Atypical Epstein-Barr virus infection during and after intermittent FK506 therapy

Atypical Epstein-Barr virus (EBV) infection developed in a patient under intermittent administration of FK506 (one dose in 10 days) after living-related liver transplantation. The clinical course was similar to severe chronic active EBV infection syndrome (SCAEBV), which is characterized by extremely high titers of antibody to EBV antigens. The clinical symptoms improved without graft rejection even after the cessation of FK506; however, the titers of antibody to EBV antigens remained at high levels. It was considered that: (i) even intermittent use of FK506 could influence the immune response, which then induced atypical EBV infection similar to SCAEBV; and (ii) the impaired immune response, especially to EBV antigens, remained after complete cessation of FK506.     

Antitumor Effect of 3-[(4-Amino-2-Methyl-5-Pyrimidinyl) Methyl]-1-(2-Chloroethyl)-1-Nitrosourea (ACNU) on Human Colon Carcinomas Transplanted into Nude Mice

Two human colon carcinomas serially transplanted into nude micewere used for experimental chemotherapy by 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea(ACNU). Human colon carcinomas Co-3 (well-differentiated adenocarcinoma)and Co-4 (poorly differentiated adenocarcinoma), were transplantedsubcutaneously into the backs of BALB/c male nude mice. Tumorsize was measured three times a week, and treatment was startedwhen the estimated tumor weight reached 100 to 300 mg. Twentyand 40 mg of ACNU per kg was administered intravenously, once,dissolved in 0.2 ml of normal saline. There were marked tumorregression and histological tumor cell destruction in Co-4,whereas no effect was observed in Co-3. Microangiography revealed a similar vascular network in Co-3and Co-4. Whole-body autoradiography was performed 5, 30, 180and 360 minutes after 20 mg (286 µC₁) of [ethylene-2-¹⁴C]-ACNUper kg was injected. ACNU concentration in the Co-3 tumor reacheda peak 30 minutes after injection and diminished promptly withthe decrease of ACNU in the blood, whereas in Co-4 tumors ACNUwas retained in the tumor until 360 minutes after ad ministration.The effect of ACNU was thought to be correlated with the concentrationof the drug in the tumor. Present address: Department of Surgery, Kitasato InstituteHospital, Tokyo, Japan.     

An infantile case of cytomegalovirus induced idiopathic thrombocytopenic purpura with predominant proliferation of CD10 positive lymphoblast in bone marrow

An infant with cytomegalovirus infection (CMV) developed idiopathic thrombocytopenic purpura (ITP) at 4 months of age. A bone marrow (BM) aspiration showed a remarkable increase of immature megakaryocytes and prominent proliferation of lymphoblasts. Flow cytometric analysis of the bone marrow cells showed that the predominant cells in the lymphocyte cluster were of B-lineage (CD19) with CD10 (common acute lymphoblastic leukemia antigen) positive. Virus study showed a high titer of CMV antibody. Cytomegalovirus DNA was detected by the polymerase chain reaction (PCR) method in urine, peripheral cells and marrow cells. Low-grade fever, diarrhea and petechiae were accompanied by mild liver dysfunction. Complete remission was made with intravenous high-dose immunoglobulin (IVIg) without progression to overt acute leukemia. The percentage of CD10⁺/CD19⁺ lymphocytes in bone marrow also diminished. We postulated that the proliferation of immature lymphocytes and megakaryocytes in bone marrow was caused by maturation arrest that might result from CMV infection.     

EXPRESSION OF CYCLIN-DEPENDENT KINASE INHIBITOR p21WAF1/CIP1 IN NON-NEOPLASTIC MUCOSA AND NEOPLASIA OF THE STOMACH: RELATIONSHIP WITH p53 STATUS AND PROLIFERATIVE ACTIVITY

The expression of the p53-inducible cyclin-dependent kinase inhibitor p21^WAF1/CIP1 in non-neoplastic mucosa, adenoma, and adenocarcinoma of the stomach was examined immunohistochemically and its relationship with p53 expression and proliferative activity was analysed. In normal gastric mucosa as well as in intestinal metaplasia the epithelial cells at the surface which showed no proliferative activity expressed p21whereas the cells in the deep area of the glands expressing Ki-67 did not. In the neoplastic lesions, the expression of p21^WAF1/CIP1 was detected in 78 per cent (112/144) of the adenomas and 76 per cent (262/343) of the adenocarcinomas. The incidence of p21^WAF1/CIP1 expression did not differ among histological types of gastric carcinoma. The strong expression of p21^WAF1/CIP1 was more frequently observed in carcinomas invading into submucosa or in cases of stages 2, 3, and 4 than in carcinomas limited to the mucosa or in stage 1 cases. The incidence of strongly positive cases was higher in carcinomas with lymph node metastasis than in those without metastasis. There was no apparent correlation between the expression of p21^WAF1/CIP1 and the abnormal accumulation of p53 or with proliferative activity measured by Ki-67 expression. These findings overall suggest that p21^WAF1/CIP1 might be associated with the senescence of non-neoplastic gastric epithelial cells; that a p53-independent pathway might be substantially involved in the induction of p21^WAF1/CIP1 in gastric neoplasia; and that the proliferative activity of gastric cancer might not be solely dependent on control of the cell cycle by p21^WAF1/CIP1.     

Evaluation of Oral Mucoadhesive Microspheres in Man on the Basis of the Pharmacokinetics of Furosemide and Riboflavin,Compounds with Limited Gastrointestinal Absorption Sites

When sustained-release adhesive and non-adhesive microspheres which release the same drugs at similar rates are administered orally, drug absorption after administration of adhesive microspheres should, if the gastrointestinal residence of adhesive microspheres is prolonged as a result of mucoadhesion, be higher than that after administration of non-adhesive microspheres. The gastrointestinal transit of oral adhesive microspheres in man has been evaluated pharmacokinetically using furosemide and riboflavin, compounds with limited absorption sites in the upper small intestine. In a preliminary experiment with fasted rats it was confirmed that a higher percentage of the drug remained in the stomach and that plasma drug levels were higher when furosemide was administered in the form of adhesive rather than non-adhesive microspheres. Two kinds of sustained-release microsphere, adhesive and non-adhesive, containing furosemide and riboflavin in hard gelatin capsules were prepared and orally administered to 10 healthy fasted volunteers in a cross-over design. Areas under the plasma concentration-time curves (AUC) were 1.8 times larger for furosemide and urinary recovery was 2.4 times higher for riboflavin when adhesive microspheres rather than when non-adhesive microspheres were used. When adhesive microspheres containing riboflavin were administered to fed volunteers, urinary recovery was 2.1 times higher and mean residence time (MRT) was more prolonged than when the microspheres were administered to fasted volunteers. Adhesive microspheres were found to adhere to the gastric or intestinal mucosa with high affinity in man and rats, resulting in prolonged gastrointestinal residence.     

A case of prolonged human parvovirus B19 DNA-emia associated with polyclonal B cell activation

The current paper reports an 8 year old girl with arthralgia and polyclonal B cell activation induced by human parvovirus B19 infection (HPV B19). The infection was diagnosed by the presence of the virus genome in sera. The patient presented with transient arthritis in the wrist, ankle joint and neck and elevation of immunoglobulin IgM antibodies to HPV B19 and rubella, antibodies to Mycoplasma and antistreptolysin O but without the typical clinical features of erythema infectiosum. The polyclonal B cell activation was paralleled by the presence of the virus genome of HPV B19 in sera. In some children with arthralgia, it is important to examine the genomes of viruses that may cause arthritis as well as the antibody titers to the viruses.