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Biomedical subjects

A Wolf

Publications and source records attributed to A Wolf.

At least 91 records · Page 5Linked to original sources
PubMed2000

Surgical treatment of postoperative, incidentally diagnosed small sporadic C-cell carcinomas of the thyroid.

BACKGROUND AND AIMS: The surgical strategy in small sporadic C-cell carcinomas of the thyroid that are incidentally diagnosed after goiter resection for benign disease is controversial. It remains unclear whether a completion thyroidectomy should be performed in every case. PATIENTS AND METHODS: We present nine patients who were operated on between October 1992 and October 1997 in whom an unexpected, small sporadic C-cell carcinoma (seven with pT1, two with pT2) was found in the postoperative histology. RESULTS: All patients were calcitonin negative and there were no signs of the disease being inherited (no familial history, negative RET proto-oncogene). No patient underwent a completion thyroidectomy. All patients had a follow-up with pentagastrin-stimulated calcitonin and carcinoembryonic antigen (CEA) 3 months, 6 months and annually after the operation. No patient became calcitonin positive or showed any other signs of tumor recurrence after a follow-up period of 2-7 years. CONCLUSION: A completion thyroidectomy is not necessary in small sporadic C-cell carcinoma that is incidentally diagnosed after resection for benign disease if there is no sign of familial cancer and if calcitonin is negative. A close follow-up is necessary.

Adult↗
PubMed2000

Spatial orientation of atherosclerotic plaque in non-branching coronary artery segments.

It has been postulated that atherosclerotic plaque deposition is spatially related to regions of low shear in non-branching vessel segments. Intravascular ultrasound (IVUS) allows precise spatial orientation of coronary artery plaque formation in humans. The objective of this study was to test the hypothesis that coronary plaques have a higher prevalence on the myocardial side in regions that encounter low surface shear stress. IVUS allows the determination of the inner versus the outer curve of the vessel based on vascular and perivascular landmarks. We studied 30 consecutive patients pre-intervention using IVUS and measured vessel area, lumen area and plaque area (vessel-lumen area) during a motorized pullback at 1 mm intervals. Vessel segments near a side branch (within two times the diameter of the vessel) were excluded from analysis because of flow disturbances. All plaques were classified as concentric or eccentric and all eccentric plaques were further divided with respect to their spatial orientation in the vessel into quadrants: myocardial (inner curve, lower shear stress), epicardial (outer curve, higher shear stress) and lateral (two quadrants intermediate). A total of 613 cross-sections were analyzed in 14 left anterior descending, six left circumflex, and ten right coronary arteries. Plaque distribution was found to be concentric in 321 (52.4%) and eccentric in 292 (47.6%) cross sections. Of all eccentric plaques, 184 cross sections were oriented toward the myocardial side (62.6%) compared to only 54 toward the epicardial side (17.3%) and 54 in the 2 lateral quadrants (19.5%, P<0.001). No difference in plaque area (6.75+/-2.70 vs. 6.76+/-2.60 mm(2)), vessel area (15.28+/-4.73 vs. 15.35+/-4.40 mm(2)), or plaque thickness (1.26+/-0.37 vs. 1.25+/-0.43 mm) was noted between myocardial or epicardial plaques. These results suggest that atherosclerotic plaques develop more frequently on the myocardial side of the vessel wall, which may relate to lower shear stress. However, plaque size is similar on the epicardial and myocardial side.

Aged↗
PubMed2000

Effect of PSC 833, verapamil and amiodarone on adriamycin toxicity in cultured rat cardiomyocytes.

