Acute Effect of Selective Chemical Inactivation of Sympathetic or Parasympathetic Atrial Ganglionated Plexus Structures on Atrial Fibrillation Inducibility in Pigs.

We studied the role of both parts of the autonomic intracardiac nervous system in the pathogenesis of atrial fibrillation (AF). In 12 pigs weighing 39±3 kg, AF was induced by burst stimulation. Chemical inactivation of intrinsic cardiac neurons within the right atria was performed by transendocardial injections of liposomal neuromodulators into the dorsal part of the right atrial wall. Sympathetic and parasympathetic terminals were inactivated with 6-hydroxydopamine (6-OHDA, n=6) and ethylcholine aziridinium ion (AF64A, n=6), respectively. Neuromodulators were encapsulated in liposomes (LS) with diameters of 310±50 nm for OHDA and 290±50 nm for AF64A. LS-6-OHDA and LS-AF64A were injected into the ganglionated plexuses after measuring the baseline effective refractory period and assessing myocardial resistance to AF. These measurements were repeated 90 min after the injections. The optimal doses were 0.2 mg/kg for LS-6-OHDA and 0.4 mg/kg for LS-AF64A (in 4 ml of suspension). Immediately after injections of liposomal neuromodulators, almost all pigs showed an increase in HR, and a short-term BP elevation was observed in the LS-AF64A group. At the end of the experiment, similar decrease in the effective refractory period and similar increase in the resistance to AF were observed in all animals. Thus, selective chemical inactivation of cholinergic and adrenergic terminals of the intracardiac nervous system with liposomal neuromodulators increased the resistance to AF in an acute experiment. However, the short observation period does not allow making a definite conclusion about the role of the autonomic nervous system in the pathogenesis of AF, which requires verification of the obtained data in a chronic experiment.

Pseudomorphic GeSiSn, SiSn and Ge layers in strained heterostructures.

The GeSiSn, SiSn layer growth mechanisms on Si(100) were investigated and the kinetic diagrams of the morphological GeSiSn, SiSn film states in the temperature range of 150 °C-450 °C at the tin content from 0% to 35% were built. The phase diagram of the superstructural change on the surface of Sn grown on Si(100) in the annealing temperature range of 0 °C-850 °C was established. The specular beam oscillations were first obtained during the SiSn film growth from 150 °C to 300 °C at the Sn content up to 35%. The transmission electron microscopy and x-ray diffractometry data confirm the crystal perfection and the pseudomorphic GeSiSn, SiSn film state, and also the presence of smooth heterointerfaces between GeSiSn or SiSn and Si. The photoluminescence for the multilayer periodic GeSiSn/Si structures in the range of 0.6-0.8 eV was detected. The blue shift with the excitation power increase is observed suggesting the presence of a type II heterostructure. The creation of tensile strained Ge films, which are pseudomorphic to the underlying GeSn layer, is confirmed by the results of the formation and analysis of the reciprocal space map in the x-ray diffractometry. The tensile strain in the Ge films reached the value in the range of 0.86%-1.5%. The GeSn buffer layer growth in the Sn content range from 8% to 12% was studied. The band structure of heterosystems based on pseudomorphic GeSiSn, SiSn and Ge layers was calculated and the valence and conduction band subband position dependences on the Sn content were built. Based on the calculation, the Sn content range in the GeSiSn, SiSn, and GeSn layers, which corresponds to the direct bandgap GeSiSn, SiSn, and Ge material, was obtained.

Environmental estrogens and reproductive health: a discussion of the human and environmental data.

