Biomedical subjects

E Vogel

Publications and source records attributed to E Vogel.

At least 37 records · Page 2Linked to original sources

PubMed1999

The effects of melatonin on the behavioural disturbances induced by chronic mild stress in C3H/He mice.

In rodents, exposure to chronic mild stress (CMS) is known to induce unresponsiveness to environmental stimuli, as well as sleep disturbances, suggesting some analogies between this syndrome and human depression. Furthermore, numerous studies reported a decrease in nocturnal melatonin concentration in depressed patients, compared with controls. The present study was conducted to test a possible preventative action of daily treatment with melatonin on behavioural alterations induced in C3H/He mice by CMS exposure. In addition to daily spontaneous locomotor activity and preference for sucrose solution, the emotional behaviour of mice was examined in a stressful situation (light/dark choice test), as well as in a situation devoid of constraining components (free-exploratory paradigm), after three weeks of CMS. The results showed that the behaviour of C3H/He mice was disrupted after CMS. Stressed mice exhibited blunted emotional reactivity in both the light/dark choice test and the free-exploratory situation. While unstressed mice presented no variation in their preference for a sucrose solution, stressed mice presented a decrease in such preference towards the end of the CMS exposure. Furthermore, daily spontaneous locomotor activity of the mice was reduced after CMS. Daily treatment of stressed mice with melatonin was able to prevent several CMS-induced disturbances, except in the light/dark choice test, where melatonin was ineffective. Compared to the effects of 10 mg/kg of fluoxetine, which completely prevented CMS-induced dysregulation of behaviour, melatonin was less effective. The present results support the idea that melatonin may be implicated in an homeostatic system which protects animals from disruptions induced by chronic stress.

Animals↗

PubMed1999

Regulation of emotional behaviour by day length in mice: implication of melatonin.

Pineal melatonin secretion occurs at night in all vertebrates and the duration of its secretion is negatively correlated with day length. As short-day exposure was previously shown to decrease emotional behaviour of mice toward an unfamiliar environment, the present study was designed to determine whether such behavioural changes could be mediated by melatonin. In a first experiment, the effects of a 3-week exposure to various day lengths (18h-6h, 12h-12h and 6h-18h light-dark conditions) on neophobic behaviour (free-exploratory paradigm) were examined in both BALB/c mice, which exhibit a very transitory melatonin peak of low amplitude in a 12h light-12h dark cycle, and C3H/He mice, which present a clear melatonin rise during the night-time. A second experiment was designed to determine if the decrease of emotional reactivity induced by a short-day exposure (6h-18h light-dark cycle during 3 weeks) in C3H/He mice could be counteracted by a daily treatment with a melatonin antagonist, S 22153 (1, 5 and 25 mg/kg/day). The short-day exposure was found to decrease neophobic reactions in both C3H/He and BALB/c mice. In contrast, the long-day exposure enhanced neophobia in C3H/He mice only. S 22153 was found to counteract, in a dose-dependent manner, the anxiolytic-like effects induced by the short-day exposure in C3H/He mice. The present results provide evidence that the modulation of circulating melatonin could be involved in the emotional changes related to day-length variations. Further studies are needed to investigate whether pinealectomy could counteract the photoperiod-related changes in anxiety.

Animals↗

PubMed1998

Modulation of mice anxiety in response to cat odor as a consequence of predators diet.

The effectiveness of predator odours as repellents was assessed, and the behavioral antipredatory responses were characterized. Mice had free access to an unfamiliar runway containing different olfactory stimuli: modelling clay, or feces of a cat subjected either to a vegetarian or a carnivorous diet. The first experiment revealed various indices of a spontaneous behavioral pattern that included exploratory activity, different kinds of emotionality, and a range of active or passive defensive reactions until the appearance of absence of risk assessment strictly related to presence or absence of anxiety. These reactions differ with larger responses to feces resulting from a carnivorous as opposed to vegetarian diets. In the second experiment, chlordiazepoxide (0, 2.5, 5, or 7.5 mg/kg) had a dose-related anxiolytic effect on exploration in mice of both vegetarian and carnivorous groups but could not totally reverse the strong anxiogenic effect of carnivorous stimulus on defensive mechanisms. These differences are related to the nature of the mammalian cues. This paradigm may be a fear-motivated model of animal anxiety.

Animals↗

PubMed1998

Effects of a daylight cycle reversal on locomotor activity in several inbred strains of mice.

