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H Helge

Publications and source records attributed to H Helge.

At least 19 recordsLinked to original sources
PubMed2000

Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system: 3. Plasma immunoglobulins and cytokines of workers with quantified moderately-increased body burdens.

The concentrations of immunoglobulins (IgA, IgD, IgG, IgM) and of several cytokines were measured in the plasma of volunteers with clearly, but moderately, increased body burdens of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDF), using monoclonal antibodies and an enzyme-linked immuno-sorbant assay. Two groups of workers with different body burdens of PCDD/PCDF were studied: (trial I) persons with mainly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and (trial II) persons with mainly penta- and hexachlorinated dibenzofurans (P5CDF/H6CDF) in their blood fat. Including the reference group, 158 volunteers were investigated. A slight but statistically significant decrease was observed in the plasma concentration of IgG1 in persons exposed to TCDD, but not in persons exposed to P5CDF/H6CDF. When the data of both groups were pooled and a multi-regression analysis against international TCDD toxicity equivalencies (I-TEq, NATO/CCMS) was performed, taking several confounding factors into account, no influence of the dioxin exposure could be revealed. There were no changes in the plasma concentrations of the other immunoglobulins studied. In the same volunteers, no deviation from the reference range was found for the concentrations of the cytokines: IL-1alpha, IL-1beta, IL-6 and TNFalpha in blood plasma.

Adult↗
PubMed2000

Assessing lymphocyte functions in neonates for revealing abnormal prenatal development of the immune system.

Because it is difficult to assess prenatally induced functional deficits of the human immune system, we developed an ex vivo method for differentiation and maturation of peripheral lymphocytes of newborn, preferentially using umbilical cord blood. Many lymphocyte subsets of newborn infants are "immature" with respect to defined surface receptors. An example of such an immaturity is the almost complete lack of "memory"-type helper T cells (also designated as helper-inducer cells), characterized by expressing the surface receptors: CD4(+)CD45R0(+)CD45RA(-)CD29(high). On the other hand, umbilical cord blood contains many "naive"-type helper T cells (often designated as suppressor-inducer cells), with the receptors: CD4(+)CD45R0(-)CD45RA(+)CD29(low). In this report, we demonstrate that the immature helper lymphocyte population of umbilical cord blood is capable of differentiating to mature cells following stimulation with pokeweed mitogen (PWM) and other stimulants ex vivo. The obtained receptor pattern is virtually indistinguishable from the one observed on the mature cells of adults. Such an extensive differentiation can only be achieved with cells of newborns. As intermediates during differentiation in culture, CD45R0(+)CD45RA(+) cells may be observed which are rather rare in vivo. Additionally, the appearance of several activation (CD25, CD69, HLA-DR) and adhesion (CD11a, CD11b, CD11c, CD18, CD49b, CD49d, CD54) receptors on CD4 cells were analyzed. With this model system evidence for the sequence of events during differentiation and maturation may be obtained. This ex vivo-model is capable of studying the capacity of lymphocytes for differentiation and activation processes barely accessible in vivo. It may also be expected to represent an interesting tool for measuring the capacity for maturation and differentiation in the blood of children of different ages under normal and pathological conditions ex vivo. In addition, substance-induced effects may be studied in vitro with this approach on immature cells from newborn, or infants during culturing. Teratogenesis Carcinog. Mutagen. 20:171-193, 2000.

Antigens, CD20↗
PubMed1998

Evaluation of the age-dependent development of lymphocyte surface receptors in children.

Components and functions of the immune system change during postnatal development, not only in the first years of life, but well through adolescence and even into adult life. These age-dependent changes within the immune system greatly complicate any attempt to assess pathological alterations of immunologic variables in children. The need for studies on possible substance-induced changes, including risk assessment of environmental chemicals, has increased the necessity to establish reference ranges for certain immunologic variables against which an abnormal developmental status can be evaluated. In the present study age-related changes of surface receptors on peripheral white blood cells were studied in 82 children, aged between 2 months and 17 years. The blood samples were triple labeled with monoclonal antibodies followed by a whole blood lysis technique and were subsequently analyzed by flow cytometry. Complex statistical analyses were performed in order to determine probability ranges for some immunological variables. In this paper we describe the age-dependent development of components involved in major maturational processes, including the appearance and varying expression of adhesion receptors (CD11a, CD18, CD28, CD29, CD44, CD49d and CD54) on CD4+ "helper" cells and CD8+ "suppressor and cytotoxic" cells. A clear-cut increase of high epitope density expression of the integrins on both CD4+ and CD8+ cells was noted. These results suggest that the components of immune T cells for performing adhesion by interacting with other cells and many matrix components are largely acquired during postnatal development. Maximal levels of adhesion receptor expression are reached at different ages depending on the specific T cell subpopulation.

