A history of robots: from science fiction to surgical robotics.

Surgical robotics is an evolving field with great advances having been made over the last decade. The origin of robotics was in the science-fiction literature and from there industrial applications, and more recently commercially available, surgical robotic devices have been realized. In this review, we examine the field of robotics from its roots in literature to its development for clinical surgical use. Surgical mills and telerobotic devices are discussed, as are potential future developments.

Child abuse and the otolaryngologist: part I.

Nearly 1 million infants and children are neglected and abused yearly in the United States, with a greater than 1% resulting mortality rate. One half of these children are seen by physicians for abuse-related injuries, and nearly 75% have injuries of the head and neck. Physicians, however, account for reporting only 11% of all cases. As experts trained in diseases and injuries of the head and neck, otolaryngologists are particularly well positioned to recognize abuse in the clinic and in the emergency room and during other consultations. We present an overview of child abuse definitions, risk factors, and legal obligations of the physician. We also review the manifestations of child abuse within the head and neck, with particular attention to the role of the otolaryngologist. We briefly discuss some conditions that may be mistaken for abuse and suggest a practical protocol for management of suspected cases in the clinic.

Assessment of congenital bony nasal obstruction by 3-dimensional CT volume rendering.

The nature and extent of congenital bony nasal obstruction is best determined by X-ray computed tomography (CT) imaging. Three-dimensional volume rendering of CT images provides an integrated perspective that can assist in clinical decision making and in operative planning. Clinical cases of choanal atresia and pyriform aperture stenosis are reviewed with their images. The authors propose this modality as an evolving standard for imaging of congenital bony nasal obstruction.

Securing cochlear implants to the skull: two alternate methods.

In view of the various problems encountered with the traditional methods of securing cochlear implants--including dural tear and suture dissolution following infection--we devised two alternate methods of performing this procedure. We use a titanium mesh or a Gore-Tex patch secured with two 4-mm screws to fix the receiver to the skull. No patient who has undergone either of these procedures at our institution has experienced any of the complications that are associated with the older silk, nylon, and Dacron sutures. Moreover, our two alternate methods are less technically difficult and can be performed in a shorter period of time.

A unique case of Bezold's abscess associated with multiple dural sinus thromboses.

OBJECTIVES/HYPOTHESIS: Bezold's abscess and dural sinus thromboses are rare complications of otitis media in the era of antibiotics. Although potentially fatal, they are treatable. We present a unique case report of Bezold's abscess in association with multiple dural sinus thromboses. STUDY DESIGN: Single case report. METHODS: A young female patient's clinical course is presented and discussed. We review the anatomy, incidence, pathogenesis, and treatment of Bezold's abscess and dural sinus thrombosis. RESULTS: After mastoidectomy, neck exploration, broad-spectrum intravenous antibiotics, and anticoagulation therapy, the patient recovered fully and has remained asymptomatic since her discharge from the hospital at 12 months' follow-up. CONCLUSIONS: This is the first reported case of Bezold's abscess associated with a cavernous sinus thrombosis and the third reported case of Bezold's abscess associated with lateral sinus thrombosis. Despite its rarity, Bezold's abscess must be recognized and treated aggressively. Dural sinus thrombosis is relatively more common, and treatment of the underlying cause is essential. The diagnosis and rapid, aggressive treatment of these conditions are essential for an optimal clinical outcome.

Real-time, cine magnetic resonance imaging for evaluation of the pediatric airway.

