Human variation in the peripheral air-space deposition of inhaled particles

Intersubject variability in both peripheral air-space dimensions and breathing pattern [tidal volume (VT) and respiratory frequency (f)] may play a role in determining intersubject variation in the fractional deposition of inhaled particles that primarily deposit in the lung periphery (i.e., distal to conducting airways). In healthy subjects breathing spontaneously at rest, we measured the deposition fraction (DF) of a 2.6-microns monodisperse aerosol by Tyndallometry while simultaneous measurement of VT and f were made. Under these conditions particle deposition occurs primarily in the peripheral air spaces of the lung. As an index of peripheral air-space size, we used measurements of aerosol recovery (RC) as a function of breath-hold time (t) (Gebhart et al. J. Appl. Physiol. 51: 465-476, 1981). In each subject, we measured RC (aerosol expired/aerosol inspired) of a 1.0-micron monodisperse aerosol as a function of breath-hold time for inspiratory capacity breaths of aerosol. The half time (t1/2) (the breath-hold time to reach 50% RC with no breath hold) is proportional to a mean diameter (D) of air spaces filled with aerosol. In the 10 subjects studied, we found a variable DF, range 0.04-0.44 [0.25 +/- 0.12 (SD)]. DF correlated most closely with 1/f, or the period of breathing (r = 0.96, P less than 0.01). There was no significant correlation between DF and t1/2 as an index of peripheral air-space size. In fact there was little deviation in t1/2 in these normal subjects [coefficient of variation (CV) = 0.12].(ABSTRACT TRUNCATED AT 250 WORDS)     

The variation in susceptibility to decompression sickness

The Weibull function is shown to provide a particularly good fit for published data demonstrating the variation between individuals with respect to their susceptibility to decompression sickness. These data include the distributions of minimum bends depths for men and for goats breathing air,and that of resting pilots for aerial decompression.The correlations are shown to hold only if the vital parameter for estimating the imminence of symptoms is taken as the volume fraction of gas predicted to have separated from solution in unit volume of tissue.

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Zusammenfassung Es wird gezeigt, dass die nach der Weibull-Gleichung berechneten Werte für die Variation der Empfindlichkeit von Individuen auf Caissonkrankheit besonders gut übereinstimmen mit gemessenen Werten. Diese Werte umfassen die Verteilung der minimalen Anzahl "bends" bei Menschen und Ziegen unter Luftatmung in verschiedenen Tiefen und von ruhenden Piloten bei Luftdekompression. Es wird gezeigt, dass die Korrelationen nur gültig sind,wenn als Parameter zur Bestimmung der drohenden Symptome das Gasvolumen verwendet wird,dessen Abtrennung von der Lösung in einer Volumeneinheit Gewebe vorausgesagt wird.

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Resume On démontre que les valeurs des variations de la sensibilité à la décompression calculées selon la formule de Weibull correspondent très bien aux valeurs mesurées. Ces valeurs comprennent la répartition du nombre minimum de "bends" chez des hommes ou des chèvres respirant de l'air à différentes profondeurs ainsi quepour des pilotes au repos subissant une décompression.Les corrélations ne sont toutefois valables que si le paramètre principal d'estimation de l'imminence des symptômes est exprimé par le rapport entre le volume des gaz devant se séparer de la solution et le volume des tissus.

     

Nutrient stoichiometry of aquatic hyphomycetes: Interstrain variation and ergosterol conversion factors

Ecological stoichiometry is a powerful concept. Rarely, however, has it been applied to fungi, despite their pivotal role in ecosystems. In view of the paucity of stoichiometric data, we grew 16 fungal isolates from streams in liquid culture (C:N:P = 160:16:1) and analysed them for nitrogen (N), phosphorus (P) and ergosterol as a fungal biomass marker. Interspecific differences explained up to 60% of the variation in N, P and ergosterol concentrations, and variation between strains of the same species accounted for up to another 16%. We found an average C:N:P of 136:10:1 in mycelia, while N:ergosterol and P:ergosterol ratios were 9.5 and 2.5, respectively. These ratios are an important step towards establishing reliable conversion factors to estimate the contribution of fungi to litter nutrient contents in complex field samples. Estimates could be further improved by applying the species-specific conversion factors we obtained. Additional analyses of fungal strains in conditions reflecting field situations are needed to strengthen the basis of such estimates of fungal nutrient pools in ecosystems; however, inherent variation within species limits the accuracy and precision that can be achieved.     