There is some evidence of melatonin implication in the nycthemeral regulation of running activity rhythm in rodents. Because some inbred strains of mice such as C57BL/6 and BALB/c have been generally found to present no nocturnal melatonin peak, in contrast to others such as C3H/He and CBA mice, the aim of this study was to examine the adaptation of daily locomotor activity to a light/dark cycle phase shift in these four strains. An apparatus consisting of two boxes connected by a tunnel was used to record spontaneous locomotor activity, defined as the number of transitions between the two boxes. Locomotor activity was monitored continuously during 3 days before and 14 days after a 12-h phase delay of the light/dark cycle. Results essentially showed that the adaptation of the locomotor activity rhythm to the phase shift was faster in C57BL/6 and BALB/c mice than in C3H/He and CBA mice. This could be related, at least in part, to the differences in melatonin synthesis between the former strains and the latter ones. Although melatonin nocturnal peak is not necessary to a daylight regulation of circadian functions in rodents, it could be considered as an endocrine message that takes part in the anticipation of the following light/dark cycle.

Animals↗

PubMed1998

[Prevention of health risks in the use of MRI procedures. Recommendations of the Radiation Protection Commission].

Magnetic resonance imaging is used routinely with much success for various problems in different medical disciplines. However, the patient is exposed to static as well as to time-dependent magnetic fields and radiofrequency electromagnetic fields. In 1997 the Strahlenschutzkommission, the German Radiological Protection Commission, passed a recommendation on the use of magnetic resonance in medical diagnostics. In this recommendation basic values related to thresholds for physiological effects and limits for restricted and unrestricted use are given. In the following the aim and applicability of this recommendation are discussed, as well as the thresholds and different limits for the static magnetic fields, the gradient fields and the radio-frequency fields. Additionally, advice is given for the protection of high-risk patients, personnel, and the general public, together with further safety advice as well as recommendations for users and manufacturers.

Dose-Response Relationship, Radiation↗

PubMed1998

Paternal alcohol exposure: developmental and behavioral effects on the offspring of rats.

The effect of paternal alcohol exposure on neurochemical and behavioral parameters was investigated using as a model system glial cells derived from newborn rat brain and cultured for 4 weeks. The total brain neurochemical parameters from rats born to mothers sired by an alcohol treated father were also investigated. Enzymatic markers of nerve cell development (enolase isoenzymes and glutamine synthetase) and the defense system (superoxide dismutase) against free radicals formed during alcohol degradation were measured in order to evaluate nerve cell damage. Behavioral locomotor tests (open-field, novelty-seeking, light/dark) were carried out to show long-lasting effects of paternal alcoholization on the offspring. Behavioral and developmental alterations were found until 1 year of age in the offspring and a significant growth retardation was observed in the males. Our results suggest that paternal alcohol exposure produces developmental and behavioral effects in the offspring. The consequence of either alcohol withdrawal during stage one spermatogenesis, or maternal diet supplementation with manganese during pregnancy were investigated. It was observed that some of the effects of paternal alcohol exposure on the offspring may be reversed by these treatments.

Animals↗

PubMed1997

Thalidomide: lack of mutagenic activity across phyla and genetic endpoints.