BACKGROUND: Standard magnetic resonance imaging (MRI) and computed tomographic (CT) modalities are limited in their ability to image dynamic organs. New real-time, dynamic, cine magnetic resonance imaging (CMRI) techniques have the potential to image moving structures. OBJECTIVE: We therefore investigated the feasibility of using CMRI techniques to dynamically image the human airway, to assess laryngeal and tracheal patency and function. METHODS: A cohort of 10 pediatric patients, 10 adult patients, and 10 normal volunteers underwent routine static MRI, as well as CMRI using a Siemens 1.5 T Vision system (Siemens, Erlangen, Germany). Patients also underwent endoscopic evaluation. Cine axial, coronal, and sagittal sequences of the larynx and trachea were obtained during quiet respiration, as well as during a variety of provocative maneuvers. RESULTS: CMRI readily demonstrated normal vocal cord mobility and tracheal stability in normal volunteers. Abnormal vocal mobility was easily appreciated using the CMRI imaging system. Similarly, dynamic effects of tracheomalacia were clearly demonstrated using CMRI. Dynamic extrinsic tracheal compression resulting from mass lesions or anomalous vasculature was also visualized using CMRI. CONCLUSIONS: Cine MRI of the airway has the potential to provide novel data regarding laryngeal and tracheal patency and function. This evolving modality may serve as a valuable adjunct to static MR and CT imaging, as well as endoscopy, in the assessment of the airway.

Antisense oligonucleotides against protein kinase CK2-alpha inhibit growth of squamous cell carcinoma of the head and neck in vitro.

BACKGROUND: Human squamous cell carcinomas of the head and neck (SCCHN) overexpress the protein kinase CK2, and elevated CK2 activity correlates with aggressive tumor behavior and poor clinical outcome. We therefore investigated whether interference with CK2 expression would inhibit SCCHN cell growth in vitro. METHODS: We targeted the catalytic (alpha) subunit of CK2 using an antisense oligodeoxynucleotide (ODN) strategy. Human Ca9-22 cells derived from SCCHN were transfected with CK2-alpha sense, nonsense, or antisense ODN; CK2 activity was measured; and the effect on CK2 activity and on cell growth was determined. RESULTS: Transfection of Ca9-22 cells with antisense CK2-alpha ODN resulted in significantly decreased CK2 kinase activity associated with nuclear chromatin and in dose-dependent growth inhibition of Ca9-22 cells in vitro. CONCLUSIONS: Interference with the protein kinase CK2 signal in SCCHN cells may offer a novel anticancer strategy for this malignancy.

Significance of protein kinase CK2 nuclear signaling in neoplasia.

Many stimuli play a role in influencing the structure and function of chromatin and nuclear matrix through post-translational modifications of the component proteins in these dynamic structures. We propose that the protein serine/threonine kinase CK2 (formerly casein kinase II) is one such agent that is involved in signal transduction in the nuclear matrix and chromatin in response to a variety of stimuli. Protein kinase CK2 appears to undergo rapid modulations in its association with nuclear matrix and nucleosomes in response to mitogenic signals and is involved in the phosphorylation of a variety of intrinsic proteins in these structures depending on the state of genomic activity. In addition, its association or loss from the nuclear matrix may also influence the apoptotic activity in the cell. CK2 has been found to be dysregulated in virtually all the neoplasias examined and nuclear association appears to be an important facet of its expression in tumor cells. We hypothesize that CK2 provides a functional paradigm linking the nuclear matrix and chromatin structures. Identification of precise loci of action of CK2 in these structures and how they influence the morphological appearance of the nucleus under normal and abnormal growth conditions would be an important future direction of investigation. J. Cell. Biochem. Suppl. 35:130-135, 2000. Published 2001 Wiley-Liss, Inc.

Subcellular immunolocalization of protein kinase CK2 in normal and carcinoma cells.

CK2 is a messenger-independent protein serine/threonine kinase that has been implicated in cell growth and proliferation. Our recent analysis of squamous cell carcinomas of the head and neck (SCCHN) revealed a significant elevation in CK2 activity in these tumor cells relative to normal mucosa of the upper aerodigestive tract and suggested a correlation with aggressive tumor behavior and poor clinical outcome. In order to further define the distribution of CK2 in these tissues, we have examined the immunohistochemical staining pattern of surgical specimens of both SCCHN tumors and normal upper aerodigestive tract mucosa using a monoclonal antibody directed against the catalytic subunit CK2-alpha of the kinase, and have compared these data with the subcellular distribution of CK2 activity in these same tissues. These measurements showed that CK2 is predominantly localized to the nuclei of the tumor cells, which agreed closely with the immunohistochemical staining pattern of CK2-alpha in tumor cells. The chiefly nuclear distribution of CK2-alpha immunostaining found consistently in SCCHN tumor cells and tumor-infiltrating lymphocytes contrasted with a relatively more predominant cytosolic staining pattern exhibited by various cellular constituents of normal oropharyngeal mucosa. The immunostaining pattern of CK2-alpha revealed that staining was observed in the cells stained for the proliferation-marker Ki-67; however, strong distinct immunostaining for CK2-alpha was also observed in large numbers of other cells in these same tumors, suggesting that CK2 elevation in these tumors is not a reflection of proliferative activity alone, but may also relate to the pathobiological behavior of the tumor.

