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The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas (BCCs), the most common human malignancy. Type 3 iodothyronine deiodinase (D3), the thyroid hormone-inactivating enzyme, is frequently expressed in proliferating and neoplastic cells, but its role in this context is unknown. Here we show that Shh, through Gli2, directly induces D3 in proliferating keratinocytes and in mouse and human BCCs. We demonstrate that Gli-induced D3 reduces intracellular active thyroid hormone, thus resulting in increased cyclin D1 and keratinocyte proliferation. D3 knockdown caused a 5-fold reduction in the growth of BCC xenografts in nude mice. Shh-induced thyroid hormone degradation via D3 synergizes with the Shh-mediated reduction of the type 2 deiodinase, the thyroxine-activating enzyme, and both effects are reversed by cAMP. This previously unrecognized functional cross-talk between Shh/Gli2 and thyroid hormone in keratinocytes is a pathway by which Shh produces its proliferative effects and offers a potential therapeutic approach to BCC.

Adenovirus-mediated gene transfer is a novel treatment strategy for head and neck squamous cell carcinoma (HNSCC) that may improve the unacceptable morbidity and mortality associated with conventional treatment. Efficient adenoviral (AdV) infection largely depends on cellular expression of the human coxsackie and adenovirus receptor (hCAR); however, the relatively recent identification of this receptor precludes a comprehensive description of its tissue distribution. We have created tissue culture model systems that approximate the differentiation and three-dimensional structure of stratified squamous epithelium characteristic of head and neck mucosa. Using these systems, we have found that expression of hCAR in native and modeled normal oropharyngeal epithelium decreased as cells differentiated with the most superficial and differentiated cells expressing no detectable hCAR. In contrast, modeled stratified HNSCC cells, which did not differentiate morphologically and did not express cytokeratin markers of differentiation, had equivalent expression of hCAR in superficial and basal layers. The expression of hCAR in our models correlated not only with the undifferentiated state, but also with efficiency of AdV infection. Despite expression of hCAR in underlying basal and suprabasal cells, topical application of AdV to normal modeled epithelium resulted in inefficient transduction of the most superficial cell layer without any infection of underlying cells. These data suggest that in normal epithelium the overlying squamous cells act as a barrier preventing infection of underlying cells that would otherwise be easily infected. In modeled stratified HNSCC, transduction was much more efficient and occurred up to four cell layers deep, suggesting that unlike normal superficial epithelial cells, the superficial cells of stratified HNSCC do not act as an effective barrier to adenoviral infection. The distribution of hCAR in native tissue and the enhanced susceptibility of undifferentiated oropharyngeal epithelial cells, including undifferentiated cancer cells, to AdV infection has important implications for the development of AdV-based targeting strategies for the treatment of head and neck cancer or premalignancies.

Persistent pulmonary hypertension of the newborn (PPHN) and its conventional medical treatment are associated with sensorineural hearing loss, yet current recommendations for regular audiological evaluations of PPHN survivors are lacking. We report a case of delayed-onset, progressive sensorineural hearing loss in a 3-year-old patient with a history of PPHN and a normal auditory brainstem evoked response at 6 weeks of age. The relatively late detection of significant sensorineural hearing loss in this otherwise healthy 3-year-old illustrates the need for audiological evaluation at regular intervals in patients with a history of PPHN.

Subdural empyema (SDE) is most commonly caused by sinusitis and, without early diagnosis and neurosurgical intervention, is associated with high mortality. In a patient with sinusitis who presents with mental status changes, the diagnosis of SDE should be suspected on clinical grounds, even in the absence of significant computed tomographic findings. Computed tomography with contrast is a useful aid in the diagnosis of SDE, but findings may be subtle, and contrasted magnetic resonance imaging is superior. The association of Streptococcus anginosus sinusitis and related intracranial sequelae is important owing to the potentially catastrophic complications and should be recognized by otolaryngologists. In view of the rapidly progressing nature of sinogenic SDE, physicians should strongly consider early institution of aggressive therapy consisting of craniotomy with concurrent sinus drainage in patients in whom sinogenic SDE is suspected on clinical grounds, particularly in the presence of S. anginosus-positive sinus cultures.

Root segments of vetch, barley, and pine were exposed to a nutrient solution containing (85)Sr and (45)Ca tracers. Translocation was measured from solutions containing stable ions at concentrations of 2.5 mm Ca, and at either 0.5 mm or 2.5 mm Sr. Polar transport was established between 12 and 18 hr in barley, and between 16 and 22 hr in vetch. Acropetal transport remained below 5% of basipetal transport of tracer during these intervals. Transport in both vetch and barley usually declined before an elapsed time of 24 hr unlike corn, which maintained its steady state beyond 24 hr. Pine was radically different in that it showed no difference between acropetal and basipetal transport rates and had very low rates. Sr transport in all plants studied to date paralleled that of Ca and the ratio Sr:Ca transported was equal to the ratio Sr:Ca in the nutrient. In vetch, stable Ca transport was reduced to one-fifth when Sr concentration was increased from 0.5 mm to 2.5 mm. Yet stable Sr transport did not change, indicating that the effect on transport was not due to competitive inhibition. A similar effect was less pronounced in barley, but could not be detected in pine. The magnitude of the transport rates varied considerably among the various species, corn having the greatest followed by barley, vetch, and pine in decreasing order. Transport did not correlate with root weight or surface area; it amounted to from 0.03 to 0.60 nanomoles per hr in these experiments as compared to 7 nanomoles per hr previously established in corn (in all cases, 55 mm segments, sectioned 10 mm from apex).

Root segments of Zea mays 55 mm long, were exposed to nutrient containing (85)Sr and (45)Ca tracers. Translocation rather than uptake was measured, using a newly-designed glass compartmentation system and validated tracer analytic model. Ca transport from solutions containing between 0.25 and 5.0 mm Ca was only slightly affected by concentration, but translocation from 0.25 to 0.05 mm solutions was markedly reduced. Maximum transport of strontium from nutrient containing 0.05 mm Ca was twice that from 2.5 mm Ca, and also twice the maximum calcium transported. Thus, under the condition simulating calcium depletion, i.e., 0.05 mm Ca, greater amounts of strontium were transported. In these cases the solutions also contained stable strontium at concentrations between 0.25 and 5.0 mm. In simultaneous determinations, the ratio of Sr to Ca moved was exactly equal to the ratio of their concentrations in nutrient solution, and there was no evidence of discrimination. Dinitrophenol reduced transport of Sr and Ca to an equivalent extent, amounting to between 2 and 9% of non-treated control levels.