Adolescent↗
PubMed1997

Prevalence of Helicobacter pylori infection in Nicaraguan children with persistent diarrhea, diagnosed by the 13C-urea breath test.

BACKGROUND: The impairment of gastric acid barrier caused by Helicobacter pylori (H. pylori) at the onset of infection may predispose to small bowel bacterial overgrowth, which could contribute to persistent diarrhea. METHODS: Using the 13C-urea breath test, we determined the prevalence of H. pylori infection in 123 Nicaraguan children from Tipitapa, aged 1 to 65 months, from a low socioeconomic background. RESULTS: The overall prevalence of H. pylori infection was 77.2% (95/123). The prevalence varied with age and was significantly (p < 0.001) higher in infants < or = 12 months than in children aged 13-65 months, 91% (57/63) as against 63% (38/60). H. pylori infection was present in 44 of 59 (75%) children suffering from persistent diarrhea compared with 51 of 64 (80%) age-matched asymptomatic controls. In the diarrheal group, 20 of 59 (34%) children presented with malnutrition, and 16 (80%) of them showed H. pylori infection. In the control group, 20 of 64 (31%) were malnourished, and 14 (70%) of them showed H. pylori infection. CONCLUSIONS: In Nicaragua, H. pylori is acquired in early infancy. The high prevalence among children in the first 12 months of life and the lower infection rate between 1 and 5 years of age suggest a loss or clearance of infection, also an occasional finding in adults. H. pylori infection appears to be not a risk factor for persistent diarrhea or malnutrition in Nicaraguan children.

Age Factors↗
PubMed1996

Cross-reactivity of antihuman monoclonal antibodies with cell surface receptors in the common marmoset.

In this report we demonstrate that a large number of monoclonal antibodies (mAbs) against human epitopes cross-react with surface receptors on white blood cells of Callithrix jacchus, indicating species similarities. However, a variety of other mAbs do not exhibit any cross-reactivity, thus also providing evidence for distinct differences in the structure of these receptors among nonhuman primates. Such differences have to be known and taken into consideration when attempting extrapolations between species. The results presented provide the prerequisite for performing extensive studies on immunological structures and functions in marmosets under normal and pathological conditions. We conclude that the immune system of Callithrix jacchus is a convenient model for studies on immunotoxicity with relevance for man, and for this purpose it is clearly superior to that of any rodent species.

Animals↗
PubMed1996

Antiepileptic drug treatment in pregnancy: drug side effects in the neonate and neurological outcome.

Antiepileptic drugs taken by pregnant epileptic women are known human teratogens. They may also cause pharmacological side effects in the newborn, i.e. sedation and or withdrawal symptoms. We examined the relationship between the maternal antiepileptic therapy, neonatal behaviour and later neurological functions in infancy. The study comprised 40 children exposed in utero to a single antiepileptic drug (phenobarbitone, phenytoin, valproic acid). Valproic-acid-exposed children were the highest compromised, except for apathy, which was most profound in phenobarbitone-exposed neonates. Valproic acid serum concentrations at birth correlated with the degree of neonatal hyper-excitability and neurological dysfunction when children were re-examined 6 years later. We suggest that valproic acid may not only cause malformations but also cerebral dysfunction immediate and long term.

Anticonvulsants↗
PubMed1996

Intake, fecal excretion, and body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans in breast-fed and formula-fed infants.

To assess toxicokinetics of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), oral intake and fecal excretion were measured in two breast-fed infants and one formula-fed infant during the 1st y of life. The intake of these compounds was up to 50 times higher in the breast-fed infants. In these children, fecal excretion of the main tetra- to hexachlorinated congeners was less than 9% of the intake at age of 1 and 5 mo, indicating almost complete intestinal absorption during breast-feeding. In contrast, distinctly higher fecal excretion rates were observed for the hepta- and octachlorinated compounds. Despite much lower PCDD/PCDF intake after weaning, concentrations in stool fat did not decrease substantially. We conclude that concentrations in fecal fat more or less reflect those in body fat. Additionally, PCDD/PCDF concentrations were measured in blood fat of all infants (and in a second formula-fed baby) at the age of 11 mo. International toxicity equivalent (I-TEq) concentrations in the formula-fed infants were less than 25% of maternal values and about 10 times lower than in the infants breast-fed for 6-7 mo. In the latter, a distinct accumulation was found for the tetra- to hexachlorinated congeners compared with maternal concentrations. We conclude that accumulation of PCDDs and PCDFs in infants is as high as expected on the basis of intake data and assuming complete absorption and negligible elimination during the 1st y of life.

