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Biomedical subjects

G Shah

Publications and source records attributed to G Shah.

At least 37 records · Page 2Linked to original sources

Size-Exclusion Chromatography of Carboxyl-terminated Dendrimers as a Model for Permeation of Charged Particles into Like-Charged Cavities

In order to examine the permeation of small charged colloids into cavities of like charge, size-exclusion chromatography was carried out with carboxyl-terminated dendritic polymers on a porous glass stationary phase. Chromatographic partition coefficients KSEC were measured for solute diameters ranging from 2 to 8 nm, at neutral pH, and ionic strengths from 0.01 to 0.09 M, and were reported relative to those of noninteracting solutes of equal size (pullulan and Ficoll). The experimental results were compared to values calculated using the treatment of F. G. Smith III and W. M. Deen for charged spheres in cylindrical pores of like charge (J. Colloid Interface Sci. 78, 44 (1980); 91, 571 (1983)). The measured degrees of permeation were typically 20-100% larger than the calculated values, the discrepancies being greatest for the larger solutes at high ionic strength. It is shown that the tendency of the calculations to overestimate the repulsion are likely to arise from linearization of the Poisson-Boltzmann equation.

Journal Article↗

D-cycloserine enhances rapid tolerance to ethanol motor incoordination.

In a recent study, we showed that D-cycloserine, an agonist at the glycine site of the NMDA receptor, enhances the development of rapid tolerance to ethanol. In the present study, we report that the acquisition of rapid tolerance to the motor incoordination effect of ethanol (tilt-plane test) was increased only when D-cycloserine was injected before, but not after, the intoxicated practice under ethanol. The effect of D-cycloserine on tolerance when this agonist was administered in divided doses before and after test was similar to that obtained when D-cycloserine was injected before test. Higher doses of D-cycloserine did not produce a further enhancement of rapid tolerance. Moreover, when the dose of ethanol on day 1 was large enough to induce rapid tolerance per se, D-cycloserine did not further enhance the tolerance. The enhancement of tolerance by D-cycloserine was antagonized by previous administration of ketamine. The enhancement of ethanol tolerance by D-cycloserine and the antagonism of this effect by ketamine cannot be attributed to changes in pharmacokinetics of ethanol. Taken together, these results confirm the participation of the NMDA receptor system in the development of tolerance to ethanol, and reinforce earlier findings about the involvement of learning in tolerance.

Animals↗

Influence of nitric oxide synthase inhibition on the development of rapid tolerance to ethanol.

We recently reported that the nitric oxide (NO) synthase inhibitor L-nitroarginine (L-NA) blocks the development of rapid tolerance to the motor incoordinating effect of ethanol in the tilt-plane test. To clarify the mechanism of L-NA blockade of tolerance, four additional experiments were carried out using the same test. The first demonstrated that L-NA prevented the development of rapid tolerance to ethanol when injected prior to ethanol either on both Days 1 and 2 or only on Day 1. In the second experiment, tolerance was blocked only when L-NA was injected before but not after behavioral testing on Day 1. In the third, L-NA blocked the enhancement of rapid tolerance to ethanol induced by D-cycloserine (CS), an agonist at the N-methyl-D-aspartate (NMDA) receptor. In the last experiment, L-NA pretreatment did not influence blood ethanol disappearance curves on Day 1, or ethanol concentrations in brain, tail blood or decapitated trunk blood on Day 2. These data argue against state-dependent learning as the basis of the L-NA effect, and confirm and extent our previous observation that NO plays a role in the development of rapid tolerance to ethanol.

Amino Acid Oxidoreductases↗

Isolation of three novel human genes encoding G protein-coupled receptors.

We have cloned and mapped the chromosomal location of three novel human genes encoding G protein-coupled receptors that we have named GPR6, GPR5, and GPR4. The entire coding region for each of these genes was contained on single exons. Gene GPR6 encoded a receptor that shared closest identity (71% in the transmembrane regions) with the human orphan receptor GPR3 and was localized to chromosome 6 (q21-q22.1). Northern blot analysis revealed that GPR6 transcripts were abundant in the human putamen and to a lesser extent in the frontal cortex, hippocampus, and hypothalamus. Gene GPR5 encoded a receptor that most closely resembled the orphan receptor RBS11 (48% in the transmembrane regions) and the MIP 1 alpha/RANTES receptor (45% in the transmembrane regions) and was localized to chromosome 3 (p21.3-p21.1). Gene GPR4 shared identity (40% in the transmembrane regions) with the human platelet-activating factor receptor and was localized to chromosome 19 (q13.2-q13.3).

