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PubMed1985

Mesangial fenestrations, sieving, filtration, and flow.

Small tracers in the circulation enter the rat mesangium rapidly and in large amounts that indicate a sizable plasma flow into the mesangium. Entrance is effected through mesangial fenestrations with a mean width in scanning electron microscopy of 376 A, a size similar to fenestrations in peripheral glomerular capillary walls. This is considerably smaller than the mean size of 678 A found with transmission electron microscopy, but the difference is probably due largely to the anionic surface coat on endothelial cells. Measurements of asymmetric thorium dioxide particles show that smaller ones with a mean length of 315 A enter the mesangium preferentially and that larger particles with a mean length of 405 A are partially restricted, supporting the idea that the measured width in scanning electron microscopy is close to the actual width in vivo. Fluid flow into the mesangium requires fluid flow out. The appearance time and accumulation of tracers suggest the following exit paths of flow from the mesangium: through the overlying epithelium into the urinary space contributing to glomerular filtration and concentrating large tracers beneath the basement membrane in the paramesangial region, into the efferent glomerular capillaries after tracers have been filtered out by the fibrillar matrix, and through the hilus into the juxtaglomerular apparatus (quantitatively small).

Animals↗
PubMed1988

Lack of lysosomal fusion with phagosomes containing Ehrlichia risticii in P388D1 cells: abrogation of inhibition with oxytetracycline.

Fusion of lysosomes with phagosomes containing Ehrlichia risticii, an obligate intracellular parasite, was evaluated in P388D1 murine macrophagelike cells. Lysosomes in cells ranging in infectivity from 30 to 70% were labeled cytochemically with acid phosphatase or via endocytosis of thorium dioxide or cationized ferritin to document phagosome-lysosome (P-L) fusion in untreated cells and cells treated with oxytetracycline. Regardless of the marker used, P-L fusion was generally not observed in E. risticii-containing vacuoles in untreated cells, while significantly greater P-L fusion with ehrlichia-containing vacuoles was observed after oxytetracycline treatment. When latex beads were introduced into uninfected cell cultures, P-L fusion was observed with vacuoles containing latex. Fusion of lysosomes with latex-containing vacuoles in cells was significantly greater than fusion of lysosomes with ehrlichia-containing vacuoles in the same infected cells. These findings indicate that E. risticii is able to inhibit P-L fusion, whereas oxytetracycline deprives organisms of this ability.

Acid Phosphatase↗
PubMed1991

Tissue misrepair hypothesis for radiation carcinogenesis.

Dose-response curves for chronic leukemia in A-bomb survivors and liver tumors in patients given Thorotrast (colloidal thorium dioxide) show large threshold effects. The existence of these threshold effects can be explained by the following hypothesis. A high dose of radiation causes a persistent wound in a cell-renewable tissue. Disorder of the injured cell society partly frees the component cells from territorial restraints on their proliferation, enabling them to continue development of their cellular functions toward advanced autonomy. This progression might be achieved by continued epigenetic and genetic changes as a result of occasional errors in the otherwise concerted healing action of various endogenous factors recruited for tissue repair. Carcinogenesis is not simply a single-cell problem but a cell-society problem. Therefore, it is not warranted to estimate risk at low doses by linear extrapolation from cancer data at high doses without knowledge of the mechanism of radiation carcinogenesis.

Animals↗
PubMed1996

Intermittent diplopia and strabismus caused by ocular neuromyotonia.

PURPOSE: Two cases illustrate the symptoms, signs, etiologies, and treatment of ocular neuromyotonia (ONM). METHODS: The histories, neuroradiologic tests, and/or biopsy revealed the etiologies of ONM in both patients. Clinical observations, videotaping, and electronic eye movement recordings documented the eye movements. RESULTS: A 72-year-old man with chronic arachnoiditis following myelography with thorium dioxide (Thorotrast) developed intermittent diplopia and a partial right third nerve palsy. Left gaze induced spasm of the right medial rectus. Right gaze produced right lateral rectus spasm. A 66-year-old woman, who had radiation treatment for a pituitary tumor and acromegaly, had intermittent spasm of the left medial rectus muscle and left esotropia. The episodes occurred spontaneously and were induced by right gaze. A left internuclear ophthalmoplegia was also found. Carbamazepine (Tegretol) abolished the ONM in both patients. CONCLUSIONS: Although ONM is an unusual cause of intermittent diplopia and strabismus, its distinctive clinical features identify it. Injury to the peripheral cranial nerves probably leads to segmental demyelination, axonal hyperexcitability, and a self-perpetuating, reverberating circuit, which causes spasms of the extraocular muscles.