Benzofurans↗
PubMed1995

Thalidomide and the immune system. 4. Down-regulation of the CD26 receptor, probably involved in the binding of HIV components to T cells in primates.

Thalidomide (Thd) is capable of down-regulating the CD26 receptor on CD4+ lymphocytes after treatment of healthy volunteers. Similar effects are observed when marmosets (Callithrix jacchus) are treated with Thd. The Ta1 epitope of the CD26 receptor has recently been shown to bind the HIV-1 Tat trans-activating protein, and CD26 has also been suggested to be a coreceptor for the binding of the V3 loop of the gp120 HIV envelope protein. This might provide a hint for possible therapeutic interventions.

Animals↗
PubMed1995

Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 2. In vitro proliferation of lymphocytes from workers with quantified moderately-increased body burdens.

Lymphocyte proliferation responses were studied in workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs, calculated as International Toxicity Equivalencies [I-TE]). Mitogens (pokeweed mitogen [PWM], phytohemagglutinine [PHA], concanavalin A [Con A]), as well as an anti-human monoclonal antibody against CD3 were used as proliferation stimulators in vitro. Additionally, the feasibility of using the lymphocyte response to tetanus toxoid was assessed, and the response to this recall-antigen was included in this trial. No decrease in the capacity of 3H-thymidine incorporation was observed with any of the proliferation stimulators in the group of volunteers with the increased TCDD-body burden when compared with volunteers exhibiting TCDD-concentrations in blood fat within the reference range. Regression analysis revealed a slight trend towards an increase for 3H-thymidine incorporation during the stimulation with PHA only. It can be concluded from our data that moderate increases in the TCDD- or I-TE-body burdens do not induce any medically significant changes in the capacity for proliferation of lymphocytes, measured as 3H-thymidine incorporation.

Adult↗
PubMed1995

Proliferative capacity of marmoset lymphocytes after tetanus vaccination and lack of 2,3,7,8-tetrachlorodibenzo-p-dioxin to reduce a booster effect.

Marmosets (Callithrix jacchus) were vaccinated with tetanus toxoid and boostered 3 months and 1 year following the initial immunization. During this period, the proliferative response of lymphocytes (3H-thymidine incorporation) to the recall antigen was measured in vitro in blood samples 7 times. The experimental procedure proved to be suitable to monitor a defined but complex function of the immune system, and to assess possible substance-induced alterations with minimal stress or discomfort for the non-human primates. As a first example, a possible interference by a single very small dose (100 ng/kg body weight) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given at the time of the second booster was evaluated. No reduction in the in vitro response of the lymphocytes to recall antigen was observed under the experimental conditions used, and the extent of the 3H-thymidine incorporation was not significantly different in the groups. When the ratio of the responses between the first and the second booster was taken as a measure, there was a slight but statistically significant increase in this ratio for the lymphocytes of the TCDD-treated marmosets over that of reference animals. The limitations of these attempts to develop a test system and evaluate a substance-induced effect, and possible improvements of the test, e.g. with multivaccination, are discussed. It is suggested to use this approach also after routine multivaccination in children to assess possible substance-induced effects on immunological variables. This would allow an excellent comparison of experimental and clinical data obtained in primates with an identical technology.

Animals↗
PubMed1994

Dependence of the utilization of a phenylalanine-free amino acid mixture on different amounts of single dose ingested. A case report.

