PubMed Health⌕ Search

Biomedical subjects

M M Stahl

Publications and source records attributed to M M Stahl.

At least 19 recordsLinked to original sources
PubMed2001

Tolerability of concurrent use of nicotine gum and smoking in healthy volunteers.

Although nicotine replacement therapy (NRT) is mainly licensed as an aid for smoking cessation, many smokers alternate NRT with cigarettes. This study evaluated the cardiovascular tolerability of nicotine gum plus smoking. This open, three-way, randomized, multiple-dose, crossover study involved 19 healthy adult volunteer smokers. Three treatments (placebo gum+cigarette vs. nicotine 4-mg gum+unlit cigarette vs. nicotine 4-mg gum+cigarette) were each administered hourly seven times during one study day. Plasma nicotine, ECG variables (ST60 and ST(slope)), heart rate, and blood pressure were measured at rest and during/after 5 min exercise tests. Mean plasma nicotine levels were higher with gum plus smoking than with either gum or smoking alone. After the final administration, mean levels with gum plus smoking were 39.5 (range 27.6-54.4) ng/ml vs. 19.6 (11.8-30.1) ng/ml with gum and 22.6 (6.6-36.6) ng/ml with smoking alone. No signs of myocardial ischaemia were observed during concomitant use of gum plus smoking, despite high plasma nicotine levels. Decreases of ST60 and ST(slope) were observed in all treatment groups during exercise but were asymptomatic. Concomitant gum plus smoking did not increase the incidence of extrasystoles or arrhythmia. No serious adverse events occurred during the study. In conclusion, there were no signs of myocardial ischaemia during multiple submaximal exercise tests in healthy volunteers while smoking and using nicotine 4-mg gum.

Adult↗
PubMed1997

Single-strand DNA intermediates in phage lambda's Red recombination pathway.

An assay was developed to assess early intermediates arising in lambda's Red recombination pathway. Double-strand breaks were delivered in vivo to nonreplicating lambda chromosomes. Analysis by blot hybridization of total DNA extracts revealed the following: (i) long (>1.4 kilobases) single-strand DNA (ssDNA) intermediates; (ii) resection proceeding bidirectionally from the break site; (iii) single-strand overhangs of 3' polarity; and (iv) in the absence of lambda's ninR functions, a requirement of the red alpha gene product for the production of ssDNA. Therefore, the physical characteristics exhibited by these ssDNA molecules are consistent with their being an early recombination intermediate in the Red recombination pathway as proposed previously from genetic and in vitro biochemical analyses.

Bacteriophage lambda↗
PubMed1997

In vivo packaging of bacteriophage lambda monomeric chromosomes.

There is an apparent paradox between the reported requirements for lambda DNA packaging in vivo and in vitro. In vivo, DNA concatemers are required for packaging. On the other hand, in vitro, packaging extracts can encapsidate either linear or circular monomeric lambda DNA. Perhaps cellular nucleases restrict the in vivo ability of monomers to package by degrading a free double chain end present as an intermediate in the packaging reaction. Consistent with this hypothesis, enhanced packaging of monomers was found in an ExoV- host. No additional enhancement was noted in a host also mutant for sbcB and sbcC. We isolated a mutant phage for which in vivo packaging of monomeric lambda chromosomes is increased about 10(3)-fold. The responsible mutation (plm1 for packages lambda monomers) was mapped to cro, sequenced, and found to cause a change from Ala29 to Ser in the alpha3 helix of Cro's DNA binding domain. Density transfer experiments showed that packaging of both plm1 and wild-type lambda was aided by allowing some DNA synthesis. However, the packaged chromosomes had not themselves undergone a full round of replication and therefore were not part of a canonical concatemer made by replication. Other tests showed that packaged phage had not been part of concatemers made by recombination or by annealing at cos. Our results with wild-type lambda also favor models in which two cos sites are needed for packaging, but these sites need not be in cis. In lambda plm1, replication intermediates may serve as substrates for encapsidation.

Bacteriophage lambda↗
PubMed1997

Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system.

