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PubMed1988

The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.

The study of human hematopoietic cells and the human immune system is hampered by the lack of a suitable experimental model. Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells after engraftment into mice with genetically determined severe combined immunodeficiency. The resultant SCID-hu mice are found to have a transient wave of human CD4+ and CD8+ T cells and human IgG (immunoglobulin G) in the peripheral circulation. The functional status of the human immune system within this mouse model is not yet known.

Animals↗
PubMed2005

Indications for nonoperative management of ureteroceles.

PURPOSE: Ureteroceles have traditionally been managed surgically. We report our indications and outcomes of nonoperative management of ureteroceles in a select cohort. MATERIALS AND METHODS: We identified prospectively for nonoperative management 11 females and 2 males with ureteroceles associated with hydronephrosis or multicystic dysplasia (MCD). Patients presented with either a febrile urinary tract infection (3) or prenatal hydronephrosis (10). All patients were evaluated with renal and bladder ultrasound, voiding cystourethrography and mercaptoacetyltriglycine-3 furosemide renography. Two subgroups were identified, consisting of 10 duplex system upper pole ureteroceles associated with nonobstructed functional systems and 3 ureteroceles associated with a completely nonfunctional single system (2) or duplex (1) kidneys with or without MCD. Median followup was 41 months (range 13 months to 8 years). RESULTS: Of the 13 patients 9 required no surgical intervention. Of these 9 patients 3 had either a nonfunctional upper pole moiety (1) or MCD (2) that involuted, and 6 had good function of the upper pole segments relative to the lower pole without high grade obstruction on furosemide renography. Mean upper pole relative to lower pole differential function as determined by isotope renogram in these 6 patients was 40.8% (range 28% to 65%) and median drainage half-time was 5.3 minutes (4.5 to 19.3). On sonography, hydronephrosis improved in all 6 cases, with 5 (83%) decreasing to grade 0 (3) or I (2). Of these 6 cases of duplex system ureteroceles 5 had associated ipsilateral lower pole reflux of grade III (2) or IV (3). Reflux resolved in all cases. Surgery was necessary for progressive obstruction 1 patient and for breakthrough urinary tract infection in 3. The mean upper pole differential function in the operative group of 24.3% was lower than that of the nonoperative group. The initial median drainage half-time was 12.5 minutes (range 6.9 to 20). There was no significant difference between the nonoperative and operative groups in regard to hydronephrosis grade, reflux grade or ureterocele size. CONCLUSIONS: Furosemide renography can identify a select subgroup of patients with ureteroceles who are candidates for nonoperative management. Ureteroceles with nonobstructed duplex systems have better preservation of renal function and a high rate of natural resolution of hydronephrosis and reflux. Ureteroceles associated with MCD or completely nonfunctioning upper pole moieties may never require surgical management.

Female↗
PubMed1993

Suppression of monocyte function and differential regulation of IL-1 and IL-1ra by IL-4 contribute to resolution of experimental arthritis.

IL-4 has diverse effects on hematopoietic cells, including the ability to suppress certain mononuclear cell functions. To evaluate the effect of IL-4 on the evolution of acute and chronic arthritis, murine recombinant IL-4 was administered systemically to animals receiving an arthropathic dose of group A streptococcal cell wall fragments. Daily treatment with IL-4 had a minimal effect on the acute phase, but significantly suppressed the chronic, destructive phase. By 4 wk after initiation of disease, the articular index of IL-4-treated animals was reduced > 60% (articular index = 4 +/- 0.9) compared with the untreated rats (11.5 +/- 0.48, p < 0.001). A substantial decrease in the influx of inflammatory cells and virtual elimination of pannus and erosions occurred after IL-4 therapy. Associated with the reduced accumulation of mononuclear leukocytes was a decrease in their proinflammatory functions including cytokine production and reactive oxygen intermediate metabolism. These observations are consistent with the selective effects of IL-4 on phagocytic cell function demonstrated in vitro. Furthermore, IL-4 induced gene expression for IL-1ra, a protein that antagonizes the action of IL-1 by binding to the IL-1 receptor without agonist activity. Through an expanding spectrum of effects on monocyte-macrophage phenotypic and functional parameters, IL-4 is emerging as an important inhibitor of cell-mediated immune responses and pathogenic processes.

Animals↗
PubMed1991

cAMP-dependent protein kinase regulates renal epithelial cell properties.

Previous studies have implicated adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) in regulation of both growth and expression of differentiated function in the pig renal epithelial cell, LLC-PK1. To investigate this possible regulatory mechanism, we compared growth behavior, morphology, and appearance of two differentiated functions, Na-hexose symport (SYMP) and gamma-glutamyl transpeptidase (gamma-GT), in the LLC-PK1 line and two PKA-deficient mutants (FIB4 and FIB6). Compared with the wild-type cell line, the mutant lines continued to proliferate at higher population densities and exhibited altered cell morphology, poorer formation of the brush-border structure, and decreased or lack of expression of SYMP and gamma-GT activities. Wild-type and mutant cells exhibit an identical logarithmic growth rate. Both lines form cell-cell junctions and exhibit identical kinetic properties of expressed SYMP activity. These results strongly support the hypothesis that PKA modulates a defined subset of cellular processes, including aspects of growth control and expression of the differentiated phenotype, in this renal epithelial cell line.

