Tp63 in oral development, neoplasia, and autoimmunity.

The Tp63 gene encodes for multiple isoforms of the p63 transcription factor, a member of the p53 family of proteins. Much like its more famous sibling, the biological role of p63 is quite complex, with wide-ranging effects on development, differentiation, and cellular lineage choices. The crucial function of p63 is epitomized by the striking phenotype of p63 knockout mice. These animals have a profound block in the development of stratified epithelia and aplasia of multiple ectodermal appendages, as well as orofacial clefting and limb defects. Remarkably, a similar spectrum of phenotypic alterations is observed in human syndromes resulting from Tp63 gene mutations. p63 is an important hub in the transcriptional and signaling networks of epithelial cells; thus, it is not surprising that dysregulation of this transcription factor is associated with squamous cell carcinoma. Finally, as a testament to the growing repertoire of p63-associated diseases, autoantibodies to p63 are associated with chronic ulcerative stomatitis, an oral immunologically mediated disease. Over the past decade, our understanding of the broad biologic and pathophysiological roles of p63 has grown significantly. In this review, we discuss the molecular attributes of Tp63 and the clinical consequences of Tp63 dysregulation, particularly as it pertains to oral tissues.

ELISA test for p63 antibodies in chronic ulcerative stomatitis.

OBJECTIVE: To develop a novel test for chronic ulcerative stomatitis (CUS), a chronic immunologically mediated condition that produces oral ulcerations. Current diagnostic methods require expensive and technically demanding in situ immunofluorescence (IF) studies. DESIGN: An Enzyme-Linked ImmunoSorbent Assay (ELISA) was prepared and tested with serum samples from patients with CUS and negative controls. MATERIALS AND METHODS: The N-terminal portion of the CUS autoantigen, DeltaNp63alpha, was produced as a purified recombinant protein and used to coat ELISA plates. Sera from 25 patients with CUS and 16 negative controls were analyzed for reactive antibodies. The optimal cut-offs for positive and negative samples were determined. MAIN OUTCOME MEASURES: The optimal cut-off of 0.236 resulted in a sensitivity and specificity of the ELISA of 0.80 and 0.75, respectively (exact 95% confidence intervals, P-value of <0.001). RESULTS: The ELISA developed in this study provides a novel and reliable diagnostic assessment to distinguish CUS from other oral ulcerative diseases. CONCLUSIONS: Immunoassay will allow the true incidence and prevalence of CUS to be determined in future studies. When combined with clinical correlations, the ELISA results will facilitate the evaluation of the prognostic utility of antibody titers and allow correlation with treatment responses in individual CUS cases.

Chronic ulcerative stomatitis.

Chronic ulcerative stomatitis (CUS) is a recently described condition with specific immunopathologic findings. Demographics indicate that white women in their late middle age are more susceptible to this condition. The clinical history of CUS patients is of painful, exacerbating and remitting oral erosions, and ulcerations. The histologic features are non-specific, with a chronic inflammatory infiltrate, often appearing similar to oral lichen planus (OLP). Diagnosis of CUS requires surgical biopsy with immunofluorescence microscopic examination. Accurate diagnosis is important because the usual treatment option for immunologically mediated diseases, glucocorticoids, is often not effective in treating CUS. However, hydroxychloroquine pharmacotherapy is beneficial in many cases. The lack of awareness of the condition among clinicians and the technical challenges in specimen processing make diagnosis of CUS a challenge, and hence the true prevalence is unknown. Immunofluorescence studies show circulating and tissue-bound autoantibodies to a protein, DeltaNp63alpha, which is a normal component of stratified epithelia. It is unknown if the antibodies are pathogenic, thus the etiology of CUS is also unknown. Studies are needed to elucidate the pathogenesis of CUS, optimize clinical management, and clarify its relationship to OLP and neoplasia.

Autoimmunity to deltaNp63alpha in chronic ulcerative stomatitis.