OBJECTIVE: The present study was performed both to investigate whether there might be a difference between the selective serotonin re-uptake inhibitors, (SSRIs) with regard to the incidence of withdrawal reactions, and to describe the associated symptoms. From the WHO database, therefore, all case reports from the year of introduction for each of the SSRIs, fluoxetine, paroxetine and sertraline, were retrieved. Sales figures were obtained from Intercontinental Medical Statistics International. The reporting rates were calculated as the number of reports per million defined daily doses (DDDs) sold per year. RESULTS: The reporting rate of withdrawal reactions for paroxetine was found to be higher than that for sertraline and fluoxetine in each of the countries selected for detailed analyses (US, UK and Australia), as well as for all 16 countries combined. Moreover, using the WHO system of organ classification, the ratio of central nervous system to psychiatric withdrawal symptoms was 1.9 and 2.1 for paroxetine and sertraline, respectively, whereas that for fluoxetine was 0.48, indicating a possible qualitative difference between the SSRIs with respect to the nature of the withdrawal syndrome.

1-Naphthylamine↗
PubMed1997

Annealing vs. invasion in phage lambda recombination.

Genetic recombination catalyzed by lambda's Red pathway was studied in rec+ and recA mutant bacteria by examining both intracellular lambda DNA and mature progeny particles. Recombination of nonreplicating phage chromosomes was induced by double-strand breaks delivered at unique sites in vivo. In rec+ cells, cutting only one chromosome gave nearly maximal stimulation of recombination; the recombinants formed contained relatively short hybrid regions, suggesting strand invasion. In contrast, in recA mutant cells, cutting the two parental chromosomes at non-allelic sites was required for maximal stimulation; the recombinants formed tended to be hybrid over the entire region between the two cuts, implying strand annealing. We conclude that, in the absence of RecA and the presence of non-allelic DNA ends, the Red pathway of lambda catalyzes recombination primarily by annealing.

Alleles↗
PubMed1997

Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity.

The aim of this study was to determine the pharmacokinetics, pharmacodynamics, and safety of tolterodine following single oral and intravenous doses in healthy volunteers. A secondary aim was to identify major urinary metabolites and determine mass balance. Single oral doses of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 mg of tolterodine (as the tartrate salt) were given to 17 healthy male volunteers. Two intravenous doses (0.64 and 1.28 mg) were administered to 8 of the volunteers and mass balance was studied after a single oral dose of 5 mg (14C)-tolterodine in 6 subjects. Tolterodine was rapidly absorbed following oral administration (time to peak serum concentration 0.9 +/- 0.4 h). The absolute bioavailability was highly variable, ranging from 10 to 70%. The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg, which resulted in a terminal half-life of 2-3 h. Tolterodine exhibited high first-pass metabolism and 2 hepatic metabolic pathways were identified: oxidation and dealkylation. Independent of route of administration, < 1% of the parent compound was excreted unchanged in urine. Five metabolites were structurally identified in urine. Following oral administration of (14C)-tolterodine, the excretion of radioactivity into urine and feces was 77 +/- 4.0% and 17 +/- 3.5%, respectively. Tolterodine decreased stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg. The lack of a direct relationship between tolterodine serum concentrations and effects on stimulated salivation suggested the presence of pharmacologically active metabolite(s).

Adult↗
PubMed1995

Urodynamic and other effects of tolterodine: a novel antimuscarinic drug for the treatment of detrusor overactivity.

Tolterodine, a novel compound intended for treatment of urgency and urge incontinence, has been characterized as a potent muscarinic receptor antagonist in pharmacological in vitro and in vivo studies. In cats, tolerodine was shown to reduce bladder pressure at doses significantly lower than those affecting salivation. To predict clinical effectiveness, an open pilot study was performed in healthy male volunteers. Efficacy was measured by cystometry and by spontaneously reported effects after administration of a single oral dose of tolterodine, 6.4 mg, given as a water solution. Tolterodine had distinct inhibitory effects on urinary bladder function, both at 1 and 5 hours post-dose. At 1 hour, but not at 5 hours post-dose tolterodine also significantly reduced stimulated salvation. In addition to the objectively demonstrated changes in urodynamic parameters, most volunteers experienced voiding difficulties. No significant changes in blood pressure, heart rate, or near point of accommodation were registered. Tolterodine, in the dosage used, was both objectively and subjectively shown to exert a marked inhibitory effect on micturition in healthy subjects, and the data suggest a more pronounced effect on bladder function than on salivation.

Adult↗
PubMed1995

On the clustered exchanges of the RecBCD pathway operating on phage lambda.

