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Biomedical subjects

J A Oliver

Publications and source records attributed to J A Oliver.

At least 37 records · Page 2Linked to original sources
PubMed1998

Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.

Thromboxane A2 (TXA2) is a labile metabolite of arachidonic acid that has potent biological effects. Its actions are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated in the pathogenesis of cardiovascular diseases. To investigate the physiological functions of TP receptors, we generated TP receptor-deficient mice by gene targeting. Tp-/- animals reproduce and survive in expected numbers, and their major organ systems are normal. Thromboxane agonist binding cannot be detected in tissues from Tp-/- mice. Bleeding times are prolonged in Tp-/- mice and their platelets do not aggregate after exposure to TXA2 agonists. Aggregation responses after collagen stimulation are also delayed, although ADP-stimulated aggregation is normal. Infusion of the TP receptor agonist U-46619 causes transient increases in blood pressure followed by cardiovascular collapse in wild-type mice, but U-46619 caused no hemodynamic effect in Tp-/- mice. Tp-/- mice are also resistant to arachidonic acid-induced shock, although arachidonic acid signifi-cantly reduced blood pressure in Tp-/- mice. In summary, Tp-/- mice have a mild bleeding disorder and altered vascular responses to TXA2 and arachidonic acid. Our studies suggest that most of the recognized functions of TXA2 are mediated by the single known Tp gene locus.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

An endothelial growth factor involved in rat renal development.

In the kidney, there is a close and intricate association between epithelial and endothelial cells, suggesting that a complex reciprocal interaction may exist between these two cell types during renal ontogeny. Thus, we examined whether metanephrogenic mesenchymal cells secrete endothelial mitogens. With an endothelial mitogenic assay and sequential chromatography of the proteins in the media conditioned by a cell line of rat metanephrogenic mesenchymal cells (7.1.1 cells), we isolated a protein whose amino acid analysis identified it as hepatoma-derived growth factor (HDGF). Media conditioned with Cos-7 cell transfected with HDGF cDNA stimulated endothelial DNA synthesis. With immunoaffinity purified antipeptide antibodies, we found that HDGF was widely distributed in the renal anlage at early stages of development but soon concentrated at sites of active morphogenesis and, except for some renal tubules, disappeared from the adult kidney. From a 7.1.1 cells cDNA library, a clone of most of the translatable region of HDGF was obtained and used to synthesize digoxigenin-labeled riboprobes. In situ hybridization showed that during kidney development mRNA for HDGF was most abundant at sites of nephron morphogenesis and in ureteric bud cells while in the adult kidney transcripts disappeared except for a small population of distal tubules. Thus, HDGF is an endothelial mitogen that is present in embryonic kidney, and its expression is synchronous with nephrogenesis.

Amino Acid Sequence↗
PubMed1998

Renin inhibits the vasorelaxation induced by nitroso albumin.

Nitrosated proteins exhibit actions characteristic of free NO. As the vasorelaxation effect of nitrosated albumin is rapidly inactivated in plasma, we postulated that a protease could remove or modify the NO attached to albumin. We found that the ability of plasma to inactivate the vasorelaxing action of NO-bovine serum albumin (NO-BSA) is restricted to a plasma fraction containing macromolecules. We also found that a crude preparation of renal renin also inactivated the vasorelaxation action of NO-BSA and UV-spectrophotometric analysis showed that the 335-nm signal of NO-BSA was significantly decreased by renin. This decrease could be prevented by a renin inhibitor or by immunodepleting the renin preparation with a monoclonal antibody to renin. The data suggest that renin accelerates the uncoupling of NO to albumin. Such a function may be important in the control of vascular tone and blood pressure.

Animals↗
PubMed1998

Pseudotumor cerebri: an unusual complication of brachiocephalic vein thrombosis associated with hemodialysis catheters.

We report a case of pseudotumor cerebri (PC) in a maintenance hemodialysis patient that was associated with thrombosis of the right and left brachiocephalic veins caused by repeated subclavian and jugular vein catheterizations. Symptoms and signs of PC appeared when a right forearm Gortex graft was inserted. PC secondary to intracranial venous outflow obstruction is an important diagnostic consideration for hemodialysis patients with headache, visual disturbance, and papilledema.

Aged↗
PubMed1998

Left ventricular mass and diastolic function in normotensive young adults with autosomal dominant polycystic kidney disease.

