Clinical Research Activities
Loma Linda University Medical Center's (LLUMC) Department of Otolaryngology, Head & Neck Surgery & Facial Plastic Surgery was ranked in 2008 by the U.S. News & World Report as the 45th best hospital under the ENT specialty. With expertise in both the clinical and research settings, LLUMC doctors pride themselves in this national distinction and stay actively involved in advancing the field by conducting clinical research activities.
The clinical research trials are listed below each designated doctor leading the study: Alfred Simental, MD
Utilization of Videoassisted Thyroid and Parathyroidectomy
- This is a prospective clinical study to the utilization, complication and techniques of minimally invasive thyroid and parathyroid surgery.
Dr. O'neil W. Guthrie
Dr. Guthrie's research laboratory is focused on identifying and manipulating endogenous molecular/cellular/organ and organismal mechanisms that mediate morphologic and physiologic repair from injury.
Augmenting cellular repair with multifunctional chemotypes.
Dr. Guthrie's lab has shown that specific low molecular weight chemotypes can enhance functional repair of the adult mammalian cochlea following injury. Therefore, the goals of this project are to 1) determine the underlying molecular mechanisms that facilitate cellular repair. 2) Optimize dose and treatment regiments to achieve maximal repair. 3) Identify other chemotypes that have the capacity to augment cellular repair and 4) conduct clinical trials to determine efficacy among patients.
Epigenetic regulation of genomic integrity.
Genomic integrity is vital to all cells including terminally differentiated cells such as neurons and hair cells and non-terminally differentiated cells such as stem cells (e.g., quiescent endogenous stem cells and active proliferating stem cells). This project is based on the hypothesis that both cellular repair and regeneration is dependent on genomic integrity. Unlike the transcriptionally active genome, the global genome (non-transcribing genes) among quiescent cells (whether stem cells or other types of cells) is particularly susceptible to DNA lesions. The goal of this project is to employ molecular constructs that regulate one or more epigenetic mechanisms that regulate genomic integrity in order to facilitate cellular repair and regeneration.
Inducible DNA damage response among sensory neurons.
The death of spiral ganglion neurons is a consistent finding in human temporal bones from patients with various forms of acquired sensorineural hearing loss (e.g., loud noise, ototoxic xenobiotics and aging). Although a significant proportion of spiral ganglion neurons consistently die, a small proportion neurons always survive. This suggests that some spiral ganglion populations are more vulnerable to cell death than others. This neuronal death may occur independent of the loss of other cochlear cell-types, such as hair cells. In order to develop rational strategies to preserve spiral ganglion neurons and auditory function, it will be necessary to identify the mechanisms that account for differences in vulnerability to cell death. DNA repair capacity is one of the most potent molecular mechanisms that determine cellular resistance or susceptibility to cell death. Therefore, this project is focused on the role of DNA repair mechanisms in the death or survival of spiral ganglion neurons. Dr. Guthrie's lab has discovered that a proportion of spiral ganglion neurons fail to express DNA repair enzymes under stressful conditions. However, a cohort of neurons was found to exhibit a mosaic of inducible DNA damage responses. Therefore the goals of this project are to:
- Determine whether or not neurons that fail to express DNA repair enzymes under stress are hyper-vulnerable to cell death.
- Determine whether or not one or more inducible DNA damage response phenotypes mediates vulnerability to cell death.
- Determine the underlying mechanism for the difference in DNA damage response phenotypes among sensory neurons.
Noise exposure inhibits DNA excision repair activity.
Noise ;exposure has been shown to precipitate free radical induced DNA damage products in the cochlea. Free radical DNA damage products can result in mutated gene fragments that alter cellular functions and/or induce cell death. The nucleotide excision repair (NER) pathway is particularly adapted to protecting both active and inactive genes through genetically distinct subpathways call global genomic and transcription coupled NER pathways. Dr. Guthrie's lab has shown that noise exposure alters both pathways. The magnitude of the effect and the specific pathway affected dependent on basal, middle or apical coils of the cochlea. These observations are important because they provide a mechanism for interpreting noise induced primary neuropathy and provide a basis for noise induced mutagenesis. The goals of this project are to:
- Determine whether noise exposure induces DNA damage among active and inactive genes.