Primary cultures of heart myocytes from neonatal rats were used as an in vitro cardiac cell system to study the effects of the p-170kDa glycoprotein (Pgp) blockers PSC 833 [(3'-keto-Bmt1)-(Val2)-cyclosporine], verapamil and amiodarone on adriamycin cardiotoxicity. Immunostaining revealed the presence of Pgp in the cardiomyocytes. Adriamycin induced a concentration-dependent increase in creatine kinase (CK) leakage, a parameter indicating cell death. None of the Pgp blockers was toxic up to 10 microM, but amiodarone markedly increased CK leakage at 25 microM. 1 microM of the Pgp blockers did not increase adriamycin induced CK leakage, whereas 10 microM of the Pgp blockers significantly augmented adriamycin-induced CK leakage. In parallel, cytoplasmic vacuolization and plasma membrane disruptions were observed. Frequency of contraction of cardiomyocytes, as determined by digital image analysis, was concentration-dependently decreased by adriamycin. 1 microM PSC 833 had no additional effect on contractility, only 10 microM PSC 833 enhanced the impairment of contractility induced by adriamycin. Amiodarone and verapamil alone and in combination with adriamycin already at concentrations of 1 microM completely blocked contractility of cardiomyocytes. The results suggest that the increased toxicity of adriamycin in the presence of amiodarone, verapamil and PSC 833 is mediated by an effective blockage of the Pgp efflux pump. The results further indicate that the combination of adriamycin and PSC 833 might be better tolerated with regard to cardiac side-effects, than the combination of adriamycin and verapamil or amiodarone.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Variation in the gene for human peroxisome proliferator activated receptor gamma (PPARgamma) does not play a major role in the development of morbid obesity.

OBJECTIVE: To determine the extent of variation in the gene for peroxisome proliferator activated receptor gamma (PPARgamma) in patients with morbid obesity. SUBJECTS: Two hundred morbidly obese patients who underwent gastric banding surgery and 192 healthy blood donors. Diabetics were excluded. EXPERIMENTAL: The frequency of the P115Q and P12A variants in the PPARgamma gene was determined. Single strand conformational polymorphism (SSCP) analysis was performed on all exons, exon/intron boundaries and part of the promoter of the PPARgamma gene on a sub-group of 67 morbid obese patients. RESULTS: None of the morbid patients or the blood donors were carriers of the P115Q mutation. The frequency of the P12A polymorphism did not differ significantly between morbid obese patients and controls and there was no statistically significant association between P12A and BMI. Male blood donors who were A12A homozygotes had statistically significant higher serum leptin concentrations (P = 0.001). Mutation screening revealed that one patient had a T -->G transversion at -208 in the promoter of PPARgamma-2, two had silent mutations, one a T-->C transition in the third base of codon 144 and the other a C-->T transition in codon 297. The fourth patient had a CGC-->TGC transition in codon 316 resulting in the replacement of an arginine with a cysteine. This mutation was not found in any other morbidly obese patient. CONCLUSION: Variation in the PPARgamma gene is unlikely to play a major role in the development of morbid obesity.

Adult↗
PubMed2000

Frequency of and interaction between polymorphisms in the beta3-adrenergic receptor and in uncoupling proteins 1 and 2 and obesity in Germans.

OBJECTIVE: To determine the role of polymorphisms in the genes for beta3-adrenergic receptor (beta3-AR) and in uncoupling proteins 1 and 2 (UCP-1, UCP-2) in obesity. DESIGN: Association study with three polymorphisms and obesity. SUBJECTS: Two hundred and thirty-six morbidly obese patients who underwent gastric banding surgery, 381 patients from the medical clinic and 198 healthy blood donors. MEASUREMENTS: The frequencies of the W64R in beta3-AR, the 3826A-->G in UCP-1 and the 45bp insertion in the 3 untranslated region of exon 8 in UCP-2 polymorphisms were determined. RESULTS: There were no significant differences in the frequencies of the beta3-AR and UCP-1 polymorphisms between obese (body mass index, BMI > 30 kg/m2) and lean subjects. Lean, but not obese, carriers of the R allele of beta3-AR had a significantly higher BMI. The mean age of obese subjects (excluding diabetics) who were carriers of the G allele of the UCP-1 polymorphism, 36y, was significantly younger than wild-type, 40y (P= 0.007). This effect was not seen in lean subjects. The effect of the G allele on the mean age of obese subjects was more apparent in subjects who were also carriers of the R allele of the beta3-AR polymorphism. The frequency of the ins allele of UCP-2 was significantly higher in obese subjects, 0.31, than in lean, 0.24 (P= 0.002) and carriers of the ins allele had a significantly higher BMI, 38 vs 35 (P= 0.005). There was no association between any of the polymorphisms and type II diabetes. CONCLUSION: In a German population, there was no association between the W64R in beta3-AR or the 3826A-->G in UCP-1 polymorphisms and obesity. However, they act synergistically to accelerate the development of obesity. The 45bp insertion in the 3 untranslated region of exon 8 in UCP-2 polymorphism is associated with obesity.

