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PubMed2002

Restricting the selection of antibiotic-resistant mutant bacteria: measurement and potential use of the mutant selection window.

The selection of antibiotic-resistant mutant bacteria is proposed to occur in a drug concentration range (the mutant selection window) that extends from the minimum inhibitory concentration (MIC) of susceptible cells to the MIC of the least susceptible, single-step bacterial mutants (the mutant prevention concentration [MPC]). MPCs were estimated for tobramycin, chloramphenicol, rifampicin, penicillin, vancomycin, and several fluoroquinolones by use of Escherichia coli and Staphylococcus aureus. Comparisons among reported serum drug levels indicate that new fluoroquinolones are the least likely to enrich populations of resistant mutant bacteria during monotherapy. These data partly explain the selective enrichment of populations of resistant mutant bacteria in medical practice. The mutant selection window range (MPC:MIC) was narrowed for fluoroquinolones by structure modification, pointing to a new direction in antibiotic refinement. The mutant selection window and the MPC were determined for combinations of rifampicin and tobramycin, using S. aureus, as a guide for combination therapy with compounds that alone cannot block enrichment of mutant bacterial populations.

Bacteria↗
PubMed2005

Experimental removal and elevation of sexual selection: does sexual selection generate manipulative males and resistant females?

Sexual conflict over reproduction can occur between males and females. In several naturally promiscuous insect species, experimental evolution studies that have enforced monogamy found evidence for sexual conflict. Here, we subjected the naturally promiscuous, sperm-heteromorphic fruit fly Drosophila pseudoobscura to enforced monogamy, standard levels of promiscuity, and elevated opportunities for promiscuity in four replicate lines. We examined the effect of male and female selection history and the proximate effect of variation in male density on female fitness parameters. We found that male density rather than male selection history explained a greater degree of female fecundity, egg hatching success, and productivity. Additionally, females selected under elevated promiscuity had greater fecundity and hatching success than did enforced monogamy females. Selection line males do not differ in their capacity to coerce females to remate, suggesting no divergence in precopulatory manipulative ability. However, these males did vary in their ability to suppress female remating, suggesting postcopulatory manipulation. These results indicate that sexual conflict can be manifested through both the proximate effects of male density and the historical levels of sexual selection and that the sexes respond differentially to these factors and further stress the multifarious channels of sexual communication that contribute to fitness.

Animals↗
PubMed1999

Positive selection of thymocytes induced by gene transfer: MHC class II-mediated selection of CD8 lineage cells.

Recombinant adenovirus vectors are powerful tools for inducing de novo gene expression in vivo. Here we have exploited them to study the specificity of CD4/CD8 lineage commitment during thymocyte positive selection, transferring MHC class II genes directly into thymi of mice deficient in both class I and II molecules. Expression of class II molecules was induced on cortical stroma, provoking the selection of a large population of mature CD4(+)CD8(-) cells, as expected, but also of a significant number of CD4(-)CD8(+) cells. The latter constituted a diverse population, containing both immature precursors and, though less frequent, cells that were mature according to several criteria. CD4(-)CD8(+) cells appeared with the same kinetics as their CD4(+)CD8(-) counterparts, but tended to be more prevalent at early times or when thymocyte reconstitution was only modest. These observations, derived from a dynamic selection system, indicate that CD4/CD8 lineage commitment is not irredeemably linked to the class of MHC molecule driving positive selection, a conclusion most compatible with selective models of commitment.

Adenoviridae↗
PubMed1998

Comparison of in vivo activities of 5'-connected and 3'-connected cis-acting ribozymes: selection of intracellularly active ribozymes using the gene for dihydrofolate reductase (DHFR) as a selective marker in Escherichia coli.