Modulation of nuclear matrix protein phosphorylation by histones: possible involvement of NM-associated protein kinase CK2 activity.

Nuclear matrix (NM), a proteinaceous network of filaments, dictates nuclear morphology and the structure/function of DNA. Phosphorylation of NM proteins is a potential signal for regulating matrix functions. Histones also are intimately involved in DNA structure and transcription. Here, we report that various histones enhanced 32P incorporation into certain NM proteins. Modulation of NM protein phosphorylation by histones is mediated through regulation of protein kinase CK2, a messenger-independent serine/threonine kinase, which is significantly associated with the NM. The stimulatory effect of histones was mitigated by prior incubation of histones with DNA in the reaction. Phosphorylation of NM proteins was extensively reduced when an excess of the CK2-specific peptide substrate was included in the phosphorylation reaction as a competitor. Also, enhancement in the NM-associated CK2 activity by histones was blocked by inhibitors of CK2. Histone H1 effect appeared to be mediated mainly by charge effect since a stretch of polylysine induced a similar effect. Various histones also differentially affected the autophosphorylation of NM-associated CK2 subunits. This may contribute to the observed effects of histones on the NM, resulting in an enhancement and differential pattern of NM protein phosphorylation. Such a regional modification of NM protein phosphorylation might influence the nuclear functions that require histone displacement, namely, replication and transcription.

Apoptosis and growth inhibition of head and neck tumor cell line induced by epidermal growth factor receptor tyrosine kinase inhibitor.

Overexpression of the epidermal growth factor (EGF) receptor, a hallmark of aerodigestive squamous cell carcinoma of the head and neck (SCCHN), correlates with aggressive tumor behavior. There is evidence that SCCHN cells auto-activate their EGF receptors. The receptor has therefore attracted interest as a potential therapeutic target. We tested the in vitro therapeutic efficacy of PD153035--a potent, specific inhibitor of the tyrosine kinase intrinsic to the EGF receptor--by employing a well-characterized cell line derived from human gingival SCCHN. DNA-synthesis and cell number were assayed for growth-inhibitory effects, phosphorylation of the EGF receptor was quantitated by immunoblot, and cell apoptosis was detected by terminal deoxytransferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) in situ assay. PD153035, at nanomolar concentrations, inhibited autophosphorylation of the EGF receptor induced by EGF stimulation and the inhibition occurred in a dose-dependent manner. Under the same conditions, PD153035 inhibited cell growth, and induced apoptosis of SCCHN cells in vitro. We conclude that selective inhibition of the EGF receptor tyrosine kinase completely abolishes EGF receptor phosphorylation resulting from receptor stimulation, and results in growth inhibition and apoptosis of SCCHN cells in vitro. By inducing cytostasis and apoptosis, this new class of inhibitors may be of therapeutic value against SCCHN.

The near complete tracheal ring deformity.

Congenital complete and near-complete tracheal rings are extremely rare tracheal deformities. There are fewer than 100 cases of congenital complete tracheal rings, and only four cases of near-complete described in the literature. Long-segment occurrences of these anomalies are usually incompatible with life. We describe the presentation of the long-segment near complete tracheal ring deformity and long-segment anterior fusion of cartilage rings (cartilage sleeve deformity) in a living infant. The literature is reviewed, and the embryology, presentation, and management of these extremely rare anomalies are discussed.

Results of esophageal biopsies performed during triple endoscopy in the pediatric patient.