Amino Acid Sequence↗

Transformation of naturally competent Streptococcus mutans with replicative and non-replicative Tn916-containing plasmids: implications for a mechanism of transposition.

Based on the observations reported here and what is known concerning transformation of naturally competent strains of S. mutans and other streptococcal species such as S. gordonii, we propose the model shown in Figure 2. The Tn916-intermediate transforms S. mutans as originally proposed for B. subtilis by Scott and coworkers [8]. It is not clear in either system (B. subtilis or S. mutans) whether the Tn916 intermediate enters the cell as ds-DNA or ss-DNA. Because it is likely that transformation of B. subtilis via formation of protoplasts involves a mechanism quite different from natural transformation in S. mutans, it would be unwise to extrapolate findings from their studies. If Tn916 enters S. mutans in a manner similar to plasmid or chromosomal DNA, we would assume that Tn916 binds to a cell receptor and as one strand enters, the other is degraded [9]. This leaves open the question of whether Tn916 recircularizes as ds-DNA before it inserts into the chromosome or whether it remains as ss-DNA, if, indeed, it enters as ss-DNA. The transformation efficiency for the Tn916 intermediate (approximately 10(-7) precluded kinetics studies such as those performed with pAM118. Poyart-Salmeron and coworkers [11] however, described a model in which Tn1545 inserts into the target site as a ds-DNA circular molecule, similar to that seen with lambda phage. Perhaps the most interesting finding presented here is that the predominant mechanism of insertion of Tn916 into the chromosome of the recipient occurs after Tn916 enters the cell. The replicative plasmid pAM118 evidently forms by two-hit kinetics followed by intracellular excision and transposition of Tn916. The helper-rescue experiment shows that in this system, the formation of Tcr transformants, and hence the integration of Tn916, was a function of the transformation efficacy of plasmid pAM118. Since intracellular excision of Tn916 probably follows the re-formation of the plasmid pAM118, the rate-limiting step in this system would be the formation of the transient, intracellular plasmid pAM118. (The transient white colony phenotype probably denotes the slower growth rate of transformants that acquire the large replicative plasmid pAM118). Our findings demonstrate that a practical way of promoting Tn916 insertions into chromosomal DNA for the purpose of obtaining mutations is to use a helper-rescue system. Our model supports the concept that the majority of Tn916 inserts arise from a mechanism similar to 'zygotic induction' as proposed for S. sanguis (gordonii) [1]. However, the frequencies for the co-establishment of the replicative plasmid (Emr) and Tn916 inserts (Tcr) in their paper (10(-6)) differ from our observations for S. mutans. We found nearly 100% of Tcr white colonies to be Emr whereas in S. gordonii, only a fraction (approximately 1%) exhibited the TcrEmr phenotype. If both phenotypes arose independently, the frequency of the TcrEmr phenotype would be 10(-8) rather than 10(-6) survivors/recipients as observed. It was surmised that both Tcr and Emr transformants arise dependently [1] where both the Tn916 intermediate and pAM118 contribute to the formation of Tn916 inserts. We conclude from their data, however, that most Tcr arose from the Tn916-intermediate formed in the donor, in agreement with the explanation of these data by Scott [12]. Support for the contention that the Tcr arose in S. gordonii from transformation by the Tn916-intermediate as in S. mutans (yellows), and not from intracellular excision from pAM118, comes from the observation that so few Tcr are Ems and because pAM150 (rep-) yields Tcr at the same frequency as the rep+ pAM118 in their experiments. In summary, the Tn916 intermediate is capable of transforming S. mutans. In contrast to the hypothesis of Scott [12], however, the Tn916 intermediate is not the only form involved in the transformat++t

Chromosomes, Bacterial↗

The conformation of the sialyl Lewis X ligand changes upon binding to E-selectin.

High-field NMR spectroscopy has been used to study the complex formed by the tetrasaccharide sialyl Lewis X and its receptor, E-selectin. Transferred NOEs demonstrate a specific interaction between the protein and ligand and enable measurement of the dissociation constant for the complex to be between approximately 1.1 and 2.0 mM. Differences between Overhauser spectra for free and bound sialyl Lewis X highlight a conformational change upon binding. This can be pinpointed to a change in the torsion angle of the glycosidic link between the sialyl and galactosyl residues and used to select a likely "bound" conformation from four low-energy species. Docking the bound form of sialyl Lewis X onto a model of the lectin domain of E-selectin suggests that the conformational change upon binding results primarily from steric interactions.

