RESUMEN
In 1992 a 54-year-old man underwent transsphenoidal adenomectomy to remove a clinically nonfunctioning pituitary adenoma during which there was a transient cerebrospinal fluid (CSF) leak. He received radiotherapy to a small residual remnant. Follow-up magnetic resonance imaging (MRI) scan in 1997 showed an increase in the tumour in the pituitary stalk region and an additional intradural lesion at C1 level. In the absence of neurological symptoms and signs, an observational policy was followed. By 1999 the cervical dural lesion had enlarged and laminectomy was performed, during which three intradural lesions were removed. Histology and immunohistochemistry of the metastases were identical to those of the initial pituitary adenoma. Follow-up MRI scan showed extension of the pituitary remnant above the chiasma, requiring transfrontal surgery. Operation was complicated by secondary brain haemorrhage from which the patient died. Autopsy revealed a small amount of residual tumour at the top of the stalk and several small intradural tumour nodules at the level of the foramen magnum. Genetic analysis of the initial pituitary tumour identified significant allelic losses in keeping with its invasive nature, while that of the metastases indicated a separate clone as shown by retention of alleles lost in the primary tumour. The regrown pituitary tumour also appeared to be of a different clone to the initial tumour and the same as two of three of the first metastases (C1 level). The foramen magnum metastasis showed the same loss of heterozygosity (LOH) pattern as one of the original C1 metastases and the pituitary tumour tissue obtained at autopsy. We speculate that at the initial pituitary surgery, cells seeded into the CSF and grew in the dura. These cells were from a different clone, implying that the original pituitary tumour contained at least two clones, possibly three, providing evidence for the contemporaneous oligoclonality of the original pituitary tumour.
Asunto(s)
Adenoma/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Neoplasias Hipofisarias/genética , Adenoma/cirugía , Neoplasias Encefálicas/cirugía , Resultado Fatal , Eliminación de Gen , Humanos , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Siembra Neoplásica , Neoplasia Residual , Neoplasias Hipofisarias/cirugíaRESUMEN
CONTEXT: Oculopharyngeal muscular dystrophy (OPMD) is a rare myopathy caused by polyalanine triplet repeat expansion in the gene for poly(A) binding protein 2 (PABP2) and is found in isolated cohorts throughout the world. We have observed numerous cases of OPMD in New Mexico. OBJECTIVE: To characterize the clinical, genetic, and demographic features of the OPMD population in New Mexico. DESIGN, SETTING, AND PARTICIPANTS: Cohort study with analysis of outpatient clinic medical records from 1965 to 2001 at the University of New Mexico Hospital and the New Mexico VA Health Care System in Albuquerque, which serve the entire state. MAIN OUTCOME MEASURES: Clinical phenotype, supplemented with genetic confirmation (n = 10 patients) and in-depth clinical evaluations (n = 49 patients). RESULTS: We identified 216 cases of OPMD (99 women and 117 men) from 39 kindreds of New Mexicans spanning up to 4 generations. All patients were Hispanic, and the majority of probands came from northern New Mexico. In patients who had both ocular and pharyngeal muscle weakness, ptosis was just as likely to occur before or concurrent with dysphagia. Proximal limb muscle weakness and gait abnormalities were common and occurred later than ocular or pharyngeal weakness. The clinical expression of OPMD caused marked debility, although life-table analysis showed no decrease in life expectancy compared with unaffected family members (P =.81). Ten individuals from different kindreds were found to have an identical polyalanine triplet repeat expansion ([GCG](9)) in the PABP2 gene. CONCLUSIONS: Individuals in this cohort had clinical and genetic characteristics of classic OPMD. Longevity was not affected, but patients experienced considerable morbidity. The origin of the PABP2 mutation in New Mexican OPMD patients is unclear, although the geographic and genetic isolation of northern New Mexicans with a long ancestry in this region may have contributed to the development of this cohort. This disease cohort represents a large and previously unrecognized health care issue in the state of New Mexico and should serve to raise the awareness of this disorder among clinicians who treat Hispanics in the Southwest and throughout the United States.
