Drug-induced anomalous contraction of gastrointestinal tract of mice with impaired c-kit function

Drug-induced contraction of gastrointestinal tracts seems to depend upon the extent of their rhythmic contraction that is driven by the activity of gastrointestinal pacemaker cells. In BALB/c mice chronically administrated with a neutralizing anti-c-Kit monoclonal antibody (ACK2), rhythmic contraction of the gastrointestinal tract was impaired and contractile responses to drugs, including acetylcholine, prostaglandin F(2alpha), and bradykinin, were anomalously augmented. Histochemical analysis of the c-kit-positive cells in the gastrointestinal tract revealed the decreased number of c-kit-positive cells in the ACK2-treated animals, which lead to the impaired rhythmic contraction. Since the intestinal c-kit-positive cells in primary culture developed Ca(2+)-dependent rhythmic Cl(-) current, the rhythmic current is supposed to be an origin of gastrointestinal pacemakers. The extent of anomaly in drug-induced contraction correlated with the extent of impairment in rhythmic contraction. The drug-induced anomalous contraction in the preparation from ACK2-treated animals, which is accompanied by the impaired rhythmic contraction, was mimicked when the gastrointestinal segments from control animals were superfused with a low temperature organ bath solution at 25 degrees C. These results suggest that rhythmic discharge of excitation of smooth muscle cells, which is triggered by rhythmic excitatory input from c-kit cells, regulates the extent of drug-induced contraction.     

Transforming growth factor-beta1 induced hepatocyte apoptosis--a possible mechanism for growth of colorectal liver metastasis

The mechanisms of colonization and growth of metastatic liver tumors from colorectal cancers remain obscure. Forty-three resected colorectal metastatic liver tumors with surrounding livers were evaluated for apoptotic index (AI), proliferation index (PI), and immunohistochemical expressions of TGF-beta1. TGF-beta receptor II, Fas, and Fas-ligand. All the parameters were significantly higher in the peri-tumoral livers than in the tumors with the exception of PI, which was significantly high in tumors. Enhanced TGF-beta1 expression was noticed at the interface between the metastatic tumor and the adjacent liver parenchyma. The AIs of hepatocytes in the TGF-beta1-positive areas (8.7 +/- 7.5%, n = 43) were significantly higher when compared with those in the TGF-beta1-negative areas (2.4 +/- 4.5%, n = 42) (p < 0.001). However, the same kind of correlation could not be found in metastatic tumors. The enhanced expression of TGF-beta1 and hepatocyte apoptosis in the peri-tumoral liver parenchyma may suggest that TGF-beta1 plays a substantial role in the development of colorectal liver metastasis.     

Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer

OBJECTIVE: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer. METHODS: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m(2) and escalated in 10 mg/m(2) increments. RESULTS: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m(2)) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m(2). Nine of 21 (42.9%) patients demonstrated a therapeutic response. CONCLUSION: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m(2) of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.     

A small outbreak of pulmonary tuberculosis in non-close contact patrons of a bar

Four habitual drinking and smoking patients with pulmonary tuberculosis who were thought to have had no contact with one another were admitted to our hospital. During admission, we found that they were regular visitors of the same bar. To investigate the possibility of outbreak, we analyzed the tuberculosis isolates from them by restriction fragment length polymorphism. Such analysis showed identical chromosomal DNA restriction patterns of these 4 culture isolates. We concluded that these patients were considered to represent a mini-outbreak of pulmonary tuberculosis, although there was little, if any, contact among them while in or out of the bar.     

Computed tomography lymphography with intrapulmonary injection of iopamidol for sentinel lymph node localization