Carbohydrate Sequence↗

Age-related changes in tissue content of malondialdehyde-modified proteins.

One of the possible mechanisms of the age-related modifications of proteins is the result of reaction with malondialdehyde (MDA), a lipid peroxidation byproduct. To determine the effect of age on the extent of MDA derivatization of proteins in plasma and various tissues, male Fisher 344 rats at 4, 12 and 26 months of age were studied. Protein electrophoresis and immunoblotting was carried out using a specific antiserum against MDA-protein complexes. The concentration of MDA-proteins in plasma (mean +/- SD of optical density in 50 micrograms protein) was 201.6 +/- 47.7 in 4 month old rats, 197.4 +/- 67 in 12 month old rats and 101.4 +/- 22.7 in 26 month old rats (P < 0.01). The MDA protein content of testicle, liver and heart was increased in 12 month old rats compared to 4 and 26 months old rats. There were no age-related differences in MDA-protein content of lung, brain, and kidney. Because of the interindividual variability of MDA-protein profiles within an age group distinct age-related changes in the distribution of various MDA protein bands could not be documented.

Aging↗

Tissue-specific distribution of malondialdehyde modified proteins in diabetes mellitus.

A potential mechanism of diabetes-related tissue damage is modification of various proteins by lipid peroxidation by-products such as malondialdehyde (MDA). To determine the extent of MDA derivatization of various proteins in diabetes mellitus, Western blots were carried out using a specific anti-MDA antiserum to study proteins in plasma and various tissues of control and streptozotocin (STZ)-induced diabetic rats. The concentration of MDA-proteins was highest in plasma compared to other tissues tested. Diabetes was associated with a reduction in MDA-protein content of plasma, lung and liver while in the heart, testicle, cerebrum and kidney the MDA-protein concentration was not altered. Insulin treatment of diabetic rats normalized MDA-protein content of plasma but not in the lung or liver. A large interindividual variability in various protein species was observed within a group. This was partly attributed to polymerization of MDA-proteins. It is concluded that although diabetes is associated with increased lipid peroxidation the content of MDA-proteins in plasma and in some tissues is decreased.

Animals↗

Effect of NMDA antagonists on rapid and chronic tolerance to ethanol: importance of intoxicated practice.

Recent studies from our laboratory have shown that NMDA antagonists ((+)MK-801 and ketamine) inhibit the development of both rapid and chronic tolerance to the motor-impairing (moving belt test) and hypothermic effects of ethanol. The present experiments were designed to determine a) the generality of this inhibition, by using a different test of motor function, the tilt-plane test, and b) the possible importance of the experimental paradigm (i.e., with and without intoxicated practice), for the effect of the NMDA antagonist on ethanol tolerance. Daily administration of ethanol 3.3 g/kg for 5 days produced the same degree of tolerance on this test, whether it was given as a single dose of 3.3 g/kg before the daily training session or as divided doses of 2.3 g/kg before and 1 g/kg immediately after the session. The inhibitory effect of a single dose of (+)MK-801 (0.25 mg/kg IP) on rapid tolerance did not last longer than 1 day. Therefore, daily administration of the NMDA antagonists was necessary to block development of chronic tolerance. Daily injection of (+)MK-801 (0.25 mg/kg IP) failed to block chronic tolerance, but inclusion of a second dose of (+)MK-801 daily, and progressive increase of this second dose during the chronic treatment period did block chronic tolerance. Unlike (+)MK-801, ketamine does not have motor-impairing effects of its own, and does not potentiate those of ethanol; it was, therefore, used in the remaining experiments. Groups of rats received ethanol (3.3 g/kg) or saline, either before a daily practice session on the tilt-plane or after it.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Interaction between N-methyl-D-aspartate (NMDA) and serotonin (5-HT) on ethanol tolerance.

Earlier work from this laboratory had shown that 5-HT is involved in the development of tolerance to ethanol, and that enhancement of 5-HT levels by L-tryptophan accelerated tolerance development. To explore the possibility that NMDA receptors are involved in the 5-HT effect on tolerance, we examined the effect of a noncompetitive N-methyl-D-aspartate (NMDA) antagonist [(+)MK-801] on the ability of L-tryptophan to enhance tolerance to the effect of ethanol on tilt-plane test performance by the rat. L-Tryptophan treatment resulted in the development of rapid tolerance to a dose of ethanol that failed to produce such tolerance by itself. However, prior administration of (+)MK-801 blocked the L-tryptophan effect on rapid tolerance development, in a dose-dependent manner. These results suggest that NMDA receptors are involved in the 5-HT enhancement of ethanol tolerance.

