RESUMEN
The Page kidney phenomenon is a well recognized entity where an extrinsically compressed kidney results in hypertension and loss of function. This compression is usually caused by a subcapsular hematoma secondary to blunt abdominal trauma or an invasive procedure such as a renal biopsy. We describe an unusual case involving the spontaneous development of a Page kidney 24 days after renal transplantation without any history of preceding trauma. The subcapsular hematoma was detected by a computerized tomographic scan performed as part of the work-up for acute allograft dysfunction. Prompt recognition and early intervention are essential if renal function is to be restored before irreversible damage occurs.
Asunto(s)
Trasplante de Riñón , Riñón/patología , Femenino , Humanos , Riñón/diagnóstico por imagen , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
The presence of toxic cyanobacteria in drinking water reservoirs renders the need to develop treatment methods for the 'safe' removal of their associated toxins. Chlorine has been shown to successfully remove a range of cyanotoxins including microcystins, cylindrospermopsin and saxitoxins. Each cyanotoxin requires specific treatment parameters, particularly solution pH and free chlorine residual. However, currently there has not been any investigation into the toxicological effect of solutions treated for the removal of these cyanotoxins by chlorine. Using the P53(def) transgenic mouse model male and female C57BL/6J hybrid mice were used to investigate potential cancer inducing effects from such oral dosing solutions. Both purified cyanotoxins and toxic cell-free extract cyanobacterial solutions were chlorinated and administered over 90 and 170 days (respectively) in drinking water. No increase in cancer was found in any treatment. The parent cyanotoxins, microcystins, cylindrospermopsin and saxitoxins were readily removed by chlorine. There was no significant increase in the disinfection by-products trihalomethanes or haloacetic acids, levels found were well below guideline values. Histological examination identified no effect of treatment solutions except male mice treated with chlorinated cylindrospermopsin (as a cell free extract). In this instance 40% of males were found to have fatty vacuolation in their livers, cause unknown. It is recommended that further toxicology be undertaken on chlorinated cyanobacterial solutions, particularly for non-genotoxic carcinogenic compounds, for example the Tg. AC transgenic mouse model.
Asunto(s)
Toxinas Bacterianas/metabolismo , Cianobacterias/química , Uracilo/análogos & derivados , Contaminantes Químicos del Agua/toxicidad , Abastecimiento de Agua/análisis , Acetatos/metabolismo , Alcaloides , Animales , Cloro/farmacología , Cianobacterias/crecimiento & desarrollo , Toxinas de Cianobacterias , Femenino , Heterocigoto , Concentración de Iones de Hidrógeno , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microcistinas , Modelos Animales , Péptidos Cíclicos/metabolismo , Saxitoxina/metabolismo , Trihalometanos/metabolismo , Proteína p53 Supresora de Tumor/genética , Uracilo/metabolismo , Contaminación Química del Agua/análisisRESUMEN
The toxicities and uptake mechanisms of two hepatotoxins, namely cylindrospermopsin and lophyrotomin, were investigated on primary rat hepatocytes by using microcystin-LR (a well-known hepatotoxin produced by cyanobacteria) as a comparison. Isolated rat hepatocytes were incubated with different concentrations of hepatotoxins for 0, 24, 48 and 72 h. The cell viability was assayed by the tetrazolium-based (MTT) assay. Microcystin-LR, cylindrospermopsin and lophyrotomin all exhibited toxic effects on the primary rat hepatocytes with 72-h LC(50) of 8, 40 and 560 ng/ml, respectively. The involvement of the bile acid transport system in the hepatotoxin-induced toxicities was tested in the presence of two bile acids, cholate and taurocholate. Results showed that the bile acid transport system was responsible for the uptake, and facilitated the subsequent toxicities of lophyrotomin on hepatocytes. This occurred to a much lesser extent with cylindrospermopsin. With its smaller molecular weight, passive diffusion might be one of the possible mechanisms for cylindrospermopsin uptake into hepatocytes. This was supported by incubating a permanent cell line, KB (devoid of bile acid transport system), with cylindrospermopsin which showed cytotoxic effects. No inhibition of protein phosphatase 2A by cylindrospermopsin or lophyrotomin was found. This indicated that other toxic mechanisms besides protein phosphatase inhibition were producing the toxicities of cylindrospermopsin and lophyrotomin, and that they were unlikely to be potential tumor promoters.