If ribozymes are to be exploited in vivo, it is necessary to select ribozymes that are functional in the intracellular environment. Ribozymes selected in the intracellular environment should retain their function in vivo as well as in vitro. We have devised a novel system for selection of active ribozymes from pools of active and inactive ribozymes using the gene for dihydrofolate reductase (DHFR) as a selective marker. In our first attempt, a sequence encoding either an active or an inactive ribozyme was connected upstream of the gene for DHFR. Each plasmid was designed such that, when the ribozyme was active, the ribozyme would cleave the target site and, as a result, the rate of production of DHFR would be high enough to endow resistance to trimethoprim (TMP). However, a critical defect may be associated with introduction of a ribozyme upstream of the DHFR gene because, during actual screening for active ribozymes on the 5' side from a pool of random sequences, there is the danger of selecting sequences that are not related to the activity of ribozymes. Indeed, some upstream linker sequences affected the level of expression of the DHFR protein and, as a result, the resistance of Escherichia coli to TMP. Therefore, we newly constructed a 3'-connected ribozyme system, and activities in vivo of 5'-connected and 3'-connected ribozymes were compared. We found that the cleavage efficiencies in vivo were nearly identical for the two types of ribozyme, 24% for the 5'-side ribozyme and 23% for the 3'-side ribozyme, indicating that polysomes did not seem to inhibit the action of the 3'-connected ribozyme. In both cases, when cells were transformed with a 1 : 1 mixture of active and inactive ribozyme-coding plasmids, it was mainly the cells that harbored the active ribozyme that survived in the presence of TMP.

Base Sequence↗
PubMed1998

The effect of divergent selection for total plasma phosphorus in Japanese quail on fearfulness and selected blood and heart parameters.

A selection experiment utilizing Japanese quail was initiated to study the genetic relationship of growth and reproduction traits. In this study, lines were selected for increased (HP line) and decreased (LP line) total plasma phosphorus at the beginning of lay. The HP and LP lines were derived from a randombred control population (R1 line) that was maintained with the selected lines to remove environmental variation over generations. During the course of selection, it was observed that blood from HP line females was more viscous than that of the LP and R1 females. In later generations of selection, mortality of females during a 120-d egg production period was higher in the HP line than in the LP and R1 lines. The purpose of this experiment was to identify possible factors contributing to the increased mortality in the HP line. Fearfulness, as measured by tonic immobility, was greater in the HP and LP lines than in the R1 line. Indirect blood pressure measurements were made near the beginning and near the end of the 120-d egg production period. No significant line differences were observed in either measurement. Weight of the heart at the end of the laying period was higher in the HP and LP lines than in the R1 line. Histological study of the hearts of the HP and R1 lines indicated significant increases in the HP line in collagen content of the coronary arteries and in myocardial fibrosis. The data suggest that the increased mortality of females of the HP line relative to the R1 line during the laying period may be related to increased fearfulness and changes in the coronary structure leading to heart abnormalities.

Animals↗
PubMed2002

Platelet function is inhibited by non-selective non-steroidal anti-inflammatory drugs but not by cyclo-oxygenase-2-selective inhibitors in patients with rheumatoid arthritis.

BACKGROUND: Interaction with platelet function by non-steroidal anti-inflammatory drugs (NSAIDs) is related to the inhibition of cyclo-oxygenase-1 (COX-1). In patients with rheumatoid arthritis (RA), only one of the COX-2-selective NSAIDs (nabumetone) has been demonstrated to spare platelet function partially. OBJECTIVE: To compare the effects of the COX-2-selective inhibitor, meloxicam, with those of the non-selective NSAID, naproxen, on platelet function and thromboxane levels in RA patients. METHODS: In this randomized, controlled, cross-over trial, 10 RA patients used meloxicam 7.5 mg bid and naproxen 500 mg bid, each during a 2-week period. Washout periods were applied. Before and after each 2-week period of NSAID intake, laboratory studies were performed. RESULTS: Platelet aggregation was significantly less influenced, thromboxane levels were less inhibited (246 vs 117 pg/ml) and bleeding times were less prolonged with meloxicam than with naproxen (3.2 vs 2.3 min). Moreover, the results of all tests during meloxicam exposure were comparable with baseline values. CONCLUSION: In RA patients, meloxicam, a representative of the selective COX-2 inhibitors, does not interfere with platelet function and thromboxane levels, in contrast with naproxen (a non-selective COX inhibitor).

Adult↗
PubMed2006

The dilemma of female mate selection in the brown bear, a species with sexually selected infanticide.

