Showing papers by "Research Triangle Park published in 1993"

Requirement of Salicylic Acid for the Induction of Systemic Acquired Resistance

Abstract: It has been proposed that salicylic acid acts as an endogenous signal responsible for inducing systemic acquired resistance in plants. The contribution of salicylic acid to systemic acquired resistance was investigated in transgenic tobacco plants harboring a bacterial gene encoding salicylate hydroxylase, which converts salicylic acid to catechol. Transgenic plants that express salicylate hydroxylase accumulated little or no salicylic acid and were defective in their ability to induce acquired resistance against tobacco mosaic virus. Thus, salicylic acid is essential for the development of systemic acquired resistance in tobacco.

Generalized linear mixed models a pseudo-likelihood approach

Abstract: A useful extension of the generalized linear model involves the addition of random effects andlor correlated errors. A pseudo-likelihood estimation procedure is developed to fit this class of mixed models based on an approximate marginal model for the mean response. The procedure is implemented via iterated fitting of a weighted Gaussian linear mixed model to a modified dependent variable. The approach allows for flexible specification of covariance structures for both the random effects and the correlated errors. An estimate of an additional dispersion parameter for underlying exponential family distributions is optionally automatic. The method allows for subject-specific and population-averaged inference, and the Salamander data example from McCullagh and Nelder (1989) is used to illustrate both.

Field Performance of Elite Transgenic Maize Plants Expressing an Insecticidal Protein Derived from Bacillus thuringiensis

Abstract: We introduced a synthetic gene encoding a truncated version of the CryIA(b) protein derived from Bacillus thuringiensis into immature embryos of an elite line of maize using microprojectile bombardment. This gene was expressed using either the CaMV 35S promoter or a combination of two tissue specific promoters derived from maize. High levels of CryIA(b) protein were obtained using both promoter configurations. Hybrid maize plants resulting from crosses of transgenic elite inbred plants with commercial inbred lines were evaluated for resistance to European corn borer under field conditions. Plants expressing high levels of the insecticidal protein exhibited excellent resistance to repeated heavy infestations of this pest.

Jakes fading model revisited

Abstract: The Jakes fading model is a deterministic method for simulating time-correlated Rayleigh fading waveforms and is still widely used today. However, since it is difficult to create multiple uncorrelated fading waveforms with this model, the authors propose modifications to the model which solve this problem.< >

Biochemical Basis of DNA Replication Fidelity

Abstract: DNA polymerase is the critical enzyme maintaining genetic integrity during DNA replication. Individual steps in the replication process that contribute to DNA synthesis fidelity include nucleotide ...

Impact of Migraine in the United States: Data from the National Health Interview Survey

Abstract: Data from the 1989 National Health Interview Survey concerning migraine occurrence and impairment were analyzed to assess the impact of migraine on the US population. About four of every one hundred persons in the United States were found to have migraine, accounting for nearly 10 million individuals. Migraine was most prevalent in those aged 25 to 44 years and was about 2.5 times more frequent in females than males. Migraine was most common in whites (85%) and those with low household income. In women, migraine prevalence increased with the level of education. About 10% of migrainous children missed at least one day of school over a two-week period due to migraine; nearly 1% missed four days. Migraineurs were bedridden for about three million days per month and had an estimated 74.2 million days per year of restricted activity due to migraine. The potential cost of lost productivity was estimated at $1.4 billion per year for the estimated 6,196,378 migraineurs who worked outside the home. It is difficult to derive similar estimates for costs of lost productivity in housewives; however, housewives experienced an estimated 38 million days per year of restricted activity. Eighty-five percent of females and 77% of males reported a physician visit at some point for their migraine. Migraine is a relatively common disease whose social and financial impact has been poorly understood.

Peer group structure and adolescent cigarette smoking: a social network analysis.

