PubMed Health⌕ Search

Biomedical subjects

D Voet

Publications and source records attributed to D Voet.

At least 19 recordsLinked to original sources
PubMed1996

Rational design of granulocyte-macrophage colony-stimulating factor antagonist peptides.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a member of the four-helix bundle family of cytokines/growth factors which exhibit several activities. It is a hematopoietic growth factor, a cytokine involved in inflammatory and immune processes, an adjunct for cancer therapy, and an anti-tumor immunomodulator. Studies of interactions between GM-CSF and its receptor and identification of small peptides presenting binding capacity to the receptor are important goals for the development of GM-CSF analogs. Here we describe the study of two cyclic peptides, 1785 and 1786, developed based on structural analysis of the GM-CSF region mimicked by anti-anti-GM-CSF recombinant antibody 23.2. These peptides were designed to structurally mimic the positions of specific residues on the B and C helices of human GM-CSF implicated in receptor binding and bioactivity. Both 1785 and 1786 were specifically recognized by polyclonal anti-GM-CSF antibody (stronger for 1786 than 1785). 1786 also competitively inhibited binding of GM-CSF to the GM-CSF receptor on HL-60 cells and demonstrated antagonist bioactivity, as shown by its reversal of GM-CSF's ability to inhibit apoptosis of the GM-CSF-dependent cell line MO7E. These studies support the role of residues on the GM-CSF B and C helices in receptor binding and bioactivity and suggest strategies for mimicking binding sites on four-helix bundle proteins with cyclic peptides.

Amino Acid Sequence↗
PubMed1996

Effect of nifedipine on superior mesenteric artery impedance in humans.

OBJECTIVE: In a randomized, double-blind placebo-controlled study the acute effect of sublingual nifedipine (10 mg) on the superior mesenteric artery pulsatility index (p.i.) was studied over 60 min in 12 healthy subjects (Age 43 y). METHODS: p.i. was considered as a parameter of vascular resistance and was calculated as the peak-to-peak amplitude of the waveform divided by the mean amplitude. p.i. measurements were performed with the subject resting and fasting and were made 5, 10, 15, 30, 45 and 60 min for 1 hour after nifedipine (10 mg) or placebo. Arterial blood pressure and heart rate were measured at the same times. RESULTS: Placebo administration failed to change arterial blood pressure, heart rate or p.i. 5 min after 10 mg sublingual nifedipine, p.i. had significantly decreased from 5.0 to 3.8, with a nonsignificant decrease in arterial blood pressure and an increase in heart rate. By 15 min after nifedipine administration p.i. had further decreased to 3.1, and there was a concomitant significant decrease in mean arterial blood pressure and increase in heart rate. Sixty minutes after drug intake p.i. and arterial blood pressure were still below baseline not significant but the heart rate remained significantly increased. CONCLUSION: Our data indicate that in healthy subjects sublingual administration of nifedipine had a vasodilator effect (decrease in p.i.) on the superior mesenteric vascular bed.

Adult↗
PubMed1996

Use of tissue type plasminogen activator in neonates: case reports and review of the literature.

Recombinant tissue type plasminogen activator (rt-PA) has been used successfully in neonates for resolution of thrombotic processes, both arterial and venous. We report on 2 neonates with vena cava inferior thrombosis and with biochemical evidence of liver dysfunction in whom rt-PA treatment had to be interrupted because of significant bleeding tendency, without complete resolution of the thrombus. Therapy failure may be due to the age of the thrombus and the systemic way of administration, bypassing the site of the thrombus by collateral circulation. Impaired liver function may result in decreased degradation of rt-PA with prolonged effect and higher risk for bleeding complications. We suggest that lower doses should be administered in these patients.