Chronic ulcerative stomatitis (CUS) is a recently described mucocutaneous condition in which patients experience chronic, painful, ulcerative lesions of the oral mucosa. CUS is diagnosed by immunofluorescence studies that demonstrate antinuclear antibodies. These autoantibodies are specific for a protein, deltaNp63alpha, which is normally expressed in basal cell nuclei of stratified squamous epithelia. The purpose of this study was to characterize the autoimmune response in CUS. Protein antigens were produced by in vitro transcription/translation of polymerase chain-reaction (PCR)-amplified cDNAs. We used immunoblotting and immunoprecipitation experiments with serum from CUS patients to examine the (1) antibody isotype, (2) immunogenic functional domains of the deltaNp63alpha antigen, and (3) cross-reactivity with homologous p53, p73, and p63 proteins. Results demonstrate CUS patient antibodies to deltaNp63alpha, and 52% of cases have circulating IgA isotype antibodies. The N-terminal and DNA-binding domains are the immunodominant regions, and antibody cross-reactivity with p53, p63, and p73 isoforms is limited.

Percutaneous suture closure for management of large French size arterial puncture in aortic valvuloplasty.

Percutaneous aortic valvuloplasty produces acute hemodynamic and clinical improvement in patients with aortic stenosis who are poor candidates for surgical valve replacement. The benefits of this procedure are mitigated by the high restenosis rates and 1--2 year mortality, in addition to significant vascular complications associated with the large arterial puncture necessary for retrograde arterial approaches. We describe the use of suture closure techniques to reduce the vascular morbidity associated with this procedure. We reviewed 31 consecutive patients who underwent percutaneous aortic valvuloplasty and suture closure with the Perclose device between April 1998 and September 2000. After diagnostic catheterization using 6--8 French (Fr) sheaths, an 8 or 10 Fr Perclose device was preloaded into the artery and the untied sutures left in place. A 12.5 or 14 Fr sheath was passed over the wire, through the sutures. The sutures were tied at the conclusion of the procedure, in conjunction with sheath removal. Twenty-seven out of 31 patients (87%) had successful suture closure of the arteriotomy and did not require prolonged bed rest, manual compression or a compression device. There were 4 failures of percutaneous suture closure, requiring conventional manual compression and bed rest for hemostasis. No patient required surgical repair of the arteriotomy, nor were there any limb complications. Compared to 39 consecutive prior patients who had their arterial puncture managed with manual compression, length of stay was shorter (2.2 days versus 5.3 days) and fewer patients received blood transfusions (0% versus 29%). Preloaded suture closure of the arterial puncture is a useful technique for achieving hemostasis after removal of the large sheaths used for percutaneous valvuloplasty, and reduces the post-procedure patient discomfort and prolonged bed rest associated with this procedure.

Left ventricular aneurysmectomy in advanced left ventricular dysfunction.

Despite widespread application in clinical practice and extensive laboratory investigations, many basic issues regarding left ventricular aneurysmectomy remain to be resolved. Analysis of clinical data from the authors' three centers and application of powerful modern imaging techniques provide important information to resolve these issues.

Linear left ventricular aneurysmectomy: modern imaging studies reveal improved morphology and function.

It remains uncertain whether left ventricular aneurysmectomy (LVA) improves ventricular function and whether LVA improves or distorts left ventricular contour. We applied the powerful imaging techniques of multiple-gated acquisition scanning, intraoperative transesophageal echocardiography, and magnetic resonance imaging to assess functional and morphologic changes after LVA in 75 consecutive patients undergoing LVA by conventional resection and linear closure. Fifty-two patients (69%) underwent concomitant coronary artery bypass grafting, 25 (33%) had directed endocardial resection, and 4 (5%) had valve replacement. The hospital mortality rate was 6.7% (5/75). Actuarial survival rates were 86%, 80%, and 64% at 1 year, 2 years, and 5 years, respectively. Mean anginal class improved from 3.49 to 1.24 (p < 0.0001). Mean congestive heart failure class improved from 3.04 to 1.70 (p < 0.0001). By multiple-gated acquisition scan (48 patients), mean ejection fraction improved from 0.25 preoperatively to 0.33 postoperatively (p < 0.0001). Intraoperative transesophageal echocardiography (28 patients) revealed no cases of distortion and demonstrated normalization of left ventricular contour in 69% of patients. Mean wall motion score improved from 16.4 to 18.8 (p < 0.001). Mean cross-sectional area of the left ventricle decreased from 18.7 cm2 to 12.8 cm2 (p < 0.006). Magnetic resonance imaging confirmed normalization of left ventricular contour without distortion. We conclude that linear LVA is clinically effective and objectively improves left ventricular morphology and function. On this basis, we have extended application of LVA to include patients with at least moderate-sized aneurysms undergoing coronary artery bypass grafting, despite the absence of traditional indications of arrhythmia, embolism, and frank congestive heart failure.