The human and rabbit teratogen thalidomide has been tested for mutagenicity in a wide range of assays, ranging from bacterial gene mutation assays conducted in vitro to in vivo cytogenetic assays conducted using rabbits, and including a variety of human-derived tissues. Thalidomide was not mutagenic to 6 strains of Salmonella when tested both in the presence and absence of Aroclor-induced rat liver S9 mix. This inactivity was confirmed in strains TA98 and TA100 using a 1-h pre-incubation assay protocol with the same S9 mix (10% S9), and additionally, in strain TA98 using 3 concentrations of S9 (4%, 10% and 30% S9 in S9 mix). Thalidomide was not clastogenic either to cultured human lymphocytes (whole blood cultures, minus S9 mix) or to Chinese hamster ovary (CHO) cells treated in vitro. Further, no cytotoxicity was observed in purified human lymphocytes when exposed to thalidomide up to the limit of its solubility in the medium in the presence and absence of liver S9 from Aroclor-induced pregnant rabbit. The CHO assays were conducted without metabolic activation and in the presence of a variety of sources of auxiliary metabolic activation (PB/beta NP-induced rat liver S9 mix, pooled male and female human liver S9 mix, uninduced and Aroclor-induced pregnant rabbit liver S9 mix and foetal rabbit S9 mix). Thalidomide did not induce micronuclei in isolated human lymphocytes (minus S9 mix) and it was non-mutagenic to mouse lymphoma L5178Y TK+/- cells when tested to the limits of its solubility in the culture medium (+/- S9 mix). No indication of recombinogenic or clastogenic activity was observed for thalidomide when tested in Drosophila. In addition, it failed to induce chromosome aberrations in grasshopper neuroblasts when tested in the presence and absence of Aroclor-induced rat liver S9 mix. Some unusual chromosome morphologies were observed in the grasshopper cytogenetic preparations indicating a potential of thalidomide to interact with chromosomal proteins. However, this potential was not evident in the human lymphocyte micronucleus assay, and thalidomide was apparently not reactive to the proteins of the mouse skin, as it gave negative results in a mouse local lymph node assay for skin sensitizing agents. Thalidomide was inactive in bone marrow micronucleus assays conducted using males and females from two strains of mice, and female New Zealand white rabbits. It is concluded that thalidomide is neither a mutagen nor an aneugen. This conclusion is discussed within the context of the results of earlier mutagenicity studies, the recent claim that thalidomide may be a heritable germ cell mutagen to humans, and the current interest in thalidomide for the treatment of immune system-related diseases.

Abnormalities, Drug-Induced↗

PubMed1997

Effects of various modes of androgen substitution therapy on erythropoiesis.

In order to investigate differential effects of androgens on erythropoiesis, 55 men with clincally and biochemical confirmed hypogonadism were randomly assigned to 4 groups receiving different forms of androgen substitution: Mesterolone (MES) 100 mg/d, testosterone undecanoate (TU) 160 mg/d, testosterone enanthate (TE) 250 mg i.m./21 days or 1200 mg crystalline testosterone (TPEL) subcutaneously implanted at study begin. Previous testosterone medication had been suspended at least 3 months prior to study begin. Testosterone (T), dihydrotestosterone (DHT), hemoglobin (HB) and hematocrit (HC) were assessed before, during and after substitution of androgens. MES did not increase serum T and TU raised average T levels during substitution to 5.7 +/- 0.3 nmol/l, thereby doubling baseline concentrations. TE resulted in a 6fold increase of baseline T yielding 13.5 +/- 0.7 nmol/l and TPEL increased serum T 8.5fold to 23.2 +/- 1.1 nmol/l. Average DHT levels during substitution were 4.3 +/- 0.2 (MES), 3.3 +/- 0.2 (TU), 4.0 +/- 0.4 (TE) and 5.5 +/- 0.4 (TPEL) nmol/l. The groups receiving TPEL, TU or TE showed a significant rise of HB and HC compared to baseline, whereas in the MES group these parameters did not change significantly. MES increased HB by 5.6 +/- 1.8 g/l, TU by 12.7 +/- 2.8 g/l, TE by 21.1 +/- 2.6 g/l and TPEL by 21.7 +/- 4.0 g/l. HC was raised by 1.8 +/- 0. 4% in the MES group, 3.9 +/- 1.1% in the TU group and 6.4 +/- 0.9% and 6.5 +/- 1.6% in the TE and TPEL groups, respectively. Except for 1 subject in the TPEL group, the HB and HC stayed within the normal limits. We conclude that, T, but not DHT, stimulates erythropoiesis in a dose dependent manner. T levels within the low normal range for men are required for maximal stimulation of erythropoiesis.

Adult↗

PubMed1997

Pain management: a quality improvement project.

Pain management in the PACU is vital to patient care and favorable outcomes. Understanding all aspects of pain management is essential when caring for surgical patients. Most PACUs have quality improvement (QI) and/or risk management projects that involve pain management. This article discusses a QI project on the management of pain and the effect it had on nursing practice. The QI committee developed an improvement program that identified a patient care need and changed practice to improve patient care. The project began with the question "Are we accurately assessing patients' pain, or is the pain assessed only what the nurse perceives?" The QI data collected indicated that 100% of patients were discharged with adequate pain relief. The question was answered by following the recommendations of the Joint Commission on Accreditation of Healthcare Organizations for the QI process, in addition to using a model for linking outcomes to care processes developed by Windle and Houston.

Humans↗

PubMed1997

Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men.

