RESUMEN
BACKGROUND: The PALB2 (FANCN) gene was identified as a component of endogenous BRCA2 complex that encodes a DNA repair protein participating along with BRCA1 and BRCA 2 proteins in DNA double-strand break repair. Hereditary PALB2 mutations are associated with an increased risk of breast and pancreatic cancers in heterozygotes. Breast cancer risk for PALB2 mutation carriers has recently been estimated at 33-58% depending on family history of breast cancer; pancreatic cancer risk in carriers of PALB2 mutations has not been precisely quantified, yet. MATERIALS AND RESULTS: Results of a study identifying PALB2 mutations in high-risk, BRCA1/2-negative, breast and/or ovarian cancer patients in the Czech Republic indicate that the frequency of hereditary PALB2 mutations in our population is quite high. Interestingly, almost 20% of all recognized mutations comprised large genomic rearrangements. The highest proportion of PALB2 mutations (comparable with the number of mutations reported for BRCA2) was found in a subgroup of hereditary breast cancer patients (5.5%). Frequency of mutations in an independent group of Czech unselected pancreatic cancer patients was approximately 1.3%. CONCLUSION: Considering the frequency of pathogenic, hereditary PALB2 mutations in our population, their phenotypic similarity to BRCA2, and expected risk of breast cancer associated with PALB2 mutations, its screen-ing (including large genomic rearrangements) should be encouraged in patients from hereditary breast cancer families. The follow-up of pathogenic PALB2 mutation carriers should be similar to that in BRCA2 mutation carriers, enabling early diagnosis, prevention, and possible targeted therapy. Preventive surgical interventions for the carriers could be considered in case of strong family cancer history and evident segregation of a pathogenic mutation with a tumor phenotype. Additional analysis of various cancer patient populations and further meta-analyses will be necessary for accurate assessment of PALB2 gene penetrance and its significance for the risk of pancreatic and other cancers.
Asunto(s)
Pruebas Genéticas , Mutación , Proteínas Nucleares/genética , Proteínas Supresoras de Tumor/genética , Neoplasias de la Mama/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Femenino , HumanosRESUMEN
The two major susceptibility genes, BRCA1 and BRCA2, are involved in hereditary breast and ovarian cancer syndrome. Early detection of mutation carriers has crucial clinical importance, as it allows identification of women who may benefit from intensive clinical follow-up or prophylactic surgery. Generally accepted inclusion criteria for BRCA1/2 mutation testing are based either upon family history of breast or ovarian cancer or young age at cancer diagnosis. In order to analyze the impact of BRCA1/2 mutations on breast cancer development in the Czech population and to confront the clinical and histopathological data of mutation carriers with current criteria for mutation testing we examined the frequency of mutations in unselected breast cancer cases. Mutational analysis of BRCA1/2 genes performed in 679 unselected female breast cancer patients included all recurrent deleterious alterations previously identified in the Prague area and truncating mutations in the whole exon 11 of BRCA1. Within analyzed gene sequences more than 80% of mutations were identified previously in high-risk patients. A total of 16 breast cancer patients (2.4%) carried a mutation. BRCA1 mutations were identified in 14 (2.1%) whereas BRCA2 in 2 (0.3%) women. Family history of ovarian cancer was a strong predictor of a BRCA1/2 mutation (OR = 8.3; p = 0.01), however, family history of breast cancer was not indicative of carrier status. A significant association between medullary breast cancer and mutation status was observed. Current criteria for BRCA1/2 mutation testing would distinguish only 6 out of 16 (37.5%) carriers identified in our study. Ten breast cancer patients with confirmed BRCA1/2 germ-line mutation exhibited no clinical characteristics that would predict their carrier status. Therefore, we believe that the testing for BRCA1/2 mutations in the Czech Republic may not be restricted only to high-risk patients. Our results indicate that analysis of locally prevalent BRCA1/2 mutations in all breast cancer patients might extend substantially the percentage of identified mutation carriers.