Asunto(s)
Hispánicos o Latinos/genética , Distrofias Musculares/etnología , Adulto , Anciano , Proteínas de Unión al ADN/genética , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Tablas de Vida , Masculino , Persona de Mediana Edad , Distrofias Musculares/diagnóstico , Distrofias Musculares/epidemiología , Distrofias Musculares/genética , New Mexico/epidemiología , Fenotipo , Proteína II de Unión a Poli(A) , Expansión de Repetición de TrinucleótidoRESUMEN
Components of the pRb/p16/cyclin D1/CDK4 pathway are frequent targets in numerous tumour types, including those of pituitary origin. However, previous studies of pituitary tumours have examined individual components of this pathway. Therefore, to determine their overall contribution we have simultaneously examined the immunohistochemical status of pRb, p16 and cyclin D1 and analysed the CDK4 gene for a characterized activating mutation. Of the total pituitary tumour cohort (29 clinically non-functioning adenomas and 16 somatotrophinomas) abnormal expression of either pRb, p16 or cyclin D1 was observed in 36 of 45 (80%) tumours and was significantly (P = 0.005) associated with non-functioning tumours (27/29; 93%) compared with somatotrophinomas (9/16, 56%). Loss of either pRb or p16 expression was mutually exclusive in 23 of 45 (51%) tumours, whilst concomitant loss of pRb and p16 expression was observed in five tumours. Cyclin D1 overexpression was observed in 22 of 45 (49%) tumours, however, there was no significant association between overexpression of cyclin D1 and the expression status of either pRb or p16. In addition, no activating mutations within codon 24 of the CDK4 gene were detected. This study provides evidence for the first time that components of the pRb/p16/cyclin D1/CDK4 pathway, either alone or in combination, are frequently deregulated in human pituitary tumours, suggesting that this pathway may be a useful target in drug or gene therapeutic approaches.
Asunto(s)
Adenoma/metabolismo , Ciclina D1/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Quinasas Ciclina-Dependientes/genética , Fase G1 , Neoplasias Hipofisarias/metabolismo , Proteínas Proto-Oncogénicas , Proteína de Retinoblastoma/metabolismo , Fase S , Adenoma/genética , Adenoma/patología , Codón , Quinasa 4 Dependiente de la Ciclina , Cartilla de ADN , Humanos , Inmunohistoquímica , Mutación , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patologíaRESUMEN
Sporadic human pituitary tumors are benign adenomas of monoclonal origin. This implies that they arise from de novo somatic mutation(s) within a single pituitary cell. The availability of original and recurrent/regrown tumors from the same patient allowed testing of the prediction that recurrent/regrown tumors have identical genetic abnormalities as the original tumor sample. We used PCR amplification, from archival slide-extracted DNA, to allelotype microsatellite polymorphisms as an indication of clonality and confirmed this by X chromosome inactivation analysis in samples from women. Tumors from 33 of 49 (67%) patients with two or more specimens showed loss of heterozygosity (LOH) of at least one marker in at least one of their samples. Two patterns of LOH were observed. In pattern A in 14 of 33 (42%) of patients, the LOH pattern of the first tumor was preserved in the second recurrent sample, with some recurrent tumors also showing additional LOH. In these patients, the original and second tumors are presumed to arise from the same original clone with or without progressive accumulation of LOH. In pattern B [19 of 33 (58%) patients], LOH seen in the first tumor was not preserved in the second or subsequent tumors, as evidenced by retention of heterozygosity compared with the first tumor. The simplest explanation is that the second tumor, although still monoclonal, arises from another independently abnormal clone. This was confirmed by X chromosome inactivation analysis in all 11 women where this was informative. These results show that initial and recurrent tumors, of a benign tumor type, are frequently derived from separate independent clones. This suggests that either: (a) more than one abnormal clone is present from the outset though only one dominates; or (b) several clones arise independently at different times. In both scenarios, the initiating event(s) that predisposes to transformation might result in multiclonal hyperplasia, possibly as a consequence of exogenous stimulation.