The ob gene product leptin (OB) is a feedback signal from the adipocyte to the hypothalamus and is involved in regulation of food intake and energy expenditure in rodents. A major determinant of serum OB levels is fat mass. Several studies suggest that men have lower OB levels than women even after adjustment for percent body fat. We, therefore, investigated the influence of testosterone (T) substitution in hypogonadal men on serum OB levels. Hypogonadal men with T levels of 3.6 nmol/L or less and off substitution therapy for at least 3 months were assigned to two treatment groups: testosterone enanthate (TE; 250 mg, i.m., every 21 days; n = 10) or a single s.c. implantation of 1200 mg crystalline T (TPEL; n = 12). Blood samples for determination of T, 5 alpha-dihydrotestosterone (DHT), sex hormone-binding globulin, and 17 beta-estradiol were obtained before therapy and then every 21 days until day 189 and at follow-up visits on days 246 and 300. Serum OB levels were assessed on days 0, 42, 84, 126, 168, and 300. OB levels were referred to a normal range for men based on the analysis of OB levels in 393 adult men. Substitution with T led to a large rise in T and DHT in both groups compared to baseline values (average T, days 21-189: TE, 14.33 +/- 2.63 nmol/L; TPEL, 24.98 +/- 1.64; average DHT, days 21-189: TE, 4.20 +/- 0.57 nmol/L; TPEL, 5.11 +/- 0.56; P < or = 0.05). Concomitantly, 17 beta-estradiol increased in both groups, and sex hormone-binding globulin levels were significantly decreased. At baseline, serum OB levels in hypogonadal men were 3-fold elevated compared to those in normal men (12.39 +/- 2.93 micrograms/L vs. 4.28 +/- 0.52; P < 0.01) and not different between groups (TE, 13.7 +/- 5.6; TPEL, 11.3 +/- 2.9 micrograms/L). This elevation was retained after adjustment for body mass index in the normal control group [TE, 1.45 +/- 0.51 SD score (P < 0.0001); TPEL, 0.98 +/- 0.35 SD score (P < 0.0008)]. During T substitution serum OB was completely normalized (trough levels: TE, 4.6 +/- 1.0 micrograms/L; TPEL 4.3 +/- 0.9 micrograms/L). In multiple regression analysis, the androgen (T plus DHT)/estrogen ratio was the only significant determinant of OB levels (r = -0.32; P < 0.01). At baseline, OB levels did not correlate with body mass index, but during substitution, the correlation was considerably improved. We conclude that hypogonadal men exhibit elevated OB levels that are normalized by substitution with T. The only determinant of OB levels was the androgen/estrogen ratio, indicating a major influence of sex steroids on OB production. The interaction of T and OB might be part of a hypothalamic-pituitary-gonadal-adipose tissue axis that is involved in body weight maintenance and reproductive function.

Adult↗

PubMed1996

Somatic recombination, gene amplification and cancer.