Aged↗
PubMed1995

Lack of apparent excess of malignant mesothelioma but increased overall malignancies of peritoneal cavity in Japanese autopsies with Thorotrast injection into blood vessels.

The carcinogenicity of thorium dioxide sol (Thorotrast), an X-ray contrast medium used in 1930-1955, in the liver and bone marrow has been established and agrees well with the effects of a high dosage of alpha radiation in the organs. Recently, however, German and Danish epidemiologic studies have shown excess mesotheliomas in the pleura and peritoneum that are unlikely to have been heavily irradiated by alpha particles. To confirm these observations, we examined the incidence of the cancer in those who underwent Thorotrast injections into blood vessels (n = 370) by using autopsy files of the Japanese Thorotrast study. Only one malignant mesothelioma of the peritoneum was registered, whereas three peritoneal or retroperitoneal sarcomas were observed. Thus, our study did not find any increment of mesothelioma in Thorotrast patients. However, when we took the pleuroperitoneal and retroperitoneal malignancies altogether, the incidence (4/370 = 1.1%) was five times more frequent than that (344/162,000 = 0.2%) in the controls (P < 0.005). Clinicopathological data of the four cases are also presented.

Adult↗
PubMed1976

Residual splenic function in the presence of thorotrast-associated hepatic tumor: case report.

A 50-year-old man had received intravenous colloidal thorium dioxide (thorotrast) 27 years previously. Scintiscans with both 99mTc-sulfur colloid and 131I-rose bengal revealed an extensive intrahepatic defect. At operation, the lesion proved to be an infiltrating hemangiosarcoma. The spleen was small but the chronic internal radiation of the spleen had not completely destroyed the function of radiocolloid uptake. Review of the literature disclosed other cases in which the spleen was still capable of accumulating radiocolloid some years after thorotrast administration. In at least one other instance, radiocolloid uptake was not accompanied by splenic ability to clear Howell-Jolly bodies: a disassociation of splenic functions. The effects of the internal radiation dose to the spleen from thorotrast are discussed and compared with the effects of external radiation. The discrepancy between the effects of the two doses may be related to the high relative biologic effectiveness of the alpha rays from thorotrast compared with gamma-radiation, to nonuniformity of distribution, and to the effects of reticuloendothelial blockade.

Colloids↗
PubMed1983

Effects of Thorotrast in humans.

Thorotrast, a patented radiological contrast medium that was widely used from 1930-1950, is a thorium dioxide colloid that has been neutralized and stabilized by protective colloids, which are decomposition products of starch, and which are now generally known as dextrans. The deposition of Thorotrast depends on its radiological use, its method of preparation, and the age of the preparation; however, the major site is the reticulo-endothelial system, where it is retained for long times. Some of its decay products, principally 228Ra and 224Ra, escape from the colloidal particles and deposit in the skeleton. The biological end-points that have been observed in the several human populations that are known to have received Thorotrast are Thorotrastomas, malignant hepatic neoplasms, and other neoplasms of the reticulo-endothelial system (RES), skeletal sarcomas, and leukemias in excess of the number expected. The question to be reviewed in this paper is whether irradiation, or chemical and mechanical effects on the reticulo-endothelial system, or a combination thereof, is the causative factor in the occurrence of these RES neoplasms.

Aluminum↗
PubMedDate not supplied

On the problem of the phagocytic capacity of Sertoli cells. Electron microscopic study in the rat.

To study the real phagocytic capacity of Sertoli cells the following experiments were carried out: carbon colloidal solution or thorium dioxide of particle size 0.01--0.03 micrometer as 2% solution were injected in rat testes at a speed of 50 microliter per minute by means of a infusion pump. The site of injection was made either in the intertubular species under the albuginea or in the lumen of seminiferous tubules using glass 120 micrometer-gauge needles connected to the pump syringe. 30 to 240 minutes after the injection the tissues were fixed by perfusion of 2% glutaraldehyde and embedded for EM. It was observed: 1) particles injected into the intertubular species were not able to pass through the tubular wall and were either trapped by the connective tissue macrophages or drained by the lymphatic vessels; 2) intraluminal particles were not phagocyted by the Sertoli cells and remained in the lumen. The behavior of the Sertoli cells did not match that of phagocytes since they did not show their devouring capacity for the inert particles. These results are consistent with the interpretation that the current disposal of either debris by Sertoli cells depends on autophagic dissolution rather than n macrophagic capacity.

