Therapeutic Efficacy of Cintredekin Besudotox (IL13-PE38QQR) in Murine Lung Fibrosis Is Unaffected by Immunity to Pseudomonas aeruginosa Exotoxin A

Background

We have previously explored a therapeutic strategy for specifically targeting the profibrotic activity of IL-13 during experimental pulmonary fibrosis using a fusion protein comprised of human IL-13 and a mutated form of Pseudomonas aeruginosa exotoxin A (IL13-PE) and observed that the intranasal delivery of IL13-PE reduced bleomycin-induced pulmonary fibrosis through its elimination of IL-13-responsive cells in the lung. The aim of the present study was to determine whether the presence of an immune response to P. aeruginosa and/or its exotoxin A (PE) would diminish the anti-fibrotic properties of IL13-PE.

Methodology/Principal Findings

Fourteen days after P. aeruginosa infection, C57BL/6 mice were injected with bleomycin via the intratracheal route. Other groups of mice received 4 doses of saline or IL13-PE by either intranasal or intraperitoneal application, and were challenged i.t. with bleomycin 28 days later. At day 21 after bleomycin, all mice received either saline vehicle or IL13-PE by the intranasal route and histopatological analyses of whole lung samples were performed at day 28 after bleomycin. Intrapulmonary P. aeruginosa infection promoted a neutralizing IgG2A and IgA antibody response in BALF and serum. Surprisingly, histological analysis showed that a prior P. aeruginosa infection attenuated the development of bleomycin-induced pulmonary fibrosis, which was modestly further attenuated by the intranasal administration of IL13-PE. Although prior intranasal administration of IL13-PE failed to elicit an antibody response, the systemic administration of IL13-PE induced a strong neutralizing antibody response. However, the prior systemic sensitization of mice with IL13-PE did not inhibit the anti-fibrotic effect of IL13-PE in fibrotic mice.

Conclusions

Thus, IL13-PE therapy in pulmonary fibrosis works regardless of the presence of a humoral immune response to Pseudomonas exotoxin A. Interestingly, a prior infection with P. aeruginosa markedly attenuated the pulmonary fibrotic response suggesting that the immune elicitation by this pathogen exerts anti-fibrotic effects.     

Abo blood groups and completed reproductive performance of rural Haryanavi couples: analysing measures of selection intensities

The possible differential effects of ABO blood group materno-paternal (fetal) incompatibility on completed reproductive performance were investigated on a sample of 100 couples (100 fathers and 100 mothers) from three villages in the Jind district of Haryana state, India. The average number of live births per mating couple was slightly higher for the incompatible matings (5.32) than the compatible ones (5.05). This advantage was offset by higher postnatal mortality in the former. Consequently, the average number of living children in the compatible matings (4.64) was higher than in the incompatible ones (4.18). With reference to individual ABO matings, the index of relative fertility (Irf) was the highest in A x AB followed by B x A type of incompatible matings. No decrease in live births in O x A and O x B incompatible matings was observed compared with their reciprocal compatible ones, i.e. A x O and B x O matings, as has been hypothesized in previous studies. The total pregnancy wastage was substantially higher in ABO-incompatible matings (24.59%) than compatible matings (8.45%). About 71% of the postnatal deaths took place within one year of the birth in the case of incompatible matings compared with 50% in the case of compatible matings. The study supports the hypothesis that selection is operative at the ABO locus as revealed by the measures of selection intensity. The loss of fitness in the present sample was associated with differential mortality. There were no differences in the proportions of average number of male live births in the compatible (0.55) and incompatible matings (0.58). However, in the individual mating types, there was some evidence of higher or lower proportions of male live births.     

Predictors of mortality of patients with acute respiratory failure secondary to chronic obstructive pulmonary disease admitted to an intensive care unit: A one year study

Background

Patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) commonly require hospitalization and admission to intensive care unit (ICU). It is useful to identify patients at the time of admission who are likely to have poor outcome. This study was carried out to define the predictors of mortality in patients with acute exacerbation of COPD and to device a scoring system using the baseline physiological variables for prognosticating these patients.

Methods

Eighty-two patients with acute respiratory failure secondary to COPD admitted to medical ICU over a one-year period were included. Clinical and demographic profile at the time of admission to ICU including APACHE II score and Glasgow coma scale were recorded at the time of admission to ICU. In addition, acid base disorders, renal functions, liver functions and serum albumin, were recorded at the time of presentation. Primary outcome measure was hospital mortality.

Results

Invasive ventilation was required in 69 patients (84.1%). Fifty-two patients survived to hospital discharge (63.4%). APACHE II score at the time of admission to ICU {odds ratio (95 % CI): 1.32 (1.138–1.532); p < 0.001} and serum albumin (done within 24 hours of admission) {odds ratio (95 % CI): 0.114 (0.03-0.432); p = 0.001}. An equation, constructed using the adjusted odds ratio for the two parameters, had an area under the ROC curve of 91.3%. For the choice of cut-off, sensitivity, specificity, positive and negative predictive value for predicting outcome was 90%, 86.5%, 79.4% and 93.7%.

