Neuropathology of bovine herpesvirus type 5 (BHV-5) meningo-encephalitis in a rabbit seizure model

CI-994 (acetyldinaline) is an orally active anticancer drug currently in Phase 1 clinical trials. To assess its preclinical toxicity, CI-994 was administered orally as suspensions to Wistar rats (10/sex/dose) and in capsules to beagle dogs (3/sex/dose) once daily for two weeks. Doses were 1.5, 5, and 15 mg/kg for rats (9, 30, and 90 mg/m2, respectively), and 0.5, 2, and 5 mg/kg for dogs (10, 40, and 100 mg/m2, respectively). Systemic exposure was dose-proportional based on toxicokinetic analysis in dogs. Severe clinical signs and mortality occurred at the highest dose in both species beginning on Day 10. Neutropenia, lymphocytopenia, thrombocytopenia, lymphoid depletion, bone marrow hypocellularity, and testicular degeneration were observed in both species, primarily at the mid- and high-doses. Despite continued treatment, neutrophil counts in dogs returned to control levels in Week 2. Other microscopic findings in rats included splenic hematopoietic depletion at all doses and epithelial cell necrosis in various tissues at 15 mg/kg. Additional bone marrow changes in dogs involved myeloid and megakaryocyte hyperplasia at 2 mg/kg and abnormal myeloid and megakaryocyte maturation at 2 and 5 mg/kg. Except for the testicular effects in both species, all changes were reversible within a 4-week (rat) or 9-week (dog) recovery period. The results of these studies show that target organ effects of CI-994 principally involve tissues with rapidly dividing cell populations and that bone marrow suppression is the dose-limiting toxicity. CI-994 also seems to interfere with the release and/or maturation of cells in the bone marrow.     

Rheumatoid nodules: MR/pathological correlation

A 62-year-old female who had a complaint of palpitation was diagnosed as bicuspid aortic stenosis and left single coronary artery by the echocardiographic examination, cardiac catheterization study and coronary artery angiography. Aortic valve replacement was performed and the patient was discharged 22 days after surgery with good post-operative course. Preoperative coronary artery angiography was important in the case of aortic valvular disease.     

A population study of the natural history of Wolff-Parkinson-White syndrome in Olmsted County, Minnesota, 1953-1989

BACKGROUND: Virtually all natural history studies of Wolff-Parkinson-White (WPW) syndrome have been case series and, as such, have been constrained by referral biases, skewed age and sex distributions, or brief follow-up periods. The purpose of our study was to examine the natural history, the development of arrhythmias, and the incidence of sudden death in an entire cohort of pediatric and adult WPW patients from a community-based local population. METHODS AND RESULTS: We identified 113 residents of Olmsted County, Minnesota, during the period 1953-1989 using the centralized records-linkage system provided by the Mayo Clinic and the Rochester Epidemiology Program Project. Medical records and ECGs were reviewed to confirm the diagnosis and to establish pathway location by ECG criteria. Follow-up, via record review and telephone interview, was complete in 95% of subjects through 1990. The incidence of newly diagnosed cases was approximately four per 100,000 per year. Preexcitation was not present on the initial ECG of 22% of the cohort. Approximately 50% of the population was asymptomatic at diagnosis, with 30% subsequently having symptoms related to arrhythmia at follow-up. Two sudden cardiac deaths (SCD) occurred over 1,338 patient-years of follow-up, yielding an overall SCD rate of 0.0015 (95% confidence interval, 0.0002-0.0054) per patient-year. No SCD occurred in patients asymptomatic at diagnosis. CONCLUSIONS: The incidence of sudden death in a local community-based population is low and suggests that electrophysiological testing should not be performed routinely in asymptomatic patients with WPW syndrome. Nevertheless, young, asymptomatic patients, particularly those < 40 years old, should return for medical follow-up should symptoms develop.     

