RESUMEN
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with a high risk of colorectal cancer. This increased cancer risk is thought to result from the cellular damage induced by the inflammatory field. The aim of this study was to determine the pattern and time course of genomic instability occurring in UC-related neoplasia. Sites of cancer, dysplasia, and nondysplasia from 14 UC colectomy cases containing cancer were analyzed for chromosomal alterations by comparative genomic hybridization (CGH) and for microsatellite instability using a series of 10 microsatellite markers. Clonal chromosomal alterations were present in 85% of cancer sites, 86% of dysplasia sites, and 36% of nondysplasia sites. Losses of chromosome 18 or 18q and chromosome 5 or 5q were common in cancer and dysplasia and were occasionally detected in nondysplasia. High-level microsatellite instability was detected in the cancer and dysplasia of two cases. Samples that demonstrated high-level microsatellite instability were unlikely to have chromosomal alterations demonstrable by CGH. These studies suggest that the predominant type of genomic instability in UC-related neoplasia is associated with chromosomal alterations and that this type of genomic instability frequently occurs before the development of histologically defined dysplasia.
Asunto(s)
Transformación Celular Neoplásica/genética , Colitis Ulcerosa/complicaciones , Neoplasias Colorrectales/genética , Adulto , Anciano , Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 20/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 8/genética , Neoplasias Colorrectales/complicaciones , Femenino , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Lesiones Precancerosas/genéticaRESUMEN
BACKGROUND & AIMS: It is unclear whether genomic derangement precedes the histological development of dysplasia in ulcerative colitis (UC)-related neoplastic progression. The primary aim of this study was to determine if chromosomal alterations occur early in the progression pathway of UC-related neoplasia. METHODS: Fluorescence in situ hybridization (FISH) was performed on nuclei dissociated from sites of cancer, dysplasia, and UC-involved nondysplastic epithelium in five UC-related cancer colectomy specimens using a panel of pericentromeric probes. Comparative genomic hybridization (CGH) was used to detect clonal chromosomal losses and gains in DNA extracted from these sites. RESULTS: FISH analysis revealed significant and often dramatic alterations in chromosome copy number compared with controls in all biopsy specimens of cancer, dysplasia, and nondysplastic UC-involved epithelium. Clonal chromosomal losses and gains were detected by CGH in all but one analyzed site of dysplasia and cancer and in two of the five nondysplastic sites. FISH and CGH frequently detected the relative loss of chromosome 18. CONCLUSIONS: Chromosomal alterations may occur early in UC-related neoplastic progression and seem to precede the histological development of dysplasia. Relative loss of 18q may be important in the progression of UC-related neoplasia. The detection of chromosomal alterations as an intermediate end point may prove useful in identifying patients at high risk for the development of colorectal cancer.
Asunto(s)
Aberraciones Cromosómicas/genética , Colitis Ulcerosa/complicaciones , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/patología , Adulto , Deleción Cromosómica , Trastornos de los Cromosomas , Colitis Ulcerosa/patología , Colon/patología , Progresión de la Enfermedad , Epitelio/patología , Femenino , Dosificación de Gen , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Hibridación de Ácido NucleicoRESUMEN
It has been widely held that systemic acidemia represents the proximate event signaling the kidney to elicit its acidification response to chronic metabolic acidosis. However, a previous study from this laboratory has cast serious doubt on the validity of this conventional viewpoint. When a large acid load (7 mEq/kg/day) was fed chronically to dogs as HCl, H2SO4 or HNO3, net acid excretion increased similarly in all three groups of animals despite wide variability in the prevailing systemic acid-base composition. Marked or moderate hypobicarbonatemia and acidemia were observed in the HCl- or H2SO4-fed animals respectively, but strikingly, plasma [HCO3-] and pH did not change significantly from the control in the HNO3-fed animals. That study concluded that the renal response to chronic mineral acid feeding appears to be triggered, not by acidemia, but by the interplay of sodium delivery to and sodium avidity of the distal nephron as modulated by the reabsorbability of the "acid" anion. We have re-examined the above provocative conclusion in the light of the observation that the only evidence for a dissociation of the renal response from systemic acidemia in that study was derived from preprandial (8:00 a.m.) blood samples obtained some 23 hr after the ingestion of the daily acid load (administered at 9:00 a.m.). We investigated the diurnal variation of plasma acid-base composition in two groups of dogs fed chronically a large acid load (7 mEq/kg/day) as either HCl or HNO3. Both groups exhibited significant diurnal oscillations of plasma acid-base composition.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Acidosis/fisiopatología , Riñón/fisiopatología , Equilibrio Ácido-Base , Acidosis/sangre , Animales , Bicarbonatos/sangre , Ritmo Circadiano , Dieta , Perros , Femenino , Ácido Clorhídrico/administración & dosificación , Concentración de Iones de Hidrógeno , Riñón/metabolismo , Nitratos/administración & dosificación , Ácido NítricoRESUMEN
Eighteen patients on chronic dialysis (15 haemodialysis, three peritoneal) were evaluated to determine whether certain clinical features and/or in vitro indicators of immune function correlated with the response to hepatitis B vaccine. Only 44% of patients developed antibody to hepatitis B surface antigen (anti-HBS) following vaccination and neither duration of dialysis, history of renal transplant, peripheral T cell numbers, T4/T8 ratios, nor mitogen induced lymphocyte proliferation correlated with response to vaccination. Advanced age, history of multiple blood transfusions and depressed levels of IgM may be associated with a poor antibody response to the vaccine. Future studies need to consider these variables when evaluating immunogenicity of new hepatitis B vaccine preparations.