The principle objective of this research programme, to analyse chemical induction of somatic recombination and related endpoints, i.e., mobilization of transposing elements and gene amplification, has been approached by means of several assay systems. These have included Drosophila, Saccharomyces and mammalian cell cultures. 6.1. Screening assays for mitotic recombination. A large number of chemicals have been investigated in the three Drosophila assay systems employed--the multiple wing hair/flare wing spot system developed by Graf et al., 1984, the white-ivory system developed by Green et al., 1986 and the white/white+ eye spot assay developed by Vogel (Vogel and Nivard, 1993). Particularly the screening of 181 chemicals, covering a wide array of chemical classes, by the last mentioned assay has shown that measurement of somatic recombination in Drosophila constitutes a sensitive and efficient short-term test which shows a remarkably good correlation with the agent score of 83 short-term tests analysed by ICPEMC (Mendelsohn et al., 1992; Table 2) as well as the assay performance in international collaborative programmes measuring carcinogen/non-carcinogens (de Serres and Ashby, 1981; Ashby et al., 1985, 1988). Also the wing spot assay has gained wide international recognition as a similarly sensitive test. These two assay systems in Drosophila measure both intrachromosomal events and interchromosomal recombination. The white-ivory system on the other hand is based on the loss of a tandem duplication in the white locus, the mechanism of which is less known, but probably involves intrachromosomal recombination. The difference in the mechanism between this assay and the former two was indicated by the lack of response to methotrexate in the white-ivory assay, while this compound was strongly recombinogenic in both the wing spot and white/white+ assays. The use of different strains of Drosophila with the white/white+ assay demonstrated the importance of the background genotype for the outcome of the test. Up to a 60-fold variation was found between the different genotypes in the response to procarcinogens, evidently dependent on differences in the metabolic activation of procarcinogens. In 1989 Schiestl presented results on intrachromosomal recombination in the strain RS112 of Saccharomyces, which indicated a capability to detect a range of chemical carcinogens, which gave negative results in Ames Salmonella assay. Such a test system, which could identify a larger range of potential carcinogens than conventional short-term tests evidently would be of great value and it therefore seemed of importance to follow up the observations by Schiestl. However, studies within this programme on the same strain of Saccharomyces, as well as the strains D7 (measuring intragenic recombination, intergenic recombination, and point mutation) and JD1 (measuring intragenic recombination at two loci) could not support the observations and interpretation by Schiestl (1989). The Drosophila white-ivory system, which presumably responds primarily by intrachromosomal recombination, did not give positive results with these Salmonella-negative agents either. One system to measure mitotic recombination in mammalian cell cultures was developed in the present programme. It was based on heterozygous mutations in both alleles of the adenosine deaminase gene (ADA). The system selects for proficient recombinants generated by the deficient cells. So far only pilot experiments, indicating that this experimental system operates as planned, have been performed. 6.2 Mechanisms of mitotic recombination The induction of mosaic spots in the wing spot and the white/white+ assays is predominantly dependent on interchromosomal recombination. This is evident from the fact that heterozygous inversions reduce the frequency of spots. A relationship between the length of inversions and the reduction of spots was demonstrated in the white/white+ assay--the long inversion ln(l)sc4L

Animals↗

PubMed1996

The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice.

The neurosteroid pregnenolone sulfate (PREG-S) has been shown to modulate positively NMDA receptor activity and to have memory enhancing properties in mice. The present study was designed to evaluate the effects of post-training administration of PREG-S, alone or in combination with D-2-amino-5-phosphonovalerate (D-AP5), a competitive NMDA receptor antagonist, in Y-maze avoidance and appetitively motivated lever-press learning tasks and in a traction reflex test in mice. Intracerebroventricular (i.c.v.) administration of PREG-S (0.01-0.1 nmol/mouse) blocked the selective retention deficits induced by 0.02 nmol D-AP5 in the Y-maze avoidance task. PREG-S (0.1 nmol, i.c.v.) also blocked the retention deficits induced by 0.02 nmol D-AP5 in the lever-press task. Post-training administration of PREG-S alone (0.001-0.1 nmol, i.c.v.) had no effect on retention performance in the Y-maze and the lever-press tasks. PREG-S (1-10 nmol, i.c.v.) significantly reduced the impairment of the traction reflex induced by 2 nmol D-AP5. The ability of PREG-S to block retention performance deficits as well as motor impairment induced by D-AP5 is in agreement with its positive modulatory action at NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1996

[A review of epidemiologic studies on ultrasound during pregnancy].

This article reviews most of the more recent epidemiological studies on the effectiveness and possible risks of conventional sonography. With the help of such a review, case reports, very often cited out of context, can be better evaluated. Publications which have attempted to study the number of malformations, diagnosable by ultrasound, and to the effect of ultrasound on postnatal mortality and morbidity are scrutinized. Furthermore the question of possible late effects of ultrasound is addressed, such as effects on birth weight, neural development and cancer incidence. Routine sonography is of great value; no negative late effects on the child have been found. The effectiveness and risks of Doppler flow ultrasound have not been studied sufficiently well to allow a similar conclusion.

Congenital Abnormalities↗

PubMed1996

Pharmacokinetics and pharmacodynamics of subcutaneous testosterone implants in hypogonadal men.

