Herpesvirus type 2 isolated from cervical tumor cells grown in tissue culture.

A herpesvirus has been isolated from spontaneously degenerating cultures of cervical tumor cells grown in vitro. The virus was identified as a type 2 herpesvirus on the basis of biologic properties, including plaque morphology and microtubule formation in infected HEp-2 cells, and of immunologic specificity as determined by neutralization. Herpesvirus antigens and virus particles were not seen in duplicate cultures of viable cervical tumor cells.

Statistical models of tumour onset and growth for modern breast cancer screening cohorts.

Historically, multi-state Markov models have been used to study breast cancer incidence and mammography screening effectiveness. In recent years, more biologically motivated continuous tumour growth models have emerged as alternatives. However, a number of challenges remain for these models to make use of the wealth of information available in large mammography cohort data. In particular, methodology is needed to address random left truncation and individual, asynchronous screening. We present a comprehensive continuous random effects model for the natural history of breast cancer. It models the unobservable processes of tumour onset, tumour growth, screening sensitivity, and symptomatic detection. We show how the unknown model parameter values can be jointly estimated using a prospective cohort with diagnostic data on age and tumour size at diagnosis, and individual screening histories. We also present a microsimulation study calibrated to population breast cancer incidence data, and to data on mode of detection and tumour size. We highlight the importance of adjusting for random left truncation, derive tumour doubling time distributions for screen-detected and interval cancers, and present results concerning the relationship between tumour presence time and age at diagnosis.

Comparison of spontaneous and experimentally induced canine prostatic hyperplasia.

Spontaneous prostatic hyperplasia in the beagle appears to progress with age from a glandular to a cystic histological appearance. Prostatic hyperplasia can be induced in young beagles with intact testes by treatment for 4 mo with either dihydrotestosterone or 5 alpha-androstane-3 alpha, 17 beta-diol, alone, or with either of these steroids in combination with 17 beta-estradiol. In contrast, the induction of prostatic hyperplasia in young castrated beagles, in which the gland had been allowed to involute for 1 mo, requires the administration of both 17 beta-estradiol and either 5 alpha-androstane-3 alpha, 17 beta-diol or dihydrotestosterone. Testosterone and 17 beta-estradiol, either singly or in combination, did not produce the hyperplastic condition in intact or castrated beagles. The experimentally induced prostatic hyperplasia is identical in pathology to the glandular hyperplasia that occurs naturally in the aging dog with intact testes. However, cystic hyperplasia was not produced by any of the treatments tested in young animals.

Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate.

This paper is a cross-sectional study of spontaneous benign prostatic hyperplasia (BPH) in a single canine species. The effects of aging and hormonal changes on the growth, histology, and glandular secretory function of the canine prostate were studied in 42 male beagles ranging in age from 8 mo to 9 yr. The beagle prostate enlarges for at least 6 yr, whether normal or hyperplastic. In contrast, prostatic secretory function, determined by ejaculate volume and total ejaculate protein, declines markedly after 4 yr of age. These reciprocal growth and functional changes in the prostate are closely associated with a progressive increase in the incidence of BPH, which is already apparent in some dogs by age two. With age there is a modest decrease in serum androgen levels with no apparent change in serum 17 beta-estradiol levels. This suggests that the growth and functional changes that are associated with the development of BPH and are initiated very early in life reflect an altered sensitivity of the prostate to serum androgens or a response to the relative decrease in the serum androgen to estrogen ratio.

Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages.

Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P=2.66 × 10-10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P=3.07 × 10-19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the central nervous system. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter and cytoskeletal signalling occurs during early fetal brain development of BD I patients.

Sarcoma in a hamster inoculated with BK virus, a human papovavirus.

An undifferentiated sarcoma occurred in 1 of 52 hamsters inoculated when newborn with BK virus (BKV), A SIMIAN VIRUS 40 (SV40)-related human papovavirus. It was transplantable and grew in tissue culture. Sera of tumor-bearing hamsters were without antibodies reactive to BKV virion antigens in hemagglutination-inhibition and neutralizationtexts, but contained antibodies reactive in immunofluorescence (IF) tests to SV40 T antigen in SV40-TRANSFORMED CELLS AND TO ANTIGENS IN CELLS ACUTELY INFECTED WITH BKV or SV40. The IF reaction between tumor cells and sera of tumor-bearing hamsters was minimal in texts of tumor cells of an early passage but satisfactory in tests of cells from a later passage. Fusion of tumor cells with permissive (monkey and human) cells, induced by inactivated Sendai virus, did not lead to recovery of infectious BKV. Immunization of hamster with BKV or SV40 failed to protect against challenge with tumor cells. There was considerable cross-reactivity between the T antigens of BKV and SV40 viruses

Histopathology of neoplastic and nonneoplastic hepatic lesions in mice fed diets containing tetrachlorvinphos.

