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Biomedical subjects

R J Smith

Publications and source records attributed to R J Smith.

At least 289 records · Page 16Linked to original sources
PubMed1994

Angiotensin II as a risk factor for cyclosporin nephrotoxicity in patients with psoriasis.

Abnormalities of the renin-angiotensin system after low-dose cyclosporin (5 mg/kg/day or less) have not been adequately defined in patients with normal kidneys. 27 patients with psoriasis were assessed before starting cyclosporin, after three months of cyclosporin (5 mg/kg/day or less) and then finally three months after finishing cyclosporin. On each occasion plasma renin activity (PRA), aldosterone, angiotensin II and atrial natriuretic peptide (ANP) were measured together with total renal blood flow (RBF), GFR and filtration fraction (FF) following an i.v. bolus injection of Tc-99m DTPA. Significant renal hemodynamic toxicity was defined as > 25% fall in RBF or > 20% fall in GFR. Using these criteria we identified 12 patients with hemodynamic toxicity (Group A) and 15 patients whose GFR and RBF did not fall significantly (Group B). In Group A a significant fall in GFR (p < 0.001) and reduction in renal blood flow (p < 0.04) were associated with significant rises in both ambulant and recumbent angiotensin II (p < 0.0005). PRA, aldosterone and ANP did not significantly alter. GFR partially recovered after withdrawal of cyclosporin although RBF remained significantly lower compared to initial values. In Group B there was no significant change in GFR or RBF although there was a reversible fall in FF (p < 0.02). There were no significant differences in angiotensin II, PRA, aldosterone or ANP. Circulating angiotensin II rises in patients who develop cyclosporin nephrotoxicity and may be responsible for mediating the hemodynamic effects.

Adult↗
PubMed1994

Model-based time extrapolation for quantal response studies.

It is often desired to compare chemicals with respect to toxicity for purposes of priority setting in regulation. Long-term carcinogenicity studies are frequently used as the basic data for such exercises. When the results of these studies for different chemicals are compared, many confounders potentially arise. One confounder is that these studies may have been conducted for different study lengths. In this case, converting the results of these studies to a common "standard" time length would be of interest. We propose an adjustment to modify the results of a study with a particular study length to a standard time length. This adjustment is based on a simple stochastic model for carcinogenicity studies. We illustrate the application of this adjustment with an example of a chemical that has been studied by the National Toxicology Program.

Animals↗
PubMed1994

Arteriovenous fistula formation after punch graft hair transplantation in the frontal region.

A case of arteriovenous fistula formation following punch hair grafting is presented. This is indeed a potential complication of a hair plug transplantation procedure in both recipient and donor sites. Surgical excision of the fistula in the frontal or midline scalp region requires resection of the overlying skin because the involved vessels lie within the subdermal plexus.

Adult↗
PubMed1993

Regulation of proliferation-specific and differentiation-specific genes during senescence of human epidermal keratinocyte and mammary epithelial cells.

The expression of proliferation-associated genes, cdc2 and E2F-1 and squamous-specific genes transglutaminase type I and cornifin were examined in senescing human epidermal keratinocytes. Cultured keratinocytes underwent 34 population doublings before senescing. Senescence in keratinocytes was characterised by reduced thymidine incorporation, a change in morphology and the inability of cells to undergo mitosis. This was accompanied by downregulation of cdc2 and E2F-1 mRNA's. In addition, senescing keratinocytes started to express genes such as cornifin, that are specific for squamous differentiation. These changes were similar to those observed in keratinocytes induced to differentiate with phorbol ester or by confluence. E2F-1, cdc2 and cornifin were similarly altered in senescing human mammary epithelial cells. Our data suggest that events regulating senescence may also be linked to squamous differentiation.

Base Sequence↗
PubMed1993

Evidence for two insulin-like growth factor I receptors with distinct primary structure that are differentially expressed during development.

We have previously presented evidence for two IGF I receptor species in rat skeletal muscle. One form of IGF I receptor is selectively expressed in fetal and early postnatal life, and the second is present in both fetal and adult animals. These two IGF I receptors were shown to have similar tryptic phosphopeptide maps but to differ in beta subunit molecular weight (105,000 for the fetal vs. 95,000 for the adult type receptor). In this study, we have used specific antibodies to investigate the structural relationships between the two IGF I receptors. Anti-IGF I receptor beta subunit antibodies were generated against synthetic peptides corresponding to residues 1284-1293 and 1308-1318 of the cloned human IGF I receptor, and the capacity of these antibodies to interact with the two IGF I receptors was investigated. Both anti-peptide antibodies selectively immunoprecipitated the higher molecular weight fetal receptor and not the adult receptor from rat muscle. Human placenta and muscle were shown to contain two receptors similar to those observed in rat muscle. In human muscle, the anti-peptide antibodies and the human-specific monoclonal alpha subunit antibody alpha-IR3 also selectively immunoprecipitated the fetal type receptor. The presence of a 95,000 M(r) IGF I receptor beta subunit distinct from the insulin receptor beta subunit in human muscle was confirmed by the demonstration of an IGF I sensitive receptor with a beta subunit of this size after insulin receptor immunodepletion. These data strongly support the conclusion that the fetal and adult type IGF I receptors differ in primary structure. The fetal receptor corresponds to the cloned and sequenced IGF I receptor, and the primary structure of the adult type receptor has not yet been established.

