Biomedical subjects
Publications and source records attributed to E B Pedersen.
Differential diagnostic problems may occur in a patient with a cold, pale and swollen leg. Especially when the peripheral blood pressure is reduced, it is particularly difficult to distinguish cases caused by venous thrombosis from those caused by arterial embolism. Colour-Doppler ultra-sonography might be helpful for establishing the correct diagnosis. A case history is presented.
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Ethyl 2-alkyl-4-aryl-3-oxobutyrates were synthesized from the corresponding arylacetonitriles and 2-bromo esters. Condensation of the butyrates with thiourea followed by treatment with chloroacetic acid afforded the 5-alkyl-6-(arylmethyl)uracils. Condensation of the uracils with acetals using trimethylsilyl triflate (TMS triflate) as a catalyst gave acyclic 5-alkyl-6-(arylmethyl)uracil derivatives. 6-Benzyl-5-ethyluracil was also condensed with methyl 5-O-(tert-butyldiphenylsilyl)-2-deoxy-3-O-(phenoxythiocarbonyl+ ++)-alpha,beta-D-erythro-pentofuranoside, followed by Barton reduction and deprotection, to give the anomers of 6-benzyl-5-ethyl-2',3'-dideoxyuridine. Alkylation of the uracils with alkyl chloromethyl sulfides gave new thio analogues of HEPT. All new N1-substituted uracils were tested for activity against HIV-1, and the thio analogues were found extremely potent.
The purpose of this study was to investigate the self-reported incidence of needlesticks and other exposures to patients' blood or body fluids among employees at Glostrup County Hospital, Copenhagen. Furthermore the nature of and circumstances under which these exposures occurred were explored. Four hundred and thirty-two reports of exposure were received from 389 health care workers during a period of four years (1990-1994). Ninety-three percent of the exposures were percutaneous, 7% mucocutaneous. The incidence rates of exposure per full-time employee per year were as follows: Midwives: 0.11; doctors: 0.093; laboratory - technicians: 0.084; registered nurses: 0.068; auxiliary nurses: 0.025; porters: 0.024 and housekeeping staff: 0.016. Accidents related to disposal containers, where the health care worker is injured while disposing a needle or handling the disposal container, account for 10% of all percutaneous exposures. Improper placing of sharp instruments account for 7% and recapping is responsible for 6% of all percutaneous exposures. Mucocutaneous exposure was caused by unexpected splash during the procedure, in 86% of the cases the conjunctivae were contaminated. No occupationally acquired infections were observed. It is concluded that occupational exposure to blood and body fluids among health care workers is considerable. To reduce the frequency of blood exposure education of the health care workers and safer equipment are needed. A good strategy for preventing exposures must be based on careful registration of the accidents, which is obtained by encouraging reporting of the exposures among the health care workers. Data base registration would be desirable.
Acute unilateral obstruction (UUO) of the pig kidney is associated with an increased secretion of intrarenally generated angiotensin II (ANG II). In order to clarify the importance of this intrarenal ANG II generation during acute UUO, ipsilateral and contralateral renal blood flow and renal secretion rate of ANG II were determined in pigs during continuous infusion of an angiotensin I converting enzyme (ACE) inhibitor. Pigs were operatively equipped with electromagnetic flow probes and catheters in the renal veins and aorta. Intravenous administration of the ACE inhibitor SQ14225 (captopril), 1 mg/kg per hour, resulted in a significant increase in renal blood flow in the contralateral kidney from 340 +/- 28 ml/min to 435 +/- 36 ml/min (P < 0.01), whereas renal blood flow in the ipsilateral kidney was significantly reduced from 388 +/- 23 ml/min to 248 +/- 24 ml/min, similar to the reduction in controls. Captopril reduced mean aortic blood pressure, renal vascular resistance consistently on both sides, and plasma concentrations of ANG II and aldosterone from all sample sites. Renal secretion rate of ANG II showed a clear tendency to be reduced from the ipsilateral kidney. The results suggest that in UUO a compensatory increase in renal blood flow may be inhibited in part due to an enhanced secretion of ANG II in the ipsilateral kidney. However, a captopril-mediated inhibition of bradykinin breakdown may also explain some of the observed changes.
