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Biomedical subjects

S Downing

Publications and source records attributed to S Downing.

At least 19 recordsLinked to original sources
PubMed2000

Identification of monozygotic twins that are concordant for preeclampsia.

Preeclampsia is thought to be discordant in monozygotic twins. While recruiting for a genetic study into preeclampsia, we identified 4 sets of twins and a triplet gestation; all were monozygous on deoxyribonucleic acid "fingerprinting." Two twins were concordant for preeclampsia, and 2 of the triplets had pregnancy-induced hypertension, although only 1 of them had proteinuria. Hence we confirm the existence of monozygotic twins that are concordant for preeclampsia.

Diseases in Twins↗
PubMed1999

Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort.

Preeclampsia is a heritable condition that develops as a result of widespread vascular endothelial dysfunction. The thrombotic tendency in this condition has suggested a number of candidate genes, and there have been recent reports of positive association with the Leiden variant of factor V and the thermolabile variant of methylenetetrahydrofolate reductase. We attempted to reproduce these results in a large cohort of well-characterized women with preeclampsia, recruited prospectively within the East Anglian region of the United Kingdom. Women in the preeclampsia cohort (n=283) were genotyped for both the Leiden variant (G1691A) of factor V and the thermolabile variant (C677T) of methylenetetrahydrofolate reductase. Genotype and allele frequencies were compared with those of 2 control groups, one consisting of women recruited prospectively (n=100) from the same maternity hospital as the subjects and another consisting of normotensive women (n=100) from East Anglia. No significant differences were detected. Specifically, the carrier rate for the Leiden variant was 5.3% in the preeclampsia group and 5. 5% in the combined control group. T677 homozygotes for methylenetetrahydrofolate reductase were 11% and 11.5% in the 2 groups, respectively. We conclude that there is no evidence of association of preeclampsia with either of these 2 polymorphisms in our study population.

Base Sequence↗
PubMed1999

Fostering hope in the clinical setting.

Investigators agree that hope is an important coping skill for patients. Hope is stronger than optimism and influences one's physical well being. Suggestions and strategies that can be used in the clinical setting to increase hope begin with an admission of its important role.

Attitude to Health↗
PubMed1998

Biaryl acids: novel non-nucleoside inhibitors of HIV reverse transcriptase types 1 and 2.

A series of biaryl acids has been found to show micromolar inhibition of the HIV reverse transcriptase (RT) from types 1 and 2 with IC50S in the micromolar range. The series was discovered by consideration of the polymerase active site and sub-structure searching of the company compound collection. Synthesis of analogues to investigate the SAR is described. Two of these compounds have shown inhibition of HIV-2 RT only.

Anti-HIV Agents↗
PubMed1992

Factors determining the specificity of signal transduction by guanine nucleotide-binding protein-coupled receptors. I. Coupling of alpha 2-adrenergic receptor subtypes to distinct G-proteins.

