Erythropoietin receptor contributes to melanoma cell survival in vivo.

Erythropoietin (Epo) is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of Epo treatment on cancer patient survival. However, controversy exists whether Epo receptor (EpoR) is functional in cancer cells. In this study, we demonstrated that EpoR mRNA expression was detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the Epo and EpoR loci occurred in 30 and 24.6% of 130 primary melanomas, respectively. EpoR knockdown in melanoma cells resulted in diminished ERK phosphorylation in response to Epo stimulation, decreased cell proliferation and increased response to the inhibitory effect of hypoxia and cisplatin in vitro. EpoR knockdown significantly decreased melanoma xenograft size and tumor invasion in vivo. On the contrary, constitutive activation of EpoR activated cell proliferation pathways in melanoma cells and resulted in increased cell proliferation and resistance to hypoxia and cisplatin treatment in vitro. EpoR activation resulted in significantly larger xenografts with increased tumor invasion of surrounding tissue in vivo. Daily administration of recombinant Epo fails to stimulate melanoma growth in vivo, but the treatment increased vascular size in the xenografts. Increased local recurrence after excision of the primary tumors was observed after Epo treatment. Epo induced angiogenesis in Matrigel plug assays, and neutralization of Epo secreted by melanoma cells results in decreased angiogenesis. These data support that EpoR is functional in melanoma and EpoR activation may promote melanoma progression, and suggest that Epo may stimulate angiogenesis and increase survival of melanoma cells under hypoxic condition in vivo.

Lymphatic vessel density is significantly increased in melanoma.

BACKGROUND: Melanoma is well known for its ability to involve regional lymph nodes in the early stage. However, the presence of lymphangiogenesis in melanoma is still controversial due to lack of lymphatic-specific markers. The purpose of this study was to determine the intra- and peritumoral lymphatic vessel density (LVD) using a novel lymphatic vessel-specific marker D2-40 and compare it to general vessel density (GVD) as determined by CD31 immunostaining in a series of melanocytic lesions. METHODS: The intra- and peritumoral GVD and LVD were examined by immunohistochemistry using D2-40 and CD31 antibodies in a series of melanocytic lesions. RESULTS: We found significantly higher intratumoral LVD in melanomas as compared to either common acquired or dysplastic nevi (p < 0.01). Although peritumoral LVD in melanoma and malignant melanoma in situ was higher compared to nevi, the difference did not reach statistical significance (p = 0.059). There was no significant difference in GVD among the various groups of melanocytic lesions. CONCLUSIONS: Our results show that intratumoral LVD is significantly increased in melanomas compared to benign nevi. The higher intratumoral lymphatic density in invasive melanomas suggests that melanoma cells might promote lymphangiogenesis. In addition, assessment of intratumoral LVD may be potentially useful in the differential diagnosis of melanocytic lesions.

Systemic and regional hemorheological consequences of warm and cold hind limb ischemia-reperfusion in a canine model.

We have studied systemic and regional changes in hemorheological parameters after complete acute limb ischemia and reperfusion (I/R) in 24 mongrel dogs. Unilateral cooled and non-cooled vascular ischemia (3 h)-reperfusion (4 h), and sham-operations were performed. Blood samples were collected from the excluded region, during reperfusion and for 5 days. Whole blood and plasma viscosity (WBV, PV), relative cell transit time (RCTT) of erythrocytes, fibrinogen level and hematological parameters were determined. In I/R groups WBV of excluded blood was significantly higher compared to the base (p < 0.05), and RCTT increased during the reperfusion. On 2nd-3rd days RCTT increased significantly in both I/R groups. In each group PV and fibrinogen showed continuous increase during the postoperative period, prominently in cooled I/R group, and furthermore WBV corrected for hematocrit (40%) was the highest in cooled I/R group. These suggest that surgical acute limb I/R may cause hemorheological changes, which are more serious after cooling. (Grants: OTKA-T032571, 6003/1/2001/ETT.)

Perceived outcomes and parental satisfaction following dental rehabilitation under general anesthesia.

