Krishnan Chakravarthy

Gold nanorod delivery of an ssRNA immune activator inhibits pandemic H1N1 influenza viral replication

The emergence of the pandemic 2009 H1N1 influenza virus has become a world-wide health concern. As drug resistance appears, a new generation of therapeutic strategies will be required. Here, we introduce a nanotechnology approach for the therapy of pan-demic and seasonal influenza virus infections. This approach uses gold nanorods (GNRs) to deliver an innate immune activator, pro-ducing a localized therapeutic response. We demonstrated the utility of a biocompatible gold nanorod, GNR-5′PPP-ssRNA nanoplex, as an antiviral strategy against type A influenza virus. In human respiratory bronchial epithelial cells, this nanoplex activated the retinoic acid-inducible gene I (RIG-I) pathogen recognition pathway, resulting in increased expression of IFN-β and other IFN-stimulated genes (ISGs) (e.g., PKR, MDA5, IRF1, IRF7, and MX1). This increase in type I IFN and ISGs resulted in a decrease in the replication of H1N1 influenza viruses. These findings suggest that further evaluation of biocompatible nanoplexes as unique antivirals for treatment of seasonal and pandemic influenza viruses is warranted.

Doxorubicin-conjugated quantum dots to target alveolar macrophages and inflammation

UNLABELLED The ability to provide targeted therapeutic delivery in the lung would be a major advancement in pharmacological treatments for many pulmonary diseases. Critical issues for such successful delivery would require the ability to target specific cell types, minimize toxicity (e.g., inflammatory response), and deliver therapeutic levels of drugs. We report here on the ability of nanoconjugates of CdSe/CdS/ZnS quantum dots (QDs) and doxorubicin (Dox) to target alveolar macrophages (aMØs), cells that play a critical role in the pathogenesis of inflammatory lung injuries. Confocal imaging showed the release of Dox from the QD-Dox nanoconjugate, as was evident by its accumulation in the cell nucleus and induction of apoptosis, implying that the drug retains its bioactivity after coupling to the nanoparticle. Inflammatory injury parameters (albumin leakage, proinflammatory cytokines, and neutrophil infiltration) were recorded after in vivo administration of QD-Dox and Dox, observing no significant effect after QD-Dox treatment compared with Dox. These results demonstrate that nanoparticle platforms can provide targeted macrophage-selective therapy for the treatment of pulmonary disease. FROM THE CLINICAL EDITOR Pulmonary inflammatory diseases still often remain challenging to treat, despite decades of advances and several available agents. In this study, a quantum dot-based alveolar delivery system is presented, targeting macrophages with doxorubicin.

Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management.

Recent human and animal studies provide growing evidence that vagal nerve stimulation (VNS) can deliver strong analgesic effects in addition to providing therapeutic efficacy in the treatment of refractory epilepsy and depression. Analgesia is potentially mediated by vagal afferents that inhibit spinal nociceptive reflexes and transmission and have strong anti-inflammatory properties. The purpose of this review is to provide pain practitioners with an overview of VNS technology and limitations. It specifically focuses on clinical indications of VNS for various chronic pain syndromes, including fibromyalgia, pelvic pain, and headaches. We also present potential mechanisms for VNS modulation of chronic pain by reviewing both animal and human studies.

Epidural steroid injections: an updated review on recent trends in safety and complications.

Epidural steroid injections (ESIs), which can provide significant but temporary pain relief in well-selected patients, are the most commonly performed procedure in pain management. The anatomy of the epidural space provides a framework for understanding risks associated with ESIs, a topic relevant to both patients and physicians in interventional pain, surgery and primary care. Safety considerations of epidural steroids include drug preparation and myriad physiological effects stemming from steroid exposure. Although major complications associated with ESI occur rarely, potentially catastrophic events resulting from infectious, hematologic and neurologic morbidity may lead to permanent injury. The safety profile of ESIs may improve with development and dissemination of sound injection technique, safer compounds manufactured in a sterile manner and deficient of thromboembolic potential and the application of existing technology.

Review of Recent Advances in Peripheral Nerve Stimulation (PNS)

Peripheral nerve stimulation (PNS) for the treatment of chronic pain has become an increasingly important field in the arena of neuromodulation, given the ongoing advances in electrical neuromodulation technology since 1999 permitting minimally invasive approaches using an percutaneous approach as opposed to implantable systems. Our review aims to provide clinicians with the recent advances and studies in the field, with specific emphasis on clinical data and indications that have been accumulated over the last several years. In addition, we aim to address key basic science studies to further emphasize the importance of translational research outcomes driving clinical management.