OBJECTIVE: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements. METHODS: Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1-2 week interval. Plasma drug concentrations were followed for 2 days after drug intake. RESULTS: For cyclosporine, Cmax was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and Cmax (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and Cmax were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg). CONCLUSION: A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and Cmax of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine.
In essential hypertension, cardiovascular structure is believed to be influenced by hormonal and by hemodynamic factors. The objective of the present study was, in essential hypertensives, to investigate the relationship between blood pressure (BP) level as well as circulating hormones on the one hand and cardiovascular structure on the other. Seventy-nine untreated essential hypertensives were examined by 24-h ambulatory BP monitoring, echocardiography, microscopy of subcutaneous resistance vessels and analyzes of plasma for angiotensin II (P-Ang II), aldosterone, atrial natriuretic factor and 24-h urinary excretion of catecholamines. Multiple regression analysis showed a statistically significant correlation between P-Ang II and the end diastolic interventricular septal diameter (IVSDd) (R = 0.32, P = .005) and a weak correlation between P-Ang II and the left ventricular posterior wall diameter (R = 0.22, P = .049). These correlations were closer in the subgroup of patients (N = 54) who had never received antihypertensive treatment (R = 0.42/0.32, respectively). A weak, though statistically significant, correlation was found between the catecholamine excretion and systolic BP (R = 0.26, P = .03). A statistically negative correlation existed between catecholamines and end-diastolic left ventricular internal diameter index (R = -0.36, P = .001). No significant relationship was found between hormonal levels and the tunica media structure of the resistance arteries. In conclusion, P-Ang II was in this study significantly correlated to IVSDd, but not to resistance artery structure. In essential hypertension a complex relationship exists between humoral and hemodynamic factors and cardiovascular remodeling.
The present work examined the effects induced by dibutyryl cyclic adenosine monophosphate (dB-cAMP) on microglial cells in primary glial cell cultures from newborn rats. Microglial cells were identified by OX42 immunohistochemistry and nucleoside diphosphatase histochemistry. Double staining for astrocytes was carried out by combination with glial fibrillary acidic protein immunolabeling. Addition of 0.25 mM dB-cAMP to the cultures decreased the microglial cell number about sixfold. The findings suggest that the effect of dB-cAMP on the microglial cells might be either a direct action of dB-cAMP on the microglial cells or an indirect effect mediated by the astroglial cells.
1. In a placebo-controlled, randomized dose-response study the effect of the prostaglandin analogue epoprostenol (Flolan) on the plasma level of atrial natriuretic peptide has been investigated in 14 healthy control subjects. 2. During epoprostenol infusion, atrial natriuretic peptide increased significantly in a dose-dependent manner, while it remained unchanged during placebo infusion [2 ng min-1 kg-1: epoprostenol 13.2% versus placebo -2.9%; 4 ng min-1 kg-1: epoprostenol 13.4% versus placebo -6.1%; 8 ng min-1 kg-1: epoprostenol 40.7% versus placebo -7.8% (medians), P < 0.01 for all]. 3. Mean blood pressure and heart rate increased significantly after epoprostenol, but were unchanged during placebo infusion [8 ng min-1 kg-1; mean blood pressure: epoprostenol -5.6% versus placebo 3.2%; heart rate: epoprostenol 32.7% versus placebo 3.1% (medians), P < 0.01]. 4. It is concluded that epoprostenol given intravenously increases the plasma level of atrial natriuretic peptide. The results support the hypothesis of an interaction between the prostaglandin system and atrial natriuretic peptide.