Adult↗
PubMed2000

[Doppler ultrasonographic diagnosis of increased intracranial pressure by comparison of flow velocities in the extra- and intracranial secitons of the internal carotid artery].

AIM: By comparison of the flow velocities in the intracranial and extracranial parts of the internal carotid artery the influence of an increased intracranial pressure on cerebral perfusion can be determined. Aim of the study was to establish normal values in healthy infants not displaying clinical signs of increased intracranial pressure. METHOD: 108 healthy infants (35 girls, 73 boys) with a gestational age of 42 +/- 14 weeks and a weight of 2440 +/- 2310 g were investigated. In all infants Doppler sonographic flow measurements were performed within the petrosal part (extracranial) and the cerebral part (intracranial) of the internal carotid artery. From the flow profile the peak systolic (Vs), enddiastolic (Ved) and time average (TAV) flow velocities were estimated. In all infants the I/E-ratio of the intracranial and extracranial flow velocities was calculated. RESULTS: Flow velocities within the intracranial section of the vessel were lower than in the extracranial part, due to the greater angle of incidence (33 +/- 8 degrees) between the pars cerebralis and the Doppler beam. In the pars petrosa of the internal carotid artery Vs was 59.7 +/- 21.4, Ved 14.6 +/- 9.5 and TAV 17.2 +/- 11.8 cm/sec. Within the pars cerebralis Vs was 48.8 +/- 22.1, Ved 12.3 +/- 8.4 and TAV 12.9 +/- 7.5 cm/sec. I/E-ratio of intracranial and extracranial flow velocities was 0.83 +/- 0.14 for Vs, 0.88 +/- 0.29 for Ved and 0.82 +/- 0.24 for TAV. CONCLUSION: The relation between intracranial and extracranial flow velocities within the internal carotid artery as described by the I/E-ratio is constant. Alterations of the flow velocities intracranially such as in cases of increased intracranial pressure, may cause changes of the I/E-ratio. Determining the I/E-ratio may be a valuable method for the assessment of increased intracranial pressure.

Blood Flow Velocity↗
PubMed2000

Inhibition of ovulation by a novel progestogen (drospirenone) alone or in combination with ethinylestradiol.

OBJECTIVE: To investigate ovulation inhibition with drospirenone, a novel progestogen that has a profile similar to natural progesterone, when given alone or in combination with ethinylestradiol. METHOD: Hormonal parameters (LH, FSH, 17beta-estradiol and progesterone) and peripheral parameters (cervical score, spinnbarkeit and crystallization), as well as follicle size assessed by ultrasonography, were measured in two groups of healthy women. Forty-eight women aged 19-35 years were randomly assigned to receive 0.5 mg, 1.0 mg, 2.0 mg or 3.0 mg of drospirenone over a single treatment cycle, and 52 women aged 20-35 years were randomized to receive either 2 mg drospirenone/30 microg ethinylestradiol or 3 mg drospirenone/30 microg ethinylestradiol over three treatment cycles. Baseline measurements were taken during a control pretreatment cycle. RESULTS: Adequate ovarian suppression with drospirenone alone was evident at dose levels of 2 and 3 mg, and at 3 mg all subjects had anovulatory cycles. Although both combined preparations (2 mg and 3 mg drospirenone/30 microg ethinylestradiol) inhibited the hypothalamic-pituitary-ovarian axis, follicular maturation leading to escape ovulation was observed in three subjects in the 2 mg drospirenone/30 microg ethinylestradiol group. Only one of these ovulations was considered to be definitely the result of treatment failure. All cycles in the 3 mg drospirenone/30 microg ethinylestradiol group were anovulatory. No statistically significant difference was found between treatment groups. CONCLUSION: The combination of 3 mg drospirenone/30 microg ethinylestradiol (Yasmin, Schering AG) reliably inhibits ovulation, with a low frequency of follicular maturation, and provides a reasonable safety margin.

