An extreme magneto-ionic environment associated with the fast radio burst source FRB 121102.

Fast radio bursts are millisecond-duration, extragalactic radio flashes of unknown physical origin. The only known repeating fast radio burst source-FRB 121102-has been localized to a star-forming region in a dwarf galaxy at redshift 0.193 and is spatially coincident with a compact, persistent radio source. The origin of the bursts, the nature of the persistent source and the properties of the local environment are still unclear. Here we report observations of FRB 121102 that show almost 100 per cent linearly polarized emission at a very high and variable Faraday rotation measure in the source frame (varying from +1.46 × 105 radians per square metre to +1.33 × 105 radians per square metre at epochs separated by seven months) and narrow (below 30 microseconds) temporal structure. The large and variable rotation measure demonstrates that FRB 121102 is in an extreme and dynamic magneto-ionic environment, and the short durations of the bursts suggest a neutron star origin. Such large rotation measures have hitherto been observed only in the vicinities of massive black holes (larger than about 10,000 solar masses). Indeed, the properties of the persistent radio source are compatible with those of a low-luminosity, accreting massive black hole. The bursts may therefore come from a neutron star in such an environment or could be explained by other models, such as a highly magnetized wind nebula or supernova remnant surrounding a young neutron star.

A direct localization of a fast radio burst and its host.

Fast radio bursts are astronomical radio flashes of unknown physical nature with durations of milliseconds. Their dispersive arrival times suggest an extragalactic origin and imply radio luminosities that are orders of magnitude larger than those of all known short-duration radio transients. So far all fast radio bursts have been detected with large single-dish telescopes with arcminute localizations, and attempts to identify their counterparts (source or host galaxy) have relied on the contemporaneous variability of field sources or the presence of peculiar field stars or galaxies. These attempts have not resulted in an unambiguous association with a host or multi-wavelength counterpart. Here we report the subarcsecond localization of the fast radio burst FRB 121102, the only known repeating burst source, using high-time-resolution radio interferometric observations that directly image the bursts. Our precise localization reveals that FRB 121102 originates within 100 milliarcseconds of a faint 180-microJansky persistent radio source with a continuum spectrum that is consistent with non-thermal emission, and a faint (twenty-fifth magnitude) optical counterpart. The flux density of the persistent radio source varies by around ten per cent on day timescales, and very long baseline radio interferometry yields an angular size of less than 1.7 milliarcseconds. Our observations are inconsistent with the fast radio burst having a Galactic origin or its source being located within a prominent star-forming galaxy. Instead, the source appears to be co-located with a low-luminosity active galactic nucleus or a previously unknown type of extragalactic source. Localization and identification of a host or counterpart has been essential to understanding the origins and physics of other kinds of transient events, including gamma-ray bursts and tidal disruption events. However, if other fast radio bursts have similarly faint radio and optical counterparts, our findings imply that direct subarcsecond localizations may be the only way to provide reliable associations.

Reproduction and fetal development in mice chronically exposed to enflurane.

Reproductive indices and developmental toxicity were evaluated in Swiss/ICR mice chronically exposed to a subanesthetic (0.01 or 0.1 per cent) or an anesthetic (0.5/1.0 per cent) concentration of enflurane. Pregnant mice (443) and fetuses (4743) were examined. In one experiment, groups of females were exposed to 0.01, 0.1, or 0.5/1.0 per cent enflurane for 4 hours per day, 7 days per week for 3 weeks; they were then mated with unexposed males. Exposure of females was continued daily throughout pregnancy. No adverse effects on fertility were observed at any dosage. At the highest dosage, 1.0 per cent, minor developmental variations occurred (i.e., lumbar ribs and increased renal pelvic cavitation). In a second experiment, groups of mice were exposed to 0.01, 0.1 or 1.0 per cent enflurance only on days 6 through 15 of pregnancy for 4 hours per day, after having been mated with untreated males. Abnormalities (i.e., increased incidence of cleft palate, minor skeletal and visceral anomalies, and developmental variants) were again seen only at the highest dosage. In a third experiment, male mice were exposed to 0.01, 0.1 or 0.5/1.0 per cent enflurane for 11 weeks for 4 hours per day, 5 days per week, prior to mating with unexposed females; results of this experiment were negative. In general, enflurane treatments did not adversely affect reproductive indices. Effects on fetal development were minimal, being somewhat greater than those reported in previous experiments with methoxyflurane but less than those seen with halothane. The smallest exposure at which effects were seen was approximately 100 times greater than the level of human occupational exposure in unscavenged operating rooms.