Left ventricular hypertrophy is often found very early in the course of autosomal dominant polycystic kidney disease (ADPKD). Diastolic dysfunction has been shown in hypertensive adult patients with ADPKD with increased left ventricular mass (LVM), but there are no data about diastolic function in the young ADPKD population without hypertension and with normal renal function. To evaluate very early alterations in cardiac structure and diastolic function in young normotensive patients with ADPKD, color Doppler echocardiography was performed in 46 young normotensive patients with ADPKD and 35 healthy subjects. LVM, transmitral pulsed Doppler flow (diastolic function), and valvular abnormalities were studied. Patients with ADPKD showed higher LVM indices (LVMIs) than controls (89.7+/-17.3 v 68.5+/-17.2 g/m2; P < 0.0001). Peak early diastolic velocity (E wave) deceleration time and isovolumic relaxation time were significantly prolonged in patients with ADPKD compared with controls (E wave deceleration time, 182.5+/-51.3 v 149.4+/-34 msec; P=0.002; isovolumic relaxation time, 97.7+/-17.5 v 79+/-15 msec; P=0.0001). No differences were found in valvular abnormalities in the two groups. In conclusion, young normotensive patients with ADPKD showed increased LVMIs and Doppler abnormalities consistent with early diastolic dysfunction.

Adolescent↗
PubMed1998

Newer concepts of blood coagulation.

In this report we describe an in vitro model of blood coagulation reactions that mimics as closely as possible the in vivo condition. Our model indicates that the tissue factor-factor VIIa complex initiates coagulation by activating small amounts of both factor IX and factor X in the environment of the tissue factor bearing cell. Factor Xa and factor IXa formed in the initial reaction then play very distinct roles in the subsequent interactions of the clotting mechanism leading to a burst of thrombin generation on the platelet surface. Our results also indicate that factor XI can be activated by thrombin in the absence of factor XII and that the function of factor XI is simply to enhance conversion of factor IX to factor IXa resulting in enhanced thrombin generation on the platelet surface.

Animals↗
PubMed1998

Microalbuminuria in normotensive patients with autosomal-dominant polycystic kidney disease.

Microalbuminuria (MA) is present in hypertensive autosomal-dominant polycystic kidney disease (ADPKD) patients, but has not been reported in normotensive ADPKD patients. We examined the prevalence of MA and the effect of different determinants on urinary albumin excretion in a group of 42 normotensive ADPKD patients. Metabolic parameters, plasma renin activity and aldosterone and serum angiotensin-converting enzyme (ACE) activity were determined. A 24-h urine sample two or three times over a 6-month period was collected to evaluate MA. Each patient underwent an echocardiography to measure left ventricular mass. Eight patients (19%) showed MA (61.6 mg/day, range 37-164), whereas 34 patients (81%) were normoalbuminuric (8.8 mg/day, range 2-29). The groups were matched for all possible confounding variables, but microalbuminuric patients showed a tendency towards greater systolic blood pressure, plasma renin activity and left ventricular mass. There was no correlation between MA and age, sex, body mass index, systolic or diastolic blood pressure, plasma renin activity, serum ACE levels or left ventricular index. The present study demonstrates a high prevalence of MA in normotensive ADPKD patients. MA may be a predictor of early renal and vascular damage in these patients.

Adult↗
PubMed1998

Recovery of minimal change nephrotic syndrome and acute renal failure in a patient withRenal cell carcinoma.

We describe a 78-year-old patient with nephrotic syndrome due to minimal-change glomerulopathy, associated with a renal adenocarcinoma. Oliguric acute renal failure requiring hemodialysis was also observed. Surgical removal of the tumor and corticosteroid therapy resulted in resolution of the nephrotic state and improvement of the renal function. Nephrotic syndrome is an unusual complication of renal cell carcinomas, and the association of minimal-change glomerulopathy (MCG) and solid tumors is particularly uncommon. In spite of this, MCG should be considered in the nephropathies causing nephrotic syndrome and acute renal failure in patients with renal malignancies.

Acute Kidney Injury↗
PubMed1998

Cloning, expression, and characterization of mouse tissue factor pathway inhibitor (TFPI).

