Direct synaptic projections to the myenteric ganglion of the rat subdiaphragmatic esophagus from the dorsal motor nucleus of the vagus

We have examined the ultrastructure of the myenteric ganglion of the subdiaphragmatic esophagus and determined whether the ganglion neurons receive direct projections from the dorsal motor nucleus of the vagus (DMV) using wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) as an anterograde tracer. The neurons (22.2 microm x 13.3 microm) of myenteric ganglion in the esophagus contained dark cytoplasm having many free ribosomes, mitochondria, and an oval nucleus, and received only a few axon terminals contacting somata. All axon terminals formed asymmetric synaptic contacts with dendrites or somata. Approximately 85% of the axon terminals contacting dendrites and about 50% of the axon terminals contacting somata contained pleomorphic vesicles, while the rest contained round synaptic vesicles. When WGA-HRP was injected into the DMV, anterogradely labeled fibers and terminals were found in the myenteric ganglia. The WGA-HRP labeled terminals were large (1.97 microm) and contained round clear vesicles and small granular vesicles. These labeled terminals contacted exclusively the small dendrites, but not the somata. These results suggest that the DMV neurons project directly to the myenteric ganglion neurons and regulate the esophageal muscles via the ganglion neurons.     

Ligand-dependent interaction between estrogen receptor alpha and adenomatous polyposis coli

Numerous independent clinical and experimental studies indicate that estrogens confer a protective effect against development of intestinal tumors, however the molecular mechanisms involved remain unclear. Physiological effects of estrogens are predominantly mediated by the action of nuclear estrogen receptors (ERs). A multifunctional protein adenomatous polyposis coli (APC) is a tumor suppressor and thought to act as a gatekeeper in colon tumorigenesis, as loss of function APC mutations trigger the development of colorectal cancer. Here we report that APC physically associates with ERa in the ligand-dependent manner. We have shown in the endogenous setting that the ligand-activated ERa recruits APC to the promoters in ER target genes and that increased levels of ER-dependent recruitment of APC enhances the ER transactivation through stimulation of histone acetylation. Found in majority of human colon tumors APC truncation mutants lost the ability to interact with ER. Thus, here we present the first evidence of a functional interaction between APC and ER that may be accounted for a tumor protective action of estrogens.     

Cytokines modulate cilomilast response in lung fibroblasts

Fibroblasts, as a major source of extracellular interstitial connective tissue matrix, play an important role in wound healing and the development of fibrosis. The phosphodiesterase (PDE) 4 inhibitor cilomilast inhibits fibroblast chemotaxis and fibroblast-mediated gel contraction. Using the Boyden blindwell chamber chemotaxis assay and the type I collagen gel contraction model, this study investigated whether specific cytokines modulate cilomilast's inhibitory effect through regulation of endogenous PGE(2) production. Human recombinant IL-1beta stimulated PGE(2) production and shifted the cilomilast concentration-dependence curve to the left in both assay systems, indicating increased sensitivity to cilomilast. In contrast, human recombinant IL-4 inhibited PGE(2) production and shifted the cilomilast concentration-dependence curve to the right in both systems. In summary, the inhibitory effect of cilomilast on fibroblast migration and collagen gel contraction is modulated by IL-1beta and IL-4 through regulation of PGE(2) production.     

Clinical classification of congenital extrahepatic portosystemic shunts

Aim: Congenital extrahepatic portosystemic shunt (CEPS) is a rare anomaly in which the enteric blood bypasses the liver and drains into the systemic veins through various venous shunts. Patients with CEPS often have liver tumors and complications such as cardiac or other anomalies, but portosystemic encephalopathy and gastrointestinal bleeding occur only occasionally. The clinical problems differ for each individual with CEPS, and establishing a prognosis can be very difficult. Methods: We reviewed the clinical features of 136 reported cases of CEPS and classified these cases according to their portosystemic shunts. Results: We classified portal blood flow directly into the inferior vena cava (IVC) as type A (88 cases), portal blood flow into the renal vein as type B (36 cases), and portal blood flow into the iliac vein via an inferior mesenteric vein as type C (12 cases). Type A patients were complicated with cardiac anomalies at a higher rate than other types. Type C patients had lower prevalences of cardiac anomalies and portosystemic encephalopathy than the other types, but the prevalence of gastrointestinal bleeding was significantly higher (P < 0.0001). The prognosis of CEPS has improved, and only six deaths have been previously reported, all of which occurred in type A patients. Conclusions: We reviewed the previously reported cases of CEPS. Classification according to the portosystemic shunt system might be useful for investigating the clinical features of CEPS.     

