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1.
World J Gastroenterol ; 20(30): 10553-63, 2014 Aug 14.
Article in English | MEDLINE | ID: mdl-25132775

ABSTRACT

AIM: To test the ability of adult-derived human liver stem/progenitor cells (ADHLSC) from large scale cultures to conjugate bilirubin in vitro and in bilirubin conjugation deficient rat. METHODS: ADHLSC from large scale cultures were tested for their phenotype and for their capacity to conjugate bilirubin in vitro after hepatogenic differentiation. In vivo, Gunn rats [uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) deficient animal] were injected with ADHLSC and cryopreserved hepatocytes (positive control). Two, 4, 13 and 27 wk post-transplantation, transplanted Gunn rat bilirubin serum levels were determined by high performance liquid chromatography. Human transplanted cell engraftment was assessed 27 wk post-transplantation using immunohistochemistry and RTqPCR. RESULTS: Large scale culture conditions do not modify ADHLSC phenotype, ADHLSC were able to specifically conjugate bilirubin. ADHLSC were intraportally injected into Gunn rats and blood UCB was measured at different times post-transplantation, infused-Gunn rats exhibited a metabolic effect 3 mo post-transplantation and maintained over a 6 mo period. ADHLSC engraftment into Gunn rat's liver was demonstrated by RTqPCR and immunohistochemistry against albumin and UGT1A1. CONCLUSION: ADHLSC from large scale cultures are efficient in conjugating bilirubin in vitro and in restoring a deficient metabolic function (reducing bilirubin level) in hyperbilirubinemic rats.


Subject(s)
Bilirubin/blood , Hepatocytes/metabolism , Hepatocytes/transplantation , Hypotension, Orthostatic/surgery , Stem Cell Transplantation , Stem Cells/metabolism , Animals , Biomarkers/blood , Cell Differentiation , Cells, Cultured , Child , Disease Models, Animal , Down-Regulation , Glucuronosyltransferase/deficiency , Glucuronosyltransferase/genetics , Glucuronosyltransferase/metabolism , Hepatocytes/enzymology , Humans , Hypotension, Orthostatic/blood , Hypotension, Orthostatic/diagnosis , Hypotension, Orthostatic/enzymology , Hypotension, Orthostatic/genetics , Male , Phenotype , Rats, Gunn , Serum Albumin/metabolism , Stem Cells/enzymology , Time Factors
2.
Am J Med Genet A ; 152A(3): 732-6, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20186791

ABSTRACT

Dopamine beta-hydroxylase (DBH) deficiency is characterized by a lack of sympathetic noradrenergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function. The diagnosis of DBH deficiency is based on clinical findings, biochemical studies, and sequencing of DBH gene. We report here the characterization of a mosaic cytogenetic abnormality detected by array-CGH in a 16-year-old female with primary DBH deficiency together with dysmorphic features. These features could not be explained by DBH deficiency leading to further investigation. Karyotype was reported normal (46,XX), while a targeted genomic array-CGH revealed a mosaic loss for a segment of at least 1 Mb across 11p13. This segmental loss included the PAX6 and WT1 genes within the WAGR syndrome critical region. Interestingly, the derivative chromosome 11 was observed only in about 28% of cells analyzed. Utilizing a genome-wide oligonucleotide-based array, the deletion segment was estimated to encompass a segment of approximately 10 Mb. Mosaic deletions of 11p13 in WAGR are extremely uncommon. In this case it is distinctly possible that the patient's bilateral iris colobomata might be a manifestation, albeit abbreviated, of the haploinsufficiency for PAX6. This case highlights the importance of cytogenetic analysis when a mutation alone cannot account for the complete phenotype. It also emphasizes the enhanced ability of high-resolution array-CGH techniques in accurately detecting subtle rearrangements in a mosaic form. Finally, it demonstrates the possible phenotypic effects of low-level PAX6 haploinsufficiency in a dosage-sensitive manner.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 11/genetics , Dopamine beta-Hydroxylase/deficiency , Mosaicism , Abnormalities, Multiple/genetics , Adolescent , Coloboma/genetics , Comparative Genomic Hybridization , Eye Proteins/genetics , Female , Gene Dosage , Genes, Wilms Tumor , Homeodomain Proteins/genetics , Humans , Hypotension, Orthostatic/enzymology , Hypotension, Orthostatic/genetics , In Situ Hybridization, Fluorescence , PAX6 Transcription Factor , Paired Box Transcription Factors/genetics , Repressor Proteins/genetics
3.
Physiol Meas ; 28(2): 199-211, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17237591

