Biomedical subjects
Publications and source records attributed to E J Kelly.
A case of iatrogenic atlantoaxial subluxation after bilateral otoplasty is presented. Cineradiography was required for definitive diagnosis. Bed rest and Halter traction successfully resolved the condition. Great care is required while turning the head during skin preparation, draping, planning, and surgery, especially in young children. A high index of suspicion is necessary when a child develops torticollis after otoplasty.
Synthesis of mouse metallothionein (MT)-I and MT-II is transcriptionally induced by the synthetic glucocorticoid, dexamethasone (DEX) or both in vivo as well as in numerous cell lines. However, the location(s) of a glucocorticoid response element (GRE) has not been described. The observation that a marked MT-I gene, as well as heterologous genes, when placed in the context of 17 kb of flanking sequence from the MT locus, are inducible by DEX and lipopolysaccharide in transgenic mice renewed the search for the GRE. Analysis of a series of deletion constructs from this 17-kb region in cultured cells identified a single 455-bp region that conferred DEX induction on a reporter gene. This 455-bp region contains two GREs that bind to the glucocorticoid receptor as assessed by gel mobility shift. Deletion of this fragment from the 17-kb flanking region eliminates the DEX responsiveness of reporter genes. The two GREs, which are located approximately 1 kb upstream of the MT-II gene and approximately 7 kb upstream of the MT-I gene, are necessary for induction of both genes and can function independently of elements within the proximal promoter region of either gene.
AIMS: To determine whether epidermal growth factor (EGF) or the related transforming growth factor alpha (TGF alpha) may have a role in the developing human stomach; to substantiate the presence of EGF in human liquor in the non-stressed infant and whether EGF in amniotic fluid is maternally or fetally derived. METHODS: The temporal expression and localisation of EGF, TGF alpha, and their receptors during fetal and neonatal life were examined in 20 fetal and five infant stomachs. Simultaneously, samples of amniotic fluid and fetal urine from 10 newborn infants were collected and assayed for EGF by radioimmunoassay. RESULTS: EGF immunoreactivity was not noted in any of the specimens examined. In contrast, TGF alpha immunoreactivity was shown in mucous cells from 18 weeks of gestation onwards. EGF receptor immunoreactivity was seen on superficial mucous cells in gastric mucosa from 18 weeks of gestation onwards. The median concentration of EGF was 30 and 8.5 pg/ml in amniotic fluid and fetal urine, respectively, suggesting that EGF is not produced by the fetus. CONCLUSIONS: This study adds weight to the hypothesis that swallowed EGF, probably produced by the amniotic membranes, and locally produced TGF alpha, may have a role in the growth and maturation of the human stomach.
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OBJECTIVE: To determine an accurate rapid method for determination of blood glucose concentration in cattle under field conditions. DESIGN: Prospective, randomized, controlled trial. ANIMALS: 62 clinically normal Holstein cattle: 34 cows and 28 calves. PROCEDURE: Glucose concentrations in venous blood samples were measured in duplicate using a rapid, dry-slide chemistry technique for determination of blood glucose concentration and a laboratory-based method for determination of plasma glucose concentration. Analyses of variance were used to determine whether the relationship between results of the 2 methods was affected by the status of the animals (cows vs calves) or the PCV of the blood samples. Simple linear regression was performed to determine the correlation between the 2 methods and the slope, intercept, and residual error variance of the relationship between the methods. RESULTS: There as a significant linear relationship between the 2 methods throughout the range of glucose concentrations. Mean difference between results of the 2 methods (results for laboratory-based method - results for rapid method) was 12.95 mg/dl (SD, 7.20 mg/dl). The PCV did not affect the relationship, and there was no difference between results of the 2 methods for cows versus calves. Correlation between means of the duplicative values determined by use of the 2 methods was high (r = 0.9462). CLINICAL IMPLICATIONS: The good correlation between the 2 procedures and the comparable precision estimates (coefficient of variation, 7.17% for laboratory-based method; coefficient of variation, 10.11% for rapid methods) indicates that using the rapid method to measure blood glucose concentration is valid in cows and calves.
