Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model

Alpha-toxin (AT) is a major virulence determinant in Staphylococcus aureus skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents S. aureus disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of S. aureus skin and soft tissue infections.     

Identification of Metal Dithiocarbamates as a Novel Class of Antileishmanial Agents

Dithiocarbamates have emerged as potent carbonic anhydrase (CA) inhibitors in recent years. Given that CAs are important players in cellular metabolism, the objective of this work was to exploit the CA-inhibitory property of dithiocarbamates as a chemotherapeutic weapon against the Leishmania parasite. We report here strong antileishmanial activity of three hitherto unexplored metal dithiocarbamates, maneb, zineb, and propineb. They inhibited CA activity in Leishmania major promastigotes at submicromolar concentrations and resulted in a dose-dependent inhibition of parasite growth. Treatment with maneb, zineb, and propineb caused morphological deformities of the parasite and Leishmania cell death with 50% lethal dose (LD₅₀) values of 0.56 μM, 0.61 μM, and 0.27 μM, respectively. These compounds were even more effective against parasites growing in acidic medium, in which their LD₅₀ values were severalfold lower. Intracellular acidosis leading to apoptotic and necrotic death of L. major promastigotes was found to be the basis of their leishmanicidal activity. Maneb, zineb, and propineb also efficiently reduced the intracellular parasite burden, suggesting that amastigote forms of the parasite are also susceptible to these metal dithiocarbamates. Interestingly, mammalian cells were unaffected by these compounds even at concentrations which are severalfold higher than their antileishmanial LD₅₀s). Our data thus establish maneb, zineb, and propineb as a new class of antileishmanial compounds having broad therapeutic indices.     

Are alterations of tight junctions at molecular and ultrastructural level different in duodenal biopsies of patients with celiac disease and Crohn's disease?

Abnormalities of transmembrane and cytoplasmic proteins of tight junctions (TJ) have been implicated in pathogenesis of both celiac (CeD) and Crohn’s diseases (CD). Since disease pathogenesis in CeD and CD are different, we planned to study if there is any differential expression pattern of TJ marker proteins and ultrastructural changes, respectively, in duodenal villi vs crypts. Endoscopic duodenal biopsies from treatment naïve patients with CeD (n?=?24), active CD (n?=?28), and functional dyspepsia (as controls, n?=?15), both at baseline and 6 months after treatment, were subjected to light microscopic analysis (modified Marsh grading); immune-histochemical staining and Western blot analysis to see the expression of key TJ proteins [trans-membrane proteins (claudin-2, claudin-3, claudin-4, occludin, and JAM) and cytoplasmic protein (ZO-1)]. Transmission electron microscopy and image analysis of the TJs were also performed. There was significant overexpression of claudin-2 (pore-forming) and occludin (protein maintaining cell polarity) with under-expression of claudin-3 and claudin-4 (pore-sealing proteins) in treatment naïve CeD and active CD with simultaneous alteration in ultrastructure of TJs such as loss of penta-laminar structure and TJ dilatation. Normalization of some of these TJ proteins was noted 6 months after treatment. These changes were not disease specific and were not different in duodenal villi and crypts. Overexpression of pore-forming and under-expression of pore-sealing TJ proteins lead to dilatation of TJ. These changes are neither disease specific nor site specific and the end result of mucosal inflammation.     

Guidelines for prevention of hospital acquired infections

These guidelines, written for clinicians, contains evidence-based recommendations for the prevention of hospital acquired infections Hospital acquired infections are a major cause of mortality and morbidity and provide challenge to clinicians. Measures of infection control include identifying patients at risk of nosocomial infections, observing hand hygiene, following standard precautions to reduce transmission and strategies to reduce VAP, CR-BSI, CAUTI. Environmental factors and architectural lay out also need to be emphasized upon. Infection prevention in special subsets of patients - burns patients, include identifying sources of organism, identification of organisms, isolation if required, antibiotic prophylaxis to be used selectively, early removal of necrotic tissue, prevention of tetanus, early nutrition and surveillance. Immunodeficient and Transplant recipients are at a higher risk of opportunistic infections. The post tranplant timetable is divided into three time periods for determining risk of infections. Room ventilation, cleaning and decontamination, protective clothing with care regarding food requires special consideration. Monitoring and Surveillance are prioritized depending upon the needs. Designated infection control teams should supervise the process and help in collection and compilation of data. Antibiotic Stewardship Recommendations include constituting a team, close coordination between teams, audit, formulary restriction, de-escalation, optimizing dosing, active use of information technology among other measure. The recommendations in these guidelines are intended to support, and not replace, good clinical judgment. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments.     

Self-assembled pearl-necklace patterned upconverting nanocrystals with highly efficient blue and ultraviolet emission: femtosecond laser based upconversion properties

This work reports new findings on the formation of a pearl-necklace pattern in self-assembled upconverting nanocrystals (UCN-PNs) which exhibit strong upconversion emission under an NIR excitation source of a femtosecond laser (Fs-laser). Each nano-necklace consists of several upconversion nanoparticles (UCNPs) having a size ca. 10 ± 1 nm. UCN-PNs are arranged in a self-organized manner to form necklace type chains with an average length of 140 nm of a single row of nanoparticles. Furthermore, UCN-PNs are comprised of UCNPs with an average interparticle separation of ca. 4 nm in each of the nanonecklace chains. Interestingly, these UCN-PNs exhibit high energy upconversion especially in the UV region on interaction with a 140 Fs-laser pulse duration at 80 MHz repetition rate and intense blue emission at 450 nm on interaction with a 900 nm excitation source is obtained. The preparation of self-assembled UCNPs is easy and they are very stable for a longer period of time. The emission (fluorescence/luminescence) intensity is very high which can make them unique in innumerable industrial and bio-applications such as for disease diagnosis and therapeutic applications by targeting the infected cells with enhanced efficiency.

Self-assembled pearl necklace patterned-upconverting nanoparticles and their femtosecond laser based upconversion properties.     

Our experience of coronary angiography with and without heparin

AimCoronary angiography is usually done with heparin. Our aim is to see whether it can be done without heparin through femoral route and its effect on local complications.MethodWe have studied 3780 patients from 2006 to 2010 using standard dose Heparin (5000 units), low dose heparin (2000 units) and no heparin. We have compared safety and complications in these three groups.ResultsLocal complications were lowest in no heparin group. Blood transfusion requirements and surgical interventions were lowest in no heparin group. Thrombosis rate did not increase in no heparin group.ConclusionCoronary angiography can be done safely without heparin through femoral route.