IL-4 depletion enhances host resistance and passive IgA protection against tuberculosis infection in BALB/c mice

The influence of Th2 cytokines in tuberculosis has been a matter of dispute. Here we report that IL-4 has a profound regulatory effect on the infection of BALB/c mice with Mycobacterium tuberculosis. Depletion of IL-4 with a neutralizing mAb caused only evanescent reduction of lung infection, but when combined with i.n. inoculations of IgA anti-mycobacterial alpha-crystallin mAb and mouse rIFN-gamma, we observed a 40-fold reduction of the bacterial counts in the lungs at 3 wks following i.n. infection (p<0.001). In genetically deficient IL-4-/- BALB/c mice, infection in both lung and spleen was substantially reduced for up to 8 wks without further treatment. Reconstitution of IL-4-/- mice with rIL-4 increased bacterial counts to wild-type levels and made the mice refractory to protection by IgA/IFN-gamma. Analysis of the lungs showed increased granulomatous infiltration and proinflammatory mediators in anti-IL-4/IgA/IFN-gamma-treated and infected mice. We conclude that the action of IL-4 in tuberculosis is targeted at macrophages and that it may include an antagonistic effect on their IgA/IFN-gamma-induced activation and nitric oxide production. The described novel immunotherapy, combining treatments with anti-IL-4, IgA antibody and IFN-gamma, has potential for translation toward the passive immunoprophylaxis of tuberculosis.     

Bioreducible Poly(Amino Ethers) Based mTOR siRNA Delivery for Lung Cancer

Purpose

Lung cancer is one of the leading causes of deaths in the United States, but currently available therapies for lung cancer are associated with reduced efficacy and adverse side effects. Small interfering RNA (siRNA) can knock down the expression of specific genes and result in therapeutic efficacy in lung cancer. Recently, mTOR siRNA has been shown to induce apoptosis in NSCLC cell lines but its use is limited due to poor stability in biological conditions.

Methods

In this study, we modified an aminoglyocisde-derived cationic poly (amino-ether) by introducing a thiol group using Traut’s reagent to generate a bio-reducible modified–poly (amino-ether) (mPAE). The mPAE polymer was used to encapsulate mTOR siRNA by nanoprecipitation method, resulting in the formation of stable and bio-reducible nanoparticles (NPs) which possessed an average diameter of 114 nm and a surface charge of approximately +27 mV.

Results

The mTOR siRNA showed increased release from the mTS-mPAE NPs in the presence of 10 mM glutathione (GSH). The polymeric mTS-mPAE-NPs were also capable of efficient gene knockdown (60 and 64%) in A549 and H460 lung cancer cells, respectively without significant cytotoxicity at 30 μg/ml concentrations. The NPs also showed time-dependent cellular uptake for up to 24 h as determined using flow cytometry. Delivery of the siRNA using these NPs also resulted in significant inhibition of A549 and H460 cell proliferation in vitro, respectively.

Conclusions

The results demonstrate that the mPAE polymer based NPs show strong potential for siRNA delivery to lung cancer cells. It is anticipated that future modification can help improve the efficacy of nucleic acid delivery, leading to higher inhibition of lung cancer growth in vitro and in vivo.

     

Maternal Mortality: A FOGSI Study (Based on Institutional Data)

Objective

The aim of this study of maternal deaths through FOGSI members is to see its current STATUS.

Method

A three-year retrospective observational study from January 2005 to December 2007 formed the basis for collection of the data for analysis.

Results

A wide variation of maternal mortality ratio (MMR) in the five zones (West—342; South—229; East—709; North East—709 and North—814) was observed. Leading causes of maternal deaths also varied among the zones [hemorrhage in West (31 %), South (26 %), and North East (21.5 %); hypertension in East (34 %) and North (22 %)]. When the data were analyzed as a whole, the leading causes of deaths were determined as hypertension (29.4 %), hemorrhage (21.56 %), sepsis (15.05 %), and medical disorders (12 %). Analysis of data in India (including Kerala State) for the year 2005 revealed significant drop in MMR to 147.