Lytic cycle crosses of Red- Gam- phage lambda were conducted in rec+ Escherichia coli carrying one or another plasmid with homology to lambda. Lambda x lambda recombinants and lambda x plasmid recombinants were formed by RecBCD-mediated recombination. We showed previously that the act of recombining with a plasmid alters the disposition of selected lambda x lambda exchanges. This work reports that the relationships between the lambda x plasmid and the lambda x lambda exchanges is unaltered by the removal from one lambda parent of the homology shared with the plasmid. This result supports our view that a reciprocal exchange, allowing for cointegrate formation, is associated with but mechanistically separable from a (presumably) nonreciprocal lambda x lambda exchange. The nature of this relationship is independent of lambda's Rap function, which is shown to alter the ratio of cointegrate formation (splices) to marker pick-up (patches) in lambda x plasmid recombination mediated by the RecBCD pathway.

Bacteriophage lambda↗
PubMed1995

Chi recombination activity in phage lambda decays as a function of genetic distance.

In Escherichia coli, chi is a recombination hotspot that stimulates RecBCD-dependent exchange at and to one side of itself. chi activity is highest at chi and decreases with distance from chi. The decrease in chi activity may be a simple property of the physical distance over which chi can stimulate recombination. Alternatively, the decay in chi activity with distance may reflect the high likelihood that chi-stimulated recombination occurs in a single chi-proximal act, to the exclusion of additional chi-stimulated exchanges more distal to chi. To test the models, we determined if chi activity decreases as a function of physical distance (i.e., DNA base pairs) or genetic distance (homologous DNA base pairs). Our results indicate that chi activity decays as a function of genetic distance. In addition, we found that the sbcB gene product (exonuclease I, a 3'-->5' ssDNA exonuclease) modulates the distance over which chi can act. In contrast, the recJ gene product (a 5'-->3' ssDNA exonuclease) does not alter the decay of chi activity.

Bacterial Proteins↗
PubMed1993

Vasoactive peptides in Bartter's syndrome.

Patients with Bartter's syndrome exhibit an increased vascular resistance to the pressor effects of angiotensin II and noradrenaline. Further, an increased production of vasodilating renal prostaglandins, perhaps mediating the vascular unresponsiveness, has been hypothesized in this syndrome based on high urinary prostaglandins. To determine whether different peptides might contribute to blood pressure control in this syndrome, the basal immunoreactive plasma levels of an array of vasoactive peptides and catecholamines were analysed in six patients with Bartter's syndrome. Among the vasoconstrictors analyzed, the mean plasma levels of noradrenaline (NA), adrenaline (A) and neuropeptide Y-like immunoreactivity (NPY-LI) were significantly increased as compared to healthy subjects (P = 0.030, 0.046 and 0.001, respectively). The plasma level of the vasodilator substance P (SP-LI) was also higher in these patients (P = 0.057). These results indicate that in Bartter's syndrome the vasoconstrictive effect of catecholamines and angiotensin II may be enhanced by concomitant NPY release. Whether a release of the vasodilator substance P is an independent mechanism or represents a reflex response to the increased secretion of angiotensin II, catecholamines and/or NPY remains to be established. However, the significance of these biochemical findings for blood pressure maintenance in Bartter's syndrome remains to be settled.

Adult↗
PubMed1991

Heteroduplex chain polarity in recombination of phage lambda by the red, RecBCD, RecBC(D-) and RecF pathways.

We have examined the chain polarity of heteroduplex DNA in unreplicated, bacteriophage lambda splice recombinants when recombination was by the RecBCD, RecBC(D-), or RecF pathway of Escherichia coli or the Red pathway of lambda. For each of these pathways, recombination is activated by the cutting of cos that accompanies chromosome packaging, and is effected by recombination enzymes acting at the right end created by that cutting. For exchanges occurring near cos, one parent makes a lesser physical and genetic contribution than does the other. For each pathway, when the phage carried standard cos, this minority contribution was predominantly on the r chain, ending 5' at the right end of lambda. When standard cos was replaced by a cloned inverted cos located centrally on the standard lambda genetic map, minority contribution was predominantly on the l chain. In each case, the polarity of the overlap was usually that formed by 3' overhangs of parental information and material. These results are discussed in the context of current models of recombination for the different pathways.

Alleles↗
PubMed1990

Break-join recombination in phage lambda.

In phage lambda, when DNA replication is blocked, recombination mediated by the Red pathway occurs only near the double-chain break site, cos, that defines the termini of the virion chromosome. The recombinants initiated by cos contain newly synthesized DNA near cos, in amount corresponding to a few percent of the length of lambda. A restriction enzyme cut delivered to one parent far from cos results in elevated recombination near the restriction site. Recombinants induced by this cut have a similarly small amount of DNA synthesis in these replication-blocked crosses. When restriction cuts are introduced in the presence of normal amounts of all of the DNA replication enzymes, many of the resulting recombinants still enjoy, at most, a small amount of DNA synthesis associated with the exchange event. Thus, these experiments fail to support the previously considered possibility that Red-mediated recombination in lambda proceeds largely through a break-copy pathway.