Conclusion

APACHE II score at admission and SA levels with in 24 hrs after admission are independent predictors of mortality for patients with COPD admitted to ICU. The equation derived from these two parameters is useful for predicting outcome of these patients.     

Selection and characterization of an L-thiazolidine-4-carboxylic acid resistant callus culture of Vigna radiata (L.) Wilczek var. radiata

Callus cultures were established from seedling root tips of mungbean (Vigna radiata (L.) Wilczek var. radiata) cv. K 851. The growing calli were exposed to increasing concentrations of thioproline — an analog of proline, in the medium. A concentration of 3.0 mM thioproline completely inhibited the growth of the cells. However, after 25 days incubation 5 cell clones were obtained which could grow on this concentration of thioproline. Out of them one vigorously growing cell clone was further characterized. This selected clone contained higher endogenous levels of free proline (5 fold) and K⁺ (1.5 fold) and exhibited elevated tolerance, not only to thioproline but also to exogenously applied NaCl in the growth medium, as compared to the normal sensitive callus cells. Higher endogenous levels of free proline and K⁺ appear to impart dual resistance to thioproline and NaCl to the selected cell strain.     

The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network

Secreted Wnt proteins play essential roles in many biological processes during development and diseases. However, little is known about the mechanism(s) controlling Wnt secretion. Recent studies have identified Wntless (Wls) and the retromer complex as essential components involved in Wnt signaling. While Wls has been shown to be essential for Wnt secretion, the function(s) of the retromer complex in Wnt signaling is unknown. Here, we have examined a role of Vps35, an essential retromer subunit, in Wnt signaling in Drosophila and mammalian cells. We provide compelling evidence that the retromer complex is required for Wnt secretion. Importantly, Vps35 colocalizes in endosomes and interacts with Wls. Wls becomes unstable in the absence of retromer activity. Our findings link Wls and retromer functions in the same conserved Wnt secretion pathway. We propose that retromer influences Wnt secretion by recycling Wntless from endosomes to the trans-Golgi network (TGN).     

Involvement of<Emphasis Type="Italic">Leishmania donovani</Emphasis> major surface glycoprotein gp63 in promastigote multiplication

The major surface glycoprotein gp63 of the kinetoplastid protozoal parasiteLeishmania is implicated as a ligand mediating uptake of the parasite into, and survival within, the host macrophage. By expressing gp63 antisense RNA from an episomal vector inL. donovani promastigotes, gp63-deficient transfectants were obtained. Reduction of the gp63 level resulted in increased generation times, altered cell morphology, accumulation of cells in the G2/M phase of the cell cycle, and increased numbers of binucleate cells with one or two kinetoplasts. Growth was stimulated, and the number of binucleate cells reduced, by addition to the culture of a bacterially expressed fusion protein containing the fibronectin-like SRYD motif and the zinc-binding (metalloprotease) domain of gp63. These observations support an additional role of gp63 in promastigote multiplication; the fibronectin-like properties of gp63 may be important in this process     

Correspondence regarding October 31, 2003, Breakthroughs and Views by K. Brown and P.L. Carmichael

A. Fuglsang [Biochem. Biophys. Res. Commun. 317 (2004) 957-964] suggested that effective number of codons for individual amino acids (Nc-values) should be re-adjusted to the number of synonymous codons of those amino acids, in order to prevent the overestimation of the effective number of codons. Here, it is shown that re-adjustment at the level of individual amino acids results in loss of considerable amounts of information. Furthermore, we have shown that theoretical Nc-values are functions of GC3s (and GC1s); as a result, when an amino acid Nc-value exceeds the related theoretical Nc-value, the implication of re-adjustment depends on the GC composition of the gene.     

Establishment of <Emphasis Type="Italic">lacZ</Emphasis> marked strain of phosphate solubilizing bacterium in the rhizosphere and its effect on plant growth in mungbean

The establishment of lacZ marked strain of P-solubilizing bacterium Pseudomonas in the rhizosphere of mungbean (Vigna radiata) under pothouse conditions was studied. The lacZ marker was transferred to Pseudomonas P-36 on LB medium using donor strain of E. coli. The lacZ marked strain formed blue colonies on selective media and could be identified from soil on the basis of this character. The lacZ marked strain was able to survive in rhizosphere of mungbean under pothouse conditions and maintained a population of about 10⁴ g^?1 of rhizosphere soils up to 60 days study period. Positive effect of inoculation with P-solubilizing bacterium on dry matter yield, P and N-uptake was observed using rock phosphate and single super phosphate as P sources with and without farmyard amendment.     

Development of polymorphic EST-SSR markers and their applicability in genetic diversity evaluation in Rhododendron arboreum

Molecular Biology Reports - The genus Rhododendron, known for large impressive flowers is widely distributed throughout the world. Rhododendrons have limited genetic information, despite of...