Hemorrhage↗
PubMed1996

Rational design, analysis, and potential utility of GM-CSF antagonists.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important cytokine involved in many immune and inflammatory processes and is believed to act in the early stages of immune responses. GM-CSF stimulates antigen-presenting cells, enhancing antigen presentation and inducing macrophage tumoricidal activity. GM-CSF binds to specific cellular receptors that are potential targets for pharmacological design. Rational design of small-molecule mimics is an important approach to pharmacophore design. One of the strategies in the development of small-molecular mimics of larger polypeptyde ligands is analysis of alternative ligands that bind the same site as does the native ligand. Molecular studies of GM-CSF-receptor interactions have led to the development of interaction site analogs and the development of an "anti-anti-GM-CSF" recombinant antibody (rAb) analog of a site on GM-CSF important for biological activity and receptor binding. This rAb and a peptide derived from the rAb first complementarity determining region (CDR) sequence bind to a monoclonal anti-GM-CSF antibody that mimics the GM-CSFR alpha chain, compete with GM-CSF for binding to GM-CSF receptor alpha chain (GM-CSFR alpha), and are specific biological antagonists. Molecular modeling of the rAb suggests structural similarity with a site previously implicated in GM-CSF binding to the GM-CSFR alpha. Two cyclic peptides, 1785 and 1786, also were developed on the basis of structural analysis of the GM-CSF region mimicked by anti-anti-GM-CSF recombinant antibody (rAb) 23.2. These peptides were designed to mimic structurally the positions of specific residues on the B and C helicies of human GM-CSF implicated in receptor binding and bioactivity. Both 1785 and 1786 were recognized specifically by polyclonal anti-GM-CSF antibody. 1786 also competitively inhibited binding of GM-CSF to the GM-CSF receptor and demonstrated antagonist bioactivity, as shown by its reversal of GM-CSF's ability to inhibit apoptosis of the GM-CSF-dependent cell line MO7E. These studies support the role of residues on the GM-CSF B and C helicies in receptor binding and bioactivity and suggest strategies for mimicking binding sites on four-helix bundle proteins with cyclic peptides.

Amino Acid Sequence↗
PubMed1995

Recombinant antibodies in bioactive peptide design.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is important in many immune and inflammatory processes. GM-CSF binds to specific cellular receptors which belong to a recently described supergene family. These receptors are potential targets for pharmacologic design, and such design depends on a molecular understanding of ligand-receptor interactions. One approach to dissecting out critical intermolecular interactions is to develop analogs of specific interaction sites of potential importance. Monoclonal antibodies have been employed for these purposes in prior studies. Here we present application of recombinant antibody technology to the development of analogs of a site on GM-CSF bound by a neutralizing anti-GM-CSF monoclonal antibody. Polyclonal antisera with high titer neutralizing activity against human GM-CSF were developed in BALB/c mice. Purified immunoglobulins were prepared and used to immunize syngeneic mice. Anti-anti-GM-CSF was developed which demonstrated biological antagonist activity against GM-CSF-dependent cellular proliferation. RNA was extracted from spleen cells of mice with biologically active anti-anti-GM-CSF, cDNA synthesized, and polymerase chain reaction performed with primers specific for murine kappa light chain V regions. Polymerase chain reaction products were cloned into the pDABL vector and an expression library developed. This was screened with anti-GM-CSF neutralizing mAb 126.213, and several binding clones isolated. One clone (23.2) which inhibited 126.213 binding to GM-CSF was sequenced revealing a murine kappa light chain of subgroup III. Comparison of the 23.2 sequence with the human GM-CSF sequence revealed only weak sequence similarity of specific complementarity determining regions (CDRs) with human GM-CSF. Structural analysis revealed potential mimicry of specific amino acids in the CDR I, CDR II and FR3 regions of 23.2 with residues on the B and C helices of GM-CSF. A synthetic peptide analog of the CDR I was bound by 126.213, specifically antagonized GM-CSF binding to cells and blocked GM-CSF bioactivity. These studies indicate the feasibility of using recombinant antibody libraries as sources of interaction site analogs.

Amino Acid Sequence↗
PubMed1995

Influence and interference of isosorbide dinitrate and food intake on superior mesenteric artery impedance in humans.

The influence of isosorbide dinitrate (ISDN) and food ingestion on superior mesenteric artery impedance was investigated in 24 healthy volunteers (age 40 +/- 2.7 years). Superior mesenteric artery circulation was assessed by duplex ultrasound. Pulsatility index (PI) was considered as a parameter of vascular resistance and was calculated as the peak-to-peak amplitude of the waveform divided by the mean amplitude. The subjects were randomly allocated to four groups (ISDN, meal, ISDN + meal, meal + ISDN). PI measurements were performed in resting and fasting conditions and serially for 1 h after sublingual 5 mg ISDN, ingestion of a 300-kcal, 300-ml mixed liquid meal; sublingual 5 mg ISDN followed 10 min later by the test meal; and ingestion of the test meal followed 5 min later by sublingual 5 mg ISDN. Five minutes after 5 mg sublingual ISDN, PI had increased from 6.8 to 12.4, while after intake of a meal PI had decreased from 7.6 to 4.9. Separate effects of 5 mg ISDN and meal intake lasted for at least 1 h. The reflex vasoconstrictive effect of 5 mg ISDN on the superior mesenteric artery circulation was counterbalanced by ingestion of a meal in healthy volunteers.