Adult↗
PubMed2000

Intravenous clonidine infusion in critically ill children: dose-dependent sedative effects and cardiovascular stability.

Clonidine is used for analgesia and sedation in paediatric anaesthesia, but there are no data on its sedative properties and side effects in critically ill children. We studied 30 ventilated children aged 10 yr and under to determine an effective i.v. dosing range and to assess its cardiovascular effects. Twenty non-paralysed, ventilated children were given a background infusion of midazolam 50 micrograms kg-1 h-1 combined with a variable clonidine infusion (0.1-2 micrograms kg-1 h-1) to maintain optimal sedation. The effects of clonidine 1 microgram kg-1 h-1 on cardiac index were measured in 10 postoperative cardiac patients using a reverse Fick method. Dose-dependent sedation was achievable (713 out of 861 h) without cardiovascular side effects, but an infusion limit of clonidine 1 microgram kg-1 h-1 was inadequate in two patients. An increased dose limit of 2 micrograms kg-1 h-1 combined with midazolam 50 micrograms kg-1 h-1 achieved satisfactory sedation scores for 602 out of a total of 672 h studied with no failures. Clonidine in combination with midazolam at 1 microgram kg-1 h-1 was not associated with significant changes in heart rate arterial pressure or cardiac index.

Adrenergic alpha-Agonists↗
PubMed2000

Induction of apoptosis by the O-hydroxyethyl-D(Ser)(8)-cyclosporine A derivative SDZ IMM 125 in rat hepatocytes.

The immunosuppressive cyclosporine A derivative, O-hydroxyethyl-D(Ser)(8)-cyclosporine (SDZ IMM 125), was examined for its ability to induce apoptosis in rat hepatocytes cultured for 4 or 20 h. Four hours after SDZ IMM 125 treatment, chromatin condensation and fragmentation, and the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeled and Annexin V-positive cells increased dose dependently without any observable lactate dehydrogenase leakage. The activity of the cysteine protease, caspase-3, was increased, but not that of caspase-1 and -6. The specific caspase-3 inhibitor, Ac-Asp-Glu-Val-Asp-aldehyde, inhibited caspase-3 activation and attenuated SDZ IMM 125-induced apoptosis and lactate dehydrogenase leakage. After 20 h of SDZ IMM 125 incubation, the parameters of apoptosis were further increased. Decreased mitochondrial membrane potential (measured by rhodamine 123 uptake) and cytochrome c release went in parallel with ultrastructural mitochondrial changes, and might be regarded as early events that trigger the apoptotic cascade. Transmission electron microscopy showed cytoplasmic blebbing after 4 h of SDZ IMM 125 incubation. As observed by transmission electron microscopy, treatment with SDZ IMM 125 resulted in an increase in the number of necrotic cells after 20 h, but not after 4 h. Our findings suggest that in rat hepatocyte cultures, SDZ IMM 125 is a specific inducer of apoptosis after short-term incubation, and this overlaps with necrosis after longer treatment periods. It is very likely that the necrosis occurring later is the result of the early apoptotic events.

Animals↗
PubMed2000

Gamma knife surgery for epilepsy related to hypothalamic hamartomas.

