There are currently no approved antifibrotic therapies for liver cirrhosis. We used vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to hepatic stellate cells. Our approach exploits the key roles of these cells in both fibrogenesis as well as uptake and storage of vitamin A. Five treatments with the siRNA-bearing vitamin A-coupled liposomes almost completely resolved liver fibrosis and prolonged survival in rats with otherwise lethal dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent manner. Rescue was not related to off-target effects or associated with recruitment of innate immunity. Receptor-specific siRNA delivery was similarly effective in suppressing collagen secretion and treating fibrosis induced by CCl(4) or bile duct ligation. The efficacy of the approach using both acute and chronic models of liver fibrosis suggests its therapeutic potential for reversing human liver cirrhosis.

Central venous catheter-related blood stream infections (CR-BSIs) are a serious complication in patients with hematological malignancies. However, it remains unclear whether there is a difference in the rate of CR-BSI associated with the conventional type of central venous catheters (cCVCs) and peripherally inserted CVCs (PICCs) in such patients. To address this question, we retrospectively investigated the incidence of CR-BSIs associated with PICCs versus cCVCs in patients with hematological malignancies. We used PICCs in all consecutive patients requiring CVC placement between February 2009 and February 2013. We compared the CR-BSI rate in patients with PICCs with that in patients with cCVCs treated between September 2006 and January 2009 (control group). Eighty-four patients received PICCs and 85 received cCVCs. The most common reason for removal due to catheter-related complications was CR-BSI. The CR-BSI rate in the PICC group was significantly lower than that in the cCVC group (PICCs: 1.23/1000 catheter days; cCVCs: 5.30/1000 catheter days; P < 0.01). Catheter-related complications other than CR-BSIs occurred at an extremely low rate in the PICC group. The median catheter-related complication-free survival duration was significantly longer in the PICC group than in the cCVC group. Our study shows that PICCs are useful in patients with hematological malignancies.

P rark seminal vesicle adenocarcinoma was found in a 109-wk-old Fischer 344 (F344) rat. At necropsy, the right seminal vesicle was enlarged, containing a 15-X 18-Xl8-mm mass. The neoplasm occupied almost the entire seminal vesicle lumen and consisted of epithelial cells arranged in papillary, glandular, and solid patterns. Tumor cells were larger than their normal counterparts in the seminal vesicles and had round nuclei and abundant cytoplasm. Clusters of macrophagelike cells with less abundant cytoplasm and indented nuclei were apparent in the lumina of the glandular structures formed by the tumor cells. No metastasis to other tissues or organs was observed. Immunohistochemically, tumor cells were positive for keratin and S-100, and the macrophagelike cells bound antibodies against vimentin and ED-I. Ultrastructurally, the tumor cells exhibited many small secretory granules, some microvilli, and intercellular junctions. The macrophagelike cells, in contrast, were characterized by lysosomes and abundant rough endoplasmic reticulum. Therefore, a diagnosis of seminal vesicle adenocarcinoma with intraluminal macrophage infiltration was made. This is the first case report of such a seminal vesicle tumor in an F344 rat.Keyvords. Neoplasm; keratin; vimentin; S-100; ED-I; PCNA Spontaneous neoplasms of the seminal vesicles are extremely rare in laboratory and domestic animals and in humans. Even in rats that have a high incidence of spontaneous prostate tumors, almost no proliferative lesions develop in the seminal vesicles. Based on the records for 51,230 male Fischer 344 (F344) rats used in more than 300 long-term toxicity and carcinogenicity studies in the National Toxicology Program, an incidence of only 0.004% was reported for seminal vesicle adenomas; only 2 lesions were found (6). As part of background data for life span studies of male F344 rats, 1 seminal vesicle adenocarcinoma (0.19%) was found in 529 control males (9). There are a small number of reports of spontaneous seminal vesicle tumors in the rat, but most of these reports did not give detailed descriptions (2, 3, 10) and no ultrastructural observations have been documented. Neoplasms of the seminal vesicle, however, can be experimentally induced in rats by several agents such as Nnitrosobis(2-oxopropyl)amine, N-methylnitrosourea, and irradiation (5, 7, 8).In this report, we describe 1 case of a spontaneous seminal vesicle adenocarcinoma in an aged F344 rat maintained as a control for a carcinogenicity study. This is the first such case reported for F344 rats.The tumor was found in a 109-wk-old male F344/' DuCrj strain rat (Charles River Japan, Kanagawa), one of 150 controls for each sex in a 2-yr carcinogenicity study. The rat was housed in a plastic cage with woodchip bedding in an air-conditioned barrier-system animal FIG. 1 .-Seminal vesicle adenocarcinoma filling the seminal vesicle lumen of a rat. Note the continuation from the normal glandular epithelium of the seminal vesicle to the tumor (arrows) and the compression of the coagulating ...

We have developed a new method to evaluate the transfer of macromolecular drugs to intrapulmonary lymph nodes in rats after intrapulmonary administration. By using this method, we observed that the transfer of fluorescein isothiocyanate dextrans (FDs) to the intrapulmonary lymph nodes was markedly higher than that to iliac lymph node, a non-intrapulmonary lymph node. The transfer of FDs to the intrapulmonary lymph nodes increased with increasing their molecular weights and the threshold for a high lymph node-to-plasma level ratio (CLN/CP) was between 10 and 20 kDa. The effects of absorption enhancers on the transfer of FDs to intrapulmonary lymph nodes were also examined in rats. Absorption enhancers used in this study were EDTA, sodium glycocholate (Na-GC), mixed micelles (MM), N-lauryl-beta-D-maltopyranoside (LM), sodium caprate (Na-Cap). The transfer of FD-20, FD-40 and FD-70 to intrapulmonary lymph nodes after intrapulmonary administration increased in the presence of LM. In particular, the lymphatic transfer of FD-40 was remarkably increased in the presence of LM. Similarly, Na-GC and MM improved the transfer of FD-40 to intrapulmonary lymph nodes. These results suggest that absorption enhancers such as LM, Na-GC and MM are effective for improving the transfer of macromolecular drugs to intrapulmonary lymph nodes.

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