Abstract: Social network theory and analysis are applied to examine whether adolescents who fill various social positions that characterize peer group structure differ in prevalence of current smoking. One thousand and ninety-two (1,092) ninth graders in one school system named their three best friends, allowing the identification of each adolescent as clique member, clique liaison, or isolate. At four of five schools, the odds of being a current smoker were significantly higher for isolates than for clique members and liaisons. The relationship was not explained by demographic variables or by the number of friends who smoke.

Selective inhibition of constitutive nitric oxide synthase by L-NG-nitroarginine.

Abstract: L-NG-Nitroarginine (NA) inhibited both the L-arginine oxidation and the L-arginine-independent NADPH oxidation reactions catalyzed by the calcium/calmodulin-dependent constitutive nitric oxide synthase (cNOS) from bovine brain. NA binding did not require calmodulin, calcium, or NADPH. The onset of inhibition was slow with a second-order association rate constant (k(on) of 4.4 x 10(4) M-1 s-1. The dissociation rate constant (k(off) was 6.5 x 10(-4) s-1. The Kd value (k(off)/k(on)) of bovine brain cNOS for NA was 15 nM. L-Arginine was a competitive inhibitor of NA binding with a Ks value of 0.8 microM. The Km for L-arginine in the cNOS reaction was 1.2 microM. The NA binding sites of cNOS were titrated with NA, which enabled a kcat of 0.7 s-1, for the oxidation of L-arginine, to be calculated. Finally, a brain cNOS-(3H)NA complex was isolated. In contrast to the potent and slow onset of NA inhibition of brain cNOS, NA inhibition of inducible mouse macrophage NOS (iNOS) was weaker (Ki = 4.4 microM) and rapidly reversible. Thus, NA was a 300-fold more potent inhibitor of bovine brain cNOS than mouse macrophage iNOS.

In Vivo Antitumor Activity of 5-Fluorocytosine on Human Colorectal Carcinoma Cells Genetically Modified to Express Cytosine Deaminase

Abstract: A human colorectal carcinoma cell line, WiDr, was genetically engineered to express the nonmammalian enzyme, cytosine deaminase (CD) Expression of CD in WiDr cells (WiDr/CD) did not alter the growth rate of these cells when grown in vitro or as solid tumor xenografts in nude mice However, expression of CD did increase the sensitivity of these cells to the nontoxic prodrug, 5-fluorocytosine (FCyt), decreasing the 50% inhibitory concentration for FCyt from 26,000 µm in parental WiDr cells to 27 µm in WiDr/CD cells The increase in sensitivity to FCyt in WiDr/CD cells was the result of the CD-mediated conversion of FCyt to 5-fluorouracil (FUra) and subsequent FUra anabolites The half-life of the prodrug, FCyt, was determined to be approximately 40 min in nude mice A single ip injection of 500 mg FCyt/kg body weight resulted in a transient FCyt plasma level of approximately 4000 µm while osmotic minipumps or constant tail vein infusions of FCyt achieved continual FCyt plasma levels of 5 µm and 50 µm, respectively, with no overt signs of toxicity Significant antitumor effects were observed in nude mice bearing tumors derived from WiDr/CD cells when these animals were given 500 mg FCyt/kg ip for 10 consecutive days These antitumor effects were demonstrated by decreases in tumor growth rate, tumor size, tumor weight, and thymidine incorporation into tumor DNA This antitumor effect was significant but less profound if FCyt was administered by constant tail vein infusion WiDr and WiDr/CD cells were very sensitive to FUra in vitro (50% inhibitory concentration approximately 5 /am) However, no significant antitumor effects were observed in nude mice bearing tumors derived from either WiDr or WiDr/CD cells when these animals were treated with various doses of FUra Taken collectively, these data indicate that nontoxic plasma levels of FCyt can be attained which can produce profound antitumor effects on tumors engineered to express CD and that these antitumor effects are significantly better than those that can be achieved using FUra These positive data support the continued development of a gene therapy approach to colorectal carcinoma involving the selective expression of CD in colorectal tumors with subsequent administration of FCyt

Zidovudine treatment of the AIDS dementia complex: Results of a placebo-controlled trial