Animals↗
PubMed2002

The relationship between internally deposited alpha-particle radiation and subsite-specific liver cancer and liver cirrhosis: an analysis of published data.

Chronic exposure to high LET radiation has been shown to cause liver cancer in humans based on studies of patients who received Thorotrast, a colloidal suspension of thorium dioxide formerly used as a radiological contrast agent, and on studies of Russian nuclear weapons workers exposed to internally ingested plutonium. Risk estimates for these exposures and specific subtypes of liver cancer have not been previously reported. Combining published data with tumor registry data pertinent to the Thorotrast cohorts in Germany, Denmark, Portugal, and Japan and to Russian workers, we generally found significantly elevated risks of three major histologic types of liver tumors: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and hemangiosarcoma (HS) for Thorotrast exposures. In contrast, HS was the only liver tumor significantly associated with the lower alpha-particle doses experienced by the Russian workers. Excess cases per 1,000 persons exposed to Thorotrast were similar for the three liver cancer subtypes but lower for plutonium exposure. Odds ratios (OR) of HS and CC for Thorotrast were from 26 to 789 and from 1 to 31 times higher than those for HCC, respectively. ORs of liver cirrhosis for Thorotrast exposure ranged from 2.7 (95% confidence interval (CI): 2.2-3.4) to 6.7 (5.1-8.7).

Alpha Particles↗
PubMed1980

Localization of electron-dense tracers during entry of Rickettsia tsutsugamushi into polymorphonuclear leukocytes.

The invasion of Rickettsia tsutsugamushi, Gilliam strain, into guinea pig polymorphonuclear leukocytes (PMNs) and the localization and distribution of tracers were followed during the process by electron microscopy. The seven tracers used were: cationized ferritin, ferritin, thorium dioxide (ThO2), carbon particles, latex spheres, paraffin oil, and Escherichia coli. These markers were added to the incubation medium containing the PMNs before or simultaneously with R. tsutsugamushi-infected BHK-21 cells. Both morphologically intact and degenerating rickettsiae were present in the phagosomes in PMNs, but only the viable-appearing rickettsiae were free in the cytoplasm. The intact rickettsiae were singly and selectively phagocytized in tightly enclosed phagosomal membranes which usually excluded the tracers, except when ThO2 or ferritin was used. When ThO2, which labels the plasma membrane of PMNs, was used. ThO2-labeled phagosomal membranes enclosing rickettsiae were observed and short membrane fragments still labeled with this tracer were found in the vicinity of rickettsiae in the cytoplasmic matrix of PMNs. When ferritin or ThO2 was used as a tracer, some of the phagosomes contained rickettsiae still enclosed in an envelope of BHK-21 cytoplasm and cell membrane. Phagolysosomes preloaded with electron-dense markers fused with subsequently formed phagosomes containing degenerated rickettsiae but not with those containing intact rickettsiae. These results support our interpretation that viable rickettsial entry into PMNs is by selective phagocytosis and escape from these phagosomes.

Animals↗
PubMed1991

[Synchronous development of benign cholangiomas and a cholangiocarcinoma in the liver of a patient 43 years after thorotrast administration].

This is a report on a 59-year-old patient in whom the synchronous occurrence of benign cholangiomas and a cholangiocarcinoma was observed in the liver 43 years after single intraarterial application of thorotrast. Despite a half-life of over 130 years (alpha radiation), X-ray contrast media containing thorium (colloidal thorium dioxide) were used up to the 1950's in X-ray diagnosis, particularly for angiographies. Thorotrast is mainly stored in the liver, in the spleen and in epigastric lymph nodes and can therefore be easily detected radiologically in a survey radiograph of the abdomen. International studies have shown that thorotrast patients have an up to 100 times greater risk of contracting hepatic malignancies compared to control collectives. Among the causes of death of thorotrast carriers in the (old) Federal Republic of Germany, 15% are attributed to primary hepatic tumours (cholangiocarcinomas, malignant haemangioendotheliomas, hepatic cell carcinomas). In the patient presented here, a cystic mass approximately 2 cm in diameter was detected in the right lobe of the liver during computed tomography of the epigastric region conducted as part of the German Thorotrast Study at the German Cancer Research Centre in Heidelberg, as well as in sonography. Intraoperatively, this finding corresponded to a cystic cholangioma. By chance, a cholangiocarcinoma approximately 1 cm in size and several benign cholangiofibromas were also found in the left lobe of the liver. All of the tumours were excised in toto by atypical segment resection. As shown by this case report, thorotrast-induced hepatic tumours are still to be expected, even 40 years after thorotrast was removed from the market.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Bile Duct↗
PubMed2002

Implanted depleted uranium fragments cause soft tissue sarcomas in the muscles of rats.