Tetrachlorvinphos was fed at 8,000 or 16,000 ppm in diets to male and female (C57BL/6N X C3H/HeN)F1 mice for 80 weeks. Surviving mice were killed at 92 weeks, and all mice were completely necropsied. A high incidence of unusual nonneoplastic hepatic lesions in treated mice was present and characterized by pericellular fibrosis, hepatocyte nuclear pleomorphism, and intrasinusoidal foci of macrophages with intracytoplasmic crystalline structures. From 84 to 94% of the treated male mice and from 21 to 23% of the treated females had hepatocellular neoplasms. Only 17% of the control males and 7% of the control females had liver tumors. The induced tumors were frequently multiple in the liver, whereas the tumors in the controls were usually singular. The morphology of 241 liver tumors in 110 treated mice was different from that of tumors in controls. Liver tumors in control mice were generally composed of small basophillic hepatocytes. In treated mice, tumors were hepatocellular carcinomas composed of solid sheets of large basophilic or eosinophilic hepatocytes. Foci of prominent trabecular formation were seen in 51 tumors. Fifteen tumors were composed of small basophilic hepatocytes with oval cells interposed among them. Foci of capillary formation were noted in 3 of these tumors. In addition, 7 more typical hemangiosarcomas forming sinusoids and with thrombosis were observed.

Induction of liver tumor in Sherman strain female rats by polychlorinated biphenyl aroclor 1260.

Sherman strain female rats (200) were fed 100 ppm of polychlorinated biphenyl (Aroclor 1260) for apporximately 21 months, and 200 female rats were kept as controls. The rats were killed when 23 months old. Twenty-six of 184 experimental animals and 1 of 173 controls had hepatocellular carcinomas. None of the controls but 146 of 184 experimental rats had neoplastic nodules in their livers, and areas of hepatocellular alteration were noted in 28 of 173 controls and 182 of 184 experimental animals. Thus the polychlorinated biphenyl Aroclor 1260, when fed in the diet, had a hepatocarcinogenic effect in these rats. The incidence of tumors in other organs did not differ appreciably between the experimental and control groups.

Long-term effect of 2-hydroxyethyl retinamide on urinary bladder carcinogenesis and tumor transplantation in Fischer 344 rats.

The effects of HER upon early and late stages of BBN-induced bladder cancer in rats were examined. Female Fischer 344 rats were administered HER in the diet either before and during or continuously after BBN administration and were monitored periodically for up to 2 years. The total dose of BBN was 600 mg administered over a 6-week period. In a separate experiment, the effects of HER administration to syngeneic recipients of a transplanted primary bladder cancer were examined. No effects on neoplastic development were observed as the result of HER treatment before and during carcinogen administration. However, at the 1-year sacrifice, there was a significant increase in bladder tumor incidence in the animals receiving BBN followed by continuous retinoid treatment versus animals receiving BBN only. At the 2-year sacrifice, there was a significant increase in tumor progression in the continuous retinoid group versus the animals receiving BBN alone, based upon grading and staging of tumors, although tumor incidences were not significantly different. In the transplantation experiment, more recipients (9/20 versus 2/20) receiving continuous HER had large, anaplastic tumors following 9 months of observation than did control animals. This study supports the view that retinoids should not be considered as only inhibitors of carcinogenesis, but rather as modifiers which vary in their effects depending upon factors yet to be understood.

Photodynamic therapy in the canine prostate using motexafin lutetium.

Our purpose was to determine the feasibility of comprehensive treatment of the canine prostate with photodynamic therapy (PDT) using motexafin lutetium (Lu-Tex) and to evaluate the toxicity and tissue effects associated with this treatment. Twenty-five adult male beagles with normal prostate glands were given an i.v. injection of the second-generation photosensitizer Lu-Tex (2-6 mg/kg). An additional two dogs were used as controls and did not receive any photosensitizing drug. All 27 dogs underwent laparotomy to expose the prostate. Three hours postinjection, a total dose of 75-150 J/cm of 732 nm laser light was delivered interstitially and/or transurethrally to the prostate via cylindrical diffusing fibers. Dogs were euthanized between 2 days and 3 months after PDT. All subjects were monitored for clinical evidence of toxicity. Specimens were examined macroscopically and microscopically to characterize the tissue reaction and assess extent of tissue effect as a result of treatment. Interstitial and/or transurethral PDT were successfully delivered in all dogs with no perioperative complications. No clinical evidence of acute urinary obstruction or rectal bleeding was noted. At all dose levels, macroscopic and microscopic evaluation revealed a prostatic tissue reaction characterized initially (within 48 h) by inflammation and necrosis followed by fibrosis and glandular epithelial atrophy. Comprehensive treatment of the entire prostate could be achieved using the interstitial alone approach or combined transurethral and interstitial approach. The transurethral alone approach did not result in complete coverage of the prostate. Dogs receiving transurethral or combined interstitial and transurethral treatment developed erythema and urethral epithelial disruption at all dose levels. Those receiving combined treatment at the highest dose level (Lu-Tex 6 mg/kg, 150 J/cm light) developed urethral fistulae and peritonitis. Dogs treated with the interstitial alone approach were found to have the least amount of urethral damage. Comprehensive treatment of the canine prostate with Lu-Tex PDT is feasible using an interstitial alone or combined interstitial and transurethral approach. The interstitial alone technique results in the least amount of toxicity. The prostatic tissue reaction to treatment is characterized by initial inflammation and necrosis followed by fibrosis and glandular epithelial atrophy.

