Prognostication of small-sized primary pulmonary adenocarcinomas by histopathological and karyometric analysis

To reveal useful prognostic factors in cases of small-sized pulmonary adenocarcinoma, we conducted a histological and karyometric analysis of 116 small-sized pulmonary adenocarcinomas measuring less than 2 cm in maximum diameter and four specimens of atypical adenomatous hyperplasia (AAH). The small-sized pulmonary adenocarcinomas were classified by using criteria described previously [Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Lung Cancer 1995:75;2844-52]. There were 99 tumors of replacement-type adenocarcinoma, comprising 11 type A, localized bronchioloalveolar adenocarcinoma (LBAC); 6 type B, LBAC with alveolar collapse; and 82 type C, LBAC with foci of fibroblastic proliferation. The 17 remaining tumors were non-replacement-type adenocarcinomas. Among the potential prognostic factors examined, histological subtype was the most closely correlated with 5-year relapse-free survival rate. Furthermore, in patients with type C adenocarcinomas, a small fibroblastic proliferation (F) to fibrosis area (f) ratio (F-f ratio) (<10%) of the tumor and a small maximum nuclear diameter (Max ND; <13.50 microm) of tumor cells were closely associated with an excellent prognosis. Histological subtypes of type A and B adenocarcinomas, a small F-f ratio, and a small Max ND of type C adenocarcinomas were closely correlated with an excellent prognosis in small-sized adenocarcinoma.     

Role of the mucous/glycocalyx layers in insulin permeation across the rat ileal membrane

The contribution of mucous/glycocalyx layers, as a diffusional or enzymatic barrier, to the absorption of insulin was investigated in situ and in vitro studies using rats. To remove the mucous/glycocalyx layers, ileal segments were exposed to a hyaluronidase solution in situ. The removal of the layers was confirmed by transmission electron microscopy, and the safety of the hyaluronidase pretreatment was established based on light microscopy, a constant mucosal membrane electrical resistance and the absence of lactate dehydrogenase leakage. In the in situ loop absorption experiment, hyaluronidase pretreatment significantly increased the plasma insulin level accompanied by an obvious hypoglycemic response. In the in vitro transport experiment, the apparent permeability coefficient of insulin was significantly increased by the hyaluronidase pretreatment, whereas that of 4.4 kDa fluorescein isothiocyanate-labeled dextran and of antipyrine, respective markers for passive para- and transcellular permeation, was unaffected. In the insulin degradation experiment in vitro, a significant amount of insulin was degraded in the compartment removed by hyaluronidase pretreatment. Thus, the mucous/glycocalyx layers functioned in insulin absorption as an enzymatic barrier and insignificantly affected diffusive absorption. In addition, co-administration of aprotinin, a protease inhibitor, further increased insulin absorption from ileum pretreated with hyaluronidase, implying the existence of another enzymatic barrier that influences insulin mucosal absorption.     

Effects of isoflurane on gastrointestinal motility after brief exposure in rats

In pre-clinical studies, investigation of oral formulations often necessitates the use of general anesthesia to facilitate deposition of material directly into the stomach. Since the effectiveness of intestinal drug absorption is dependent on gastric emptying (GE) and intestinal motility, drugs that influence either will also influence drug absorption. This study investigated gastrointestinal motility in rats after brief exposure to Isoflurane (ISO) general anesthesia for orogastric gavage. The use of metochlopramide was also evaluated. Twenty-five fasted rats were induced with brief ISO anesthesia (<6 min). Rats were gavaged a gelatin capsule (8mm (L) x 2.0mm (o.d.)) containing 9 mg of activated charcoal powder (gastrointestinal marker) and rapidly recovered. Gavage was performed using a 15 cm feeding device with a soft hollow tip to hold the capsule. Study included three groups (60 and 120 min recovery, metochlopramide pre-treatment with 60 min recovery) and control. Animals were sacrificed for exposure and examination of the gastrointestinal tract following the allocated recovery period. Gastrointestinal transit of charcoal was reduced approximately 50% 120 min after brief ISO anesthesia. Metochlopramide pre-treatment did not increase gastrointestinal propulsion despite increased GE. These data warrant consideration in intestinal drug absorption studies where ISO is the anesthetic of choice.     

