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PubMed2005

Evaluation of industrial, hospital and domestic wastewater genotoxicity with the Salmonella fluctuation test and the SOS chromotest.

An evaluation of the genotoxic potential of different wastewaters collected in the Rouen area was performed with the SOS chromotest (on Escherichia coli PQ37) and the Salmonella fluctuation test on Salmonella typhimurium strains TA98, TA100 and TA102 with or without metabolic activation. The samples were taken during two 1-week periods, one in January and one in April 2003. Six sites were selected for wastewater sampling in order to allow a comparative study between an area of mixed discharge (industrial, hospital and domestic) and an area of primarily domestic discharge. Out of a total of 71 daytime samples tested, 46 (65%) were positive in at least one assay: 22 samples out of 33 in January (67%), and 24 samples out of 38 in April (63%). The two genotoxicity tests have different sensitivities. Indeed, the Salmonella fluctuation test allowed the detection of 56% of the samples as genotoxic in January (18 out of 33), and 63% in April (24 out of 38) while the SOS chromotest allowed the detection of 18% of the samples as genotoxic, whatever the sampling period. The samples collected in domestic wastewater are at least as genotoxic as the samples collected in mixed wastewater. The possible source of the detected genotoxicity (industrial, hospital or domestic) is discussed. The results of this study show that the different types of wastewaters present a genotoxic risk. Additional studies should be undertaken in the analytical field in order to try to identify and quantify the compounds responsible for the genotoxicity. This difficult task will be necessary in order to identify the sources of toxicants and thus to take preventive and/or curative measures to limit the toxicity of the wastewater.

France↗
PubMed1997

Recording of electroencephalograms and electrocardiograms during daytime sleep in trained canines: preparation of the sleeping dogs.

Although respiration in trained canines is well investigated, the process of preparing dogs has not been described in any great detail. Moreover, their daytime patterns of sleep and wakefulness during 1 or 2 h of electroencephalogram (EEG) and electrocardiogram (ECG) recordings are not clear. Therefore, we describe the process of selecting and training dogs, in which we recorded EEG and ECG in the laboratory. First, 14 of 1242 dogs dealt with over a 1 year period were chosen. They were trained for 2 h to lie quietly and to sleep in the laboratory; this training procedure was repeated 152 times. Three dogs were then selected and a permanent tracheostomy was performed in one. Finally, EEG and ECG were recorded with the bipolar fine needle electrodes; respiration was recorded simultaneously through a tube inserted to a tracheostomy in one dog. Wakefulness, slow wave sleep (SWS) and rapid eye movement (REM) sleep (REMS) were identified according to the EEG pattern and on the basis of the behavioral criteria. Recordings were performed 12 or 13 times in each dog. Complete sleep cycles, including wakefulness, SWS and REMS in this sequence, were observed 3.9-4.1 times. The mean duration of SWS was 2.2-4.4 min and that of REMS was 3.5-4.6 min. The REMS latency was 33.9-41.8 min. Fluctuation of heart rate with respiration, termed respiratory sinus arrhythmia, was noted in the ECG. Heart beat increased with inspiration and decreased with expiration. The present study demonstrates how to select and train sleeping dogs and shows their undisturbed daytime sleep and wakefulness patterns.

Animals↗
PubMed1993

Otosyphilis: diagnostic and therapeutic update.

The thorough investigation of patients presenting with sudden or fluctuating hearing loss, ringing or vertigo includes serology to exclude otosyphilis. Treatment of otosyphilis with penicillin and corticosteroids has achieved improvement in hearing, tinnitus and vertigo, but not in all patients. Selecting which patient with positive serology will benefit from treatment remains a difficult clinical problem. All patients presenting to The New York Eye and Ear Infirmary with cochleovestibular dysfunction of unknown aetiology and positive syphilis serology were assumed to have otosyphilis and were treated with intravenous penicillin, if non-allergic, and steroids. Lumbar puncture and HIV testing were performed. Eighteen patients were treated. Hearing (SRT and/or discrimination) improved in 4 of 16 patients with hearing loss (25%), tinnitus decreased in 10 of 14 (71%) and dysequilibrium improved in 6 of 9 (66%). Factors associated with a good response included fluctuating symptoms, especially hearing, hearing loss less than five years, and age less than 60. Improvement was unrelated to the severity of the loss or previous therapy. Patients with CSF abnormalities, including two patients with HIV disease, had subjective improvement. A summary of our results and a treatment protocol are presented.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Selection against hypermutability in Escherichia coli during long term evolution.

