Twice-daily administration of a long-acting angiotensin-converting enzyme inhibitor has greater effects on neurohumoral factors than a once-daily regimen in patients with chronic congestive heart failure

Although many clinical trials have evaluated the use of long-acting angiotensin-converting enzyme (ACE) inhibitors in patients with chronic congestive heart failure (CHF), there are no data regarding whether a once-daily or twice-daily regimen is preferable with respect to effects on the neuroendocrine system. To address this issue, the authors evaluated the comparative effects of the administration schedule on neurohumoral factors and autonomic nervous activity in patients with CHF. Thirty-two patients with mild compensated CHF received lisinopril (5-20 mg/d) orally either once a day (n = 17) or twice a day (n = 15) for more than 3 months. After this initial therapy, patients receiving a once-daily regimen switched to a twice-daily regimen and vice-versa, and patients were followed for an additional 3 months. Neurohumoral factors and the coefficient of variance in the electrocardiographic R-R interval (CVRR) were measured. Hemodynamic parameters, renal function, plasma concentrations of brain natriuretic peptide and aldosterone, and CVRR did not differ between the two regimens. However, the plasma concentration of norepinephrine was significantly lower, and plasma renin activity tended to be lower with the twice-daily regimen. These findings suggest that twice-daily administration of long-acting ACE inhibitors may have better effects on the neuroendocrine system than a once-daily regimen in patients with mild CHF.     

Primary structures of guinea pig high- and low-molecular-weight kininogens

Guinea pig high-molecular-weight and low-molecular-weight (HMW and LMW) kininogen cDNA were amplified from liver mRNA by RT-PCR. Their nucleotide sequences were analyzed and deduced to amino acid sequences. The HMW kininogen, composed of 607 amino acid residues with a 18-residue signal sequence, possessed the cysteine protease inhibitor domains I and II, the bradykinin domain, the histidine-rich region, and the prekallikrein-binding region. The amino acid sequence preceding the bradykinin domain was found not to be -Leu-Met-Lys- but -Leu-Thr-Arg-. Therefore, kallidin (Lys-bradykinin) and Met-kallidin are not liberated from the guinea pig kininogens. We purified the HMW kininogen protein from plasma and prepared the kinin-free form using guinea pig plasma kallikrein. Although the amino-terminal of the HMW kininogen was modified, the 25 amino-terminal residues of the light chain of the kinin-free kininogen corresponded to the deduced sequence just after the bradykinin moiety of the HMW kininogen. With regard to the LMW kininogen, the nucleotide sequence down to T(1200) as well as the amino acid sequence till Thr(382) was identical to that of the HMW kininogen. We also examined the localization of the guinea pig kininogen gene on the prometaphase lymphocyte chromosomes by fluorescence in situ hybridization method. Two pair signals were observed on a pair of homologous chromosomes, each of which is composed of two chromatids. Based on these findings, we concluded that HMW and LMW kininogens are produced from the single kininogen gene in guinea pig as in the cases of the other mammalian species reported so far.     

Terpene isocyanides, isocyanates, and isothiocyanates from the Okinawan marine sponge Stylissa sp

Seven new nitrogenous terpenoids, (1R,6R,7S,10S)-10-isothiocyanatocadin-4-ene (1), (1S,2S,5S,6S,7R,8S)-13-isothiocyanatocubebane (2), (1R,3S,4R,7S,8S,12S,13S)-7-isocyanoamphilecta-10,14-diene (3), (1S,3S,4R,7S,8S,12S,13S)-8-isocyanoamphilecta-11(20),14-diene (4), (3S,4R,7S,8S,11S,13S)-8-isocyanoamphilecta-1(12),14-diene (5), 8-isocyanatocycloamphilect-10-ene (6), and 8-isothiocyanatocycloamphilect-10-ene (7), were isolated from the Okinawan sponge Stylissasp., along with 12 known related compounds. Structural determinations of these compounds were made by spectroscopic analysis, and assessment was made of their cytotoxicity toward HeLa cells.     