Aging↗
PubMed1993

Transmembrane signaling in human polymorphonuclear neutrophils: 15(S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid modulates receptor agonist-triggered cell activation.

15(S)-Hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid (15-HETE) exerted a time- and concentration-dependent inhibition of superoxide anion (O2-) production and exocytosis of both azurophil and specific granule constituents from human polymorphonuclear neutrophils (PMN) stimulated with the receptor-specific agonists, N-formylmethionylleucylphenylalanine (FMLP), platelet-activating factor, and leukotriene B4, but not that elicited by phorbol 12-myristate 13-acetate. 15-HETE did not alter the binding of FMLP to its specific receptors on PMN but, rather, appeared to interfere with a subsequent process in signal transduction. Receptor-coupled production of inositol 1,4,5-trisphosphate (InsP3) and increases in cytosolic free calcium elicited with FMLP, platelet-activating factor, and leukotriene B4 were suppressed by 15-HETE. 15-HETE did not, however, inhibit the mobilization of 45Ca from intracellular stores elicited by the addition of InsP3 to permeabilized PMN. 15-HETE suppressed O2- production and increases in intracellular [Ca2+] induced when cell-surface receptors were bypassed and the PMN were activated directly by the guanine nucleotide-binding protein (G protein) activators aluminum fluoride (AlF4-) and mastoparan. 15-HETE, however, did not perturb all G protein functions because cAMP production in FMLP-activated PMN was essentially unaffected by 15-HETE. These data support the proposition that 15-HETE modulates receptor-triggered activation of PMN either by uncoupling G protein stimulation of phospholipase C or by directly inhibiting phospholipase C, thus inhibiting the InsP3-dependent rise in intracellular [Ca2+] that is prerequisite for PMN responsiveness to receptor agonists.

Aluminum↗
PubMed1993

Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.

Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.

Animals↗
PubMed1993

Fine-needle aspiration biopsy of subcutaneous fat necrosis of the newborn.

This report provides the first description of the fine-needle aspiration biopsy findings in a case of subcutaneous fat necrosis of the newborn. While initial interpretation of the aspirate smears was suspicious for a neoplastic process, subsequent incisional biopsy confirmed the benign nature of the lesion. Review of the cytologic material revealed rare, negatively stained, needle-shaped crystals within histiocytes and multinucleate giant cells. In the appropriate clinical setting, and given a mixture of lymphocytes, histiocytes, and multinucleate giant cells in the aspirate smears, we believe the finding of negatively stained needle-shaped crystals can strongly suggest the diagnosis of subcutaneous fat necrosis of the newborn.

Adipose Tissue↗
PubMed1993

Alteration in intestinal permeability after ileal pouch-anal anastomosis.

PURPOSE: The physiologic changes that occur when the small bowel is used as a reservoir, as in the ileal pouch-anal anastomosis, are poorly understood. Alterations in bowel permeability, which may lead to bacterial translocation that could result in illness or dysfunction of the pouch, may be one such consequence of the pouch procedure. METHODS: Whole-bowel permeability was evaluated in patients with and without the pouch through the use of an orally consumed nonmetabolizable sugar clearance technique. Patients in whom the ileal pouch-anal anastomosis was performed for ulcerative colitis (17 patients) and patients with familial polyposis (7 patients) were compared with normal healthy volunteers (10 patients) and patients with ulcerative colitis with and without curative colectomy and ileostomy (6 and 5 patients, respectively). RESULTS: Measured by this technique, no differences were noted in bowel permeability between the volunteers and patients with ulcerative colitis, even after colectomy and ileostomy (1.7 +/- 0.4 in normal healthy volunteers, 1.8 +/- 0.5 in patients with ulcerative colitis without stoma, and 1.4 +/- 0.2 in patients with ulcerative colitis with ileostomy). The group of patients with an ileal reservoir, however, had a significantly increased index of measured bowel permeability (3.5 +/- 0.5 in patients with ulcerative colitis and 5.1 +/- 0.7 in patients with familial polyposis; P < 0.05 by analysis of variance compared with normal healthy volunteers and patients with ulcerative colitis with or without ileostomy). CONCLUSION: The exact site, cause, and consequence of this possible alteration of bowel permeability are unclear but appear to be related to the presence of the pouch and are not caused by the underlying pathologic diagnosis.