Because of differential investment in gametes between sexes, females tend to be the more selective sex. Based on this concept, we investigate mate selection in a large carnivore: the brown bear (Ursus arctos). We hypothesize that, in this species with sexually selected infanticide (SSI), females may be faced with a dilemma: either select a high-quality partner based on phenotypic criteria, as suggested by theories of mate choice, or rather mate with future potentially infanticidal males as a counter-strategy to SSI. We evaluated which male characteristics were important in paternity assignment. Among males available in the vicinity of the females, the largest, most heterozygous and less inbred and also the geographically closest males were more often the fathers of the female's next litter. We suggest that female brown bears may select the closest males as a counter-strategy to infanticide and exercise a post-copulatory cryptic choice, based on physical attributes, such as a large body size, reflecting male genetic quality. However, male-male competition either in the form of fighting before copulation or during the post-copulatory phase, in the form of sperm competition, cannot entirely be ruled out.

Animals↗
PubMed1979

Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective and selective beta adrenoceptor blockade in humans.

The cardiovascular and adrenergic responses to cigarette smoking during acute selective and non-selective beta adrenoceptor blockade were studied in seven young healthy volunteers in a double blind cross-over fashion. Heart rate, arterial blood pressure, forearm blood flow and plasma levels of adrenaline and noradrenaline were determined before and during the terminal 5 min period of 15 min smoking test. During smoking, plasma concentrations of adrenaline increased markedly and evenly by approximately 0.3 ng/ml in all three experimental sessions. Plasma concentrations of noradrenaline remained unchanged. Propranolol, a non-selective beta blocker, caused a marked rise in diastolic and mean blood pressure and forearm vascular resistance during smoking. This response was not seen in the control series or after selective beta-1 blockage with atenolol. This difference is attributable to propranolol's blockade of adrenaline's vasodilating effect mediated by beta-2 receptors in the resistance vessels. Furthermore, atenolol attenuated the systolic blood pressure and tachycardiac responses induced by cigarette smoking by comparison with placebo. This study suggests that selective beta-1 blockers are preferable in the management of patients who are habitual smokers.

Adult↗
PubMed1994

The effects of clozapine on behavioural responses to the selective 'D1-like' dopamine receptor agonist, A 68930, and to the selective 'D2-like' agonist, RU 24213.

1. The influence of the atypical antipsychotic clozapine on D1 dopamine receptor-mediated function was examined in terms of its effects on behavioural responses to the new isochroman selective D1 agonist, A 68930, and to the selective D2 agonist, RU 24213. 2. In rat striatal membrane preparations, radioligand binding studies with [3H]-SCH 23390 and [3H]-spiperone confirmed clozapine to show weak and non-selective affinity for both D1 and D2 receptors. 3. Using a rapid time-sampling behavioural check list technique, clozapine (4.0-36.0 mg kg-1) exerted only modest antagonism of RU 24213 (15.0 mg kg-1)-induced sniffing and locomotion, and weakly released some episodes of myoclonic jerking; such antagonism with release of jerking has been shown previously to occur only during concurrent stimulation of D2 receptors and attenuation of D1 function. 4. Over the same dose-range, clozapine completely blocked A 68930 (0.25 mg kg-1)-induced intense grooming but failed to influence the vacuous chewing response; this profile was similar to that demonstrated previously for selective D1 antagonists. 5. On the basis of complete blockade of typical D1 agonist-induced grooming and weak release of atypical jerking to D2 agonism in the face of modest reduction in typical D2-stimulated behaviours, clozapine appears to exert some preferential but not selective attenuation of D1 receptor-mediated function. Clozapine may attenuate activity through a classical D1 receptor at a level beyond the recognition site, for which it has little affinity, or by way of new, putative 'D1-like' site(s) that subserve distinct elements of dopaminergic behaviour.

Animals↗
PubMed1982

Selection of filters and evaluation in vitro of the selective dual filtration artificial kidney, SEDUFARK.