N-acetylglucosaminyltransferase V-deficiency increases susceptibility to murine malaria

It is considered that several glycoproteins on erythrocytes in mammalian species are involved in malaria parasite infection. To elucidate the role of N-glycans on malaria parasite infection, we induced experimental murine malaria infection (using Plasmodium berghei ANKA) in mice deficient in N-acetylglucosaminyltransferase V (Mgat5), which is one of the enzymes involved in β1,6-GlcNAc N-glycan biosynthesis. After infection, Mgat5^-/- mice showed severe body weight loss and parasitemia compared with wild-type mice. The Mgat5^-/- mice, but not wild-type mice, also showed severe pathology accompanied by marked infiltration of plasma cells into the lungs and liver. These results suggest that β1,6-GlcNAc N-glycans on/in host erythrocytes may interfere with invasion of the parasites and progression to severe malaria.     

Interstrain heterochromatin polymorphisms in Drosophila melanogaster

Neuroblast chromosomes of 16 Drosophila melanogaster laboratory stocks (15 wild type and 1 carrying the mutant vermilion) were carefully analyzed for Q-banding patterns and morphological characteristics, in all the mitotic phases. Two forms of intraspecific heterochromatin variations, involving three types of chromosomes, are described: 1) differences in the fluorescence pattern with regard to the Y chromosome and the centromeric heterochromatin of the pair II; 2) differences in the size of the heterochromatic segment of the X chromosome. An unambigous evidence of such variants was obtained by comparing homologous chromosomes in the F1 hybrids, as well as in the F2 offspring, where differences in appearance of the heteromorphic chromosomes was readily identified as to the parental origin. The possible evolutionary significance and the usefulness of such cytologically detectable genetic differences between various strains, are considered.This paper is dedicated to Prof. Claudio Barigozzi with gratitude for his guidance and the long collaboration     

Modification of susceptibility to Klebsiella pneumoniae during murine cytomegalovirus infection

The effect of murine cytomegalovirus (MCMV) infection on susceptibility to bacterial infection was studied in mice by a combination of intraperitoneal (ip) inoculation of a sublethal dose of MCMV with subsequent ip challenge of 2 X 10(3) cfu of a strain of Klebsiella pneumoniae (KP). When given alone, KP produced a mortality of 30-40%. Mortality was increased when KP was given 1 to 7 days after MCMV injection with the peak increase at the 4th to 5th day when 100% mortality occurred. Virus levels in various organs of mice infected with MCMV alone, or superinfected with KP did not differ. Bacterial counts on the other hand, showed that increased mortality in mixed MCMV and KP infected mice was due to an uncontrolled growth of bacteria at the site of primary lodgment, i.e., the peritoneum, and severe systemic infection. Neutrophil response to growth of KP during the first 3 days of bacterial infection was defective in MCMV infected mice. While the initial clearance of KP from the blood was more efficient in MCMV infected mice, probably due to activated reticuloendothelial function, it did not protect the mice against KP infection. Using the in vivo model, it was shown that poor neutrophil response and possibly other defective neutrophil functions were responsible for increased mortality to KP infection in MCMV infected mice.     

Genetic variation in the susceptibility of Eucalyptus globulus to drought damage

Genetic variation in drought damage in Eucalyptus globulus was studied in a sublined trial series across four neighbouring sites in Western Australia linked by ten common families. The trials included approximately 400 open-pollinated families, encompassing 51 native stand collection localities and 19 subraces from throughout the geographic range of the species. Data were analysed using mixed models, with spatial analysis used to better identify genetic effects. Significant subrace differences in drought damage were detected, with both broad-scale, regional and localised clines evident. The quantitative genetic differentiation between subraces as measured by Q _ST (0.39?±?0.091) was significantly greater than the F _ST for neutral marker expectations and consistent with diversifying selection shaping the patterns of subrace divergence in drought susceptibility. This conclusion is supported by the significant association of subrace drought susceptibility with bioclimatic parameters, particularly those associated with temperature seasonality. Less drought damage was observed in subraces originating from areas with more temperature seasonality, but also less radiation and rainfall seasonality, less winter rainfall, higher radiation and higher temperatures in the warmest month. Significant additive genetic variation in drought damage was detected within subraces, with narrow-sense heritabilities ranging from 0.14 to 0.20. We argue that spatial genetic variation in drought susceptibility of E. globulus has been shaped by natural selection acting at multiple scales and discuss opportunities for exploiting this genetic variation in breeding and deployment programs.     