Adenomatous Polyposis Coli↗
PubMed1993

Cloning and characterization of alpha PS1, a novel Drosophila melanogaster integrin.

The Drosophila position-specific integrins (PS integrins or PS antigens) comprise two heterodimeric complexes, alpha PS1 beta PS and alpha PS2 beta PS. With the cloning of alpha PS1 described here, we complete the characterization of the primary structure of the three PS integrin subunits. We have purified the alpha PS1 subunit, obtained peptide sequence and isolated genomic and cDNA clones. The encoded alpha PS1 protein contains the cysteine pattern of the cleaved alpha integrins, three putative metal binding domains and shows the other characteristic features of alpha integrins. Regions of sequence variation indicate that alpha PS1 is distinct from all other alpha chains. The transcript analysis shows that the patterns of both alpha PS1 mRNA and protein expression are the same, suggesting that the gene is controlled transcriptionally. We compare the gene structures of the Drosophila alpha PS1, alpha PS2, the human alpha IIb and alpha X (p150,95) and the C. elegans F54G8.3 integrins. We find several positions and phases of introns conserved which, supported by conservation also in the amino acid sequence, indicates that they all derive from a common ancestral gene.

Amino Acid Sequence↗
PubMed1993

Application of computer-based histomorphometry to the quantitative analysis of methylprednisolone-treated adjuvant arthritis in rats.

Analyses of paw edema and histomorphometry were performed on tibio-talar joints to determine arthritic pathological responses in untreated 28-day adjuvant-induced polyarthritis (AIP) rats, and to determine the drug effect on inhibiting these responses in AIP rats treated with methylprednisolone. Histomorphometric measurements were performed on regions including articular joint space, synovial tissue, articular and epiphyseal cartilage, epiphyseal and metaphyseal bone marrow, and endosteal and periosteal cortical bone surfaces. Analysis of paw edema indicated that paw volume was significantly increased in untreated AIP rats. This increase in paw volume was partially prevented in AIP rats treated with 0.3 mg methylprednisolone/kg per day, and completely prevented in AIP rats treated with the two higher dose levels (1 and 3 mg/kg per day). Histomorphometric analysis of untreated AIP tibio-talar joints showed decreased articular joint space whereas synovial tissue area increased and a minor, but significant, articular cartilage erosion area occurred. Epiphyseal growth cartilage area was decreased. Trabecular bone area in distal tibial epiphyseal and metaphyseal regions was markedly decreased whereas bone marrow area increased involving a large number of macrophages and osteoclasts. Eroded endocortical bone area was increased while cortical bone area decreased. Marked osteophyte proliferation occurred on the periosteal surface. These arthritic pathological changes were inhibited by the treatment of methylprednisolone in a dose-dependent fashion. The animals treated with the highest dose of methylprednisolone complete prevented the development of the AIP-induced pathological changes. These data confirmed qualitative histological evaluation of arthritic changes but did not correlate with the anti-edema effects of methylprednisolone (100% inhibition at 1.0 and 3.0 mg/kg, p.o.). It is suggested that quantitative histomorphometry be used to determine more precisely the AIP rat model and the effects of drugs on different histopathological features in this experimental model of arthritis in preference to paw edema which gives a more limited picture of the arthritic response.

Analysis of Variance↗
PubMed1993

Effects of orthodontics on the facial profile: a comparison of changes during nonextraction and four premolar extraction treatment.

Cephalometric radiographs were used to examine soft tissue profiles of 198 orthodontic patients treated with full fixed appliances without extraction of any permanent teeth. Records were selected at random from five sources: cases treated by a Tweed Foundation instructor using the Tweed technique, patients treated with the Begg appliance, patients treated in one of two different practices with pretorqued, preangulated edgewise appliances, and patients treated in two stages with a functional appliance followed by full fixed edgewise appliances. The criteria for selection of cases and the methods of data collection were designed to allow comparisons with data collected by Drobocky and Smith on patients treated with extraction of four first premolars. Although the mean value of soft tissue changes were smaller in the nonextraction patients, the variability of these changes were generally as great as in the four premolar extraction cases. In addition, the percentage of undesirable facial changes was similar in the extraction and nonextraction samples. The results provide additional evidence that it is simplistic and incorrect to blame undesirable facial esthetics after orthodontic treatment on the extraction of premolars.

Analysis of Variance↗
PubMed1993

Positive selection of human blood cells using improved high gradient magnetic separation filters.