alpha 2-Adrenergic receptor (alpha 2-AR) subtypes couple to pertussis toxin (PT)-sensitive G-proteins to elicit both stimulatory and inhibitory cell responses. Signal specificity may be generated by the ability of the receptor subtypes to "recognize" distinct G-proteins with different affinity. To address this issue we stably expressed three alpha 2-AR subtypes, RNG alpha 2 (alpha 2B-AR), RG10 (alpha 2C-AR), and RG20 (alpha 2D-AR), in NIH-3T3 fibroblasts, which express two PT-sensitive G-proteins (Gi alpha 2, Gi alpha 3), and analyzed receptor/G-protein interactions by determining: 1) functional coupling to adenylylcyclase and 2) the ability of the receptors to exist in a high affinity state for agonist. In alpha 2D-AR transfectants expressing 200 or 2,200 fmol of receptor/mg of protein, epinephrine (10 microM) inhibited forskolin-induced elevation of cellular cAMP by 26 +/- 4.8% and 72 +/- 6.2%, respectively. Similar results were obtained in alpha 2B-AR transfectants. However, in alpha 2C-AR transfectants (200 fmol/mg) the forskolin-induced elevation of cellular cAMP was not altered by agonist treatment. In alpha 2C-AR transfectants expressing higher receptor densities (650-1,200 fmol/mg), epinephrine inhibited the effect of forskolin by 30 +/- 3.2%. This difference in functional coupling among the alpha 2-AR subtypes is reflected at the receptor/G-protein interface. In membrane preparations of alpha 2B and alpha 2D-AR but not alpha 2C-AR transfectants, agonist competition curves were biphasic, indicating high and low affinity states of the receptor for agonist. The high affinity state was guanyl-5'-yl imidodiphosphate- and PT-sensitive, indicative of receptor/G-protein coupling. These data suggest that the alpha 2C-AR differs from the alpha 2B and alpha 2D-AR subtypes in its ability to recognize PT-sensitive G-proteins expressed in NIH-3T3 fibroblasts. The alpha 2C-AR may couple preferentially to PT-sensitive G-proteins (Gi1, Go1,2) not expressed in NIH-3T3 fibroblasts and thereby elicit different cellular responses.

3T3 Cells↗
PubMed1991

Isolation of rat genomic clones encoding subtypes of the alpha 2-adrenergic receptor. Identification of a unique receptor subtype.

alpha 2-Adrenergic receptors (alpha 2-AR) exist as subtypes that are expressed in a tissue-specific manner and differ in 1) their ligand recognition properties, 2) their extent of receptor protein glycosylation, and possible 3) their mechanism of signal transduction. Genomic or cDNA clones encoding three receptor subtypes have been characterized; however, both functional and radioligand binding studies in rodents suggest the existence of a fourth receptor subtype. To isolate the rat genes encoding receptor subtypes we screened a rat genomic library with an oligonucleotide probe encompassing the third membrane span of the human C-4 alpha 2-AR. Two intronless rat genes were isolated that encode distinct receptor subtypes (RG10, RG20). RG10 and RG20 encode proteins of 458 and 450 amino acids, respectively, that are 56% homologous and possess the structural features expected of this class of membrane-bound receptors. RG10 identifies a mRNA species of approximately 2500 nucleotides that is found primarily in brain, whereas RG20 identifies a larger mRNA species (approximately 4000 nucleotides) that is found in several tissues including brain, kidney, and salivary gland. RG10 is 88% homologous to the human C-4 alpha 2-AR and exhibits similar binding properties ( [3H]rauwolscine KD = 0.7 +/- 0.3 nM) as determined following transient expression of the receptor in COS-1 cells. RG20 exhibits ligand binding properties distinct from the three receptor subtypes identified by molecular cloning. Saturation binding studies indicate an affinity constant of 15 +/- 1.2 nM for the alpha 2-AR antagonist [3H]rauwolscine, a value 6-20 times higher than that observed for the three cloned receptor subtypes. In competition binding studies the potency order of competing ligands for RG20 is phentolamine greater than idazoxan greater than yohimbine greater than rauwolscine greater than prazosin. Of the three previously cloned alpha 2-AR, RG20 is most closely related to the human C-10 alpha 2-AR (89% homology) and is also capable of mediating adenylylcyclase inhibition as determined following its stable expression in NIH-3T3 fibroblasts. However, in contrast to RG20, [3H] rauwolscine exhibits a KD of 2 nM for the C-10 receptor, and the potency order for competing ligands is rauwolscine greater than or equal to yohimbine greater than idazoxan greater than phentolamine greater than prazosin. RG20 and C-10 are also distinguished by their affinity for SKF-10478 (RG20 Ki = 531 nM, C-10 Ki = 101 nM), a compound that may functionally distinguish pre- and postsynaptic alpha 2-AR. These data suggest that RG20 represents a fourth alpha 2-AR subtype distinct from the known alpha 2A-C receptor subtypes.