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Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Tamización de Portadores Genéticos , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: Detection of melanoma cells in peripheral blood is a promising method for monitoring haematogenous spread of melanoma cells. It enables us to detect early metastasis and to better stratify candidates for adjuvant immunotherapy. Inconsistent data on the sensitivity and clinical relevance of this method have been reported. STUDY DESIGN: We developed a multimarker real-time reverse transcription-PCR (RT-PCR) for quantification of five melanoma markers: Melan-A, gp100, MAGE-3, MIA and tyrosinase. In this prospective study, 65 patients with resected cutaneous melanoma stage IIB-III were screened. Peripheral blood samples were collected every 3 months for the following 18 months, and circulating melanoma cells were examined and compared with clinical staging results. RESULTS: Eighteen patients relapsed during the trial and showed different types of melanoma progression. All these patients experienced statistically significant tumour marker elevation in the period from 0 to 9 months before the disease progression. MAGE-3 was the most sensitive progression marker. In patients with progression, we observed three concordant positive markers in 39% of cases, two concordant positive markers in 28%, and finally one marker in 33%. CONCLUSIONS: This report describes a multiple-marker real-time RT-PCR, which is able to provide quantitative data on melanoma markers in the peripheral blood of melanoma patients. Measurement of the studied molecular markers in our hands represents a prognostic factor and a useful method for early detection of metastasis and treatment response of melanoma patients.
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Biomarcadores de Tumor/sangre , Melanoma/sangre , Melanoma/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Adulto , Anciano , Antígenos de Neoplasias/sangre , Antígenos de Neoplasias/genética , Antígenos de Carbohidratos Asociados a Tumores/sangre , Antígenos de Carbohidratos Asociados a Tumores/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Humanos , Antígeno MART-1 , Masculino , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Monofenol Monooxigenasa/sangre , Monofenol Monooxigenasa/genética , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Estudios Prospectivos , ARN Mensajero/sangre , ARN Mensajero/genética , Sensibilidad y Especificidad , Antígeno gp100 del MelanomaRESUMEN
Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5-10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the majority of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian cancer risk group to characterize the spectrum of its mutations in the Czech Republic. Five overlapping fragments amplified on both genomic DNA and cDNA were used to screen for the whole protein-coding sequence of the BRCA1 gene. These fragments were analysed by the protein truncation test (PTT) and direct sequencing. Three inactivating mutations were identified in the group of 30 Czech ovarian cancer patients: the 5382insC mutation in two unrelated patients and a deletion of exons 21 and 22 in another patient. In addition, we have found an alternatively spliced product lacking exon 5 in two other unrelated patients. The 5382insC is the most frequent alteration of the BRCA1 gene in Central and Eastern Europe. The deletion of exons 21 and 22 affects the BRCT functional domain of the BRCA1 protein. Although large genomic rearragements are known to be relatively frequent in Western European populations, no analyses have been performed in our region yet.
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Genes BRCA1 , Neoplasias Ováricas/genética , Adulto , Anciano , Neoplasias de la Mama/genética , República Checa , Análisis Mutacional de ADN , Femenino , Mutación de Línea Germinal/genética , Humanos , Persona de Mediana EdadRESUMEN
Part of breast and ovarian cancer cases develops on the hereditary predisposition, i.e. mutation in one of predisposing genes. Although this proportion is relatively small, 5-10% of all breast and ovarian carcinomas, it represents a group with clearly defined etiologic factor. Predictive analysis of unaffected family members allows to identify individuals at high risk of cancer and to include them into the programme of primary and secondary cancer prevention. Following article presents basic review of the hereditary predisposition to breast and ovarian cancer focusing especially on BRCA1 and BRCA2 genes, which are responsible for almost three-quarters of those hereditary tumours.