Abstract: The efficacy of two doses of zidovudine was examined for the treatment of the acquired immunodeficiency syndrome (AIDS) dementia complex in a randomized, double-blinded, placebo-controlled trial conducted at nine study centers. For the initial 16 weeks, 40 subjects with mild to moderate AIDS dementia complex were randomized to one of three treatment arms: 400 mg of zidovudine five times daily, 200 mg of zidovudine five times daily, or placebo five times daily. After week 16, patients initially randomized to the placebo group were rerandomized to one of the two zidovudine treatment arms. The primary efficacy end point was improvement in performance on a battery of seven neuropsychological tests; the secondary end point was improvement on a protocol neurological evaluation directed at the cardinal features of the AIDS dementia complex. For the initial 16-week period, average z scores based on the neuropsychological test battery revealed a significant improvement in the combined treatment groups compared to the placebo group; however, when the two treatment groups were compared separately to the placebo group, only the group receiving the higher zidovudine dose exhibited significant improvement. After rerandomization of the placebo patients to one of the two treatment arms at week 16, this group also showed significant improvement in the average neuropsychological z score by week 32. These results extend previous observations that indicate a therapeutic benefit of zidovudine for the treatment of AIDS dementia complex.

Particle Total Exposure Assessment Methodology (PTEAM) study: distributions of aerosol and elemental concentrations in personal, indoor, and outdoor air samples in a southern California community.

Abstract: Particle concentrations were measured for a probability-based sample of 178 nonsmoking individuals aged 10 or older residing in Riverside, California, in the fall of 1990. Two 12-hr personal-exposure PM10 samples were obtained for each participant, along with fixed-location PM10 and PM2.5 indoor and outdoor air samples at their residences. The particle samples were also analyzed via X-ray fluorescence (XRF) to determine elemental concentrations for selected elements, including some toxic metals, crustal elements, and combustion- and industrial-source related elements. About 25% of the target population was estimated to have 24-hr personal exposures to PM10 that exceeded the national ambient air concentration standard of 150 micrograms/m3. The daytime personal exposure levels (median of 130 micrograms/m3) tended to exceed both indoor and outdoor levels by about 50%; nighttime personal exposure levels were lower and were only slightly higher than nighttime indoor levels. Several possible reasons for the elevated daytime personal PM10 levels (relative to indoor levels) are considered. Certain activities such as house cleaning and smoking were found to be associated with elevated personal exposure levels.

Comparison of Ondansetron Versus Placebo to Prevent Postoperative Nausea and Vomiting in Women Undergoing Ambulatory Gynecologic Surgery

Abstract: BACKGROUND:Postoperative nausea and emesis, especially in ambulatory surgical patients, remains a troublesome problem. This study was performed to compare the incidence of nausea and emesis during the 24-h postoperative period in ondansetron-treated patients versus placebo-treated patients. METHODS:Using a randomized prospective double-blind study design, women between the ages of 18 and 70 yr undergoing gynecologic surgical procedures with general opioid anesthesia on an outpatient basis were enrolled. Ondansetron or placebo was administered prior to induction of anesthesia. Patients were stratified according to history of nausea and emesis during previous exposure to general anesthesia and randomized to dose received. RESULTS:Data from the 544 women showed that all doses of intravenous ondansetron tested (1, 4, and 8 mg) were significantly more effective (62%, 76%, and 77%, respectively) than placebo (46%) in reducing the incidence of emesis following surgery until 24 h after recovery room entry. All these doses were more effective than placebo in patients with no prior history of emesis following surgery and the 4- and 8-mg doses were more effective than placebo in patients with a prior history of emesis following surgery. All doses of ondansetron tested were generally well tolerated with adverse events, clinical laboratory tests, and recovery room vital signs similar to those of placebo. Serum aspartate transaminase (AST) was increased in five patients (1 mg, 2 patients; 4 mg, 1 patient; 8 mg, 2 patients). In the three patients in whom subsequent analysis were performed, the serum AST had decreased to preoperative levels. CONCLUSIONS:Ondansetron given intravenously to prevent postoperative nausea and emesis was highly effective in the 4- and 8-mg doses in women having ambulatory gynecologic surgery.