BACKGROUND: Endoscopic examination (direct laryngoscopy and bronchoscopy) is the method of choice for diagnosis of respiratory symptoms of unknown cause in children. However, gastroesophageal reflux is being recognized increasingly often as a cause of pediatric respiratory symptoms and is difficult to diagnose on the basis of findings from direct laryngoscopy and bronchoscopy. In cases in which gastroesophageal reflux was included in the differential diagnosis, we additionally performed esophagoscopy with esophageal mucosal biopsies. OBJECTIVES: To determine the feasibility, safety, and efficacy of routinely performing esophageal biopsies during triple endoscopy in children. METHODS: Twenty-four children ranging in age from 2 weeks to 10 years were referred for airway evaluation. Under general anesthesia, children underwent direct laryngoscopy and bronchoscopy and esophagoscopy with mucosal biopsy. RESULTS: Esophageal mucosa biopsy specimens were quickly and safely obtained during endoscopic evaluation. There were no complications. Reflux esophagitis was present in 54% of biopsy specimens, as suggested by basal cell hyperplasia, papillary elongation, and/or inflammatory cell infiltrates. CONCLUSION: Gastroesophageal reflux is often difficult to diagnose in the pediatric population. When direct laryngoscopy and bronchoscopy is performed during examination of the child with airway symptoms, the addition of esophagoscopy with mucosal biopsies will safely and quickly provide data regarding the potential contribution of gastroesophageal reflux.

Chemical warfare agents: estimating oral reference doses.

Health risk assessments for sites contaminated with chemical warfare agents require a comparison of the potential levels of exposure with a characterization of the toxic potency of each chemical. For noncancer health effects, toxic potency is expressed in terms of Reference Doses (RfD). A RfD is a daily exposure level or dose (usually expressed in units of milligrams of chemical per kilogram body weight per day) for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects. A daily exposure at or below the RfD is not likely to be associated with health risks, but as the amount of chemical that an individual is exposed to increases above the RfD, the probability that an adverse effect will occur also increases. A RfD is derived by first examining the available human or animal toxicity data to identify a dose or exposure that corresponds to a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the exposure level at which there are no statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Effects may be produced at this level, but they are not considered to be adverse if they do not result in functional impairment or pathological lesions that affect the performance of the whole organism or which reduce an organism's ability to cope with additional challenge. The LOAEL is the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. If only a LOAEL is identified by the toxicity data, a NOAEL is estimated by dividing the LOAEL by a factor no greater than 10. This extrapolation factor of 10 or less is termed the LOAEL-to-NOAEL Uncertainty Factor (UFL). The NOAEL is also adjusted by the application of other Uncertainty Factors, including (1) a UFH < or = 10 to ensure that the resulting RfD protects segments of the human population that may be more sensitive to the chemical than the average person; (2) a UFA < or = 10 to extrapolate from the experimental animal species to humans; (3) a UFS < or = 10 to extrapolate from an experimental subchronic exposure study to a potential chronic exposure; and (4) a UFD < or = 10 to ensure that the resulting RfD is protective for all possible adverse effects, particularly those that may not have been adequately evaluated in the available studies. A Modifying Factor (MF), based on a qualitative professional assessment of the data, may also be used to account for other factors (e.g., deficiencies in the critical study) that are not adequately covered by the standard Uncertainty Factors. 1. Agent HD (Sulfur Mustard). RfDe = 7 x 10(-6) mg kg-1 d-1. A LOAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be "mild" in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level.

Noncancer inhalation toxicology of crystalline silica: exposure-response assessment.

Silicosis from inhalation of silica has long been recognized as an occupational hazard. Concern has arisen regarding the potential risk of silicosis from ambient silica (primarily quartz dust). This presentation reviews available data regarding ambient silica levels and estimates of the risk of silicosis at low exposure levels as they relate to the current U.S. Environmental Protection Agency National Ambient Air Quality Standards (NAAQS) for particulate matter. Current data indicate that for individuals not compromised by other respiratory ailments and for ambient environments expected to sustain 10% or less silica fraction in particulate matter with a mean aerodynamic diameter of < or = 10 microns (PM10), maintenance of the 50 micrograms/m3 annual NAAQS for PM10 is adequate to protect against fibrotic effects from ambient silica exposures. Issues such as the large divergence of risk estimates within the occupational setting (particularly at high cumulative exposures) and factors to consider for extrapolating risk in an occupational setting to risk from ambient exposure are discussed.

