In the mouse carcinogenicity study, an apparent increase in lung adenocarcinoma was observed in male mice at 7000 ppm. Based on the overall evaluation of toxicology, oncology, pathology and statistics, we concluded that the apparent increase in lung tumors is not relevant for evaluation of carcinogenicity of imiprothrin (Regul Toxicol Pharmacol, 105, 1-14, 2019). To investigate whether imiprothrin has any mitogenic effect on mouse Club cells, the present study examined its effects on replicative DNA synthesis of Club cells and lung histopathology in male mice treated with imiprothrin for 7 days at 3500 and 7000 ppm in the diet. Isoniazid, a known mouse lung mitogen and tumor inducer, was also examined at 1000 ppm in the diet as a positive control of Club cell mitogenesis and morphological changes. Neither imiprothrin nor isoniazid caused any necrotic changes in lung by light or electron microscopy. There were no increases observed in the bromodeoxyuridine (BrdU) labeling index in the imiprothrin groups, while there was a statistically significant increase in the BrdU labeling index in the isoniazid group. These findings demonstrate that imiprothrin does not induce mouse Club cell proliferation or morphologic changes, supporting our previous conclusion described above. Thus, imiprothrin should not be classified as a carcinogen. Furthermore, this study indicates that short-term studies focusing on cell proliferation can be reliable for predicting a lack of carcinogenic potential of test chemicals.

Astrocytes play an important role in the physiological functions of the central nervous system. In this study, contact potential differences (CPD) and capacitance gradients of the cell bodies and glial filaments of astrocytes were measured. Charge propagation properties in the astrocyte gap junctions were also studied using multimode Atomic Force Microscopy (AFM) at nanometre resolution. The CPD of the cell bodies and glial filaments were 324.2 ± 138.4 and 119.1 ± 31.7 mV, respectively. The measured capacitance gradients were 1.51 ± 0.31 and 1.98 ± 0.32 zF nm-1 , respectively. The gap junctions in the astrocytes showed no charge propagation and were not electrically sensitive. This furthers our understanding of astrocytes and other types of neuroglia. LAY DESCRIPTION: Neuroglia cells play important structural and functional roles in central nervous system (CNS). Neuroglia cells exceed the number of neurons by 10∼50 and can be divided into macroglia and microglia. Astrocytes are macroglia and are the largest and most abundant cells in the CNS. Astrocytes lack axons and dendrites and do not propagate action potentials. They have few cytoplasmic organelles, but possess abundant glial filaments, the main components of the cytoskeleton. Glial filaments are composed of the glial fibrillary acidic protein (GFAP). Astrocytes produce intercellular calcium waves in their gap junctions mediated through receptor activator (such as glutamate) to permit signal transduction._ENREF_5 In addition to their role in the support and nutrition of neurons, astrocytes are involved in various types of CNS activity including: (1) cytokine secretion for neuronal survival, growth and differentiation; (2) protection from brain injury; (3) modulation of the blood brain barrier; and (4) neuronal immunity. Bidirectional crosstalk between the astrocytes and neurons exists. Astrocytes can be activated by neurotransmitters released and can themselves release gliotransmitters to act upon neurons. Astrocytes are closely related to various disease states, including epilepsy and Alzheimer\'s disease. In this study, the electrical properties of astrocytes, including the contact potential difference (CPD) and capacitance gradients of the cell bodies and glial filaments, and charge propagation in the gap junctions were investigated at the nanometer level using quantitative Kelvin Probe Force Microscopy (KPFM) and Electrostatic Force Microscopy (EFM). The CPD of the cell bodies and glial filaments of the astrocytes were 324.2 mV and 119.1 mV, respectively. Capacitance gradients of the cell bodies and glial filaments of the astrocytes were 1.51 zF/nm and 1.98 zF/nm, respectively. Gap junctions in the astrocytes do not perform charge propagation functions and the astrocytes are not electrically sensitive. One should note that these results from KPFM and EFM were measured on dried cell and the situation might be different when studying in operando environment, still these findings aid our understanding of the electrical properties and functions of astrocytes, and further our knowledge of the electrical properties of the CNS.

The etiology and pathophysiology of anxiety and mood disorders is linked to inappropriate regulation of the central stress response. To determine whether microRNAs have a functional role in the regulation of the stress response, we inactivated microRNA processing by a lentiviral-induced local ablation of the Dicer gene in the central amygdala (CeA) of adult mice. CeA Dicer ablation induced a robust increase in anxiety-like behavior, whereas manipulated neurons survive and appear to exhibit normal gross morphology in the time period examined. We also observed that acute stress in wild-type mice induced a differential expression profile of microRNAs in the amygdala. Bioinformatic analysis identified putative gene targets for these stress-responsive microRNAs, some of which are known to be associated with stress. One of the prominent stress-induced microRNAs found in this screen, miR-34c, was further confirmed to be upregulated after acute and chronic stressful challenge and downregulated in Dicer ablated cells. Lentivirally mediated overexpression of miR34c specifically within the adult CeA induced anxiolytic behavior after challenge. Of particular interest, one of the miR-34c targets is the stress-related corticotropin releasing factor receptor type 1 (CRFR1) mRNA, regulated via a single evolutionary conserved seed complementary site on its 3\' UTR. Additional in vitro studies demonstrated that miR-34c reduces the responsiveness of cells to CRF in neuronal cells endogenously expressing CRFR1. Our results suggest a physiological role for microRNAs in regulating the central stress response and position them as potential targets for treatment of stress-related disorders.