Ingested particles reduce susceptibility of insect larvae to Bacillus thuringiensis

Susceptibility to Bacillus thuringiensis of mosquito and lepidopteran larvae is affected by feeding behaviour and nutritional value of the available food. Reduced mortality is attributed to feeding inhibition and dilution of the pathogen in the presence of nutritional and inert particles, which limit the amount of ingested toxin. These reasons are, however, not sufficient to explain the data presented here. Values of LC₅₀ (the concentration that kills 50% of exposed population) of B. thuringiensis subsp. israelensis (Berliner) against Aedes aegypti (L.) larvae and of B. thuringiensis subsp. kenyae (Berliner) against Spodoptera littoralis (Boisduval) larvae were about 20–217 and 2.3–44‐fold higher, respectively, in the presence of nutritional or biologically inert (non‐nutritional) particles than without. The number of B. thuringiensis spores in carcasses of B. thuringiensis ‐killed A. aegypti and S. littoralis larvae were between 1.9 and 5.6‐fold and between 8.5 and 12‐fold higher, respectively, in the presence of particles than without. In all cases, non‐nutritional particles better protected the exposed larvae than nutritious particles. We propose that another basic mechanism exists, that ingested particles protect midgut epithelial cells by covering their surface and thus preventing availability of the toxin to the gut receptors. Understanding the defence mechanisms of insects against B. thuringiensis toxicity may lead to improved pest management methods.     

Strain-dependent, route of challenge-dependent, murine susceptibility to toxoplasmosis

The response to an intraperitoneal (i.p.) parasite challenge was compared with that caused by an oral challenge, in five different strains of mice. The results are consistent with the hypothesis that murine susceptibility to toxoplasmosis is route of challenge-dependent as well as strain-dependent. The phenomenon occurs in both sexes and appears to be a recessive trait. The finding that the susceptibility of C57BL/6j mice to oral or i.p. challenge is almost the reverse of that of LACA mice, and that BALB/c mice are resistant to challenge by either route, offers an excellent laboratory model for studies on susceptibility to toxoplasmosis.     

Evolutionary determinants of genetic variation in susceptibility to infectious diseases in humans

Although genetic variation among humans in their susceptibility to infectious diseases has long been appreciated, little focus has been devoted to identifying patterns in levels of variation in susceptibility to different diseases. Levels of genetic variation in susceptibility associated with 40 human infectious diseases were assessed by a survey of studies on both pedigree-based quantitative variation, as well as studies on different classes of marker alleles. These estimates were correlated with pathogen traits, epidemiological characteristics, and effectiveness of the human immune response. The strongest predictors of levels of genetic variation in susceptibility were disease characteristics negatively associated with immune effectiveness. High levels of genetic variation were associated with diseases with long infectious periods and for which vaccine development attempts have been unsuccessful. These findings are consistent with predictions based on theoretical models incorporating fitness costs associated with the different types of resistance mechanisms. An appreciation of these observed patterns will be a valuable tool in directing future research given that genetic variation in disease susceptibility has large implications for vaccine development and epidemiology.     

Innate immunity and the pathogenicity of inhaled microbial particles

Non-infectious inhaled microbial particles can cause illness by triggering an inappropriate immunological response. From the pathogenic point of view these illnesses can be seen to be related to on one hand autoimmune diseases and on the other infectious diseases.In this review three such illnesses are discussed in some detail. Hypersensitivity pneumonitis (HP) is the best known of these illnesses and it has also been widely studied in animal models and clinically. In contrast to HP Pulmonary mycotoxicosis (PM) is not considered to involve immunological memory, it is an acute self-limiting condition is caused by an immediate "toxic" effect. Damp building related illness (DBRI) is a controversial and from a diagnostic point poorly defined entity that is however causing, or attributed to cause, much more morbidity than the two other diseases.In the recent decade there has been a shift in the focus of immunology from the lymphocyte centered, adaptive immunity towards innate immunity. The archetypal cell in innate immunity is the macrophage although many other cell types participate. Innate immunity relies on a limited number of germline coded receptors for the recognition of pathogens and signs of cellular damage. The focus on innate immunity has opened new paths for the understanding of many chronic inflammatory diseases. The purpose of this review is to discuss the impact of some recent studies, that include aspects concerning innate immunity, on our understanding of the pathogenesis of inflammatory diseases associated with exposure to inhaled microbial matter.     

Phytochemical variation mediates the susceptibility of insect herbivores to entomoviruses

It has been reported that the susceptibility of insect herbivores to entomoviruses is affected by phytochemicals ingested during the acquisition of viral inoculum on the foliage of host plants. However, the relationship between this susceptibility and phytochemicals is poorly understood. To test this hypothesis of plant‐mediated effects on this susceptibility, we measured the effects of foliage from three plants, soybeans (Glycine max), collards (Brassica oleracea) and water convolvuluses (Ipomoea aquatica), on the susceptibility of larval beet armyworm (Spodoptera exigua) to nucleopolyhedrovirus (NPV), and analysed six foliar chemicals (total phenolics, peroxidase [POD], catalase [CAT], superoxide dismutase [SOD], endochitinase and exochitinase) in the three plants, respectively. The results of exponential modelling indicated that the LD_50s (median lethal dose) of NPV to larvae increased with the increase in both phenolics and POD but declined with the increase in four other foliar chemicals, while the opposite trend was found between median lethal time (LT₅₀) of NPV and the six foliar chemicals. This study reveals that phenolics and POD decrease host susceptibility to the entomoviruses and that CAT, SOD, endochitinase and exochitinase increase this susceptibility.     