Bacteriophage lambda↗
PubMed1990

Further tests of a recombination model in which chi removes the RecD subunit from the RecBCD enzyme of Escherichia coli.

When one of two infecting lambda phage types in a replication-blocked cross is chi + and DNA packaging is divorced from the RecBCD-chi interaction, complementary chi-stimulated recombinants are recovered equally in mass lysates only if the chi + parent is in excess in the infecting parental mixture. Otherwise, the chi 0 recombinant is recovered in excess. This observation implies that, along with the chi 0 chromosome, two chi + parent chromosomes are involved in the formation of each chi + recombinant. The trimolecular nature of chi +-stimulated recombination is manifest in recombination between lambda and a plasmid. When lambda recombines with a plasmid via the RecBCD pathway, the resulting chromosome has an enhanced probability of undergoing lambda x lambda recombination in the interval into which the plasmid was incorporated. These two observations support a model in which DNA is degraded by Exo V from cos, the sequence that determines the end of packaged lambda DNA and acts as point of entry for RecBCD enzyme, to chi, the DNA sequence that stimulates the RecBCD enzyme to effect recombination. The model supposes that chi acts by ejecting the RecD subunit from the RecBCD enzyme with two consequences. (1) ExoV activity is blocked leaving a highly recombinagenic, frayed duplex end near chi, and (2) as the enzyme stripped of the RecD subunit travels beyond chi it is competent to catalyze reciprocal recombination.

Crosses, Genetic↗
PubMed1989

Recombination of bacteriophage lambda in recD mutants of Escherichia coli.

RecBCD enzyme is centrally important in homologous recombination in Escherichia coli and is the source of ExoV activity. Null alleles of either the recB or the recC genes, which encode the B and C subunits, respectively, manifest no recombination and none of the nuclease functions characteristic of the holoenzyme. Loss of the D subunit, by a recD mutation, likewise results in loss of ExoV activity. However, mutants lacking the D subunit are competent for homologous recombination. We report that the distribution of exchanges along the chromosome of Red-Gam-phage lambda is strikingly altered by recD null mutations in the host. When lambda DNA replication is blocked, recombination in recD mutant strains is high near lambda's right end. In contrast, recombination in isogenic recD+ strains is approximately uniform along lambda unless the lambda chromosome contains a chi sequence. Recombination in recD mutant strains is focused toward the site of action of a type II restriction enzyme acting in vivo on lambda. The distribution of exchanges in isogenic recD+ strains is scarcely altered by the restriction enzyme (unless the phage contains an otherwise silent chi). The distribution of exchanges in recD mutants is strongly affected by lambda DNA replication. The distribution of exchanges on lambda growing in rec+ cells is not influenced by DNA replication. The exchange distribution along lambda in recD mutant cells is independent of chi in a variety of conditions. Recombination in rec+ cells is chi influenced. Recombination in recD mutants depends on recC function, occurs in strains deleted for rac prophage, and is independent of recJ, which is known to be required for lambda recombination via the RecF pathway. We entertain two models for recombination in recD mutants: (i) recombination in recD mutants may proceed via double-chain break--repair, as it does in lambda's Red pathway and E. coli's RecE pathway; (ii) the RecBC enzyme, missing its D subunit, is equivalent to the wild-type, RecBCD, enzyme after that enzyme has been activated by a chi sequence.

Bacterial Proteins↗
PubMed1987

Double-chain-cut sites are recombination hotspots in the Red pathway of phage lambda.

The Red recombination pathway of phage lambda is shown to target recombination to double-chain ends of DNA. A double-chain cut, delivered in vivo to only one of two parents participating in a lambda lytic cross by a type II restriction endonuclease, increases the proportion of crossing over in the interval containing the cut compared with other intervals. The stimulating effect of a cut is evident whether replication is inhibited or permitted. Cut stimulation can move away from the initial cut-site, presumably by double-chain degradation. Movement of the stimulating effect of a cut is dependent on the Escherichia coli gene recA when the cross is carried out under conditions that inhibit phage replication. When replication is permitted, all aspects of cut-stimulated recombination are independent of recA. Evidence is presented to show that the reaction that is stimulated by cutting is often non-reciprocal at the molecular level.

Bacteriophage lambda↗