Asunto(s)
Hepatocitos/patología , Oligopéptidos/toxicidad , Uracilo/análogos & derivados , Uracilo/toxicidad , Alcaloides , Animales , Toxinas Bacterianas , Ácidos y Sales Biliares/farmacología , Supervivencia Celular/efectos de los fármacos , Toxinas de Cianobacterias , Inhibidores Enzimáticos/toxicidad , Hepatocitos/efectos de los fármacos , Humanos , Técnicas In Vitro , Células KB , Masculino , Toxinas Marinas/toxicidad , Microcistinas , Oligopéptidos/metabolismo , Péptidos Cíclicos/toxicidad , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Proteína Fosfatasa 2 , Ratas , Ratas Wistar , Uracilo/metabolismoRESUMEN
Cylindrospermopsin (CYN) is a hepatotoxin isolated from the blue-green alga Cylindrospermopsis raciborskii. The role of both glutathione (GSH) and the cytochrome P450 enzyme system (P450) in the mechanism of toxicity of CYN has been previously investigated in in vitro systems. We have investigated the role of GSH and P450 in vivo in mice. Mice pre-treated with buthionine sulphoximine and diethyl maleate to deplete hepatic GSH prior to dosing with 0.2mg/kg CYN showed a seven-day survival rate of 5/13 while the control group rate was 9/14. Dosing mice with 0.2mg/kg CYN produced a small decrease in hepatic GSH with a characteristic rebound effect at 24h. The magnitude of this effect is however small and combined with the non-significant difference in survival rates after GSH depletion suggest depletion of GSH by CYN could not be a primary mechanism for CYN toxicity. Conversely, pre-treatment with piperonyl butoxide, a P450 inhibitor, protected mice against CYN toxicity giving a survival rate of 10/10 compared with 4/10 in the control group (p < 0.05 Chi squared) and was protective at doses up to 0.8 mg/kg, suggesting activation of CYN by P450 is of primary importance in the mechanism of action.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Glutatión/metabolismo , Uracilo/análogos & derivados , Uracilo/metabolismo , Alcaloides , Animales , Toxinas Bacterianas , Butionina Sulfoximina , Toxinas de Cianobacterias , Hígado/enzimología , Masculino , Maleatos/administración & dosificación , Maleatos/farmacología , Ratones , Sinergistas de Plaguicidas/administración & dosificación , Sinergistas de Plaguicidas/farmacología , Butóxido de Piperonilo/administración & dosificación , Butóxido de Piperonilo/farmacologíaRESUMEN
The hepatotoxin cylindrospermopsin (CYN) has been isolated from the cyanobacterium Cylindrospermopsis raciborskii (C. raci.). Efforts to study this toxin have been hampered by the time-consuming requirement to extract it from cultures of the organism. It is usually extracted from lyophilized cells collected from a laboratory culture. Our preliminary work suggested far more of the toxin is available in solution in the culture media than in the cells collected. We have therefore investigated the use of commercially available solid phase extraction sorbents to extract CYN from culture media in which C. raci. has been grown. A range of reverse phase and ion-exchange sorbents were tested across a range of pHs for their ability to retain CYN without success. Subsequently, graphitized carbon cartridges were found to retain CYN strongly. Elution with 5% formic acid in methanol allowed the CYN to be regained for final purification by HPLC. Deoxy-CYN, an analog of CYN can also be extracted using this procedure.
Asunto(s)
Alcaloides/aislamiento & purificación , Cianobacterias , Uracilo/análogos & derivados , Uracilo/aislamiento & purificación , Absorción , Alcaloides/análisis , Alcaloides/química , Toxinas Bacterianas , Técnicas de Química Analítica/métodos , Cromatografía Líquida de Alta Presión , Medios de Cultivo , Toxinas de Cianobacterias , Uracilo/análisis , Uracilo/químicaRESUMEN
The broad-leaved paper bark tree Melaleuca quinquenervia (Cav) (Myrtaceae) was introduced into Florida (USA) early in this century it has proliferated to such an extent that urgent measures are now required to control it. The sawfly Lophyrotoma zonalis (Pergidae) has been introduced as a possible biological control agent due to its ability to defoliate M. quinquenervia. Because toxic D-amino acid- containing peptides have been isolated from some sawfly species, L. zonalis larvae were processed using the previously reported method for the recovery of these compounds. The toxins lophyrotomin (as the free C-terminal acid) and a mixture of pergidin and Val (4)-pergidin were isolated at 0.36 and 0.43% yield of the dried larvae, respectively. Both compounds when dosed intraperitoneally to C57/Bl6 male mice were hepatotoxic with lowest lethal doses of 8 and 32 mg/kg, respectively. The pathology of the liver was different for each compound, with the lophyrotomin free acid causing a periportal haemorrhagic necrosis and the pergidin causing a periacinar coagulative necrosis.
