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Biomedical subjects

A Ryan

Publications and source records attributed to A Ryan.

At least 73 records · Page 4Linked to original sources
PubMed1998

Photosensitivity associated with the Smith-Lemli-Opitz syndrome.

A case of severe photosensitivity in a girl with the Smith-Lemli-Opitz syndrome is reported. Children with this recessively inherited metabolic disorder of cholesterol metabolism present with a variety of congenital abnormalities of the nervous system and internal organs in association with varying degrees of mental retardation. Photosensitivity is a feature which has previously only briefly been mentioned in the literature in association with this syndrome. However, more recently, it has become apparent that photosensitivity is not uncommon among children with the Smith-Lemli-Opitz syndrome, although the nature of the photosensitivity in these patients has remained undefined. Our patient has suffered from sunlight intolerance since early infancy, with redness and pruritus of sun-exposed skin developing within minutes of sun exposure. Monochromator ultraviolet (UV) radiation and visible light testing revealed an immediate and persistent reaction to low-dose UVA at 350 nm, and an abnormal erythemal response to visible light at 400 nm.

Child, Preschool↗
PubMed1998

Treatment changes in Class I and mild Class II malocclusions using the en masse removable appliance.

The aim of this retrospective study was to examine the dental changes which occurred during buccal segment retraction in 39 subjects considered suitable for treatment with headgear to the maxillary dentition. Initially, a removable en masse appliance was fitted to distalize the buccal segments. Once the molar relationship was corrected, fixed appliances were placed for upper arch consolidation and/or alignment. Only five subjects required lower appliance therapy. Twenty-nine individuals had upper second molars extracted as an adjunct to treatment: in the remaining 10 patients these teeth were left in situ. Corresponding lower second molars were extracted in 19 children, whilst 20 pairs of teeth were not removed. Measurements were made at the start of treatment, the completion of buccal segment retraction, and when active treatment was complete. After the first stage, molars and premolars had been retracted nearly 4 mm, whilst the canines showed 2 mm spontaneous distal drift. The inter-molar width had increased by 4 mm and arch perimeter by 5 mm. There was a 5 per cent reduction in crowding. Spontaneous changes were also seen in the lower arch, despite the absence of any therapy. Crowding was slightly improved and inter-molar width increased, apparently as a response to the expansion in the opposing jaw. At the end of treatment, upper arch retraction and expansion were reduced as the teeth were integrated with the lower dentition: the canines required less than 1 mm further retraction. In the lower arch, the expansion of the molars was essentially stable. The extraction of upper second molars did not appear to influence the outcome of treatment. Although slightly more movement appeared to occur in the extraction group, few measurements showed statistical significance.

Adolescent↗
PubMed1998

Tbx genes and limb identity in chick embryo development.

Tbx-2, Tbx-3, Tbx-4 and Tbx-5 chick genes have been isolated and, like the mouse homologues, are expressed in the limb regions. Tbx-2 and Tbx-3 are expressed in anterior and posterior domains in wings and legs, as well as throughout the flank. Of particular interest, however, are Tbx-5, which is expressed in wing and flank but not leg, and Tbx-4, which is expressed very strongly in leg but not wing. Grafts of leg tissue to wing and wing tissue to leg give rise to toe-like or wing-like digits in wing and leg respectively. Expression of Tbx-4 is stable when leg tissue is grafted to wing, and Tbx-5 expression is stable when wing tissue is grafted to leg. Induction of either extra wings or legs from the flank by applying FGF-2 in different positions alters the expression of Tbx-4 and Tbx-5 in such a way that suggests that the amount of Tbx-4 that is expressed in the limb determines the type that will form. The ectopic limb always displays a limb-like Tbx-3 expression. Thus Tbx-4 and Tbx-5 are strong candidates for encoding 'wingness' and 'legness'.

Amino Acid Sequence↗
PubMed1997

Glutathione pretreatment lessens the acute liver injury induced by carbon tetrachloride.

We explored the protective activity of glutathione (GSH) in a rat model of carbon tetrachloride-induced acute liver damage. Histological examination of livers from GSH-pretreated rats revealed minor damage, confirmed by biochemical parameters of liver cell necrosis evaluated both 24 and 48 hr after hepatotoxin delivery. In addition we quantified changes in hepatic steady-state levels of albumin, type I procollagen, transforming growth factor-beta 1 and tumour necrosis factor-alpha mRNAs. Even at the molecular level and above all for the albumin gene, it appears that GSH lessens the effect of the hepatotoxin, however the protection of the thiol is restricted to the first 24 hrs and is almost totally exhausted after 48 hr. Since, only 24 hr after CC14 delivery, GSH abundance determined in erythrocytes and liver is almost equal in the controls and in the GSH injected rats, but significantly higher than in the only intoxicated animals (P < 0.05, intraerythrocyte content), we conclude that the thiol pretreatment exerts an effective but transient protection.

