TLR4 gene variants modify endotoxin effects on asthma

BACKGROUND: Environmental exposure to endotoxin might have a crucial role in immune maturation and development of asthma. OBJECTIVE: The aim of this study was to investigate whether the effect of endotoxin concentration in settled house dust on asthma is modified by the presence of variation in the TLR4 gene. METHODS: We performed a cross-sectional study within the German follow-up of the European Community Respiratory Health Survey. Multivariate logistic regression analysis and nonparametric effect estimates (S-Plus) were applied to examine the association between endotoxin exposure and diagnosed asthma, related clinical symptoms, and bronchial hyperreactivity (BHR) stratified for noncarriers and carriers of G299/I399 polymorphism in the TLR4 gene. RESULTS: In the noncarrier group (n = 279), the prevalence of asthma was significantly increased with elevated endotoxin levels in house dust with adjusted odds ratio 6.24 (95% CI, 1.33-29.17) in the second tertile, and 4.54 (95% CI, 0.94-21.96) in the third tertile compared with the lowest endotoxin tertile. The carriers of the polymorphisms (n = 55) showed a nonsignificant trend to have a lower risk of asthma (crude odds ratio, 0.67; 95% CI, 0.06-8.06 for the second tertile and 1.33; 95% CI, 0.17-10.58 for the third tertile). We found a similar association for wheeze and endotoxin exposure that was also attenuated in subjects with G299/I399 polymorphisms. CONCLUSIONS: The G299/I399 polymorphisms were associated with a modified response to endotoxin, but the functional relationship still needs clarification.     

Effect of sodium citrate on the rate of cholesterol esterification and on the formation of primary products of lipid peroxidation in human blood. Are these processes related?

In vitro experiments show that sodium citrate in a final concentration of 130 mM induces a 4- to 5-fold increase in the activity of lecithin-cholesterol acyltransferase. A parallel determination of the blood content of primary products of lipid peroxidation reveals a 20–30% decrease in diene and triene conjugates and lipid hydroperoxides. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 9, pp. 323–325, September, 1995 Presented by A. N. Klimov, Member of the Russian Academy of Medical Sciences     

Histochemical Distribution of Carbonic Anhydrase After Ligation of the Pancreatic Duct

The distribution of carbonic anhydrase in the exocrine pancreas of the rat has been examined during the first 3 weeks after duct ligation. The normal pattern of positive reaction in ducts, centroacinar cells and capillaries changed, by the end of the first week, to one in which all the cells in the dilated ducts showed the enzyme. This situation persisted through the third week. By electron microscopy, the enzyme was found on the apical membranes of ductular, centroacinar and acinar cells, as well as on the surface membranes of the modified cells seen at 1 week. The significance of these findings with respect to function and cell origin is discussed.     

Ultrastructural aspects of bubble formation in human fatal accidents after exposure to compressed air

Summary Electron microscopic investigations were performed on samples of human tissue obtained from subjects following fatal decompression sickness, associated with hyperbaric air-therapy. Intra- and extracellular gas bubbles of varying size were identified throughout the entire body. Each bubble was covered by an osmiophilic non-homogeneous coat of cloudy and flocculent material, native to its specific locality. This envelope measured from 30 to 560 Angstroem-units in thickness. Association of this covering with an electrokinetic zonal activity, detected biophysically by Lee and Hairston (1971) is assumed. We consider this surface coat prevents nitrogen from being eliminated via the blood-lung-barrier.     

Presynaptic depolarization in myelinated vagal afferent fibres terminating in the nucleus of the tractus solitarius in the cat

The presynaptic influences that act on terminals of slowly adapting lung stretch receptor afferents and aortic baroreceptor afferents within the nucleus of the solitary tract were assessed using intracellular recording and antidromic stimulation techniques.Central respiratory influences on the axcitability of lung stretch receptor terminals were observed in 29% (4 of 14) of measurements. These were confirmed in intracellular recordings where membrane depolarizations in synchrony with phrenic nerve discharge were seen in 17% (4 of 24) of fibres. In three cases membrane depolarization also occurred synchronously with artificial lung inflation.Neither tests of excitability nor intracellular recording revealed any evidence for equivalent presynaptic influences on 16 myelinated aortic baroreceptor terminals.Stimulation of the superior laryngeal nerve evoked depolarizations in 50% (7 of 14) of lung stretch receptor terminals. These took the form of complex waves of depolarization with both short (3–8 ms) and long latency (27–35 ms) components. The amplitude of the long latency response increased during the period of phrenic nerve discharge, i.e. during central inspiration.These effects are discussed in relation to the central respiratory influences on both respiratory and cardiovascular reflexes.     

Surface immunoglobulins in human chronic leukemia cells

By means of the cytotoxic and immunofluorescence tests, frequency of various classes of immunoglobulins (IgG, IgA, IgM, IgD, IgE) and light chains was examined in peripheral pathologic blood cells of patients with chronic granulocytic and lymphatic leukemia. The dominant immunoglobulins were of the IgD and IgE classes. Light chains of both types were present in cells of chronic granulocytic leukemia, and kappa type in chronic lymphatic leukemia. Use of the method of resynthesis of digested immunoglobulins in vitro confirmed the monoclonal origin of chronic lymphatic leukemia in humans.     