OBJECTIVE: Drug-resistant epilepsy associated with hypothalamic hamartomas (HHs) can be cured by microsurgical resection of the lesions. Morbidity and mortality rates for microsurgery in this area are significant. Gamma knife surgery (GKS) is less invasive and seems to be well adapted for this indication. METHODS: To evaluate the safety and efficacy of GKS to treat this uncommon pathological condition, we organized a multicenter retrospective study. Ten patients were treated in seven different centers. The follow-up periods were more than 12 months for eight patients, with a median follow-up period of 28 months (mean, 35 mo; range, 12-71 mo). All patients had severe drug-resistant epilepsy, including frequent gelastic and generalized tonic or tonicoclonic attacks. The median age was 13.5 years (range, 1-32 yr; mean, 14 yr) at the time of GKS. Three patients experienced precocious puberty. All patients had sessile HHs. The median marginal dose was 15.25 Gy (range, 12-20 Gy). Two patients were treated two times (at 19 and 49 mo) because of insufficient efficacy. RESULTS: All patients exhibited improvement. Four patients were seizure-free, one experienced rare nocturnal seizures, one experienced some rare partial seizures but no more generalized attacks, and two exhibited only improvement, with reductions in the frequency of seizures but persistence of some rare generalized seizures. Two patients, now seizure-free, were considered to exhibit insufficient improvement after the first GKS procedure and were treated a second time. A clear correlation between efficacy and dose was observed in this series. The marginal dose was more than 17 Gy for all patients in the successful group and less than 13 Gy for all patients in the "improved" group. No side effects were reported, except for poikilothermia in one patient. Behavior was clearly improved for two patients (with only slight improvements in their epilepsy). Complete coverage of the HHs did not seem to be mandatory, because the dosimetry spared a significant part of the lesions for two patients in the successful group. CONCLUSION: We report the first series demonstrating that GKS can be a safe and effective treatment for epilepsy related to HHs. We advocate marginal doses greater than or equal to 17 Gy and partial dose-planning when necessary, for avoidance of critical surrounding structures.

Adolescent↗
PubMed2000

[Intake of heavy metals (lead, cadmium, zinc) originating from colored paints and their incorporation into organs and tissues of heifers].

In a feeding trial the effect of heavy metals as lead, cadmium and zinc originating from colour paints was investigated. The study included 30 early pregnant heifers subdivided in five groups with six animals each with an average body weight of 419 kgs. During the testing period the trial was carried out in a three factorial fashion with two time sections: section one--mineral supplementation and lead preexposure; section two--Exposure to heavy metal containing colour paint pigments. The investigation led to the following results: A short time uptake of daily 10 g lead containing colour paint (i.e. 22-24 mg Pb/per animal and day) did not cause any change of general health and normal behavior of the respective animals. A storage of lead in the body tissue could be observed by way of a hint. An additional prestress with lead (145-158 mg Pb/animal/day over a period of 84 days did not influence the general health of the animals significantly. Both the fodder uptake and the body weight gain was inconspecious. A storage of lead could be traced in the skeleton, kidney and liver and--on a reduced level--also in the muscle. Only the content of lead in the kidney exceeded the maxmium tolerated value (> 1.0 mg/kg) of the German Meat Hygiene regulation. A mineral deficient feeding regimen (especially lack of calcium) enhance an increased storage of lead in the tissues (skeleton).

Animals↗
PubMed1999

5-HT2C receptor involvement in female rat lordosis behavior.

Adult, hormone-primed, ovariectomized rats (CDF-344) with bilateral implants within the ventromedial nucleus of the hypothalamus (VMN), were injected with 0.5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone. This priming produced rats with 2 different levels of sexual receptivity. Rats with a lordosis to mount ratio (L/M)>/=0.5 were used to examine the potential lordosis-inhibiting effects of the 5-HT2A receptor antagonist, R(+)-a-(2, 3-dimethoxyphenyl)-1-[2(4-fluoro-phenylethyl)]-4-piperidine-methanol (MDL 100,907), and the 5-HT2C receptor antagonist, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2, 3-f]indole (SB 206553). Rats with low sexual receptivity (L/M<0.5) were bilaterally infused with the 5-HT2A/2C receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), or DOI plus either MDL 100,907 or SB 206553 to determine if either drug would attenuate the lordosis-facilitating effects of DOI. The 5-HT2C receptor antagonist, but not the 5-HT2A receptor antagonist, effectively inhibited lordosis behavior. Similarly, SB 206553 was more effective than MDL 100,907 in reducing the DOI-induced increase in lordosis responding. However, both drugs limited the duration of lordosis responding initiated by DOI. These results are consistent with prior suggestions that 5-HT2A/2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that 5-HT2C, rather than 5-HT2A, receptors are primarily responsible for the effects of 5-HT2 receptor-active drugs on lordosis behavior.