Tissue factor pathway inhibitor (TFPI) acts to regulate the initiation of coagulation by first inhibiting factor Xa. The complex of factor Xa/TFPI then inhibits the factor VIIa/tissue factor complex. The cDNA sequences of TFPI from several different species have been previously reported. A high level of similarity is present among TFPIs at the molecular level (DNA and protein sequences) as well as in biochemical function (inhibition of factor Xa, VIIa/tissue factor). In this report, we used a PCR-based screening method to clone cDNA for full length TFPI from a mouse macrophage cDNA library. Both cDNA and predicted protein sequences show significant homology to the other reported TFPI sequences, especially to that of rat. Mouse TFPI has a signal peptide of 28 amino acid residues followed by the mature protein (in which the signal peptide is removed) which has 278 amino acid residues. Mouse TFPI, like that of other species, consists of three tandem Kunitz type domains. Recombinant mouse TFPI was expressed in the human kidney cell line 293 and purified for functional assays. When using human clotting factors to investigate the inhibition spectrum of mouse TFPI, it was shown that, in addition to human factor Xa, mouse TFPI inhibits human factors VIIa, IXa, as well as factor XIa. Cloning and expression of the mouse TFPI gene will offer useful information and material for coagulation studies performed in a mouse model system.

Amino Acid Sequence↗
PubMed1998

Active site-inactivated factors VIIa, Xa, and IXa inhibit individual steps in a cell-based model of tissue factor-initiated coagulation.

Factors VIIa, Xa, and IXa play different roles in the initiation of tissue factor-dependent coagulation. The consequences of competing with the different enzymes were investigated, thereby examining the effects of inhibiting the initiation process at different steps. Active site-inactivated factors VIIa, Xa, and IXa (FVIIai, FXai, and FIXai, respectively) were added to various cell-based assays mimicking the individual steps in tissue factor-initiated coagulation. In an assay involving tissue factor-expressing monocytes, coagulation proteins and unactivated platelets, FVIIai and FXai inhibited platelet activation and thrombin generation while FIXai only inhibited thrombin generation. FVIIai inhibited factor Xa generation and subsequent thrombin generation on monocytes, while FXai inhibited thrombin generation on the monocytes as well as on the activated platelets. FIXai had no effect on factor Xa or thrombin generation on the monocytes, but inhibited factor Xa and subsequent thrombin generation on the activated platelets. FVIIai had no effect on the reactions taking place on the activated platelets. The data confirm a model where tissue factor/factor VIIa mediates factor Xa generation and subsequent prothrombin activation on the tissue factor-bearing cells. Thrombin then activates platelets, which serve as the physiologically important surface for large-scale thrombin generation.

Adult↗
PubMed1998

A possible mechanism of action of activated factor VII independent of tissue factor.

We have used a cell-based model system to examine some aspects of coagulation. Unactivated platelets and tissue factor (TF)-bearing cells were mixed with plasma levels of zymogen factors IX (FIX), FVIII, FX, FV, and prothrombin, as well as coagulation inhibitors antithrombin III and TF pathway inhibitor. Reactions were initiated with plasma levels (0.2 nmol/l) of activated factor VII (FVIIa). We were able to measure platelet activation and subsequent thrombin generation in this system and have established parameters for the normal amount of thrombin generation and the range of values seen with different individuals. If FIX or FVIII were not added to this system, platelet activation but not thrombin generation was seen. We have used this system to examine the mechanism of action of high-dose FVIIa. If platelets were activated with the thrombin receptor agonist peptide SFLLRN and incubated with inhibitors and zymogen factors X, V, and prothrombin, no thrombin generation was observed. Addition of increasing amounts of FVIIa gave increasing amounts of thrombin generation. At the FVIIa concentrations present in the plasma of patients given 60 microg/kg recombinant FVIIa (NovoSeven, Novo Nordisk, Bagsvaerd, Denmark), 10-40 nmol/l, thrombin generation in the model system approached the normal amount seen in the TF-initiated model system. When FIX and FVIII were included in the above reaction, FVIIa could initiate thrombin generation at levels three to four times the amount seen in the TF-initiated model system. We speculate that this platelet-localized thrombin generation may, in part, account for the clinical efficacy of high-dose FVIIa.

Blood Platelets↗
PubMed1998

The effects of activated factor VII in a cell-based model for tissue factor-initiated coagulation.

The importance of activated factor VII (FVIIa) in coagulation initiated by tissue factor (TF) was illustrated by competition of active site-inhibited FVIIa (FFR-FVIIa; FVIIa treated with D-Phe-Phe-Arg-chloromethyl ketone) with FVIIa in various cell-based assays mimicking TF-initiated coagulation. FFR-FVIIa inhibited the overall initiation process as measured by platelet activation and large-scale thrombin generation on the activated platelet surface. When the individual steps in the initiation process were separated, FFR-FVIIa affected only the reactions taking place on TF-bearing cells, demonstrating that FVIIa takes part only in the very first step in the initiation process. The dissociation constant (Kd) for FVIIa binding to TF and the inhibition constant (Ki) for FFR-FVIIa competing with FVIIa in binding to TF, measured in a factor X activation assay, were both around 10 pmol/l, showing that FVIIa and FFR-FVIIa bound to TF in the extrinsic pathway tenase complex with the same affinity.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Vasopressin deficiency contributes to the vasodilation of septic shock.