Asunto(s)
Alelos , Pérdida de Heterocigocidad , Neoplasias Hipofisarias/genética , Adolescente , Adulto , Factores de Edad , Anciano , Compensación de Dosificación (Genética) , Evolución Molecular , Femenino , Humanos , Inmunohistoquímica , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Neoplasias/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/radioterapia , Polimorfismo Genético , Prolactinoma/genética , Estudios Retrospectivos , Factores Sexuales , Secuencias Repetidas en Tándem , Factores de Tiempo , Cromosoma XRESUMEN
BACKGROUND: The influence of an increased left ventricular end-diastolic pressure (LVEDP) on the development of lethal arrhythmias in chronic heart failure is unclear. We investigated the effect of chronic and acute LVEDP increase on the epicardial activation time of sinus (SB) and paced (PB) beats. METHODS: Six dogs underwent rapid ventricular pacing at 220-280[emsp4 ]beats/min for 6-14 weeks for induction of heart failure. On the study day, baseline (ba) LVEDP was determined for the surviving heart failure animals (HF-ba), and for seven control animals (C-ba). The epicardial activation time (EAT, time between the earliest and latest epicardial activation) for five consecutive SB and five ventricular PB during the baseline hemodynamic state were recorded using a 504 electrode mapping-sock. In the control animals a 2-litre volume (vl) was infused over 10[emsp4 ]min to acutely increase the LVEDP (C-vl) to a level comparable to the chronic increased LVEDP of the HF-ba. The same volume challenge was performed in two HF animals (HF-vl) and the EAT for SB and PB was redetermined. RESULTS: Three of six HF animals died during induction of heart failure. In the three remaining HF animals, chronic LVEDP increased from 6+/-1 to 17+/-10.8[emsp4 ]mmHg (P=0.07), EAT for SB increased by 68 % compared to control animals (HF-ba vs. C-ba, P<0.05). In contrast, in the control animals the acute rise in LVEDP from 6.8+/-4.5 to 14.7+/-6.2 mmHg P<0.05), shortened the EAT for SB (C-ba vs. C-vl, P<0.05). A similar decrease in EAT for SB caused by acute volume load was seen in the HF animals, but did not reach significance due to the small sample size (one of the three remaining HF animals died of spontaneous ventricular fibrillation before the volume load). Chronic LVEDP elevation significantly prolonged the EAT for PB from 72+/-11 to 120+/-31[emsp4 ]ms (C-ba vs. HF-ba) while acute LVEDP increase had no significant effect on EAT for PB. CONCLUSION: Chronic HF increases LVEDP and prolongs EAT, while an acute increase in LVEDP shortens the EAT for sinus beats. A prolongation of EAT in heart failure may make the heart more susceptible to ventricular arrhythmias and electromechanical dissociation.
Asunto(s)
Estimulación Cardíaca Artificial/métodos , Insuficiencia Cardíaca/terapia , Disfunción Ventricular Izquierda/terapia , Enfermedad Aguda , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Perros , Ecocardiografía/métodos , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/mortalidad , Hemodinámica/fisiología , Presión , Valores de Referencia , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/mortalidadRESUMEN
Cyclin D1 plays an important role in the regulation of cell progression through G1 of the cell cycle and has been demonstrated to have oncogenic properties. Using RFLP-PCR, an A/G polymorphism within the cyclin D1 (CCND1) gene was analyzed in 151 sporadic human pituitary tumors, of which 60 were informative at this locus. Further analysis showed that in 15 of 60 (25%) tumors, there was evidence of allelic imbalance, which is indicative of gene amplification. Allelic imbalance was observed more frequently in invasive tumors (11 of 29 tumors; 38%) than in their noninvasive counterparts (4 of 31 tumors; 13%; P = 0.02). Forty-six of the tumors informative for the polymorphism were available for immunohistochemical analysis. Cyclin D1 expression (nuclear and/or cytoplasmic) was detected in 25 of 46 (54%) tumors. Of these cases, expression of nuclear cyclin D1 was detected in 9 of 46 (20%) tumors, whereas 16 of 46 (35%) tumors showed cyclin D1 staining exclusively confined to the cytoplasm. Neither nuclear staining nor cytoplasmic staining was observed in any of the normal pituitaries or in the negative control. Expression of cyclin D1 was observed in significantly more nonfunctional tumors (18 of 27 tumors; 67%) than in somatotrophinomas (7 of 19 tumors; 37%; P = 0.046). Nuclear cyclin D1 expression was observed more frequently in nonfunctional tumors (8 of 27 tumors; 30%) than in somatotrophinomas (1 of 19 tumors; 5%; P = 0.04). There was no correlation between cyclin D1 expression and tumor grade or between allelic imbalance of CCND1 and cyclin D1 expression. We conclude that amplification of CCND1 occurs in pituitary tumors and that the overexpression of cyclin D1 may be an early event in tumorigenesis. Cyclin D1 overexpression occurring in the absence of CCND1 allelic imbalance suggests that additional mechanisms responsible for deregulated cyclin D1 expression are involved in human pituitary tumorigenesis.