Estrogen and progesterone receptors in meningiomas.

Two-thirds of all meningiomas and four-fifths of intraspinal and sphenoidal meningiomas occur in women. Meningiomas frequently enlarge or become symptomatic during pregnancy or during the luteal phase of the menstrual cycle. There is an increased incidence of meningiomas in women with breast carcinoma. In a series of 23 patients with meningiomas, the authors assayed biopsy specimens of the tumor for the presence of estrogen (ER) and progesterone (PR) receptors, using glycerol density gradient centrifugation and dextran-coated charcoal techniques. Significant levels of ER were found in only 17% of the patients, while significant PR levels were detected in 39%. Only one of the 16 tumors from female patients had significant ER levels, whereas three of the seven tumors from men had significant ER levels. Eight of the 16 tumors in women had significant PR levels, whereas only one of the seven tumors in men had a significant PR level. Thus, three out of four tumors with definite ER were from men, whereas eight of nine tumors with definite PR were from women. Of the eight women whose tumors contained PR, three were premenopausal and five postmenopausal. The single tumor with high levels of PR in the male patient was histologically atypical. The results of this series were compared with six published series of sex steroid assays in meningiomas. These seven series were divided into two groups: one group included two reports from the same laboratories in France, and the other the remaining five reports. Much higher percentages of both ER- and PR-positive tumors were reported from the French group. The authors suggest that this discrepancy may be due to the use of preoperative glucocorticoid therapy in the series from the United States. Since meningiomas are known to enlarge during periods when levels of circulating progestins are high, the presence of significant quantities of PR in a high percentage of tumors may have therapeutic implications for recurrent, malignant, or incompletely excised tumors, or for medically fragile patients. Conversely, since meningiomas are not known to enlarge during the proliferative phase of the menstrual cycle or with exogenous estrogen therapy, the small number of tumors positive for ER may indicate that ER lacks clinical significance. High levels of PR found in a small group of histologically aggressive tumors in several series may indicate that hormonal therapy may be especially useful in this difficult subset of patients.

Vitamin A induced hypertriglyceridemia in cholesterol-fed rats.

The effects of level and feeding frequency of retinoic acid (OIC) or retinyl acetate (YL) on the accumulation of lipids in the serum and liver of rats were investigated. Male Sprague-Dawley rats were fed ad libitum 1% cholesterol diets with or without supplemental OIC or YL. Vitamin A-fed groups included (per g of dry diet): 105 microgram of OIC or 113 microgram YL daily for 28 days, 735 microgram OIC or 791 microgram YL once each week for 28 days; and 735 or 105 microgram OIC on day 1 or 105 microgram OIC daily for the week experiment. Daily feeding of OIC or YL increased serum triglyceride concentrations as compared to conrols. Several days after removal of OIC or 1 week after removal of supplemental YL from the rat diets, serum triglyceride concentrations returned to basal levels. Cholesterol feeding elevated serum cholesterol as well as hepatic cholesterol, total lipids and vitamin A concentrations. Daily OIC feeding depressed serum and hepatic cholesterol concentrations. These results show that daily supplement of vitamin A increased serum triglycerides and reduced serum and hepatic cholesterol concentrations. Serum and liver alterations were dependent on continued feeding.