ABSTRACT

We have previously used a continuous four-wavelength near-infrared spectrometer to measure changes in the cerebral concentrations of oxy-haemoglobin (Delta[HbO(2)] and deoxy-haemoglobin (Delta[HHb]) during head-up tilt in patients with primary autonomic failure. The measured changes in light attenuation also allow calculation of changes in the concentration of oxidized cytochrome-c-oxidase (Delta[(ox)CCO]), and this paper analyses the Delta[(ox)CCO] during the severe episodes of orthostatic hypotension produced by this experimental protocol. We studied 12 patients during a passive change in position from supine to a 60 degrees head-up tilt. The challenge caused a reduction in mean blood pressure of 59.93 (+/-26.12) mmHg (Mean (+/-SD), p < 0.0001), which was associated with a reduction in the total concentration of haemoglobin (Delta[HbT] = Delta[HbO(2)] + Delta[HHb]) of 5.02 (+/-3.81) microM (p < 0.0001) and a reduction in the haemoglobin difference concentration (Delta[Hb(diff)] = Delta[HbO(2)] - Delta[HHb]) of 14.4 (+/-6.73) microM (p < 0.0001). We observed a wide range of responses in Delta[(ox)CCO]. Six patients demonstrated a drop in Delta[(ox)CCO] (0.17 +/- 0.15 microM); four patients demonstrated no change (0.01 +/- 0.12 microM) and two patients showed an increase in Delta[(ox)CCO] (0.21 +/- 0.01 microM). Investigation of the association between the changes in concentrations of haemoglobin species and the Delta[(ox)CCO] for each patient show a range of relationships. This suggests that a simple mechanism for crosstalk, which might produce artefactual changes in [(ox)CCO], is not present between the haemoglobin and the (ox)CCO NIRS signals. Further investigation is required to determine the clinical significance of the changes in [(ox)CCO].


Subject(s)
Brain/enzymology , Electron Transport Complex IV/chemistry , Hypotension, Orthostatic/enzymology , Adult , Aged , Algorithms , Blood Pressure/physiology , Data Interpretation, Statistical , Female , Hemoglobins/metabolism , Humans , Male , Middle Aged , Oxidation-Reduction , Oxyhemoglobins/metabolism , Spectroscopy, Near-Infrared , Supine Position/physiology
5.
Article in English | MEDLINE | ID: mdl-12144872

ABSTRACT

Cardiovascular deconditioning, sometimes manifested in astronauts during standing postflight, may be related to the impairment of autonomic function and/or excessive production of endothelium-dependent relaxing factors. In the present study, we examined the cardiovascular responses to 7-day 30 degrees tail-suspension and a subsequent 6-h post-suspension period in conscious male Sprague-Dawley rats to determine the role of prostacyclin in the observed post-suspension reduction in mean arterial pressure (MAP). The specific prostacyclin synthase inhibitor U-51605 (0.3 mg/kg), or saline, was administered intravenously prior to release from suspension and at 2 and 4 h post-suspension. During 7 days of suspension, MAP did not change, however, there was a post-suspension reduction in MAP which was associated with significant increases in plasma prostacyclin and nitric oxide. U-51605 attenuated the observed post-suspension hypotension and reduced plasma prostacyclin levels, but not nitric oxide levels. The baroreflex sensitivity for heart rate was modified by U-51605: increased MAP threshold and effective MAP range. Thus, the post-suspension reduction in mean arterial pressure may be due to overproduction of prostacyclin and/or other endothelium-dependent relaxing factors and alteration in baroreflex activity.


Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Hypotension, Orthostatic/prevention & control , Intramolecular Oxidoreductases/antagonists & inhibitors , Prostaglandins H/pharmacology , Animals , Baroreflex/drug effects , Baroreflex/physiology , Blood Pressure/drug effects , Blood Pressure/physiology , Cardiovascular Deconditioning , Cytochrome P-450 Enzyme System , Dose-Response Relationship, Drug , Eicosanoids/blood , Head-Down Tilt , Heart Rate/drug effects , Heart Rate/physiology , Hindlimb Suspension , Hypotension, Orthostatic/drug therapy , Hypotension, Orthostatic/enzymology , Hypotension, Orthostatic/etiology , Male , Nitric Oxide/blood , Rats , Rats, Sprague-Dawley , Time Factors , Weightlessness Simulation/adverse effects
6.
Ann Neurol ; 4(1): 6-17, 1978 Jul.
Article in English | MEDLINE | ID: mdl-211929