Asunto(s)
Dípteros/química , Oligopéptidos/aislamiento & purificación , Toxinas Biológicas/aislamiento & purificación , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Relación Dosis-Respuesta a Droga , Larva/química , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Oligopéptidos/toxicidad , Péptidos/aislamiento & purificación , Péptidos/toxicidad , Toxinas Biológicas/toxicidadRESUMEN
We have utilised the combination of sensitivity and specificity afforded by coupling high-performance liquid chromatography (HPLC) to a tandem mass spectrometer (MS-MS) to produce an assay which is suitable for assaying glutathione (GSH) concentrations in liver tissue. The sensitivity suggests it may also be suitable for extrahepatic tissues. The method has been validated for GSH using mouse liver samples and also allows the assay of GSSG. The stability of GSH under conditions relevant to the assay has been determined. A 20-microl amount of a diluted methanol extract of tissue is injected with detection limits of 0.2 pmol for GSH and 2 pmol for GSSG. The HPLC uses an Altima C18 (150 x 4.6 mm, 5 microm) column at 35 degrees C. Chromatography utilises a linear gradient from 0 to 10% methanol in 0.1% formic acid over 5 min, with a final isocratic stage holding at 10% methanol for 5 min. Total flow rate is 0.8 ml/min. The transition from the M+H ion (308.1 m/z for GSH, and 613.3 m/z for GSSG) to the 162.0 m/z (GSH) and 355.3 m/z (GSSG) fragments are monitored.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Disulfuro de Glutatión/análisis , Glutatión/análisis , Hígado/química , Espectrometría de Masas/métodos , Animales , Ratones , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The transcription factor PAX6 plays a critical, evolutionarily conserved role in eye, brain and olfactory development. Homozygous loss of PAX6 function affects all expressing tissues and is neonatally lethal; heterozygous null mutations cause aniridia in humans and the Small eye (Sey) phenotype in mice. Several upstream and intragenic PAX6 control elements have been defined, generally through transgenesis. However, aniridia cases with chromosomal rearrangements far downstream of an intact PAX6 gene suggested a requirement for additional cis-acting control for correct gene expression. The likely location of such elements is pinpointed through YAC transgenic studies. A 420 kb yeast artificial chromosome (YAC) clone, extending well beyond the most distant patient breakpoint, was previously shown to rescue homozygous Small eye lethality and correct the heterozygous eye phenotype. We now show that a 310 kb YAC clone, terminating just 5' of the breakpoint, fails to influence the Sey phenotypes. Using evolutionary sequence comparison, DNaseI hypersensitivity analysis and transgenic reporter studies, we have identified a region, >150 kb distal to the major PAX6 promoter P1, containing regulatory elements. Components of this downstream regulatory region drive reporter expression in distinct partial PAX6 patterns, indicating that the functional PAX6 gene domain extends far beyond the transcription unit.
Asunto(s)
Aniridia/genética , Desoxirribonucleasa I/metabolismo , Proteínas del Ojo/genética , Genes Reguladores/fisiología , Proteínas de Homeodominio/genética , Translocación Genética , Animales , Cromosomas Artificiales de Levadura/genética , Cartilla de ADN/química , Proteínas del Ojo/metabolismo , Regulación de la Expresión Génica/genética , Genes Reporteros , Proteínas de Homeodominio/metabolismo , Humanos , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , ARN/metabolismo , Proteínas Represoras , Análisis de Secuencia de ADNRESUMEN
Radiolabelled 14C cylindrospermopsin (CYN) has been prepared and used to investigate the distribution and excretion of CYN in vivo in male Quackenbush mice. At a dose of 0.2 mg/kg (i.e., approx. median lethal dose) the following mean (SD) urinary and faecal recoveries (cumulative) were obtained, respectively: (0-6 hours, n = 4) 48.2 (29.3)%, 11.9 (21.4)%; (0-12 hours, n = 12) 66.0 (27.1)%, 5.7 (5.6)%; (0-24 hours, n = 12) 68.4 (26.7)%, 8.5 (8.1)%. Mean (SD) recoveries from livers at 6 hours were 20.6 (6.4)% (n = 4), at 48 hours 13.1 (7.7)% (n = 8), and 5-7 days were 2.1 (2.1)% (n = 8). A substantial amount (up to 23%) can be retained in the liver for up to 48 hours with a lesser amount retained in the kidneys. The excretion patterns show substantial interindividual variability between predominantly faecal or urinary excretion, but these patterns are not related in any simple manner to the outcome in terms of toxicity. There is at least one methanol-extractable metabolite as well as a nonmethanol-extractable metabolite in the liver. The methanol-extractable metabolite was not found in the kidney and is more hydrophilic than CYN itself on reverse phase.
