Neuropathology of progressive multifocal leukoencephalopathy]

Progressive multifocal leukoencephalopathy (PML) is caused by opportunistic infection of JC virus which belongs to Papovavirus, and presents with progressive demyelinating lesion in the central nervous system. PML was originally reported as a rare complication of hematologic disorders, but later greatly increased in number in association with acquired immunodeficeincy syndrome (AIDS). Original neuropathological features of PML consist of demyelination lacking inflammatory reaction or necrosis, accompanying oligodendroglial nuclear inclusions in the periphery of demyelination. The lesion is preferentially localized to gray-white junction of the cerebral hemisphere and manifests as characteristic demyelinating lesion, called scallopping. Detection of JC virus is essential for the final diagnosis of PML and is achieved via immunohistochemical detection of JC virus with antibodies raised against their components, ultrastructural demonstration of virions characteristic of JC virus, or detection with in-situ hybridization of the genome of JC virus. JC virus can replicate only in oligodendroglial cells, but astrocytes are frequently infected by the virus. The resume of immunological function through therapeutic intervention develops new pathology in PML, exhibiting severe inflammatory reaction with edema and necrosis. This new pathological feature is called immune reconstruction syndrome and clinically presents with severe progression in symptoms of the central nervous system. Nevertheless, treatment of PML is directed for the elimination of the viruses by host immune system. The modification of the above immune reconstruction syndrome is essential for successful outcome of such therapeutic trial.     

Remote Connection to the Kyushu University Medical Center LAN Using Digital and Analog Telephone Lines

SOHO (Small Office/Home Office) has recently become popular, as it makes working at home possible. Computers or Local Area Networks(LAN) connected to the office network from home are necessary for the implementation of this concept. Kyushu University has begun a service connecting home computers to the campus LAN for researchers, staff and students of the Faculty of Medicine. We have two different telephone connection methods. One connects the campus LAN and the home computer LAN using routers through the Integrated Services Digital Network (ISDN). The other connects computers at home to the workstation in the university, using modems and the PPP (Point to Point Protocol) through a public telephone analog line. This paper outlines our university SOHO connection system and discusses the merits and demerits of using telephone line connections.     

Congenital esophageal atresia successfully treated by early ligation of a tracheoesophageal fistula and delayed repair of the esophagus in a premature infant: Report of a case

We report herein the case of a premature infant with esophageal atresia (EA) and a tracheoesophageal fistula (TEF) associated with cardiac anomalies who was successfully treated by an early ligation of the TEF following gastrostomy, and delayed repair of the esophagus. A 1212-g male was born prematurely at 31 gestational weeks, at which time he was diagnosed as having EA with TEF and patent ductus arteriosus (PDA), ventricular septal defect (VSD), and atrial septal defect (ASD). A gastrostomy was initially performed but following extubation he gradually became tachypneic. A chest roentogenogram revealed atelectasis and ground-glass appearance, and reintubation was required. Ligation of the TEF was performed 53h after his birth. Following the improvement of his respiratory condition through ventilatory support and the intratracheal administration of pulmonary surfactant, he underwent repair of the esophagus on the 6th day of life. Postoperatively, he suffered from heart failure, but was treated with peritoneal dialysis and pharmacological closure of the PDA. Weaning the infant from the ventilator proved difficult, but it was finally achieved when he had reached a weight of 2268g at 3 months of age by enteral feeding. Our experience of this case demonstrates that early ligation of TEF should be performed for a premature infant with EA and TEF before respiratory distress syndrome (RDS) has developed. If a gastrostomy is required to prevent gastric distention, it should be followed by simultaneous or immediate ligation of the TEF.     

Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

Lipopolysaccharide Induces CD25-Positive, IL-10-Producing Lymphocytes Without Secretion of Proinflammatory Cytokines in the Human Colon: Low MD-2 mRNA Expression in Colonic Macrophages

Despite the huge number of colonized Gram-negative bacteria in the colon, the normal colon maintains its homeostasis without any excessive immune response. To investigate the potential mechanisms involved, human colonic lamina propria mononuclear cells (LPMCs) obtained from uninflamed mucosa were cultured with lipopolysaccharide (LPS) prepared from Bacteroides vulgatus (BV-LPS) or Bacteroides fragilis (BF-LPS), as representatives of indigenous flora, or pathogenic Salmonella minnesota (SM-LPS). Colonic LPMCs failed to produce inflammatory cytokines in response to any type of LPS. Colonic macrophages barely expressed mRNA for MD-2, an essential association molecule for LPS signaling via Toll-like receptor 4. Further, BV-LPS induced CD25 and Foxp3 expression in lymphocytes and CD4(+)CD25(+) cells expressed IL-10 mRNA. Thus, the low expression of functioning LPS receptor molecules and induction of IL-10-producing CD4(+)CD25(+) lymphocytes by indigenous LPS may play a central role in the maintenance of colonic immunological homeostasis.     

Treatment with aflatoxin B1 for immortalization of human fibroblasts from Li-Fraumeni patients

Immortalization of normal human fibroblasts is a very rare event. Multiple genes such as p53 and cellular senescence genes are possibly involved in immortalization of human fibroblasts, suggesting that multiple treatments with carcinogens are required for the immortalization. We describe here the procedure for immortalization of human fibroblasts (MDAH 087) from Li-Fraumeni cancer syndrome with a germ-line p53 mutation. The cells were subjected to multiple treatments with aflatoxin B₁ (AFB₁) in the presence of exogenous metabolic activation with rat liver post-mitochondrial supernatant (PMS), and 3 of 9 MDAH 087 cell cultures treated 1–3 times with 0.1–1 µg/ml AFB₁ became immortal, defined as continuous growth for over 300 population doublings after the first treatment. However, cultures of human fibroblasts from a normal embryo treated under the same conditions failed to escape senescence. The results indicate that the model of human fibroblasts with a mutated p53 allele exposed to AFB₁ is potentially useful for studying mechanisms of chemically induced immortalization.