For patients with phenylketonuria the daily ingested phenylalanine-free amino acid mixture is the most important source of nitrogen. It is recommended to ingest one third of the total amount combined with main meals. Some patients, especially the older ones, do not follow this recommendation; they ingest the entire daily amount of amino acid mixture in one portion. This intake mode leads to an increased oxidative utilization of the amino acids. To set up an example for this metabolic phenomenon, a 13C-leucine breath test was performed in one female phenylketonuric patient. She ingested a third of her daily amount of the amino acid mixture combined with an oral tracer of 3 mg 13C-leucine/kg body weight at breakfast. The breath test was carried out by a standardized time schedule over 5 h. Three days later the breath test was repeated when she ingested the total amount of amino acid mixture in only one portion at breakfast. Total daily caloric intake and food composition were not changed. On both days a 24 h urine was collected to determine total nitrogen loss. The 13C-content of expired air was analysed by gas isotope ratio mass spectrometry, the total nitrogen content was determined using a combustion unit. The 13C-elimination rate as a percentage of the applied 13C-tracer was 9.5% on the first test day as compared to 19.6% on the 2nd day. The corresponding total nitrogen excretion was increased (4.3-6.9 g/24 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells.

Time-dependent changes in the surface receptor expression of various maturational and integrin receptors on peripheral blood cells were studied in two healthy human volunteers following oral applications of thalidomide (Thd). In each measurement the receptor density was quantified by prior calibration of the flow cytometer with latex beads bearing a determined number of fluorescence molecules. The effects observed in the course of the Thd-treatment were practically identical or at least very similar in both the volunteers during four different trials, and were in accord with previous results obtained in large-scale studies (68 treated animals) with non-human primates. It should be stressed that no clear-cut changes were observed in the percentage or absolute numbers of primary lymphocyte subsets such as CD3, CD4 and CD20. After the first two doses of 7 mg Thd/kg body wt the CD18 (the common beta-chain of the beta 2-integrins) marker already decreased in surface density or was no longer detectable on granulocytes, monocytes and lymphocytes. This effect persisted throughout the treatment period and slowly subsided after discontinuation of treatment. With a few days lag phase, the surface density of CD54 (ICAM-1) on granulocytes increased and many cells previously not bearing this receptor newly acquired such surface markers. On monocytes however, the CD54 receptor was lost on many cells. Within the lymphocyte fraction a loss of the CD54 marker could be noted on CD4 cells but not on CD8 cells, where an increase of the receptor expression could be observed. Other markers, such as the alpha chains of the beta 1 integrins CD49b (VLA alpha 2) and CD49d (VLA alpha 4) showed contrasting reactions to the Thd-treatment. Whereas a pronounced loss of the receptor density of CD49d was observed and only few cells with high epitope density were left in the blood at the end of the complete dosing schedule, no such effect was observable on cells bearing the CD49b epitope. A distinct reduction of the number of receptors was also noticeable on L-selectin (Leu8) bearing cells. On CD4 positive lymphocytes, the majority of the described effects on the integrin and adhesion receptors was seen on cells bearing the CD45R0 maturational epitope. This functional receptor is strongly down-regulated and the pathway of CD45RA to CD45R0 maturation is apparently altered by Thd-treatment. These multiple changes we observed may explain the large variety of therapeutic effects experienced in the treatment with Thd.

Carrier Proteins↗
PubMed1994

The psychological development of children of epileptic parents. I. Study design and comparative findings.

We studied the genetic, neurobiological, teratogenic and psychosocial risks for the development of children born to epileptic parents in (a) children of epileptic mothers with intrauterine exposure to anticonvulsants, (b) children of epileptic mothers without intrauterine exposure to anticonvulsants and (c) children of epileptic fathers. In addition, three matched control groups were also considered. The longitudinal design of the study covered newborns to children of six years of age. A wide range of developmental and psychological tests and a structured interview for the assessment of psychiatric symptoms were used. It was shown that teratogenic factors are operant, whereas there was no indication that the condition of epilepsy in the parents per se had any effect on the developmental outcome of the children. The possible teratogenic effect of anticonvulsants should be studied in more detail.

Adult↗
PubMed1994

The psychological development of children of epileptic parents. II. The differential impact of intrauterine exposure to anticonvulsant drugs and further influential factors.

After obtaining evidence that tetratogenic effects were operant in a sample of children born to epileptic mothers, we analyzed the effects of type of medication and further influential factors. Children with prenatal exposure to polytherapy had significantly lower scores than controls for a large number of psychological tests. In addition to polytherapy, there were even stronger effects of socioeconomic status and sex was found to be less influential than polytherapy. Among further epilepsy variables, only seizure frequency of the mother during pregnancy had a modest impact on the child's developmental outcome, whereas a score of obstetric abnormality was less effective in predicting developmental outcome, as measured and defined by various standardized psychological tests.

