The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of beta-amyloid across the blood-brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of beta-amyloid out of the brain. To determine whether there are Alzheimer's disease (AD)-related changes in these BBB-associated beta-amyloid receptors, we studied RAGE, LRP-1, and beta-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and beta-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and beta-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.

Purpose:The seven transmembrane receptor, GPR30, is linked to estrogen binding and heparanbound epidermal growth factor release. Here, the significance of GPR30 in human breast cancer was evaluated by comparing its relationship to steroid hormone receptor expression and tumor progression variables. Experimental Design: Immunohistochemical analysis of a National Cancer Instituteŝ ponsored tumor collection comprised of 361 breast carcinomas obtained at first diagnosis (321 invasive and 40 intraductal tumors). Biopsies from 12 reduction mammoplasties served as controls. The distribution pattern of GPR30, estrogen receptor (ER), and progesterone receptor (PR) was correlated with clinicopathologic variables obtained at diagnosis. Results: GPR30, ER, and PR were positive in all 12 normal controls. In contrast, GPR30 expression varied in breast tumors, in which 62% (199 of 321) of invasive tumors and 42% (17 of 40) of intraductal tumors were positive. Codistribution of ER and GPR30 was measured in 43% (139 of 321) of invasive breast tumors, whereas both receptors were lacking (ER(61of 321) of the tumors analyzed, indicating a significant association between ER and GPR30 (P < 0.05).The coexpression of PR and ER did not influence GPR30 expression, yet coexpression of GPR30 and ER was linked to PR positivity. Unlike ER, which varied inversely with HER-2/neu and tumor size, GPR30 positively associated with HER-2/neu and tumor size. In addition, GPR30 showed a positive association with metastasis (P = 0.014; odds ratio, 1.9). Conclusions: GPR30 and ER exhibited distinct patterns of association with breast tumor progression variables, including HER-2/neu, tumor size, and metastatic disease. Thus, these results support the hypothesis that GPR30 and ER have an independent influence on estrogen responsiveness in breast carcinoma.Estrogen promotes the development and homeostasis of the mammary gland, and the growth of tumors that arise from this tissue. It is widely accepted that estrogen manifests its physiologic and pathophysiologic actions through its interaction with specific receptors. Estrogen receptor (ER) a and its structural homologue, ERh, belong to the nuclear steroid hormone family, and function indisputably as hormonedependent transcription factors. The blockade of estrogenbinding sites on the ER has proven to be an effective means to inhibit the growth of breast tumors expressing ER, and today, this modality of treatment remains the standard endocrine therapy for ER + tumors. Although there is general concordance between ER expression and responsiveness to ER antagonism, as indicated in greater disease-free survival at 5-year follow-up for postmenopausal patients with ER + tumors receiving tamoxifen (1), roughly one in four patients do not respond to tamoxifen therapy. A variety of explanations have been offered to account for nonresponsiveness to ER antagonism, including: (a) intratumoral heterogeneity in ER expression, (b) evolution of mutant ERs with reduced affinity for ER antagonists, (c) drug resista...

We demonstrate for the first time that CU duration is associated with clinical parameters such as severity and angioedema, and with laboratory parameters such as autologous serum test and anti-thyroid antibodies. The ability to predict CU duration may facilitate decisions regarding the possible early initiation of cyclosporine A as a means by which to reduce disease severity and duration.

