Entrainment during Ablation of Ischemic Ventricular Tachycardia. What is explanation for Post Pacing Interval shorter than the tachycardia cycle length?

Entrainment mapping of ischemic ventricular tachycardia at a site in the left ventricle where radiofrequency ablation was successful in terminating the tachycardia revealed a post-pacing interval shorter than the tachycardia cycle length. The reason for the same is explained in the current report.     

Spontaneous demonstration of counterclockwise right atrial activation following successful isthmus ablation

We describe an uncommon case of typical flutter with symptomatic sinus node dysfunction, in which a permanent junctional rhythm developed following ablation of the cavo-tricuspid isthmus. This rhythm activated the right atrium in counter clockwise manner thus providing spontaneous proof of unidirectional isthmus block, a phenomenon that is usually demonstrated by proximal coronary sinus pacing.     

RiDs db: Repeats in diseases database

The non-coding fraction of the human genome, which is approximately 98%, is mainly constituted by repeats. Transpositions, expansions and deletions of these repeat elements contribute to a number of diseases. None of the available databases consolidates information on both tandem and interspersed repeats with the flexibility of FASTA based homology search with reference to disease genes. Repeats in diseases database (RiDs db) is a web accessible relational database, which aids analysis of repeats associated with Mendelian disorders. It is a repository of disease genes, which can be searched by FASTA program or by limitedor free- text keywords. Unlike other databases, RiDs db contains the sequences of these genes with access to corresponding information on both interspersed and tandem repeats contained within them, on a unified platform. Comparative analysis of novel or patient sequences with the reference sequences in RiDs db using FASTA search will indicate change in structure of repeats, if any, with a particular disorder. This database also provides links to orthologs in model organisms such as zebrafish, mouse and Drosophila. AVAILABILITY: The database is available for free at http://115.111.90.196/ridsdb/index.php.     

Macrophage-Specific Targeting of Isoniazid Through Mannosylated Gelatin Microspheres

Active targeting of drug molecules can be achieved by effective attachment of suitable ligands to the surface of carriers. The present work was attempted to prepare mannosylated gelatin microspheres (m-GMs) so as to achieve targeted delivery of isoniazid (INH) to alveolar macrophages (AMs) and maintain its therapeutic concentration for prolonged period of time. Microspheres were prepared by emulsification solvent extraction method and evaluated for physicochemical characteristics, drug release, ex vivo drug uptake by AMs and pharmacokinetic characteristics. Fourier transform infrared spectroscopy and nuclear magnetic resonance spectral analysis confirmed that mannosylation took place through Schiff base formation between aldehyde and amino groups of mannose and gelatin, respectively. Prepared microspheres offered suitable physicochemical characteristics for their delivery to AMs. Their average size was about 4 μm and drug entrapment efficiency of 56% was achieved with them. Ex vivo uptake results indicated that in comparison to plain microspheres, m-GMs were selectively uptaken and were found to be associated with phago-lysosomal vesicles of AMs. Pharmacokinetic studies showed the formulation could maintain the therapeutic concentration of INH for prolonged period of time even with a reduced clinical dose. m-GMs were found to be stable in broncheo-alveolar lavage fluid. The study concluded that ligand decorated carriers could be a potential strategy to improve the therapeutic properties of INH.     

Genome-wide RNAi screens identify genes required for Ricin and PE intoxications

Protein toxins such as Ricin and Pseudomonas exotoxin (PE) pose major public health challenges. Both toxins depend on host cell machinery for internalization, retrograde trafficking from endosomes to?the ER, and translocation to cytosol. Although both toxins follow a similar intracellular route, it is unknown how much they rely on the same genes. Here we conducted two genome-wide RNAi screens identifying genes required for intoxication and demonstrating that requirements are strikingly different between PE and Ricin, with only 13% overlap. Yet factors required by both toxins are present from the endosomes to the ER, and, at the morphological level, the toxins colocalize in multiple structures. Interestingly, Ricin, but not PE, depends on Golgi complex integrity and colocalizes significantly with a medial Golgi marker. Our data are consistent with two intertwined pathways converging and diverging at multiple points and reveal the complexity of retrograde membrane trafficking in mammalian cells.     