Transport properties of different artificial kidney membranes have been studied employing substances with molecular weights ranging from 60 daltons (urea) to 62,000 daltons (dextran). The results from these studies were used to select filters for the SElective DUal Filtration ARtificial Kidney, SEDUFARK. Selection criteria for filters to be used in long-term clinical trials with SEDUFARK were based on biological tests showing toxicity of large molecular weight substances in uremic blood plasma and clinical advantages of returning middle molecular weight substances to the patient. The filters selected were used for evaluation in vitro of the complete SEDUFARK system. The results confirmed a theoretical analysis of this system, demonstrating that selective removal of substances within given molecular weight ranges from uremic blood plasma is feasible with a combination of commercial filters. The efficiency of the system, however, is limited due to the "cut-off" characteristics and hydraulic permeabilities of membrane types currently available.

Biological Transport↗
PubMedDate not supplied

Effect of chronic treatment with ICI D7114, a selective beta 3-adrenoceptor agonist, on macronutrient selection and brown adipose tissue thermogenesis in Sprague-Dawley rats.

ICI D7114 is a selective beta 3-agonist which stimulates brown adipose tissue thermogenesis. In the present study the effects of 18 days treatment with ICI D7114 (2 mg/kg/day orally) on macronutrient selection and brown adipose tissue thermogenesis were investigated in Sprague-Dawley rats. The rats were maintained on a free-feeding self-selection paradigm with three pure macronutrient diets of carbohydrate, fat and protein. Treatment with ICI D7114 did not change the macronutrient selection or total calories consumed by the rats. To monitor the thermogenic activation of brown adipose tissue the binding of [3H]GDP to brown adipose tissue mitochondria was measured. The treatment with ICI D7114 increased the binding of GDP both when expressed as total binding per lobe (P < 0.001) and per mg of protein (P < 0.01). It is concluded that ICI D7114, used in doses affecting brown adipose tissue thermogenesis, does not change the macronutrient selection or total energy intake in Sprague-Dawley rats.

Adipose Tissue, Brown↗
PubMed1987

Strategies for selective cancer photochemotherapy: antibody-targeted and selective carcinoma cell photolysis.

A principle objective in chemotherapy is the development of modalities capable of selectively destroying malignant cells while sparing normal tissues. One new approach to selective photochemotherapy, antibody-targeted photolysis (ATPL) uses photosensitizers (PS) coupled to monoclonal antibodies (MAbs) which bind to cell surface antigens on malignant cells. Selective destruction of human T leukemia cells (HBP-ALL) was accomplished by coupling the efficient PS chlorin e(6) to an anti-T cell MAb using dextran carriers. Conjugates with chlorin: MAb ratios of 30:1 retained > 85% MA b binding activity, and had a quantum yield for singlet oxygen production of 0.7 +/- 0.1, the same as that of free chlorin e(6). Cell killing was dependent on the doses of both MAb-PS and 630-670 nm light and occurred only in target cell populations which bound the MAb. On the order of 10(10) singlet oxygen molecules were necessary to kill a cell. A second approach to specific photochemotherapy, selective carcinoma cell photolysis (SCCP), relies on preferential accumulation of certain cationic PS by carcinoma cell mitochondria. We have evaluated several classes of cationic dyes, and in the case of N,N'-bis-(2-ethyl-1,3-dioxolane)-kryptocyanine (EDKC) and some of its analogs, have demonstrated highly selective killing of human squamous cell, bladder and colon carcinoma cells in vitro. In isolated mitochondria, EDKC uptake and fluorescence depended on membrane potential, and the dye specifically photosensitized damage to Complex I in the electron transport chain. N,N'-bis-(2-ethyl-1,3-dioxolane)-kryptocyanine and some of its analogs accumulated within subcutaneous xenografts of human tumors in nude mice with tumor:skin ratios > 8. Photoirradiation caused significant inhibition of tumor growth, without cutaneous phototoxicity.

Animals↗
PubMed1979

Secondary selective enrichment of salmonellae from naturally contaminated specimens by using a selective motility system.