Animals↗
PubMed1999

Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31.

The chromo and SET domains are conserved sequence motifs present in chromosomal proteins that function in epigenetic control of gene expression, presumably by modulating higher order chromatin. Based on sequence information from the SET domain, we have isolated human (SUV39H1) and mouse (Suv39h1) homologues of the dominant Drosophila modifier of position-effect-variegation (PEV) Su(var)3-9. Mammalian homologues contain, in addition to the SET domain, the characteristic chromo domain, a combination that is also preserved in the Schizosaccharyomyces pombe silencing factor clr4. Chromatin-dependent gene regulation is demonstrated by the potential of human SUV39H1 to increase repression of the pericentromeric white marker gene in transgenic flies. Immunodetection of endogenous Suv39h1/SUV39H1 proteins in a variety of mammalian cell lines reveals enriched distribution at heterochromatic foci during interphase and centromere-specific localization during metaphase. In addition, Suv39h1/SUV39H1 proteins associate with M31, currently the only other characterized mammalian SU(VAR) homologue. These data indicate the existence of a mammalian SU(VAR) complex and define Suv39h1/SUV39H1 as novel components of mammalian higher order chromatin.

Amino Acid Sequence↗
PubMed1999

Both lobes of the soluble receptor of the periplasmic histidine permease, an ABC transporter (traffic ATPase), interact with the membrane-bound complex. Effect of different ligands and consequences for the mechanism of action.

The histidine permease of Salmonella typhimurium is an ABC transporter (traffic ATPase). The liganded soluble receptor, the histidine-binding protein HisJ, interacts with the membrane-bound complex HisQMP2 and stimulates its ATPase activity, which results in histidine translocation. In this study, we utilized HisJ proteins with mutations in either of the two lobes and wild type HisJ liganded with different substrates to show that each lobe carries an interaction site and that both lobes are involved in inducing (stimulating) the ATPase activity. We suggest that the spatial relationship between the lobes is one of the factors recognized by the membrane-bound complex in dictating the efficiency of the induction signal and of translocation. Several of the key residues involved have been identified. In addition, using constitutive ATPase mutants, we show that the binding protein provides some additional essential function(s) in translocation that is independent of the stimulation of ATP hydrolysis, and one possible mechanism is proposed, which includes the notion that liganded HisJ has different optimal conformations for signaling and for translocation.

ATP-Binding Cassette Transporters↗
PubMed1999

Reduced efficacy of 8-OH-DPAT's inhibition of lordosis behavior by prior estrogen treatment.

The effects of bilateral VMN infusion with the 5-HT1A receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 200, 1000, or 2000 ng), on lordosis behavior were examined in hormonally primed ovariectomized rats. When rats were given a single injection with 25 microg estradiol benzoate followed 48 h later with 500 microg progesterone, inhibition of lordosis behavior was evident at all doses of 8-OH-DPAT. However, when rats were treated with 25 microg estradiol benzoate followed 7 days later with a second injection of 25 microg estradiol benzoate and then progesterone, none of the doses of 8-OH-DPAT effectively inhibited lordosis behavior. In some rats, cannulae were located near the most rostral portion of the VMN. In these rats, there was no effect of the second estrogen treatment on the response to 8-OH-DPAT. Therefore, a second experiment was performed to specifically evaluate the effects of two estradiol benzoate treatments on the response to bilateral 8-OH-DPAT infusion in the rostral VMN. In contrast to the reduced effectiveness of the 8-OH-DPAT infusion in the mid to caudal VMN in rats given two injections with estradiol benzoate, 2000 ng 8-OH-DPAT continued to effectively inhibit lordosis behavior following the 5-HT1A receptor agonist's infusion into the more rostral areas. These findings are discussed in relation to earlier studies in which the potency, but not the efficacy, of 8-OH-DPAT was reduced following systemic treatment with the 5-HT1A receptor agonist.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