Asunto(s)
Adenoma/genética , Adenoma/metabolismo , Ciclina D1/biosíntesis , Ciclina D1/genética , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/metabolismo , Alelos , Ciclo Celular , Amplificación de Genes , Hormona del Crecimiento/biosíntesis , Humanos , Inmunohistoquímica , Leucocitos/metabolismo , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Fracciones Subcelulares/metabolismoRESUMEN
The majority of pituitary tumours are monoclonal in origin and arise sporadically or occasionally as part of multiple endocrine neoplasia type 1 (MEN1). Whilst a multi-step aetiology involving both oncogenes and tumour suppressor genes has been proposed for their development, the target(s) of these changes are less clearly defined. Both familial and sporadic pituitary tumours have been shown to harbour allelic deletion on 11q13, which is the location of the recently cloned MEN1 gene. We investigated 23 sporadic pituitary tumours previously shown to harbour allelic deletion on 11q13 with the marker PYGM centromeric and within 50 kb of the MEN1 locus. In addition, the use of intragenic polymorphisms in exon 9 and at D11S4946, and of telomeric loci at D11S4940 and D11S4936, revealed that five of 20 tumours had loss of heterozygosity (LOH) telomeric to the menin gene. However, the overall pattern of loss in informative cases was indicative of non-contiguous deletion that brackets the menin gene. Sequence analysis of all MEN1 coding exons and flanking intronic sequence, in tumours and matched patient leucocyte DNA, did not reveal mutation(s) in any of the 23 tumours studied. A benign polymorphism in exon 9 was encountered at the expected frequency, and in seven patients heterozygous for the polymorphism the tumour showed retention of both copies of the menin gene. Reverse transcription polymerase chain reaction analysis of ten evaluable tumours and four normal pituitaries revealed the presence of the menin transcript. Whilst these findings suggest that gene silencing is unlikely to be mechanistic in sporadic pituitary tumorigenesis, they do not exclude changes in the level or stability of the transcript or translation to mature protein. Our study would support and extend very recent reports of a limited role for mutations in the MEN1 gene in sporadic pituitary tumours. Alternatively, these findings may point to an, as yet, unidentified tumour suppressor gene in this region.
Asunto(s)
Cromosomas Humanos Par 11/genética , Pérdida de Heterocigocidad , Neoplasia Endocrina Múltiple Tipo 1/genética , Proteínas de Neoplasias/genética , Neoplasias Hipofisarias/genética , Proteínas Proto-Oncogénicas , ADN de Neoplasias/aislamiento & purificación , Humanos , Repeticiones de Microsatélite , Polimorfismo Genético , ARN Neoplásico/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADNRESUMEN
The two goals of this study were (1) to develop a closed-chest animal model of monomorphic ventricular tachycardia; and (2) to investigate the effect of dual site pacing on inducibility of ventricular tachycardia. In the first part of the study, 10 of 14 sheep underwent successful induction of myocardial infarction by temporary balloon occlusion of the left anterior descending coronary artery. After a follow-up period of 21-43 days, sustained monomorphic ventricular tachycardia could be induced during programmed electrical stimulation using a "clinical" stimulation protocol in 8 of the 10 sheep. The number of ventricular tachycardia episodes per animal varied between 5 and 70. Ventricular fibrillation was never induced during programmed electrical stimulation. Ventricular tachycardia episodes lasted from 30 seconds up to 15 minutes and were terminated by antitachycardia pacing or DC cardioversion. In the second part of the study, the effect of dual site stimulation on ventricular tachycardia inducibility was investigated. High current stimuli from an area within the infarcted zone were given with the S1 programmed stimulation protocol. This dual site stimulation showed no effect on ventricular tachycardia induction during programmed electrical stimulation. This animal model shows a high induction rate of sustained monomorphic ventricular tachycardia in the chronic phase of myocardial infarction. The high incidence of ventricular tachycardia inducibility provides a reliable tool to study new techniques for the prevention of ventricular tachyarrhythmias.