A selective motility medium was used as a secondary selective enrichment medium to examine specimens naturally contaminated with salmonellae. The medium, incubated at 37 degrees C, was inoculated from either selenite brilliant green sulfa enrichment broth or Müller-Kauffman tetrathionate broth, both of which had been incubated at 42 degrees C. The use of the selective motility medium resulted in an increase in the number of positive specimens from 65 and 74% to 80 and 82%, when inoculated at 24 and 48 h, respectively, from tetrathionate broth. Tetrathionate broth, when used singly, was significantly better than selenite brilliant green sulfa broth, which detected 55% of positive specimens at both 24 and 48 h. The use of the selective motility medium of Harper and Shortridge (J. Hyg. 67: 181--186, 1969) for the further examination of specimens culturally negative on primary selective enrichment is advocated.

Animal Feed↗
PubMed1987

Tip size of ion-exchanger based K+-selective microelectrodes. I. Effects on selectivity.

Double-barreled ion-exchanger based K+-selective microelectrodes (K+ ISMs) of a variety of tip diameters were used to study the dependency of ion selectivity upon tip size. The selectivity of K+ ISMs depended on tip size and barrel configuration. Within the range of tip diameters tested (approximately 0.5-6 micron) all K+ ISMs constructed of two barrels glued side by side ("figure-eight glass") exhibited sensitivity to K+ and NH4+. Figure-eight K+ ISMs with tip diameters less than 1.5 micron were not sensitive to tetramethylammonium, tetraethylammonium, or choline, whereas K+ ISMs with tip diameters greater than or equal to 1.5 micron sensed all of the quaternary amines. Tip size dependent selectivity was not present in K+ ISMs made from thick septum theta glass. The explanation for tip size dependent changes in ion selectivity is unknown but a discussion of theoretical possibilities is given.

Amines↗
PubMed2001

Target selection for saccadic eye movements: direction-selective visual responses in the superior colliculus.

We investigated the role of the superior colliculus (SC) in saccade target selection in rhesus monkeys who were trained to perform a direction-discrimination task. In this task, the monkey discriminated between opposed directions of visual motion and indicated its judgment by making a saccadic eye movement to one of two visual targets that were spatially aligned with the two possible directions of motion in the display. Thus the neural circuits that implement target selection in this task are likely to receive directionally selective visual inputs and be closely linked to the saccadic system. We therefore studied prelude neurons in the intermediate and deep layers of the SC that can discharge up to several seconds before an impending saccade, indicating a relatively high-level role in saccade planning. We used the direction-discrimination task to identify neurons whose prelude activity "predicted" the impending perceptual report several seconds before the animal actually executed the operant eye movement; these "choice predicting" cells comprised approximately 30% of the neurons we encountered in the intermediate and deep layers of the SC. Surprisingly, about half of these prelude cells yielded direction-selective responses to our motion stimulus during a passive fixation task. In general, these neurons responded to motion stimuli in many locations around the visual field including the center of gaze where the visual discriminanda were positioned during the direction-discrimination task. Preferred directions generally pointed toward the location of the movement field of the SC neuron in accordance with the sensorimotor demands of the discrimination task. Control experiments indicate that the directional responses do not simply reflect covertly planned saccades. Our results indicate that a small population of SC prelude neurons exhibits properties appropriate for linking stimulus cues to saccade target selection in the context of a visual discrimination task.

Animals↗
PubMed2003

Morphological features of rat gastric mucosa after acute and chronic treatment with amtolmetin guacyl: comparison with non-selective and COX-2-selective NSAIDs.

BACKGROUND/AIMS: The compound amtolmetin guacyl (AMG) has been characterized in both animal and human studies as a novel non-selective non-steroidal anti-inflammatory drug (NSAID) endowed with lower ulcerogenicity in comparison with traditional NSAIDs due to a unique mechanism of action, namely the increase in endogenous production of gastric nitric oxide. METHODS: Conscious rats were treated either acutely (4 h) or chronically (3 and 14 days) with intragastric AMG (50 and 150 mg/kg), the non-selective NSAID tolmetin (TOL, 30 and 100 mg/kg) or the COX-2-selective NSAID celecoxib (CXIB, 20 and 60 mg/kg). Macroscopically visible and histologic lesions were evaluated. The ultrastructure of mucosal microvasculature was assessed. RESULTS: (1) TOL and CXIB caused quantitatively greater endothelial damage and inflammatory cell infiltration than that induced by AMG; (2) AMG and CXIB, unlike TOL, did not cause epithelial damage after acute or chronic treatment, and (3) gastric lesions induced by TOL underwent adaptation during chronic treatment. CONCLUSION: Endothelial cell damage in the gastric microvasculature is an early event following both non-selective and COX-2-selective inhibitors. The low gastric mucosal toxicity of AMG is confirmed after acute and chronic treatment.