Age Factors↗
PubMed1994

Evaluation of possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other congeners on lymphocyte receptors in Callithrix jacchus and man.

Using fluorescence-labeled monoclonal antibodies and flow cytometry (FACScan analysis) we measured surface receptors on peripheral lymphocytes in marmosets (Callithrix jacchus) treated with TCDD in the lower nanogram per kilogram range. Additionally, some polybrominated congeners were studied as well as a 2,3,7,8-substituted dioxin containing chlorine and bromine in the same molecule. Callithrix was found to be very sensitive to the action of TCDD and the other tetrahalogenated congeners; single doses of 10-30 ng/kg body weight reproducibly induced a decrease in the percentage and absolute number of 'memory' helper T cells [CD4+CD29(bright)] and of B cells (CD20+). Subsequently, according to the hypothesis based on the marmoset data, extensive analyses on surface receptors of white blood cells were performed in workers with moderately increased body burdens of TCDD, and for further hypothesis generation > 60 triple-labeling assays were performed with each of the blood samples. No decrease in typical surface receptors (CD4+CD45R0+CD45RA-CD29(bright) or CD20+) was found in the human adult volunteers studied, but a trend toward an increase was noted. It cannot be decided whether this may be a substance-related effect, or results from a confounder (possibly age differences between the groups).

Adult↗
PubMed1994

Risk assessment for possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related substances on components and functions of the immune system.

Numerous reports have been published on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on components and functions of the immune system of animal species, almost exclusively of rodents. Many of the data, obtained with very different dosing schedules, are conflicting or have not been confirmed. Since the overwhelming majority of evaluations were performed with rodents, it is not possible to perform a reliable quantitative or even qualitative risk assessment for TCDD in man based on immunological data obtained from these experiments and to extrapolate them to the situation in humans. In addition to the fact that the doses needed to induce measurable effects in the different species studied varies from 1- to 10,000-fold, there are intrinsic and general difficulties for extrapolations to human beings in the field of immunotoxicology due to the influence of different individual risk factors, e.g. smoking and drinking as well as the lack of experience and validation in this new field of toxicology. Some immunological variables were studied in populations highly exposed to dioxins. In comparison to the results obtained from nonhuman primates, no convincing evidence for substance-related effects was revealed, however, information on only a few immunological components and functions in exposed adults could be assessed so far. Except for one group of studied persons all other subjects were generally exposed to cocktails of several chemicals, vastly complicating the interpretation with respect to one isolated component of these mixtures. Results from studies on exposed children are not available yet.

Animals↗
PubMed1993

Effects of small doses of dioxins on the immune system of marmosets and rats.

There is no doubt that TCDD is capable of inducing effects on a variety of components and functions of the immune system in a variety of species. In fact, such changes seem to belong to the most sensitive variables affected by TCDD. Some of the biological effects, induced at rather high doses of TCDD exhibiting general toxicity (> 3 micrograms TCDD/kg body wt), may be considered unspecific or the result of the pronounced thymus involution. However, other effects (such as that on lymphocyte subtype patterns in marmosets or a reduced resistance of mice to influenza viruses) have been reported to occur at dose levels far from those leading to thymic involution or general toxicity. It should be remembered that the pathognomonic relevance for man of subtle modifications in the pattern of lymphocyte surface receptors is largely unknown. Until now, such deviations are considered rather as biological phenomena than indications or causes of specific diseases. Nevertheless, such changes represent clear-cut biological effects induced by TCDD. Since effects of TCDD on components and defined functions of the immune system have been revealed in several species, it would be surprising if humans were largely resistant to such effects, but reliable data in humans with high exposures to defined dioxins verified by an appropriate quantification of the exposure are scarce as of now. Data published so far have not revealed pronounced alterations of such variables. However, no studies of well-defined human populations with quantified body burdens have been performed with modern methods (such as flow cytometry) analyzing a wide variety of surface receptors. Performance of such studies is essential for a better and reliable risk assessment, and the technology is available. Some of the effects observed (such as the changes in the pattern of lymphocyte subpopulations) must certainly be considered as biological effects induced by TCDD, and the situation is similar to the induction of hepatic monooxygenases, which are also observable in this dose range. However, the relevance of such changes with respect to adverse health effects in humans is presently difficult to judge in the absence of clear-cut functional deficits demonstrated so far either in vivo or in vitro.

Animals↗