Complement-like activity in the sea star, Asterias forbesi.

The coelomic fluid (CF) of Asterias forbesi was examined for the presence of complement-like activity. Cell-free CF contains hemolytic activity for unsensitized rabbit erythrocytes (E) but not unsensitized or antibody-coated sheep E. Target E sensitivity is not dependent upon phylogenetic proximity of erythrocyte species to Asterias. The activity is optimally assayed at 25 degrees C, has a sigmoidal dose-response curve, and is heat-sensitive (56 degrees C). The activity is divalent cation dependent, although Ca++ and Mg++ are not required. Nonlytic CF does not contain an inhibitor; rather, combining nonlytic and lytic CFs results in an increase in hemolysis. Activity can be consumed by treatment with zymosan, pronase, trypsin, and PMSF. Enzymatic desialidation converts sheep E into activators of the hemolytic pathway. No phospholipase activity is present in CF. Biological function is demonstrated by bactericidal activity against Vibrio tubiashii by lytic CF. These results suggest that a primitive complement system is operating in Asterias.

Longevity and age-related pathology of LVG outbred golden Syrian hamsters (Mesocricetus auratus).

A colony of male Lakeview Golden (LVG) Syrian hamsters has been maintained for the last nine years as a source of various tissues for cellular aging studies. Observations on this colony also yielded data on survival time and physical and pathological manifestations of aging in this strain. Based on 150 spontaneous deaths, the median life span was found to be 19.5 months. The maximum life span was 36 months and the minimum 6 months. A cross-sectional pathological survey of sacrificed and spontaneously dying members of the population revealed a low rate of neoplasia and a variety of degenerative lesions that increased with age. These observations of a varied pathology and a low frequency of neoplasia provide justification for the continued development of the male LVG Syrian hamster as an animal model system for use in studies on the mechanism of both in vivo and in vitro aging.

Intestinal Cryptosporidium sp. infection in the Egyptian tortoise, Testudo kleinmanni.

An adult Egyptian tortoise (Testudo kleinmanni) presented with clinical signs of enteritis and died 5 weeks after initiation of antibiotic therapy. Histological examination of the small intestine revealed heavy infection with Cryptosporidium sp.; over 80% of epithelial cells harboured the pathogen. No Cryptosporidium developmental stages were present in the stomach or the lungs. The intestinal lamina propria and mucosa were infiltrated by heterophils, lymphocytes and macrophages. The present study constitutes the first report of Cryptosporidium sp. infection in T. kleinmanni, and the first histological documentation of intestinal cryptosporidiosis in Chelonia.

Real-time bronchoscope tip localization enables three-dimensional CT image guidance for transbronchial needle aspiration in swine.

STUDY OBJECTIVE: To determine the feasibility of using real-time bronchoscope position technology coupled with previously acquired three-dimensional CT data to enhance transbronchial needle aspiration (TBNA). DESIGN: Eight swine were given percutaneously created target lesions for TBNA. A miniature position sensor was placed at the tip of a bronchoscope, and real-time position information during bronchoscopy was presented on a monitor simultaneously displaying previously acquired three-dimensional CT data. INTERVENTIONS: TBNA of target lesions and submucosal ink-spot injection of computer-generated targets. MEASUREMENTS AND RESULTS: TBNA specimens revealed successful aspiration of target material. Distances between ink marks made at computer-generated tracheal targets varied, on average (+/- SD), 4.2 mm +/- 2.6 mm from predetermined computer-distance coordinates. CONCLUSION: Real-time bronchoscope position technology coupled with previously acquired CT images may aid with TBNA of nonvisible extrabronchial lesions.

Long term follow-up of transcatheter embolization with autologous clot, oxycel and gelfoam in domestic swine.

