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Biomedical subjects

I Vermes

Publications and source records attributed to I Vermes.

At least 37 records · Page 2Linked to original sources
PubMed2001

Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin.

OBJECTIVE: Because clinical data about the therapeutic consequences of polymorphic oxidation of simvastatin by CYP2D6 have not been well reported, we sought to investigate the possible link between polymorphism of CYP2D6 and the efficacy and tolerability of simvastatin treatment in a group of 88 patients with hypercholesterolemia. METHODS: The CYP2D6 genotype was determined with use of polymerase chain reaction and restriction fragment analysis, whereas the CYP2D6 phenotype was determined by monitoring the dextromethorphan metabolism. RESULTS: Four of 5 patients with 2 defective CYP2D6 alleles discontinued the therapy at a low daily dose because of adverse events, with a significant mean decrease in the cholesterol levels of 0.23 mmol/L per milligram of simvastatin in the daily dose. In the group of 28 patients with 1 mutated CYP2D6 gene, 13 did not tolerate the therapy, whereas a mean decrease in the cholesterol levels of 0.20 mmol/L per milligram of simvastatin was found. One patient with a multiplication of the CYP2D6 gene showed a cholesterol reduction of only 0.01 mmol/L per milligram of simvastatin, at a maximal daily dose of 40 mg. Only 9 patients of the group of 54 persons who were homozygous for the wild-type allele discontinued the therapy because of intolerance. In that group, a mean decrease of cholesterol of 0.10 mmol/L per milligram of simvastatin was observed. CONCLUSIONS: Our data provide evidence that the cholesterol-lowering effect of simvastatin is influenced by CYP2D6 polymorphism. The clinical use of this knowledge may allow for more efficient individual therapies.

Adult↗
PubMed2001

Macrophage migration inhibitory factor and hypothalamo-pituitary-adrenal function during critical illness.

In patients with septic shock (n = 32), multitrauma (n = 8), and hospitalized matched controls (n = 41), we serially measured serum macrophage inhibitory factor (MIF), cortisol, plasma ACTH, tumor necrosis factor-alpha, and interleukin-6 (IL-6) immunoreactivity during 14 days or until discharge/death. MIF levels were significantly elevated on day 1 in septic shock (14.3 +/- 4.5 microg/L), as opposed to trauma (3.1 +/- 1.7 microg/L) and control patients (2.5 +/- 2.1 microg/L). The time course of MIF, parallel to cortisol, but in contrast to ACTH, showed persistently elevated levels in septic patients. On admission, nonsurvivors of septic shock (n = 11) showed significantly higher MIF levels than survivors (18.4 +/- 4.8 and 10.2 +/- 4.2 microg/L, respectively). Patients with septic adult respiratory distress syndrome (ARDS; n = 8) showed higher MIF levels than those who did not develop ARDS (19.4 +/- 4.7 vs. 9.2 +/- 4.3 microg/L, respectively). Multiple logistic regression analysis demonstrated that both MIF and ARDS were independent predictors of adverse outcome. On admission, tumor necrosis factor-alpha, IL-6, procalcitonin, and lipopolysaccharide-binding protein levels were higher in patients with septic shock than in patients with multitrauma. In septic patients, regression analysis showed significant correlations between MIF and cortisol as well as between MIF and IL-6 levels and disease severity scores. No relation was found between MIF and markers of the acute phase response (procalcitonin, C- reactive protein, and lipopolysaccharide-binding protein). In multitrauma patients, MIF levels were not elevated at any time point and were not related to other variables. Our data suggest that during immune-mediated inflammation (such as septic shock) MIF is an important neuroendocrine mediator: a contraregulator of the immunosuppressive effects of glucocorticoids.

Aged↗
PubMed2000

Flow cytometry of apoptotic cell death.

The term apoptosis or programmed cell death defines a genetically encoded cell death program, which is morphologically and biochemically distinct from necrosis or accidental cell death. The characteristic morphological signs of apoptosis (cellular shrinkage, membrane blebbing, nuclear condensation and fragmentation) are the final results of a complex biochemical cascade of events which is an integral part of physiological homeostasis. Techniques designed to identify, quantitate and characterize apoptosis are numerous, but flow cytometry (FCM) remains the methodology of choice to study the apoptotic cascade in relation to cell type, trigger and time. This review outlines the main stages of the apoptotic cascade together with current FCM methods. All FCM apoptosis assays described have a solid experimental basis and have been used successfully in basic research on molecular and biochemical mechanisms of apoptosis. In various clinical settings the ability to follow the apoptotic process in patient samples may offer the rationale for optimal treatment schedules.

Apoptosis↗
PubMed2000

[Apoptosis as a focal point for prognostic and therapeutic interventions in clinical medicine].

