Intramuscular administration of hexachloroplatinate reverses cyanide-induced metabolic derangements and counteracts severe cyanide poisoning.

Cyanide is a highly toxic industrial chemical that is widely used by manufactures. Smoke inhalation during household fires is the most common source of cyanide poisoning while additional risks to civilians include industrial accidents and terrorist attacks. Despite the risks to large numbers of individuals, an antidote capable of administration at scale adequate for a mass casualty, prehospital scenario does not yet exist. Previously, we demonstrated that intravenous cisplatin analogues accelerate recovery from cyanide poisoning in mice and rabbits. Of the dozens of platinum-based organometallic complexes tested, hexachloroplatinate (HCP) emerged as a promising lead compound, exhibiting strong affinity for cyanide and efficacy across model systems. Here, we show HCP is an antidote to lethal cyanide exposure and importantly is effective when delivered intramuscularly. The pharmacokinetic profile of HCP exhibited bioavailability in the systemic circulation 2.5 minutes post-treatment and subsequent renal clearance of HCP-cyanide. HCP restored parameters of cellular physiology including cytochrome oxidase redox state and TCA cycle metabolism. We next validated these findings in a large animal model (swine). Finally, preclinical safety studies in mice revealed minimal toxicity. Cumulatively, these findings demonstrate hexachloroplatinate is a promising lead compound for development of an intramuscular injectable cyanide antidote for mass casualty scenarios.

Faraday Waves-Based Integrated Ultrasonic Micro-Droplet Generator and Applications.

An in-depth review on a new ultrasonic micro-droplet generator which utilizes megahertz (MHz) Faraday waves excited by silicon-based multiple Fourier horn ultrasonic nozzles (MFHUNs) and its potential applications is presented. The new droplet generator has demonstrated capability for producing micro droplets of controllable size and size distribution and desirable throughput at very low electrical drive power. For comparison, the serious deficiencies of current commercial droplet generators (nebulizers) and the other ultrasonic droplet generators explored in recent years are first discussed. The architecture, working principle, simulation, and design of the multiple Fourier horns (MFH) in resonance aimed at the amplified longitudinal vibration amplitude on the end face of nozzle tip, and the fabrication and characterization of the nozzles are then described in detail. Subsequently, a linear theory on the temporal instability of Faraday waves on a liquid layer resting on the planar end face of the MFHUN and the detailed experimental verifications are presented. The linear theory serves to elucidate the dynamics of droplet ejection from the free liquid surface and predict the vibration amplitude onset threshold for droplet ejection and the droplet diameters. A battery-run pocket-size clogging-free integrated micro droplet generator realized using the MFHUN is then described. The subsequent report on the successful nebulization of a variety of commercial pulmonary medicines against common diseases and on the experimental antidote solutions to cyanide poisoning using the new droplet generator serves to support its imminent application to inhalation drug delivery.

Recent advances in optical coherence tomography for the diagnoses of lung disorders.

There have been many advances in the field of diagnostic and therapeutic pulmonary medicine in the past several years, with major progress in the field of imaging. Optical coherence tomography (OCT) is a high-resolution (micron level) imaging modality currently being advanced with the potential to image airway wall structures in real time and at higher resolution than previously possible. OCT has the potential to increase the sensitivity and specificity of biopsies, create 3D images of the airway to guide diagnostics, and may have a future role in diverse areas such as the evaluation and treatment of patients with obstructive sleep apnea, tracheal stenosis, airway remodeling and inhalation injury. OCT has recently been investigated to monitor airway compliance in chronic obstructive pulmonary disease and asthma patients as well as differentiate causes of pulmonary hypertension. In future clinical and research applications, OCT will likely be combined with other endoscopic based modalities such as ultrasound, spectroscopy, confocal, and/or photoacoustic tomography to determine functional and biomolecular properties. This article discusses the current uses of OCT, its potential applications, as it relates to specific pulmonary diseases, and the future directions for OCT.

Multimodal imaging guidance for laser ablation in tracheal stenosis.

OBJECTIVE/HYPOTHESIS: Laser-induced damage of tracheal wall microstructures might contribute to recurrence after bronchoscopic treatment of tracheal strictures. The purpose of this study was to demonstrate how multimodal imaging using white light bronchoscopy (WLB), endobronchial ultrasound (EBUS), and optical coherence tomography (OCT) might identify in vivo airway wall changes before and resulting from Nd:YAG laser ablation and dilation of tracheal stenosis. STUDY DESIGN: Case study. METHODS: Commercially available WLB, high frequency EBUS using a 20-MHz radial probe and time-domain, frontal imaging OCT systems were used to characterize the extent, morphology, and airway wall microstructures at the area of hypertrophic fibrotic tissue formation before, during and after treatment of postintubation tracheal stenosis. RESULTS: WLB revealed the location of a complex, extensive, severe stricture. EBUS showed a homogeneous layer overlying a hyperechogenic layer corresponding to disrupted cartilage. OCT showed a homogeneous light backscattering layer and absence of layered microstructures, confirming absence in close proximity of normal airway wall. After laser ablation, OCT of charred tissue showed high backscattering and shadowing artifacts. OCT of noncharred tissue showed a thinner, homogeneous, light backscattering layer. EBUS showed thinner but persistent hypertrophic tissue suggesting incomplete treatment. WLB revealed improved airway patency postprocedure and recurrence 3 weeks later. CONCLUSIONS: EBUS identified cartilage disruption and residual hypertrophic tissue, the evidence of which might contribute to recurrence. OCT revealed homogeneous light backscaterring representing persistent noncharred hypertrophic tissues but it did not visualize cartilage disruption. Future studies are warranted to confirm whether these technologies can help guide bronchoscopic treatments.