Transcatheter embolization of the distal gastrosplenic artery as well as the distal right renal artery or one of its bifurcational branches was performed in 9 domestic swine. The animals were embolized with fresh autologous clot, oxycel or gelfoam in groups of 3. The embolic material was opacified with tantalum in several animals. At 4 months, none of the initial occlusions was sustained and recanalization without residuals was found in the left gastroepipolic artery with only one minor exception. Organized thrombi as sole vascular residuals regardless of embolic substance were found in both the terminal splenic artery as well as in the right renal artery distribution in various degrees together with infarcts in both organs. No trace of either oxycel or gelfoam remained, nor tissue reaction against either material. All 3 agents are therefore regarded equivalent in their long term effects and are not suitable for permanent vascular occlusion.

Organ ablation by fluid emboli. An experimental study comparing two solidifying liquids.

Embolization for ablation of organs and tumor infarction requires uniform permanent occlusion of the distal vasculature. This is best accomplished through the use of solidifying liquids. The study on 15 dogs reported here compares the degree of peripheral vascular embolization and its relation to tissue infarction both acutely and chronically following embolization of the renal arteries with two solidifying liquids, a low viscosity silicone and the occlusion gel Ethibloc. Silicone produced quite uniform distal distribution including 50 to 80% (mean 66%) of renal glomeruli, whereas Ethibloc occluded more proximally and reached only 10 to 50% (mean 22%) of all glomeruli. After three months complete cortical infarction of all nine kidneys embolized with silicone was found, whereas two of the three kidneys embolized with Ethibloc retained nests of viable glomeruli. Balloon occlusion of the entire renal artery inflow during embolization prevented distal venous emboli whereas partial inflow occlusion allowed systemic venous embolization. It is concluded that due to its more uniform distal penetration low viscosity silicone is a more suitable embolization agent than Ethibloc for organ ablation. Total arterial inflow occlusion during embolization effectively prevents systemic venous embolization.

Metrizamide, the ideal radiopaque filling material for detachable silicone balloon embolization.

Porcine visceral and extremity arteries were embolized with detachable silastic balloons; 10 balloons were filled with isoosmolar metrizamide, five were filled with 30% meglumine-sodium diatrizoate and five were filled with 3:1 mixtures of blood and 76% meglumine-sodium diatrizoate. Follow-up radiographs were obtained weekly for 2 weeks, at 4 weeks and at 5 months. At 3 months, arteriography was performed. All balloons occluded the vessel completely upon detachment. Balloons filled with metrizamide did not change their volume or radiopacity during the entire observation period and all remained inflated. The balloons filled with diatrizoate salts enlarged by osmotic growth during the first two weeks and there was a decrease in opacity. Thereafter, one balloon filled with 30% diatrizoate salt solution and one filled with blood-76% diatrizoate deflated. In the former, the embolized artery remained occluded, while in the latter, the vessel reopened and the balloon was found incorporated into the vessel wall at the site of detachment. It is concluded that isoosmolar metrizamide is an ideal filler for detachable silastic balloons since it does not lead to changes in volume or radiopacity and also guarantees long-term vascular occlusion.

Therapeutic embolization with detachable silicone balloons: long-term effects in swine.

Twenty-one embolizations were performed in 12 swine using a detachable silicone balloon-catheter system. In 11 embolizations, balloons were filled with 60% meglumine sodium diatrizoate (R-60); 30% meglumine sodium diatrizoate (R-30) was used in 10 embolizations. Serial radiographs were obtained to determine the duration of balloon inflation. Repeat angiography and autopsy examinations were performed three to six months following embolization. Eighty percent of balloons filled with R-30 were still inflated after 10 days, as opposed to 27% of the balloons filled with R-60. Balloons which remained inflated for more than 10 days caused permanent occlusion of the embolized arteries. The vessels were occluded precisely at the point at which the balloons were initially attached. Pathologically, the occluded vessels exhibited organized thrombi with minimal inflammation. Detachable balloons appear to be an effective, safe method of performing selective vascular occlusion in many circulatory systems. Careful control of the volume and osmolarity of the contrast medium used to inflate the balloons produces permanent arterial occlusion.

Transcatheter embolization with microfibrillar collagen in swine.

Transcatheter embolization of the gastrosplenic and renal arteries was performed in 7 domestic swine with suspensions of microfibrillar collagen (MFC), a recently developed topical hemostatic agent. Embolized vessels remained occluded 2 days following embolization. Recanalization occurred by 14 days, although some occlusion in distal vessel persisted at 3 months. Pathologically a marked granulomatous arteritis was noted at 14 days which resolved by 3 months. Gastric ulcers or infarcts were present in two animals. The severe vasculitis and gastric pathology observed with MFC in this study would seem to preclude its use as a general embolic agent. It may be useful, however, in the preoperative embolization of neoplasms, especially in pediatric patients since its physical characteristics allow it to be easily injected through small diameter catheters.