Precision determination of absolute neutron flux.

A technique for establishing the total neutron rate of a highly-collimated monochromatic cold neutron beam was demonstrated using an alpha-gamma counter. The method involves only the counting of measured rates and is independent of neutron cross sections, decay chain branching ratios, and neutron beam energy. For the measurement, a target of 10B-enriched boron carbide totally absorbed the neutrons in a monochromatic beam, and the rate of absorbed neutrons was determined by counting 478 keV gamma rays from neutron capture on 10B with calibrated high-purity germanium detectors. A second measurement based on Bragg diffraction from a perfect silicon crystal was performed to determine the mean de Broglie wavelength of the beam to a precision of 0.024%. With these measurements, the detection efficiency of a neutron monitor based on neutron absorption on 6Li was determined to an overall uncertainty of 0.058%. We discuss the principle of the alpha-gamma method and present details of how the measurement was performed including the systematic effects. We also describe how this method may be used for applications in neutron dosimetry and metrology, fundamental neutron physics, and neutron cross section measurements.

Improved determination of the neutron lifetime.

The most precise determination of the neutron lifetime using the beam method was completed in 2005 and reported a result of τ(n)=(886.3±1.2[stat]±3.2[syst]) s. The dominant uncertainties were attributed to the absolute determination of the fluence of the neutron beam (2.7 s). The fluence was measured with a neutron monitor that counted the neutron-induced charged particles from absorption in a thin, well-characterized 6Li deposit. The detection efficiency of the monitor was calculated from the areal density of the deposit, the detector solid angle, and the evaluated nuclear data file, ENDF/B-VI 6Li(n,t)4He thermal neutron cross section. In the current work, we measure the detection efficiency of the same monitor used in the neutron lifetime measurement with a second, totally absorbing neutron detector. This direct approach does not rely on the 6Li(n,t)4He cross section or any other nuclear data. The detection efficiency is consistent with the value used in 2005 but is measured with a precision of 0.057%, which represents a fivefold improvement in the uncertainty. We verify the temporal stability of the neutron monitor through ancillary measurements, allowing us to apply the measured neutron monitor efficiency to the lifetime result from the 2005 experiment. The updated lifetime is τ(n)=(887.7±1.2[stat]±1.9[syst]) s.

The Fundamental Neutron Physics Facilities at NIST.

The program in fundamental neutron physics at the National Institute of Standards and Technology (NIST) began nearly two decades ago. The Neutron Interactions and Dosimetry Group currently maintains four neutron beam lines dedicated to studies of fundamental neutron interactions. The neutrons are provided by the NIST Center for Neutron Research, a national user facility for studies that include condensed matter physics, materials science, nuclear chemistry, and biological science. The beam lines for fundamental physics experiments include a high-intensity polychromatic beam, a 0.496 nm monochromatic beam, a 0.89 nm monochromatic beam, and a neutron interferometer and optics facility. This paper discusses some of the parameters of the beam lines along with brief presentations of some of the experiments performed at the facilities.

Measurement of the Neutron Lifetime by Counting Trapped Protons.

We measured the neutron decay lifetime by counting in-beam neutron decay recoil protons trapped in a quasi-Penning trap. The absolute neutron beam fluence was measured by capture in a thin (6)LiF foil detector with known efficiency. The combination of these measurements gives the neutron lifetime: τ n = (886.8 ± 1.2 ± 3.2) s, where the first (second) uncertainty is statistical (systematic) in nature. This is the most precise neutron lifetime determination to date using an in-beam method.

Measurement of the neutron lifetime using a proton trap.

We report a new measurement of the neutron decay lifetime by the absolute counting of in-beam neutrons and their decay protons. Protons were confined in a quasi-Penning trap and counted with a silicon detector. The neutron beam fluence was measured by capture in a thin 6LiF foil detector with known absolute efficiency. The combination of these simultaneous measurements gives the neutron lifetime: tau(n)=(886.8+/-1.2[stat]+/-3.2[syst]) s. The systematic uncertainty is dominated by uncertainties in the mass of the 6LiF deposit and the 6Li(n,t) cross section. This is the most precise measurement of the neutron lifetime to date using an in-beam method.

Operant-self-administration of ethanol in mice prenatally exposed to cocaine.

