Enhancement of apomorphine-induced penile erection in the rat by a selective alpha(1D)-adrenoceptor antagonist

1. Effects of A-322312 (alpha(1B)-adrenoceptor (AR) antagonist), A-119637 (alpha(1D)-AR antagonist), prazosin (non-selective alpha(1)-AR antagonist), and yohimbine (alpha(2)-AR antagonist) were studied in rat corpus cavernosum (CC) and cavernous artery (Acc) preparations. Effects of intracavernous (i.c.) or intraperitoneal (i.p.) administration of alpha(1)-AR antagonists on apomorphine-induced erections were investigated. 2. A-119637 attenuated electrically induced contractions in isolated CC (-logIC(50); 8.12+/-0.15), and relaxed noradrenaline (NA)-contracted preparations by more than 90% at 10(-7) M. At the same concentration, the -logEC(50) value for NA in Acc was altered from 6.79+/-0.07 to 4.86+/-0.13. In the CC and Acc, prazosin similarly inhibited contractile responses. 3. Inhibitory effects of A-322312 (10(-7) M) in electrically activated CC were 32.3+/-5.1%, whereas no effect on concentration-response curves for NA was observed in the Acc. Yohimbine (10(-8) M and 10(-7) M), enhanced electrically-induced contractions in isolated CC by 20 to 50%. At 10(-6) M, inhibitory effects of yohimbine were obtained. 4. A-119637 (0.3 micromol kg(-1), i.p.) tripled the number of erections, and produced a 6 fold increase in the duration of apomorphine-induced erectile responses. A-322312, prazosin, or yohimbine did not enhance erections induced by apomorphine. None of the alpha(1)-AR antagonists significantly increased ICP upon i.c. administration. Decreases in blood pressure were seen with A-119637 and prazosin. 5. The present findings show that there is a functional predominance of the alpha(1D)-AR subtype in the rat erectile tissue, and that blockade of this receptor facilitates rat penile erection induced by a suboptimal dose of apomorphine.     

Aquaporin-2 regulation by vasopressin in the rat inner ear

Our previous studies have suggested a close relationship between vasopressin and endolymphatic hydrops, or the increased volume of endolymph in the inner ear. Endolymphatic hydrops is also thought to occur in Ménière's disease patients. In the kidney collecting duct, vasopressin induces the expression of aquaporin-2 (AQP2), resulting in increased water reabsorption. We explored the possibility, using a quantitative PCR method, that vasopressin regulates the expression of AQP2 mRNA in the rat inner ear, as it does in the kidney. The levels of AQP2 mRNA in the cochlea and endolymphatic sac were significantly higher in rats treated with vasopressin than the levels in control animals. We speculate that over-expression of AQP2 may be involved in the formation of endolymphatic hydrops.     

Time-dependent contribution of the hippocampal complex when remembering the past: a PET study

Previous studies of brain-damaged patients and functional neuro-imaging have consistently shown the importance of the hippocampal complex, i.e. the hippocampus and parahippocampal gyrus, in episodic memory retrieval. We wished to determine whether patterns of brain activation during memory retrieval as measured by PET are same or different when the oldness of a to-be-retrieved episode is manipulated. Using cue words, subjects remembered related episodes from three periods of their life, childhood, adolescence and recent period. The results showed an increase of parahippocampal activities during recall of episodes from childhood and recent period, but not from adolescence. These data suggest a possibility of time-dependent hippocampal contribution in episodic recall, which cannot be understood in simple terms of recent remote memory dichotomy.     