A novel dimer configuration revealed by the crystal structure at 2.4 Å resolution of human interleukin-5

Abstract: Interleukin-5 (IL-5) is a lineage-specific cytokine for eosinophilpoiesis and plays an important part in diseases associated with increased eosinophils, such as asthma. Human IL-5 is a disulphide-linked homodimer with 115 amino-acid residues in each chain. The crystal structure at 2.4 A resolution reveals a novel two-domain structure, with each domain showing a striking similarity to the cytokine fold found in granulocyte macrophage and macrophage colony-stimulating factors, IL-2 (ref. 5), IL-4 (ref. 6), and human and porcine growth hormones. IL-5 is unique in that each domain requires the participation of two chains. The IL-5 structure consists of two left-handed bundles of four helices laid end to end and two short beta-sheets on opposite sides of the molecule. Surprisingly, the C-terminal strand and helix of one chain complete a bundle of four helices and a beta-sheet with the N-terminal three helices and one strand of the other chain. The structure of IL-5 provides a molecular basis for the design of antagonists and agonists that would delineate receptor recognition determinants critical in signal transduction. This structure determination extends the family of the cytokine bundle of four helices and emphasizes its fundamental significance and versatility in recognizing its receptor.

Pharmacokinetics of methamphetamine self-administered to human subjects by smoking S-(+)-methamphetamine hydrochloride.

Abstract: S-(+)-methamphetamine hydrochloride ("ice") is abused by smoking (inhaling the vapors of the material). Male human volunteers inhaled the drug from a pipe heated at 300 degrees-305 degrees C for an average inhaled dose of 21.8 +/- 0.3 (SE) mg. The same volunteers were given an intravenous injection of 15.5 mg of S-(+)-methamphetamine hydrochloride. Methamphetamine and its metabolite amphetamine were analyzed in plasma, saliva, and urine by gas chromatography. The bioavailability of smoked methamphetamine was 90.3 +/- 10.4%. (Oral bioavailability calculated from this study and a previous one was 67.2 +/- 3.1%). The geometric mean plasma half-life was 11.1 hr for smoked methamphetamine and 12.2 hr for the intravenous drug. These values agreed with urinary excretion rate data. The volume of distribution in the elimination phase was 3.24 +/- 0.36 liter/kg for the smoked dose and 3.73 +/- 0.59 liter/kg for the intravenous dose. The mean residence times were 11.5 +/- 0.5 hr and 11.3 +/- 1.74 hr for the two routes. Metabolic clearance represented 58 and 55%, respectively, of the total clearance. Significant amounts of the drug (37-45% of the nominal dose) were excreted in urine as methamphetamine and lesser amounts (7% of the nominal molar dose) as amphetamine. Renal clearance was equivalent for the two routes. Methamphetamine concentrations in plasma after inhalation showed a plateau. A model involving both a fast and a slow input function fit the data from 4 of the 6 subjects and indicated a terminal elimination rate that agreed with results from model-independent pharmacokinetic calculations. The drug caused significant subjective and cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)

A dosing study of nonoxynol-9 and genital irritation.

Abstract: The objective of this study was to assess the symptoms and signs of genital irritation produced by different frequencies of nonoxynol-9 (N-9) use 35 women were randomized to each of 5 groups and used a vaginal suppository for 2 weeks Group 1: N-9 once every other day; Group 2: N-9 once a day; Group 3: N-9 twice a day; Group 4: N-9 four times a day; and Group 5: placebo 4 times a day Study women were examined at admission one week and 2 weeks with a colposcope for erythema and epithelial disruption and were interviewed about vaginal itching and burning The rates of reported symptoms for N-9 users were not significantly different from that of placebo users The rate of epithelial disruption for women using N-9 every other day was essentially the same as that of women using placebo The rates of epithelial disruption for women using N-9 1/day and 2/day were 25 times greater than that of placebo users The rate of epithelial disruption for women using N-9 4/day was five times greater than that of placebo users Genital irritation was located primarily on the vagina or cervix and vulvitis was not a significant problem Women who infrequently use N-9 products may not experience an increase in genital irritation Women who choose to use N-9 frequently may experience an increase in epithelial disruption (authors)

