Lipooligosaccharide of Campylobacter jejuni prevents myelin-specific enteral tolerance to autoimmune neuritis--a potential mechanism in Guillain-Barre syndrome?

Campylobacter jejuni-induced enteritis is the most common infection preceding Guillain-Barre syndrome (GBS), an immune-mediated polyradiculoneuritis. The acute autoimmune attack is thought to be based on C. jejuni antigens which may mimick antigens of the peripheral nervous system. Additional pathomechanisms, like disturbance of natural T cell immunoregulation by C. jejuni, have not been evaluated so far. In experimental autoimmune neuritis (EAN), a T lymphocyte-mediated animal model of human GBS, tolerance to myelin-derived autoantigens can be induced by oral feeding of the respective antigen. Here we investigated whether the lipooligosaccharide (LOS) fraction of C. jejuni may directly alter immunologic tolerance through gastrointestinal pathways. While EAN, actively induced by immunization with bovine peripheral nerve myelin could be ameliorated by precedent feeding of myelin, feeding of C. jejuni LOS along with the myelin antigen not only prevented the tolerizing effects of oral myelin but even accelerated the onset of overt EAN and augmented the myelin-specific B cell response. These findings provide evidence that LOS of C. jejuni, as produced in the gut during C. jejuni-induced enteritis, can disturb natural tolerance to definite proteins which may be or may mimic peripheral nerve antigens. In human patients this may be one of the potential mechanisms to explain why C. jejuni enteritis is a common trigger of GBS.     

Seasonal malaria transmission and variation of anopheline density in two distinct endemic areas in Brazilian Amazonia

Studies on seasonal anopheline fauna variation were performed in two distinct settlements in the State of Rond?nia, Brazil: one at the Madeira River banks (Portuchuelo) with stable native Amazonian population; the other at an inland lumber-extracting farm (Urupá) in dry land, in which adults are mostly migrants. During a 6-yr period (1994-2000), 8,638 adult anophelines were collected: 2,684 in Urupá and 5,954 in Portuchuelo. Anopheles darlingi represented >95% of total mosquitoes caught. Dissection of 4,424 A. darlingi females yielded a very low sporozoite infection index below 0.1%. Oocysts were found in both localities in approximately 0.1% of dissected mosquitoes. Determination of the hour biting rates disclosed seasonal variations in both localities. However, in Portuchuelo, mosquito density peaked at the acme of the rainy season, whereas at Urupá it peaked in the dry season. The increase in mosquito density and incidence of malaria cases were coincident. The high mosquito densities observed in the riverine settlement of Portochuelo sector B, which permits evaluation in > 10,000 mosquitoes' bites/person/year, could explain, in spite of the low mosquito's infection index, the previously described development of natural immunity in the local population that is not observed in the dry land agroindustrial settlement of Urupá.     

Phagocytosis and Chemiluminescence Response of Granulocytes to Monodisperse Latex Particles of Varying Sizes and Surface Coats

The response of human granulocytes to polystyrene latex beads of diameter 0.1–7 m was measured by luminol-dependent chemiluminescence. In all instances, the response to beads of 3–7 m was definitely higher than with smaller beads. In protein-free medium, the chemiluminescence response was slow compared to that of opsonized zymosan, and the highest response was only 9% of the response to opsonized zymosan. Scanning electron microscopy showed that granulocytes in suspension bound the particles, occasionally by extending rope-like protrusions. When the beads were coated with albumin, the chemiluminescence diminished to about 1/3 of that seen with uncoated beads; however, preincubating the beads in serum led to a large increase with beads of 1.1 m (to 25% of the maximal response to opsonized zymosan) and 3.19 m (to 42%), but with the smallest beads, no increase was noted. "Priming" of the cells with tumor necrosis factor- caused a further increase with serum-coated beads. When uncoated beads of 1.1 m were tested with "primed" cells, there was an increase of 6 times in the chemiluminescence compared to un-"primed" cells.     

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.     

The cytotoxic HLA-DQ3 reactive human hybridoma antibody 4166 that May distinguish DQ7 + 8 from DQ9

The human cytotoxic hybridoma antibody 4166 (IgM_χ) was generated by fusing an in vitro EBV-transformed B-LCL from a multiparous woman with the mouse-human heteromyeloma fusion partner CB-F7. In microcytotoxicity and IIF tests with B-LCLs as target cells, the mAb 4166 was specific for DQ3 ( = DQ7 + 8 + 9). However, when used for DQ typing of class-II-positive PBMCs, 4166 could be rendered functionally specific for DQ7 + 8and did not react with DQ9⁺ PBMCs. Binding of mAb 4166 to DQ8-positive cells was efficiently blocked by several allotype-specific mAbs recognizing DQ8. Other HLA class-II-specific mAbs were unable to inhibit. With the use of mAb 4166, it is possible to discriminate DQ7 + 8 from DQ9 in serologic DQ typing.     