Analysis of Variance↗

Effect of NMDA receptor antagonists on rapid tolerance to ethanol.

Hypothermia and motor impairment (tilt-plane test) were used to assess whether N-methyl-D-aspartate (NMDA) receptors play a role in the development of rapid tolerance to ethanol, i.e., tolerance to a second dose of ethanol given 24 h after the effect of the first dose of ethanol had disappeared. Results showed that (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol on both tests. Since these drugs did not modify blood or brain alcohol levels in any of the groups, the blockade of ethanol rapid tolerance cannot be attributed to changes in pharmacokinetics of ethanol. These data suggest that the role of NMDA receptors in ethanol tolerance may be similar to their role in memory and learning, involving a facilitation of transmission in certain synapses.

Animals↗

Mechanism of induction of c-fos by ultraviolet B (290-320 nm) in mouse JB6 epidermal cells.

The UVB (290-320 nm) portion of the solar spectrum possesses the highest activity for the induction of skin cancer and has the capacity to stimulate epidermal proliferation. We report that UVB is a transcriptional inducer of the c-fos protooncogene in mouse JB6 epidermal cells. Induction is biphasic with an immediate early peak at 30-60 min and a second broader peak 8 h following irradiation. The immediate early phase is suppressed by inhibitors of nuclear adenosine diphosphoribose transferase. For UVB induction, the formation of full-length messages is less efficient than of early, short messages, while both types of messages are produced at similar rates following serum stimulation. Experiments with stable transfectants with reporter constructs linked to 5'-upstream sequences of c-fos indicate that UVB and serum stimulation both require the sequences from -345 to -285 which contain the joint DSE-AP-1 enhancer motifs for efficient induction. Mobility shift data reveal that the complement of c-Fos and c-Jun proteins which bind to the fos-AP-1 octanucleotide decrease immediately following irradiation. Increased binding of Fos and Jun is observed 8-24 h later. UVB did not cause an observable change in the nuclear proteins which bind to the dyad symmetry element oligonucleotide in vitro. Fos protein was detected among the binding proteins. We propose that the two phases of UVB-induced c-fos expression occur by quite different mechanisms. The immediate early phase is inhibited by adenosine diphosphoribose transferase inhibitors because poly-ADP ribosylation of chromosomal proteins is required for the resealing of UVB-induced DNA strand breaks which otherwise retard message elongation. The production of an autocrine factor may be responsible for the late phase of c-fos induction.

Animals↗

Types, causes, and therapies of hepatitis occurring in liver transplant recipients.

Liver transplantation (OLTx) has become a common life-saving procedure for individuals with chronic advanced liver disease. It is also used in the clinical treatment of patients with fulminant hepatic failure and those with primary neoplastic disease of the liver. Despite its overall success in restoring meaningful life to those who undergo the procedure, the posttransplant life of a liver allograft recipient is not without hazard. A common problem following liver transplantation is the finding of abnormal liver injury tests reflecting a "hepatitis" that can not be ascribed to allograft rejection. The majority of such cases are a consequence of either a technically flawed operation, drug-induced liver injury, or one or another form of viral hepatitis. Each of these problems is discussed in the following clinical review.

Chemical and Drug Induced Liver Injury↗

Effect of D-cycloserine on rapid tolerance to ethanol.

We recently reported that the noncompetitive NMDA antagonists, (+)MK-801 and ketamine, block the development of rapid tolerance to ethanol. In the present article, we show that D-cycloserine (CS), an agonist at the glycine site of the NMDA receptor that enhances learning and memory, also enhances the development of rapid tolerance to ethanol. Rats were pretreated on day 1 with saline or CS, followed 30 min later by ethanol (2.3 g/kg, IP) or saline. At the end of motor impairment testing on the tilt-plane apparatus, a second injection of CS (3 mg/kg, IP, each time) or saline was given, followed 30 min later by ethanol or saline. Ethanol pretreatment alone (at this dose) did not result in rapid tolerance to ethanol on day 2. However, the group pretreated with CS and ethanol on day 1 showed significant tolerance on day 2 compared to other groups. Pretreatment with CS on day 1 did not affect the motor impairment response to the first exposure to ethanol whether this was on day 1 or day 2. In another experiment, administration of (+)MK-801 (0.25 mg/kg, IP) prior to CS abolished the rapid tolerance enhancement by CS. These findings are further evidence that the NMDA system, which requires activation by the glycine receptor, plays a major role in the development of at least some forms of ethanol tolerance.