Interstrain conservation of the murine GAT-specific antibody V kappa repertoire as analyzed at the germline gene level

A cDNA library was constructed in pBR322 from mRNA encoding an anti-GAT (Glu60 Ala30 Tyr10) monoclonal antibody kappa chain. Two cDNA clones were extensively characterized. One, L XI 62, was derived from an aberrant V kappa-J kappa rearrangement which resulted in a frame-shift at position 96, leading to a stop codon at the very beginning of the constant region. The second, L XIX 27, 1150 bp long, was unequivocally assigned to a GAT-specific kappa chain, by comparison of its nucleotide sequence with the previously determined NH2-terminal amino acid sequence of the isolated kappa chain. A specific probe, containing the leader and most of the V kappa gene-encoded region, was prepared from this clone and hybridized to EcoRI and BamHI restriction fragments of liver (unrearranged) DNA extracted from the BALB/c, DBA/2 and C57BL/6 mouse strains. Under stringent conditions, similar patterns were observed for all three strains, and consisted of a small number of bands (3-5). Under nonstringent conditions, patterns were again very similar when the different strains were compared, although 15-20 bands could be identified. These observations support the hypothesis that the GAT-specific kappa chains found in antibodies expressing the public CGAT idiotypes are encoded by a very small number of germline genes. This V kappa repertoire seems extremely conserved between the three strains that were analyzed, an observation which correlates with the interstrain conservation of these public idiotypic specificities.     

Antigenic variation and the murine immune response to Giardia lamblia

The protozoan parasite Giardia lamblia is an important causative agent of acute or chronic diarrhoea in humans and various animals. During infection, the parasite survives the hosts reactions by undergoing continuous antigenic variation of its major surface antigen, named VSP (variant surface protein). The VSPs form a unique family of cysteine-rich proteins that are extremely heterogeneous in size. The relevance of antigenic variation for the survival in the host has been most successfully studied by performing experimental infections in a combined mother/offspring mouse system and by using the G. lamblia clone GS/M-83-H7 (human isolate) as model parasite. In-vivo antigenic variation of G. lamblia clone GS/M-83-H7 is characterised by a diversification of the intestinal parasite population into a complex mixture of different variant antigen types. It could be shown that maternally transferred lactogenic anti-VSP IgA antibodies exhibit cytotoxic activity on the Giardia variant-specific trophozoites in suckling mice, and thus express a modulatory function on the proliferative parasite population characteristics. Complementarily, in-vitro as well as in-vivo experiments in adult animals indicated that non-immunological factors such as intestinal proteases may interfere into the process of antigen variation in that they favour proliferation of those variant antigen-type populations which resist the hostile physiological conditions within the intestine. These observations suggest that an interplay between immunological and physiological factors, rather than one of these two factor alone, modulates antigenic diversification of a G. lamblia population within an experimental murine host and thus influences the survival rate and strategy of the parasite.     

Identification of a murine locus conveying susceptibility to cadmium-induced forelimb malformations

The heavy metal cadmium (Cd), an environmentally ubiquitous contaminant, is a potent teratogen in mice. When administered parenterally, it induces an array of malformations that vary in scope and severity with the route, dose, time of administration, and the strain of the animal. When administered intraperitoneally on day 9.0 of gestation, 4 mg/kg cadmium chloride produces forelimb defects (predominantly ectrodactyly) in over 80% of fetuses of the C57BL/6 mouse strain, while no limb defects are observed in the identically treated SWV strain. Like other examples of strain-specific teratogenic activity, the underlying nature of the differential susceptibility remains unknown. The present study investigates the segregation of sensitivity to Cd-induced forelimb defects in crosses between C57BL/6 and SWV mice and provides evidence for the involvement of both maternal and fetal factors in the determination of defect expression. In addition, quantitative trait loci (QTL) analysis of the fetal genetic component was performed among 198 backcross progeny, utilizing a genomic linkage map of 149 informative microsatellite markers. One QTL demonstrating significant linkage to expression of the defect, designated Cadfar (cadmium-induced forelimb autopod reduction), was mapped to the distal end of chromosome 6 with a lod score of 3.1.