Role of disturbance of ependymal ciliary movement in development of hydrocephalus in rats

We have developed a new in vitro method of quantitatively analyzing ciliary movement in the ependymal wall of the aqueduct in rats. An axial slice of the midbrain containing ependymal wall was placed in a culture dish filled with a culture medium containing latex beads 1 m in diameter at a concentration of 10⁷ beads/ml. The movement of the beads caused by flow of culture medium generated by the to-and-fro ciliary movement was recorded by a high speed video system attached to an inverted phase-contrast microscope. Ciliary movement was expressed by the speed of the latex beads (m/s). Aqueductal ciliary movement in congenitally hydrocephalic HTX rats, congenitally hydrocephalic WIC-Hyd rats, and other normal rats was evaluated. The results suggest that in congenitally hydrocephalic WIC-Hyd rats the degree of hydrocephalus related strongly to the degree of ciliary dyskinesia, but in congenitally hydrocephalic HTX rats it did not. Considering this discrepancy, we attempted to see whether or not hydrocephalus was caused by artificial disturbance of ependymal ciliary movement in vivo. We found that continuous infusion of metavana date, an inhibitor of ciliary movement, into the III ventricle of normal Sprague-Dawley rats for 7 days induced dilatation of the ventricular system. Although the question whether or not disturbance of aqueductal ependymal ciliary movement is related to the development of human congenital hydrocephalus is debatable, the results of the present in vitro and in vivo experimental investigations appear to suggest that the disturbance of ciliary movement in the aqueduct could at least be one of the factors contributing to the inducement of hydrocephalus in experimental conditions.     

Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations

According to linear pharmacokinetics, the time course of plasma concentration of a drug, C_p,is expressed by a sum of exponential functions, C_p= _i=1 ⁿ a_i .This article describes a statistical technique to estimate the number of exponential terms, n,for the time course of drug by the application of Akaike's information criterion (AIC). Plasma concentrations of ethoxybenzamide, sulfisoxazole, bishydroxycoumarin, and diazepam measured following bolus intravenous injection were used as clinical examples for this method. Selection of models is compared between the AIC method and an Ftest method at significance levels of 5% and 1%.     

Seven-year survivor with malignant melanoma of the anus without radical surgery

We report a case of a long-term survivor with malignant melanoma of the anus who did not undergo radical surgery. A 71-year-old woman who presented with anal bleeding and anal tumor underwent an excisional biopsy in September 1985. The biopsy specimen was a lobulated, polypoid, pigmented mass 2 cm in diameter, that had been located on the anterior wall of the anus. A satellite nodule 7 mm in diameter was found on the left wall of the anus at the level of the dentate line. Both tumors were histologically diagnosed as malignant melanoma. The primary tumor was 6 mm thick. Melanoma cells were present microscopically at the cut end of the rectum. Because of her history of ischemic heart disease, the patient rejected our recommendation that she undergo radical surgery, and received 10 courses of carboplatin 20 mg intramuscularly and OK-432 10 K.E. (Klinische Einheit) intradermally every week. A single, pigmented metastatic inguinal lymph node developed and was excised in June 1987. A recurrent tumor was detected in the rectum in October 1992, so again we recommended radical surgery. The patient rejected radical surgery again, and received 12 courses of carboplatin 10 mg intramuscularly every 2 weeks. She died of disease at home in July 1993 after surviving for 7 years and 10 months. An autopsy was not performed. This case shows that local excision of the primary lesion may be appropriate to preserve the quality of life of patients with early-stage malignant melanoma of the anus.     

A Proposal for a New Histological Classification Scheme for Predicting Short-term Tumor Recurrence and Death in Patients with Invasive Ductal Carcinoma of the Breast

Tumor recurrence rate (TRR) and mortality rate (MR) of invasive ductal carcinoma (IDC) of the breast in short-term follow-up are relatively low. Nevertheless, it is extremely important to identify patients at risk of early recurrence or death after surgery. The aim of this study was to establish a new histological prognostic classification scheme for IDC in order accurately to predict the short-term outcome. The following histological parameters were analyzed in 201 IDCs: 1) tumor size, 2) structural atypia, 3) nuclear atypia, 4) number of mitotic figures, 5) fibrotic focus (FF), 6) vascular invasion, 7) tumor necrosis, 8) skin invasion, 9) muscle invasion, 10) nodal status and 11) extramammary fat invasion. Multivariate analysis showed that nuclear atypia, presence of FF, and the invasive length of fat invasion (ILFI) were the most important histological parameters correlated with TRR or MR of IDCs. Accordingly, a new histological classification based on nuclear atypia, FF and ILFI (Nucleus-Fibrotic focus-Fat invasion, NFF) was devised. Comparative studies were performed with the following existing prognostic classifications: 1) histological grade, 2) modified Scarff-Bloom-Richardson histological grade, 3) prognostic index and 4) pathological TNM (pTNM) stage classifications. Patient grouping defined by NFF classification significantly correlated with tumor recurrence or death of IDCs in all cases, cases at stages I and II, those without lymph node metastasis and those who were estrogen receptor (ER)-positive after adjustment for the other four classifications, using multivariate analysis. NFF classification appeared superior to existing prognostic classifications for the accurate prediction of the short-term outcome for patients with IDCs in low risk groups.     