Transduction of soluble Flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastric cancer

The prognosis of gastric cancer with peritoneal metastasis has not improved. Despite many promising studies, gene therapy has limited clinical application because of the lack of suitable vector systems to enable selective gene transduction to tumor cells. The aim of this study was to clarify whether gene therapy targeted to peritoneal mesothelial cells (PMCs) can inhibit peritoneal dissemination of gastric cancer. In vitro experiments showed that adenovirus expressing LacZ infected human omental tissue-derived PMCs more efficiently than human gastric cancer cell lines MKN1 and MKN45. When adenovirus expressing LacZ was injected into the peritoneal cavity of nude mice, the expression was detected in the peritoneum for at least 4 weeks. Furthermore, when adenovirus expressing soluble Flt-1 (Ad-sFLT-1) was i.p. administered in vivo, a high level of sFlt-1 protein could be detected in peritoneal lavage for 8 weeks. When MKN45 cells were i.p. inoculated 3 days after adenoviral vector injection, Ad-sFLT-1 markedly reduced the number of metastatic nodules larger than 1 mm in diameter on the peritoneal surface, and significantly prolonged the survival of nude mice without any significant side effects. Thus, peritoneal dissemination was significantly suppressed by a single i.p. injection of Ad-sFlt-1. Anti-angiogenic gene therapy targeted to PMCs could be a novel and practical strategy against peritoneal dissemination of gastric cancer, because it does not require tumor-specific gene transfer.     

Host stromal bradykinin B2 receptor signaling facilitates tumor-associated angiogenesis and tumor growth

We evaluated the significance of the host kallikrein-kinin system in tumor angiogenesis and tumor growth using two rodent models genetically deficient in a kallikrein-kinin system. Inoculation of Walker 256 carcinoma cells into the s.c. tissues of the back of normal Brown Norway Kitasato rats (BN-Ki rats) resulted in the rapid development of solid tumors with marked angiogenesis. By contrast, in kininogen-deficient Brown Norway Katholiek rats (BN-Ka rats), which cannot generate intrinsic bradykinin (BK), the weights of the tumors and the extent of angiogenesis were significantly less than those in BN-Ki rats. Daily administration of B(2) receptor antagonists significantly reduced angiogenesis and tumor weights in BN-Ki rats to levels similar to those in BN-Ka rats but did not do so in BN-Ka rats. Angiogenesis and tumor growth were significantly suppressed in B(2) receptor knockout mice bearing sarcoma 180 compared with their wild-type counterparts. Immunoreactive vascular endothelial growth factor (VEGF) was localized in Walker tumor stroma more extensively in BN-Ki rats than in BN-Ka rats, although immunoreactive B(2) receptor also was detected in the stroma to the same extent in both types of rats. Cultured stromal fibroblasts isolated from BN-Ki rats and BN-Ka rats produced VEGF in response to BK (10(-8)-10(-6) m), and this stimulatory effect of BK was abolished with a B(2) receptor antagonist, Hoe140 (10(-5) m). These results suggest that BK generated from kininogens supplied from the host may facilitate tumor-associated angiogenesis and tumor growth by stimulating stromal B(2) signaling to up-regulate VEGF production mainly in fibroblasts.     

Successful Removal After Radiotherapy and Vascular Embolization in a Huge Tentorial Epithelioid Hemangioendothelioma: A Case Report

Intracranial epithelioid hemangioendothelioma (E-HE) is an extremely rare, vasoformative tumor with variable biological behavior. A huge E-HE confined to the upper side of the tentorium has not been documented previously. Recognizing E-HE as a specific vascular tumor is important, and complete tumor removal guarantees long-term survival. Here, we report an intracranial E-HE of a 24-year-old woman with the initial symptoms of progressive headache over several years. Magnetic resonance imaging revealed a huge tumor attached to the upper side of the right tentorium, with tentorial and tonsillar herniation, and secondary syringomyelia in the upper cervical spinal cord. The initial surgical attempt to remove the lesion was abandoned due to profuse bleeding from the tumor. One year after irradiation and 5 days after vascular embolization, the tumor could be removed totally. The final definitive diagnosis as E-HE was made by special immunohistochemical and electron microscopic study. The patient is free from the tumor 9 years after the second operation. Thus, E-HE is a highly vascular-rich tumor to excise, and we stress need for preoperative embolization and/or irradiation to remove huge tumor completely.