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OBJECTIVE: To ascertain if hydrosalpinges are associated with reduced pregnancy rates and increased pregnancy loss after IVF-ET. Increased volume and leakage of hydrosalpinx fluid may exert negative effects on follicular development and embryo quality and/or render the uterine environment hostile to embryogenesis. We undertook this study to examine the effect of hydrosalpinx fluid on murine embryogenesis in vitro.
METHODS: Descriptive study.
METHODS: Tertiary care facility.
METHODS: Premenopausal females undergoing salpingectomy or salpingostomy for hydrosalpinges.
METHODS: Collection of discarded hydrosalpinx fluid and development of a dose response curve for the effect of hydrosalpinx fluid on murine embryogenesis.
METHODS: Development of single cell mouse embryos in vitro.
RESULTS: All samples of tubal fluid obtained from hydrosalpinges demonstrated a significant embryo toxic effect at either the 100% or 10% concentration. Hydrosalpinx fluid demonstrated pH values (8.45 to 8.65) significantly higher than the physiologic range. Correction of pH to that of media did not affect cavitation rate.
CONCLUSIONS: There is a well-defined and significant toxic effect of hydrosalpinx fluid. Procedures such as salpingectomy or proximal tubal occlusion to circumvent the passage of hydrosalpinx fluid into the uterine cavity may have beneficial effects on the developmental environment for embryos in vivo.

We previously reported on a patient exposed simultaneously to methyl chloride and chloramine gas who developed metabolic acidosis and permanent blindness [M. Minami et al., Hum Exp Toxicol 11: 27-34, 1992]. The case report suggested the possibility of potentiation of methyl chloride toxicity by chloramine. The potentiating mechanism was investigated by exposing mice to methyl chloride followed by ammonia chloramine, and then the level of formate in urine samples was measured with an enzyme coupling method to detect disturbance of formate metabolism. Mice dosed with 0.05 mL 1.0 mM chloramine after methyl chloride exposure excreted a significantly larger amount of urinary formate than mice treated with only methyl chloride. There was no difference in urinary formate levels between mice treated with only 0.05 mL 1.0 mM chloramine and those given only the vehicle (0.1 M phosphate buffer pH 6.0) for chloramine. The underlying biochemical mechanism of deterioration of formate metabolism was found to be the inhibition of the enzyme, N10-formyl tetrahydrofolate (N10-f-THF) dehydrogenase by 0.56-3.35 microM chloramine in the in vitro experiment using the purified enzyme. Positive control mice, given orally 0.1 mL 10% methanol in 0.1 M phosphate buffer (pH 6.0) excreted the same amount of urinary formate as those receiving 0.05 mL 1.0 mM chloramine after methanol administration. This was ascribed to the inhibitory effect of chloramine on formaldehyde dehydrogenase and depletion of substrate for further metabolism. The inhibition of the enzyme by chloramine (2.7-100.8 microM) was confirmed by in vitro experiments, using the purified enzyme, formaldehyde dehydrogenase.

In view of the trend towards single drug therapy of epilepsy, the experimental background for thr combination of phenobarbital (PB) and phenytoin (PHT) was reassessed. Since potentiation of the anticonvulsant activity is in itself neither sufficient nor necessary to demonstrate the superiority of a drug combination, protection against maximal electroshock seizures as well as neurotoxicity were determined in mice. This allowed one to separate the neurotoxic from the anticonvulsant interaction and to base the analysis on changes in the therapeutic index (TI). Pharmacokinetic interactions were excluded from the analysis by expressing all results in terms of brain concentrations. The anticonvulsant interaction between PB and PHT was found to be additive, whereas the neurotoxic interaction was antagonistic. These results provide experimental documentation of one of the theories behind antiepileptic drug combinations. However, because PB had a markedly lower TI than PHT in this model, the TI of the drug combination was lower than the TI of PHT. Thus, the antagonism with regard to neurotoxicity was not sufficient to raise the TI of the combination above the TI of PHT.

The tail flick assay was used to evaluate pain perception in mice treated acutely with either of the two classical antidepressant drugs (AD) imipramine or amitriptyline, or the atypical antidepressant iprindole. A sustained hypoalgesic effect, sensitive to the opiate antagonist naloxone, was detected for the AD used in this study. Administration of the aminopeptidase inhibitor bestatin or the enkephalinase blocker thiorphan made subeffective doses of AD hypoalgesic. This synergistic effect was reversed by naloxone. The antinociceptive action of the AD wore off in mice rendered tolerant to morphine by subcutaneous implantation of a pellet of the opiate. Subchronic treatment with p-chlorophenylalanine did not alter the effect of AD on pain perception, but in animals whose serotonin (5-HT) receptors were blocked by methysergide AD did not produce any change in pain threshold. It was concluded on the basis of these findings that short-chain opioids and 5-HT appear to have a role in the hypoalgesic effect of either classical or atypical AD.