Lymph nodes of patients with regional metastases from head and neck squamous cell carcinoma as a predictor of pathologic outcome: size changes at CT before and after radiation therapy

BACKGROUND AND PURPOSE: Viable tumor in a neck dissection specimen is important in predicting prognosis and directing treatment. Our purpose was to clarify the importance of size changes of regional metastases from head and neck squamous cell carcinoma on CT scans obtained before and after radiation therapy (RT) as a predictor of pathologic outcome. METHODS: Thirty-seven heminecks in 34 patients who underwent pre-RT CT, RT, post-RT CT, and post-RT neck dissection were reviewed. Thirteen hemineck specimens were pathologically positive. Decrease ratios of the largest axial dimension of the lymph nodes between the pre- and post-RT CT studies were calculated. RESULTS: Six of 37 heminecks had a decrease ratio greater than 50%. These yielded negative specimens after planned neck dissection. In two of 37 heminecks, the largest axial dimension of the largest node increased between studies, resulting in negative decrease ratio. One (decrease ratio, -20%) had a positive specimen, and the other (decrease ratio, -3%) had a negative specimen. No interval change in size in the largest node was noted in one of the 37 heminecks; its specimen was positive. Average decrease ratios were 41.2% (range, -3% to 62%) in the negative specimen group (n = 24) and 27.2% (range, -20% to 50%) in the positive specimen group (n = 13). Univariate analysis revealed that the decrease ratio was not a significant predictor of a positive surgical specimen (P =.154). CONCLUSION: Heminecks in which the decrease ratio was greater than 50% tended to have a negative surgical specimen. However, this trend was not statistically significant.     

CyberKnife stereotactic irradiation for metastatic brain tumors

BACKGROUND: The CyberKnife provides a new technique for performing frameless stereotactic irradiation. So far, few reports have been published on clinical outcomes obtained with the CyberKnife. This report summarizes our clinical experience with CyberKnife irradiation for metastatic brain tumors. MATERIALS AND METHODS: Seventy-seven lesions (48 patients) were evaluated and analyzed, and 66 lesions in 41 patients were treated with stereotactic radiosurgery (SRS). The prescribed dose was 9 to 30 Gy. RESULTS: Freedom from progression of the tumors was more likely with a prescribed dose of at least 24 Gy than with one of less than 20 Gy (p=0.0244; log-rank test). The CR (complete response) rate was significantly higher when D99 was at least 24 Gy (p=0.0045). There were no severe side effects. CONCLUSION: Stereotactic irradiation with the CyberKnife for metastatic brain tumors is effective and safe. D99 should be at least 24 Gy for CyberKnife SRS treatment.     

Monte Carlo calculation of depth doses for small field of CyberKnife

PURPOSE: A Monte Carlo (MC) model of CyberKnife was developed as a quality assurance tool. The percentage depth dose (%dd) was verified by using this model. MATERIALS AND METHODS: An MC model was developed with Electron Gamma Shower version 4 (EGS4) in two steps: (1) a model of the CyberKnife treatment head and (2) a model of the collimator and phantom. The bremsstrahlung spectrum was calculated using the first model, and this spectrum was then used to calculate %dds with the second model. The calculated %dds for a large field (60 mm diameter) and three small fields (30, 15, and 5 mm diameter) were compared with those measured with a diamond detector. RESULTS AND DISCUSSION: The MC-calculated and measured %dd-curves for the 60 mm diameter field were in excellent agreement (<1.85%), thus confirming the validity of the model. Discrepancies between the calculated and measured %dd-curves increased with decreasing field size, with considerable discrepancy (11.62%) for the 5 mm diameter field due to lateral electron disequilibrium. Accurate dose can be determined with MC even in small fields. CONCLUSION: The MC technique can provide reliable standard data for accurate dose delivery with high-technology radiotherapies using small beams.     

High dose rate endovascular brachytherapy in aorto-iliac lesion for the prevention of restenosis

This study examined the applicability of endovascular brachytherapy to larger del arteries such as the abdominal aorta and iliac artery. Endovascular brachytherapy using an Ir-192 HDR source was administered 11 times to nine patients who had undergone percutaneous transluminal angioplasty (PTA) between 1995 and 1999. The follow-up lasted 13 to 55 months after treatment (median, 24 months). Eight of the 11 lesions have been controlled so far. Although one case developed thrombus inside the stent five months later, recanalization was achieved by means of retreatment. One patient who underwent low-dose irradiation (6 Gy) without stent implantation showed restenosis five months after treatment. We used a centering catheter that did not block the blood stream for exact centering of the radiation source in larger vessels such as the abdominal aorta. Although endovascular brachytherapy is a promising and safe procedure, careful follow-up is needed to detect untoward reactions such as thrombosis.     