PURPOSE: Experimental and clinical evaluation of the potential utility of indirect computed tomographic lymphography (CT-LG) with intrapulmonary injection of iopamidol for preoperative localization of sentinel lymph node station in non-small cell lung cancer. METHODS: CT-LG with intrapulmonary injection of 0.5 mL of undiluted iopamidol was performed in 10 dogs using a multidetector-row CT unit, followed by postmortem examination of enhanced lymph nodes in 5 of these dogs. The CT-LG with peritumoral injection of 1 mL of the contrast agent was also performed in 9 patients with non-small cell lung cancer without lymphadenopathy. At surgery, enhanced lymph nodes were resected under CT-LG guide, followed by standard lymph node dissection with macroscopic and histologic examination. A significant enhancement of lymph nodes was determined when CT attenuation value was increased with 30 Hounsfield units (HU) compared with precontrast images. RESULTS: CT-LG visualized a total of 15 enhanced lymph nodes (on average, 1.5 nodes per animal) within 2 minutes after contrast injection in the 10 dogs, with average size of 6.7+/- 1.9 mm and average maximum CT attenuation of 149 +/- 41 HU. All the 8 enhanced nodes in 5 dogs were found in the appropriate anatomic locations in postmortem examinations. Without noticeable complications, CT-LG visualized 30 ipsilateral intrathoracic lymph nodes including 19 hilar/pulmonary and 11 mediastinal nodes in the 9 patients (on average, 2.2 hilar/pulmonary and 1.1 mediastinal nodes per patient) within 2 minutes after contrast injection, with average size of 4.7+/- 0.4 mm and average maximum CT attenuation of 134 +/- 52 HU. At surgery, all these enhanced nodes could be accurately found and resected under CT-LG guidance. Metastasis was not evident in either of these enhanced lymph nodes or the remaining distant nodes in all patients. CONCLUSION: Quick and accurate localization of sentinel lymph node station on detailed underlying lung anatomy by using indirect CT-LG may be of value to guide selective lymph node dissection for minimally invasive surgery in non-small cell lung cancer.     

Examination of occupational exposure to medical staff (primarily nurses) during 131I medical treatments

Recently, a new amendment to protect against radiation damage to humans has been enacted based on a 1990 recommendation by the ICRP. Consequently, the dose limits of occupational exposure to medical staff were cut down sharply compared with conventional readjustments. This amended bill, however, may be triggering a reduction in the number of applicants, which hope to engage in radiotherapy. This being the case, we measured the dose levels of the occupational exposure to medical staff (doctor's group, nuclear medicine technologist's group, nurse's group and pharmacist's group) from 1999 to 2002. Moreover, we investigated what the main factor is in nurse's occupational exposure to 131I. The highest doses of occupational exposure were 3.640 mSv to doctors, 7.060 mSv to nuclear medicine technologists, 1.486 mSv to nurses and 0.552 mSv to pharmacists. According to our results, it was clear that the highest doses in each group were far below the legally mandated upper limits of exposure doses. Although we investigated the correlations between the factors of nurse's occupational exposure to 131I with the number of inpatients, the amount of 131I and the number of servicing times for patients, there were no correlations found. Furthermore, to analyzing the factors in detail, it became clear that the main factor in the nurse's occupational exposure was due to the existence of patients who needed many more servicing times for their care than ordinary patients.     

Deactivation by benzodiazepine of the basal forebrain and amygdala in normal humans during sleep: a placebo-controlled [15O]H2O PET study

OBJECTIVE: The authors' goal was to identify differences in regional brain activity between physiological and benzodiazepine-induced sleep to clarify the brain structures involved in the drug's hypnotic effect. METHOD: Using positron emission tomography, they compared regional cerebral blood flow during non-REM sleep in nine volunteers treated with placebo or triazolam, a short-acting benzodiazepine, in a double-blind, crossover design. RESULTS: Blood flow in the basal forebrain and amygdaloid complexes was lower during non-REM sleep when subjects were given triazolam than when they were given placebo. CONCLUSIONS: The hypnotic effect of the benzodiazepines may be mediated mainly by deactivation of the forebrain control system for wakefulness and also by the anxiolytic effect induced by deactivation of the emotional center.     

Advances in the development of a reliable assay for the measurement of stool decay-accelerating factor in the detection of colorectal cancer

We have previously shown that stool concentrations of decay-accelerating factor (DAF; CD55), a membrane-bound complement-regulatory protein, are significantly elevated in patients with colorectal cancer and that the measurement of stool DAF may be a valuable test for the detection of colorectal cancer. Accordingly, we are working to develop a clinically useful immunoassay for fecal DAF. A requirement for such assay is a plentiful and reliable supply of anti-DAF antibodies. We developed a sandwich enzyme-linked immunosorbent assay (ELISA) for DAF in stool specimens, using two monoclonal anti-DAF antibodies recognizing different epitopes on the DAF molecule. When we first used a biotin-labeled antibody and enzyme-linked streptavidin method, we often observed stool interference, probably due to the presence of a substance(s) with biotin activity which non-specifically bound to the Fc portion of IgG of the first anti-DAF antibody on the ELISA wells. By the use of inorganic salts in the sample-dilution buffer and HRP-labeled anti-DAF as second antibody, we circumvented the stool interference and established that the new ELISA system could reliably measure DAF at low concentrations in stool specimens. Because the new assay system uses only monoclonal antibodies, we can now consistently supply ample amounts of antibodies for routine measurement of stool DAF.