Apoptosis, physiological cell death, has a major role in the pathogenesis of many diseases, notably malignancies, degenerative conditions and diseases of aging. Present knowledge about the mechanisms of apoptosis facilitates development of biologically targeted drugs directed at specific aberrations in the diseased tissues. Clinical medicine is to test the therapeutic potential of these substance. Drugs currently under development are targeted at regulators of apoptosis, signal transduction, growth factors and growth factor receptors. This involves gene therapy and the application of antisense DNA fragments. Recent results in biologically anticancer therapy are promising and leave space for more intensive tumour eradication by combining with traditional cytotoxic therapy. It is to be expected that the years to come will see the development of a biological approach to the treatment of degenerative diseases by inhibition of apoptosis.

Apoptosis↗
PubMed2000

Measuring apoptosis in human spermatozoa: a biological assay for semen quality?

OBJECTIVE: [1] To determine whether apoptosis can be measured in ejaculated spermatozoa by flow cytometry using the Annexin V assay, which measures expression of phosphatidylserine on the outer leaflet of the cell membrane, or the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP [deoxy-uridine triphosphate] nick end labeling) assay, which measures occurrence of DNA strand breaks and [2] to correlate the outcome with routine semen variables and the hypoosmotic swelling (HOS) test. DESIGN: Pilot study and clinical trial. SETTING: Large teaching hospital and fertility center. PATIENT(S): Men whose semen was studied for various reasons. MAIN OUTCOME MEASURE(S): Percentage of apoptotic spermatozoa by two different assays, percentage of necrotic spermatozoa, concentration and motility of spermatozoa, and outcome of the HOS test. RESULT(S): Apoptosis can be measured in spermatozoa by flow cytometry using the Annexin V assay and the TUNEL assay. Twenty percent of spermatozoa were apoptotic according to both assays. A significant inverse correlation was seen between phosphatidylserine expression (Annexin V assay) and sperm concentration (r = -0.389; P<.05) and motility (r = -0.289; P<.05). A highly significant inverse correlation was seen between DNA double-strand breaks (TUNEL assay) and sperm concentration (r = -0.629; P<.0001). CONCLUSION(S): Flow cytometry can easily and reliably detect phosphatidylserine expression on the outer leaflet of the cell membrane and DNA strand breaks, both of which are hallmarks of apoptosis. About 20% of ejaculated spermatozoa are apoptotic, and the concentration of spermatozoa is lower in men with more apoptotic spermatozoa.

Annexin A5↗
PubMed2000

The low dose (1 microg) ACTH stimulation test for assessment of the hypothalamo-pituitary-adrenal axis.

Traditional testing of the hypothalamo-pituitary-adrenal axis function has relied essentially upon the insulin tolerance test or the metyrapone challenge: both tests are not only uncomfortable, but carry also real dangers. The standard ACTH stimulation test uses an extremely hyperphysiological amount (250 microg) of ACTH to evaluate a physiologic response, which may result in false normal responses. The proposed low dose (1 microg) ACTH test is more physiological and more sensitive, especially in cases of mild adrenal insufficiency and allows also to assess pituitary-adrenal suppression after long-term treatment with glucocorticoids. According to the rules of evidence-based medicine, the low dose ACTH test should replace the conventional 250 microg test when evaluating for central adrenal insufficiency.

Adrenal Insufficiency↗
PubMed1999

[Arsenic trioxide, a new drug for the treatment of acute promyelocytic leukemia resistant to tretinoine].

Chinese clinical investigators in 1986 demonstrated the therapeutic potential of tretinoin and in 1992 that of arsenic trioxide in the treatment of acute promyelocytic leukaemia. These observations have been confirmed in European and American centres. In acute promyelocytic leukaemia there is an abnormal receptor for retinoids, designated PML/RAR-alpha. This receptor binds retinoids inadequately so that extra retinoids (in the form of tretinoin) are required to restart the normal cellular maturation, after which the promyelocytes can mature into granulocytes. Arsenic trioxide has a different mode of action, possibly related to its effects on sulfhydryl-rich proteins, resulting in dysplastic leukaemic promyelocytes, ending up in apoptotic cell death. Since 1990 tretinoin has been included worldwide in the treatment of acute promyelocytic leukaemia. The use of arsenic trioxide has not yet been included in treatment protocols for promyelocytic leukaemia in western medicine.

Antineoplastic Agents↗
PubMed1999

Neurogenetic correlates of Parkinson's disease: apolipoprotein-E and cytochrome P450 2D6 genetic polymorphism.

Brain tissue of 50 patients with morphological confirmed Parkinson's disease (PD), blood samples from 149 patients with clinical parkinsonism and from 96 healthy control subjects were collected. Apolipoprotein-E (apo E) and cytochrome P450 2D6 (CYP2D6) genotyping were performed by PCR followed by restriction fragment analysis. A significantly higher allele frequency of CYP2D6*4 was found in patients with PD (35%) but not with parkinsonism (14.1%) compared to control subjects (19.8%). The combined alleles frequency of CYP2D6*3 + apoE4 was significantly higher not only in the PD group (33.3%) but also in patients with parkinsonism (22.3%) compared to control subjects (1.6%). These results suggest that there is a substantial overlap not only in the clinical manifestation but also in the genetic risk factors between Parkinson's and Alzheimer's diseases.