ABL/BCR gene variant with two-step mechanism: Unusual localization and rare/novel chromosomal rearrangements in CML patients

Aims: Variant translocations involving 9q, 22q and at least one additional genomic locus occur in 5-10% of the patients with chronic myeloid leukemia (CML). The mechanisms for the formation of these variant translocations are not fully characterized. Here we report CML cases presenting a variant translocation indicating two-step mechanism with rare/novel chromosomal rearrangement. Methods: Karyotype analysis was performed on metaphases obtained through short-term cultures of bone marrow and blood. Detection of BCR-ABL fusion gene was performed using dual-color dual-fusion (D-FISH) and extra signal (ES) translocation probes. BAC-FISH was also carried out. Results: In Patient 1, the third partner chromosome was der(11)(p15) with a 2F2G1R signal pattern, which is an unusual signal pattern with the two-step mechanism. Patients 2 and 3 showed typical positive (2F1G1R) signal pattern. In Patient 2, both the chromosome 22s were involved in variant formation. The second fusion was observed below the BCR gene of the second homologue. In Patient 3 the third chromosome was der(13)(q14). The fourth patient showed a variant pattern with BCR/ABL-ES probe involving der(X)(q13) region. Conclusion: The presence of different rearrangements of both 9q34 and 22q11 regions highlights the genetic heterogeneity of this subgroup of CML. In each case with variants, further studies with FISH, BAC-FISH or more advanced technique such as microarray should be performed. Future studies should be performed to confirm the presence of true breakpoint hot spots and assess their implications in CML with variant Ph.     

Assessment of Polycyclic Aromatic Hydrocarbons (PAH) and Heavy Metals in the Vicinity of an Oil Refinery in India

Petroleum products are one of the major sources of energy for industry and daily life. Growth of the petroleum industry and shipping of petroleum products has resulted in the pollution. Populations living in the vicinity of oil refinery waste sites may be at greater risk of potential exposure to polycyclic aromatic hydrocarbons (PAH) through inhalation, ingestion, and direct contact with contaminated media. PAH have often been found to coexist with environmental pollutants including heavy metals due to similar pollution sources. The levels and distribution patterns of Σ16 PAH (sum of the 16 PAH) and heavy metals (lead, copper, nickel, cobalt, and chromium) were determined in soil and sediment in the vicinity (5 km radius) of an oil refinery in India. Concentrations of Σ16 PAH in the soils and sediments were found to be 60.36 and 241.23 ppm, respectively. Higher amount of PAH in sediments as compared to soil is due to low water solubility of PAH, settled in the bottom of aquatic bodies. The levels of lead, copper, nickel, cobalt, and chromium (total) in soil were 12.52, 13.52, 18.78, 4.84, and 8.29 ppm, while the concentrations of these metals in sediments were 16.38, 47.88, 50.15, 7.07, and 13.25 ppm, respectively. Molecular diagnostics indices of PAH (Ratio of Phenanthrene/Anthracene, Fluranthene/Pyrene) calculated for soil and sediment samples indicate that the oil refinery environment is contaminated with PAH from petrogenic as well as pyrolytic origin and heavy vehicular traffic on the Agra- Delhi National highway. Sixteen PAH priority pollutants were detected in the United States in entire samples collected near oil refinery areas and concentrations of Σ16 PAH in soil was found to be 1.20 times higher than the threshold value for PAH in soil by ICRCL (Inter-Departmental Committee on the Redevelopment of Contaminated Land). This concentration could lead to disastrous consequences for the biotic and abiotic components of the ecosystem and may affect the soil quality, thus impairing plant growth and its bioaccumulation in food chain.     