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Neoplasias de la Mama/genética , Neoplasias Ováricas/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad , HumanosRESUMEN
OBJECTIVE: Mutations in the BRCA1 gene confer a high risk for the development of breast or ovarian cancer. The aim of this study was to establish the frequency and spectrum of BRCA1 mutations in Czech breast or ovarian cancer families. SUBJECTS AND METHODS: We have screened 28 patients with early-onset cancer and 54 patients from risk families for germ-line mutations in BRCA1. All coding exons were analyzed by the protein truncation test (PTT) and the reverse transcription polymerase chain reaction (RT-PCR). Detected variants were characterized by direct sequencing of PCR products. RESULTS: Five distinct deleterious mutations have been identified in six families. All the mutations led to the premature termination of translation. One mutation was detected in a group of 11 (9.1%) patients with early-onset breast cancer. Two mutations were observed in 32 (6.3%) families with a history of breast cancer only. Three mutations were found in 22 (13.6%) families with both breast and ovarian cancer. The 5382insC mutation was the only abnormality detected twice. In addition, two variant transcripts, the loss of exon 5 and in-frame 3-bp deletion at the beginning of exon 8, were identified only at the cDNA level. Their biological significance remains unknown. CONCLUSION: PTT analysis enables examination of long PCR products. The technique is useful for rapid detection of mutations in hereditary breast cancer.
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Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Genes BRCA1 , Mutación de Línea Germinal/genética , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Adulto , Edad de Inicio , República Checa/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The authors investigated a group of 51 patients (29 men and 22 women) with intraocular melanoma: 41 patients with melanoma of the chorioid, 10 patients with melanoma of the ciliary body. They evaluated the clinical and pathological finding according to the TNM classification recommended by UICC (International Union Against Cancer). In all investigated patients they assessed circulating tumour cells (melanocytes) in the peripheral blood stream based on the detection of mRNA tyrosinase and marker MART 1. When evaluating the presence of markers according to the diagnosis irrespective of time, they found in patients in the clinical stage of T2 choroidal melanoma a 19% positivity of different markers and very rare a concurrent positivity of both markers. Patients in the clinical stage T3 had a 51% positivity of one marker and 34% concurrent positivity of both markers. In melanoma of the ciliary body evidence of individual markers was positive in 17% and only in 11% both markers were positive concurrently. On comparison of therapeutic procedures from the aspect of development in time in patients treated by brachytherapy only rare positivity was found at the time of administration the radioactive plaque, following an eight-month interval after brachytherapy the positivity of markers increased to 28%. On evaluation of markers of choroidal melanoma and ciliary body melanoma resolved by enucleation had their positivity at the time of operation was 36%, and during check-ups up to one year or longer it persisted at similar levels. Concurrent presence of both markers before this operation was rare, during postoperative check-up examinations it was within a range of 23 and 33%. The presence of both markers was repeatedly proved in five patients with chooidal melanoma after enucleation of the eye, in four of them in direct correlation with a metastatic process.
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Neoplasias del Ojo/diagnóstico , Melanoma/diagnóstico , Células Neoplásicas Circulantes , Antígenos de Neoplasias , Biomarcadores de Tumor/sangre , Neoplasias del Ojo/sangre , Femenino , Humanos , Antígeno MART-1 , Masculino , Melanoma/sangre , Monofenol Monooxigenasa/genética , Proteínas de Neoplasias/análisis , Células Neoplásicas Circulantes/química , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The benefit of percutaneous transluminal angioplasty (PTA) of transplant renal artery stenosis for ischemic nephropathy may be adversely affected by rejection or other complications. As a result, assessment of the effect of PTA on renal function or blood pressure is often difficult. In this paper, we evaluated the effect of PTA using the method of integrated glomerular filtration rate (GFR) based upon the area under the curve over a follow-up period (AUC0-1), to express the level of GFR in a simple manner despite its significant fluctuations. A similar procedure was used to evaluate mean arterial pressure (MAP). The method was employed to assess the outcome in 20 individuals before PTA, and 1, 3, 6, 9 and 12 months after PTA. In eight cases, rejection was detected while there was one case of glomerulonephritis in the graft during the follow-up period. Evaluation (AUCCcr)0-12 related to the integrated pre-PTA value of Ccr [(Ccr)0 x 12] revealed a rise in GFR by more than 20 % in 65 % of cases. No improvement was observed in seven individuals with post-PTA complications. When assessing the integrated value of MAP, success of PTA (a reduction by at least 10 %) was found in 85 % of cases. No significant correlation was found between the relative changes of integrated GFR and MAP. Our data suggest that evaluation of the integrated value of GFR or MAP on the basis of AUC0-t allows to characterize, in a simple manner, the level of graft function and MAP throughout the follow-up period in individual cases. Furthermore, it may provide additional information on the average values obtained at different time intervals after the therapeutic procedure.
