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Biomedical subjects

S A Phillips

Publications and source records attributed to S A Phillips.

At least 19 recordsLinked to original sources
PubMed2001

Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant.

Resistance to thyroid hormone (RTH) is a syndrome in which patients have elevated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-old female presented to the NIH with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain magnetic resonance imaging showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T3 and free T4 levels of more than 2000 pg/dl (normal, 230-420 pg/dl) and more than 64 pmol/liter (normal, 10.3-20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6-6.3 mU/liter). These are the highest TH levels reported for a heterozygous RTH patient. A T3 stimulation test confirmed the diagnosis of RTH in the pituitary and peripheral tissues. Molecular analyses of the patient's genomic DNA by PCR identified a single base deletion in exon 10 of her TRbeta gene that resulted in a frameshift and early stop codon. This, in turn, encoded a truncated receptor that lacked the last 20 amino acids. Cotransfection studies showed that the mutant TR was transcriptionally inactive even in the presence of 10(-6) M T3 and had strong dominant negative activity over the wild-type receptor. It is likely that the severely defective TRbeta mutant contributed to the extreme RTH phenotype and resistance in our patient.

Bone Development↗
PubMed2001

The timing of reduction and stabilisation of the acute, unstable, slipped upper femoral epiphysis.

We reviewed the management of 100 cases of slipped upper femoral epiphysis treated over a period of 26 years. A total of 14 slips was identified as unstable on admission. These underwent reduction and stabilisation within 24 hours of the onset of severe symptoms. Of the 86 stable slips four progressed to avascular necrosis (AVN), which was not seen in the unstable slips. The literature on slipped upper femoral epiphysis suggests that the acute unstable slip is at higher risk of developing AVN. We recommend reduction and stabilisation of unstable slips within 24 hours of the onset of symptoms in order to reduce the risk of AVN.

Acute Disease↗
PubMed2000

Activation of serum- and glucocorticoid-induced protein kinase (Sgk) by cyclic AMP and insulin.

Sgk (serum- and glucocorticoid-induced protein kinase) is a serine/threonine-specific protein kinase that is transcriptionally regulated by serum, glucorticoids, and mineralocorticoids. Sgk regulates the amiloride-sensitive sodium channel in kidney principal cells. Insulin and insulin-like growth factor-1 stimulate activity of Sgk by a mechanism mediated by phosphoinositide-dependent kinases (PDK)-1 and -2. In this study, we demonstrate that incubation of transfected cells with 8-(4-chlorophenylthio)-cAMP (8CPT-cAMP; 0.2 mm) led to a 2-fold activation of recombinant Sgk expressed in COS7 cells. Furthermore, the combination of insulin plus 8CPT-cAMP elicited a larger response than either agent alone. The effect of insulin was inhibited by wortmannin (100 nm), but not by the cyclic AMP-dependent protein kinase (PKA) inhibitor, H89 (10 microm). As expected, the effect of 8CPT-cAMP was completely blocked by H89. Surprisingly, the effect of 8CPT-cAMP was also inhibited by wortmannin, suggesting that phosphorylation of Sgk by PDK-1 and/or -2 is required for activation by 8CPT-cAMP. Mutational analysis led to similar conclusions. The Thr(369) --> Ala mutant, lacking the PKA phosphorylation site, was activated by insulin but not 8CPT-cAMP. In contrast, the Ser(422) --> Ala mutant, lacking a PDK-2 phosphorylation site, was inactive and resistant to activation by either insulin or 8CPT-cAMP. In summary, Sgk is subject to complex regulatory mechanisms. In addition to regulation at the level of gene expression, the enzymatic activity of Sgk is regulated by multiple protein kinases, including PKA, PDK-1, and PDK-2. Cross-talk among these signaling pathways may play an important role in the pathogenesis of the hypertension associated with hyperinsulinemia, obesity, and insulin resistance.

Androstadienes↗
PubMed2000

Identification and characterization of SNX15, a novel sorting nexin involved in protein trafficking.