Radioresponse of Thymomas Verified with Histologic Response

Patterns of radiologic response of 10 thymomas treated by preoperative radiotherapy (RT) (18-20 Gy/2 weeks) were determined in conjunction with histologic response. Changes in tumor volume were evaluated with CT scans obtained 5 to 36 days before and 14 to 24 days after the initiation of RT and before surgery. The extent of tumor volume reduction (TR) varied widely (40-78%), while the mean daily volume decrement expressed as a percentage of the pre-RT tumor volume correlated significantly with the pre-RT tumor volume. Histologically, the tumors, all of which were resected 17 to 33 days after RT initiation, generally consisted of predominant fibrous tissues, rare necrotic foci, and few epithelial cells. The TR did not correlate with pre-RT tumor volume, observation period, histologic subtype, or quantity of remaining epithelial cells. The TR of thymomas does not predict RT impact on tumor cells but does reflect the quantity of inherent tumor stroma.     

Mutation Analysis of the WT1 Gene in Myelodysplastic Syndromes

The WT1 tumor suppressor gene was examined for mutations in a panel of 44 patients with myelo-dysplastic syndromes (MDS) including acute myelogenous leukemias (AML) secondary to MDS, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis and sequencing analysis. A WT1 mutation was detected in one out of 17 cases of AML secondary to MDS. This mutation exists upstream of the zinc finger region and is predicted to produce a truncated WT1 protein lacking the zinc finger region. No mutations were detected in 27 MDS patients who had not progressed to AML. This is the first report of analysis for WT1 mutations in a large number of MDS patients, suggesting that WT1 mutations are uncommon in MDS. Abnormalities in this gene may, however, contribute to a small proportion of cases showing progression from MDS into AML.     

Heterogeneity of Proliferative Activity in Nodule-in-Nodule Lesions of Small Hepatocellular Carcinoma

Surgically resected small hepatocellular carcinomas showing "nodule-in-nodule'formation were analyzed in terms of cell proliferative activity. The analysis was achieved by successful immunohistochemical demonstration of proliferating cell nuclear antigen in formalin-fixed paraffin-embedded tissue sections. Eight nodules (up to 3 cm in diameter) examined were either atypical adenomatous hyperplasia or hepatocellular carcinoma of low histologic grade, containing a discrete inner nodular area composed of obvious hepatocellular carcinoma of higher histologic grade. In all cases, the proliferating cell nuclear antigen labeling index of the latter area was much higher than that of the former, which in turn was slightly higher than that of the non-cancerous liver of the patient in 6 cases. The data presented here provide supporting evidence that the successive emergence and expansion of a more rapidly proliferating subclone within a nodule result in the stepwise progression of malignancy of human hepatocellular carcinoma.     

High REE in Sumo wrestlers attributed to large organ-tissue mass

PURPOSE: It is unknown whether high resting energy expenditure (REE) in athletes is attributable to changes in organ-tissue mass and/or metabolic rate. The purpose of this study was to examine the contribution of organ-tissue mass of fat-free mass (FFM) components to REE for Sumo wrestlers who have large FFM and REE. We investigated the relationship between the REE measured by indirect calorimetry and the REE calculated from organ-tissue mass using a previously published approach. METHODS: Ten Sumo wrestlers and 11 male untrained college students (controls) were recruited to participate in this study. FFM was estimated by two-component densitometry. Contiguous magnetic resonance imaging (MRI) images with a 1-cm slice thickness were obtained from the top of head to the ankle joints, and the cross-sectional area and volume were determined for skeletal muscle (SM), liver, kidney, and brain. The volume of adipose tissue, heart, and residual was calculated from each equation. The volume units were converted into mass by an assumed constant density. The measured REE was determined by indirect calorimetry. The calculated REE was estimated as the sum of individual organ-tissue masses (seven body compartments) multiplied by their metabolic rate constants. RESULTS: The measured REE for Sumo wrestlers (2286 kcal x d(-1)) was higher (P<0.01) than for controls (1545 kcal x d(-1)). Sumo wrestlers had a greater amount of FFM and FFM components (e.g., SM, liver, and kidney), except for brain. The ratio of measured REE to FFM and the measured REE adjusted by FFM were similar between the two groups. The measured REE values for Sumo wrestlers were not significantly different from the calculated REE values. CONCLUSIONS: The high REE for Sumo wrestlers can be attributed not to an elevation of the organ-tissue metabolic rate, but to a larger absolute amount of low and high metabolically active tissue including SM, liver, and kidney.     

Increased insulin sensitivity and hypoinsulinemia in APS knockout mice

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.