Adult↗
PubMed1995

Influence of central command and ergoreceptors on the splanchnic circulation during isometric exercise.

The splanchnic circulation can make a major contribution to blood flow changes. However, the role of the splanchnic circulation in the reflex adjustments to the blood pressure increased during isometric exercise is not well documented. The central command and the muscle chemoreflex are the two major mechanisms involved in the blood pressure response to isometric exercise. This study aimed to examine the behaviour of the superior mesenteric artery during isometric handgrip (IHG) at 30% maximal voluntary contraction (MVC). The pulsatility index (PI) of the blood velocity waveform of the superior mesenteric artery was taken as the study parameter. A total of ten healthy subjects [mean age, 21.1 (SEM 0.3) years] performed an IHG at 30% MVC for 90 s. At 5 s prior to the end of the exercise, muscle circulation was arrested for 90 s to study the effect of the muscle chemoreflex (post exercise arterial occlusion, PEAO). The IHG at 30% MVC caused a decrease in superior mesenteric artery PI, from 4.84 (SEM 1.57) at control level to 3.90 (SEM 1.07) (P = 0.015). The PI further decreased to 3.17 (SEM 0.70) (P = 0.01) during PEAO. Our results indicated that ergoreceptors may be involved in the superior mesenteric artery vasodilatation during isometric exercise.

Adult↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor mimicry and receptor interactions.

Development of small molecular mimics of larger polypeptide ligands is an important approach to pharmacophore design. One strategy for the development of such mimics is analysis of alternative ligands that bind to the same site as the native ligand. These allow examination of the structural and chemical constraints for binding within the setting of diverse backbone geometries. The use of antireceptor antibodies as alternative ligands has allowed the development of biologically active peptides in several ligand-receptor systems. This technology has been applied to the study of interactions between human granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFR). GM-CSF is one of a family of signal-transducing cytokines and growth factors characterized by a four-helix bundle core structure. The GM-CSFR is comprised of an alpha-chain (GM-CSFR alpha) specific for GM-CSF, and a beta-chain (beta c) shared with the interleukin-3 and interleukin-5 receptors. At least two sites on GM-CSF have been implicated in the GM-CSF-GM-CSFR alpha/beta c ternary complex. In studies summarized here, synthetic peptide analogs of GM-CSF sequences were designed and used to map neutralizing epitopes. One neutralizing epitope corresponded to the A helix of GM-CSF, and a synthetic analog displayed biological activity as a GM-CSF antagonist in vitro, suggesting interaction with the GM-CSFR alpha/beta c complex. A second peptide comprising the B and C helices was recognized by monoclonal neutralizing antibodies and similarly displayed antagonist activity. Recombinant antibody (rAb) technology was also employed. An expression library of rAbs from mice immunized with neutralizing anti-GM-CSF antibodies was developed and screened with a neutralizing anti-GM-CSF monoclonal antibody. One clone which displayed receptor binding activity exhibited structural similarity with epitopes on GM-CSF previously implicated as interaction sites with the neutralizing monoclonal antibody. A synthetic peptide analog of the rAb inhibited GM-CSF bioactivity. Critical contact residues were predicted on the basis of structural similarity of the rAb peptide and GM-CSF. These studies indicate the feasibility of using rAbs in bioactive peptide design, providing lead compounds and information regarding contact residues for drug design.

Amino Acid Sequence↗
PubMed1993

Influence of isosorbide dinitrate on superior mesenteric artery impedance in humans.

In a randomized, double-blind, placebo-controlled crossover study the acute effect of isosorbide dinitrate (ISDN) on the superior mesenteric artery velocity waveform was studied in 10 healthy subjects (mean age 48.2 years) over a 10-minute period. The superior mesenteric artery pulsatility index (PI), which quantifies the blood velocity waveform, increased from the second minute following sublingual administration of 5 mg ISDN (basal PI 4.88 +/- 0.32) and reached its upper level (8.22 +/- 1.38) from the fourth minute on. In comparison with placebo, the significant rise of PI (second minute) occurred before the significant decrease of systolic blood pressure (ninth minute) and before the significant increase in the heart rate (fourth minute). Diastolic and mean arterial blood pressures remained unchanged. These observations suggest an immediate vasoconstrictive effect of ISDN on the resistance vessels of the vascular bed of the superior mesenteric artery.

Aged↗
PubMed1993

Neurosyphilis presenting with optic neuropathy. Report of a case and review.