In order to study the renal and hormonal actions of atrial natriuretic peptide (ANP) during background infusions with angiotensin II (ANG II) or noradrenaline (NA), 69 healthy subjects were examined in three main groups receiving a 90-min infusion with either placebo, ANG II (1.5 ng kg-1 min-1), or NA (25 ng kg-1 min-1). Each of these three main groups were subdivided into two groups receiving an infusion with either placebo or ANP (10 ng kg-1 min-1) for the last 60 min of the background infusion. Lithium clearance was used to evaluate segmental tubular reabsorption. ANG II alone caused a decrease in glomerular filtration rate (GFR), renal plasma flow, urinary absolute and fractional excretion of sodium, both proximal and distal fractional tubular sodium reabsorption, and urinary flow. NA alone caused a decrease in renal plasma flow. ANP alone caused a decrease in renal plasma flow. Urinary absolute and fractional excretion of sodium were increased and the distal fractional tubular reabsorption of sodium decreased, whereas the proximal fractional tubular reabsorption was unchanged by ANP. ANG II + ANP: during a background ANG II infusion, ANP still increased fractional excretion of sodium. Proximal fractional reabsorption was decreased, whereas distal fractional reabsorption of sodium was unchanged by ANP during ANG II infusion. The ANP-induced decreases in proximal absolute (-147 vs. +714 mumol min-1 1.73 m-2, P = 0.05) and fractional (-1.7% vs. +0.6%, P < 0.01) tubular sodium reabsorption were more pronounced, and the decrease in distal fractional tubular reabsorption of sodium (-0.1% vs -1.4%, P < 0.05) less pronounced compared with when ANP was given alone. NA + ANP: during a background NA infusion, ANP still increased urinary sodium excretion and decreased distal fractional reabsorption. None of the ANP-induced absolute changes seen during background infusion with NA were significantly different from the ANP-induced changes seen during placebo background infusion. It is concluded that the natriuretic action of low-dose ANP seems to be preserved during background infusions with ANG II and NA in man. Net sodium excretion during the combined infusion with ANG II and ANP seems to reflect the sum of the opposing influences of each peptide. Low-dose ANP had a very modest but significant inhibitory effect on proximal tubular sodium reabsorption prestimulated by ANG II infusion.
FK-506 has been shown to be an effective immunosuppressive drug with possible nephrotoxic side effects. In this study we have investigated the acute effects of FK-506 on renal haemodynamics, water, sodium and lithium excretion rates and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide (ANP) and vasopressin in 29 anaesthetized Lancaster/Yorkshire female pigs. A continuous intravenous infusion was given over a 2-h period to 4 groups: A: 0.075 mg kg-1 (n = 7), B: 0.15 mg kg-1 (n = 8), C: 0.3 mg kg-1 (n = 6) and P: placebo vehicle (n = 8). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion clearance technique using 125-I-iothalamate and 131-I-hippuran as reference substances. Hormonal parameters were measured by radioimmunoassay. In all three FK-506 groups, fractional lithium excretion was significantly decreased 2 h after FK506 infusion (P: +0.4%, A: -8.8% (P < 0.05), B: -12.9% and C: -11.2% (P < 0.01 for both). Mean arterial blood pressure (MBP) was significantly increased in the two highest dosage groups (B,C) at 2 h of infusion: (MBP; P: +2.9%, A: +3.5%, B: +12.0%, C: +15.3% (P < 0.01 for both). GFR and RPF showed minor and inconsistent changes while all other parameters measured showed similar or no changes. In conclusion, acute infusion of FK-506 to pigs does not change overall renal function significantly, but increases mean arterial blood pressure and decreases fractional excretion of lithium.
Animal studies have implicated an important role of nitric oxide (NO) in the regulation of blood pressure, renal hemodynamics, and renal excretion of sodium. NG-monomethyl-L-arginine (L-NMMA) is a specific, competitive inhibitor of NO synthesis interfering with NO synthase. The purpose of the present study was to investigate the effect of L-NMMA on renal plasma flow (RPF), glomerular filtration rate (GFR), urinary sodium excretion (UNa), fractional sodium excretion (FENa), fractional lithium excretion (FELi), mean arterial blood pressure (MAP), and heart rate (HR) in healthy humans. In a randomized placebo-controlled study, 23 healthy subjects were randomized to receive either bolus injection of L-NMMA (3 mg/kg in 10 ml saline, n = 12 subjects) or placebo (10 ml saline, n = 11). GFR and RPF were measured using the renal clearances of 51Cr-labeled EDTA and 125I-labeled hippuran by the constant infusion technique. L-NMMA treatment induced 60 min after injection a 14.6% decrease in RPF, a 5.8% decrease in GFR, a 9.8% increase in filtration fraction, a 34.7% decrease in UNa a 28.6% decrease in FENa, and a 12.1% decrease in FELi. These changes were still evident 120 min after injection. None of the effect parameters were changed after placebo, except FENa, which increased 9.9% 60 min after injection. Ten minutes after L-NMMA injection, MAP increased significantly (80 vs. 88 mmHg), and HR decreased (58 vs. 47 beats/min). The changes in HR and MAP normalized within 30 min. L-NMMA significantly reduced the plasma level of cGMP 60 min (3.0 vs. 3.7 pmol/l) and 120 min after injection (2.5 vs. 3.7 pmol/l). It is concluded that, in healthy humans, NO is a regulator of renal hemodynamics as a tonic vasodilator and a regulator of sodium excretion, due at least in part to a proximal tubular effect.