PURPOSE: The objective of this study was to evaluate parents' perceptions of their child's quality of life following dental rehabilitation under general anesthesia and to assess their satisfaction with that treatment modality. METHODS: A survey was sent to 400 parents of patients who had undergone dental rehabilitation. Quality of life outcomes, such as continued presence of pain and inability to eat or sleep, were assessed. Additionally, parental satisfaction with outcomes and processes was evaluated, as was outcome expectation. Descriptive statistics were collected on outcome measures. Contingency testing was employed to compare outcomes by medical or developmentally compromising conditions, gender, or continued use of the initial treatment facility for routine care. RESULTS: Fifty seven percent of parents returned surveys. A descending hierarchy of improved treatment outcomes was noted, with improvement in pain the predominant outcome, followed by improved abilities to eat and sleep, reported by 86, 69, and 41% of parents, respectively, 72% perceived an improvement in their child's health. Children with medically or developmentally compromising conditions were significantly more likely to have improved abilities to eat and sleep, and had a significantly improved overall health status. Satisfaction and expectations were consistently achieved and were not related to continued use of the initial treatment facility. CONCLUSIONS: Children with early childhood caries receiving comprehensive treatment under general anesthesia achieved improvements in their quality of life as well as overall health. A hierarchy of improvement was noted, with the greatest improvement noted in pain experience followed by improved abilities to eat and sleep. Parents were overwhelmingly satisfied with outcomes and the process of care, and reported that their expectations had been met.

A 20-year perspective on the changing use of hand over mouth (HOM) and restraint in postdoctoral pediatric dental education.

PURPOSE: This study assessed the current teaching and utilization of the hand over mouth technique in advanced educational programs in pediatric dentistry and compared these results to previous surveys. METHODS: A survey, identical to those used in 1979 and 1989, was sent to pediatric dentistry program directors. Descriptive and comparative statistics evaluated the use of HOM, HOMAR, and restraint. Additionally, changing patterns of responses for programs and directors that responded to both the 1989 and 1999 surveys were assessed. RESULTS: Eighty-seven percent of directors returned surveys. There was a significant decrease in the number of programs utilizing the HOM technique in the past 10 years (P< 0.0001). Among respondents that returned surveys in 1989 and 1999, 50% of the previous HOM users discontinued its use (P<0.03). Technique non-users were significantly less likely to describe the technique consistent with AAPD guidelines (P

Diabetic mastopathy in men: imaging findings in two patients.

The classic imaging findings of diabetic mastopathy, an uncommon entity manifesting in patients with a history of long-standing insulin-dependent diabetes mellitus, have been reported in the literature in women but not, to the authors' knowledge, in men. Two men with diabetic mastopathy presented with palpable breast masses. The clinical histories of the men in whom this condition was diagnosed were similar to those reported for women with the condition. The mammographic findings in both men, at presentation, were suggestive of gynecomastia.

Erythropoietin and erythropoietin receptor expression in human cancer.

Erythropoietin (EPO) stimulates the growth of erythroblasts in the bone marrow (C. Lacombe and P. Mayeux, NEPHROL: DIAL: TRANSPLANT:, 14 (SUPPL: 2): 22-28, 1999). We report basal and hypoxia-stimulated expression of EPO and its receptor, EPOR, in human breast cancer cells, and we demonstrate EPO-stimulated tyrosine phosphorylation and the proliferation of these cells in vitro. In 50 clinical specimens of breast carcinoma, we report high levels of EPO and EPOR associated with malignant cells and tumor vasculature but not with normal breast, benign papilloma, or fibrocystic tissue. Hypoxic tumor regions display the highest levels of EPO and EPOR expression. Enhanced EPO signaling may contribute to the promotion of human cancer by tissue hypoxia.

Differential expression of E-cadherin in lobular and ductal neoplasms of the breast and its biologic and diagnostic implications.