Measurement of fatty acid oxidation in premature newborn infants with the 13C-triolein breath test

The 13C-triolein breath test is a method giving evidence of extent and rate of fatty acid oxidation in newborn infants on parenteral nutrition. The test has the special advantage of being non-invasive. Triolein labeled with the stable carbon isotope 13C and emulsified in soybean-oil is used as a tracer. 10 mg of 13C triolein per kg body weight are administered intravenously. The 13CO2 resulting from the fatty acid oxidation is analysed in expired breath by ratio-mass-spectrometry. The calculated 13C elimination is representative of the rate of fatty acid oxidation during the examination period. First studies on 15 premature infants have shown that an average of 27.0 +/- 1.8% of the dose administered is oxidized within 4 h. The present results suggest that the oxidation rate may be related to the maturity of the prematurely born infants.     

Working conditions and health behavior as causes of educational inequalities in self-rated health: an inverse odds weighting approach

Objective:Using a novel mediation method that presents unbiased results even in the presence of exposure–mediator interactions, this study estimated the extent to which working conditions and health behaviors contribute to educational inequalities in self-rated health in the workforce.Methods:Respondents of the longitudinal Survey of Health, Ageing, and Retirement in Europe (SHARE) in 16 countries were selected, aged 50–64 years, in paid employment at baseline and with information on education and self-rated health (N=15 028). Education, health behaviors [including body mass index (BMI)] and working conditions were measured at baseline and self-rated health at baseline and two-year follow-up. Causal mediation analysis with inverse odds weighting was used to estimate the total effect of education on self-rated health, decomposed into a natural direct effect (NDE) and natural indirect effect (NIE).Results:Lower educated workers were more likely to perceive their health as poor than higher educated workers [relative risk (RR) 1.48, 95% confidence interval (CI) 1.37–1.60]. They were also more likely to have unfavorable working conditions and unhealthy behaviors, except for alcohol consumption. When all working conditions were included, the remaining NDE was RR 1.30 (95% CI 1.15–1.44). When BMI and health behaviors were included, the remaining NDE was RR 1.40 (95% CI 1.27–1.54). Working conditions explained 38% and health behaviors and BMI explained 16% of educational inequalities in health. Including all mediators explained 64% of educational inequalities in self-rated health.Conclusions:Working conditions and health behaviors explain over half of the educational inequalities in self-rated health. To reduce health inequalities, improving working conditions seems to be more important than introducing health promotion programs in the workforce.     

The pharmacokinetics of high-dose medroxyprogesterone acetate (MPA) in the therapy of advanced breast cancer

Summary Oral MPA 1.5 g/day leads to plasma concentrations between 1 and 12 g/ml, with a broad intra-and interindividual variance. The plateau state is reached in between 4 and 16 days. Plasma concentrations in the plateau state are very sensitive to dose modifications. After cessation of administration, the decline in plasma levels seems to proceed in two phases, with half-times of about 20 h and 4 days. Extraction procedures reveal no benefit in discriminating between MPA and its metabolites.     

Lanzoprazole promotes gastric carcinogenesis in rats with duodenogastric reflux

Background Duodenogastric reflux is known to cause an increased frequency of cancer in the glandular portion of the stomach in rats. Furthermore, it is debated whether inhibition of gastric acid secretion may promote gastric carcinogenesis. In the present study we examined the combined effect of gastroduodenal reflux and acid inhibition with respect to the development of gastric carcinoma in the rat.Methods Following the construction of a gastrojejunostomy in male Wistar rats, half of them were given the proton pump inhibitor lanzoprazole for 1 year. The rats were then killed and the pH in the stomach and gastrin in blood were measured. The stomach was examined macroscopically as well as histologically.Results Gastrin levels at autopsy were significantly increased in treated rats compared to the control group, confirming an effect of lanzoprazole on gastric acid secretion. Body weight was significantly reduced in the treated rats. Thirty of 79 rats developed gastric cancer, and they were all adenocarcinomas of the Lauren intestinal type. Gastric cancers occurred significantly more often in lanzoprazole-treated rats (50%) compared with controls (27%).Conclusion Lanzoprazole given orally enhances the carcinogenic effect of duodenogastric reflux in rats.