A population of a mutT strain of E. coli was maintained in a chemostat for 2,200 generations. Afterwards the rate, of mutation to resistance to three antibiotics was determined by the Luria-Delbrück fluctuation test. It was found that the strain had a distinctly reduced mutability after the long-term cultivation compared with the original strain. Nevertheless the mutability was still much higher than that of a wild-type strain. After transduction of the mutT gene into another genetic background the transductants showed the same mutability as the original strain indicating that the mutT allele itself had not changed. Our results support the hypothesis that under new environmental conditions mutator strains have an advantage due to their more efficient production of beneficial mutations. After optimal adaptation there is selection against high mutation rates due to the increased mutational load in the mutator population.

Biological Evolution↗
PubMed2006

The mutant selection window in rabbits infected with Staphylococcus aureus.

BACKGROUND: The mutant selection window hypothesis, originally based on agar plate assays, may lead to new antimicrobial dosing strategies that severely restrict the acquisition of resistance. However, it has not been directly tested in an animal model of infection. METHODS: Local infection with Staphylococcus aureus was established in rabbits, and the infected animals were treated orally with various doses of levofloxacin. Changes in levofloxacin concentration, levofloxacin susceptibility, and counts of total and resistant viable bacteria were monitored at the site of infection. RESULTS: S. aureus lost levofloxacin susceptibility when drug concentrations at the site of infection fluctuated between the lower and upper boundaries of the window, defined in vitro as the minimum inhibitory concentration (MIC)(99) and the mutant prevention concentration (MPC), respectively. The upper boundary of the selection window in vivo was estimated as an AUC(24)/MPC value of ~25 h, where AUC(24) is the area under the drug concentration time curve in a 24-h interval. The lower boundary was estimated as an AUC(24)/MIC value of ~20 h. CONCLUSIONS: The mutant selection window exists in vivo, and its boundaries fit well with those determined in vitro. Maintenance of antimicrobial concentrations above the window is expected to suppress the outgrowth of resistant mutant subpopulations.

Administration, Oral↗
PubMed2005

Adenosine A2A receptor antagonists for Parkinson's disease: rationale, therapeutic potential and clinical experience.

Long-term disability in Parkinson's disease (PD) is related to progression of the underlying disease and the emergence of complications of chronic levodopa therapy. There is a need for new medications that can slow the underlying progression of degeneration, improve PD symptoms in early disease without inducing dyskinesia, and improve motor fluctuations and 'off' time in advanced disease without worsening dyskinesia. Much interest has focused on the development of nondopaminergic therapies, with antagonists of the adenosine A2A receptor emerging as leading candidates. A2A receptors are selectively expressed in the basal ganglia and specific A2A antagonists reverse motor deficits without causing dyskinesia in animal models of PD. The antiparkinsonian potential of A2A receptor blockade has been expanded further by convergent epidemiological and laboratory findings suggesting a possible neuroprotective effect of A2A receptor antagonists in PD. Istradefylline (KW-6002) is the first of several adenosine A2A receptor antagonists in development for PD to advance to phase III clinical trials. Initial studies indicate that in patients with motor fluctuations on levodopa, addition of istradefylline reduces 'off' time. Additional studies are necessary to evaluate the benefit of istradefylline as monotherapy in early disease, its effect on the development of dyskinesia, and its effect on disease progression.

Adenosine A2 Receptor Antagonists↗
PubMed2004

Adaptation varies through space and time in a coevolving host-parasitoid interaction.

One of the central challenges of evolutionary biology is to understand how coevolution organizes biodiversity over complex geographic landscapes. Most species are collections of genetically differentiated populations, and these populations have the potential to become adapted to their local environments in different ways. The geographic mosaic theory of coevolution incorporates this idea by proposing that spatial variation in natural selection and gene flow across a landscape can shape local coevolutionary dynamics. These effects may be particularly strong when populations differ across productivity gradients, where gene flow will often be asymmetric among populations. Conclusive empirical tests of this theory have been particularly difficult to perform because they require knowledge of patterns of gene flow, historical population relationships and local selection pressures. We have tested these predictions empirically using a model community of bacteria and bacteriophage (viral parasitoids of bacteria). We show that gene flow across a spatially structured landscape alters coevolution of parasitoids and their hosts and that the resulting patterns of adaptation can fluctuate in both space and time.