High gradient magnetic separators (HGMS) create magnetic field gradients that can be used to attract much smaller and less magnetic particles than those required for conventional magnetic separation techniques. As a result cells can be labeled with submicron magnetic particles and still be separated using an HGMS filter. Typically, HGMS filters consist of random arrays of wire such as stainless steel wool. Wire elements arranged regularly in a filter should allow more efficient separation of cells. Filters were constructed containing ordered wire arrays composed of 430 series stainless steel wire mesh with wire diameters of 50, 100, or 150 microns. The ability of these filters to separate T cells from peripheral blood mononuclear cell suspensions was tested and found superior to random arrays of 302 series stainless steel wire (Thomas et al, 1992). Target cells recognized by OKT5 monoclonal antibody were cross-linked to dextran-iron particles of approximately 20 nm in diameter. Separation conditions were optimized and after one passage through the filter 88% of the OKT5+ cells were recovered in the enriched fraction with 85% purity (%OKT5+). Multiple passages (3 times) could achieve 99% purity with 68% recovery. Variations in separation flow rate had a large effect on the balance between purity and recovery. Optimum separation efficiencies were achieved only when > 10(8) cells were processed. The primarily cause of nonspecific entrapment of CD8- cells was not nonspecific magnetic labeling of cells but the physical (nonmagnetic) characteristics of the filter/filter chamber.

Adult↗
PubMed1993

Neonatal screening for congenital cytomegalovirus infection by detection of virus in saliva.

A rapid assay for detection of cytomegalovirus (CMV) in saliva was evaluated as a screening method for congenital infection. Samples of saliva were examined by detection of early antigen fluorescent foci (DEAFF) and standard tissue culture (TC). Results were compared with those from urine DEAFF. CMV was detected in saliva from 31 (1.7%) of 1870 newborns, 26 by DEAFF and TC, 1 by DEAFF alone, and 4 by TC alone. Urine DEAFF was positive in 28 of these 31 newborns. The sensitivities of various tests were saliva TC, 96.8%; saliva DEAFF, 87.1%; and urine DEAFF, 90.3%. A change in transport medium for 825 saliva samples resulted in improved sensitivities: saliva TC and saliva DEAFF, 100%; urine DEAFF, 92.3%. Screening saliva of newborns for CMV appears to be at least as sensitive a method for detecting congenital infection as detection of viruria; saliva can be collected with less difficulty and expense than urine.

Cytomegalovirus↗
PubMed1993

Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo.

To test the hypothesis that glucocorticoid-induced insulin resistance might originate from abnormalities in insulin receptor signaling, we investigated the effects of glucocorticoids on in vivo tyrosine phosphorylation of the insulin receptor and the insulin receptor substrate IRS-1 in rat skeletal muscle. Male Sprague-Dawley rats were treated with cortisone (100 mg/kg for 5 d) and compared to pair-fed controls. Cortisone treatment of rats resulted in both hyperglycemia and hyperinsulinemia. Anesthetized animals were injected with 10 U/kg insulin via cardiac puncture and, after 2 min, hindlimb muscles were removed, snap-frozen, and homogenized in SDS. Protein tyrosine phosphorylation was studied by immunoblotting with phosphotyrosine antibody. Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. Cortisone treatment increased the amount of insulin receptor protein by 36%, but decreased the total level of receptor tyrosine phosphorylation (69 +/- 4% of control, P < 0.05). The decreased level of receptor phosphorylation was explained by a reduced number of receptors containing phosphorylated tyrosine residues (64.6 +/- 5% of control, P < 0.05). Glucocorticoid excess decreased skeletal muscle IRS-1 content by 50%, but did not significantly alter the total level of IRS-1 tyrosine phosphorylation. The apparent M(r) of IRS-1 was reduced by approximately 10 kD. Treatment with protein phosphatase-2A reduced IRS-1 M(r) in control but not in glucocorticoid-treated muscle indicating that the lower M(r) likely results from lower phosphoserine and/or phosphothreonine content. To investigate the role of hyperinsulinemia in the glucocorticoid response, rats were made insulin-deficient with streptozotocin (100 mg/kg, i.p.). Subsequent treatment with cortisone for 5 d had no effects on insulin levels, tyrosine phosphorylation of insulin receptors or IRS-1, or the M(r) of IRS-1. In conclusion, glucocorticoid-treated skeletal muscle is characterized by: (a) decreased total tyrosine phosphorylation of insulin receptors as a result of a reduction in the pool of receptors undergoing tyrosine phosphorylation; (b) decreased IRS-1 content and reduced serine and/or threonine phosphorylation of IRS-1. Glucocorticoid-induced hyperinsulinemia appears to be essential for the development of these alterations.

Amino Acid Sequence↗