BACKGROUND: The hypotension of septic shock is due to systemic vasodilation. On the basis of a clinical observation, we investigated the possibility that a deficiency in vasopressin contributes to the vasodilation of septic shock. METHODS AND RESULTS: In 19 patients with vasodilatory septic shock (systolic arterial pressure [SAP] of 92 +/- 2 mm Hg [mean +/- SE], cardiac output [CO] of 6.8 +/- 0.7 L/min) who were receiving catecholamines, plasma vasopressin averaged 3.1 +/- 1.0 pg/mL. In 12 patients with cardiogenic shock (SAP, 99 +/- 7 mm Hg; CO, 3.5 +/- 0.9 L/min) who were also receiving catecholamines, it averaged 22.7 +/- 2.2 pg/mL (P < .001). A constant infusion of exogenous vasopressin to 2 patients with septic shock resulted in the expected plasma concentration, indicating that catabolism of vasopressin is not increased in this condition. Although vasopressin is a weak pressor in normal subjects, its administration at 0.04 U/min to 10 patients with septic shock who were receiving catecholamines increased arterial pressure (systolic/diastolic) from 92/52 to 146/66 mm Hg (P < .001/P < .05) due to peripheral vasoconstriction (systemic vascular resistance increased from 644 to 1187 dyne.s/cm5; P < .001). Furthermore, in 6 patients with septic shock who were receiving vasopressin as the sole pressor, vasopressin withdrawal resulted in hypotension (SAP, 83 +/- 3 mm Hg), and vasopressin administration at 0.01 U/min, which resulted in a plasma concentration (approximately 30 pg/mL) expected for the level of hypotension, increased SAP from 83 to 115 mm Hg (P < .01). CONCLUSIONS: Vasopressin plasma levels are inappropriately low in vasodilatory shock, most likely because of impaired baroreflex-mediated secretion. The deficiency in vasopressin contributes to the hypotension of vasodilatory septic shock.

Adult↗
PubMed1997

Platelet activity of high-dose factor VIIa is independent of tissue factor.

High-dose recombinant factor VIIa has been successfully used as therapy for haemophiliacs with inhibitors. The mechanism by which high-dose factor VIIa supports haemostasis is the subject of some controversy. Postulating a mechanism in which activity is dependent on tissue factor at the site of injury explains the localization of activity but not the requirement for high doses. Postulating a mechanism in which factor VIIa acts on available lipid independently of tissue factor explains the requirement for high doses but not the lack of systemic procoagulant activity. We report that factor VIIa bound weakly to activated platelets (Kd approximately 90 nM). This factor VIIa was functionally active and could initiate thrombin generation in the presence of plasma concentrations of prothrombin, factor X, factor V, antithrombin III and tissue factor pathway inhibitor. The activity was not dependent on tissue factor. The concentration of factor VIIa required for detectable thrombin generation agreed well with the lowest concentration of factor VIIa required for efficacy in patients. High-dose factor VIIa may function on the activated platelets that form the initial haemostatic plug in haemophilic patients. These observations are in agreement with clinical trials which have shown that high-dose factor VIIa was haemostatically effective without causing systemic activation of coagulation.

Blood Platelets↗
PubMed1997

Spatial and temporal expression of cell surface molecules during nephrogenesis.

Cell-to-cell interaction is fundamental to the development of the kidney. Ureteric bud cells, through cell contact or short-distance interactions, induce the metanephric mesenchyme to convert, to epithelia and begin the process of tubulogenesis. To identify new molecules that are involved in these processes, we generated a panel of monoclonal antibodies (MAbs) to the surface of induced mesenchymal cells taken from a day 15 rat embryonic kidney rudiment. MAbs were chosen for further study based either on a distinctive pattern of expression of their antigens or their functional effect on tubulogenesis. We identified a set of MAbs that preferentially stained the glomerular crevice, the first site for formation of the glomerular anlage. Another MAb inhibited tubulogenesis by producing widespread apoptosis in induced mesenchymal cells. This approach promises to identify new molecules that are central to kidney development.

Animals↗