Sorting nexins are a family of phox homology domain containing proteins that are homologous to yeast proteins involved in protein trafficking. We have identified a novel 342-amino acid residue sorting nexin, SNX15, and a 252-amino acid splice variant, SNX15A. Unlike many sorting nexins, a SNX15 ortholog has not been identified in yeast or Caenorhabditis elegans. By Northern blot analysis, SNX15 mRNA is widely expressed. Although predicted to be a soluble protein, both endogenous and overexpressed SNX15 are found on membranes and in the cytosol. The phox homology domain of SNX15 is required for its membrane association and for association with the platelet-derived growth factor receptor. We did not detect association of SNX15 with receptors for epidermal growth factor or insulin. However, overexpression of SNX15 led to a decrease in the processing of insulin and hepatocyte growth factor receptors to their mature subunits. Immunofluorescence studies showed that SNX15 overexpression resulted in mislocalization of furin, the endoprotease responsible for cleavage of insulin and hepatocyte growth factor receptors. Based on our data and the existing findings with yeast orthologs of other sorting nexins, we propose that overexpression of SNX15 disrupts the normal trafficking of proteins from the plasma membrane to recycling endosomes or the trans-Golgi network.

Amino Acid Sequence↗
PubMed2000

Overexpression of a novel sorting nexin, SNX15, affects endosome morphology and protein trafficking.

Sorting nexin (SNX) 15 is a novel member of the SNX family of proteins. Although the functions of most SNXs have not yet been determined, several family members (e.g., SNX1, SNX2, SNX3, and SNX8) are orthologs of yeast proteins involved in protein trafficking. Overexpression of myc-tagged SNX15 in COS-7 cells altered the morphology of several endosomal compartments. In transient transfection experiments, myc-SNX15 was first seen in small punctate spots and small ring structures. Later, myc-SNX15 was found in larger rings. Finally, myc-SNX15 was observed in large, amorphous membrane-limited structures. These structures contained proteins from lysosomes, late endosomes, early endosomes, and the trans-Golgi network. However, the morphology of the endoplasmic reticulum and Golgi was not affected by overexpression of myc-SNX15. In myc-SNX15-overexpressing cells, the endocytosis of transferrin was severely inhibited and endocytosis of tac-trans-Golgi network (TGN) 38 and tac-furin was slowed. In addition, the recycling of internalized tac-TGN38 and tac-furin was also inhibited. Both the morphological and biochemical data indicate that SNX15 plays a crucial role in trafficking through the endocytic pathway. This is the first demonstration that a mammalian SNX protein is involved in protein trafficking.

Animals↗
PubMed2000

Physical and chemical evidence remaining after the explosion of large improvised bombs. Part 1: firings of ammonium nitrate/sugar and urea nitrate.

Recent criminal acts in the United Kingdom, United States and other countries have demonstrated the dangers to public safety from the criminal use of improvised explosives on a large scale. Four sets of trials were carried out over four years, partly in collaboration with the United States Federal Bureau of Investigation, involving the firing of large bombs, mostly fertilizer based. The principal objectives of the firings were to measure the physical effects of the explosions upon objects representative of those that would be found at a real bomb scene and to recover any chemical traces deposited on these objects. The results are intended for use as an aid in determining the approximate size and type of an explosive employed in a terrorist attack. This paper describes the background behind the trials, the procedures for preparation of witness materials and charges, and the collection and analysis of physical and chemical evidence.

Criminology↗
PubMed1995

All trans retinoic acid enhances human LAK activity.

All trans retinoic acid has various effects on normal and malignant cells. Lymphokine-activated killer (LAK) activity can be derived from T lymphocytes and natural killer cells. This study shows that all trans retinoic acid significantly enhances this activity by increasing production of tumour necrosis factor and gamma interferon, which results in enhanced expression of the p55 part of the interleukin 2 receptor. This effect is dependent on the concentration of all trans retinoic acid and the length of time of culture.

Cells, Cultured↗
PubMed1994

Assessing consumer health information needs in a community hospital.