1-Methyl-3-isobutylxanthine↗
PubMed1993

CDRK and DRK1 K+ channels have contrasting localizations in sensory systems.

Molecular cloning of mammalian potassium channels has revealed an extensively heterogeneous superfamily of potassium channels derived from four basic subfamilies, Shaker, Shaw, Shal and Shab, each with multiple members. The families were first identified in Drosophila, in which subfamily heterogeneity is derived by alternative splicing, while in mammals mainly distinct genes give rise to channel subtypes. Further diversity of mammalian potassium channels is demonstrated by the identification of some which do not belong to any of the four main subfamilies. Although potassium channels are differentiated into fast-inactivating and delayed rectifier types, differential functions of the many mammalian potassium channels are unclear. Moreover, potassium channels function as homotetramers, though in principle heterotetramers might have a physiological role as is the case with heteromers of neurotransmitter receptor subunits. Insight into differential functions of potassium channels may be provided by their regional and subcellular localizations. In the rat brain in situ hybridization and immunohistochemistry have revealed distinct regional localizations for various subfamilies. In one instance a particular subfamily predominated in cell bodies and another in axons. We demonstrated dramatically different localizations for two members of the Shab subfamily, circumvallate papilla delayed rectifier K+ channel (CDRK) and delayed rectifier potassium channel 1 (DRK1), which in major portions of their sequences display more than 90% amino acid identity. In a number of brain regions they occur in distinct neuronal cell types or subcellular compartments, with CDRK predominantly localized diffusely over soma and in fibers and DRK1 most evident in soma and dendritic process.

Animals↗
PubMed1998

Lower moiety heminephroureterectomy in the duplex refluxing kidney: the accuracy of isotopic scintigraphy in functional assessment.

OBJECTIVE: To determine the accuracy of dimercaptosuccinic acid (DMSA) scintigraphy in assessing the differential function between upper and lower moieties of a refluxing duplex system. PATIENTS AND METHODS: Between 1990 and 1996, 20 patients underwent lower moiety heminephroureterectomy. All patients had their differential renal function assessed by DMSA scintigraphy before and after surgery, the results being assessed by comparing the predicted and actual loss of renal function. RESULTS: The mean (SD, range) function attributed to the scarred lower moiety (predicted loss of function) was 4.3 (4.9, 0-14)%, which compared with an actual mean loss of function of 6.8 (5.1, +4 to -16)%. Thus the mean (SD, range) difference between the predicted and actual loss of renal function was -2.1 (3.2, +4 to -8)%. CONCLUSION: DMSA scintigraphy provides an accurate assessment of the differential renal function between upper and lower moieties in a duplex system. The decision to proceed to lower moiety heminephroureterectomy can be logically based on the information gained from DMSA scintigraphy.

Adolescent↗
PubMed1981

Development of the adrenal cortex in the fetal foal: an ultrastructural study.

The adrenal cortex from twelve fetal foals (gestational ages from 61 to 300 days) was examined by light and electron microscopy. Adrenal glands from three newborn foals were also examined by light microscopy. Between 61 and 100 days of gestation the adrenal cortex became organised into two distinct regions, the zona glomerulosa and zona fasciculata, which grew steadily in thickness until the 300th day. Between 300 days and birth there was a dramatic increase in the width of the zona fasciculata. From 200 days a narrow band of compact cells marked the cortico-medullary border. Though these cells were ultrastructurally indistinguishable from those of the overlying zona fasciculata it seems possible that they may later give rise to the zona reticularis of the adult gland. The cells of the zona glomerulosa were columnar in shape and were tightly packed together into cell clusters. They contained smooth and rough endoplasmic reticulum and mitochondria with lamellar cristae. The ultrastructural characteristics of the cells of the zona glomerulosa changed little throughout the course of gestation. In the zona fasciculata the predominant cell type was angular in profile, and its cytoplasm contained smooth and rough endoplasmic reticulum and mitochondria with lamellar cristae. The second and larger cell type was situated nearer the cortico-medullary border. It contained an abundance of smooth endoplasmic reticulum, mitochondria with lamellar and/or vesicular cristae, and large perinuclear Golgi complexes. These cells, which appeared to be derived from the smaller more angular cells of the zona fasciculata, showed signs of a high level of metabolic and synthetic activity. As gestation progressed the number of functionally differentiated cells increased slowly in a radial direction towards the zona glomerulosa. Indirect evidence from two newborn foals suggests a rapid increase in the functional differentiation of zona fasciculata cells between 300 days and birth.

Adrenal Cortex↗
PubMed1993

Mitogenic and dedifferentiating effect of the K-fgf/hst oncogene on rat thyroid PC clone 3 epithelial cells.