Asunto(s)
Infarto del Miocardio/complicaciones , Taquicardia Ventricular/etiología , Animales , Estimulación Cardíaca Artificial , Cateterismo , Distribución de Chi-Cuadrado , Vasos Coronarios/patología , Modelos Animales de Enfermedad , Cardioversión Eléctrica , Estimulación Eléctrica , Electrocardiografía , Estudios de Seguimiento , Ventrículos Cardíacos , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Arteria Pulmonar , Reproducibilidad de los Resultados , Ovinos , Taquicardia Ventricular/prevención & control , Taquicardia Ventricular/terapia , Factores de TiempoRESUMEN
Two recent studies have described allelic loss of an RB1 intragenic marker on chromosome 13q in aggressive and metastatic pituitary tumors that did not correlate with loss of pRB. The second report also showed that losses were more frequently associated with a more centromeric marker. Because both of these studies suggest the presence of another or other tumor suppressor genes (TSGs) on 13q, we carried out an allelotype analysis encompassing known and recently described TSG loci on 13q, together with immunohistochemical analysis of pRB. We analyzed 82 nonfunctional tumors and 53 somatotrophinomas subdivided into invasive and noninvasive cohorts. A significantly higher frequency of loss, at one or more of 13 markers, was evident in the invasive nonfunctional tumors (54%, 26 of 48) than in their noninvasive counterparts (29%, 10 of 34). An approximately equal frequency of loss was apparent in invasive (28%, 5 of 18) and noninvasive (31%, 11 of 35) somatotrophinomas at one or more markers. In those tumors harboring deletion, loss at two or more markers was more frequent in invasive nonfunctional tumors 65% (17 of 26) compared with 36% (4 of 11) of their noninvasive counterparts. In somatotrophinomas, 40% (2 of 5) of invasive tumors as compared with 64% (7 of 11) of noninvasive tumors had evidence of two or more deletions. In tumors showing loss at two or more loci, the majority showed large deletions; however, loss of the RB1 intragenic marker D13S153 was infrequent. In most cases, loss at individual markers was more frequent in invasive tumors than their noninvasive counterparts. A marker 3 cM telomeric to RB1 (D13S1319) showed the highest frequency of deletion in both invasive cohorts (29% of somatotrophinomas and 24% of nonfunctional tumors). Immunohistochemical analysis of pRB showed frequent loss in somatotrophinomas (27%, 9 of 33) in comparison with 4% (2 of 53) of non-functional tumors. Although loss of pRB did not correlate with loss of an intragenic marker or tumor grade, it was significantly associated with the somatotrophinoma subtype (P = 0.002). These data suggest that chromosome 13q is a frequent target for allelic deletion in pituitary tumors and point to another or other TSG loci in these regions.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 13 , Genes de Retinoblastoma , Neoplasias Hipofisarias/genética , Proteína de Retinoblastoma/análisis , Mapeo Cromosómico , Humanos , Inmunohistoquímica , Repeticiones de MicrosatéliteRESUMEN
The cyclin-dependent kinase inhibitor 2A/multiple tumor suppressor gene 1 (CDKN2A/MTS//p16) plays an important role in the control of progression from G to S-phase of the cell cycle through the inhibition of CDK4-mediated RBI phosphorylation. In this study we investigated 46 nonfunctional pituitary tumors and 21 somatotrophinomas for aberrant methylation of the CpG island contained within the CDKN2A gene as an alternative mechanism of gene silencing. We demonstrate methylation in 32/46 (70%) of nonfunctioning tumors, in contrast to 2/21 (9.5%) somatotrophinomas and 0/15 histologically normal postmortem pituitaries. Methylation in noninvasive and invasive nonfunctional tumors was approximately equal at 15/20 (75%) and 17/26 (65%), respectively. Immunohistochemical analysis showed an absence of CDKN2A protein in 25/32 (78%) methylated nonfunctioning tumors, demonstrating a highly significant overall correlation (P = 0.00007) between hypermethylation of the gene and absence of the p 16 protein. The association between hypermethylation and absence of CDKN2A protein remained when the cohort of nonfunctional tumors was further subdivided into noninvasive 12/15 (80%; P = 0.004) and invasive 13/17 (76%; P = 0.01), suggesting this to be an early event in pituitary tumorigenesis. In contrast, a single invasive methylated somatotrophinoma failed to express the CDKN2A protein. These data show that hypermethylation of the CpG island within exon 1, but not exon 2, of the CDKN2A gene is frequently associated with loss of protein expression in nonfunctional pituitary tumors, but not somatotrophinomas, suggesting different tumorigenic pathways.