A patient with neurosyphilis, presenting with severe ocular impairment due to optic neuropathy, is described. In such a case, a low index of clinical suspicion and improper use of syphilitic serologic tests may delay diagnosis. However, specific tests of serum and cerebrospinal fluid are mandatory for the diagnosis. Treatment evaluation necessitates the follow-up of serology and cerebrospinal fluid cell count. Recent changes of therapy recommendations in subjects with neurosyphilis and in those syphilitic patients co-infected with HIV are mentioned.

Aged↗
PubMed1992

Leptomeningeal cyst: early diagnosis by color Doppler imaging.

A newborn with a leptomeningeal cyst over the anterior fontanelle due to birth trauma is described. Color Doppler flow sonograms were helpful to diagnose the leptomeningocele in its early stages and to differentiate it from a cephalhematoma or subgaleal haemorrhage by demonstrating cerebro-fugal flow in an arterial connection between the extracranial fluid collection and the dural space.

Arachnoid Cysts↗
PubMed1992

Noninvasive diagnosis of superior sagittal sinus thrombosis in a neonate.

A newborn boy presented within the first day of life with moaning, anemia, and thrombocytopenia. The clinical syndrome resulted from thrombosis of the posterior part of the superior sagittal sinus due to impression at birth of the tip of the occipital squama. Both computed tomography and ultrasound scans were valuable noninvasive tools for documentation of the thrombus itself and the cerebral sequelae. Color Doppler ultrasound scan confirmed the absence and reappearance of flow in the superior sagittal sinus.

Birth Injuries↗
PubMed1992

Arcuate ligament syndrome mimicking celiac occlusion.

In a patient with weight loss and a systolic epigastric murmur, aortography demonstrated positional celiac axis occlusion. Color Doppler imaging of the celiac axis showed occlusion in the supine position, but patency was documented during deep inspiration and with the patient in the upright position. This report documents a rare example of extreme celiac axis compression with position-dependent celiac patency.

Adult↗
PubMed1991

Pseudoxanthoma elasticum: similar autosomal recessive subtype in Belgian and Afrikaner families.

A multidisciplinary survey of the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with biopsy-proven pseudoxanthoma elasticum (PXE) was undertaken. The major PXE phenotype emerging from this study is very similar in both patient groups and is characterized by severe ophthalmologic manifestations with variable, mild cutaneous and vascular symptoms. In the families with more than one affected relative, segregation analysis is compatible with autosomal recessive inheritance in both groups. It is suggested that the PXE phenotype of these Belgian and Afrikaner patients is distinct from the other recognized PXE subtypes. The phenotypic resemblance in both patient groups raises the question whether a similar genetic mechanism is involved.

Adult↗
PubMed1991

Floating thrombi: diagnosis and follow-up by duplex ultrasound.

The clinical features and evolution of floating thrombi (FT) diagnosed by duplex ultrasound were examined. In 76 consecutively diagnosed above-knee deep venous thromboses the prevalence of FT was 18%. Of 44 FT diagnosed in 39 patients, 18 (39%) were located in the common femoral, 12 (26%) in the popliteal and seven (15%) in the external iliac veins. Serial duplex examinations revealed that 31% of FT in the iliofemoral segment disappeared 33% remained unchanged and 36% adhered to the vein wall within 2 weeks following diagnosis. After 3 months, 87% of the floating segments had disappeared, irrespective of the localization or therapeutic regimen. Thirteen patients experienced pulmonary embolism before (12/13) or following (4/13) diagnosis of floating thrombosis; three of four superficial femoral vein FT embolized. Fifteen per cent of the patients with FT died during the study period and 28% of the thrombi were associated with a malignant neoplasm; the incidence of malignancy was 60% in superficial and 39% in common femoral vein FT.

Adult↗
PubMed1989

Crystallization and preliminary X-ray studies of recombinant human granulocyte-macrophage colony stimulating factor.

Human granulocyte-macrophage colony stimulating factor (hGM-CSF) is an important regulator of growth and differentiation for mononuclear and polymorphonuclear phagocytes. Here we report the crystallization and preliminary X-ray studies of Escherichia coli-expressed hGM-CSF. The crystals are orthorhombic, with the space group P212121, and have unit cell dimensions a = 46.62 A, b = 58.73 A and c = 126.42 A. Recombinant hGM-CSF crystals diffract X-rays to 2.4 A resolution and are thus suitable for X-ray structural studies.

Colony-Stimulating Factors↗