Asunto(s)
Alcaloides/farmacocinética , Uracilo/análogos & derivados , Uracilo/farmacocinética , Alcaloides/toxicidad , Alcaloides/orina , Animales , Toxinas Bacterianas , Radioisótopos de Carbono , Toxinas de Cianobacterias , Heces/química , Riñón/efectos de los fármacos , Riñón/metabolismo , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos , Miocardio/metabolismo , Factores de Tiempo , Distribución Tisular , Uracilo/toxicidad , Uracilo/orinaRESUMEN
This paper describes the natural occurrence of the toxin, cylindrospermopsin, in two species of cyanobacteria found in Australia. The structure and chemical properties of this compound are described along with a nontoxic analog of cylindrospermopsin. The results of both intraperitoneal (IP) and oral dosing of mice show that hepatotoxicity is the main effect of cylindrospermopsin in vivo, but that a thrombohemorrhagic phenomenon is observed in a proportion of dosed animals. It has been shown that the toxin can be metabolized in vivo and that a bound metabolite occurs in the liver. Cytotoxicity experiments using cell cultures show that cylindrospermopsin is more cytotoxic to isolated rat liver hepatocytes than to other cell types. Risk assessment calculations show that guideline values for cylindrospernopsin in drinking water should lie in the low microgram per liter range.
Asunto(s)
Cianobacterias/química , Uracilo/análogos & derivados , Uracilo/toxicidad , Alcaloides , Animales , Australia , Toxinas Bacterianas , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Toxinas de Cianobacterias , ADN/metabolismo , Aductos de ADN/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratas , Ratas Wistar , Bazo/patología , Uracilo/análisisRESUMEN
Post-mitotic neurons generated at the rhombic lip undertake long distance migration to widely dispersed destinations, giving rise to cerebellar granule cells and the precerebellar nuclei. Here we show that Pax6, a key regulator in CNS and eye development, is strongly expressed in rhombic lip and in cells migrating away from it. Development of some structures derived from these cells is severely affected in Pax6-null Small eye (Pax6(Sey)/Pax6(Sey)) embryos. Cell proliferation and initial differentiation seem unaffected, but cell migration and neurite extension are disrupted in mutant embryos. Three of the five precerebellar nuclei fail to form correctly. In the cerebellum the pre-migratory granule cell sub-layer and fissures are absent. Some granule cells are found in ectopic positions in the inferior colliculus which may result from the complete absence of Unc5h3 expression in Pax6(Sey)/Pax6(Sey) granule cells. Our results suggest that Pax6 plays a strong role during hindbrain migration processes and at least part of its activity is mediated through regulation of the netrin receptor Unc5h3.
Asunto(s)
Cerebelo/embriología , Proteínas de Unión al ADN/metabolismo , Anomalías del Ojo/genética , Proteínas de Homeodominio , Animales , Diferenciación Celular , División Celular , Movimiento Celular , Cerebelo/citología , Cruzamientos Genéticos , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/genética , Células Epiteliales/citología , Células Epiteliales/fisiología , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Ratones , Ratones Noqueados , Neuritas/fisiología , Neuronas/citología , Neuronas/fisiología , Técnicas de Cultivo de Órganos , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box , Proteínas Represoras , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Pyrrolizidine alkaloids are the leading plant toxins associated with disease in humans and animals. Upon ingestion, metabolic activation in liver converts the parent compounds into highly reactive electrophiles capable of reacting with cellular macromolecules forming adducts which may initiate acute or chronic toxicity. The pyrrolizidine alkaloids present a serious health risk to human populations that may be exposed to them through contamination of foodstuffs or when plants containing them are consumed as medicinal herbs. Some pyrrolizidine alkaloids (PA) adducts are persistent in animal tissue and the metabolites may be re-released and cause damage long after the initial period of ingestion. PAs are also known to act as teratogens and abortifacients. Chronic ingestion of plants containing PAs has also led to cancer in experimental animals and metabolites of several PAs have been shown to be mutagenic in the Salmonella typhimurium/mammalian microsome system. However, no clinical association has yet been found between human cancer and exposure to PAs. Based on the extensive reports on the outcome of human exposure available in the literature, we conclude that while humans face the risk of veno-occlusive disease and childhood cirrhosis PAs are not carcinogenic to humans.