Animals↗

Inhibition of nitric oxide synthesis impairs rapid tolerance to ethanol.

To examine whether nitric oxide was involved in the development of rapid tolerance to the motor-incoordinating effects of ethanol (tilt-plane test), three experiments were undertaken in a rapid tolerance paradigm in rats. The first experiment tested the effect of the nitric oxide synthase inhibitor, L-nitro-arginine, on the acquisition of ethanol tolerance. The second compared the effects of L-nitro-arginine with those of its inactive isomer, D-nitro-arginine. The third examined whether overload with the substrate L-arginine would prevent the action of L-nitro-arginine on rapid tolerance. The results demonstrated that L-nitro-arginine prevented the development of rapid tolerance, while D-nitro-arginine was ineffective. An excess of the substrate L-arginine reversed the inhibitory action of L-nitro-arginine on tolerance development. These data suggest that nitric oxide may play a role in the development of tolerance to ethanol. The role of nitric oxide in ethanol tolerance may be similar to its role in memory and learning, involving facilitation of transmission in certain NMDA synapses.

Animals↗

Frequency and severity of HCV infection following orthotopic liver transplantation. Effect of donor and recipient serology for HCV using a second generation ELISA test.

HCV is the principal etiologic agent of post-transfusion (PTH) hepatitis. The incidence and course of HCV hepatitis in liver transplant recipients is not well established. To resolve this information deficit, all records of recipients of single liver transplant (OLTx) between March 1986 and March 1990 at the University of Pittsburgh in whom both the donor and recipients' pre-OLTx sera were available (n = 516) were reviewed. All sera were assayed for HCV antibody using a second generation ELISA method developed by Abbott Laboratories. On the basis of the anti-HCV status of the donor and recipient pre-OLTx sera, four groups could be classified: group I (donor-, recipient-) n = 375; group II (donor-, recipient+) n = 111; group III (donor+, recipient-) n = 25; and group IV (donor+, recipient+) n = 5. Post OLTx liver biopsies were obtained for a clinical indication in 473 of these 516 patients. The prevalence of anti-HCV among recipients pre-OLTx was 22.5% (116/516) which is three times greater than the 5.8% (30/516) prevalence in the donors. Histologic hepatitis not ascribable to any cause other than HCV occurred in 76/516 (15%) recipients: 42 in group I; 28 in group II; 6 in group III and none in group IV. The overall risk of HCV hepatitis at 6 months, 1 year and 2 years post-OLTx was 4.8% (25/516), 7.6% (39/516) and 10.1% (52/516), respectively. At each of these time intervals, no significant difference between groups for the prevalence of HCV hepatitis was evident.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Oxidant carcinogenesis and antioxidant defense.

Growth promotion by oxidants is observed with cultured human and mouse fibroblasts as well as epidermal cells. It is expected to play a role in inflammation, fibrosis, and tumorigenesis. Indeed, oxidants trigger (patho)physiological reactions that resemble those induced by growth and differentiation factors. For example, active oxygen activates protein kinases, causes DNA breakage, and induces the growth competence-related protooncogenes c-fos and c-myc. The cellular antioxidant defenses affect the consequences of oxidant exposure. Transfectants of mouse epidermal cells that overproduce Cu,Zn-superoxide dismutase (SOD) were sensitized to the toxic effects of an extracellular burst of O2-. plus H2O2, whereas overproducers of catalase (CAT) were protected. Transfection of SOD overproducers with CAT corrected their hypersensitivity. Inducibility of the protooncogene c-fos by oxidants was diminished in SOD and CAT overproducers, albeit probably for different reasons. It is concluded that a fine balance of the multiple components of the antioxidant defense determines the growth response of cells to oxidative stress. In studies of the mechanism of the transcriptional induction of c-fos by oxidants, we identified the joint DSE-AP1 elements (dyad symmetry element, DSE) as major enhancer motifs in the 5'-upstream regulatory sequences of c-fos. Oxidants also increased the de novo synthesis of protein factors that bind to the fos-AP1 enhancer motif. Protein kinase and ADPR transferase inhibitors suppressed the transcriptional induction of c-fos as well as the increase in factor binding to fos-AP1. We conclude that protein phosphorylation and protein polyADP-ribosylation are required for the transcriptional induction of c-fos and the synthesis of protein factors that bind to fos-AP1. It is likely that the FOS and JUN proteins are among these factors and that they participate in the regulation of c-fos expression by oxidants.

Animals↗