Faculty Bibliography

PURPOSE: The association between tobacco smoking and oral squamous cell carcinoma is well established. However, few studies have evaluated the smoking history based on a smoking versus never-smoking history or analyzed the relationship between smoking history and site and stage of presentation. The purpose of this study was to examine the relationship between smoking versus never-smoking history and the stage and site of presentation of oral squamous cell carcinoma. PATIENTS AND METHODS: The design of this study was a retrospective review of all patients presented at the Legacy Emanuel Hospital Head and Neck Tumor Board in Portland, Oregon, with a biopsy-proven oral squamous cell carcinoma between 1998 and 2000. Data collected included age, gender, smoking history (smoker versus never smoker), pack-years of tobacco, site, and stage (T, N, and group stage) at presentation. RESULTS: A total of 67 patients were reviewed; 33% of patients were never smokers and 67% of patients had a history of smoking with an average of 49.4 pack-years. The floor of mouth and gingiva were the most commonly affected sites. There was a statistically significant difference between site of presentation and a history of smoking (P =.0007). The 2 sites that showed a significant association with smoking were posterolateral tongue and floor of mouth. CONCLUSIONS: The findings of this study demonstrate that approximately one third of patients with oral squamous cell carcinoma will report that they have never smoked. There was a strong association between a history of smoking and carcinoma involving the posterolateral tongue and floor of mouth

PURPOSE: Maxillary reconstruction after maxillectomy remains a great challenge for the reconstructive oral and maxillofacial surgeon. This article is a clinical retrospective analysis of patients reconstructed with zygomaticus implants after maxillary ablation. PATIENTS AND METHODS: The design of the study was a retrospective review of 9 patients requiring near-total or total maxillectomy for pathologic reasons. Clinical records, photographs, and radiographs were studied. Financial billing statements were reviewed to determine charges for implant reconstruction and method of payment. RESULTS: Maxillary reconstruction using zygomaticus and standard endosseous implants was performed in 9 patients. Maxillary resection was performed for the following reasons: salivary gland malignancy (n = 2), squamous cell carcinoma (n = 5), maxillary mucormycosis (n = 1), and extensive maxillary atrophy and infection secondary to subperiosteal maxillary implant placement (n = 1). A total of 28 zygomaticus implants and 10 standard endosseous implants were used to reconstruct the 9 patients. Six zygomaticus implants and 3 standard endosseous implants failed. The time of zygomaticus implant placement ranged from placement at the time of resection to 3.2 years after the resection. Five patients received radiation therapy. Five patients have been reconstructed with a maxillary obturator and have been functioning with the prosthesis for a minimum of 2 years. CONCLUSION: The combination of zygomaticus and standard endosseous implants can be used to reliably reconstruct patients after extensive resection of the maxilla

Orthostatic tolerance is a measure of the ability to prevent hypotension during gravitational stress. It is known to be dependent on the degree of vasoconstriction and the magnitude of plasma volume, but the possible influence of packed cell volume (PCV) is unknown. High altitude residents have high haematocrits and probably high packed cell volumes. However, it is not known whether plasma volume and blood volume are affected, or whether their orthostatic tolerance is different from low altitude residents. In this study we determined plasma volume, PCV and orthostatic tolerance in a group of high altitude dwellers (HA), including a subgroup of highland dwellers with chronic mountain sickness (CMS) and extreme polycythaemia. Plasma volume and PCV were determined using Evans Blue dye dilution and peripheral haematocrit. Orthostatic tolerance was assessed as the time to presyncope in a test of head-up tilting and lower body suction. All studies were performed at 4338 m. Results showed that plasma volumes were not significantly different between CMS and HA, or in highland dwellers compared to those seen previously in lowlanders. PCV and haematocrit were greater in CMS than in HA. Orthostatic tolerance was high in both CMS and HA, although the heart rate responses to orthostasis were smaller in CMS than HA. Orthostatic tolerance was correlated with haematocrit (r= 0.57, P < 0.01) and PCV (r= 0.54, P < 0.01). This investigation has shown that although high altitude residents have large PCV, their plasma volumes were similar to lowland dwellers. The group with CMS have a particularly large PCV and also have a very high orthostatic tolerance, despite smaller heart rate responses. These results are compatible with the view that PCV is of importance in determining orthostatic tolerance.

In the vertebrate limb, the posteriorly located zone of polarizing activity (ZPA) regulates digit identity through the morphogen Sonic Hedgehog (Shh). By genetically marking Shh-responding cells in mice, we have addressed whether the cumulative influence of positive Shh signaling over time and space reflects a linear gradient of Shh responsiveness and whether Shh could play additional roles in limb patterning. Our results show that all posterior limb mesenchyme cells, as well as the ectoderm, respond to Shh from the ZPA and become the bone, muscle, and skin of the posterior limb. Further, the readout of Shh activator function integrated over time and space does not display a stable and linear gradient along the A-P axis, as in a classical morphogen view. Finally, by fate mapping Shh-responding cells in Gli2 and Gli3 mutant limbs, we demonstrate that a specific level of positive Hh signaling is not required to specify digit identities