The effect of oral prednisolone treatment on renal haemodynamics, tubular function and various hormones during amino acid infusion was studied in 14 normal men. A balanced amino acid solution was infused for 120 min, before and after 4 days of prednisolone treatment (40 mg day-1). During amino acid infusion before prednisolone glomerular filtration rate, renal plasma flow, urinary sodium excretion, fractional excretion of sodium, lithium clearance, fractional excretion of lithium, serum insulin (s-insulin), plasma glucagon (p-glucagon) and s-growth hormone increased, whereas p-atrial natriuretic peptide, p-aldosterone, p-vasopressin and s-insulin-like growth factor 1 were unchanged, and potassium excretion and fractional excretion of potassium fell. After prednisolone treatment the most important differences during amino acid infusion were a significantly lower fractional excretion of sodium after 120 min (before prednisolone 26%; after prednisolone-7%; p < 0.05), a more pronounced increase in s-insulin after 120 min (before 118%; after 200%; p < 0.05) and a lower s-potassium. In conclusion, amino acid infusion increased fractional sodium excretion in healthy men, and this increase was reduced by prednisolone due to increased reabsorption in the distal tubules. It is suggested that the more pronounced the increases in plasma insulin and the decrease in serum potassium are mediators of the increased distal tubular sodium reabsorption during amino acid infusion during prednisolone treatment.
The aim of this study was to assess the blood pressure profile and vasoactive hormones in valvular aortic disease. Thirteen aortic stenosis and/or aortic regurgitation patients were matched with 13 control subjects. Ambulatory blood pressure monitoring was performed for 24 h. Arterial and venous plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin, atrial natriuretic peptide, immunoreactive endothelin and cyclic-GMP were measured. The mean 24-h blood pressure was higher in the patient group (94.9 mmHg) compared with control subjects (88.2 mmHg) (p < 0.0001), despite no differences in daytime blood pressures. The nocturnal blood pressure fall was attenuated in the patients (systolic/diastolic blood pressure -8.5/-3.5; -20.3/-14.3 mmHg (p < 0.001/p < 0.01)); in heart rate too the nightly fall was blunted in the patients (-4.8/ -13.4/min (p < 0.0013)). PRA, Ang II, AVP, ANP, ir-ET and cGMP were significantly increased in the patients compared to the controls. Nightly systolic blood pressure fall was inversely related to arterial (r = -0.75, p < 0.003) and venous (r = -0.65, p < 0.04) plasma renin activity and arterial aldosterone (r = -0.64, p < 0.05) in valvular aortic disease patients. In conclusion, valvular aortic disease patients have attenuated falls in blood pressure and heart rate during the night. Increased activity in the renin aldosterone system may be involved in this abnormal blood pressure regulation.
The purpose of the study was to compare the positive and negative predictive values of conventional renography (Reno-A), captopril renography (Reno-B) and ultrasound Doppler (UD) with regard to the diagnosis renal artery stenosis. These three tests, and in addition a renal angiography, were performed in consecutively admitted patients with arterial hypertension, owing to either suspicion of renovascular hypertension or refractoriness to treatment. Patients with occlusion of a renal artery or a serum creatinine level higher than 300 mumol/l, or a previous investigation for renovascular hypertension at another hospital, were excluded from the analysis. The European Multicenter Study (EMS) criteria and local criteria for abnormal renography were compared. Of 131 patients, 28 had a renal artery stenosis (RAS) exceeding 50% reduction in diameter of the artery and 19 exceeding 70%. Using the EMS criteria for renography the predictive values of a negative test for a RAS more than 50% were 0.88 for Reno-A, 0.90 for Reno-B, 0.86 for changes from Reno-A to Reno-B, 0.92 for abnormalities either in Reno-A, Reno-B or changes from Reno-A to Reno-B, and 0.91 for UD. The corresponding values for a RAS more than 70% were 0.94, 0.97, 0.93, 0.98 and 0.96, respectively. The predictive values of a positive test were clearly lower, ranging from 0.20 to 0.75, but best when changes from Reno-A to Reno-B were used, 0.69-0.75. Using local criteria for renography the predictive values of a negative test were almost equal to those obtained by using the EMS criteria, but the predictive values of a positive test were slightly lower. It is concluded that conventional renography, captopril renography and ultrasound Doppler all are very good screening tests for renal artery stenosis, but the positive predictive values are clearly highest when using changes from conventional renography to captopril renography. It is suggested that captopril renography always should be performed when conventional renography is abnormal and vice versa to obtain the highest positive predictive value, on the assumption that total renal function is normal or almost normal, and that renal function is not absent in the affected kidney.