Conclusion

MMR in India varied widely in zones. There is significant difference in MMR for the whole country as well as for the south zone with or without inclusion of Kerala. Areas of discrepancy in data had been observed in different sources. Prioritization of causes of death and appropriate allocation of resources are needed. A prospective study for evaluation of exact MMR in India is an immediate necessity.     

Clinical experience of ovarian neoplasm in childhood and adolescence

Clinical behaviour of 12 cases of ovarian neoplasm in childhood and adolescence was reviewed. Diagnostic work-up required a great deal of time, gentleness and patience. Of all ovarian tumours, 58.4% were epithelial, 33.3% were germ cell group and 8.3% were sex cord stromal tumours. Pleuripotent nature of gonads is reflected by the complex variety of ovarian tumours in children. Seventy-five per cent among the tumours were malignant. Amongst the epithelial tumours 85.7% were malignant. Because of certain reasons, comparison of results was felt difficult.     

Immunodominant PstS1 antigen of <Emphasis Type="Italic">mycobacterium tuberculosis</Emphasis> is a potent biological response modifier for the treatment of bladder cancer

Background  

Bacillus Calmette Guérin (BCG)-immunotherapy has a well-documented and successful clinical history in the treatment of bladder cancer. However, regularly observed side effects, a certain degree of nonresponders and restriction to superficial cancers remain a major obstacle. Therefore, alternative treatment strategies are intensively being explored.     

Apolipoprotein E gene polymorphism alters lipids before pancreas transplantation

BACKGROUND: Pancreas transplantation (PTX) improves lipids in patients with type 1 diabetes mellitus. However, there are patients who have persistent abnormal lipids or develop new hyperlipidemia despite PTX. One factor that may influence the lipid profile is apolipoprotein E (Apo E) genotype. Apo E polymorphism, particularly E2 and E4 alleles, increases the risk of dyslipidemia. Apo E2 has also been found to increase risk of diabetic nephropathy and so may be more prevalent in PTX candidates. METHODS: This study evaluated fasting-lipid profiles in type 1 diabetes patients who were pancreas transplant candidates to prospectively evaluate the impact of Apo E genotype on dyslipidemia before and after PTX. RESULTS: Presence of one or more E4 alleles resulted in higher triglycerides ( =0.0446), lower HDL ( =0.0247), and a higher cholesterol-to-HDL (C/H) ratio ( =0.0405) before PTX when compared with those with E3/3 genotype. After PTX, lipids improved so there was no longer a difference in fasting lipids between patients with an E4 allele and E3/3 genotype. Presence of an E2 allele had no significant impact on fasting lipids before or after PTX. CONCLUSIONS: Presence of an Apo E4 allele worsened HDL, triglycerides, and C/H ratio before PTX compared with those with E3/3 genotype, whereas the presence of an Apo E2 allele had no significant effect on lipids before or after PTX. Thus, Apo E4 has a larger impact than Apo E2 on fasting-lipid profile in PTX candidates, and Apo E gene polymorphism does not worsen lipid dyslipidemia after PTX, despite introduction of immunosuppressant medications known to cause dyslipidemia.     

HSP70 peptide binding mutants separate antigen delivery from dendritic cell stimulation

Microbial heat shock proteins (HSPs) have been implicated in the induction of both the innate and adaptive arms of the immune response. We now show that human dendritic cells (DC) pulsed with peptide-loaded mycobacterial HSP70 complexes generate potent antigen-specific cytotoxic lymphocyte (CTL) responses, which are dependent on an HSP70-stimulated calcium signaling cascade. From the calculated peptide binding affinity of mycobacterial HSP70 (K(D) = 14 microM) we show that 120 pM HSP70 bound peptide is sufficient to generate a peptide-specific CTL response that is up to four orders of magnitude more efficient than peptide alone. The minimal 136 amino acid, mycobacterial HSP70 peptide binding domain can generate CTL responses, and a single amino acid mutant HSP70 designed to prevent peptide binding but retain stimulatory capacity has allowed us to separate antigen delivery from DC immunostimulation.