Asunto(s)
Dieta , Alcaloides de Pirrolicidina/química , Alcaloides de Pirrolicidina/toxicidad , Animales , Carcinógenos/metabolismo , Ciclo Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas , Miel/toxicidad , Humanos , Hígado/efectos de los fármacos , Leche/toxicidad , Mitosis/efectos de los fármacos , Modelos Biológicos , Modelos Químicos , Plantas Medicinales/toxicidad , Ratas , Teratógenos/metabolismoRESUMEN
D-Amino acid containing peptides have been found to be responsible for sawfly larvae poisoning in many parts of the world. These compounds, unique in the animal kingdom, were isolated from three different species of sawfly indigenous to Australia, Denmark and South America. The octapeptide, lophyrotomin, is the major toxin in the Australian and Danish species and is present in small amounts in the South American sawfly. Pergidin, the main toxin in the South American sawfly, is a heptapeptide containing a phosphoseryl residue. This, as far as we are aware, is the first example of such a peptide to be isolated from an animal source. Small amounts of pergidin have been found in the other two species. All available evidence suggests that both peptides are biosynthesised 'de novo' possibly as a protective device, however it cannot be excluded that microorganisms may be responsible. These compounds are stable to enzymatic breakdown because of their configuration and their strong chemical bonding and lipophilic character provide a potential for residues to remain in the host animal and cause significant changes.
Asunto(s)
Himenópteros/química , Péptidos/toxicidad , Toxinas Biológicas/aislamiento & purificación , Animales , Australia , Dinamarca , Larva/química , América del SurRESUMEN
Monocrotaline is a pyrrolizidine alkaloid known to cause toxicity in humans and animals. Its mechanism of biological action is still unclear although DNA crosslinking has been suggested to a play a role in its activity. In this study we found that an active metabolite of monocrotaline, dehydromonocrotaline (DHM), alkylates guanines at the N7 position of DNA with a preference for 5'-GG and 5'-GA sequences. In addition, it generates piperidine- and heat-resistant multiple DNA crosslinks, as confirmed by electrophoresis and electron microscopy. On the basis of these findings, we propose that DHM undergoes rapid polymerization to a structure which is able to crosslink several fragments of DNA.
Asunto(s)
Alquilantes/farmacología , Reactivos de Enlaces Cruzados/farmacología , Fragmentación del ADN/efectos de los fármacos , Guanina/metabolismo , Calor , Monocrotalina/análogos & derivados , Alquilación/efectos de los fármacos , Animales , Aductos de ADN/química , Aductos de ADN/metabolismo , Aductos de ADN/ultraestructura , Huella de ADN , Fragmentación del ADN/genética , Humanos , Modelos Químicos , Monocrotalina/farmacología , Mutagénesis , Plásmidos/genética , Plásmidos/ultraestructuraRESUMEN
A cluster of 6 cases of equine granulomatous enteritis is described. Aluminium was demonstrated in the tissues and lesions of these horses and in the intimal bodies of intestinal vessels. The relationship between granulomatous lesions, aluminium, acidity and invading microorganisms, particularly parasites, is presented and discussed.
Asunto(s)
Aluminio/toxicidad , Enfermedad de Crohn/veterinaria , Enfermedades de los Caballos/inducido químicamente , Aluminio/farmacocinética , Animales , Huesos/metabolismo , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/patología , Femenino , Enfermedades de los Caballos/patología , Caballos , Riñón/metabolismo , Hígado/metabolismo , Masculino , Espectrofotometría AtómicaRESUMEN
Bracken fern (Pteridium spp.) produces cancer of the urinary bladder and oesophagus in grazing animals and is a suspected human carcinogen. The carcinogenic principle ptaquiloside (PT), when activated to a dienone (APT), forms DNA adducts which eventually leads to tumor. Two groups of female Sprague-Dawley rats were given a chronic dose of 3 mg APT weekly for 10 weeks either by intravenous (i.v.) tail vein or by intragastric (i.g.) route. A third group was given a weekly dose of 6 mg of APT for 3 weeks by the i.g. route corresponding to acute dosing. Both chronic i.v. and i.g. dosed animals showed ischemic tubular necrosis in the kidney but only i.v. dosed animals developed adenocarcinomas of the mammary glands. Acutely dosed i.g. animals produced apoptotic bodies in the liver, necrosis of blood cell precursors in the bone marrow and ischemic tubular necrosis in the kidney but they did not develop tumors. No mutations were found in the H-ras and p53 genes in the mammary glands of either the i.g. rats or the tumor-bearing i.v. rats. However, the mammary glands of a fourth group of rats, which received APT by i.v. and killed before tumor development, carried Pu to Pu and Pu to Py double mutations in codons 58 and 59 of H-ras. This study indicates that the route of administration plays a role in the nature of the disease expression from ptaquiloside exposure. In addition to confirming the role of APT in the PT-induced carcinogenesis our finding suggests that activation of H-ras is an early event in the PT-carcinogenesis model.