In this study, we determined the carcinogenicity of depleted uranium (DU) metal fragments containing 0.75% titanium in muscle tissues of rats. The results have important implications for the medical management of Gulf War veterans who were wounded with DU fragments and who retain fragments in their soft tissues. We compared the tissue reactions in rats to the carcinogenicity of a tantalum metal (Ta), as a negative foreign-body control, and to a colloidal suspension of radioactive thorium dioxide ((232)Th), Thorotrast, as a positive radioactive control. DU was surgically implanted in the thigh muscles of male Wistar rats as four squares (2.5 x 2.5 x 1.5 mm or 5.0 x 5.0 x 1.5 mm) or four pellets (2.0 x 1.0 mm diameter) per rat. Ta was similarly implanted as four squares (5.0 x 5.0 x 1.1 mm) per rat. Thorotrast was injected at two sites in the thigh muscles of each rat. Control rats had only a surgical implantation procedure. Each treatment group included 50 rats. A connective tissue capsule formed around the metal implants, but not around the Thorotrast. Radiographs demonstrated corrosion of the DU implants shortly after implantation. At later times, rarifactions in the radiographic profiles correlated with proliferative tissue responses. After lifetime observation, the incidence of soft tissue sarcomas increased significantly around the 5.0 x 5.0 mm squares of DU and the positive control, Thorotrast. A slightly increased incidence occurred in rats implanted with the 2.5 x 2.5 mm DU squares and with 5.0 x 5.0 mm squares of Ta. No tumors were seen in rats with 2.0 x 1.0 mm diameter DU pellets or in the surgical controls. These results indicate that DU fragments of sufficient size cause localized proliferative reactions and soft tissue sarcomas that can be detected with radiography in the muscles of rats.

Animals↗
PubMed1972

The interaction between Toxoplasma gondii and mammalian cells. II. The absence of lysosomal fusion with phagocytic vacuoles containing living parasites.

Electron microscope methods have been used to study delivery of macrophage primary or secondary lysosomal contents to phagocytic vacuoles containing living or dead toxoplasmas. Secondary lysosomes were labeled by culturing the cells in colloidal thorium dioxide (thorotrast) or in ferritin. Acid phosphatase cytochemistry was employed for detection of primary as well as secondary lysosomal constituents. These various lysosomal labels were present in nearly all vacuoles containing toxoplasmas killed with glutaraldehyde, or in vacuoles containing those parasites undergoing degeneration 1 hr after the uptake of living toxoplasmas. In contrast, at times ranging from 1 to 20 hr after infection, no vacuoles containing morphologically normal, apparently viable toxoplasmas were thorotrast or ferritin positive, and only rarely did these vacuoles react for acid phosphatase. In many instances vacuoles containing viable toxoplasmas and no lysosomal markers were situated in the same cell nearby to vacuoles containing degenerating toxoplasmas and lysosomal constituents, thus indicating that the determinants of lysosomal fusion were operating locally in the immediate vicinity of the phagocytic vacuole, and not operating to influence general cell function. Thus, some toxoplasmas are able to prevent the delivery of lysosomal contents, and apparently the phagocytic vacuole provides for these parasites a sheltered microenvironment ideal for their growth. Morphologic evidence indicated that living toxoplasmas altered the phagocytic vacuolar membrane in macrophages, fibroblasts, and HeLa cells. Within minutes after phagocytosis, the vacuole became surrounded by closely apposed strips of endoplasmic reticulum and mitochondria; somewhat later, microvillous protrusions of the membrane into the vacuole were seen. These morphologic features of phagocytic vacuoles containing living toxoplasmas may be of importance in relation to the absence of lysosomal fusion, or they may serve some function in protecting the host cell or in nourishing the parasite.

Acid Phosphatase↗
PubMed1991

Neoplastic diseases induced by chronic alpha-irradiation--epidemiological, biophysical and clinical results of the German Thorotrast Study.