Multimodality bronchoscopic imaging of recurrent respiratory papillomatosis.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) of the central airways requires removal to potentially reduce recurrence and risk for malignant transformation. Analogous to the principles of treatment for early lung cancer, a precise determination of the extent of cartilage invasion could help guide therapeutic decisions and monitor response to treatment. The purpose of this study was to determine whether a bronchoscopy platform comprised of white light bronchoscopy (WLB), endobronchial ultrasound (EBUS), and optical coherence tomography (OCT) could identify layered microstructure of RRP and underlying cartilage. STUDY DESIGN: Case study. METHODS: A bronchoscopy platform consisting of commercially available WLB, EBUS using a 7.5 MHz convex probe (BF-UC 160F; Olympus Optical Co. Ltd, Tokyo, Japan), and a time-domain OCT with front imaging and inside actuation (Niris Imaging System; Imalux Corp., Cleveland, OH) was used in a patient with tracheal stenosis from RRP. Findings are compared with results of histology and the characteristics of imaging modalities are discussed. RESULTS: WLB revealed tracheal pedunculated lesions. EBUS showed a 1-cm hypoechogenic density corresponding to the papilloma, visualized above a hyperechogenic density corresponding to tracheal cartilage. There was no sonographic evidence of cartilage disruption or adjacent lymphadenopathy. OCT revealed a layer of heterogeneous light backscattering suggesting the mucosal papilloma, and a layer of high-degree scattering, corresponding to the central fibrovascular core noted on histology. CONCLUSIONS: Layered microstructures of RRP and underlying airway cartilage can be identified using a combination of acoustic and optical bronchoscopic imaging modalities with different resolution and depth of penetration characteristics.

Multimodality bronchoscopic [corrected] imaging of tracheopathica osteochondroplastica.

Results of a commercial optical coherence tomography system used as part of a multimodality diagnostic bronchoscopy platform are presented for a 61-year-old patient with central airway obstruction from tracheopathica osteochondroplastica. Comparison to results of white-light bronchoscopy, histology, and endobronchial ultrasound examination are accompanied by a discussion of resolution, penetration depth, contrast, and field of view of these imaging modalities. White-light bronchoscopy revealed irregularly shaped, firm submucosal nodules along cartilaginous structures of the anterior and lateral walls of the trachea, sparing the muscular posterior membrane. Endobronchial ultrasound showed a hyperechoic density of 0.4 cm thickness. optical coherence tomography (OCT) was performed using a commercially available, compact time-domain OCT system (Niris System, Imalux Corp., Cleveland, Ohio) with a magnetically actuating probe (two-dimensional, front imaging, and inside actuation). Images showed epithelium, upper submucosa, and osseous submucosal nodule layers corresponding with histopathology. To our knowledge, this is the first time these commercially available systems are used as part of a multimodality bronchoscopy platform to study diagnostic imaging of a benign disease causing central airway obstruction. Further studies are needed to optimize these systems for pulmonary applications and to determine how new-generation imaging modalities will be integrated into a multimodality bronchoscopy platform.

In vivo three-dimensional spectral domain endoscopic optical coherence tomography using a microelectromechanical system mirror.

A biopsy is a well-known medical test used to evaluate tissue abnormality. Biopsy specimens are invasively taken from part of a lesion and visualized by microscope after chemical treatment. However, diagnosis by means of biopsy is not only variable due to depth and location of specimen but may also damage the specimen. In addition, only a limited number of specimens can be obtained, thus, the entire tissue morphology cannot be observed. We introduce a three-dimensional (3-D) endoscopic optical biopsy via optical coherence tomography employing a dual-axis microelectromechanical system scanning mirror. Since this technique provides high-resolution, noninvasive, direct, and multiple visualization of tissue, it could function as a clinical biopsy with advanced performance. The device was integrated with a conventional endoscope and utilized to generate in vivo 3-D clinical images in humans and animals.

In vivo multiphoton fluorescence imaging: a novel approach to oral malignancy.

BACKGROUND AND OBJECTIVE: Current techniques for oral diagnosis require surgical biopsy of lesions, and may fail to detect early malignant change. Non-invasive, sensitive tools providing early detection of oral cancer and a better understanding of malignant change are needed. These studies evaluated in vivo multiphoton excited fluorescence (MPM) techniques to (1) map epithelial and subepithelial changes through out oral carcinogenesis and (2) serve as an effective diagnostic modality. STUDY DESIGN/MATERIALS AND METHODS: In the hamster model (n = 70), epithelial and subepithelial change was imaged in vivo throughout carcinogenesis. MPM- and histopathology-based diagnoses on a scale of 0 (healthy)-6 (squamous cell carcinoma [s.c.c.]) were scored by two pre-standardized investigators. RESULTS: Collagen matrix and fibers, cellular infiltrates, blood vessels, and microtumors were clearly visible. MPM agreed with the histopathology for 88.6% of diagnoses. CONCLUSIONS: In vivo MPM images provide (1) high resolution information on specific components of the carcinogenesis process (2) an excellent basis for oral diagnostics.

Innovative approaches to lung volume reduction for emphysema.

The 10 years of resurgent interest in lung volume reduction surgery (LVRS) and recent National Emphysema Treatment Trial findings for emphysema have stimulated a range of innovative alternative ideas aimed at improving outcomes and reducing complications associated with current LVRS techniques. Concepts being actively investigated at this time include surgical resection with compression/banding devices, endobronchial blockers, sealants, obstructing devices and valves, and bronchial bypass methods. These novel approaches are reaching the stage of clinical trials at this time. Theory, design issues, methods, potential advantages and limitations, and available results are presented. Extensive research in the near future will help to determine the potential clinical applicability of these new approaches to the treatment of emphysema symptoms.