We studied the pattern of E-cadherin expression in 183 invasive carcinomas (100 ductal, 42 lobular, 41 with mixed ductal and lobular features) and 198 in situ carcinomas (131 ductal, 53 lobular, 14 in situ with ductal and lobular features) by immunohistochemistry. We found a highly significant correlation of E-cadherin membrane expression with the histologic phenotype of the tumors. While moderate to strong membrane expression of E-cadherin was seen in all invasive and in situ ductal carcinomas, 41 of 42 invasive and 50 of 53 in situ lobular carcinomas showed complete loss of expression. All in situ carcinomas diagnosed histologically as showing mixed ductal and lobular features demonstrated complete loss of staining. Invasive carcinomas with ductal and lobular features showed 3 staining patterns: (1) complete or almost complete lack of membrane staining similar to that seen in lobular carcinomas, (2) uniform membrane expression throughout the tumor similar to ductal carcinomas, and (3) focal loss of E-cadherin staining, which correlated well with the histologic impression of focal lobular features. In tumors with histologically equivocal features, immunohistochemical detection of E-cadherin expression can be a useful diagnostic tool for the differentiation of ductal and lobular carcinomas of the breast.

Loss of membrane expression of E-cadherin in leukemic erythroblasts.

CONTEXT: The special societal relationships existing between various cell types in bone marrow suggests that there may be a link between the adhesive characteristics of hematopoietic cells and their maturation. Egress of the developing hematopoietic cells is also a highly regulated process governed by adhesive interactions. In leukemia, immature blasts are not retained within the marrow, suggesting a breakdown of adhesive mechanisms. Recent reports suggest that E-cadherin, an epithelial adhesion molecule, is expressed on erythroid precursors and megakaryocytes, but not on other hematopoietic marrow elements. OBJECTIVE: To characterize the expression pattern of E-cadherin in normal and leukemic erythroid precursors by immunohistochemistry in paraffin-embedded tissue and bone marrow aspirate smears. METHODS: Five normal bone marrow specimens from rib resections, 15 trephine bone marrow biopsy specimens, and 6 bone marrow aspirate smears from the iliac crest of patients with no known leukemia were selected. Fourteen bone marrow biopsy specimens from patients with erythroleukemia were also studied. Immunoperoxidase staining of paraffin-embedded tissue and air-dried aspirate smears for E-cadherin (1:200 dilution, HECD-1 clone) was performed using the avidin-biotin peroxidase technique. RESULTS: In paraffin-embedded bone marrow biopsy and rib specimens and in air-dried bone marrow aspirate smears, strong membrane expression of E-cadherin was seen in the normal erythroid precursors in all cases. In contrast, no membrane expression of E-cadherin was present in any of the bone marrow biopsy specimens from patients with erythroleukemia. CONCLUSIONS: Immunohistochemical detection of membrane expression of E-cadherin may be a useful tool for identification of erythroid precursors. Cells of erythroleukemia lack membrane expression of E-cadherin, in contrast to their normal counterparts. Further studies are needed to define the potential role of E-cadherin in the maturation of erythroid precursors and to ascertain the significance of loss of membrane expression of E-cadherin in erythroleukemia.

The influence of medical history on restorative procedure failure rates following dental rehabilitation.

PURPOSE: This study evaluated the association between patient medical history and the outcomes of restorative procedures performed under general anesthesia. METHODS: The dental records of patients who had dental rehabilitation under general anesthesia at Children's Hospital in Boston (1990-1992) and Children's National Medical Center in Washington, DC (1994-1998) were examined. Data regarding restorative outcomes and the association between patient medical history and restorative failures were assessed using chi-square tests with correction for continuity. T-tests were performed on parametric data. RESULTS: Significantly higher stainless steel crown failure rates were found in young patients diagnosed with developmental disabilities when compared to patients without such disabilities (p<0.025, x2 = 5.50). However, there was no difference in the failure rates of SSCs in young patients with significant medical histories compared to patients without significant medical histories. Regarding amalgam and composite restorations, there were no differences in failure rates among patients with and without significant medical histories, including developmental disabilities. CONCLUSIONS: SSC failures were higher in young children with developmental disabilities compared to children without these disabilities.

Causes of death of patients with multiple injuries in Debrecen, Hungary.

OBJECTIVE: To find out the main causes of death of people who had multiple severe injuries. DESIGN: Retrospective study. SETTING: Teaching hospital, Hungary. SUBJECTS: 86 people with severe multiple injuries, of whom 59 died and had necropsies. MAIN OUTCOME MEASURE: Establishment of a database. RESULTS: Consumption of alcohol was a common precursor. Head and chest injuries predominated. More pedestrians than people in vehicles were killed, and there were 8 suicides and 3 murders. There were no gunshot injuries. CONCLUSIONS: Reduction of deaths from multiple injuries is as much a socioeconomic as a medical matter.