Asunto(s)
Angioplastia de Balón , Presión Sanguínea , Tasa de Filtración Glomerular , Trasplante de Riñón , Obstrucción de la Arteria Renal/cirugía , Resultado del Tratamiento , Adulto , Femenino , Rechazo de Injerto , Humanos , Isquemia/cirugía , Riñón/irrigación sanguínea , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana EdadRESUMEN
The benefit of percutaneous transluminal angioplasty (PTA) of renal transplant artery stenosis for renal hemodynamics is frequently adversely affected by rejection or another complication. As a result, evaluation of the effect of PTA is often difficult. Our study was designed to assess the effect of PTA using a method of integrated value of the glomerular filtration rate (GFR) calculated on the basis of the area under the curve over the follow-up period (AUC0-t). A similar procedure was employed to evaluate mean arterial pressure (MAP). The method was used to assess the outcome in 20 individuals before to PTA, and at 1, 3, 6, 9 and 12 months after angioplasty. A rejection episode was diagnosed in eight cases and glomerulonephritis of the graft in one. Using the evaluation of (AUCCcr)0-12 in relation to the integrated value before PTA (Ccr) x 12, a rise in GFR > 20% was found in 65% of cases. PTA failure was observed in seven individuals developing post-PTA complications. When assessing the integrated value of MAP, PTA was found to be successful (a reduction by at least 10%) in 85% of cases. No significant correlation was demonstrated between the integrated values of GFR and MAP. The results support the assumption that the evaluation of the integrated values of GFR or MAP using AUC0-t allows to characterize, in a simple manner, the degree of renal transplant function or MAP throughout the follow-up period, and to furnish additional information to the values obtained at individual time intervals after the therapeutic procedure.
Asunto(s)
Angioplastia de Balón , Presión Sanguínea , Tasa de Filtración Glomerular , Trasplante de Riñón/fisiología , Obstrucción de la Arteria Renal/terapia , Adulto , Área Bajo la Curva , Femenino , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Obstrucción de la Arteria Renal/etiología , Obstrucción de la Arteria Renal/fisiopatologíaRESUMEN
UNLABELLED: Renovascular disease frequently escapes clinical diagnosis. Critical stenosis of the renal artery causes hypoperfusion of the kidney which in turn is the cause of renovascular hypertension and ischaemic nephropathy. Detection of renovascular disease in the population of hypertonic patients should be based on clinical symptoms. In a selected group one of the imaging methods can be used. The increasing number of patients with stenosis of the renal artery is indicated for percutaneous transluminal angioplasty or surgical revascularization as the function of the ischaemized kidney is a risk. Medicamentous treatment of hypertension, which is usually successful, is indicated in patients with atherosclerosis with a history of cardiovascular complications or a high risk of the latter. The contribution and risk of different therapeutic methods must be considered individually with regard to the clinical condition as well as the findings on the blood vessels. CONCLUSION: A unique contribution of angioplasty in stenosis of the renal artery or surgical revascularization is the possibility to improve renal haemodynamics and thus renal function. Prevention of ischaemic nephropathy calls for early diagnosis of renovascular disease.
