting MDS cells with pHXBc2, and MDS-I, by infecting MDS cells with HIV-1IIIB. In 24 hr, 1 x 10(5) MDS-T or MDS-I cells produce 46 ng of p24 per ml and reverse transcriptase that is capable of incorporating 0.2 pmol of [32P]TTP into oligo(dT).poly(A). Ultrastructural studies showed numerous mature viral particles in MDS-T and MDS-I cells that are capable of infecting T cells. HIV-1 infection could be inhibited by 25% in the MDS cells with the anti-CD4 antibody Leu 3a. For over a year MDS-T and MDS-I cells have been producing high concentrations of HIV-1 in culture. A subclone derived from the MDS cells behaves like the parent cells when transfected or infected with HIV-1. In contrast to other T-cell lines, neither phorbol 12-myristate 13-acetate nor tumor necrosis factor alpha stimulated the replication of HIV-1, whereas bromoadenosine 3',5'-cyclic monophosphate or interferon alpha caused 50% and 80% inhibition of reverse transcriptase production, respectively. These chronically infected T-cell lines are a useful model system to study the effect of anti-HIV agents and cellular factors required for HIV-1 replication.

8-Bromo Cyclic Adenosine Monophosphate↗