Apolipoproteins E↗
PubMed1999

Decreased concentration of annexin V in parkinsonian cerebrospinal fluid: speculation on the underlying cause.

Circumstantial evidence suggests that increased apoptosis is responsible for the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD). It is impossible to perform high-quality studies on human postmortem material because of the low quality of tissue preservation, and the fact that apoptosis has a duration of only hours, and that the duration of the agonal period itself will lead to massive neuronal cell death. We measured, as epiphenomenon of neuronal cell death ex vivo, the Annexin V concentration in cerebrospinal fluid (CSF) in patients with PD and control subjects. The Annexin V concentration in CSF of patients with PD was significantly lower compared with control subjects. Annexin V concentrations of the CSF did not correlate with dementia, duration of symptoms, age, sex, or treatment of PD. The rationale for measurement of Annexin V in CSF is the fact that Annexin V adheres to dying cells. It is tempting to suppose that the decrease of Annexin V in CSF of PD is the result of consumption of this protein during neuronal apoptosis as has been demonstrated to occur in the midbrain in PD.

Adult↗
PubMed1999

Sequential occurrence of mitochondrial and plasma membrane alterations, fluctuations in cellular Ca2+ and pH during initial and later phases of cell death.

The sequential occurrence of plasma and mitochondrial membrane alterations, intra-cellular pH shifts and changes in intracellular Ca2+ concentration after induction of cell death was monitored by flow cytometry in Jurkat and HSB2-cells. Cell death was induced by treatment with anti-Fas antibodies or by irradiation. Phosphatidylserine (PS) exposure and plasma membrane integrity were measured with FITC-Annexin V adhesion and by Propidium Iodide exclusion. Transition of the mitochondrial membrane potential was monitored by the occurrence of decay of DiOC6 fluorescence. Intracellular pH shifts were monitored by changes in the ratio of fluorescence at 575 nm and at 635 nm of SNARF-1-AM. Fluctuations in intracellular Ca2+ concentration were established by changes in Fura red quenching. The Jurkat cells were sensitive to anti-Fas treatment, while HSB-2 cells were not. HSB-2 cells appeared more sensitive to radiation damage than Jurkat cells. In all experiments the transition of mitochondrial membrane potential occurred first, almost immediately followed by PS exposure. Fluctuations in intracellular Ca2+ concentration occurred later and were less outspoken. A decrease in intracellular pH occurred not earlier than 24 hours after anti-Fas treatment. Chelation of intracellular Ca2+ concentration with BAPTA-AM had no effect on the time sequence of cell death related events.

Journal Article↗
PubMed1999

The use of free cortisol index for laboratory assessment of pituitary-adrenal function.

We developed a time-resolved-fluoro-immunoassay to measure cortisol binding globulin (CBG) in serum. It is a microtitre plate, solid phase, reagent excess, sandwich assay in which the same polyclonal antiserum is used as a source of capture and labeled antibodies. The results of this assay were shown to be reliable and were fully comparable with those obtained by a commercially available kit. As a reflection of the free cortisol concentration we measured cortisol and CBG concentrations in serum and calculated the Free Cortisol Index (FCI) = [cortisol]serum/[CBG]serum.100. The clinical use of this parameter, as a screening test for disturbances of the pituitary-adrenal axis, was investigated in different groups of subjects: healthy men and women, women using oral contraceptives, pregnant women at term, patients with thyroidal illnesses, patients using anti-epileptic drugs and patients suffering from adrenal diseases. In a number of groups we compared the FCI results with measurements of cortisol in saliva, another parameter used as an estimate of the concentration of free cortisol in blood. Our conclusion is that the FCI, in contrast to a total cortisol measurement alone, can prevent unnecessary further testing.

Adrenal Glands↗
PubMed1999

Apoptosis inducers endotoxin and Fas-ligation enhance the expression of vascular endothelial growth factor in human endothelial cells.

Endothelial cells in culture were exposed during four hours to the apoptosis inducing agents endotoxin (lipopolysaccharide, LPS) and Fas-ligand mimicking antibody in various concentrations. With addition of a deletion primer as internal standard a competitive RT-PCR was performed to measure semi-quantitatively the expression of mRNA of Vascular endothelial growth factor (VEGF). It appeared that endothelial cells survive increasing amounts of LPS and show a concentration- and time-dependent increase in the expression of VEGF-mRNA. The same effect was found with Fas-ligation, although at high concentrations Fas-ligation induced no further increase, but even a decrease of VEGF expression, possibly related to cell damage. Apoptotic cells were rarely observed after LPS-stimulation, but simultaneous incubation with a blocking antibody to VEGF resulted in a significant increase in apoptosis. We hypothesize that endothelial cells are resistant to apoptosis induction by autocrine expression of VEGF under stress conditions.

Apoptosis↗