Adaptation, Physiological↗
PubMed1989

Intraventricular hemorrhage in the premature infant--current concepts. Part I.

Although the incidence of periventricular-intraventricular hemorrhage (IVH) has decreased in recent years, the increasing survival rates for the smallest premature infants indicate that the lesion will continue to be a major problem in neonatal intensive care facilities. The neuropathology is characterized by an elemental lesion, bleeding into the subependymal germinal matrix, with subsequent rupture into the lateral ventricle. Important neuropathological consequences are germinal matrix destruction, posthemorrhagic hydrocephalus, and periventricular hemorrhagic infarction. The last of these appears to be a venous infarction and is a critical determinant of neurological outcome. Neuropathological accompaniments, not caused by the IVH, include periventricular leukomalacia and pontine neuronal necrosis. The pathogenesis of IVHs is related to intravascular, vascular, and extravascular factors. Intravascular factors involve primarily control of blood flow and pressure in the microcirculation of the germinal matrix. Particular pathogenetic importance can be attached to fluctuations in cerebral blood flow, abrupt increases in flow, decreases in flow with injury to matrix vessels, increases in cerebral venous pressure, and, in selected infants, disturbances of platelet function and coagulation. Vascular factors relate to the microcirculation of the matrix, the site of the initial bleeding. A maturation-dependent alteration in vascular integrity and a vulnerability of matrix vessels to ischemic injury appear important. Extravascular factors include those relevant to mesenchymal and glial support for matrix vessels and to local fibrinolytic activity in the germinal matrix. The latter may be a manifestation of the proteolytic activity now recognized to be of general importance in developmental remodeling of the mammalian central nervous system.

Blood Flow Velocity↗
PubMed1977

The effect of low dose intravenous alcohol on human information processing.

A model of multiple-stage information processing predicts alcohol to have a selective effect on mechanisms involving central processing rather than sensory input. However, behavioral effects at low alcohol doses administered orally can be overshadowed by fluctuations in gastrointestinal absorption and metabolism rate. Paid volunteers, who therefore received intravenous doses of alcohol and a barbiturate, were tested on tasks varying in sensory discriminability and in central processing difficulty. The low drug doses did not affect errors of stimulus encoding but increased error rate in memory comparison tasks. These results confirmed the predictions based on the mutiple-stage model.

Adult↗
PubMed1985

Interpretation of beat-to-beat blood pressure values in the presence of ventilatory changes.

When blood pressure is measured invasively in the operating room or intensive care unit, it is reasonable to expect useful systolic, diastolic, and mean pressure values to be displayed at all times. If blood pressure is stable from beat to beat, display of values from any beat will suffice. However, the pressure often fluctuates from beat to beat. Display of values from every beat would yield a confusing jumble of numbers. This article describes an algorithm for selecting values that appear physiological useful from blood pressure waveforms that vary with ventilation. Two classes of variation are discussed. The algorithm is optimized from the type of variation seen in pulmonary artery pressure waveforms.

Blood Pressure Determination↗
PubMed2003

Pilot plant for bioremediation of mercury-containing industrial wastewater.

Mercury is an extremely toxic pollutant that is currently being emitted mainly by low level industrial sources. It is distributed globally through the atmosphere, from where it precipitates onto the surface of the Earth, enters aquatic organisms, accumulates in fish and finally affects the health of human populations. Microbes have evolved a mechanism for mercury detoxification [mercury resistance operon ( mer)] based on intracellular reduction of Hg(2+) to non-toxic Hg(0) by the mercuric reductase enzyme and subsequent diffusional loss of Hg(0) from the cell. It was shown that Hg(0) produced by microbial detoxification can be retained quantitatively in packed bed bioreactors, in which biofilms of mercury-resistant bacteria are grown on porous carrier material. This review describes operation of this system on a technical, fully automated, scale, and its operation at a chloralkali electrolysis factory. It was shown to work with high efficiency under fluctuating mercury concentrations and to be robust against transiently toxic conditions. The gradient of mercury concentration in the technical scale system exerted a strong selective pressure on the microbial community, which resulted in a succession of mercury-resistant strains at high mercury concentrations and an increase in phylogenetic and functional diversity at low mercury concentrations. Clean-up of mercury-containing wastewater by mercury-resistant microbes is a simple, environmentally friendly and cost-effective alternative to current treatment technologies.