Nuclear matrix proteins as malignant markers in squamous cell carcinoma of the head and neck.

OBJECTIVE: To test the hypothesis that transformation of normal upper aerodigestive mucosa to squamous cell carcinoma of the head and neck (SCCHN) is associated with specific changes in nuclear matrix (NM) proteins. DESIGN: Retrospective, nonrandomized investigation using a cellular fractionation sequence followed by 2-dimensional gel electrophoresis analysis of NM proteins. SUBJECTS: Nuclear matrix proteins were extracted from a cohort of 12 pathologic SCCHN specimens and 5 normal specimens of oropharyngeal mucosa. RESULTS: All SCCHN specimens examined expressed 11 NM proteins that were not detected in normal mucosa. Conversely, at least 4 NM proteins that were expressed by all specimens of normal mucosa were absent from all SCCHN tumors. Seven NM proteins were common to carcinomas and normal specimens. Spindle cell histological variants of squamous cell carcinoma had distinct NM patterns. CONCLUSIONS: Malignant transformation of normal upper aerodigestive mucosa to SCCHN is associated with specific changes in NM composition. These data suggest that different NM proteins might serve as specific tumor markers.

Association of protein kinase CK2 with nuclear matrix: influence of method of preparation of nuclear matrix.

Nuclear matrix (NM) plays a role of fundamental structural and functional significance as the site of replication, transcription, and RNA processing and transport, acting as an anchor or attachment site for a variety of enzymes and other proteins involved in these activities. We have previously documented that protein kinase CK2 translocates from the cytosol to the nucleus, where it associates preferentially with chromatin and NM, in response to certain growth stimuli. Considering that characteristics of the isolated NM can depend on the procedural employed for its isolation, we compared three standard methods for NM preparation to confirm the association of intrinsic CK2 with this structure. Our data suggest that the method used for isolating the NM can qualitatively influence the measurable NM-associated CK2. However, all three methods employed yielded qualitatively similar results with respect to the stimulus-mediated modulation of NM-associated CK2, thus further supporting the notion that NM is an important site for physiologically relevant functions of CK2. In addition, core filaments and cytoskeleton that were isolated by two of the preparative methods had a small but significant level of associated CK2 activity.

Quantitative image analysis of HIV-1 infection in lymphoid tissue.

Tracking human immunodeficiency virus-type 1 (HIV-1) infection at the cellular level in tissue reservoirs provides opportunities to better understand the pathogenesis of infection and to rationally design and monitor therapy. A quantitative technique was developed to determine viral burden in two important cellular compartments in lymphoid tissues. Image analysis and in situ hybridization were combined to show that in the presymptomatic stages of infection there is a large, relatively stable pool of virions on the surfaces of follicular dendritic cells and a smaller pool of productively infected cells. Despite evidence of constraints on HIV-1 replication in the infected cell population in lymphoid tissues, estimates of the numbers of these cells and the virus they could produce are consistent with the quantities of virus that have been detected in the bloodstream. The cellular sources of virus production and storage in lymphoid tissues can now be studied with this approach over the course of infection and treatment.

Nuclear matrix as an anchor for protein kinase CK2 nuclear signalling.

Nuclear matrix (NM) is not only the structural basis for nuclear shape but also is intimately involved in nuclear functional activities. Among the modulatory factors that may affect these diverse activities are the signals that may influence the state or composition of the NM proteins. One such mechanism for altering the functional activity of at least some NM proteins may be the extent of their phosphorylation. Protein kinase CK2 appears to associate with NM and to phosphorylate a number of NM-associated proteins. Chromatin- and NM-associated CK2 is rapidly modulated by mitogenic signals. We propose that NM serves as a physiological anchor for nuclear signalling of protein kinase CK2 which may influence functions of NM such as transcription of active genes and growth.