Estrogenic activity of certain xenobiotics is an established mechanism of toxicity that can impair reproductive function in adults of either sex, lead to irreversible abnormalities when administered during development, or cause cancer. The concern has been raised that exposure to ambient levels of estrogenic xenobiotics may be having widespread adverse effects on reproductive health of humans and wildlife. The purpose of this review is to evaluate (a) the nature of the evidence supporting this concern, and (b) the adequacy of toxicity screening to detect, and risk assessment procedures to establish safe levels for, agents acting by this mechanism. Observations such as adverse developmental effects after maternal exposure to therapeutic levels of the potent estrogen diethylstilbestrol or male fertility problems after exposure to high levels of the weak estrogen chlordecone clearly demonstrate that estrogenicity is active as a toxic mechanism in humans. High level exposures to estrogenic compounds have also been shown to affect specific wildlife populations. However, there is little direct evidence to indicate that exposures to ambient levels of estrogenic xenobiotics are affecting reproductive health. Reports of historical trends showing decreasing reproductive capacity (e.g., decreased sperm production over the last 50 years) are either inconsistent with other data or have significant methodologic inadequacies that hinder interpretation. More reliable historical trend data show an increase in breast cancer rate, but the most comprehensive epidemiology study to data failed to show an association between exposure to persistent, estrogenic organochlorine compounds and breast cancer. Clearly, more work needs to be done to characterize historical trends in humans and background incidence of abnormalities in wildlife populations, and to test hypotheses about ambient exposure to environmental contaminants and toxic effects, before conclusions can be reached about the extent or possible causes of adverse effects. It is unlikely that current lab animal testing protocols are failing to detect agents with estrogenic activity, as a wide array of estrogen-responsive endpoints are measured in standard testing batteries. Routine testing for aquatic and wildlife toxicity is more limited in this respect, and work should be done to assess the validity of applying mammalian toxicology data for submammalian hazard identification. Current risk assessment methods appear to be valid for estrogenic agents, although the database for evaluating this is limited. In conclusion, estrogenicity is an important mechanism of reproductive and developmental toxicity; however, there is little evidence at this point that low level exposures constitute a human or ecologic health risk. Given the potential consequences of an undetected risk, more research is needed to investigate associations between exposures and effects, both in people and animals, and a number of research questions are identified herein. The lack of evidence demonstrating widespread xenobiotic-induced estrogenic risk suggests that far-reaching policy decisions can await these research findings.

Two-generation reproduction study in rats given di-isononyl phthalate in the diet.

The potential reproductive toxicity of di-isononyl phthalate (DINP: CAS RN 68515-48-0) was assessed in one- and two-generation reproductive toxicity studies. Groups of 30 male and female CRL : CD(SD)BR rats were given DINP via dietary administration at levels of either 0.0, 0.5, 1, or 1.5% (one-generation study) or 0.0, 0.2, 0. 4, or 0.8% (two-generation study). There were no changes in any of the classic reproductive parameters, i.e. mating, male or female fertility, fecundity, gestational index, or length of gestation in either study. The overall NOAELs for these effects were the highest Dietary Level (%)s tested, approximately 500 mg/kg/day in the two-generation study and 1000 mg/kg/day in the one-generation study. There were no testicular effects in parental animals exposed as juveniles and young adults at 960 mg/kg/day in the one-generation study. In the two-generation study, there were no testicular effects in either the P(1) males, exposed as juveniles and young adults or the P(2) (F(1)) offspring exposed in utero, through lactation, and continuously to terminal sacrifice. The NOAEL was 470 mg/kg/day. Offspring survival was reduced at the 1.5% level ( approximately 1100 mg/kg/day) but unaffected at the 1% level ( approximately 760 mg/kg/day). There were decreased offspring body weights both at postnatal day (PND) 0 and during lactation; however, the PND 0 effects were only clearly related to treatment at the 1.5% level. Weights of offspring during lactation were significantly reduced but within the historical control range at Dietary Level (%)s below 1%. As there was rapid recovery at the lower levels, even though treatment continued, the toxicologic significance is unclear. Adult survival was unaffected at any level in either study, but weight gain was significantly reduced at the 1% level ( approximately 600 mg/kg/day). Liver and kidney weights were elevated at Dietary Level (%)s above approximately 110 mg/kg/day, consistent with evidence from other studies of peroxisomal proliferation at these levels. This study showed that DINP treatment does not affect fertility or male reproductive development at doses of up to approximately 1000 mg/kg/day.

Developmental toxicity of di-isodecyl and di-isononyl phthalates in rats.

The developmental toxicity of di-isodecyl phthalate (DIDP; CAS RN 68515-49-1) and di-isononyl phthalate (DINP; CAS RN 68515-48-0) were investigated in Sprague-Dawley rats. DIDP and DINP were administered by gavage to mated rats at doses of 0, 100, 500, and 1000 mg/kg/d on Gestation Days (GD) 6 through 15. Cesarean sections were performed on GD 21 and the fetuses removed for evaluation. Maternal weight gain and food consumption were significantly reduced at 1000 mg/kg/d during the exposure period. No treatment-related effects were noted at cesarean section, nor were there any fetal morphologic observations except for an increased frequency of seventh cervical and rudimentary lumbar ribs at the maternally toxic exposure level of 1000 mg/kg/d. Under these study conditions, mild maternal and developmental effects were observed at 1000 mg/kg/d. Both maternal and developmental NOAELs were therefore established at 500 mg/kg/d. The results indicate that neither DIDP nor DINP is teratogenic or a selective developmental toxicant.