Direction-selective retinal ganglion cells show an increased activity evoked by light stimuli moving in the preferred direction. This selectivity is governed by direction-selective inhibition from starburst amacrine cells occurring during stimulus movement in the opposite or null direction. To understand the intrinsic membrane properties of starburst cells responsible for direction-selective GABA release, we performed whole-cell recordings from starburst cells in mouse retina. Voltage-clamp recordings revealed prominent voltage-dependent K(+) currents. The currents were mostly blocked by 1 mm TEA, activated rapidly at voltages more positive than -20 mV, and deactivated quickly, properties reminiscent of the currents carried by the Kv3 subfamily of K+ channels. Immunoblots confirmed the presence of Kv3.1 and Kv3.2 proteins in retina and immunohistochemistry revealed their expression in starburst cell somata and dendrites. The Kv3-like current in starburst cells was absent in Kv3.1-Kv3.2 knock-out mice. Current-clamp recordings showed that the fast activation of the Kv3 channels provides a voltage-dependent shunt that limits depolarization of the soma to potentials more positive than -20 mV. This provides a mechanism likely to contribute to the electrical isolation of individual starburst cell dendrites, a property thought essential for direction selectivity. This function of Kv3 channels differs from that in other neurons where they facilitate high-frequency repetitive firing. Moreover, we found a gradient in the intensity of Kv3.1b immunolabeling favoring proximal regions of starburst cells. We hypothesize that this Kv3 channel gradient contributes to the preference for centrifugal signal flow in dendrites underlying direction-selective GABA release from starburst amacrine cells

Direction-selective neurons in the primary visual cortex (V1) and the extrastriate motion area MT/V5 constitute a critical channel that links early cortical mechanisms of spatiotemporal integration to downstream signals that underlie motion perception. We studied how temporal integration in direction-selective cells depends on speed, spatial frequency (SF), and contrast using randomly moving sinusoidal gratings and spike-triggered average (STA) analysis. The window of temporal integration revealed by the STAs varied substantially with stimulus parameters, extending farther back in time for slow motion, high SF, and low contrast. At low speeds and high SF, STA peaks were larger, indicating that a single spike often conveyed more information about the stimulus under conditions in which the mean firing rate was very low. The observed trends were similar in V1 and MT and offer a physiological correlate for a large body of psychophysical data on temporal integration. We applied the same visual stimuli to a model of motion detection based on oriented linear filters (a motion energy model) that incorporated an integrate-and-fire mechanism and found that it did not account for the neuronal data. Our results show that cortical motion processing in V1 and in MT is highly nonlinear and stimulus dependent. They cast considerable doubt on the ability of simple oriented filter models to account for the output of direction-selective neurons in a general manner. Finally, they suggest that spike rate tuning functions may miss important aspects of the neural coding of motion for stimulus conditions that evoke low firing rates

The total synthesis of the molluscan polypropionate (-)-crispatene is described. The synthesis features a palladium-catalyzed cross-coupling to establish a sensitive conjugated tetraene and its Lewis acid-catalyzed cycloisomerization to yield the bicyclo[3.1.0]hexene core of the natural product. The absolute configuration of (-)-crispatene and related molecules is established.

Distribution of ascorbate into tissues is an essential process in ascorbate antioxidant defense. Hibernating animals are studied as a model of tolerance to ischemia-reperfusion because of their tolerance to fluctuations in blood flow associated with prolonged torpor and periodic arousal episodes. Throughout hibernation, plasma ascorbate concentration ([Asc](p)) repetitively increases during torpor, then falls during periodic arousal bouts. We previously proposed that high [Asc](p) provides a ready source of antioxidant protection for distribution to the central nervous system and peripheral tissues during arousal. Here we tested whether deliberate oxidation of plasma ascorbate by intravenous administration of ascorbate oxidase (AO), prior to arousal, compromised tissue levels of ascorbate or the other water-soluble antioxidants, glutathione (GSH) and urate. Although AO decreased [Asc](p) to below the level of detection during torpor and after arousal, ascorbate oxidation did not decrease post-arousal tissue levels of reduced ascorbate, glutathione, or urate in any tissue examined, except liver. The data imply that ascorbate is taken up equally well into brain and other tissues as either ascorbate or its oxidized product dehydroascorbate, with subsequent intracellular reduction of dehydroascorbate. Lack of effect of ascorbate oxidation on tissue levels of GSH or urate indicates that dehydroascorbate uptake and reduction do not compromise tissue concentrations of these other water-soluble antioxidants. Thus, we show equal availability of reduced and oxidized plasma ascorbate during metabolically demanding thermogenesis and reperfusion associated with arousal from hibernation

The development of catalytic asymmetric Nazarov reactions that require only 10 mol % of chiral Lewis acid and proceed with ee's between 72% and 97% is described.

Brain structures derived from the mesencephalon (mes) and rhombomere 1 (r1) modulate distinct motor and sensory modalities. The precise origin and cellular behaviors underpinning the cytoarchitectural organization of the mes and r1, however, are unknown. Using a novel inducible genetic fate mapping approach in mouse, we determined the fate and lineage relationships of mes/r1 cells with fine temporal and spatial resolution. We demonstrate that the mes and r1 are neuromeres that along with the isthmic organizer are partitioned along the anterior-posterior axis by lineage restriction boundaries established sequentially between E8.5 and E9.5. Furthermore, a small group of cells originating from the most posterior mes exhibit anterior intracompartmental expansion and contribute throughout the inferior colliculus. Finally, we also uncovered transient and differential genetic lineages of ventral midbrain dopaminergic and ventral hindbrain serotonergic neuronal precursors with respect to Wnt1 and Gli1 expression