OBJECTIVE: There are advantages and disadvantages with all of the presently available types of testosterone replacement for hypogonadal men. We performed this investigation to establish detailed data about the pharmacokinetics, pharmacodynamics, feasibility and side-effects of subcutaneously implanted testosterone (T) pellets. DESIGN AND MEASUREMENT: In a single-dose, open-label, non-randomized study, 6 T-pellets, each containing 200 mg of fused crystalline T, were implanted in the subdermal fat tissue of the lower abdominal wall of 14 hypogonadal men. Blood samples for determination of T, LH, FSH, 5 alpha-dihydrotestosterone (DHT), sex hormone binding globulin (SHBG) and oestradiol (E2) were obtained at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48 hours and on day 21 after implantation and then every 3 weeks until day 189, and on days 246 and 300 during follow-up. In another 36 hypogonadal men the feasibility and side-effects of T-pellets were evaluated. PATIENTS: Fourteen patients participated in the detailed pharmacokinetic study and another 36 patients in the assessment of feasibility and side-effects. All patients (age range 18-61 years) suffered from primary or secondary hypogonadism (T < 3.6 nmol/l). RESULTS: The pharmacokinetic study in 14 hypogonadal men revealed an initial short-lived burst release of T with a peak concentration of 49.0 +/- 3.7 nmol/l at 0.5 +/- 0.13 days which was followed by a stable plateau lasting until day 63 (day 2, 35.2 +/- 2.3; day 63, 34.8 +/- 2.6 nmol/l). Thereafter serum T gradually declined and was close to baseline concentrations on day 300. Apparent terminal elimination half-life (t1/2) was 70.8 +/- 10.7 days and apparent mean residence time 87.0 +/- 4.5 days. On average, serum T was below 10 nmol/l after 180 days. Absorption of T followed a zero-order release kinetic with an absorption half-time of 74.7 days (95% confidence interval: 71.1-78.5) and was almost complete by day 189 (95.9 +/- 0.84%). Serum DHT and E2 were significantly elevated from day 21 to day 105 and correlated significantly with T (DHT, r = 0.65, P < 0.0001, E2, r = 0.67, P < 0.0001). SHBG was significantly decreased from day 21 to day 168. In 6 men with primary hypogonadism T suppressed LH and FSH to the eugonadal range from day 21 to 126 and 42 to 105, respectively, with nadirs occurring at day 84 (LH) and day 63 (FSH). LH and FSH were highly inversely correlated with T (r = -0.47 and -0.57). The only side-effect observed during 112 implantations in the total group of 50 men were 6 local infections (5.4%) leading to extrusion of 5 pellets in 3 men. When given the choice, all patients except one preferred T-pellets to their previous T medication for permanent substitution therapy. CONCLUSION: T-pellets are the androgen formulation with the longest biological action and strongest pharmacodynamic efficacy in terms of gonadotrophin suppression. The pharmacokinetic features are advantageous compared to other T preparations and the patient acceptance is high.

Adolescent↗

PubMed1995

1,3-Butadiene working group report.

During the Workshop in North Carolina, the in vivo metabolism, adduct formation and genotoxicity data available from rodent and human exposure to 1,3-butadiente (BD) were reviewed and they are summarized in the present report. BD is metabolized by cytochrome P-450-dependent monoxygenases to the primary metabolite 1,2-epoxybutene-3 (epoxybutene, EB). EB is subjected to further metabolism: oxidation to 1,2:3,4-diepoxybutane (DEB), hydrolysis to 3-butene-1,2-diol and conjugation to glutathione. The first pathway seems to prevail in mice while the latter is characteristic for rats and possibly for humans. Species differences exist in adduct formation of the monoepoxide to hemoglobin, for which the following pattern has been found: mice > rats > humans. Genotoxity of BD was found in mice with all applied tests; however, negative results were obtained in rats. In exposed humans, the cytogenetic studies in peripheral blood lymphocytes did not show genotoxic effects, although one report described elevated hprt variant levels in peripheral blood lymphocytes of exposed workers. It was concluded that the presently available data are insufficient for the application of the parallelogram model to estimate genetic risk for humans. As an alternative approach, a tentative estimate of the doubling dose for induction of hprt mutations in somatic cells of mice and men was performed and the calculated values were surprisingly similar, i.e. 9000 ppmh. However, this estimate is burdened with a number of caveats which were discussed in detail. The working group identified a series of urgent research needs to provide the appropriate data for the application of the parallelogram model, such as identification of metabolic pathways in different rodent species and humans, metabolic studies in mice, rats and humans considering metabolic polymorphisms, studies of adducts to DNA and hemoglobin especially of DEB and other butadiene metabolites in rodents and humans, studies of mutational spectra (mutational fingerprinting) in somatic and germinal cells, confirmation of the human hprt mutation data, conformation of the rodent malformation data, dose-response studies in rodent germ cell tests and studies on repair kinetics of mono-adducts induced by EB as opposed to repair of cross-links produced by DEB. Finally, it was suggested that the original parallelogram consisting of data from somatic cell studies in rodents and humans plus studies of heritable effects in rodents to extrapolate to germ cell risk for humans should be supplemented with studies in sperm of experimental animals and exposed men.