Evaluation of a three-exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals

Abstract: Forty-nine chemicals were tested in a mouse bone marrow micronucleus test that employed three daily exposures by intraperitoneal injection. Bone marrow samples were obtained 24 hr following the final exposure. Twenty-five rodent carcinogens and 24 noncarcinogens were selected randomly from the 44 carcinogens and 29 noncarcinogens used by Tennant et al. (Science 236:933-941, 1987) to evaluate the performance of four in vitro genetic toxicity tests. As in that study of in vitro tests, the micronucleus tests were conducted with coded chemicals and test results (positive or negative) were determined prior to decoding. This study was conducted as part of an effort to assess the ability of the micronucleus test to discriminate between rodent carcinogens and noncarcinogens and to determine its potential role, in combination with other short-term tests, in identifying genotoxic chemicals that present a carcinogenic hazard. Nine chemicals were judged to be positive in the micronucleus test. This relatively low number of positive results, along with published and unpublished results from rodent micronucleus and chromosome aberration assays on several of these 49 chemicals, contributed to the conclusion that a single micronucleus test protocol is not adequate to detect all chemicals capable of inducing chromosomal damage in the bone marrow. However, a combination of two relatively simple assays such as the Salmonella and micronucleus tests can provide important information on the genetic toxicity of test chemicals and may provide guidance on the need for and the nature and extent of future toxicity studies.

Regulation of pathogenesis-related protein-1a gene expression in tobacco.

Abstract: Pathogenesis-related protein-1a (PR-1a) is a protein of unknown function that is strongly induced during the onset of systemic acquired resistance (SAR) in tobacco. The expression of PR-1a is under complex regulation that is controlled at least partially by the rate of transcription. In this study, we demonstrated that 661 bp of 59 flanking DNA was sufficient to impart tobacco mosaic virus and salicylic acid inducibility to a reporter gene. The PR-1a promoter did not respond significantly to treatments with either auxin or cytokinin. Experiments with the protein synthesis inhibitor cycloheximide indicated that protein synthesis is required for salicylate-dependent mRNA accumulation. At flowering, the PR-1a gene was expressed primarily in the mesophyll and epidermal tissues of the leaf blade and the sepals of the flower. Several artifacts, most importantly ectopic expression in pollen, were associated with the use of the beta-glucuronidase reporter gene.

Purification and cDNA sequence of an inducible nitric oxide synthase from a human tumor cell line

Abstract: A combination of cytokines induced the expression of nitric oxide synthase (NOS) in a human colorectal adenocarcinoma cell line, DLD-1. We have purified the enzyme and examined some of its biochemical properties. An antiserum to an inducible NOS from murine macrophages cross-reacted with the DLD-1 NOS. The purified human and murine enzymes displayed a similar lack of dependence on exogenous calcium and calmodulin for activity, which contrasts with the requirement for calcium and calmodulin of purified brain and endothelial isoforms of NOS. We have also isolated a cDNA for a cytokine-induced NOS from DLD-1 cells. Sequence analysis of this cDNA and NOS cDNAs from human liver, smooth muscle, and macrophages suggests that, at the genetic level, there is a single isoform of human-inducible NOS.

