GENERALIZED TUBERCULOSIS AFTER BCG VACCINATION –REPORT OF AN AUTOPSY CASE–

An autopsy case of generalized tuberculosis after BCG vaccination was reported. The patient, a boy BCG-vaccinated at the age of three, developed regional lymphadenitis, which was followed by subcutaneous abscesses in the chest wall. At the age of eleven, chest X-ray examination revealed an infiltrative shadow in the upper field. He died at thirteen years of age in poor condition with diarrhea and severe attacks of general convulsions. Autopsy disclosed generalized tuberculosis, especially in the skin, lymph nodes, lung, small intestine and brain. Microscopically, there was little tendency to develop tuberculous granulation tissue. Myriads of acid-fast bacilli were found in these ill-defined foci. The acid-fast bacilli were indistinguishable from BCG by bacteriological investigations. No definite causative factor could be traced. Complications induced by BCG vaccination were briefly discussed. ACTA PATH JAP. 19: 395˜407 1969.     

Growth factor-mediated interaction between tumor cells and stromal fibroblasts in an experimental model of human small-cell lung cancer

Malignant tumors induce development of their own stromal tissues during the processes of growth, progression and metastasis. Since the vascular architecture among the various stromal elements is well known to facilitate tumor growth and has been a target of therapy, the importance of stromal fibroblasts has recently been established. To elucidate the interaction between the tumor and its stromal fibroblasts, the present study took advantage of a unique experimental model consisting of a human small-cell lung cancer cell line, WA-ht, and its mouse stromal fibroblast cell line, WA-mFib, both originally derived from a xenograft tumor in a mouse subcutis. Co-culture with the WA-mFib cells significantly augmented the plating efficiency of WA-hT cells in vitro, and their co-inoculation in nude mice shortened latency and tumor doubling time. Histochemical detection of beta-gal, transfected into WA-mFib cells, demonstrated their contribution to the nude mouse xenograft tumor formation as its tumor stroma. Elevated hepatocyte growth factor (HGF) from fibroblasts followed by elevated production of vascular endothelial growth factor (VEGF) from both tumor cells and fibroblasts were demonstrated by ELISA in supernatants of their co-culture, accompanied by enhanced colonogenicity of the tumor cells; these enhanced features were not observed in their respective monocultures. Antisense oligonucleotides to HGF cancelled these augmentation effects with co-culture. The findings highlight the substantial roles of tumor stromal fibroblasts, interacting with soluble growth factors, in promoting the malignant propensity of the tumor.     

A polymorphism in the 5'-flanking region of the CYP2E1 gene and elevated lung adenocarcinoma risk in a Japanese population

Cytochrome P450 2E1 (CYP2E1) catalyzes the metabolic activation of the procarcinogen, N-nitrosodimethylamine, and cytotoxic carbon tetrachloride compounds. A tandem repeat polymorphism in the 5'-flanking region of the CYP2E1 gene was investigated in non-small cell lung carcinoma (NSCLC) patients to clarify the relationship between CYP2E1 gene polymorphism and lung cancer susceptibility. Blood samples were taken from 236 healthy control subjects (192 males and 44 females) and 111 patients (78 males and 33 females) who underwent surgery for NSCLC in Japan. DNA was isolated from these samples and the 5'-flanking region of the CYP2E1 gene was amplified by polymerase chain reaction and examined for tandem repeat polymorphisms using DNA fragment analysis. Sequence analysis confirmed the presence of three alleles, A2, A3, and A4 (361, 367, and 457 bp, respectively), with four genotypes observed in the lung cancer group and five genotypes in the control group. There was a statistically significant difference in genotype distribution between the lung adenocarcinoma and control group (P=0.0088, A4/A4 vs. non-A4/A4). In the lung adenocarcinoma group, the univariate risk estimates for the A4/A4 subgroup compared to the most common subgroup (A2/A2) was 4.300 (95% confidence interval = 1.358-13.618, P=0.0131). We conclude that the A4/A4 genotype of the 5'-flanking region of CYP2E1 was significantly more frequent in lung adenocarcinoma cases than in healthy controls and, therefore, may be involved in the development of lung adenocarcinoma.     

Altered brain penetration of diclofenac and mefenamic acid, but not acetaminophen, in Shiga-like toxin II-treated mice

It is well accepted that bacterial and virus infections elevate the levels of cytokines in serum and cerebrospinal fluids. Such high levels of cytokines might alter the integrity of the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB), subsequently affecting brain penetration of drugs. However, few reports have addressed this issue. Thus, we investigated brain penetration of cyclooxygenase (COX) inhibitors, commonly used as antipyretics, in mice treated with Shiga-like toxin II (SLT-II) derived from E. coli O157:H7, which significantly elevates cytokine levels. As antipyretics, we used diclofenac, mefenamic acid, and acetaminophen. We found that SLT-II significantly increased the brain-to-plasma concentration ratio (Kp) of diclofenac and mefenamic acid, but not of acetaminophen. Moreover, the Kp of diclofenac and mefenamic acid was increased by probenecid, an anionic compound. These results suggest that efflux anion transporters might be involved in the transport of diclofenac and mefenamic acid. Western blot analysis revealed that SLT-II decreased the expression of organic anion transporter-3, an efflux transporter located on the BBB and/or BCSFB. Taken together, these results suggest that SLT-II and/or SLT-II-stimulated cytokines might change brain penetration of drugs and could possibly increase the risk of their side-effects by altering the expression of transporters.     