Transfection of rat thyroid differentiated epithelial cells, PC clone 3, with the K-fgf/hst oncogene results in alleviation of thyrotropin dependency for growth and suppression of the differentiated phenotype without the acquisition of the fully transformed phenotype. An autocrine mechanism is responsible for these effects, since the proliferation of PC clone 3 cells, induced by K-FGF-conditioned medium, is blocked by anti-K-FGF-specific antibodies. Moreover, addition of K-FGF-conditioned medium inhibits the thyroid differentiated functions. Also, such other members of the fibroblast growth factor family as basic and acidic fibroblast growth factor are able to induce thyroid cell growth and to block expression of the differentiated functions.

Animals↗
PubMed1997

The epidermal growth factor receptor is not required for tumor necrosis factor-alpha action in normal mammary epithelial cells.

Our laboratory has shown that tumor necrosis factor-alpha (TNF alpha) can regulate normal mammary epithelial cell (MEC) growth, morphogenesis, and, under certain circumstances, functional differentiation in a manner similar to epidermal growth factor (EGF). As TNF alpha has been shown to up-regulate EGF receptor (EGFR) expression and function in other systems, the present studies were undertaken to determine whether TNF alpha action in MEC was indirect through stimulation of the EGFR. An inhibitor of EGFR tyrosine kinase activity, PD158780, failed to block proliferation induced by 40 ng/ml TNF alpha and only partially inhibited growth in response to 2 ng/ml TNF alpha. PD158780 was also unable to suppress the extensive morphological development induced by either TNF alpha concentration. In contrast, the effects of TNF alpha and PD158780 on functional differentiation (i.e. casein accumulation) were time dependent. When measured on day 7 after 48 h of treatment, casein accumulation was unaffected by either concentration of TNF alpha or by PD158780. When assessed on day 21 after 16 days of treatment, however, casein levels were decreased by 40 ng/ml TNF alpha and increased by PD158780. Significantly, this PD158780-induced increase in casein was not observed in MEC that had been treated with both PD158780 and TNF alpha. These results thus suggest that EGFR tyrosine kinase activity is not necessary for TNF alpha action in normal MEC.

Animals↗
PubMed1988

Reciprocal regulation of adult rat hepatocyte growth and functional activities in culture by dimethyl sulfoxide.

Hepatocyte DNA synthesis, initiated by epidermal growth factor (EGF), is reversibly inhibited by 2% dimethyl sulfoxide (DMSO). At that concentration, both the survival of the cells in culture and the expression of differentiated functions are prolonged. DMSO does not affect thymidine uptake or EGF receptor binding. Moreover, EGF receptor binding is maintained at 84% of initial 12 hr binding when cells are cultured for several days in the presence of DMSO, whereas specific receptor binding declines to 49% of initial binding under standard culture conditions without DMSO. Studies of hepatocyte functional activity indicate that, during early culture, total cellular export protein synthesis, specific albumin synthesis, and glycogen synthesis are enhanced in the presence of DMSO. Dexamethasone is required for the effect of DMSO on survival, and although dexamethasone alone enhances hepatocyte DNA synthesis in the presence of EGF, it does not reverse the inhibitory effect of 2% DMSO on DNA replication. The correlation of prolonged survival with growth inhibition supports the hypothesis that hepatic growth and differentiated functional activity may be reciprocally regulated.

Albumins↗
PubMed2002

Granulocyte macrophage colony-stimulating factor-driven respiratory mucosal sensitization induces Th2 differentiation and function independently of interleukin-4.

The development of T helper (Th)2 responses is a key step in the pathogenesis of asthma. Interleukin (IL)-4 is thought to be important, although not strictly necessary, for Th2 differentiation, although triggers of IL-4-independent Th2 polarization have not been identified. We examined whether IL-4 is necessary for Th2-polarized responses during granulocyte macrophage colony-stimulating factor (GM-CSF)-driven respiratory mucosal sensitization. Balb/c wild type (WT) or IL-4 knockout (4KO) mice were exposed to aerosolized ovalbumin (OVA) in the context of airway GM-CSF expression. We examined the extent of Th2 polarization using real-time quantitative polymerase chain reaction on lymph node mRNA, flow cytometric analysis of lung Th cells, and measurement of cells, cytokines, and immunoglobulins in bronchoalveolar lavage (BAL) and serum. GATA-3 and CCR3, -4, and -8 were expressed in the lymph nodes of WT and 4KO mice at similar levels, as were IL-5 and IL-13 levels in the BAL, T1/ST2 on lung Th cells, and BAL eosinophils after recall challenge. With the exception of immunoglobulin production, expression of GATA-3, CCR-3, -4, -8, IL-5, and T1/ST2, and the generation of blood eosinophilia, were intact in mice doubly deficient in both IL-4 and IL-13. We conclude that IL-4 is not required for the generation of Th2-polarized responses in the presence of GM-CSF.

Animals↗
PubMed2006

Differential expression, function and response to inflammatory stimuli of 11beta-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation.

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Expression, activity and function of 11beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11beta-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-alpha or IL-1beta (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-gamma was without effect, and there was no difference in 11beta-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production--a characteristic feature of synovial derived fibroblasts--was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11beta-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