Structure, DNA minor groove binding, and base pair specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles) and bis(amidinoindoles)

Abstract: A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with varied linking chains connecting the aromatic groups and various modifications to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA).poly(dT),poly(dA-dT).poly-(dA-dT), and poly(dG-dC).poly(dG-dC)] binding properties of these compounds have been studied by thermal denaturation (delta Tm) and viscosity. The compounds show a greater affinity for poly(dA).poly(dT) and poly(dA-dT).poly(dA-dT) than for poly(dG-dC).poly(dG-dC). Viscometric titrations indicate that the compounds do not bind by intercalation. Molecular modeling studies and the biophysical data suggest that the molecules bind to the minor groove of CT DNA and homopolymers. Analysis of the shape of the molecules is consistent with this mode of nucleic acid binding. Compounds with an even number of methylenes connecting the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molecule show that the shape of the molecule, as a function of chain length, affects the strength of nucleic acid binding. Electronic effects from cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidinoindoles) show no structurally associated differential in nucleic acid base pair specificity or affinity.

A first step in the development of gene therapy for colorectal carcinoma: cloning, sequencing, and expression of Escherichia coli cytosine deaminase.

Abstract: We have developed a new approach involving gene therapy for the treatment of primary and metastatic tumors in the liver. As a first step toward the development of this gene therapy treatment for metastatic colorectal carcinoma, the Escherichia coli gene that encodes cytosine deaminase (CD) (EC 3.5.4.1) has been cloned. By using positive genetic selection, a plasmid carrying a 10.8-kilobase BamHI/EcoRI DNA insert was isolated that had CD enzymatic activity. Genetic screening, followed by enzymatic assays, identified a 3-kilobase DNA fragment that retained CD activity. Deamination of cytosine and 5-fluorocytosine (5-FC) by cloned CD was demonstrated. DNA and protein sequencing identified an open reading frame of 427 amino acids that encodes CD. To demonstrate that expression of CD in eukaryotic cells allows metabolism of the nontoxic prodrug 5-FC to the toxic metabolite 5-fluorouracil, CD was cloned into a eukaryotic expression vector and transfected into a human colorectal carcinoma cell line. Growth inhibition studies showed a shift in the IC50 for 5-FC from 17,000 microM in the parental cell line to 30 microM in cells expressing CD.

Method and apparatus for upgrading cellular mobile telephones

Abstract: An apparatus for upgrading a mobile telephone, the mobile telephone having a main memory the apparatus comprising a module reader provided in the mobile telephone and a software upgrading module card adapted to be temporarily connected to the mobile telephone by insertion into the module reader. The card comprises means for storing upgrading software to be transmitted into the main memory in the mobile telephone. The apparatus further includes means provided in the mobile telephone for transmitting the upgrading software into the main memory.

Strand-invasion of duplex DNA by peptide nucleic acid oligomers

Abstract: Polyamide oligomers, termed peptide nucleic acids (PNAs), bind with high affinity to both DNA and RNA and offer both antisense and antigene approaches for regulating gene expression. When a PNA binds to a complementary sequence in a double-stranded DNA, one strand of the duplex is displaced, and a stable D-loop is formed. Unlike oligodeoxynucleotides for which binding polarity is determined by the deoxyribose sugar, the unrestrained polyamide backbone of the PNA could permit binding to a DNA target in an orientation-independent manner. We now provide evidence that PNAs can, in fact, bind to their complementary sequence in DNA independent of the DNA-strand polarity--that is, a PNA binds to DNA in both "parallel" and "antiparallel" fashion. With a mixed-sequence 15-mer PNA, kinetic studies of PNA.DNA interactions revealed that D-loop formation was rapid and the complex was stable for several hours. However, when measured either by gel-mobility-shift analysis or RNA polymerase II-elongation termination, D-loop formation was salt dependent, but PNA-strand dissociation was not salt dependent. We observed that D-loop-containing DNA fragments had anomalous gel mobilities that varied as a function of the position of the D-loop relative to the DNA termini. On the basis of permutation analysis, the decreased mobility of the PNA.DNA complex was attributed to a bend in the DNA at or near the D-loop.