Prenatal drug exposure may affect postnatal response to the reinforcing effects of a broad array of drugs. This study investigated the effects of prenatal cocaine exposure on operant self-administration of ethanol. Eighteen male, C57BL/6J mice were divided into three groups. The first had been prenatally exposed to 30 mg/kg of cocaine twice per day while the other groups were offspring of mothers which were either pair fed and saline intubated or untreated. Once adults, the mice were trained and subsequently tested for reinforcement from ethanol. The prenatal cocaine group responded less than the two control groups, with the largest decrease during a progressive ratio schedule of reinforcement. There were no differences in responding as a function of ethanol concentrations. These findings suggest that prenatal exposure to cocaine may not affect reinforcement per se, but may decrease motivation, drive state or propensity to work for ethanol.

Ethanol teratogenesis in the C57BL/6J, DBA/2J, and A/J inbred mouse strains.

Research has shown variations in susceptibility to alcohol-related birth defects in humans. Genetic differences are one reason for this variability. This study compared three inbred mouse strains to determine whether they differ in their susceptibilities to ethanol teratogenesis because previous studies have generated conflicting data. Pregnant C57BL/6J (B6), DBA/2J (D2), and A/J (A) dams were intubated intragastrically with either an acute dose of ethanol (5.8 g/kg) or an isocaloric amount of maltose-dextrine on day 9 of pregnancy. Litters were removed on day 18 of pregnancy and examined for gross, soft-tissue, and skeletal malformations. Results showed that ethanol-exposed B6 litters had a higher percentage of digit (19%), kidney (24%), and skeletal (32%, mostly vertebral) malformations than their maltose-exposed controls (7% or below). Prenatal exposure to ethanol increased skeletal (68%, both rib and vertebral) malformations for A litters when compared to their maltose-exposed controls (4%), but did not increase digit or kidney malformations. Ethanol-exposed D2 litters did not differ from maltose-exposed controls. Maternal blood ethanol levels did not differ among the B6, D2, and A strains. These results provide additional evidence suggesting a genetic component to ethanol teratogenesis.

Effects of acute prenatal ethanol administration in a reciprocal cross of C57BL/6J and short-sleep mice: maternal effects and nonmaternal factors.

An animal model was used to see if maternal genetic factors contribute to ethanol-induced fetal malformations. Susceptible C57BL/6J (B6) and resistant Short-Sleep (SS) mice were used in a reciprocal cross-breeding design. This design produced four fetal genotypes: true-bred B6B6 and SSSS liters and hybrid B6SS and SSB6 litters. Dams were intubated with either 5.8 g/kg of ethanol or an isocaloric amount of maltose-dextrin on day 9 of pregnancy. Fetuses were removed on day 18 of pregnancy and assessed for soft tissue and gross malformations. Results show different prenatal treatment effects on malformations depending on the fetal genotype. Mean percentage of total malformations in ethanol-treated groups were 61% (B6B6), 28% (B6SS), 3% (SSB6), and 16% (SSSS), respectively. Litters exposed to maltose-dextrin showed low (< or = 4%) malformation rates regardless of fetal genotype. The difference in teratogenic response between genetically identical hybrid litters (B6SS and SSB6) suggests a maternal genetic contribution to susceptibility. Of the two major types of malformations, forelimb but not kidney malformations showed a pattern characteristic of a maternal genetic effect. It was concluded that maternal genetic effects can be distinguished from fetal genetic effects responsible for ethanol teratogenesis. Genetically based physiological responses to alcohol in the mother may confer varying degrees of risk for prenatal alcohol effects in the child.

Multiple enhancer elements mediate induction of c-fos in vascular smooth muscle cells.