Asunto(s)
Hipertensión Renovascular , Humanos , Hipertensión Renovascular/diagnóstico , Hipertensión Renovascular/etiología , Hipertensión Renovascular/terapiaRESUMEN
From previous work it is known that in subjects with a transplanted kidney treated with cyclosporin A hyperkalaemia may develop even if the glomerular filtration rate is within the normal range or only slightly reduced. The mechanism of this defect was not elucidated so far. In the present work the authors try to study the question whether and how renal potassium excretion by the transplanted kidney is influenced by the intensity of sodium excretion. Focused on renal excretion of potassium, sodium, chlorides, all osmotically active substances, glomerular filtration rate (polyfructosan clearance) and renal plasma flow (paraaminohippuric acid clearance) the authors examined 12 patients after transplantation of the kidney from a cadaverous donor (group A), 11 subjects after unilateral nephrectomy for the purpose of donorship for transplantation (group B) and 27 subjects after nephrectomy on account of a pathological process in one kidney (group C). The glomerular filtration rate in the investigated groups was greater than 1.0 ml/s/1.73 m2. The mean value of the fractional potassium excretion (FEK) in group A was 15.2 (+/- 6.3)%, in group B 18.4 (+/- 6.6)% and in group C 20.1 (+/- 8.6)%. The value of FEK in group A was significantly lower than in group C (p < 0.01). Groups B and C did not differ significantly in the mean value of FEK. Between values of FEK and FENA a significant direct correlation was found (r = 0.621, p < 0.001) in the group of subjects with a single kidney of their own (B + C). On the other hand, this correlation was not found in subjects with a transplanted kidney (A). The achieved results support the idea that in subjects with a transplanted kidney treated with cyclosporin A there are deviations in tubular potassium transport even when its serum level is not elevated. This deviation is manifested by lower FEK values and also by and inadequate response of the distal tubule to an increased sodium supply by increased tubular potassium secretion. The authors assume that when drugs with a potential potassium retaining effect are administered to subjects with a transplanted kidney it is important to check carefully the serum potassium level even when the glomerular filtration rate is within normal limits or only slightly reduced.
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Trasplante de Riñón/fisiología , Potasio/orina , Adulto , Ciclosporina/farmacología , Femenino , Tasa de Filtración Glomerular , Humanos , Inmunosupresores/farmacología , Masculino , Persona de Mediana EdadRESUMEN
Treatment of disease by gene transfer into the genome of target host cells has become possible. This article presents current clinical applications of gene therapy and describes possible corrections of genetic defects.
Asunto(s)
Terapia Genética , HumanosRESUMEN
The ability to direct gene transfer to particular target cells is important to achieve a therapeutic effect. In this review we describe the development of methods for gene delivery to specific cell types.
Asunto(s)
Terapia Genética , Vectores Genéticos , Humanos , RetroviridaeRESUMEN
The differences in glomerular filtration rate (GFR) based on creatinine clearance (Ccr) or obtained by the more exact methods are caused mainly by tubular creatinine secretion. In this study, we monitored creatinine clearance (Ccr), GFR on the basis of polyfructosan renal clearance (C(PF)) and parameters characterizing tubular creatinine secretion (Ccr/C(PF), Ccr - C(PF), Tcr/C(PF) x 100) in 12 individuals with renal grafts (Group A), 12 kidney graft donors for related transplantation (Group B), and in 27 individuals undergoing nephrectomy for a pathological process in one kidney (Group C). In the monitored groups, C(PF) and Ccr values were within the limits consistent with the normal function of a single kidney in a healthy individual. The values characterizing tubular creatinine secretion in Group A did not differ significantly from those obtained in Groups B and C. However, the parameters showed a wide range in all groups. In seven individuals with a renal graft, all the above functional parameters were monitored at three-month intervals for a period of 24 months. Significant differences in the time courses of Ccr and C(PF) due to marked intra-individual fluctuations were found in tubular creatinine secretion. The findings suggest that the rate of tubular creatinine secretion in the renal graft does not differ significantly from that in individuals with a single native (normally functioning) kidney. However, there are large inter-individual differences. The large intra-individual fluctuations in tubular creatinine secretion in the kidney graft result in significant differences in the time courses of Ccr and C(PF) and a possibility of erroneous evaluation of graft function if based exclusively on Ccr.