Developmental toxicity of methoxyflurane in mice.

The developmental toxicity of trace, subanesthetic, and anesthetic exposure to methoxyflurane was examined in Swiss/ICR mice. No adverse effects on reproduction or fetal development were demonstrated following exposure to trace (2 ppm) and subanesthetic (60 ppm) concentrations of methoxyflurane for 4 hours daily on days 6 through 15 of pregnancy. Exposure to an anesthetic concentration (2000 ppm; 0.2%) for the same period resulted in decreased fetal weight, decreased ossification, and delayed renal maturation. Additionally, the incidence of minor skeletal anomalies was increased. It is concluded that gestational exposure of mice to trace of subanesthetic concentrations of methoxyflurane does not result in reproductive loss or morphologic abnormalities in their offspring.

Metabolic and toxicologic studies with enflurane in Swiss/ICR mice.

Swiss/ICR mice were tested to determine whether the volatile ether anesthetic, enflurane, causes induction of anesthetic defluorination and organ toxicity. Mice were exposed in utero and postnatally to 0.01, 0.1 and 1.0 volumes percent enflurane vapor. Body weight was measured at frequent intervals throughout the experiment. Animals were sacrificed at 73 days of age and liver microsomal cytochrome P-450 content and the rate of defluorination of enflurane, isoflurane, methoxyflurane ans sevoflurane were determined. In addition, the liver, kidney and testis were weighed and examined histologically for drug induced damage. The maximum tolerated dose of enflurane delivered over a twelve week period was determined to be 0.5 volumes percent for four hours a day, five days a week. Even at this high dose there was no evidence in either sex of liver, kidney or testicular damage. Following enflurane exposure, neither the liver microsomal cytochrome P-450 content nor the rate of anesthetic defluorination was increased. The rate of in vitro inorganic fluoride production per unit time was greatest for methoxyflurane, and approximately equal for enflurane, isoflurane and sevoflurane. Since there was no evidence of enzyme induction or specific organ toxicity, it was concluded that enflurane is a comparatively nontoxic volatile anesthetic under conditions of this study.

Renal function in Fischer 344 rats with chronic renal impairment after administration of enflurane and gentamicin.

To assess the potential for producing nephrotoxicity in rats with abnormal renal function, the renal effects of enflurane or halothane anesthesia, 1 MAC for two hours, were examined in six groups of six Fischer 344 rats each with surgically induced chronic renal impairment. As an additional predisposing factor, gentamicin, 5 mg/kg/day, was administered for one week before and for one week after anesthesia to three of the groups, one anesthetized with enflurane, one anesthetized with halothane, and one unanesthetized. No significant change in renal function could be attributed to either anesthetic agent. Serum inorganic fluoride levels four hours and 24 hours after enflurane anesthesia were similar in the gentamicin-treated and the non-gentamicin-treated groups. Clinically small but statistically significant increases in serum creatinine concentration and urinary flow occurred in all three gentamicin-treated groups during the period of treatment. Anesthesia with either enflurane or halothane in rats with chronic renal impairment treated with gentamicin did not result in additional renal damage.

Carcinogenicity of halothane in Swiss/ICR mice.

A simplified in-vivo bioassay system was used to test the carcinogenic potential of halothane in Swiss/ICR mice. Halothane was tested only at its maximum tolerated dose, and histologic examination was performed only on tumor masses and other grossly abnormal tissues found at necropsy. Two groups, each of 15 timed pregnant mice, were exposed to either halothane, 500 ppm (0.05 per cent), or compressed air for two hours on days 10--19 of pregnancy. Five days after birth the offspring were similarly exposed, three times weekly, for 78 weeks. After a ten-week, no-treatment, observation period, all remaining mice were examined by necropsy. Mice dying or killed in extremis before final sacrifice at 88 weeks of age also underwent complete gross necropsy unless extensive cannibalism or autolysis precluded examination. The incidences of malignant tumors, hepatomas or modular hyperplasias, and benign tumors in halothane-treated mice were 7, 6, and 20 per cent, respectively; there were similar incidences of these lesions in control animals. It is concluded that under the conditions of this experiment, lifetime administration of halothane at its maximum tolerated dose is not associated with an increased incidence of neoplasia in Swiss/ICR mice.