Association of defensin beta-1 gene polymorphisms with asthma

BACKGROUND: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. OBJECTIVE: We characterized the genetic diversity in the defensin beta-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. METHODS: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. RESULTS: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5' genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma ( P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion ( P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted ( P = .04) and was more prominent in female subjects ( P = .007). CONCLUSION: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.     

Correlation of MRT imaging with real-time axiography of TMJ clicks

There is a series of tools useful for gathering diagnostic information on patients with temporomandibular joint disorders. Tracings of the joint movement (axiography) provide useful information about the motion of the joints. Since the availability of electronic axiographic tracers, the movement of the condyles can be resolved with high resolution both in space and in time. In order to obtain information about the anatomical relation of the joint surfaces and the disc, magnetic resonance tomography imaging (MRI) is routinely carried out. It is common practice to take MR images of the joints with the mouth closed and fully open. In order to correlate the MR images with the axiographic tracings, a series of images can provide much more information. In this study we examined patients with distinct temporomandibular joint (TMJ) clicks. In one case, the click occurs once a day, while in the other case the click happens every time the mouth is opened. In order to obtain information about both motion and anatomical relation of the TMJ at and around the position where the clicks occur, we recorded a series of MRI scans with the mouth gradually opened and before and after joint clicks. Real-time axiographic tracings during the click were taken with an optimized system where the polar moments were reduced as much as possible to follow the movement during the click. These tracings were correlated with the MRI scans to determine the exact internal conditions of the TMJ and the changes during the click. In particular cases, the additional information provided by this procedure can be useful in deciding whether and which therapeutic intervention is advisable.     

Efficacy of Amodiaquine in uncomplicated falciparum malaria in Nigeria in an area with high-level resistance to Chloroquine and Sulphadoxine/Pyrimethamine

Falciparum Malaria is hyperendemic in southern Nigeria and chloroquine resistance is an increasing problem. Therefore, the parasitological and haematological response to treatment with amodiaquine was studied in children under 5 years during a 14-day follow-up. Of 105 children who accomplished the study (out of 114 who were enrolled), 95.3% were parasite-negative on thick blood film on day 7, which decreased to 89.5% on day 14. The haemoglobin levels increased on average by 1.3% on day 14 (±1.9) and more pronounced in children with anaemia < 10 g/dl on enrolment. The number of patients with adverse events (mainly pruritus and nausea) was few. This study shows that amodiaquine is effective, safe and affordable in an area with high resistance to chloroquine.     

The antibody-independent cytotoxic activity of normal circulating human leucocytes. II. Failure to demonstrate effector cell-target cell interaction and target cell specificity of the circulating cytotoxic-enhancing factor.

The naturally-occurring antibody-independent cellular cytotoxic activity (NOCC) of normal circulating human monocytes and neutrophils was investigated employing a number of erythrocytes and the K-562 cell line as target cells simultaneously. The identity of the effector cell(s) was shown to be dependent upon or be a function of the type of target cell selected for the assay system. A number of erythrocyte targets (rabbit, horse, sheep and ox erythrocytes) were lysed to varying degrees by neutrophils and monocytes and not by lymphocytes. Irrespective of the red blood cell (RBC) target, the effector monocyte invariably possessed receptors for both C'3 and the Fc of IgG. In contrast, the cytotoxic cells using the K-562 target cell were lymphocytes. Monocytes and neutrophils were inactive. The cytotoxic-enhancing activity in normal human serum exhibits specific and non-specific properties which suggests that more than one factor is involved. With respect to the monocyte cytotoxic cells, only the rabbit erythrocytes could totally absorb the serum factor in a specific fashion. Absorption of the serum with horse, sheep or ox erythrocytes resulted in a significant loss of potentiating activity with respect to all of the erythrocyte targets but a more marked loss of activity using the absorbing erythrocytes as targets. With respect to the polymorphonuclear leucocyte effector cells, only the rabbit RBC were capable of specifically absorbing out the cytotoxic-enhancing factor present in the normal human serum. Absorption of the serum with sheep, horse or ox RBC resulted in total cross-absorption of the enhancing factor. Chicken and human RBC, which do not serve as targets for the NOCC assay, could not absorb out the cytotoxic-enhancing factor with respect to any of the target erythrocytes. The composition of the soluble serum factor(s) is under current investigation but it is not an immunoglobulin since pure serum albumin can substitute for normal serum in the NOCC assay. The mechanism of erythrocyte lysis by the cytotoxic monocyte was investigated. Mononuclear cells were incubated with target cell monolayers and with target cells under optimal rosetting conditions. No interaction between the effector and target cells could be detected. The monocytes did not adhere to the target cell monolayer nor did they form rosettes with the target cells. Thus, the results fail to corroborate or support the assumption that the cytotoxic activity of the monocyte is dependent upon conventionally-detectable receptors. Erythrophagocytosis was not observed to any significant degree under the assay conditions used. Therefore, the nature of the interaction between the cytotoxic monocyte and the erythroid target cell which results in lysis of the target cell remains to be elucidated.