Direct costimulation of tumor-reactive CTL by helper T cells potentiate their proliferation, survival, and effector function.

The survival and proliferation of CTL during the effector phase of the immune response is critical for the elimination of infectious agents and tumor cells. We report here that in an in vitro model system, the expansion and cytolytic function of tumor-reactive human CTL can be enhanced by CD4(+) helper T lymphocytes through costimulatory signals that are mediated by cell surface molecules. The results presented here suggest that costimulatory receptors on CTL such as CD27, CD134 (4-1BB), and MHC class II are capable of directly interacting with the corresponding ligands on T-helper lymphocytes resulting in enhanced proliferation and survival of the CTL during the effector phase of antitumor immune responses. These findings underline the importance of antigen-specific helper T lymphocytes for the regulation and maintenance of CTL immunity, and have implications for the design of therapeutic vaccines for cancer.     

Identification of an antigenic epitope for helper T lymphocytes from carcinoembryonic antigen.

PURPOSE: The product of the carcinoembryonic antigen (CEA) gene is an attractive candidate for T-cell-based immunotherapy because it is frequently expressed in epithelial solid carcinomas. Although many CEA peptide epitopes capable of stimulating CTLs have been identified, no MHC class II-restricted T helper epitope has yet been reported. Experimental Design: The amino acid sequence of CEA was examined for the presence of potential T helper epitopes, and candidate peptides were used to stimulate in vitro T-cell responses. RESULTS: We describe here that using an algorithm to identify promiscuous helper T-cell epitopes, a peptide of CEA occupying residue positions 653 to 667 (CEA(653-667)), was effective in inducing in vitro T helper responses in the context of the HLA-DR4, HLA-DR7, and HLA-DR 9 alleles. Most significantly, some of the peptide-reactive helper T lymphocytes were also capable of recognizing naturally processed antigen in the form of recombinant CEA protein or cell lysates from tumors that express CEA. Interestingly, the newly identified helper T-cell epitope was found to overlap with a previously described HLA-A24-restricted CTL epitope, CEA(652-660), which could facilitate the development of a therapeutic vaccine capable of eliciting both CTL and T helper responses in patients suffering from epithelial carcinomas. CONCLUSION: These results indicate that T helper lymphocytes are capable of recognizing CEA as a tumor antigen and that epitope CEA(653-667) could be used for immunotherapy against tumors expressing CEA.     

Isolation of a Novel Gene Showing Reduced Expression in Metastatic Colorectal Carcinoma Cell Lines and Carcinomas

To investigate genes involved in mctastatic stages of cancer, we analyzed expression of mRN As in three cell lines derived from murine colon adenocarcinoma 26 by means of a differential display method. Each of these lines exhibits distinct metastatic characteristics. Among many bands representing different expression patterns in the display, we confirmed by northern analysis that a gene corresponding to one amplified fragment, termed grm2 (gene related to metastasis 2), was expressed more abundantly in NL4, the derivative with the lowest metastatic potential, than in cell lines NL17, an experimentally metastatic derivative, and in NL22, a spontaneously metastatic derivative. Using thegrm.2 fragment as a probe, we isolated murine cDNA clones and subsequently human cDNA clones corresponding to the GRM2 gene. The human and mouse homologues both encode proteins of 600 amino-acid residues, which show weak homologies to proteins belonging to the myosin family. When we examined the expression levels of this novel gene in human colon cancers and in corresponding metastatic foci, we found that in more than half of these tissues, expression was significantly reduced in association with malignant potential. Our resultsimply that in humans the GRM2 gene product may regulate the metastatic phenotype of some colorectal cancers.