Estrogen modulation: tiered testing for human hazard evaluation. American Industrial Health Council, Reproductive and Developmental Effects Subcommittee.

Recent concerns about the potential of certain chemicals to modulate estrogen-regulated processes have led to questions as to how chemicals should be tested for such effects. Therefore, AIHC has developed a comprehensive, resource-efficient, and flexible tiered strategy for estrogen modulation (EM) testing. Levels of evaluation include Tier 0, in which exposure, along with alerts based on structure-activity, persistence, bioaccumulation, and other data, are assessed to prioritize chemicals for preliminary testing. In Tier I, short term in vitro, ex vivo, and/or in vivo assays are used to obtain a preliminary indication of EM potential. Among these, an in vivo response assay is considered the most reliable at this time. However, none of these tests are intended for risk assessment, but rather to aid in choosing chemicals for further testing and in guiding the extent of that testing. Tier II is aimed at risk assessment and involves whole animal tests that contain EM-sensitive end points (e.g., two-generation reproduction study). Tier III consists of hypothesis-driven research reserved for situations where targeted research can reduce levels of uncertainty. This tiered approach provides a framework for the strategic and effective application of EM test methods to address specific information needs on a case by case basis.

[Age and the structural organization of the EEG of children and adolescents in different functional states of the brain]. / Vozrastnye osobennosti strukturnoi organizatsii EEG detei i podrostkov pri razlichnykh funktsional'nykh sostoianiiakh mozga.

The present paper deals with age characteristics of EEG reactions, at the level of integral cues, to functional loads in children of 7-14 years and juveniles. Modelling of tense and emotional states leads to a reconstruction of the organization of the EEG of quiet waking state, with formation of integral characteristics specific for these states and reflecting various mechanisms of the brain activity. At the age of 9-12 years emotional loads bring about disturbances of EEG integral characteristics, testifying to a lowering of brain reactivity.

[Systematic organization of the symptoms of depression]. / K voprosu o sistemnoi organizatsii simptomov depressii.

Using a mathematical- locical techniques, a systemic organization of depressive symptoms at the level of components was suggested. This system may be used for evaluating the severity of the condition and determining its nosological character as well as for establishing prognostic criteria.

[Systems approach to prognostic criteria for depression]. / Sistemnyi podkhod k prognosticheskim kriteriiam depressii.

In order to elucidate the prognostic criteria of depression in the structure of schizophrenia, manic-depressive psychosis, and psychogenias, the authors, using computer-based techniques, have identified groups of clinical symptoms of variable complexity (arbitrarily named as computerized syndromes) which determine the general outcome of the disease. Computerized syndromes of favourable and unfavourable prognosis with a high diagnostic accuracy can be used for individual prognosis.

[Use of systematic organization of the EEG in the diagnosis of psychopathologic states]. / Ispol'zovanie sistemnoi organizatsii EEG pri diagnostike psikhopatologicheskikh sostoianii.

A group of patients with paranoid schizophrenia treated with aminazine and leponex were examined. Using the component analysis, the integral characteristics of the EEGs--the main components describing principal organizational variants of the background EEG--were obtained. An analysis of the components showed the generalized synchronous and activating effects of the deep cerebral structures to be involved in the formation of these variants of the EEG organization. The components obtained proved to be important for the prognosis of therapy efficacy and the selection of an optimal psychotropic agent.

[Electroencephalographic profile and dynamics of individual changes in the EEG of paranoid schizophrenics during treatment with aminazine (clinico-electroencephalographic correlation)]. / Elektroéntsefalograficheski i profil' i dinamika individual'nykh izmeneniia EEG u bol'nykh paranoidnoi schizofreniei pri lechenii aminazinom (kliniko-élektroéntsefalograficheskoe sopostavlenie).

The authors analyze the changes of the frequency and amplitude characteristics of EEGs in schizophrenic patients treated with aminazin. Under study there were changes characterizing the so-called EEG profile of aminazin, as well as changes reflecting individual reconstitution of the EEG in each patient. The changes related to the aminazin EEG profile, as well as the individual changes of the EEGs were found to be associated with the treatment efficacy ad the form of the schizophrenia course. The character of this association suggests that the EEG profile reflects the reactivity of the brain to the aminazin application, whereas the individual EEG changes are associated with the time course of the psychopathological manifestations in the patients treated.

[Clinico-electroencephalographic correlations in asthenoadynamic subdepressions]. / Kliniko-élektroéntsefalograficheskie korreliatsii pri astenoadinamicheskikh subdepressiiakh.

