COLISTIN RESISTANCE IN CARBAPENEM-RESISTANT KLEBSIELLA PNEUMONIAE STRAINS

Objective: There is an increasing use of colistin consequent to increase in the infections caused by carbapenem-resistant Klebsiella pneumoniae.The present study was conducted to determine the minimum inhibitory concentration (MIC) of colistin and the resistance pattern of colistin in carbapenem-resistant K. pneumoniae (CRKP) strains in our intensive care unit (ICU).Methods: Antibiotic susceptibility testing for other antimicrobial agents was done by Kirby-Bauer disk diffusion method. MIC of colistin was determined by agar dilution method. The results of antibiotic susceptibility testing were interpreted as per Clinical Laboratory Standard Institute guidelines 2016 and MIC of colistin were interpreted as per European Committee on Antimicrobial susceptibility testing. The carbapenem resistance was phenotypically detected by modified hodge test and imipenem/imipenem ethylenediaminetetraacetic acid disk method.Results: Out of 518 K. pneumoniae, 329 were resistant to carbapenems, and 91 isolates showed resistance to colistin. The MIC of colistin ranged between 4 and >512 ug/ml and MIC90 was 16 ug/L and MIC50 was 4 ug/ml. A majority of the colistin-resistant isolates were found in multidisciplinary ICU (85/91).Conclusion: The emergence of colistin-resistant strains is a major problem due to limited treatment options for infections caused by CRKP carbapenemase producing K. pneumoniae. Colistin should not be used alone, combination therapy should be preferred

Anti-thrombotics and their impact on inpatient epistaxis management : a tertiary centre experience

Peer reviewedPublisher PD

Mechanism of action of lenalidomide in hematological malignancies

Immunomodulatory drugs lenalidomide and pomalidomide are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that lacks the neurologic side effects of sedation and neuropathy and has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Lenalidomide has been shown to be an immunomodulator, affecting both cellular and humoral limbs of the immune system. It has also been shown to have anti-angiogenic properties. Newer studies demonstrate its effects on signal transduction that can partly explain its selective efficacy in subsets of MDS. Even though the exact molecular targets of lenalidomide are not well known, its activity across a spectrum of neoplastic conditions highlights the possibility of multiple target sites of action

CD40 Signaling Is Impaired in L. major–infected Macrophages and Is Rescued by a p38MAPK Activator Establishing a Host-protective Memory T Cell Response

Leishmania, a protozoan parasite, lives and multiplies as amastigote within macrophages. It is proposed that the macrophage expressed CD40 interacts with CD40 ligand on T cells to induce IFN-γ, a Th1-type cytokine that restricts the amastigote growth. Here, we demonstrate that CD40 cross-linking early after infection resulted in inducible nitric oxide synthetase type-2 (iNOS2) induction and iNOS2-dependent amastigote elimination. Although CD40 expression remained unaltered on L. major–infected macrophages, delay in the treatment of macrophages or of mice with anti-CD40 antibody resulted in significant reduction in iNOS2 expression and leishmanicidal function suggesting impaired CD40 signaling in Leishmania infection. The inhibition of CD40-induced iNOS2 expression by SB203580, a p38-mitogen activated protein kinase (p38MAPK)-specific inhibitor, and the reversal of the inhibition by anisomycin, a p38MAPK activator, suggested a crucial role of p38MAPK in CD40 signaling. Indeed, the CD40-induced p38MAPK phosphorylation, iNOS2 expression and anti-leishmanial function were impaired in Leishmania-infected macrophages but were restored by anisomycin. Anisomycin's effects were reversed by SB203580 emphasizing the role of p38MAPK in CD40-induced iNOS2-dependent leishmanicidal function. Anisomycin administration in L. major–infected BALB/c mice resulted in significant reduction in the parasite load and established a host-protective Th1-type memory response. Also implicated in these findings is a scientific rationale to define novel anti-parasite drug targets and to bypass the problem of drug resistance

Improving French bean yield potential through induced mutagenesis using EMS and SA