- Determine the underlying mechanism for noise induced alterations to NER pathways.
- Determine short and long-term consequences of noise induced inhibition of endogenous NER activity.
- Develop rational therapeutic approaches.
Timothy T.K. Jung, MD, PhD
Inflammatory mediators of otitis media and inner ear infection.
- This is a study of the role of eicosanoids and other inflammatory mediators (IMs) in the pathogenesis of otitis media.
- Prostaglandins, leukotrienes and platelet-activating factor (PAF) are measured in the middle ear fluids from humans and experimentally induced animal otitis media by HPLC and radioimmunoassay. Eicosanoids are also measured in human cholesteatoma and granulation tissue.
- Effects of inhibitors of arachidonic acid metabolism and PAF-blocker on the outcome of experimental otitis media are tested.
- Also effect of IMs on the inner ear function is tested after round window membrane application of these IMs by measurements of auditory brainstem response, cochlear blood flow, and otoacoustic emissions.
- Effect of IMs on morphology of isolated outer hair cells from chinchilla cochlea are tested by superfusing IMs into the media containing these cells.
Ciliary abnormality and dysfunction in the pathogenesis of radiation induced otitis media with effusion.
- The purpose of this study is to determine the role of cilia in the pathogenesis of radiation induced otitis media.
- Morphology and function of cilia of eustachian tubes in normal and radiation-treated chinchillas are studied using scanning and transmission electron microscopy, light microscopy of temporal bone histopathology, and the rate of dye transport.
- The result of this study will be helpful to find the morphologic and functional effects of radiation treatment on the cilia of the eustachian tube as a cause of otitis media. Effect of radioprotector, WR 2721 on radiation induced injury to ciliated cells of eustachian tubes is studied.
Role of arachidonic acid metabolites in salicylate ototoxicity.
- Since high doses of salicylates such as aspirin cause tinnitus and hearing loss and also inhibit PG-synthesis by blocking cyclooxygenase in the arachidonic acid (AA) cascade, we suspected that the inhibition of prostaglandin (PG) synthesis in the inner ear may be the underlying pathogenesis of ototoxicity of salicylates.
- Indeed, we found that treatment with high doses of salicylates decreased PG levels and increased leukotriene (LT) levels in the perilymph.
- Our investigation on the role of AA metabolites in salicylate ototoxicity is continuing by correlating hearing loss with levels of AA metabolites in the perilymph after treatment of AA metabolites on the round window membrane and treatment with PGI2-analog and/or leukotriene inhibitor. Changes in the cochlear blood flow after treatment of salicylates are determined also.
- Effect of leukotriene inhibitor on salicylate induced morphologic changes of cochlear isolated outer hair cells is investigated. Morphology of isolated outer hair cells from chinchilla cochlea is investigated after exposure of these cells to salicylate with or without LT inhibitors.
- Results of this study can be clinically applicable to prevent salicylate-induced ototoxicity and even other types of hearing loss by manipulating cochlear blood flow.
Arachidonic acid metabolites in nasal polyps and nasal mucosa.
- Aspirin-sensitivity associated with nasal polyposis and asthma is a well known syndrome and is probably mediated by leukotrienes in the lipoxygenase pathway of the arachidonic acid metabolism. Arachidonic acid metabolites are determined in the nasal polyps and nasal mucosa.
- Concentrations of prostaglandins and leukotrienes are determined by radioimmunoassay and high performance liquid chromatography (HPLC).
- Effects of steroids and lipoxygenase inhibitors on the growth of the polyps are assessed in vitro using tissue culture system.
- This study will provide useful information in developing medical treatment for nasal polyps.