Human Menkes disease and the murine Mottled phenotype are X-linked diseases that result from copper deficiency due to mutations in a copper-effluxing ATPase, designated ATP7A. Male mice with the Mottled-Brindled allele (Mo-brJ) accumulate copper in the intestine, fail to export copper to peripheral organs and die a few weeks after birth. Much of the intestinal copper is bound by metallothionein (MT). To determine the function of MT in the presence of Atp7a deficiency, we crossed Mo-brJ females with males that bear a targeted disruption of the Mt1 and Mt2 genes (Mt-/-). On an Mt -/- background, most Mo-brJ males as well as heterozygous Mo-brJ females die before embryonic day 11. The lethality in Mo-brJ females can be explained by preferential inactivation of the paternal X chromosome in extraembryonic tissues and resultant copper toxicity in the absence of MT. In support of this hypothesis, cell lines derived from Mt -/-, Mo-brJ embryos are very sensitive to copper toxicity.
Metallothionein (MT)-bound zinc accumulates when animals are exposed to excess zinc and is depleted under conditions of zinc deficiency, suggesting that MT serves as a means of sequestering excess zinc as well as a zinc reservoir that can be utilized when zinc is deficient. To examine the importance of MT for these processes, mice with null alleles of both MT I and MT II genes were created and the zinc concentration and histological appearance of multiple organs assessed. At birth, the hepatic zinc concentration of these MT-null mice was lower than that of wild-type controls (0.27 +/- 0.02 vs. 0.65 +/- 0.11 micromol zinc/g tissue, P < 0.05). During the next 3 wk of suckling zinc-replete (95 micrograms zinc/g diet) dams, the hepatic zinc concentration of controls fell to 0.42 +/- 0.04 micromol/g but was unchanged in the MT-null mice (0.28 +/- 0.04 micromol/g). The most prominent histological anomaly observed at 3 wk of age was the presence of swollen Bowman's capsules in the kidneys of MT-null mice. When nursing MT-null dams were fed a severely zinc-deficient (1.5 microg/g) diet, kidney development in the MT-null pups was retarded as indicated by the retention of the nephrogenic zone and incomplete tubule development. We suggest that the lack of a hepatic reservoir of zinc jeopardizes the developing kidney in the MT-null mice. In addition to being more sensitive to dietary zinc restriction, MT-null mice are more sensitive to zinc toxicity. When adult mice were challenged with a ramping dose of zinc up to a total of 3700 micromol zinc/kg body weight, MT-null mice had a greater incidence of pancreatic acinar cell degeneration compared with control mice despite accumulating less zinc (2.72 +/- 0.46 vs. 1.23 +/- 0.52 micromol zinc/g pancreas, control and MT-null, respectively, P < 0.05). The results of these experiments suggest that MT I and MT II can protect against both zinc deficiency and zinc toxicity.
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Antibodies to Neospora caninum were detected in 5 (10%) of 52 coyotes from Texas. Antibodies to Toxoplasma gondii were detected in 32 (62%) of 52 samples from these same coyotes. Four (80%) of the 5 coyotes that were seropositive for N. caninum also had antibodies to T. gondii. Nineteen (37%) of the coyotes did not have antibodies to either parasite. Three coyote pups were inoculated with the brains from mice infected with 3 strains of N. caninum originally isolated from dogs. None of the pups developed neosporosis or excreted N. caninum oocysts in their feces. The pups developed anti-N. caninum antibody titers of > or = 1:800 but did not develop antibodies to T. gondii. Results of this study indicate that antibodies to T. gondii are more common than antibodies to N. caninum in coyotes. Additionally, young coyotes appear to be resistant to experimental N. caninum infection.
Transgenic mice that express human metallothionein-III (hMT-III) were generated. Human MT-III mRNA expression was prominent in brain, resulting in a 9-fold elevation of MT-III mRNA in cortex, a 3-5-fold elevation in hippocampus, thalamus, brainstem, and olfactory bulb, and a 1.4-fold elevation in cerebellum. Human MT-III protein was detected biochemically and accounted for a 3.4-fold increase in total brain MT. The concentration of zinc (but not copper) was elevated in those brain regions that expressed the most hMT-III mRNA. The histochemically reactive pool of zinc, as measured by Timm's stain or TS-Q histofluorescence, was not appreciably altered. No changes in brain weight, morphology or histology have been noted; the mice breed normally and appear to have normal behavior.