Duodenal carcinoid tumor: report of a case diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy with immunocytochemical correlation.

Fine-needle aspiration biopsy is a reliable and accurate method for the endoscopic diagnosis of gastrointestinal malignancies and it is particularly well suited for evaluation of submucosal lesions. We report the cytopathologic findings of a case of malignant carcinoid tumor of a 44-year-old male who presented with melena and a nonhealing duodenal ulcer. Endoscopic ultrasound examination revealed a submucosal lesion in the pyloric region. Fine-needle aspiration revealed abundant cellularity with tumor cells arranged in sheets and loose groups and dispersed single cells in a clean background. Papillary fragments, capillaries cuffed by tumor cells, and rosette formation were also noted. The cells were moderate in size, round to oval, with a small subpopulation of spindle-shaped cells. The nuclei were uniform, round to oval, with smooth nuclear borders. The chromatin pattern was finely granular with a salt-and-pepper appearance. The cytoplasm of the cells was small to moderate in amount, pale, and showed fine granularity. The differential diagnosis included a neuroendocrine neoplasm vs. an epithelioid gastrointestinal stromal tumor. The tumor cells were focally positive for chromogranin and negative for CD34, supporting the diagnosis of a neuroendocrine neoplasm. The differential diagnosis of primary gastrointestinal carcinoid tumors from gastrointestinal stromal tumors can be very difficult in cytologic material. In cases when diagnostic material is scant, or only present on one smear, the use of smear division and cell transfer in order to perform immunocytochemical stains may be of considerable value to confirm the neuroendocrine nature of the neoplasms.

Glandular and squamous atypia and intraepithelial lesions in atrophic cervicovaginal smears. One institution's experience.

OBJECTIVE: To review the cytologic features and follow-up histologic findings in atrophic cervicovaginal smears with the diagnoses of glandular or squamous atypia or intraepithelial lesion. STUDY DESIGN: A total of 228 cases were included in the study. The selection criteria included: age > 48 years and a diagnosis of either atypical glandular cells (AGC) (51 cases), cellular changes suggestive of human papillomavirus (HPV) infection (S/O HPV, 97 cases), low grade squamous intraepithelial lesion (LSIL) (60 cases) or high grade squamous intraepithelial lesion (HSIL) (20 cases). Follow-up biopsy information was available for 103 cases (45%). RESULTS: From the AGC group, 35 (69%) cases had tissue studies; 14 (40%) cases showed glandular lesions; 5 (14%) showed squamous intraepithelial lesion (SIL) and atypical cells. Follow-up information was available for 32 (33%) cases classified as S/O HPV; significant lesions (glandular/squamous) were found in 11 (34%). In the LSIL category, 22 (37%) cases had follow-up; 16 (73%) showed SIL. In the HSIL category, 14 cases (70%) underwent biopsy, and all showed SIL (four LSIL and nine HSIL) or squamous cell carcinoma. CONCLUSION: Even though atrophy-related epithelial changes often pose diagnostic difficulties in the interpretation of postmenopausal smears, application of reproducible and established cytologic criteria in diagnosing SIL and/or glandular lesions can improve diagnostic accuracy and result in selection of patients for follow-up tissue studies.

Cytomorphology of high-grade neuroendocrine carcinoma of the urinary tract.

High-grade neuroendocrine carcinoma of the bladder is a rare malignant tumor with poor prognosis. We present the cytomorphologic features of six retrospectively identified cases which displayed high-grade tumors with neuroendocrine differentiation in bladder washings. Cytology specimens showed small-to-medium-sized tumor cells with powdery chromatin, inconspicuous nucleoli, and ill-defined nuclear membranes. Tumor fragments showed prominent nuclear molding and single-cell necrosis. All cases also revealed a varying proportion of tumor cells resembling the usual transitional-cell carcinoma. Biopsy specimens from five cases demonstrated high-grade transitional-cell carcinoma with areas resembling small-cell carcinoma. In one case the entire tumor consisted of classic small-cell carcinoma and failed to show any areas of transitional-cell differentiation. All cases were positive for neuroendocrine markers. Neuroendocrine carcinomas of the urinary bladder are rare, with cytological features similar to high-grade neuroendocrine carcinomas seen in other organs. They can be accurately diagnosed cytologically, and an awareness of the cytomorphologic features is important.