Analysis of Variance↗
PubMed2003

Transient in vivo selection of transduced peripheral blood cells using antifolate drug selection in rhesus macaques that received transplants with hematopoietic stem cells expressing dihydrofolate reductase vectors.

One of the main obstacles for effective human gene therapy for hematopoietic disorders remains the achievement of an adequate number of genetically corrected blood cells. One approach to this goal is to incorporate drug resistance genes into vectors to enable in vivo selection of hematopoietic stem cells (HSCs). Although a number of drug resistance vectors enable HSC selection in murine systems, little is known about these systems in large animal models. To address this issue, we transplanted cells transduced with dihydrofolate resistance vectors into 6 rhesus macaques and studied whether selection of vector-expressing cells occurred following drug treatment with trimetrexate and nitrobenzylmercaptopurineriboside-phosphate. In some of the 10 administered drug treatment courses, substantial increases in the levels of transduced peripheral blood cells were noted; however, numbers returned to baseline levels within 17 days. Attempts to induce stem cell cycling with stem cell factor and granulocyte-colony stimulating factor prior to drug treatment did not lead to sustained enrichment for transduced cells. These data highlight an important species-specific difference between murine and nonhuman primate models for assessing in vivo HSC selection strategies and emphasize the importance of using drugs capable of inducing selective pressure at the level of HSCs.

Animals↗
PubMed2004

Use of gastroprotective agents and discontinuations due to dyspepsia with the selective cyclooxygenase-2 inhibitor etoricoxib compared with non-selective NSAIDs.

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) are non-selective cyclooxygenase-1 (COX-1) and COX-2 inhibitors and are associated with upper gastrointestinal (GI) dyspeptic symptoms often resulting in GI co-medication usage or treatment discontinuation. OBJECTIVE: To compare the rates of new use of gastroprotective agents and discontinuations due to dyspepsia with the COX-2 selective inhibitor etoricoxib compared with non-selective NSAIDs. RESEARCH DESIGN AND METHODS: This pre-specified combined analysis used data from nine randomized, double-blind, controlled, clinical trials with etoricoxib in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis. The cumulative incidences of (1) new use (new prescription or increased dose) of gastroprotective agents (GPA) and (2) discontinuation due to dyspeptic symptoms were compared among patients treated with etoricoxib (60 mg, 90 mg, or 120 mg daily) vs. non-selective NSAIDs (diclofenac 50 mg. t.i.d. or naproxen 500 mg. b.i.d.). RESULTS: The overall rates/100 patient-years for new use of GPAs were 9.1 and 13.0 for etoricoxib and NSAIDs, respectively (RR = 0.75; 95% confidence interval [CI] 0.64, 0.89; p < 0.001). A benefit with etoricoxib was seen in the first 6 months when most new GPA usage occurred; after 6 months new use of GPAs was similar between etoricoxib and NSAIDs. The rates/100 patient-years of treatment discontinuation due to dyspeptic symptoms with etoricoxib and NSAIDs were 1.5 and 2.7, respectively (RR = 0.60; 95% CI 0.41, 0.87; p = 0.007). Analyses of placebo-controlled treatment periods showed significantly more new GPA use and more discontinuations due to dyspeptic symptoms with NSAIDs vs. placebo, but not with etoricoxib vs. placebo. CONCLUSION: In this combined analysis of clinical trials of patients with OA, RA, chronic low back pain, or AS, new use of gastroprotective agents was significantly lower with etoricoxib than with the comparator non-selective NSAIDs during the initial 6 months of treatment and similar thereafter. There were significantly fewer discontinuations for dyspeptic symptoms with etoricoxib than with NSAIDs over the entire follow-up period.

Anti-Inflammatory Agents, Non-Steroidal↗