A new member of the metallothionein (MT) gene family was discovered that lies about 20 kb 5' of the MT-III gene in both mouse and human. The MT-IV proteins are highly conserved in both species and have a glutamate insertion at position 5 relative to the classical MT-I and MT-II proteins. Murine MT-IV mRNA appears to be expressed exclusively in stratified squamous epithelia associated with oral epithelia, esophagus, upper stomach, tail, footpads, and neonatal skin. The MT derived from tongue epithelium contains both zinc and copper. Many of these epithelia develop parakeratosis during zinc deficiency in the rat. In situ hybridization reveals intense labeling of MT-IV mRNA in the differentiating spinous layer of cornified epithelia, whereas MT-I is expressed predominantly in the basal, proliferative layer; thus, there is a switch in MT isoform synthesis during differentiation of these epithelia. We suggest that MT-IV plays a special role in regulating zinc metabolism during the differentiation of stratified epithelia.
We inactivated the mouse metallothionein (MT)-I and MT-II genes in embryonic stem cells and generated mice homozygous for these mutant alleles. These mice were viable and reproduced normally when reared under normal laboratory conditions. They were, however, more susceptible to hepatic poisoning by cadmium. This proves that these widely expressed MTs are not essential for development but that they do protect against cadmium toxicity. These mice provide a means for testing other proposed functions of MT in vivo.
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The polymerase chain reaction (PCR) was used to detect bovine leukemia virus in bovine blood samples. When applied to leucocytes extracted from the blood samples, the standard method of DNA extraction gave good correlation with agar gel immunodiffusion, but a method in which 5 microliters of blood was the starting material was unreliable. Selection of the primers was important, and differences in results were observed when the PCR method was applied to blood samples from different geographic areas. The sensitivity varied from 50% to 90%, depending on the primer set applied to the gag gene of proviral nucleic acid. This variation was based on geographic origin of the cattle, suggesting an influence of viral strain. In some areas, more than 1 primer may needed to optimize results.
MT-III, a brain-specific member of the metallothionein gene family, binds zinc and may facilitate the storage of zinc in neurons. The distribution of MT-III mRNA within the adult brain was determined by solution and in situ hybridization and compared to that of MT-I mRNA. MT-III mRNA is particularly abundant within the cerebral cortex, hippocampus, amygdala, and nuclei at base of the cerebellum. Transgenic mice generated using 11.5 kb of the mouse MT-III 5' flanking region fused to the E. coli lacZ gene express beta-galactosidase in many of the same regions identified by in situ hybridization. MT-III mRNA was present in readily identifiable neurons within the olfactory bulb, hippocampus, and cerebellum, and beta-galactosidase activity was localized to neurons throughout the brain, but not to glia, as determined by costaining with X-Gal and neural- and glia-specific antibodies. There is marked correspondence between the neurons that are rich in MT-III mRNA and those neurons that store zinc in their terminal vesicles. MT-III is found complexed with zinc in vivo and its expression in cultured cells leads to the intracellular accumulation of zinc and enhanced histochemical detection of zinc. These results are discussed in light of the possibility that MT-III may participate in the utilization of zinc as a neuromodulator.
Little is known about the ontogeny of gastric acid secretion in the very preterm infant. In order to study this we recorded intragastric pH continuously for 24 h on 71 occasions in 22 enterally starved preterm infants. Infants ranged from 24 to 29 weeks' gestation and were studied in the first 5 days, and in the third week, of life. As the infants became more mature, both in terms of gestation and postnatal age, there was a decrease in intragastric pH from median (range) 3.7, 2.5 (0.6-3.9) and 1.8 (1.3-2.6) for infants of 24-25, 26-27 and 28-29 weeks' gestation, respectively on the first day of life to 1.8 (1.7-1.9), 2.0 (1.8-2.3) and 1.7 (1.5-2.0) on day 16. All the infants were able to maintain a gastric pH of below 4 from the first day of life. Our data lay to rest the suggestion that the preterm infant is incapable of hydrogen ion secretion. Gastric acid secretion in the newborn preterm infant should allow normal proteolytic activity and the well recognised clinical problems of intragastric bleeding, gastritis or oesophagitis may be attributable to intragastric acid.