The effect of dental rehabilitation on the body weight of children with early childhood caries.

PURPOSE: The purpose of this study was to determine the effect of comprehensive dental rehabilitation on the percentile weight and percentile growth velocity of children with early childhood caries (ECC). METHODS: The percentile weight categories of children with noncontributory medical histories and ECC were compared to caries free comparison patients, before and after comprehensive dental treatment under general anesthesia. RESULTS: Prior to dental rehabilitation, test subjects' percentile weight categories were significantly less than that of comparison counterparts (P < 0.001). Of the ECC patients, 13.7% weighed less than 80% of their ideal weight, thereby satisfying one of the criteria for the designation of failure to thrive, while none of the comparison patients did so (P < 0.05). Following therapeutic intervention, ECC children exhibited significantly increased growth velocities through the course of the follow-up period (P < 0.001), reflecting the phenomenon of catch up growth. The average length of follow-up for the test and comparison groups were 1.58 and 1.36 years, respectively. At the end of the follow-up period there were no longer any statistically significant differences noted in the percentile weight categories of the test and comparison groups. CONCLUSION: Comprehensive dental rehabilitation resulted in catch-up growth, such that children with a history of nursing caries no longer differed in percentile weights from comparison patients.

The effect of disabilities on exits from AFDC.

The Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA) of 1996 replaces AFDC, the largest means-tested cast assistance program for low-income families, with the Temporary Assistance for Needy Families (TANF) block grant. Unlike AFDC, assistance under TANF is limited to five years in a lifetime, and states are required to move families from the assistance rolls into jobs. But not all adult welfare recipients can easily move to work because either they themselves are disabled or they have a child with disabilities requiring special care. This article examines the extent and impact of disability among families on AFDC to gain insight into the potential impact of changes under TANF. Using data from the 1990 Survey of Income and Program Participation (SIPP), we find that in nearly 30 percent of the families on AFDC either the mother or child has a disability. Furthermore, we find that having a disability significantly lowers the probability that a woman leaves AFDC for work but not for other reasons, such as a change in living arrangements. Finally, we find little evidence that having a child with a disability affects the probability of leaving AFDC for any reason.

The effect of dental rehabilitation on the body weight of children with failure to thrive: case reports.

Four case reports of children with nursing caries and failure to thrive are presented. Without regard to the condition of the dentition, the various cases could be classified as organic, mixed, or nonorganic in etiology. After dental rehabilitation, all patients exhibited an acceleration of weight velocity that resulted in weights above the 5th percentile. During the period of observation, the weight velocity continued to increase with time, consistent with the "catch-up" phenomenon of growth that is observed in nutritionally deprived children.

Characterization of functional vanilloid receptors expressed by mast cells.

Capsaicin and its ultrapotent analog resiniferatoxin (RTX) act through specific vanilloid receptors on sensory neurons. The C-type receptor is coupled to 45Ca uptake, whereas the R-type is detectable by [3H]RTX binding. We describe here specific vanilloid responses in murine mast cells (MCs). In the MC lines and in bone marrow-derived mast cells, capsaicin and RTX induced 45Ca uptake similarly to that observed for cultured rat dorsal root ganglion neurons (DRGs). This response was antagonized by the antagonists capsazepine and ruthenium red. As in DRGs, pretreatment of MCs with capsaicin or RTX induced desensitization to subsequent stimulation of 45Ca uptake. The potency for desensitization by RTX in the MCs corresponded to that for 45Ca uptake, whereas in DRGs it occurred at significantly lower concentrations corresponding to that for the high-affinity [3H]RTX binding site. Consistent with this difference, in MCs we were unable to detect [3H]RTX binding. Vanilloids were noncytotoxic to the MCs, in contrast to the DRGs. Although vanilloids did not cause degranulation in MCs, in the P815 clone capsaicin evoked selective interleukin-4 release. We conclude that certain MCs possess vanilloid receptors, but only the C-type that functions as a channel. Our finding that MCs can respond directly to capsaicin necessitates a reevaluation of the in vivo pathway of inflammation in response to vanilloids.