Animals↗
PubMed1997

The use of genomic in situ hybridization (GISH) to show transmission of recombinant chromosomes by a partially fertile bigeneric hybrid, Gasteria lutzii x Aloe aristata (Aloaceae), to its progeny.

Genomic in situ hybridization (GISH) was used to study somatic chromosomes of parental and progeny plants (all 2n=2x=14) of the bigeneric hybrid between Gasteria lutzii and Aloe aristata (Aloaceae), which is partially fertile, a rare occurrence in plants. GISH successfully distinguished between the two parental genomes in the F1 hybrid and revealed numerous genomic recombinations in chromosomes transmitted by the F1 to the back-cross progeny. The results indicate high levels of meiotic compatibility between the parental genomes, even though they differ in size by 20%. Recombination occurred at a frequency that was higher than that expected from the analysis of orcein-stained meiosis in the F1. The discrepancy suggests that terminalization may occur prior to or during metaphase I, reducing the apparent chiasma frequency, or possibly reveals an under-estimation caused by difficulties in resolving closely grouped chiasmata by eye.

Aloe↗
PubMed1997

Rapid testing for the MCAD G583A mutation, by PCR-mediated site directed mutagenesis, in an Australian population of SIDS patients.

Medium Chain Acyl CoA Dehydrogenase (MCAD) deficiency is the most common genetic disorder of fatty acid metabolism and has been reported as a cause of sudden death in infants. We investigated the incidence of a rare MCAD mutation (G583A) in a large population of SIDS patients. A method utilising PCR mediated site directed mutagenesis and restriction enzyme digestion was devised to enable rapid and simple testing of large numbers of samples. The G583A mutation was not detected in 413 SIDS patients tested suggesting the mutation is not an important cause of sudden death in infants. The prevalence of this mutation in the general population was estimated to be between 0 and 0.89%.

Acyl-CoA Dehydrogenase↗
PubMed1996

Altered circadian rhythmicity in the Wocko mouse, a hyperactive transgenic mutant.

Induced changes in the level of daily activity can alter the period of the mammalian circadian clock. In this report, we examined the period of the circadian rhythm of wheel-running activity in a transgenic neurological mouse mutant, Wocko. Wocko mice display a dominant behavioral phenotype that consists of hyperactivity, circling and head tossing. The period of the circadian rhythm of wheel-running activity in constant dark conditions was significantly shorter in mice expressing the Wocko mutation than in their normal littermates. Total activity, monitored by the interruption of an array of infrared beams, was significantly elevated in Wocko mice. These findings support the view that spontaneous exercise can modulate the circadian timekeeping system.

Animals↗
PubMed1996

Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin.

Thrombopoietin (TPO) has recently been cloned and shown to regulate megakaryocyte and platelet production by activating the cytokine receptor c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were generated by gene targeting. TPO-/- mice have a >80% decrease in their platelets and megakaryocytes but have normal levels of all the other hematopoietic cell types. A gene dosage effect observed in heterozygous mice suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bone marrow from TPO-/- mice have decreased numbers of megakaryocyte-committed progenitors as well as lower ploidy in the megakaryocytes that are present. These results demonstrate that TPO alone is the major physiological regulator of both proliferation and differentiation of hematopoietic progenitor cells into mature megakaryocytes but that TPO is not critical to the final step of platelet production.

Animals↗
PubMed1996

Positional cloning of genes involved in the Beckwith-Wiedemann syndrome, hemihypertrophy, and associated childhood tumors.

The Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome that occurs with an incidence of 1:13,700 births. There is a striking incidence of childhood tumors found in BWS patients. Various lines of investigation have localized "imprinted" genes involved in BWS and associated childhood tumors to 11p15. High resolution mapping of 8 rare balanced chromosomal BWS rearrangements enabled us to identify three distinct regions on chromosome 11p15 that might harbor genes involved in the above-mentioned disorders. These results suggest genetic heterogeneity that correlates with the clinical heterogeneity seen in the patients studied. Expressed candidate gene sequences from these regions have been cloned and partly sequenced. These transcripts are either disrupted by or are at least within a few kb of these BWS chromosome breakpoints. So far, zinc-finger sequences and one Kruppel-associated box (KRAB) domain were found in independent candidate genes which are compatible with a regulating function of growth promoting genes. The abundance of expression of these genes varies from low abundant in all adult and fetal tissues tested to detectable on Northern blots of adult tissues. In addition to our 11p15 studies we have analyzed additional chromosome regions, in particular 1p. Cytogenetic, loss of heterozygosity (LOH) and comparative genomic hybridization (CGH) studies have identified 1p35 as a region of interest. A positional cloning effort to identify a balanced 1p35 translocation found in a Wilms tumor has led to the isolation of a YAC, crossing this breakpoint.

Adult↗
PubMed1996

In vivo effects of cardiotrophin-1.

Cardiotrophin-1 (CT-1) is a recently discovered cytokine that was isolated based on its ability to induce cardiac myocyte hypertrophy in vitro. In this study, the effects of chronic administration of CT-1 to mice (0.5 or 2 microg by intraperitoneal injection, twice a day for 14 days) were determined. A dose-dependent increase in both the heart weight and ventricular weight to body ratios was observed in the treated groups. The body weights of the animals were unaffected. These results indicate that CT-1 can induce cardiac hypertrophy in vivo. CT-1 was not specific for the heart, however. It stimulated the growth of the liver, kidney, and spleen, and caused atrophy of the thymus. CT-1 administration also increased the platelet counts by 70%, with no change in mean platelet volume. Red blood cell counts were increased in the treated animals, and there was a concomitant increase in haemoglobin concentration. Thus, CT-1 has a broad spectrum of biological activities in vivo. This observation is consistent with previous in-vitro findings showing that the mRNA for CT-1 is expressed in several tissues, and that CT-1 can function through binding to the leukaemia inhibitory factor (LIF) receptor and signalling through the gp130 pathway.

Animals↗
PubMed1996

Pharmacokinetics, tissue distribution, and expression efficiency of plasmid [33P]DNA following intravenous administration of DNA/cationic lipid complexes in mice: use of a novel radionuclide approach.

The pharmacokinetics, tissue distribution, and efficacy of a systemic gene transfer method were examined in male BALB/c mice (6-8 weeks old) using 33P-labeled plasmid DNA for luciferase. The DNA was delivered via tail vein injection in saline ([33P]DNA) or in a cationic lipid formulation ([33P]DNA/lipid). One group of mice received approximately equal to 1-3 microCi (45 micrograms of DNA) of either formulation, and mice were euthanized at 2 and 20 min, and 1 and 24 h postdose (2 mice/time point). Blood and plasma radioactivity were quantified, and whole body autoradiographic (WBAR) images were obtained from 20-microns whole body sections. A tissue distribution (TD) study was conducted in a second group of mice, which received approximately equal to 4-6 microCi (45-60 micrograms of DNA) of [33P]DNA/lipid. Mice were euthanized at 1.5 h (1 mouse; [33P]DNA/lipid) or 24 h (2 mice/ group), and organ radioactivity and luciferase expression were measured in lung, liver, kidney, spleen thymus, and parotid salivary gland by direct quantitation methods. Microautoradiography (MAR) was performed on a third group of mice (n = 2), which received 3 microCi (45 micrograms of DNA) of [33P]DNA/lipid and were euthanized at 24 h postdose. For WBAR, the [33P]DNA/lipid tissue distribution (% dose equiv/g) at 2 min was lung >> liver > spleen (red pulp) > kidney (cortex); at 24 h the ranking was spleen (red pulp) > liver > lung, kidney (cortex). The [33P]DNA organ distribution observed at 2 min was liver >> spleen (red pulp) > lung, blood > kidney (cortex); at 24 h the ranking was liver, spleen (red pulp) > kidney (cortex) > lung, blood. High levels of radioactivity in bone (cortical, marrow, growth plate) in both groups may represent uptake of the 33P-labeled test articles by the cellular component of the bone marrow, particularly macrophages, as well as deposition of [33P]phosphate in the bone matrix following metabolism of the [33P]DNA. In the luciferase component of the study, no expression was observed in the [33P]DNA group at 24 h. The [33P]- DNA/lip group exhibited expression as early as 1.5 h in the lung; at 24 h, expression was seen in all the organs examined. Microautoradiography of 24-h tissue samples revealed radioactivity in hepatic Kupffer cells, reticuloendothelial system cells in the marginal zone of the spleen, and diffusely along alveolar septae with scattered accumulations in alveolar macrophages. The results of the WBAR, TD, MAR, and luciferase assay show that the use of cationic lipids significantly altered the biodistribution and resulting expression of the DNA plasmid. Further, 33P (0.25 MeV beta, half-life = 25 days) was shown to be an excellent radionuclide for quantitative WBA and MAR, providing sharp images with less personal hazard and greater ease of handling than 32P (1.71 MeV beta, half-life = 14.3 days).