Asunto(s)
Hepatitis B/prevención & control , Diálisis Renal , Vacunas contra Hepatitis Viral/uso terapéutico , Adulto , Factores de Edad , Anciano , Anticuerpos Antivirales/biosíntesis , Transfusión Sanguínea , Femenino , Virus de la Hepatitis B/inmunología , Humanos , Inmunoglobulina M/análisis , Masculino , Persona de Mediana EdadRESUMEN
The antithyroid drugs propylthiouracil and methimazole exert their effects on the thyroid gland by inhibiting thyroid peroxidase. In addition to this effect, these drugs have been reported to inhibit prostaglandin production in both the thyroid gland and the kidney. The purpose of our studies was to evaluate the mechanism of the effects of these drugs on prostaglandin production. Both propylthiouracil and methimazole reversibly inhibited prostaglandin E2 production in both inner medullary slices and isolated renal papillary collecting tubule cells. The inhibition of arachidonic acid-induced increases in PGE2 production indicated that the effects of methimazole and propylthiouracil were on the enzyme complex prostaglandin H synthase, and not on the phospholipase mechanisms responsible for the release of arachidonic acid from tissue phospholipids. Propylthiouracil inhibited both arachidonic acid and hydrogen peroxide-dependent binding of 14C-N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide to protein, indicating that the effect of propylthiouracil is on the hydroperoxidase and not on the cyclooxygenase component of prostaglandin H synthase. Our data also indicate the potential of the antithyroid drugs for inhibition of metabolism of drugs and xenobiotics by prostaglandin H synthase. Metabolism of both methimazole and propylthiouracil by the hydroperoxidase component of prostaglandin H synthase was demonstrated. It is proposed that this interaction with the hydroperoxidase component of prostaglandin H synthase is at least in part the mechanism by which propylthiouracil and methimazole inhibit prostaglandin production. The inhibition of tissue peroxidase provides these agents with the capability to prevent the peroxidatic metabolism of drugs and xenobiotics.
Asunto(s)
Antitiroideos/farmacología , Inhibidores de la Ciclooxigenasa , Médula Renal/enzimología , Prostaglandinas E/biosíntesis , Animales , Ácido Araquidónico , Ácidos Araquidónicos/farmacología , Biotransformación , Bradiquinina/farmacología , Dinoprostona , FANFT/metabolismo , Técnicas In Vitro , Túbulos Renales Colectores/metabolismo , Masculino , Metimazol/metabolismo , Metimazol/farmacología , Propiltiouracilo/metabolismo , Propiltiouracilo/farmacología , Unión Proteica/efectos de los fármacos , ConejosAsunto(s)
Riñón/patología , Obstrucción Ureteral/patología , Animales , Humanos , Hidronefrosis/patología , Hipertrofia , NefrectomíaRESUMEN
Severe volume depletion from diuresis can produce potentially life-threatening hypotension, coronary and cerebral insufficiency, and significant renal impairment. Appropriate precautions include initiating diuretics at low doses and monitoring patients closely. Metabolic alkalosis, another frequent side effect of diuretic therapy, can usually be diagnosed by near absence of chloride in the urine. Corrective agents used include potassium chloride and sodium chloride.