Fetal morphology in mice exposed to halothane.

The teratogenic potential of subanesthetic and anesthetic exposure to halothane was studied in Swiss/ICR mice. Two treatment regimens were employed: daily exposure of males and females for nine weeks prior to conception and on days 1 through 17 of pregnancy; and exposure of females only on days 6 through 15 of pregnancy. Mice were exposed to subanesthetic concentrations of halothane for 0.025, 0.1, 0.4, and 1.2 MAC hours/day; anesthetic exposure was 4.0 MAC hours/day. Fetal morphologic development was normal at the two lowest exposures. Exposures of 0.4 MAC hours/day and more were associated with decreased fetal ossification. At the 1.2 MAC hour/day exposure, renal pelvic masturation was retarded and the incidence of skeletal variants was increased. The incidences of major malformations and minor anomalies were not increased following exposure to subanesthetic concentrations of halothane. Anesthetic exposure to 4.0 MAC hours/day was lethal to both dams and embryos, and resulted in major developmental malformations in surviving fetuses. These effects were probably due to altered maternal physiologic status. It is concluded that exposure of mice to subanesthetic concentrations of halothane does not result in important morphologic abnormalities in their offspring.

Mutagenicity of volatile anesthetics: halothane.

The mutagenicity of halothane was tested in an in-vitro microbial assay system employing two histidine-dependent mutants of Salmonella typhimurium, TA98 and TA100, Halothane in concentrations ranging from 0.1 to 30 per cent was incubated with bacteria in the presence or absence of a metabolic activation system prepared from either rat liver treated with Aroclor 1254 or human liver. Trifluoroacetic acid, a major metabolite of halothane, and urine from patients anesthetized with halothane also were tested. Halothane, trifluoroacetic acid, and patients' urines were not mutagenic.

Mutagenicity of halogenated ether anesthetics.

An in vitro microbial assay system employing two histidine-dependent strains of Salmonella typhimurium, TA1535 and TA100, was used to test the mutagenicities of enflurane, methoxyflurane, isoflurane and fluroxene. Enflurane, isoflurane and fluroxene in concentrations ranging from 0.01 to 30 per cent and methoxyflurane in concentrations ranging from 0.01 to 7 per cent were incubated with bacteria in the presence or absence of homogenates of liver prepared from rats pretreated with the enzyme inducer, Aroclor 1254. Enflurane, methoxyflurane, isoflurane, and urines from patients anesthetized with these agents were not mutagenic. Fluroxene, however, was highly mutagenic, and therefore poses a possible hazard for operating room personnel and patients.

Fertility, reproduction and postnatal survival in mice chronically exposed to halothane.

Reproductive studies were performed in Swiss/ICR mice chronically exposed to subanesthetic and anesthetic concentrations of halothane. Male and female mice were treated five or seven days a week for nine weeks prior to mating; exposure of females was continued daily throughout pregnancy. Halothane exposures were 0.025, 0.1, 0.4, 1.2, and 4.0 MAC hours per day. No adverse effect on reproduction was observed at the lowest two exposure levels studied. Exposures to 0.4 MAC hour per day or more were associated with decreased maternal weight gain, fetal fetal length and weight, and early postnatal weight gain. Pregnancy rate, implantation rate, and number of live fetuses per litter were significantly decreased at 1.2 MAC hours per day. The percentage of resorption or fetuses dead in utero was not increased, and postnatal survival of offspring was unaltered. Subsequent matings between untreated females and males exposed to halothane, 1.2 MAC hours per day for 17 weeks, resulted in normal reproductive performance; this suggests that the adverse reproductive changes observed when both males and females were exposed represented a primary effect on females. The least exposure at which effects were seen is approximately 40 times greater than the level of human occupational exposure is unscavenged operating rooms.