This prospective study determines the indications for and the optimal timing of laparoscopic cholecystectomy (LC) following the onset of acute cholecystitis. It also evaluates preoperative and operative factors associated with conversion from laparoscopic cholecystectomy to open cholecystectomy in the presence of acute cholecystitis. Having been established as the procedure of choice for elective cholelithiasis, LC is now also used for management of acute cholecystitis. Under these circumstances the procedure may be difficult and challenging. Certain favorable and unfavorable conditions may be present that influence the conversion and complication rates. Information about these conditions may be helpful for elucidating the optimal circumstances for LC or when the procedure is best avoided. We performed LC on an emergency basis as soon as the diagnosis was made on all patients presenting with acute cholecystitis from January 1994 to December 1995. All preoperative, operative, and postoperative data were collected on standardized forms. Of the 137 patients registered, 130 were eligible for the audit. Seven patients found by laparoscopic intraoperative cholangiography to have choledocholithiasis were converted for common bile duct exploration and were excluded from the study. Altogether 83 patients (72%) underwent successful LC and 37 (28%) needed conversion to open cholecystectomy. The conversion rate of acute gangrenous cholecystitis (49%) was significantly higher than that for uncomplicated acute cholecystitis (4.5%) (p < 0.00001) and for hydrops (28.5%) and empyema of the gallbladder (28.5%) (p = 0.004). The difference in conversion between the group with acute necrotizing (gangrenous) cholecystitis and the two groups with hydrops and empyema of the gallbladder was not statistically significant (p = 0.07). The complication rates of acute cholecystitis, hydrops, empyema of the gallbladder, and gangrenous cholecystitis were 9.0%, 9.5%, 14.0%, and 20.0%, respectively (p = NS). Patients with an operative delay of 96 hours or less from the onset of acute cholecystitis had a conversion rate of 23%, whereas a delay of more than 96 hours was associated with a conversion rate of 47% (p = 0.022). The complication rate was 8.5% in the laparoscopic group and 27% in the converted group (p = 0.013). Patients over 65 years of age, with a history of biliary disease, a nonpalpable gallbladder, WBC count over 13,000/cc, and acute gangrenous cholecystitis were independently associated with a high LC conversion rate; male patients, finding large bile stones, serum bilirubin over 0.8 mg/dl, and WBC count over 13,000/cc were independently associated with a high complication rate following laparoscopic surgery with or without conversion. Generally, LC can be performed safely for acute cholecystitis, with acceptably low conversion and complication rates. Different forms of cholecystitis carry various conversion and complication rates in selected cases. LC for acute cholecystitis should be performed within 96 hours of the onset of disea...

The neuropilin-1 (np1) and neuropilin-2 (np2) receptors form complexes with type-A plexins. These complexes serve as signaling receptors for specific class-3 semaphorins. Np1 and np2 function in addition as receptors for heparin-binding forms of vascular endothelial growth factor (VEGF), such as VEGF 165 . Human umbilical vein endothelial cells (HUVEC) express tyrosine-kinase receptors for VEGF and basic fibroblast growth factor (bFGF), as well as np1, np2, and several type-A plexins. We have found that semaphorin-3F (s3f), a semaphorin which signals through the np2 receptor, was able to inhibit VEGF 165 , as well as bFGF-induced proliferation of HUVECs. Furthermore, s3f inhibited VEGF as well as bFGF-induced phosphorylation of extracellular signalregulated kinase-1/2. Our experiments indicate that bFGF does not bind to neuropilins, nor does s3f inhibit the binding of bFGF to FGF receptors. It is therefore possible that s3f inhibits the activity of bFGF by a mechanism that requires active s3f signal transduction rather than by inhibition of bFGF binding to FGF receptors. s3f also inhibited VEGF 165 , as well as bFGF-induced in vivo angiogenesis as determined by the alginate micro-encapsulation and Matrigel plug assays. Overexpression of s3f in tumorigenic human HEK293 cells inhibited their tumor-forming ability but not their proliferation in cell culture. The tumors that did develop from s3f-expressing HEK293 cells developed at a much slower rate and had a significantly lower concentration of tumor-associated blood vessels, indicating that s3f is an inhibitor of tumor angiogenesis.