Clinical profile and prognosis of hospitalized patients with congestive heart failure in Isehara, Japan

Since the clinical profile and prognosis of heart failure depending on time of the study performed, regional characteristics of background population and different race, we attempted to evaluate the prognosis of symptoms and life expectancy of Japanese patients with heart failure. We evaluated the clinical profiles and prognoses of 1,015 consecutive patients with congestive heart failure (CHF) for whom hospitalization was required. A total of 1,015 consecutive CHF patients (584 males and 431 females) were enrolled in this study, however the total number of events investigated was 1,409. Of these patients, survival was confirmed in 413 patients, death was confirmed in 299 patients, and the prognoses of 303 patients remained unknown due to transfer to other hospitals or for some other reasons. The mean age on admission was 68.4 +/- 14.9 years. In both males and females, the peak age at the onset of CHF was in the seventies, and for patients in their eighties, the number of female patients with CHF was larger than that of male patients. Major underlying heart diseases consisted of ischemic heart disease (34%), valvular heart disease (22%), dilated cardiomyopathy (11%), and hypertension (10%). Most CHF patients who had dilated cardiomyopathy as an underlying disease were hospitalized several times, and 45% of them were hospitalized 3 times or more. The life expectancy of patients with CHF caused by ischemic heart disease was the poorest, and their 5-year and 10-year survival rates were 55% and 38%, respectively. Similarly, 5-year and 10-year survival rates of patients with CHF caused by valvular heart disease, hypertension, and dilated cardiomyopathy were 62% and 44%, 58% and 53%, and 70% and 65%, respectively. In 299 deceased patients, the mean age at death was 72.2 +/- 13.9 years. In all these deceased patients, direct causes of death were sudden death (16.1%), CHF (42.2%), others (31.4%), and unknown (10.4%). The frequency of sudden death was highest (25%) in patients with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by valvular heart disease (18%) and those with CHF caused by ischemic heart disease (17.5%). In addition, the frequency of death from CHF was highest (60%) in those with CHF caused by dilated cardiomyopathy, followed by those with CHF caused by ischemic heart disease (49.2%).     

Lansoprazole binding to the neutrophils in dextran sulfate sodium-induced rat colitis

To clarify the effector sites of lansoprazole in the colonic mucosa during the formation of colitis, dextran sulfate sodium-induced colitis was induced by the oral administration of 3% aqueous solution for 3 and 7 days. The effector sites of [³H]lansoprazole were examined by the intra-aortic infusion of the radiolabelled compound and the autoradiographic tracing of water-soluble compounds. As a result, the [³H]lansoprazole binding in the control rat colon was negligible, while in dextran sulfate sodium-treated rats specific binding sites of [³H]lansoprazole were recognized in the cytoplasm of the mesenchymal cells, and most of them coincided with polymorphonuclear leucocytes and macrophages.     

Therapeutic angiogenesis for critical limb ischemia: design of the hepatocyte growth factor therapeutic angiogenesis clinical trial

The objective of the HGF-STAT clinical trial is to determine whether perfusion can be improved by gene transfer with a plasmid DNA containing hepatocyte growth factor (HGF) in the affected limb of patients with unreconstructable critical limb ischemia (CLI). CLI results in a high rate of limb loss and impaired quality of life. The current therapeutic strategies, including bypass surgery and percutaneous interventions, are only successful in treating a subset of patients. Therapeutic angiogenesis is an investigational method that seeks to favorably impact tissue perfusion in CLI. HGF-STAT is a double-blind, parallel-group, placebo-controlled, dose-response study in 100 patients with unreconstructable CLI. Eligible subjects will be randomized 1:1:1:1 to receive saline placebo or one of three dose/regimens of HGF plasmid DNA. The selection of outcome measures, including the primary endpoint, and changes in transcutaneous oxygen pressure (TcPO2) from baseline to 3 months will be discussed. In conclusion, this study will help to determine whether therapeutic angiogenesis with HGF is a viable option in the treatment of patients with CLI.