Parapapillary choledochoduodenal fistula associated with cholangiocarcinoma

Parapapillary choledochoduodenal fistula is a rare disorder. We herein report a case of parapapillary choledochoduodenal fistula associated with cholangiocarcinoma. A 61-year-old woman was admitted to our hospital for further examination of a liver tumor. She had no clinical symptoms, but computed tomography scans showed an irregularly contoured liver tumor which was histologically confirmed to be adenocarcinoma, by a needle biopsy examination. Duodenal fiberscopy revealed a fistula orifice 1.0cm proximal to the orifice of the papilla of Vater, and endoscopic retrograde cholangiography through the fistula showed a communication to the common bile duct. Hypotonic duodenography demonstrated reflux of contrast material into the choledochoduodenal fistula. The bile sample collected from the common bile duct showed extremely high levels of pancreatic enzymes, including amylase, phospholipase-A2, and elastase-I. Furthermore, Helicobacter DNA was detected in bile by polymerase chain reaction (PCR) analysis. This experience suggests to us that parapapillary choledochoduodenal fistula may be a risk factor for biliary tract carcinoma, and surgical management is the treatment of choice for this rare condition, even when the patient has no significant clinical symptoms.     

A prognostic role of mean 24-h pulse pressure level for cardiovascular events in type 2 diabetic subjects under 60 years of age

OBJECTIVE: To assess the prognostic role of ambulatory 24-h pulse pressure (PP) on various vascular events in relatively young type 2 diabetic subjects under 60 years of age. RESEARCH DESIGN AND METHODS: In this prospective study, 237 type 2 diabetic subjects without any history of vascular complications were analyzed. After excluding 9 dropout subjects, 228 subjects (mean age, 46 years; 69% men; mean follow-up period, 100 months) entered the study. RESULTS: Distribution of 24-h PP for all subjects showed left skewed data, indicating that there may be a diabetic subgroup that had a wide PP. Therefore, further analysis was performed by stratifying the diabetic subjects by quartile of 24-h PP. Outcomes for the widest quartile (n = 58; cut point = 53.3 mmHg) was then compared with those from the other narrower quartiles (n = 170). In the diabetic subjects with a wide PP, cardiovascular events occurred more frequently than those in the diabetic subjects with a narrow one (20.7 vs. 4.1%; P < 0.001), resulting in the significant difference in the cumulative incidence of cardiovascular events (P < 0.001, log-rank test), but not cerebrovascular events, between the two subgroups. The Cox model revealed that a wide 24-h PP at baseline independently predicted subsequent cardiovascular events but not cerebrovascular events. By contrast, only duration of diabetes was the risk factor for cerebrovascular events. CONCLUSIONS: This study showed that a wide 24-h PP is predictive for cardiovascular events in relatively young diabetic subjects.     

Intraarterial concomitant chemoradiation for tongue cancer: analysis of 20 patients

Subjects were 20 patients with tongue cancer treated between April 1996 and December 2002 with intraarterial infusion of cisplatin (60-120 mg/m2) (and docetaxel 10-30 mg/m2) and intravenous infusion of sodium thiosulfate followed by 5-fluorouracil (5-FU) (800-1000 mg/m2) for 3 to 5 days. All patients underwent radiation (50-80 Gy). Ten had stage II, 4 stage III, and 6 stage IV A disease. Complete response at the primary site was achieved in 50% for T2, 67% for T3, and 0% for T4 lesions in those undergoing IA cisplatin followed by systemic 5-FU with concurrent radiation. Complete response at the primary site was achieved in all patients given IA cisplatin and docetaxel followed by systemic 5-FU with concurrent radiation. Disease-specific survival was 75% and overall survival 69% at 5 years. Side effects of treatment were tolerable, except for grade three radiomucositis in 70% of patients and grade three bone marrow depression in one treated with weekly IA chemotherapy.     

Implanted cannula-mediated repetitive administration of Abeta25-35 into the mouse cerebral ventricle effectively impairs spatial working memory

Amyloid beta (Abeta) is closely related to the onset of Alzheimer's disease (AD). To construct AD animal models, a bolus administration of a large dose of toxic Abeta into the cerebral ventricles of rodents has been performed in earlier studies. In parallel, a continuous infusion system via an osmotic pump into the cerebral ventricle has been developed to make a rat AD model. In this study, we developed a mouse AD model by repetitive administration of Abeta25-35 via a cannula implanted into the cerebral ventricle. Using this administration system, we reproducibly constructed a mouse with impaired spatial working memory. In accordance with the occurrence of the abnormal mouse behavior, we found that the number of choline acetyltransferase (ChAT)-positive neurons was reduced in paraventricular regions of brains of Abeta25-35-administered mice in a dose-dependent manner. Considering that the repetitive administration of a small dose of toxic Abeta via an implanted cannula leads to a brain status more resembling that of the AD patients than a bolus injection of a large dose of Abeta, and therapeutic as well as toxic agents are able to be repeatedly and reliably administered via an implanted cannula, we concluded that the implanted cannula-bearing AD mouse model is useful for development of new AD therapy.