IntroductionFrench bean (Phaseolus vulgaris L.) holds global significance as one of the most consumed legumes, with commercial value surpassing that of all other legume crops combined. In India, the consumption of French beans has grown steadily, especially in the North Eastern region, driven by heightened consumer interest in its nutritional benefits. Considering these factors, we initiated an induced mutagenesis program to enhance the genetic diversity of locally grown French bean genotypes, traditionally cultivated for their superior adaptability.MethodsTo achieve this, we initiated an induced mutagenesis program. Seeds from the village seed stock were subjected to treatments with varying doses of ethyl methane sulfonate (EMS) ranging from 0.1% to 0.4% and sodium azide (SA) from 0.1% to 0.4%. The objective was to increase yield potential and enhance genetic diversity.ResultsThe treatment with EMS and SA led to a non-specific, dosage-independent reduction in biophysiological characteristics in French bean mutants. Notably, the 0.4% SA treatment significantly inhibited germination and fertility, causing a decrease in chlorophyll (10.02 mg. g-1 FW) and carotenoid (1.57 mg. g-1 FW) levels. This suggests a disruption in genes associated with chlorophyll and carotenoid synthesis. However, in the M2 generation, the mutagenic treatments substantially improved yield and associated traits. The highest pod yield per plant was recorded at 79.50 gm for the 0.2% EMS treatment. A character association study revealed strong correlations (0.217 to 0.995) between pod yield and other agronomic traits.DiscussionThe results indicate that selecting mutants based on these traits in populations treated with EMS and SA can significantly increase crop yield. The 0.2% SA and 0.2% EMS M2 mutant populations exhibited the highest induced variability, making them ideal for selecting higher-yielding mutant lines for further breeding generations. The increased yields in these mutant lines, derived from a local cultivar, show promise for meeting the growing demand for French bean production through their widespread cultivation

Adjuvant Properties of Thermal Component of Hyperthermia Enhanced Transdermal Immunization: Effect on Dendritic Cells

Hyperthermia enhanced transdermal (HET) immunization is a novel needle free immunization strategy employing application of antigen along with mild local hyperthermia (42°C) to intact skin resulting in detectable antigen specific Ig in serum. In the present study, we investigated the adjuvant effect of thermal component of HET immunization in terms of maturation of dendritic cells and its implication on the quality of the immune outcome in terms of antibody production upon HET immunization with tetanus toxoid (TT). We have shown that in vitro hyperthermia exposure at 42°C for 30 minutes up regulates the surface expression of maturation markers on bone marrow derived DCs. This observation correlated in vivo with an increased and accelerated expression of maturation markers on DCs in the draining lymph node upon HET immunization in mice. This effect was found to be independent of the antigen delivered and depends only on the thermal component of HET immunization. In vitro hyperthermia also led to enhanced capacity to stimulate CD4+ T cells in allo MLR and promotes the secretion of IL-10 by BMDCs, suggesting a potential for Th2 skewing of T cell response. HET immunization also induced a systemic T cell response to TT, as suggested by proliferation of splenocytes from immunized animal upon in vitro stimulation by TT. Exposure to heat during primary immunization led to generation of mainly IgG class of antibodies upon boosting, similar to the use of conventional alum adjuvant, thus highlighting the adjuvant potential of heat during HET immunization. Lastly, we have shown that mice immunized by tetanus toxoid using HET route exhibited protection against challenge with a lethal dose of tetanus toxin. Thus, in addition to being a painless, needle free delivery system it also has an immune modulatory potential

Myeloid differentiation primary response protein 88 (MyD88)-deficient dendritic cells exhibit a skewed cytokine response to BCG

Abstract Objective Macrophages and dendritic cells (DCs) play key role in the recognition of mycobacterial infection and mounting of antimycobacterial immunity. In case of macrophages, recognition of BCG and other mycobacteria has been attributed predominantly to MyD88-dependent singling. Interestingly, in previous study with bone marrow-derived DCs, we have shown that BCG promotes the survival of wild-type and MyD88−/− cells to the comparable levels. In the present study, we further examined MyD88−/− DC’s response to BCG. Results Bone marrow-derived DCs from wild-type and MyD88−/− mice were stimulated with BCG and analyzed for cytokine secretion. As expected, BCG-stimulated wild-type DCs produced significant amount of TNF-α and IL-12p40 in response to BCG. Interestingly, BCG-stimulated MyD88−/− DCs were also found to secret significantly higher levels of TNF-α and IL-12p40, compared with unstimulated DCs. We further observed that wild-type DCs produced significant level of immunosuppressive cytokine IL-10 in response to BCG, whereas MyD88−/− DCs secreted very low amount of IL-10 when stimulated with BCG. These findings demonstrated that MyD88−/− DCs exhibit a skewed cytokine response to BCG