Murine cytomegalovirus-inhibitory effects of ImuVert

ImuVert, a sterile preparation composed primarily of Serratia marcescens membrane vesicles and ribosomes, was significantly inhibitory to murine cytomegalovirus (MCMV) infections in BALB/c mice. Antiviral activity was manifested as increased survivor number and decreased recoverable virus titers in spleens, lungs and salivary glands. Treatments were intraperitoneal (i.p.) beginning 24 h pre, 4 h post- or 24 h post-virus inoculation and then repeated 4 days later. Doses of 5, 16 or 50 micrograms/mouse were effective; 160 micrograms/mouse, which caused host weight loss in toxicity controls, was not inhibitory to the infection. A single i.p. treatment of mice substantially augmented natural killer (NK) cell activity and increased total B-cells, while reducing total T- and T-helper cells. A late (48 h) decline in T-cell function and transient increases in B-cell function were observed in the treated animals. Serum interferon was not induced. Mice pretreated with anti-asialo GM1 antibody to reduce their NK cell populations, then infected with MCMV and treated with ImuVert were protected to the same degree as normal animals. Severe combined immunodeficient mice infected with MCMV and treated with ImuVert were not protected from the infection. These data suggest ImuVert to act by a mechanism other than NK cell activation in preventing MCMV infections.     

Role of glutathione, glutathione S-transferases and multidrug resistance-related proteins in cisplatin sensitivity of head and neck cancer cell lines

Spontaneous proliferative liver lesions were found in 15 (13 males and 2 females) of 244 (122 of each sex) transgenic (Tg) mice carrying the human prototype c-H-ras gene (rasH2). The liver lesions included 3 foci of cellular alteration, 1 hepatocellular adenoma, 5 hepatocellular carcinomas, and 4 hepatic hemangiosarcomas in the males and 1 focus of cellular alteration and 1 hepatocellular carcinoma in the females. The mutation patterns of the human and endogenous mouse c-H-ras codon 61 in these proliferative liver lesions were analyzed by DNA amplification using polymerase chain reaction, single-strand conformation polymorphism (PCR-SSCP), and oligonucleotide dot blot hybridization. The hepatocellular carcinomas in 4 males and 1 female contained a point mutation in the mouse c-H-ras gene: 3, 1, and 1 carcinomas had a CAA to AAA transversion at the first base of codon 61, a CAA to CTA transversions, and a CAA to CGA transition at the second base of codon 61, respectively. No point mutations in the human c-H-ras transgene were detected in any hepatocellular carcinoma. All 4 hepatic hemangiosarcomas had a CAG to CTG transversion at codon 61 of the human c-H-ras gene, but no point mutations were detected in codon 61 of the mouse c-H-ras gene. No mutations in human or mouse c-H-ras codon 61 were detected in altered cell foci or hepatocellular adenoma. These results indicate that spontaneous liver tumors in rasH2 Tg mice contain different mutation patterns depending on the histologic type or cell origin of the tumors (i.e., hepatocellular carcinomas or hepatic hemangiosacomas). The absence of similar mutations in foci of cellular alteration and the hepatocellular adenoma suggests that the occurrence of codon 61 point mutations is a late event in the progression of hepatocellular neoplasia in rasH2 Tg mice.     

Assessment of a prototype battery operated wax-knife for domiciliary and surgery use

The aims of this study were to examine a prototype battery operated wax-knife, assess the extent to which manufacturer's claims have been achieved and determine its potential for clinical use. The mean time required for the wax-knife to achieve an operating temperature of 150 degrees C was 20.2(+/-4.3) s. The mean operating temperature of the ceramic blade was 155.4(+/-3.9) degrees C, range 150 degrees C to 162 degrees C. The mean usage time following full battery recharge was 42 (+/-2) minutes. The wax-knife provided a direct heating tool which retained many of the characteristics of the traditional wax-knife and was suitable for use in the surgery and in domiciliary situations.