Adenylyl Cyclases↗
PubMed1987

Metastatic cancer. A relative contraindication to vena cava filter placement.

From October 1979 to November 1984, 41 patients underwent placement of vena cava filters for prevention of pulmonary emboli. After filter placement, no pulmonary emboli were documented. No patient died due to filter placement. However, 20 of these 41 patients are dead. Eighteen deaths were caused by cancer. Ten (24%) patients died within 2 months of filter placement. Five (12%) patients died prior to hospital discharge. All ten of these patients had known, widely metastatic cancer. Among the ten patients who died more than 2 months after filter placement, six had well-differentiated, slow growing tumors. Only three of these patients had brain metastases. Among the 21 survivors only two suffered from cancer. Strict adherence to accepted indications for vena cava filter placement required operative procedures on a small but significant number of patients who demonstrated no significant improvement in quality of life or time out of hospital. Filter placement in patients with aggressive cancers and proven metastases should be performed only after analysis of predicted survival and after detailed discussions with patients and referring physicians. Filter placement in patients with aggressive metastatic cancer may cause discomfort, risk, and expense with little hope for improvement of hospital course, longevity, or quality of life.

Adult↗
PubMed1987

Valvular obstruction of blood flow through saphenous veins.

To measure effects of vein valves upon blood flow through venous bypass conduits, 15 human saphenous veins (mean length 40.6 cm, 5.3 valves/vein) were perfused with normal saline at constant pressure (100 mm Hg). Flow through vein was measured before and after valve bisection. Vein valves were bisected using Leather's techniques. After valve bisection, flow in antegrade and retrograde directions was measured in seven veins. These data were analyzed using paired t tests. Antegrade flow through seven veins with intact valves averaged 317.1 cc/min. With valve bisection this increased significantly (P less than 0.001) to 474.3 cc/min. Retrograde flow through veins with valves bisected increased significantly (P less than 0.0001) to 428.3 cc/min. Eleven veins (mean length 42.2 cm, 5.6 valves/vein) perfused simulated capillary beds with banked blood using pulsatile flow (mean pressure 92 mm Hg). Flow, again, was measured before and after valve bisection. Data were analyzed using the paired t test. Antegrade flow increased from 124.4 cc/min in veins with valves intact to 142.5 cc/min once valves were bisected (P = 0.02). These data demonstrate that saphenous vein valves cause significant obstruction to blood flow under conditions similar to those in the arterial system. Bisection of vein valves significantly increases flow through vein. Improved patency of vein grafts using valve bisection techniques may be explained by increased blood flow alone.

Blood Flow Velocity↗
PubMed1980

Concepts of function of peripheral non-chromatin and endosome in Entamoeba histolytica.

The distribution of RNA (to a lesser extent DNA) in the nucleus of E. histolytica appeared to be the opposite of what one found in other eukaryotic cells (originally stated by Pan and Geiman in 1955). Autoradiographs of amebae labelled with 3H-thymidine revealed primarily randomly distributed DNA-3H (probably euchromatin) in interphase cells. This DNA was so low in amount in individual cells that it usually did not stain with the Feulgen procedure. A small amount of DNA-3H was also detected by autoradiography in the peripheral chromatin (= rDNA?; occasionally it was abundant) and endosome. Clumps of DNA-3H were also observed around the endosomal area in some amebae. This labelling pattern was not observed in 3H-uridine (for RNA) incorporation experiments. These data were consistent with the possibility that the endosome, which was sometimes Feulgen +, was a site of condensation of DNA prior to nuclear division. As detected by light and electron microscopy autoradiographic analysis of 3H-uridine incorporation, RNA was synthesized (or accumulated) primarily in the peripheral chromatin; lesser amounts were evenly distributed. Most of the peripherally located amebal nuclear RNA was probably rRNA and/or precursor rRNA. If this is the case, it is probable that the peripheral chromatin, although structurally unlike nucleoli, may be "functionally" comparable to nucleoli of eukaryotes.

Chromatin↗