Leaf attributes and tree growth in a tropical dry forest

Questions: How are leaf attributes and relative growth rate (RGR) of the dominant tree species of tropical deciduous forest (TDF) affected by seasonal changes in soil moisture content (SMC)? What is the relationship of functional attributes with each other? Can leaf attributes singly or in combination predict the growth rate of tree species of TDF? Location: Sonebhadra district of Uttar Pradesh, India. Methods: Eight leaf attributes, specific leaf area (SLA); leaf carbon concentration (LCC); leaf nitrogen concentration (LNC); leaf phosphorus concentration (LPC); chlorophyll concentration (Chl), mass‐based stomatal conductance (Gs_mass); mass based photosynthetic rate (A_mass); intrinsic water use efficiency (WUEi); and relative growth rate (RGR), of six dominant tree species of a dry tropical forest on four sites were analysed for species, site and season effects over a 2‐year period. Step‐wise multiple regression was performed for predicting RGR from mean values of SMC and leaf attributes. Path analysis was used to determine which leaf attributes influence RGR directly and which indirectly. Results: Species differed significantly in terms of all leaf attributes and RGR. The response of species varied across sites and seasons. The attributes were positively interrelated, except for WUEi, which was negatively related to all other attributes. The positive correlation was strongest between Gs_mass and A_mass and the negative correlation was strongest between Gs_mass and WUEi. Differences in RGR due to site were not significant when soil moisture was controlled, but differences due to season remained significant. The attributes showed plasticity across moisture gradients, which differed among attributes and species. Gs_mass was the most plastic attribute. Among the six species, Terminalia tomentosa exhibited the greatest plasticity in six functional attributes. In the step‐wise multiple regression, A_mass, SLA and Chl among leaf attributes and SMC among environmental factors influenced the RGR of tree species. Path analysis indicated the importance of SLA, LNC, Chl and A_mass in determining RGR. Conclusion: A _mass, SMC, SLA and Chl in combination can be used to predict RGR but could explain only three‐quarters of the variability in RGR, indicating that other traits/factors, not studied here, are also important in modulating growth of tropical trees. RGR of tree species in the dry tropical environment is determined by soil moisture, whereas the response of mature trees of different species is modulated by alterations in key functional attributes such as SLA, LNC and Chl.     

Co-administration of IL-1+IL-6+TNF-α with Mycobacterium tuberculosis infected macrophages vaccine induces better protective T cell memory than BCG

BCG has been administered globally for more than 75 years, yet tuberculosis (TB) continues to kill more than 2 million people annually. Further, BCG protects childhood TB but is quite inefficient in adults. This indicates that BCG fails to induce long-term protection. Hence there is a need to explore alternative vaccination strategies that can stimulate enduring T cell memory response. Dendritic cell based vaccination has attained extensive popularity following their success in various malignancies. In our previous study, we have established a novel and unique vaccination strategy against Mycobacterium tuberculosis (M. tb) and Salmonella typhimurium by utilizing infected macrophages (IM). In short-term experiments (30 days), substantial degree of protection was observed. However, remarkable difference was not observed in long-term studies (240 days) due to failure of the vaccine to generate long-lasting memory T cells. Hence, in the present study we employed T cell memory augmenting cytokines IL-1+IL-6+TNF-α and IL-7+IL-15 for the induction of the enhancement of long-term protection by the vaccine. We co-administered the M. tb infected macrophages vaccine with IL-1+IL-6+TNF-α (IM-1.6.α) and IL-7+IL-15 (IM-7.15). The mice were then rested for a reasonably large period (240 days) to study the bona fide T cell memory response before exposing them to aerosolized M. tb. IM-1.6.α but not IM-7.15 significantly improved memory T cell response against M. tb, as evidenced by recall responses of memory T cells, expansion of both central as well as effector memory CD4 and CD8 T cell pools, elicitation of mainly Th1 memory response, reduction in the mycobacterial load and alleviated lung pathology. Importantly, the protection induced by IM-1.6.α was significantly better than BCG. Thus, this study demonstrates that not only antigen-pulsed DCs can be successfully employed as vaccines against cancer and infectious diseases but also macrophages infected with M. tb can be utilized with great efficacy especially in protection against TB.