The intravascular injection of the formerly used contrast medium Thorotrast--a colloidal suspension of thorium-dioxide--causes a chronic exposure to alpha-particles especially in the organs of the reticuloendothelial system. The German Thorotrast Study comprises 2326 Thorotrast patients and 1890 contemporary matched patients in the control group to be evaluated. 899 Thorotrast patients and 662 controls had clinical and biophysical follow-up examinations every two years since 1969. The recent most important results of the study are: A high excess rate of primary liver cancer (410/2) was observed beginning after the 15th year of exposure. 31% of the tumors are combined with cirrhosis and 6% with other neoplastic diseases. A clear (mean) dose rate effect relationship exists. The tumor frequency depends on the time of exposure or the cumulative dose to the liver respectively and not primarily on the age at injection. The lowest cumulative doses at 10 years before diagnosis of liver cancer were about 2 Gy. Risk estimates for liver cancer after 40 years of exposure are 500 malignant tumors per 10(4) person-Gy for men and 300 for women. A high excess rate exists also for leukaemias (excluding CLL) starting already 5 years after Thorotrast injection (39/4). The lowest cumulative doses to the red bone marrow at time of death were about 0.5 Gy. According to the present result, an excess rate can be expected for carcinomas of the extrahepatic bile ducts, pancreas, oesophagus, larynx, as well as Non-Hodgkin's lymphomas, bone sarcomas, plasmacytomas and mesotheliomas.

Adolescent↗
PubMed2001

Alpha-particle carcinogenesis in Thorotrast patients: epidemiology, dosimetry, pathology, and molecular analysis.

We studied the alpha-radiation risks in patients who received injections of Thorotrast, an X-ray contrast medium used in Europe, Japan, and the United States from 1930 to 1955. Thorotrast was composed of thorium dioxide (ThO2) and Th-232, a naturally occurring radionuclide. Because the physical half-life of ThO2 is 14 billion years and Thorotrast is hardly eliminated from the body, tissues in which it was deposited are irradiated by alpha-radiation for the entire lifetime of the subject. The dosimetry of Thorotrast patients is very complicated, but currently its reliability is quite high compared with other irradiated populations. The major causes of the death of Thorotrast patients are liver cancer, liver cirrhosis, leukemia, and other cancers. Three histologies of liver cancer are found: cholangiocarcinoma, hepatocellular carcinoma, and angiosarcoma. Although cholangiocarcinoma is the most frequent, angiosarcoma is characteristic of alpha-radiation. Among blood neoplasms with a higher incidence of increase than the general population, erythroleukemia and myelodysplastic syndrome were remarkable. Thorotrast patients exhaled a high concentration of radon (Rn-220), a progeny of Th-232, but no excesses of lung cancer in the patients of Japan, Germany, and Denmark were reported. Mutation analyses of p53 genes and loss of heterozygosity (LOH) studies at 17p locus were performed to characterize the genetic changes in Thorotrast-induced liver tumors. Interestingly, LOH, supposedly corresponding to large deletions was not frequent; most mutations were transitions, also seen in tumors of the general population, suggesting that genetic changes of Thorotrast-induced cancers are mainly delayed mutations, and not the result of the direct effects of radiation.

Adult↗
PubMed1999

p53 mutations in tumor and non-tumor tissues of thorotrast recipients: a model for cellular selection during radiation carcinogenesis in the liver.

Concerns over cancer development from exposure to environmental sources of densely ionizing, high linear energy transfer (LET) radiation, such as alpha-particles from radon, is a current public health issue. The study of tumors attributable to high LET irradiation would greatly augment our insights into the biological mechanisms of carcinogenesis. Chronic low-dose-rate internal exposure to alpha-radiation from thorium dioxide deposits following intravascular administration of the radiographic contrast agent Thorotrast is known to markedly increase the risk of cancer development, especially that of hepatic angiosarcomas and cholangiocarcinomas. Although the mechanism is hypothesized to be via cellular damage, DNA being a major target, wrought by the high LET alpha-particles, the specific genes and the actual sequence of events involved in the process of transforming a normal cell into a malignant one are largely unknown. To shed some light on the molecular mechanisms of cancer development during a lifetime exposure to alpha-radiation, we analyzed the most commonly affected tumor suppressor gene in humans, p53, in 20 Thorotrast recipients who developed cancer, mostly of hepatic bile duct and blood vessel origin. Of the 20 cases, 19 were found to harbor p53 point mutations. Moreover, the accompanying non-tumor tissues from these patients also had p53 mutations, albeit at lower frequency. The distribution pattern of the point mutations was significantly different between the non-tumor and tumor tissues, with most mutations in malignant tissues located in the highly conserved domains of the p53 gene. Our results support the idea that p53 mutations are important in the genesis of Thorotrast-induced tumors but that these point mutations are a secondary outcome of genomic instability induced by the irradiation. Additionally, non-tumor cells harboring p53 mutations may gain some survival advantage in situ but mutations in the domains responsible for the formation of structural elements critical in binding DNA may be necessary for a cell to reach full malignancy.

Aged↗