In patients with atypical, torpid and poorly identifiable asthenoadynamic subdepressions with predominant disorders of intellectual activity the authors analyzed the spatial structure of the ECG activity. They also studied the psychophysiologic mechanisms underlying the psychopathologic condition. The feasibility of the objective verification of the clinical status and of the prognosis of the depressive condition have been demonstrated. The data on the overactive processes of cortical excitation and deficit of the processes of active selective cortical inhibition in the studied states are presented.

[EEG factor analysis in the treatment with antidepressants]. / Faktornyi analiz EEG pri kursovoi terapii antidepressantami.

Spatial EEG factor analysis was performed in patients under gamonil and damilen treatment. Groups of EEG-factors were discovered that describe the peculiarities of the brain electrical processes spatial reorganization under pharmacotherapy. Major groups comprised the EEG factors: 1. characterizing the proper action of the drug; 2. connected to the syndromal peculiarities of depression or the course of mental state changes; 3. those depending on the efficiency of the therapy.

[Structural organization of the bioelectrical activity of the brain in neurotic children]. / O strukturnoi organizatsii bioélektricheskoi aktivnosti golovnogo mozga u detei, bol'nykh nevrozami.

Using the method of computerized primary and factorial analysis of the EEGs in children with various neurotic disturbances, the authors obtained integral age-related characteristics, both common and specific, typical of these patients. The peculiarities of the age-specific pattern of integral characteristics of the EEG indicate that in patients aged 9-12 years the process of a diffuse decrease of the amplitude of the cortical rhythms was inhibited and that the period of the maximum intensity of theta-rhythm in the anterior central portions was displaced from the age 9-10 years to the age of 11-12 years. These disorders were most prominent in children with vegetative emotional disturbances.

[Neurofunctional programs of brain activity and their structural characteristics in different psychopathological states and during treatment]. / Neirofunktsional'nye programmy deiatel'nosti mozga i osobennosti ikh struktury pri razlichnykh psikhopatologicheskikh sostoianiiakh i v protsesse lecheniia.

EEG patterns (neurofunctional systems) characteristic of certain mental states are presented from the standpoint of theoretic ideas of these patterns as neurofunctional programs of brain activity. Approaches for studying the structure of these programs are discussed.

A 90-day oral (dietary) toxicity study of arruva, an R, R-monatin salt isomer, in Crl:CD-1(ICR) mice.

R,R-Monatin [2R,4R- isomer of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid] is one of four natural constituent isomers in the root bark of Sclerochitin ilicifolius; and "arruva" is the common/usual name that is proposed to represent R,R-monatin salt forms, which have potential use as high potency sweetener food ingredients. In the present study, groups of male and female Crl:CD-1(ICR) mice were exposed to 0 (control), 5000, 10,000, 20,000, or 35,000ppm of arruva in the diet for 90days. There were no toxicologically relevant clinical or histopathological findings in any of the test article-treated groups. Significantly lower mean body weights and cumulative body weight gains were noted in the 35,000ppm group when compared to the control group. Mean body weights in the 35,000ppm group males and females were 9% and 7% less than the control group, respectively, at week 13. In the absence of observations associated with systemic toxicity and in consideration of the magnitude of body weight difference, these effects were not considered toxicologically significant. Based on the results of this study, the dietary no-observed-adverse-effect level (NOAEL) of arruva for 90days in male and female mice was 35,000ppm (equivalent to an exposure level of 5764 and 8013mg/kg bw/day, respectively).

A dietary embryo/fetal developmental toxicity study of arruva, an R,R-monatin salt isomer, in Crl:CD(SD) rats.

R,R-Monatin is an intensely sweet substance originally identified in the root bark of Sclerochiton ilicifolius. R,R-Monatin salt, commonly known as "arruva", has potential for use as a high-potency sweetener food ingredient. Previously, arruva was concluded to present no toxicologically relevant effects to Crl:CD(SD) rats and Crl:CD-1(ICR) mice fed up to 35,000 ppm arruva in the diet for 90 days. In the present study, groups of mated Sprague-Dawley rats (25 Crl:CD(SD) females/group) were exposed continuously to 0 (control), 15,000, 30,000, or 50,000 ppm arruva in the diet during gestation days 6-21. There were no fetal malformations or developmental variations that were attributable to arruva at any exposure level, nor were there any test article-related effects on intrauterine survival. Maternal toxicity, evidenced by lower mean body weights, body weight gains and feed efficiency, was observed at 50,000 ppm. A developmental effect, in the form of lower mean fetal body weight, was noted in the 50,000 ppm group in the presence of maternal toxicity. Therefore, the dietary no-observed-adverse-effect level (NOAEL) for maternal and embryo/fetal developmental toxicity of arruva in pregnant rats during gestation days 6-21 was 30,000 ppm (equivalent to 2564 mg/kg bw/day) based on reductions in maternal and fetal body weights.