Asunto(s)
Adenoma/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN , Neoplasias Hipofisarias/genética , Adenoma/química , Adenoma/metabolismo , Southern Blotting , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , ADN de Neoplasias/análisis , Hormona del Crecimiento/metabolismo , Humanos , Sueros Inmunes , Inmunohistoquímica , Neoplasias Hipofisarias/química , Neoplasias Hipofisarias/metabolismo , Análisis de Secuencia de ADNRESUMEN
INTRODUCTION: Permanent cure of reentrant ventricular tachycardia (VT) associated with coronary artery disease is difficult to achieve. Retrograde coronary venous infusion of ethanol for ablation of ventricular myocardium associated with reentrant tachyarrhythmias has several potential advantages, including use of physiologic mapping techniques and production of deeper, wider necrotic zones. METHODS AND RESULTS: Nine anesthetized dogs had baseline hemodynamic measurement, left ventriculography, coronary arteriography, occlusive coronary venography, and programmed electrical stimulation of the right ventricular apex and outflow tract. A balloon-tipped infusion catheter was advanced into a distal coronary venous branch, the balloon slowly inflated, and pure ethanol infused at volumes of 1.5, 3, or 5 cc. Hemodynamic measurements, angiography, ventriculography, and programmed electrical stimulation were repeated immediately and 1 week following ablation. Formalin-perfused hearts were serially sectioned and lesion volumes determined. Histologic examination of ablation beds then was performed. No significant difference was found in any hemodynamic measurement before or after ablation. Coronary arteriograms and left ventriculograms were unchanged after ablation. Nonsustained VT occurred in eight dogs during ethanol infusion; however, VT was not inducible in any dog before or after ablation. Infusion volumes of 3 cc or more were required to produce transmural lesions. CONCLUSION: Retrograde coronary venous infusions of ethanol using a balloon-tipped infusion catheter were effective in ablating ventricular myocardium. Retrograde chemical ablation did not itself result in inducible VT or adversely affect hemodynamic measurements or coronary arteries. Transmural myocardial necrosis, necessary in the ablation of VT associated with coronary artery disease, can be produced by higher infusion volumes.
Asunto(s)
Etanol/uso terapéutico , Ventrículos Cardíacos/efectos de los fármacos , Taquicardia por Reentrada en el Nodo Atrioventricular/tratamiento farmacológico , Animales , Cateterismo , Angiografía Coronaria , Vasos Coronarios , Modelos Animales de Enfermedad , Perros , Electrocardiografía , Imagen de Acumulación Sanguínea de Compuerta , Ventrículos Cardíacos/diagnóstico por imagen , Hemodinámica , Infusiones Intravenosas/métodos , Miocardio/patología , Taquicardia por Reentrada en el Nodo Atrioventricular/diagnóstico , Taquicardia por Reentrada en el Nodo Atrioventricular/fisiopatología , Resultado del TratamientoRESUMEN
This investigation examines the clinical response to long-term treatment of the diabetic syndrome of limited joint mobility (LJM) using an aldose reductase inhibitor (ARI) in comparison to historical controls, and proposes a potential role of aldose reductase (AR) genotype and expression in the clinical response to ARI. Clinical parameters, including quantitative hand movement and electromyogram, were followed over a decade of continuous ARI treatment with sorbinil (400 mg/day) in two patients with insulin-dependent diabetes mellitus (IDDM) and severe compromising LJM, and compared to the published 10-year prospective investigation of untreated IDDM diabetic patients with LJM. Both subjects were homozygous for the Z-2 AR allele (A-C)23 that has been linked with microvascular complications of DM. Cellular AR mRNA/beta-actin ratios for both treated patients while on ARI therapy were approximately one-half the value observed in untreated patients with the complications of nephropathy or neuropathy. This is the longest reported experience of ARI intervention for any diabetic complication, documenting sustained correction of LJM, lack of side effects, and a potential molecular basis for the therapeutic response.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus Tipo 1/complicaciones , Inhibidores Enzimáticos/uso terapéutico , Imidazoles/uso terapéutico , Imidazolidinas , Artropatías/tratamiento farmacológico , Actinas/genética , Aldehído Reductasa/genética , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Repeticiones de Dinucleótido , Electromiografía , Inhibidores Enzimáticos/farmacología , Expresión Génica , Genotipo , Mano/fisiopatología , Fuerza de la Mano , Humanos , Imidazoles/farmacología , Artropatías/etiología , Masculino , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , SíndromeRESUMEN