A Randomized Cross-over Study of High-dose Metoclopramide plus Dexamethasone versus Granisetron plus Dexamethasone in Patients Receiving Chemotherapy with High-dose Cisplatin

We carried out a randomized, single-blind, cross-over trial to compare the antiemetic effect, for both acute and delayed emesis, of granisetron plus dexamethasone (GRN+Dx) with that of high-dose metoclopramide plus dexamethasone (HDMP + Dx). Fifty-four patients with primary or metastatic lung cancer, given single-dose cisplatin (> 80 mg/m²) chemotherapy more than twice, were enrolled in this study. They were treated with both HDMP+Dx and GRN+Dx in two consecutive chemotherapy courses. On day 1, patients experienced a mean of 2.5 (SD=4.3) and 0,1 (SD = 0.4) episodes of vomiting in the HDMP+Dx and the GRN + Dx groups, respectively ( P =0.0008). Complete response rate on day 1 was 45 and 90% in the HDMP+Dx and the GRN+Dx groups, respectively ( P = 0.0001). Patients treated with GRN+Dx had a tendency to suffer more episodes of vomiting than the HDMP+Dx group on days 2–5, but it was not statistically significant. Twenty-four patients (57%) preferred the GRN+Dx treatment and 14 patients (33%), HDMP + Dx. In the HDMP + Dx group, nine patients (21%) had an extrapyramidal reaction, and 5 patients (12%) had constipation that lasted for at least two days. In contrast, no patients had extrapyramidal reactions, and IS patients (43%) had constipation in the GRN+Dx group ( P < 0.01). GRN+Dx was more effective than HDMP+Dx only in preventing the acute emesis induced by cisplatin. An effective treatment for delayed emesis is still needed.     

CPT-11: Population Pharmacokinetic Model and Estimation of Pharmacokinetics Using the Bayesian Method in Patients with Lung Cancer

In this study, we aimed to develop a population pharmacokinetic model for CPT-11 and to use the Bayesian method to estimate CPT-11 pharmacokinetic parameters in each of 43 patients who received combined therapy consisting of CPT-11 and etoposide. The group was divided into first and second data sets of 30 and 13 patients, respectively. We developed a population pharmacokinetic model of CPT-11 based on the first data set. The individual pharmacokinetic parameters [area under the concentration curve (AUC) and clearance (CD] were subsequently estimated by using the Bayesian method on the second data set. Plasma CPT-11 concentrations were measured by high-performance liquid chromatography, and compartmental pharmacokinetic models were fitted by the Bayesian method. The population pharmacokinetic model was developed by using the nonlinear mixed effect model. We selected the volume of the central compartment (Vc), CL, and distribution rate constants (K12, K21) as population pharmacokinetic parameters. The population mean values (CV%) of Vc, CL, K12, and K21 were, respectively, 31.8 (15.7%) liter/m²,14.1 (27.8%) liter/h/m²,1.1 (8.4%)/h, and 0.41 (30.3%)/h. Residual intraindivirtual variability was 22.9%. The optimal sampling regime for estimation of the AUC and CL in using the Bayesian method was the two time points of 1 and 8 h post infusion. The mean predictive error, the mean absolute predictive error, and the root mean squared error were -3.3, 9.4, 3.2% (AUC) and 6.3, 10.0, 3.5% (CL), respectively. We concluded that the AUC and CL of CPT-11 could be estimated from plasma concentrations at two times by using the Bayesian method.     

Intensive Chemotherapy with Cisplatin, Doxorubicin, Cyclophosphamide, Etoposide and Granulocyte Colony-stimulating Factor for Advanced Thymona or Thymic Cancer: Preliminary Results

A study was conducted to evaluate the impact of cisplatin, doxorubicin,cyclophosphamide and etoposide (PACE) with granulocyte colony-stimulatingfactor (G-CSF) on advanced thymoma or thymic cancer. BetweenAugust 1989 and December 1994, 14 patients with invasive, metastaticor recurrent thymoma or thymic cancer were treated with cisplatin(80 mg/m², on day 1), doxorubicin (45 mg/m², on day 1), cyclophosphamide(800 mg/m², on day 1) and etoposide (80 mg/m², on day 1–3)with G-CSF (90 mg/m², on day 5–18) at the National CancerCenter Hospital, Tokyo. Courses were repeated every 3 or 4 weeksfor a maximum of 4 cycles. Twelve patients were treated with2 or more courses of PACE. Two patients were treated with onlyone course, one refused and another required emergency thoracicradiotherapy after one course of PACE. Six patients had partialresponses (3 thymomas and 3 thymic cancers) but there were nocomplete remissions (response rates, 42.9%; 95% confidence interval,17.7% to 71.1%). Moderate hematological toxicities were observed:grade 3 or 4 leukopenia, neutropenia, anemia and thrombocytopeniain 10, 13, 8 and 6 patients, respectively. Six patients developedinfections that required antibiotics. Surgical resection orthoracic radiotherapy after PACE treatment was performed in2 and 7 patients, respectively. The overall median survivaltime was 14.7 months (range, 5.9 to 59.7 months). For 9 patientswho had received no prior treatment before chemotherapy, themedian survival time was 8.9 months, and one patient survivedfor 4 years and is still alive. In conclusion, PACE with G-CSFfrequently produces objective remissions in patients with advancedthymoma or thymic cancer. A large-scale intergroup study isnecessary to determine the impact of this regimen on advancedthymoma and thymic cancer.