In vitro models to study mechanisms involved in cyclosporine A-mediated glomerular contraction.

The immunosuppressive drug, cyclosporin A (CsA), which is successfully used to prevent rejection in organ transplantation, induces renal side-effects as shown by a decrease in glomerular filtration rate and ultrafiltration coefficient regulated by the tone of mesangial cells.The aim of the present study was to investigate the effect of CsA on isolated glomeruli and mesangial cells, which constitute appropriate in vitro models for renal vasoreactivity studies. The roles of different intracellular and extracellular mediators such as calcium, endothelin-1 (ET-1), prostaglandins (TXA(2 )and PGI(2)) and reactive oxygen intermediates (ROIs) were analysed. CsA caused a concentration- and time-dependent decrease in the planar cross-sectional areas of isolated glomeruli and mesangial cells as determined by image analysis. Intracytosolic free calcium concentration determined by fluorimetric analysis was significantly increased after 30 min CsA (10 microM) incubation. In the contraction experiment, the calcium antagonist verapamil inhibited the CsA response. ET-1, TXB(2) and keto-PGF(1alpha) were determined directly, however no changes were found statistically significantly different from respective controls. In contrast to these results, the ET-1 specific antibody was able to reduce CsA-mediated cell contraction. In the presence of a prostacyclin agonist iloprost, CsA-induced contraction was also modified. The role of ROIs using a 2'7'-dichlorofluorescein diacetate (DCFdAc) fluorimetric method was directly determined by observing, with 10 microM CsA, a significant production of hydrogen peroxide (H(2)O(2)), which was able alone to induce mesangial cell contraction. Coincubation with the antioxidants led to a significant inhibition of mesangial cell contraction. These results suggest that CsA caused an imbalance in the normal level of all investigated vasoconstrictive and vasodilator mediators, which shifted towards the advantage of vasoconstrictive action.

Animals↗
PubMed1999

Cardiovascular autonomic dysfunction in multiple sclerosis: correlation with orthostatic intolerance.

Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS), but clinical studies disagree on the frequency and type of abnormalities in autonomic function tests. Orthostatic dizziness (OD) has been reported in up to 49% of patients, but the pathophysiological mechanisms are poorly understood. This study investigated cardiovascular reflex tests and their association with OD in patients with MS in order to examine the hypothesis that the sympathetic nervous system is specifically involved in these patients. Forty patients with clinically active relapsing-remitting (n = 27) and secondary progressive MS (n = 13), aged 35.0+/-8.5 years, were studied by parasympathetic (heart rate responses to the Valsalva maneuver, deep breathing, and active change in posture) and sympathetic function tests (blood pressure responses to active change in posture and sustained handgrip), and by spectral analysis of heart rate variability during rest and during standing. Results were compared to those obtained in 24 healthy volunteers, aged 29.4+/-7.2 years. A standardized questionnaire was used to evaluate symptoms of orthostatic intolerance. Abnormal responses on at least one cardiovascular reflex test were observed in 40% of MS patients, compared to 17% of the control group, with a statistically significant involvement of the sympathetic vasomotor system. Orthostatic intolerance was reported in 50% of patients (controls: 14%, P<0.006). Subgroup comparison of patients with and without OD suggests that orthostatic intolerance results from impaired sympathetic vasoconstriction. These results provide further evidence that the sympathetic nervous system is involved in patients with MS.

Adult↗