Biodegradation, Environmental↗
PubMed1985

Differentiating opioids by their pupillary effects in the rat.

Pupillary effects of several opioids were examined as part of a broader in vivo study of multiple opioid receptors in the rat. Agonist activity, stereospecificity, and naloxone sensitivity were determined by methadone (Me), ethylketocyclazocine (EK), and N-allylnormetazocine (SKF 10,047), selected for their purportedly predominant actions at mu, kappa, and sigma receptors, respectively. After an acute, subcutaneous injection of each drug, pupil area and fluctuations in pupil size were measured by means of an infrared video pupillometer on line with a microcomputer data processing and storage system. Despite differences in the magnitude of the response, each opioid tested produced an increase in pupil size which was stereospecific, independent of behavioral responses to the drugs and, for 1-Me and 1-SKF 10,047, dose-related. Other differences among the opioids were found in their ability to induce fluctuations (1-Me and 1-EK) and a pendular nystagmus (1-SKF 10,047 only), and in their sensitivity to naloxone. Although 1.0 mg/kg naloxone completely reversed 1-Me-induced mydriasis, 10 mg/kg was needed to reverse 1-EK, and this dose only partially antagonized 1-SKF 10,047. These characteristic patterns of pupillary responses to opioids in terms of agonist activities and naloxone sensitivities indicate that the different opioid receptor types subserve different functions with respect to pupillary control.

Animals↗
PubMed1990

Arsenic in benthic bivalves of San Francisco Bay and the Sacramento/San Joaquin River Delta.

Arsenic concentrations were determined in fine-grained, oxidized, surface sediments and in two benthic bivalves, Corbicula sp. and Macoma balthica, within San Francisco Bay, the Sacramento/San Joaquin River Delta, and selected rivers not influenced by urban or industrial activity. Arsenic concentrations in all samples were characteristic of values reported for uncontaminated estuaries. Small temporal fluctuations and low arsenic concentrations in bivalves and sediments suggest that most inputs of arsenic are likely to be minor and arsenic contamination is not widespread in the Bay.

Animals↗
PubMed1999

Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle.

The hormonal milieu at time of tumor surgery seems to have a significant impact on survival in premenopausal breast cancer patients. Indeed, surgery performed during the follicular phase of the menstrual cycle was suggested to correlate with a poor prognosis. To investigate the relationship between prognosis and menstrual cycle at time of surgery, we analyzed the expression of some markers associated with tumor aggressiveness, such as the hormone receptors, HER2, p53, Bcl2, and cathepsin D in breast carcinomas obtained from 198 premenopausal women who underwent surgery during different phases of the menstrual cycle. HER2 overexpression was found to fluctuate in hormone receptor-positive tumors. In actual fact, 20% of the tumors removed during the follicular phase scored HER2-positive, versus 8% of those removed during the luteal phase. Similarly, a number of hormone receptor-positive tumor specimens, obtained from the same patients during follicular and luteal phases, were scored HER2-positive when the sample was removed during the follicular phase and HER2-negative when removed in the luteal phase. Southern blot analysis of the HER2 gene indicated that, in hormone receptor-positive cases, the overexpression of HER2 is often not associated with gene amplification. The finding that overexpression of the HER2 gene, associated with tumor aggressiveness, can fluctuate according to the hormonal milieu may explain the increased survival of patients operated during the luteal phase. It is also relevant to the selection and treatment of patients most likely to benefit from anti-HER2 antibody therapy.

Adult↗
PubMed1998

Nonequilibrium response spectroscopy of voltage-sensitive ion channel gating.

We describe a new electrophysiological technique called nonequilibrium response spectroscopy, which involves application of rapidly fluctuating (as high as 14 kHz) large-amplitude voltage clamp waveforms to ion channels. As a consequence of the irreversible (in the sense of Carnot) exchange of energy between the fluctuating field and the channel protein, the gating response is exquisitely sensitive to features of the kinetics that are difficult or impossible to adequately resolve by means of traditional stepped potential protocols. Here we focus on the application of dichotomous (telegraph) noise voltage fluctuations, a broadband Markovian colored noise that fluctuates between two values. Because Markov kinetic models of channel gating can be embedded within higher-dimensional Markov models that take into account the effects of the voltage fluctuations, many features of the response of the channels can be calculated algebraically. This makes dichotomous noise and its generalizations uniquely suitable for model selection and kinetic analysis. Although we describe its application to macroscopic ionic current measurements, the nonequilibrium response method can also be applied to gating and single channel current recording techniques. We show how data from the human cardiac isoform (hH1a) of the Na+ channel expressed in mammalian cells can be acquired and analyzed, and how these data reveal hidden aspects of the molecular kinetics that are not revealed by conventional methods.