Previous work from this and other laboratories has demonstrated that the vasoconstrictor peptide angiotensin II results in hypertrophy of rat aortic smooth muscle cells that is associated with an increase in transcription of the early growth response gene c-fos. To explore the molecular mechanism responsible for c-fos induction in rat aortic smooth muscle cells, we used a series of reporter constructs linked to the chloramphenicol acetyl transferase gene in transient transfection experiments in rat aortic smooth muscle cells. Constructs containing both the serum response element and cAMP response element exhibited a 20-fold increase in chloramphenicol acetyl transferase activity in response to either serum or angiotensin II, whereas no increase was seen in vehicle-treated cells. Mutations in either the serum response element or cAMP response element alone, which have been demonstrated to inactivate these elements in other cell types, had no effect on chloramphenicol acetyl transferase inducibility. In contrast, if both elements were mutated, inducibility was almost abolished. Electrophoretic mobility shift assays with oligonucleotides corresponding to either serum response element or cAMP response element demonstrated that these oligonucleotides are capable of forming specific complexes with proteins from rat aortic smooth muscle cell nuclear extracts. One of the proteins binding to the serum response element is the previously described serum response factor, since it was supershifted by a monospecific antibody. These studies demonstrate that c-fox induction in smooth muscle occurs by a dual mechanism that can activate transcription via the serum response element or cAMP response element. These elements appear to act equally and independently, involving a distinct set of transacting factors.

Dose-related growth deficits in LS but not SS mice prenatally exposed to alcohol.

Genetically based alcohol sensitivity may influence the severity of alcohol-related birth defects. To examine this question, measures of growth and survival were examined in offspring of the alcohol sensitive Long-Sleep (LS) and alcohol-resistant Short-Sleep (SS) mouse lines following prenatal ethanol exposure. Pregnant LS and SS mice received an ethanol dose of either 6 or 8 g/kg/day from days 7 through 18 of pregnancy. Control groups received a maltose-dextran solution made isocaloric to the 8 g/kg/day dose. Ethanol and maltose-dextrin solutions were administered as split doses, 6 h apart, via gavage. Nonintubated lab chow control groups were also included for both mouse lines. Offspring were fostered at birth to lactating mice of an outbred stock. Pregnancy was longer for ethanol-treated LS dams compared to maltose-dextrin and lab chow LS control groups, whereas pregnancy length for ethanol-treated SS dams was similar to SS controls. Prenatal ethanol exposure resulted in dose-related growth deficits in LS but not in SS litters. Line differences in postnatal growth deficits in response to prenatal alcohol exposure suggest maternal or fetal alcohol sensitivity influence alcohol-related birth defects.

Long-term consequences of prenatal cocaine exposure on biogenic amines in the brains of mice: the role of sex.

Prenatal cocaine exposure leads to multiple abnormalities in the mature offspring. We explored the effects of gestational exposure to cocaine on neurotransmitter systems of adult mice. The subjects were the mature offspring of mice (a) prenatally fed cocaine between gestational day (G) 8 and G19, (b) pair-fed chow and water, or fed chow and water ad libitum. The forebrains of the mature offspring were assayed for monoamines and amino acids. Cocaine exposure particularly affected the dopaminergic system and in a sex-specific manner. In males dopamine concentrations were decreased and dopamine turnover was increased, whereas in females dopamine concentrations were increased and turnover was decreased. Neither norepinephrine, the serotonergic system, nor neuroactive amino acids (or their precursors) were affected by cocaine. Thus, in utero exposure to cocaine produces long-lasting, specific defects in the dopaminergic system.

Disseminated histoplasmosis presenting as urinary tract obstruction in a renal transplant recipient.

Disseminated histoplasmosis occasionally involves the kidney, but the infection usually does not cause either urinary symptoms or a decrease in renal function. We present a case of disseminated histoplasmosis in a renal transplant recipient who presented with urinary obstruction in the allograft from a sloughed renal papilla infected with the fungus. At the same time the patient had chronic meningitis from Histoplasma capsulatum. The literature on renal involvement with histoplasmosis is reviewed.

Comparisons of subcolonies of selectively bred long-sleep and short-sleep mice.

The Albany subcolony of the selectively bred Long- and Short-Sleep mice was directly compared to the original Colorado colony. As expected from the additional selection applied to the Colorado colony, small differences in the selection phenotype, loss of the righting reflex duration following ethanol treatment, were observed in the Short-Sleep line. However, no colony differences existed in three other indices of ethanol effects. Clear line differences in the shape of the locomotor activity dose-response curve, thermoregulatory effects of ethanol, and ethanol elimination rate replicated earlier findings, but these differences were similar in the two colonies. These data argue for stability of the polygenic control system and provide a picture of remarkable similarity of the two sublines, which were separated by more than 30 generations.

Developmental thermoregulatory deficits in prenatal ethanol exposed long- and short-sleep mice.