Animals↗

PubMed1994

A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by an impairment of specific antibody production and a decrease in all or selected Ig isotypes. Abnormalities at the level of the B cells, T cells, and antigen-presenting cells have been described. In the present study, we have focused our attention on T-cell activation in CVID. T cells from 15 of 24 patients failed to respond to recall antigens (eg, tetanus toxoid, Escherichia coli). Of these 15 patients, 11 were studied in detail and showed significantly decreased T-cell proliferative responses and/or decreased interleukin-2 and interferon-gamma production on T-cell receptor-mediated stimulation with recall antigens and superantigens (staphylococcal enterotoxins [SE]); however, T-cell response to mitogens (anti-CD3 monoclonal antibody, phytohemagglutinin) was normal. The defect in interleukin-2 and interferon-gamma release on tetanus toxoid stimulation could also be documented in purified CD4 T cells of the patients and was present in patients with high and normal CD8 counts alike. Furthermore, patients' T cells failed to mount a significant elevation in free intracellular calcium (Ca++ flux) in response to superantigen, whereas the response to phorbol myristate acetate and ionomycin, bypassing receptor-mediated signaling, was unimpaired. These results indicate a defect in the early phase of T-cell activation after triggering of the T-cell receptor in a significant subgroup of CVID patients.

Adolescent↗

PubMed1994

Human serum IgA downregulates the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6) in human monocytes.

While the protective effect of IgA antibodies against infection of the mucosal surfaces is well documented, the mechanisms involved are not entirely clear. The aim of the current study is to investigate the effect of human serum IgA on the release of inflammatory cytokines in human monocytes activated with a particulate stimulus, Haemophilus influenzae type b (Hib), or soluble lipopolysaccharide (LPS) purified from Escherichia coli. Our results show that IgA downregulates tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production, whereas IgG examined in parallel had no effect. IgA had no inhibitory effect on Hib-induced granulocyte-macrophage colony-stimulating factor release. TNF-alpha and IL-6 release were downmodulated if IgA was present during cytokine induction, and IgA was also inhibitory if added to Hib-pretreated monocytes during the phase of cytokine release. These findings indicate that there are at least two mechanisms whereby IgA antibodies can downregulate TNF-alpha and IL-6 release in human monocytes: by a mechanism acting during the time of monocyte activation, and a mechanism that downregulates the production and/or the release of these cytokines in activated monocytes. Regulation of TNF-alpha and IL-6 release by IgA may be among the antiinflammatory mechanisms preventing an uncontrolled release of potentially noxious levels of inflammatory cytokines during acute and/or chronic inflammation.

Antigen-Presenting Cells↗

PubMed1994

Infection of human polyomaviruses JC and BK in peripheral blood leukocytes from immunocompetent individuals.

Widely disseminated infection with the human polyomaviruses JC and BK is followed by lifelong asymptomatic viral persistence that can be reactivated under prolonged immunosuppression to fatal CNS and urogenital disease. In an attempt to understand the pathogenesis of polyomavirus diseases, we asked whether leukocytes are involved in polyomavirus infection in the immunocompetent host. Peripheral blood leukocytes from 29 immunocompetent individuals and umbilical cord blood from 10 newborn children were analyzed for the presence of polyomavirus DNA. Southern blot analysis demonstrated the presence of JCV-specific full-length virus genomes and indicated involvement of the second human polyomavirus BK. In contrast to specimens from newborn children, PCR amplification of target DNA in the adult age group followed by species-specific hybridization provided evidence of concomitant JCV and BKV infection in almost all specimens. Nucleotide sequencing of virus-specific products representing DNA segments essential for virus multiplication confirmed presence of both virus species in leukocytes. The detection of a new virus subtype and single base changes or deletions in the noncoding DNA region from individual cases suggested widespread heterogeneity in the circulating virus population, although the structure of the transcriptional control elements in all cases was comparable to highly active elements found in lytically infected cells. Those findings and the localization of both virus types in the nuclei of blood cells by in situ hybridization demonstrate that JCV and BKV frequently infect peripheral leukocytes and give strong evidence that leukocytes are common sites of polyomavirus persistence in healthy individuals.

BK Virus↗