Mice homozygous for the c 14c°s albino deletion die as neonates as a result of liver dysfunction. Previous mapping studies have associated this defect with a 310-kb fragment encoding the hepatocyte-specific developmental regulation locus (alf/hsdr-1). The gene encoding fumarylacetoacetate hydrolase (Fah), a metabolic enzyme that catalyzes the last step of tyrosine catabolism, also maps to the same deletion interval. To test whether the neonatal defects found in the albino deletion mutants are attributable to loss of Fah, and not to another gene mapping to the deletion, we have generated Fah mutant mice by gene targeting in embryonic stem cells. Fah-deficient mice die within 12 hr after birth from hypoglycemia and liver dysfunction. In addition, the same pattern of altered liver mRNA expression found in the albino deletion mutants was also found in affected animals. We conclude that the neonatal lethal and liver dysfunction phenotype of the alf/hsdr-1 deletion is entirely attributable to loss of Fah.
The ␣3 subunit of the neuronal nicotinic acetylcholine receptor is widely expressed in autonomic ganglia and in some parts of the brain. The ␣3 subunit can form heteromultimeric ion channels with other ␣ subunits and with 2 and 4 subunits, but its function in vivo is poorly understood. We prepared a null mutation for the ␣3 gene by deletion of exon 5 and found that homozygous (؊͞؊) mice lacked detectable mRNA on Northern blotting. The ؊͞؊ mice survive to birth but have impaired growth and increased mortality before and after weaning. The ؊͞؊ mice have extreme bladder enlargement, dribbling urination, bladder infection, urinary stones, and widely dilated ocular pupils that do not contract in response to light. Detailed histological studies of ؊͞؊ mice revealed no significant abnormalities in brain or peripheral tissues except urinary bladder, where inf lammation was prominent. Ganglion cells and axons were present in bladder and bowel. Bladder strips from ؊͞؊ mice failed to contract in response to 0.1 mM nicotine, but did contract in response to electrical field stimulation or carbamoylcholine. The number of acetylcholine-activated single-channel currents was severely reduced in the neurons of superior cervical ganglia in ؊͞؊ mice with five physiologically distinguishable nicotinic acetylcholine receptor subtypes with different conductance and kinetic properties in wild-type mice, all of which were reduced in ؊͞؊ mice. The findings in the ␣3-null mice suggest that this subunit is an essential component of the nicotinic receptors mediating normal function of the autonomic nervous system. The phenotype in ؊͞؊ mice may be similar to the rare human genetic disorder of megacystismicrocolon-intestinal hypoperistalsis syndrome.The neuronal nicotinic acetylcholine (ACh) receptor (nAChR) gene family consists of eight ␣ subunits (␣2-␣9) and three  subunits (2-4), each containing four membranespanning domains (1-4). Expression studies in Xenopus oocytes have shown that any one of the ␣2, ␣3, or ␣4 subunits in combination with either 2 or 4 can produce functional receptors (2, 4-6). Diverse combinations of subunits occur, and even a single population of neurons can express multiple classes of nAChRs (7-9). The ␣3 subunit is widely expressed in autonomic ganglia and in some parts of the brain in multiple organisms (1, 2, 10-13). Although the role of ␣3-containing nAChRs in synaptic transmission in the central nervous system is not known, presynaptic receptors have been implicated in the modulation of the release of dopamine, norepinephrine, and glutamate (13-16).In the peripheral autonomic nervous system, efferent signals are relayed by both sympathetic and parasympathetic ganglia. The ␣3 subunit is the predominant ␣ gene expressed in these ganglia in the chicken (17). Functional deletion of the ␣3 subunit by antisense oligomers eliminated specific subtypes of channels expressed by chicken sympathetic neurons (8). In rat trigeminal sensory neurons, ␣34 is the principal subtype (18). The ␣3 subunit is expressed...
Indomethacin is a potent agent in the treatment of premature labor, but its use has been limited because of concern about its constrictive effects on the fetal ductus arteriosus. To study these effects we used serial fetal echocardiography in 13 pregnant women in premature labor who received indomethacin according to three different dose schedules, ranging from 100 to 175 mg per day, for a maximum of 72 hours. The gestational ages of the fetuses ranged from 26.5 to 31.0 weeks. The detection of ductal constriction in 7 of the 14 fetuses by echocardiography led to the discontinuation of indomethacin. Three fetuses also had tricuspid regurgitation. There was no statistically significant difference between the mean (+/- SEM) gestational age of the fetuses with ductal constriction and that of those without constriction (29.3 +/- 0.59 and 28.4 +/- 0.52, respectively). There was no relation between serum indomethacin levels in the mothers and ductal constriction. In all seven fetuses affected, ductal constriction had resolved by the time they were restudied 24 hours after the discontinuation of indomethacin. Persistent fetal circulation was not detected in any of the 11 neonates studied after delivery. Indomethacin used to treat premature labor appears to cause transient constriction of the ductus arteriosus in some fetuses, even after short-term use.
To determine the effects of age, feeding regimen, and antenatal glucocorticoids on intestinal permeability, preterm infants (n = 132) were stratified by gestational age and by diet (mothers' own milk versus preterm formula), and assigned randomly to one of four feeding regimens: early-continuous, early-bolus, standard-continuous, and standard-bolus. At 10, 28, and 50 d of age permeability was determined by measuring the ratio of lactulose/ mannitol in the urine after the two sugars were administered enterally for 30 h. The mean (+/-SE) birth weight and gestational age of the infants were 1044 +/- 13 g and 27 +/- 0.1 wk, respectively. Permeability changed as a function of age (p = 0.003). Early feeding was associated with a reduction in permeability at 10 d of age (p = 0.01). Antenatal steroid administration was associated with decreased permeability at 28 d of age (p = 0.017). The feeding of human milk (versus formula) was associated with decreased permeability at 28 d of age (p = 0.02). Continuous versus bolus feeding did not affect permeability.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.