Sensitivity to alcohol may influence the severity of prenatal alcohol effects. To examine this hypothesis, the ontogeny of thermoregulation was measured in prenatal ethanol exposed offspring of mice selected for differences in alcohol sensitivity. Pregnant long-sleep (LS) and short-sleep (SS) mice were exposed to 3 or 4 g/kg ethanol or an isocaloric amount of maltose-dextrin twice per day from day 7 through 18 of pregnancy. Doses were given six hours apart via gavage. Nonintubated lab chow controls were included for both genotypes. Offspring were fostered at birth to lactating mice of an outbred strain. Offspring temperatures were measured at 0, 60, and 120 min away from the nest on alternating days from 7 through 21 days of age. LS and SS offspring prenatally exposed to the high ethanol dose showed lower temperatures at the 60 and 120 min time points on each day of testing compared to all other treatment groups. Temperatures of offspring prenatally exposed to the low ethanol dose did not differ from controls. These results suggest a relatively steep dose-response curve for thermoregulatory deficits in LS and SS offspring prenatally exposed to alcohol. Genetically-based alcohol sensitivity did not influence the effects of prenatal alcohol exposure on this response.

Alcohol-related birth defects in long- and short-sleep mice: postnatal litter mortality.

Alcohol sensitivity may influence the severity of alcohol-related birth defects (ARBD). To examine this hypothesis, pregnancy outcome and offspring development were examined in alcohol-sensitive Long-Sleep (LS) mice and alcohol-resistant Short-Sleep (SS) mice following prenatal ethanol exposure. Dams were intragastrically intubated twice per day (6 hr apart) with either 4.5 g/kg (20% w/v) ethanol (E) or an isocaloric amount of sucrose (S) on days 7 through 18 of pregnancy. An untreated control group (C) was maintained for each line. Results showed litter mortality at 10 days of age was greater for LS-E litters compared to both LS-S and LS-C litters. Litter mortality for SS-E litters did not differ from either SS-S or SS-C litters. Maternal weight gain, blood ethanol levels, and birth weight deficits were similar for ethanol-exposed LS and SS groups. These results suggest genetically based alcohol sensitivity influences the severity of ARBD.

Maternal genetic effects on ethanol teratogenesis and dominance of relative embryonic resistance to malformations.

Maternal genetic factors and/or fetal genetic factors contribute to variations in response to prenatal alcohol exposure. To assess the contribution of maternal genotype to ethanol teratogenesis, a reciprocal cross study was conducted in an animal model using C57BL/6J (B6) and long-sleep (LS) mice. B6 mice are more susceptible than LS mice to prenatal ethanol-induced malformations but both mouse stocks are susceptible to fetal weight deficits following in utero alcohol exposure. B6 and LS dams were reciprocally mated to B6 or LS males producing four embryonic genotype groups: the true-bred B6B6 and LSLS genotypes, and the genetically similar B6LS and LSB6 genotypes (the F1 genotype). Dams were intubated with either 5.8 g/kg ethanol (E) or an isocaloric amount of sucrose (S) on day 9 of pregnancy. Fetuses were removed on gestation day 18, weighed, and assessed for soft tissue or skeletal malformations. Results showed a greater litter weight deficit and increased total malformation rate in ethanol-exposed F1 litters carried by B6 mothers compared to ethanol-exposed F1 litters carried by LS mothers. This result would be expected only if maternal genetic factors contribute significantly towards susceptibility to ethanol teratogenesis. The influence of the LS mother was to decrease susceptibility to ethanol teratogenesis compared to the B6 mother while the influence of the B6 mother was to increase susceptibility to ethanol teratogenesis compared to the LS mother. The average malformation rate for F1 litters was significantly less than the predicted midparental value. This shows that the F1 genotype exhibited dominance towards resistance to prenatal alcohol effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses to ethanol challenge in long- and short-sleep mice prenatally exposed to alcohol.