3'-Azido-2',3'-dideoxyuridines 6 and their corresponding alpha anomers 5 were synthesized by condensation of silylated 6-alkyl and 5,6-dialkyl substituted uracils 2 with methyl 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-alpha, beta-D-erythro-pentofuranoside (4). Compounds 5 and 6 were treated with tetrabutylammonium fluoride to obtain the deprotected nucleosides 7 and 8, respectively.
OBJECTIVE: To study the influence of blood pressure reduction with sodium nitroprusside on the renal glomerular and tubular actions of atrial natriuretic peptide. DESIGN: Forty-nine healthy subjects were examined in four different groups receiving placebo, sodium nitroprusside alone, atrial natriuretic peptide alone (10 ng/kg per min), or sodium nitroprusside and atrial natriuretic peptide in combination. The infusion rate of sodium nitroprusside was gradually increased until a 10 mmHg decrease in diastolic blood pressure was obtained. METHODS: Lithium clearance was used to evaluate segmental tubular reabsorption. RESULTS: In the placebo group neither renal nor hormonal parameters were changed. Except for a fall in urinary flow, sodium nitroprusside alone had no effect on renal parameters. Urinary excretion of cyclic GMP (cGMP) was slightly increased, whereas the plasma cGMP level was not changed in response to sodium nitroprusside. The plasma aldosterone level was elevated during sodium nitroprusside infusion, although neither the plasma angiotensin II level nor the plasma atrial natriuretic peptide level were changed. Atrial natriuretic peptide alone caused an increase in filtration fraction and a decrease in renal plasma flow. Urinary sodium excretion, fractional sodium excretion, and urinary flow were increased, and distal fractional tubular sodium absorption decreased, whereas lithium clearance and proximal fractional tubular re-absorption were not changed by atrial natriuretic peptide. Atrial natriuretic peptide alone caused a decrease in plasma aldosterone and an increase in plasma and urinary cGMP levels. During blood pressure reduction with sodium nitroprusside, atrial natriuretic peptide caused no changes in the renal parameters except for an increase in filtration fraction. Thus, the increase in urinary sodium excretion (-8 versus +37 micromol/min) and the decrease in distal fractional sodium excretion (0.0 versus -2.4%) caused by atrial natriuretic peptide were attenuated. The atrial natriuretic peptide-induced changes in proximal fractional tubular reabsorption (-0.5 versus +0.6%) and cGMP were not changed by blood pressure reduction. CONCLUSIONS: Blood pressure reduction causes an attenuation of the natriuretic action of atrial natriuretic peptide in normotensive humans that is at least partly caused by attenuation of the distal tubular action of atrial natriuretic peptide. The results support the hypothesis that the action of atrial natriuretic peptide on distal tubular sodium reabsorption is pressure-dependent in humans.
Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder characterized by progressive postnatal deficiency of arginine vasopressin as a result of mutation in the gene that encodes the hormone. To determine the extent of mutations in the coding region that produce the phenotype, we studied members of 17 unrelated kindreds with the disorder. We sequenced all 3 exons of the gene by using a rapid, direct dye-terminator method and found the causative mutation in each kindred. In four kindreds, the mutations were each identical to mutations described in other affected families. In the other 13 kindreds each mutation was unique. There were two missense mutations that altered the cleavage region of the signal peptide, seven missense mutations in exon 2, which codes for the conserved portion of the protein, one nonsense mutation in exon 2, and three nonsense mutations in exon 3. These findings, together with the clinical features of FNDI, suggest that each of the mutations exerts an effect by directing the production of a pre-prohormone that cannot be folded, processed, or degraded properly and eventually destroys vasopressinergic neurons.