No abstract

Tight junction associated proteins are key molecular components governing cellular adhesion, polarity and glandular differentiation. Tight junction proteins also play critical roles in cellular proliferation and neoplastic pathways via their functions as couplers of the extracellular milieu to intracellular signaling pathways and the cytoskeleton. Neoplastic cells frequently exhibit structural and functional deficiencies in the tight junction. The purpose of this study was to determine the pattern of expression and prognostic value of four tight junction associated proteins, claudin-1, claudin-4, occludin and ZO-1 in a cohort of TNM stage II colon cancer using tissue microarray technology. In this study, we retrospectively analyzed, resected and otherwise untreated paraffin embedded specimens from 129 consecutive patients with TNM stage II colonic carcinomas for claudin-1, claudin-4, occludin and ZO-1 protein expression by immunohistochemistry. Seventy-five, 58, 56 and 44% of the tumors exhibited normal to elevated expression levels ( þ 2 and þ 3 immunopositivity) of claudin-1, claudin-4, occludin and ZO-1 respectively. Low expression levels of claudin-1 and ZO-1 were directly associated with higher tumor grade (P ¼ 0.05 and 0.03 respectively). Multivariate analysis indicated that lymphovascular invasion (P ¼ 0.01) and low levels of claudin-1 (P ¼ 0.0001) expression were independent predictors of recurrence and that reduced claudin-1 expression (P ¼ 0.0001) was associated with poor survival. This study is the first to comprehensively examine the expression of several tight junction associated proteins in colonic neoplasms and to correlate their expression with disease progression. Loss of claudin-1 expression proved to be a strong predictor of disease recurrence and poor patient survival in stage II colon cancer.

Although therapeutic management of hypertrophic scars and keloids using contact or spray cryosurgery has yielded significant improvement or complete regression of hypertrophic scars and keloids, it requires one to 20 treatment sessions. This study was designed to assess the clinical safety and efficacy of an intralesional needle cryoprobe method in the treatment of hypertrophic scars and keloids. Ten patients, ranging in age from 3 to 54 years, with a total of 12 hypertrophic scars and keloids of more than 6 months duration and of diverse causes, were included in this study. The 18-month trial evaluated volume reduction of the hypertrophic scars and keloids after a single session of intralesional cryotherapy. Objective (hardness and color) and subjective (pain/tenderness and itchiness/discomfort) parameters were examined on a scale of 0 to 3 (low score was better). Pretreatment and posttreatment histomorphometric studies of the collagen fibers included spectral picrosirius red polarization and fast Fourier transformation orientation index. A specially designed cryo-needle was inserted into the long axis of the hypertrophic scars and keloids so as to maximize the volume of the hypertrophic scars and keloids to be frozen. The cryo-needle was connected by an adaptor to a cryogun filled with liquid nitrogen, which was introduced into the cryoprobe, thereby freezing the hypertrophic scars and keloids. After the hypertrophic scars and keloids were completely frozen, the cryoprobe defrosted and was withdrawn. An average of 51.4 percent of scar volume reduction was achieved after one session of intralesional cryosurgery treatment (average preoperative hypertrophic scars and keloids volume, 1.82 +/- 0.33; average posttreatment volume, 0.95 +/- 0.21; p < 0.0022). Significant alleviation of objective and subjective clinical symptoms was documented. Mild pain or discomfort during and after the procedure was easily managed. Only mild local edema and epidermolysis, followed by a short reepithelialization period, were evident. During the 18-month follow-up period, there was no evidence of bleeding, infection, adverse effects, recurrence, or permanent depigmentation. The histomorphometric analysis demonstrated rejuvenation of the treated scars (i.e., parallelization) and a more organized architecture of the collagen fibers compared with the pretreated scars. This study demonstrated the increased efficacy of this method as a result of increased freezing area of deep scar material compared with that obtained with contact/spray probes. As a result, fewer treatment cycles are needed. Because the reepithelialization period is short, treatment intervals, if any, can be shortened to 2 to 3 weeks. This intralesional cryoneedle method is simple to operate and safe to use, it necessitates less postoperative care of the wound, and it can easily be added to any preexisting cryosurgical unit.