Halothane modulates the type i interferon response to influenza and minimizes the risk of secondary bacterial pneumonia through maintenance of neutrophil recruitment in an animal model.

Background:To minimize the risk of pneumonia, many anesthesiologists delay anesthesia-requiring procedures when patients exhibit signs of viral upper respiratory tract infection. Postinfluenza secondary bacterial pneumonias (SBPs) are a major cause of morbidity and mortality. An increased host susceptibility to SBP postinfluenza has been attributed to physical damage to the pulmonary epithelium, but flu-induced effects on the immune system are being shown to also play an important role. The authors demonstrate that halothane mitigates the risk of SBP postflu through modulation of the effects of type I interferon (IFN). Methods:Mice (n = 6 to 15) were exposed to halothane or ketamine and treated with influenza and Streptococcus pneumoniae. Bronchoalveolar lavage and lung homogenate were procured for the measurement of inflammatory cells, cytokines, chemokines, albumin, myeloperoxidase, and bacterial load. Results:Halothane exposure resulted in decreased bacterial burden (7.9 ± 3.9 × 105 vs. 3.4 ± 1.6 × 108 colony-forming units, P < 0.01), clinical score (0.6 ± 0.2 vs. 2.3 ± 0.2, P < 0.0001), and lung injury (as measured by bronchoalveolar lavage albumin, 1.5 ± 0.7 vs. 6.8 ± 1.6 mg/ml, P < 0.01) in CD-1 mice infected with flu for 7 days and challenged with S. pneumoniae on day 6 postflu. IFN receptor A1 knockout mice similarly infected with flu and S. pneumoniae, but not exposed to halothane, demonstrated a reduction of lung bacterial burden equivalent to that achieved in halothane-exposed wild-type mice. Conclusion:These findings indicate that the use of halogenated volatile anesthetics modulates the type I IFN response to influenza and enhance postinfection antibacterial immunity.

Nanotechnology: A Promising New Paradigm for the Control of Pain

Objective The objective of this article is to critically review both preclinical and clinical studies that focus on the use of nanotechnology for both acute and chronic pain management, surveying both diagnostic and therapeutic applications. The article also provides information on nanotechnology for pain practitioners, so that they may better understand how this technology works and how it may be applied to their day-to-day clinical practice. Study Design Narrative review. Methods The Pubmed NCBI and EMBASE databases were utilized to review published reports of in vivo and clinical studies that focus on using nanotechnology for pain management applications in both the acute and chronic pain settings. Results Articles were screened by title, abstract, and full article review. They were then analyzed by specific clinical indications, and appropriate data were presented based on a critical analysis of those articles. Conclusions As the development of nanomedical applications in acute and chronic pain management continues, medical practitioners should consider their growing potential to enhance the care of patients who are consistently living with pain. Current barriers to implementation include manufacturing scale-up for commercial viability, long-term nanoparticle toxicity considerations, and high cost for successful passage through clinical trials. These challenges will need to be overcome with ongoing translational research efforts in collaboration with industry and government bodies such as the Food and Drug Administration (FDA).

Anesthetic Management of Pheochromocytoma Resection in Adults with Single Ventricle Physiology

Survival rates for patients with palliated congenital heart disease are increasing, and an increasing number of adults with cyanotic congenital heart disease (CCHD) might require surgical resection of pheochromocytoma-paraganglioma (PHEO-PGL). A recent study supports the idea that patients with a history of CCHD and current or historical cyanosis might be at increased risk for developing PHEO-PGL. We review the anesthetic management of two adults with single-ventricle physiology following Fontan palliation presenting for PHEO-PGL resection and review prior published case reports. We found the use of epidural analgesia to be safe and effective in the operative and postoperative management of our patients.

Superseding the Hourglass Effect Toward the Successful Commercialization of Nanotechnology in the Medical Sciences – We Require a Change in Perspective

Nanotechnology and, specifically, nanomedicine has been touted as the next breakthrough technology for medical sciences. Although there are large advances being seen in the preclinical phases of development, there is still a paucity of viable and effective nanomedicine technologies in the clinical setting. We attempt to provide some suggestions as to the stumbling blocks of meaningful translation of this technology from the bench to the bedside. We give due consideration to the role of evidence-based medicine, regulatory pathways, and the commercialization efforts of nanomedicine at various stages in playing key roles in moving this technology into clinical use.