A study was conducted by the Oakwood Hospital Library in Dearborn, Michigan, to document health information needs and opinions among staff physicians and area health consumers. The study sought to discover which community sources, besides the hospital library, consumers were consulting for health information and how helpful these sources were; what types of health information physicians were providing to patients in their offices; and whether and how physicians and health consumers might differ in their perceptions of health information. Study results, along with suggested opportunities for additional investigation, are presented.

Attitude↗
PubMed1993

Modification of the glyoxalase system in streptozotocin-induced diabetic rats. Effect of the aldose reductase inhibitor Statil.

The glyoxalase system was characterized in tissue (liver, skeletal muscle, kidney cortex and medulla, lens and sciatic nerve) and blood from streptozotocin-induced diabetic rats and normal controls. The effect of the aldose reductase inhibitor, Statil [3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazine-1-yl-acetic acid; ICI 128 436], was also investigated. Glyoxalase I and glyoxalase II activities were decreased in the liver and increased in skeletal muscle of diabetic rats and of Statil-treated diabetic rats, relative to normal controls. The concentration of non-protein sulphydryl (NPSH) was decreased in the liver and lens of diabetic rats, relative to normal controls; Statil prevented these effects. The concentrations of methylglyoxal in the kidney cortex and medulla, lens and blood were increased in diabetic rats, relative to normal controls. Statil prevented these increases except in the kidney cortex. The concentration of D-lactate was increased in the lens and blood of diabetic rats, relative to normal controls, which was partially prevented in blood but not in the lens by Statil. These data suggest that the glyoxalase system is modified in tissues and blood of streptozotocin-induced diabetic rats and some of the modifications may be prevented by Statil. The increased concentrations of methylglyoxal in the kidney, lens and blood, and the decreased concentration of NPSH in the lens may be related to the development of diabetic complications.

Aldehyde Reductase↗
PubMed1993

The assay of S-D-lactoylglutathione in biological systems.

A procedure for the assay of S-D-lactoylglutathione, the physiological intermediate of the glyoxalase system, in biological systems is described, together with sample storage, sample processing, and statistical evaluation. Specimen data are presented. S-D-Lactoylglutathione was assayed by reverse-phase high-performance liquid chromatography (HPLC) with spectrophotometric detection of the thiolester chromophore at 233 nm. The biological sample was deproteinized with perchloric acid and partially purified by strong anion-exchange solid-phase extraction prior to HPLC. The limit of detection was 3.7 nmol, the recovery 49 +/- 4%, and the intra- and interbatch coefficients of variance 0.7 and 12%, respectively. The concentration of S-D-lactoylglutathione in whole blood from normal control human subjects was (mean +/- SD, nmol/ml whole blood) 16.5 +/- 4.4 (n = 8), and from diabetic patients 21.2 +/- 9.2 (n = 25), which is a significant increase (P < 0.05) from normal controls. The assay of S-D-lactoylglutathione is of increasing interest in studies of the elevation of glyoxalase metabolites in diabetes mellitus and in investigations of the antiproliferative activity of S-D-lactoylglutathione.

Animals↗
PubMed1993

The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal.

In Krebs-Ringer phosphate buffer, the rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate was first order with respect to the triose phosphate with rates constant values of 1.94 +/- 0.02 x 10(-5) s-1 (n = 18) and 1.54 +/- 0.02 x 10(-4) s-1 (n = 18) at 37 degrees C, respectively. The rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate in the presence of red blood cell lysate was not significantly different from the non-enzymatic value (P > 0.05). Methylglyoxal formation from glycerone phosphate was increased in the presence of triose phosphate isomerase but this may be due to the faster non-enzymatic formation from the glyceraldehyde 3-phosphate isomerisation product. For red blood cells in vitro, the predicted non-enzymatic rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate may account for the metabolic flux through the glyoxalase system. The reactivity of glycerone phosphate and glyceraldehyde 3-phosphate towards the non-enzymatic formation of methylglyoxal under physiological conditions suggests that methylglyoxal formation is unavoidable from the Embden-Meyerhof pathway.

Dihydroxyacetone Phosphate↗