Universal behavior of magnetoresistance in quantum dot arrays with different degrees of disorder.

The magnetoresistance in a two-dimensional array of Ge/Si quantum dots was studied in a wide range of zero magnetic field conductances, where the transport regime changes from a hopping to a diffusive one. The behavior of the magnetoresistance is found to be similar for all samples--it is negative in weak fields and becomes positive with increasing magnetic field. The result apparently contradicts existing theories. To explain experimental data we suggest that clusters of overlapping quantum dots are formed. These clusters are assumed to have metal-like conductance, the charge transfer taking place via hopping between the clusters. Relatively strong magnetic field shrinks electron wavefunctions, decreasing inter-cluster hopping and, therefore, leading to a positive magnetoresistance. Weak magnetic field acts on 'metallic' clusters, destroying the interference of the electron wavefunctions corresponding to different paths (weak localization) inside clusters. The interference may be restricted either by inelastic processes, or by the cluster size. Taking into account weak localization inside clusters and hopping between them within the effective medium approximation, we extract effective parameters characterizing charge (magneto-) transport.

Assessment of the environmental fate and ecotoxicity of N,N-diethyl-m-toluamide (DEET).

N,N-diethyl-m-toluamide (DEET) is a key active ingredient in many insect repellents available commercially throughout the world. Owing to its popularity among consumers for nearly 30 years, considerable work conducted in the past has demonstrated-and continues to demonstrate-that human exposure to DEET poses no significant health risk to the general population. The results of several studies reported in this paper describe more recent work to understand the environmental fate of DEET, particularly in surface waters and soil, and the potential hazards to aquatic and terrestrial organisms. In summary, DEET enters the environment through several pathways: directly into air during spray application; to surface water from overspray and indirectly via wastewater treatment plant (WTTP) discharges (as a result of washing of skin and laundering of clothing); or to soil via overspray and application of treated sewage as an amendment. Multimedia environmental fate modeling predicts that DEET entering the environment is retained either in receiving waters (∼79%) or in soil (∼21%). Based on its physicochemical properties, DEET is expected to be moderately mobile in the soil column. In surface waters and soil, DEET degrades at a moderate to rapid rate (its half-life is measured in days to weeks). The small amounts of DEET retained in air are subject to rapid photo-oxidation via hydroxyl radical-mediated degradation or, if in droplet form, gravitational settling to soil or water. DEET does not interfere with ozone formation in the upper atmosphere. The bioaccumulation potential of DEET is low; it is neither a persistent, bioaccumulative toxicant nor a persistent organic pollutant. Among aquatic species, acute effect concentrations range between 4 and 388 mg/L. The chronic no-observed effect concentrations (NOEC) for daphnids and green algae range from approximately 0.5 to 24 mg/L. Measured concentrations of DEET in surface waters are several hundreds to thousands of times lower than the lowest NOEC measured, and thus the probability for adverse effects to environmental species is low. A separate paper by Aronson et al. (this issue) supports this conclusion by quantitatively exploring the risks to the aquatic environment using a combination of monitoring data and exposure modeling.

A 90-day oral (dietary) toxicity study of the 2R,4R-isomer of monatin salt in Sprague-Dawley rats.

The root bark of Sclerochitin ilicifolius contains an intensely sweet substance analytically identified as isomers of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid and generically coined "monatin." Groups of male and female Crl:CD(SD) rats were fed 0 (control), 5000, 10,000, 20,000 or 35,000 ppm R,R-monatin salt in the diet for 90 days. There were no toxicologically relevant clinical or histopathological findings in any of the test article-treated groups. Significantly lower cumulative body weight gains were noted in the 35,000 ppm group. Mean body weights in the 35,000 ppm group males and females were 7% and 12% lower, respectively, than the control group at study week 13. In the absence of other observations associated with systemic toxicity and lower food consumption, the magnitude of the body weight difference in the 35,000 ppm group females relative to the control group exceeded 10%, which indicated attainment of a maximum tolerated dose (MTD) level. Based on the results of this study, and conservatively assuming the body weight observations at the MTD to be indicative of an adverse effect, the dietary no-observed-adverse-effect level (NOAEL) of R,R-monatin salt for 90 days was 20,000 ppm in female rats (approximately 1544 mg/kg bw/day) and 35,000 ppm in male rats (approximately 2368 mg/kg bw/day).