Animals↗
PubMed1996

Automated interstudy image registration technique for SPECT and PET.

UNLABELLED: We report the extended application of an automated computer technique for three-dimensional spatial registration of SPECT and PET studies. METHODS: The technique iteratively reslices a misaligned data set until the sum of the absolute differences (SAD) from a reference data set is minimized. The registration accuracy was assessed in Hoffman brain phantom studies collected with known misalignments and transmission studies of a thorax phantom with fiducial markers. The SAD was compared with three other cost functions: stochastic sign change criterion, sum of products and standard deviation (s.d.) of ratios. In clinical neurological and myocardial perfusion studies, registration accuracy was estimated from the relative locations of landmarks in the reference and registered data sets. RESULTS: Registration accuracy in the Hoffman brain phantom studies was -0.07 +/- 0.46 mm (mean +/- s.d.) for translations and -0.01 +/- 0.20 degrees for rotations, with maximum translation and rotation errors of 1.2 mm and 0.8 degree, respectively. The SAD was the most accurate and reliable cost function. Registration errors in the thorax phantom were 3.1 +/- 1.7 mm. Mean accuracy in the neurological studies, estimated from landmark pairs, was 2.0 +/- 1.1 mm for SPECT to SPECT and 1.8 +/- 1.1 mm for PET to SPECT registrations. Average registration accuracy in 201Tl myocardial perfusion studies was 2.1 +/- 1.2 mm. CONCLUSION: Our registration method (a) provided accurate registrations for phantom and clinical SPECT and PET studies, (b) is fully automated, (c) simplifies comparison of data sets obtained at different times and with different modalities, and (d) can be applied retrospectively.

Algorithms↗
PubMed1996

Transcriptional control of cell phenotypes in the neuroendocrine system.

A fundamental aspect of the development of complex organ systems is a requirement for precise temporal and spatial coordination in the genesis of tissues of distinct embryonic origins, in order to form functional units required for physiological homeostasis and survival. Such a requirement is particularly well exemplified in mammalian development in the formation of the hypothalamic-pituitary axis. Neuronally expressed POU domain factors might exert effects on terminal differentiation events similar to those of Pit-1 in the maturation of anterior pituitary gland cell phenotypes. Neurons comprising the endocrine hypothalamus develop in tandem with their ultimate target, the pituitary gland, and arise from a primordium in which three related class III POU domain factors-Brn-2, Brn-4, and Brn-1-are initially co-expressed. These factors subsequently exhibit stratified patterns of ontogenic expression, correlating with the appearance of distinct neuropeptides that define three major endocrine hypothalamic cell types. Deletion of the Brn-2 genomic locus affects terminal differentiation and/or maintenance of hypothalamic neurosecretory neurons and development of the posterior pituitary gland. Thus, both neuronal and endocrine components of the hypothalamic-pituitary axis are critically dependent upon the action of specific POU domain factors at a penultimate step in the sequential events that underlie the appearance of mature cellular phenotypes.

Amino Acid Sequence↗
PubMed1995

Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis.

The secretion of insulin is controlled by the rate of glucose metabolism in the pancreatic beta cells. As phosphorylation by glucokinase (GLK) appears to be the rate-limiting step for glucose catabolism in beta cells, this enzyme may be the glucose sensor. To test this possibility and to resolve the relative roles of liver and beta cell GLK in maintaining glucose levels, we have generated mice completely deficient in GLK and transgenic mice in which GLK is expressed only in beta cells. In mice with only one GLK allele, blood glucose levels are elevated and insulin secretion is reduced. GLK-deficient mice die perinatally with severe hyperglycemia. Expression of GLK in beta cells in the absence of expression in the liver is sufficient for survival. These mice demonstrate the critical need for beta cell GLK in maintaining normal glucose levels and provide a novel model for one form of noninsulin-dependent diabetes.

Alleles↗