A review of the high-concentration capsaicin patch and experience in its use in the management of neuropathic pain

In the European Union, the high-concentration capsaicin patch is licensed for the management of neuropathic pain conditions in nondiabetic patients, including postherpetic neuralgia (PHN) and HIV-associated distal sensory polyneuropathy (HIV-DSP). However, in the USA, the Food and Drug Administration approved its use only in PHN patients. Capsaicin is a transient receptor potential vanilloid-1 agonist, which increases the intracellular calcium ion concentration. This triggers calcium-dependent protease enzymes causing cytoskeletal breakdown and leads to the loss of cellular integrity and ‘defunctionalization’ of nociceptor fibres. Efficacy and therapeutic effect has been shown in several clinical studies of PHN and HIV-DSP. The high-concentration capsaicin patch and its practical application are different from low-concentration creams; one application can help for up to 3 months. The process of setting up of a service to use the capsaicin 8% patch is also discussed

Phase encoded quantum key distribution up to 380 km in standard telecom grade fiber enabled by baseline error optimization

Abstract Phase encoding in quantum key distribution (QKD) enables long-distance information-theoretic secure communication in optical fibers. We present a novel theoretical model characterizing errors from various sources in practical phase encoding-based QKD systems, namely the laser linewidth, detector dark counts, and channel dispersion. This model provides optimized optical pulse parameters and less distortion in pulses, which eliminates system imperfections and leads to a reduced quantum bit error rate (QBER) for practical QKD scenario. This analysis is applicable to various fiber-based phase and time encoding protocols. In particular, we implement this to a differential phase shift (DPS) QKD scheme operating at a 2.5 GHz clock, which produces a secure key rate of 193 bits/s at a fiber length of 265 km and an unprecedented QBER < 1 $$\%$$ % up to 225 km length with standard telecom components. We show that by adjusting the quantum efficiency and dark count rates of detectors, proposed system can establish secure keys up to 380 km distance using standard telecom grade fiber with a QBER of 1.48%. Moreover, the system is compatible with existing optical fiber networks and capable of establishing a secure key exchange between two cities 432 km apart using ultra-low-loss (ULL) specialty fiber

Lipoarabinomannan from Mycobacterium indicus pranii shows immunostimulatory activity and induces autophagy in macrophages.

Mycobacterium indicus pranii (MIP) known for its immunotherapeutic potential against leprosy and tuberculosis is undergoing various clinical trials and also simultaneously being studied in animal models to get insight into the mechanistic details contributing to its protective efficacy as a vaccine candidate. Studies have shown potential immunomodulatory properties of MIP, the most significant being the ability to induce strong Th1 type of response, enhanced expression of pro-inflammatory cytokines, activation of APCs and lymphocytes, elicitation of M.tb specific poly-functional T cells. All of these form crucial components of host-immune response during M.tb infection. Also, MIP was found to be potent inducer of autophagy in macrophages which resulted in enhanced clearance of M.tb from MIP and M.tb co-infected cells. Hence, we further examined the component/s of MIP responsible for autophagy induction. Interestingly, we found that MIP lipids and DNA were able to induce autophagy but not the protein fraction. LAM being one of the crucial components of mycobacterial cell-wall lipids and possessing the ability of immunomodulation; we isolated LAM from MIP and did a comparative study with M.tb-LAM. Stimulation with MIP-LAM resulted in significantly high secretion of pro-inflammatory cytokines and displayed high autophagy inducing potential in macrophages as compared to M.tb-LAM. Treatment with MIP-LAM enhanced the co-localization of M.tb within the phago-lysosomes and increased the clearance of M.tb from the infected macrophages. This study describes LAM to be a crucial component of MIP which has significant contribution to its immunotherapeutic efficacy against TB