Asunto(s)
Carcinógenos/toxicidad , Genes ras , Indanos , Neoplasias Experimentales/inducido químicamente , Sesquiterpenos , Terpenos/toxicidad , Proteínas ras/genética , Animales , Femenino , Expresión Génica , Humanos , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: (1) establish a rat model for investigating ptaquiloside (PT) carcinogenesis via intravenous dosing; (2) determine the role of activated PT (APT) in this model; and (3) monitor changes at molecular (DNA adducts, TNF alpha levels) and cellular (histopathology) levels. METHODS: Sprague-Dawley rats were dosed with PT or APT intravenously for 10 consecutive weeks. One group of animals was sacrificed immediately for TNF alpha and DNA adduct analyses. A second group of animals was kept alive for 30 more weeks to allow for tumour formation. Tissues were collected at the end of the experiment for histopathological studies. RESULTS: Rats dosed with PT or APT showed marked increase in monocyte and TNF alpha levels. These levels remained high even 30 weeks after the last dosing. Analysis of DNA showed the presence of DNA adducts in APT-treated animals in target organs. In addition, 40% of APT-treated rats developed mammary gland carcinomas. CONCLUSION: This is the first study to demonstrate the potential of activated PT as a carcinogen in vivo. In addition, our findings suggest that PT exposure can be monitored using monocyte and TNF alpha levels.
Asunto(s)
Adenocarcinoma/inducido químicamente , Carcinógenos/toxicidad , Aductos de ADN/biosíntesis , Indanos , Neoplasias Mamarias Experimentales/inducido químicamente , Monocitos/patología , Plantas Tóxicas/toxicidad , Sesquiterpenos , Terpenos/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Esquema de Medicación , Femenino , Inyecciones Intravenosas , Recuento de Leucocitos/efectos de los fármacos , Leucocitosis/inducido químicamente , Leucocitosis/metabolismo , Leucocitosis/patología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Monocitos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Terpenos/metabolismoRESUMEN
PURPOSE: To report the results of treatment of a series of patients with superior oblique overaction using the superior oblique silicone tendon-expander technique. METHODS: A chart review of 17 patients with superior oblique overaction who had a total of 26 silicone tendon-expander procedures was conducted. RESULTS: Mean preoperative degree of superior oblique overaction was +2.7. 92% of eyes had mild (+1) or no residual overaction at last postoperative assessment (follow-up range: 6 to 59 months). Of 15 patients with preoperative A-pattern of 10 prism diopter (delta) or more, only two patients (13%) had A-pattern of 10 delta or more at last assessment. Of 13 patients with preoperative hypotropia in primary position, five patients (38%) had no vertical deviation in primary position, and seven patients (54%) had persistent, but less vertical deviation in primary position at last assessment (mean reduced from 11 delta to 4 delta). No patient manifested superior oblique palsy at their last postoperative assessment. CONCLUSIONS: We believe that the superior oblique tendon-expander technique should be strongly considered for the treatment of superior oblique overaction associated with A-pattern or hypotropia in primary position, because it has a high success rate and a low incidence of postoperative complications. Consecutive superior oblique underaction did not occur in this series.
Asunto(s)
Músculos Oculomotores/cirugía , Estrabismo/cirugía , Tendones/cirugía , Dispositivos de Expansión Tisular , Adulto , Niño , Preescolar , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Músculos Oculomotores/fisiopatología , Elastómeros de Silicona , Estrabismo/fisiopatología , Resultado del TratamientoRESUMEN
We demonstrate the use of combined SSCP and heteroduplex analysis in the detection of PAX6 mutations using non-radioactive silver staining. A panel of aniridia patients was screened by this approach and we show that a greater number of mutations was detected than would have been found by running each technique alone. Six previously unreported aniridia mutations in PAX6 are also described..