Quantized coherent rake receiver

Abstract: An implementation of coherent diversity combining in a RAKE receiver that uses energy in signal echoes by integrating information from main-path and bit-period-delayed signal propagation paths to remove echo distortion, or time dispersion, is described. If delayed by one chip in a CDMA system, such echoes appear as uncorrelated interference. The RAKE receiver correlates a despreading code with the current (main-path) signal samples and with the signal samples delayed by 1, 2, 4, . . . bit periods, and combines the correlation results to determine the information content of the signal. After appropriate conditioning, the received signal is digitized and the signal samples are stored. Groups of samples are Fast Walsh Transformed, and the real and imaginary transforms are scaled according to a table of coefficients; the scaled results are stored. Weighted, scaled transforms of groups shifted by 1, 2, 4, . . . samples are accumulated, and the index of the largest-magnitude accumulation is used to select real and imaginary transform values. The selected values are transferred to a RAKE coefficient computer and quantizer that determines from the sequence of values presented the mean value and trend of the real and imaginary components. A Kalman filter may use these values to estimate the values that will occur during the next group analysis period.

Multiple access coding for radio communications

Abstract: Individual information signals encoded with a common block error-correction code are assigned a unique scrambling mask, or signature sequence, taken from a set of scrambling masks having selected correlation properties. The set of scrambling masks is selected such that the correlation between the modulo-2 sum of two masks with any codeword in the block code is a constant magnitude, independent of the mask set and the individual masks being compared. In one embodiment, when any two masks are summed using modulo-2 arithmetic, the Walsh transformation of that sum results in a maximally flat Walsh spectrum. For cellular radio telephone systems using subtractive CDMA demodulation techniques, a two-tier ciphering system ensures security at the cellular system level by using a pseudorandomly generated code key to select one of the scrambling masks common to all of the mobile stations in a particular cell. Also, privacy at the individual mobile subscriber level is ensured by using a pseudorandomly generated ciphering key to encipher individual information signals before the scrambling operation.

Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells.

Abstract: Lamotrigine is a chemically novel anticonvulsant drug that has been reported to inhibit veratrine-induced neurotransmitter release from cortical slices in vitro. To characterize further the mechanism of action of lamotrigine, we have investigated the effects of this drug together with the anticonvulsant drugs phenytoin and carbamazepine on voltage-sensitive sodium channels present in N4TG1 mouse neuroblastoma clonal cells. Lamotrigine, phenytoin and carbamazepine produced a tonic inhibition of sodium channels with IC50 values of 91, 58 and 140 microM, respectively. At a concentration of 100 microM, all compounds shifted the voltage-dependency of steady-state inactivation toward more negative potentials by 7 to 15 mV, slowed the rate of recovery from inactivation and produced a use-dependent inhibition of sodium channels. Our data show that lamotrigine inhibits sodium channels in a manner that is similar to that produced by phenytoin and carbamazepine. This inhibition of neuronal activity is consistent with the reduction of glutamate release that was previously reported in neurochemical studies, and it expands our understanding of the mechanism of action of this anticonvulsant drug.

Acyclovir: Discovery, mechanism of action, and selectivity

Abstract: The reasons for acyclovir's activity and selectivity in cells infected with HSV or VZV may be summarized as follows: 1. Activation by a HSV- or VZV-specified TK. 2. Greater sensitivity of viral DNA polymerase than of the cellular polymerases to ACV-TP. 3. Inactivation of the viral DNA polymerase, but not the cellular polymerases, by ACV-TP. 4. Chain termination of viral DNA by incorporation of ACV-MP. For the Epstein-Barr virus, which is also sensitive to acyclovir, there is no selective activation in infected cells [Colby et al., 1981], but the viral polymerase can be inhibited by very low levels of ACV-TP [Datta et al., 1980]. For HCMV, the activation of acyclovir is very poor but the viral polymerase is also more sensitive to ACV-TP than the cellular polymerases. One of the important contributions of acyclovir was the demonstration for the first time that a compound could prevent the DNA replication of a DNA virus at concentrations far below those that affect cellular DNA synthesis. As we all know, in the past 15 years there has been a complete rejuvenation of antiviral chemotherapy. I think it is very fortunate that we changed our outlook on the possibility of making potent and selective antiviral agents in time so that, when the AIDS epidemic came along, we did not feel completely at a loss on ways to attack viral disease.