Asunto(s)
Creatinina/metabolismo , Trasplante de Riñón , Túbulos Renales/metabolismo , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular/fisiología , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Renales/metabolismo , Enfermedades Renales/fisiopatología , Enfermedades Renales/cirugía , Masculino , Persona de Mediana Edad , Nefrectomía , Cuidados Posoperatorios , Periodo Posoperatorio , Factores de TiempoRESUMEN
In subjects with a transplanted kidney frequently tubular functions are impaired even when the glomerular filtration is within the normal range. In the present work the authors are dealing in more detail with the problem of tubular sodium reabsorption in the transplanted kidney. The purpose of the investigation was to assess to what extent these changes can be explained as the consequence of adaptational changes due to reduction of the number of nephrons and whether these changes have to be taken into consideration in the differential diagnosis of acute changes of graft function. The glomerular filtration rate (GF) was assessed on the basis of polyfructosan clearance, fractional sodium and potassium excretion (FENa and FEK) in a group of 12 subjects with a stabilized function of a transplanted kidney (group A), in 11 subjects after nephrectomy in healthy donors for transplantation (group B) and in 27 subjects after nephrectomy indicated for a pathological process in one kidney (group C). The mean values of GFR were as follows: Group A: 1.21 (+/- 0.19)ml/s/1.73 sq.m Group B: 1.19 (+/- 0.17)ml/s/1.73 sq.m Group C: 1.24 (+/- 0.21)ml/s/1.73 sq.m The mean values of GFR in different groups did not differ significantly. The mean values of FENa in different groups were as follows: Group A: 3.02 (+/- 1.59)% Group B: 2.05 (+/- 0.77)% Group C: 2.01 (+/- 1.17)% The mean value of FENa in group A was significantly higher than the mean value in group B (p < 0.01) and in group C (p < 0.01). The assembled findings support the idea that reduced tubular sodium reabsorption in the transplanted kidney (with a stabilized value of GFR) cannot be explained only as a manifestation of adaptation of tubular function as a result of the reduced number of functioning nephrons. The persisting osmotic sodium diuresis in the transplanted kidney must be viewed from the aspect of possibly impaired water preservation and the development of dehydration associated with a drop of GFR and must be differentiated from rejection.
Asunto(s)
Trasplante de Riñón/fisiología , Riñón/metabolismo , Sodio/metabolismo , Adolescente , Adulto , Femenino , Tasa de Filtración Glomerular , Humanos , Donadores Vivos , Masculino , Persona de Mediana Edad , Nefrectomía , Potasio/metabolismoRESUMEN
UNLABELLED: The objective of the work was to evaluate the contribution of percutaneous transluminal angioplasty (PTA) to treatment of hypertension and the graft function of a transplanted kidney. Angioplasty of the graft artery was performed in 39 patients. Technical success rate: 85%. COMPLICATIONS: 13%--in particular during the first years after introduction of the method. Twenty seven patients were followed up on a long-term basis. Changes of the median arterial pressure (MAP) were evaluated as well as glomerular filtration (GF) assessed by creatinine clearance. Mean values: [table: see text] A statistically significant (p < 0.01) reduction of the median arterial pressure (drop by > 10 mm Hg) along with reduction of the number of antihypertensive drugs was recorded in 70% of the patients during the first year and in 80% kidney recipients in investigations extending beyond one year. A significant increase of glomerular filtration (by > 20%) was found in 40% of the patients, on average the rise was insignificant. During the follow up period 13 kidney recipients were transferred to a dialyzation programme due to failure of the grafts as a result of rejection. CONCLUSION: Percutaneous transluminal angioplasty of a stenosis of the graft artery is the method of first choice in the treatment of hypertension. It is of fundamental importance also in rare cases in order to preserve or improve graft function and thus delay dialyzation treatment.