Individual sensitivity to alcohol may influence the severity of functional deficits due to prenatal alcohol exposure. To examine this hypothesis, Long-Sleep (LS) and Short-Sleep (SS) mice, selectively bred for differences in ethanol-induced narcosis, were intubated with either 2.9 g/kg ethanol (E) or an isocaloric amount of sucrose (S) twice per day on days 7 through 15 of pregnancy. An untreated control group (C) was maintained for each line. Offspring were fostered to lactating Rockland-Swiss mice at birth. Males and females from each litter were challenged with an acute dose of ethanol (3.8 g/kg) at 30 days of age. Measures of sleep time duration, waking blood ethanol concentrations (BEC), rectal temperatures, heart rate, and ethanol clearance were obtained to examine whether the acute effects of ethanol are altered by prenatal alcohol exposure. Prenatal alcohol exposure did not differentially affect responses to ethanol challenge within either genotype. Ethanol-induced hypothermia, heart-rate depression, and sleep time did differ between genotypes, with LS more affected than SS mice. Ethanol clearance rates were faster for SS than LS mice. These results suggest postnatal pharmacological responses to acute ethanol challenge are not altered by prenatal alcohol exposure in LS and SS mice. Prenatal alcohol-exposed offspring of both mouse genotypes showed lower average heart rate responses than controls, suggesting this measure may be a sensitive indicator of prenatal alcohol effects in mice.

Ethanol teratogenesis in selectivity bred long-sleep and short-sleep mice: a comparison to inbred C57BL/6J mice.

Sensitivity to alcohol may influence the severity of ethanol teratogenesis. To examine this hypothesis, the teratogenic effects of ethanol were compared in Long-Sleep (LS) and Short-Sleep (SS) mice, selectively bred for differences in ethanol-induced narcosis. Inbred C57BL/6J (B6) mice were included to confirm previously reported teratogenic effects using our own treatment regimen and standard assessment technique. Intragastric administration of ethanol (5.8 g/kg) on Days 9 and 10 of pregnancy resulted in growth retardation and an increase in prenatal mortality in LS litters but not in SS litters. Therefore, alcohol sensitivity plays a role in the severity of prenatal alcohol effects. B6 mice showed more ethanol teratogenicity than either LS or SS mice, even though maternal blood ethanol levels were similar across genotypes. This result suggests genetic variations other than alcohol sensitivity also influence ethanol teratogenesis.

Alcohol absorption rate affects hypothermic response in mice: evidence for rapid tolerance.

Three studies were conducted to examine how absorption rate affects rapid tolerance to ethanol-induced hypothermia. Two procedures for administering alcohol were used to vary the rates of ethanol absorption: a 40-min intravenous (IV) infusion and the more rapidly absorbed intraperitoneal (IP) injection. Hypothermic responses of Long-Sleep (LS), Short-Sleep (SS), and DBA/2JIbg (DBA) mice were examined. Although IV ethanol infusions produced similar or higher blood ethanol levels (BELs) compared to IP administration, the degree of hypothermia was significantly greater with the more rapidly absorbed IP administration. It was concluded that the rate at which ethanol increases in the blood influences the degree of hypothermia: the greater the rate of blood ethanol increase, the greater the hypothermic effect. Rapid development of tolerance to ethanol may explain why a slow increase in BEL produces less hypothermia than a rapid increase in BEL. The IV route provides a precise method of drug administration for the study of acute tolerance.

Genetic influences on brain growth restriction induced by development exposure to alcohol.

Genetic factors have been implicated as contributing to the considerable variation in the severity of alcohol-related birth defects in offspring of women who drink heavily during pregnancy. Two animal models of alcohol-related developmental effects incorporated different behavior genetic approaches to examine genetic influences on brain and body growth following alcohol exposure during development. The first, extensively developed in Sprague-Dawley rats, examined the effects of three doses of alcohol administered to two inbred rat strains (MR and M520) via artificial-rearing procedures during the early postnatal brain growth spurt. In both strains, alcohol produced a dose-dependent restriction of brain weight (but not body weight) on postnatal day 10, compared to artificially reared controls. The MR strain was more susceptible to cerebellar growth restriction than the M520 strain, an effect not attributable to strain differences in blood alcohol concentrations. In the second model, pregnant female Long-sleep and Short-sleep mice, selectively bred for differences in initial sensitivity to the hypnotic effects of acute alcohol administration, were intubated with ethanol from gestational days 7-18. Controls included either sucrose or maltose/dextrin intubation controls and non-intubated controls. The LS offspring showed growth deficits and brain weight reductions in adulthood, while the SS offspring were resistant to these detrimental effects of the prenatal alcohol exposure. Thus, differences in either maternal or fetal genotype may contribute to individual differences in the severity of the effects of alcohol exposure during development.