ABSTRACT

The role of transsynaptic dysfunction in the pathogenesis of idiopathic orthostatic hypotension (IOH, or idiopathic autonomic insufficiency) was examined microscopically and biochemically in autopsy specimens. Light microscopy of the sympathetic ganglia showed abnormalities in all 4 IOH patients, including focal phagocytosis of neurons, increased numbers of satellite cells, and perivascular lymphocytic infiltrates. Electron microscopy revealed proliferation and hypertrophy of satellite cells and abnormalities in the unmyelinated axons. In contrast, the spinal cord intermediolateral columns, containing the presynaptic neurons, were unremarkable in 1 patient, exhibited only mild gliosis in another, and showed neuron loss and fibrillary gliosis in 2 patients. Postsynaptic dopamine-beta-hydroxylase (DBH) activity was decreased at least fourfold (p less than 0.02) in sympathetic ganglia of patients with IOH, while tyrosine hydroxylase (T-OH) was normal. Ganglion choline acetyltransferase (ChAc) activity, an index of presynaptic function and integrity, was normal in the IOH group. A number of our observations suggest that presynaptic disease is not an absolute requirement for adrenergic abnormalities in IOH. The intermediolateral columns of the spinal cord were histologically normal in 2 of the patients with IOH, and ultrastructural abnormalities in sympathetic ganglia were consistent with primary adrenergic degeneration. In addition, presynaptic ChAc activity was normal in IOH ganglia, whereas postsynaptic DBH activity was depressed. Finally, postsynaptic T-OH activity, which is regulated by transsynaptic mechanisms, was normal in IOH ganglia.


Subject(s)
Ganglia, Autonomic/enzymology , Hypotension, Orthostatic/enzymology , Adrenergic Fibers/physiopathology , Adult , Aged , Animals , Brain/ultrastructure , Choline O-Acetyltransferase/metabolism , Dopamine beta-Hydroxylase/metabolism , Female , Ganglia, Autonomic/ultrastructure , Humans , Hypotension, Orthostatic/pathology , Male , Microscopy, Electron , Middle Aged , Rats , Receptors, Neurotransmitter/physiopathology
7.
Arch Phys Med Rehabil ; 59(5): 212-6, 1978 May.
Article in English | MEDLINE | ID: mdl-655832

ABSTRACT

To determine whether orthostatic hypotension in patients with cervical spinal cord lesions is the result of impaired sympathetic nerve response and/or impaired renin release, serum dopamine-beta-hydroxylase (DbetaH) activity and plasma renin activity (PRA) were examined during passive tilting in 6 quadriplegic patients and in 6 able-bodied control subjects. Serum DbetaH was measured by an isotopic enzymatic method and PRA by radioimmunoassay. Following head-up tilting, quadriplegic subjects demonstrated a prompt, significant decrease in mean arterial pressure (MAP) and increase in heart rate (HR). DbetaH and PRA both increased significantly 15 minutes after tilt. In normal subjects, although HR increased, MAP was unchanged; DbetaH and PRA did not increase significantly during head-up tilt. The finding of increased DbetaH during tilt hypotension in quadriplegic patients provides evidence that reflex sympathetic nerve stimulation persists despite cervical cord transection. Increased PRA may be attributed to decreased renal perfusion pressure and increased sympathetic stimulation during tilt hypotension. These data suggest that orthostatic hypotension in quadriplegia patients cannot be attributed solely to failure of the sympathetic nervous system or the renin-angiotensin system to respond to the stimulus of orthostasis.


Subject(s)
Dopamine beta-Hydroxylase/blood , Hypotension, Orthostatic/blood , Quadriplegia/physiopathology , Renin/blood , Adolescent , Adult , Humans , Hypotension, Orthostatic/enzymology , Male , Quadriplegia/blood , Quadriplegia/enzymology
10.
Science ; 192(4242): 910-2, 1976 May 28.
Article in English | MEDLINE | ID: mdl-5774

ABSTRACT

Discrete brain areas and sympathetic ganglia obtained at autopsy from patients with idiopathic orthostatic hypotension were assayed for tyrosine hydroxylase and dopamine beta-hydroxylase. Dopamine beta-hydroxylase activity was decreased 7.5-fold in sympathetic ganglia, while tyrosine hydroxylase activity was reduced more than 50-fold in the pontine nucleus locus coeruleus. These observations indicate that noradrenergic neurons of both brain and ganglion are affected in idiopathic orthostatic hypotension, but suggest that the central and peripheral biochemical deficits differ.


Subject(s)
Dopamine beta-Hydroxylase/metabolism , Hypotension, Orthostatic/enzymology , Nerve Degeneration , Tyrosine 3-Monooxygenase/metabolism , Aged , Brain/enzymology , Caudate Nucleus/enzymology , Cerebral Ventricles/enzymology , Cerebral Ventricles/pathology , Female , Ganglia, Autonomic/enzymology , Ganglia, Autonomic/pathology , Humans , Hypotension, Orthostatic/pathology , Male , Middle Aged , Nervous System Diseases/enzymology , Substantia Nigra/enzymology , Syndrome
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