Asunto(s)
Angioplastia de Balón , Trasplante de Riñón/efectos adversos , Obstrucción de la Arteria Renal/terapia , Adulto , Femenino , Humanos , Hipertensión Renal/etiología , Masculino , Obstrucción de la Arteria Renal/etiologíaRESUMEN
To evaluate the role of insulin and hypertriglyceridaemia in the regulation of renal haemodynamics and sodium handling in insulin-dependent diabetes mellitus (IDDM), 11 IDDM patients without microalbuminuria and 13 weight-, age-, protein intake- and sex-matched healthy control subjects were studied. Clearances of inulin (Cin), para-amino-hippuric acid (CPAH), sodium (CNa), and lithium (CLi) were measured in four 60-min clearance periods (periods I, II, III and IV) during isoinsulinaemia with lipid emulsion infusion (study 1), a hyperinsulinaemic isoglycaemic clamp with Intralipid infusion (study 2), and during time-controlled isoinsulinaemia (study 3). We found that Cin, CPAH and filtration fraction were comparable in IDDM and control subjects, whereas CNa was decreased in diabetic subjects (2.01 +/- 1.11 vs 3.03 +/- 1.32 ml/min; p < 0.05) due to elevations of proximal tubular fractional and absolute reabsorptions of sodium (p < 0.05). Insulin infusion did not affect Cin, increased CPAH (p < 0.05) and, consequently, lowered the filtration fraction (p < 0.01) in both groups. While acute hyperinsulinaemia resulted in increases in distal tubular fractional and absolute reabsorptions of sodium (p < 0.01) contributing to a fall in CNa (p < 0.01) in control subjects, in diabetic subjects the sodium-retaining effect of insulin was not significant. The lipid emulsion did not alter any of the estimated parameters. We conclude that IDDM without microalbuminuria is associated with a tendency to sodium retention which is not aggravated by insulin when compared to control subjects. Acutely induced hypertriglyceridaemia does not alter renal haemodynamics or renal sodium handling.
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Diabetes Mellitus Tipo 1/fisiopatología , Emulsiones Grasas Intravenosas/farmacología , Hemodinámica/efectos de los fármacos , Inulina/farmacología , Riñón/fisiopatología , Circulación Renal/efectos de los fármacos , Sodio/orina , Adulto , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/orina , Emulsiones Grasas Intravenosas/administración & dosificación , Ácidos Grasos no Esterificados/sangre , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Técnica de Clampeo de la Glucosa , Hemoglobina Glucada/análisis , Humanos , Infusiones Intravenosas , Inulina/administración & dosificación , Inulina/sangre , Inulina/farmacocinética , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Túbulos Renales/efectos de los fármacos , Túbulos Renales/fisiología , Túbulos Renales/fisiopatología , Litio/farmacocinética , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Valores de Referencia , Triglicéridos/sangre , Ácido p-Aminohipúrico/farmacocinéticaRESUMEN
We studied the particle size distribution of plasma high-density lipoproteins (HDL) by gradient gel electrophoresis and by assay of cholesterol esterification rate (FERHDL) in plasma depleted of very low (VLDL) and low-density (LDL) lipoproteins in 32 hypertensive women (53 +/- 10 y old) and in an age-matched group of 21 apparently healthy women. There were no significant differences between the groups with respect to their plasma total, HDL- and LDL-cholesterol. The plasma triglyceride (TG) concentration was significantly higher in the group of hypertensive women, and HDL-free cholesterol was significantly lower in the hypertensive group. There were highly significantly differences in the relative proportions of HDL subclasses between the hypertensive and control women: HDL2b was significantly lower and HDL3b,c was significantly higher in hypertensive patients compared to controls. FERHDL was 12 +/- 4%/h in the control group and 18 +/- 6%/h in patients with hypertension (p < 0.001). There was a strong positive correlation between FERHDL and the relative content of HDL3b,c, and a strong negative correlation between FERHDL and HDL2b in both groups. Comparison of subgroups of healthy and hypertension pre- and postmenopausal women revealed, apart from age, no significant differences between the healthy subjects in any of the above parameters.