Cell Line↗
PubMed2001

Thermally assisted infrared multiphoton photodissociation in a quadrupole ion trap.

Thermally assisted infrared multiphoton photodissociation (TA-IRMPD) provides an effective means to dissociate ions in the quadrupole ion trap mass spectrometer (QITMS) without detrimentally affecting the performance of the instrument. IRMPD can offer advantages over collision-induced dissociation (CID). However, collisions with the QITMS bath gas at the standard pressure and ambient temperature cause IR-irradiated ions to lose energy faster than photons can be absorbed to induce dissociation. The low pressure required for IRMPD (< or = 10(-5) Torr) is not that required for optimal performance of the QITMS (10(-3) Torr), and sensitivity and resolution suffer. TA-IRMPD is performed with the bath gas at an elevated temperature. The higher temperature of the bath gas results in less energy lost in collisions of the IR-excited ions with the bath gas. Thermal assistance allows IRMPD to be used at or near optimal pressures, which results in an approximately 1 order of magnitude increase in signal intensity. Unlike CID, IRMPD allows small product ions, those less than about one-third the m/z of the parent ion, to be observed. IRMPD should also be more easily paired with fluctuating ion sources, as the corresponding fluctuations in resonant frequencies do not affect IRMPD. Finally, while IR irradiation nonselectively causes dissociation of all ions, TA-IRMPD can be made selective by using axial expansion to move ions away from the path of the laser beam.

Infrared Rays↗
PubMed1985

Heterozygosity and developmental stability in gynogenetic diploid and triploid rainbow trout.

We have previously reported that rainbow trout (Salmo gairdneri) more heterozygous at enzyme loci generally show increased developmental stability, as measured by reduced fluctuating asymmetry. We experimentally produced gynogenetic diploid and triploid individuals to test the effect of extreme heterozygosities on developmental stability. Gynogenetic diploids are identical by descent at an estimated 34 per cent of all loci and show a 50 per cent increase in the mean proportion of traits asymmetric per individual compared to normal rainbow trout. Triploids from two different strains have an estimated 30 per cent increase in genomic heterozygosity and a 14 per cent decrease in the mean proportion of traits asymmetric per individual compared to normal diploids. These changes in asymmetry induced by gynogenesis and triploidy are not as great as we expected based on the association between heterozygosity and fluctuating asymmetry in random mating populations. The narrow range of mean asymmetry in rainbow trout may result from an upper limit restricted by directional selection for developmental stability and a lower limit determined by inherent randomness in the developmental process.

Animals↗
PubMed2005

Two-electron dissociation of single molecules by atomic manipulation at room temperature.

Using the tip of a scanning tunnelling microscope (STM) to mechanically manipulate individual atoms and molecules on a surface is now a well established procedure. Similarly, selective vibrational excitation of adsorbed molecules with an STM tip to induce motion or dissociation has been widely demonstrated. Such experiments are usually performed on weakly bound atoms that need to be stabilized by operating at cryogenic temperatures. Analogous experiments at room temperature are more difficult, because they require relatively strongly bound species that are not perturbed by random thermal fluctuations. But manipulation can still be achieved through electronic excitation of the atom or molecule by the electron current tunnelling between STM tip and surface at relatively high bias voltages, typically 1-5 V. Here we use this approach to selectively dissociate chlorine atoms from individual oriented chlorobenzene molecules adsorbed on a Si(111)-7 x 7 surface. We map out the final destination of the chlorine daughter atoms, finding that their radial and angular distributions depend on the tunnelling current and hence excitation rate. In our system, one tunnelling electron has nominally sufficient energy to induce dissociation, yet the process requires two electrons. We explain these observations by a two-electron mechanism that couples vibrational excitation and dissociative electron attachment steps.

Journal Article↗