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Ésteres del Colesterol/sangre , Colesterol/sangre , Hipertensión/sangre , Lipoproteínas HDL/sangre , Adulto , Anciano , Electroforesis/métodos , Femenino , Humanos , Lipoproteínas HDL/clasificación , Menopausia/sangre , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
BACKGROUND: The cause of hyperalbuminuria in hypertonic patients can be functional or irreversible structural changes. The objective of the present investigation was an attempt to differentiate these two possibilities by comparing data of hypertonic patients with normal albuminuria (albumin excretion < 20 micrograms/min) and those with microalbuminuria in patients with renovascular hypertension by comparing findings after successful percutaneous transluminal angioplasty of the renal arteries (n = 8). METHODS AND RESULTS: The authors examined 20 patients with normal albuminuria (12 men and 8 women, mean age 46 years) and 20 patients with microalbuminuria (12 men and 8 women, mean age 49 years). Of these patients 8 were examined repeatedly after angioplasty. The examination was made in the morning, renal haemodynamics were assessed by the infusion technique (clearance of polyfructosan and paraaminohippuric acid), in blood and urine the albumin and IgG concentration (bromcresol purpur-Lachema Brno and immunoturbidometrically-Tina-quant Boheringer Mannheim). In hypertonic patients with microalbuminuria a significantly higher (p < 0.001) IgG excretion was found (14.1 as compared with 5.12 micrograms/min.) and a reduced ratio of IgG clearance to albumin clearance (p < 0.001), 0.73 as compared with 1.60. After successful angioplasty of the renal arteries there was a significant drop of the blood pressure (p < 0.05) and of the renal vascular resistance as well as a significant decrease of albuminuria (p < 0.05) on average from 137 to 48 micrograms/min. The quantitative improvement of albuminuria, however, did not go beyond the discrimination value for microalbuminuria. CONCLUSIONS: The results suggest that microalbuminuria in hypertensive patients is as a rule a manifestation of structural renal changes, while also functional and reversible changes participate. The asset of treatment of hypertension by angioplasty of the renal arteries was manifested not only in the renal haemodynamics but also by reduced albuminuria.
Asunto(s)
Albuminuria , Hipertensión/fisiopatología , Circulación Renal , Femenino , Humanos , Hipertensión/orina , Hipertensión Renovascular/fisiopatología , Hipertensión Renovascular/orina , Inmunoglobulina G/orina , Masculino , Persona de Mediana EdadRESUMEN
Thymidine kinase (EC 2.7.1.21) is an enzyme supporting DNA synthesis under conditions of increased cell proliferation. Although it has proved to be a useful marker for various malignant diseases, it has not been tested in malignant melanoma. Thymidine kinase activity was measured by means of a radioenzymic assay in two classical animal models of melanoma disease--B16 and Cloudman S91 melanoma-bearing mice. Tumour cell proliferation was assessed histochemically by measuring the expression of proliferating cell nuclear antigen (PCNA). Tumour cytosolic specific thymidine kinase activity was found to be higher in less pigmented Cloudman S91 melanoma than in differentiated, ie pigmented B16 melanoma, relative to the proliferative activity of the two tumours. Serum thymidine kinase levels were increased in melanoma-bearing animals of both types compared with healthy mice; this also reflected the efficacy of the therapy: cyclophosphamide-treated B16 melanoma-bearing mice in which the tumour development was slowed down had significantly lower serum enzyme levels in comparison with the non-treated group and the same levels compared with control, healthy mice. Our results suggest that serum thymidine kinase levels might be used as a marker to follow the effect of melanoma therapy.