We have screened 57 cases of primary, nonfunctional, pituitary adenomas for loss of heterozygosity of markers on chromosome 9p. Using a panel of 11 microsatellite markers, we found hemizygous deletion with at least one of the markers in 18 tumors (31.5%). The frequency of loss was similar in both noninvasive (8 of 26; 31%) and invasive tumors (10 of 31; 32%), suggesting that loss on this chromosome might be an early event in pituitary tumorigenesis. Two discrete areas of loss were punctuated by a region of retention of heterozygosity between the markers D9S171 and IFNA, indicative of homozygous deletion. However, multiplex PCR analysis (MTS1 and MTS2) and the presence of a 3' untranslated region polymorphism in MTS1 suggested that neither of these tumor suppressor genes was homozygously deleted. In 6 of the 18 tumors showing LOH, sufficient DNA was also available for Southern blot analysis and, in all cases, showed retention of MTS1. Cell mixing experiments of tumor cell DNA homozygously deleted for MTS1 with DNA in which neither copy of the gene was deleted only gave rise to a signal at contamination levels greater than 30% and could discriminate homozygous and hemizygous loss. These studies support the recent findings that mechanisms other than hemi- and homozygous deletion are most likely responsible for the loss of MTS1 gene product in pituitary tumors (M. Woloschak et al., Cancer Res., 56: 2493-2486, 1996.). These data show that losses on either side of 9p21-22, both or either of which may be deleted, are involved in pituitary tumorigenesis and provide evidence for distinct suppressor gene loci, in addition to MTS1, on chromosome 9p.
Asunto(s)
Adenoma/genética , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Deleción Cromosómica , Cromosomas Humanos Par 9 , Neoplasias Hipofisarias/genética , Proteínas Supresoras de Tumor , Southern Blotting , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Cartilla de ADN , Genes Supresores de Tumor/genética , Heterocigoto , HumanosRESUMEN
Abnormal cell proliferation is controlled by opposing actions of oncogene products (stimulatory) and tumour suppressor gene (TSG) products (inhibitory). The former are dominantly acting, i.e. only one copy needed for tumorigenesis, whilst for TSG both copies of the gene must be inactivated so these are recessive at a cellular level. For anterior pituitary tumours only one oncogene (Gsp) has been identified in a variable proportion (4-40%) of a single tumour subtype (somatotrophinomas). Contrariwise, allelic deletion studies, using a PCR-based microsatellite polymorphism analysis of DNA extracted from archival specimens, have shown significant loss of heterozygosity in 20-40% of all tumour subtypes at the locus of the putative MEN-1 gene (chr. 11q13); the retinoblastoma gene (chr. 13q 12-14), and 10q26. Moreover, these DNA microdeletions were concentrated in radiologically invasive tumours compared to noninvasive tumours (modified Hardy gdes 3 and 4 vs. 1 + 2). In addition, 50% of Cushing's adenomas showed presence of p53 immunopositivity, though no point mutations in exons 4-9 were found, by SSCP analysis, to account for this. These studies show that analysis of TSGs in pituitary adenomas may provide clues to their pathogenesis, and more importantly relate to clinical behaviour of the tumour, and hence aid decisions regarding management.
Asunto(s)
Genes Supresores de Tumor , Neoplasias Hipofisarias/genética , División Celular , Eliminación de Gen , Heterocigoto , Humanos , OncogenesRESUMEN
To define the quantitative relationship between peripheral nerve structure and function imposed by endoneurial oedema in the diabetic state, we determined values for sural nerve hydration structure as measured by magnetic resonance spectroscopy, and for neurological function with scores for nerve conduction properties (NCV-score), neuropathic symptoms (NS-score), and examination signs (NE-score). The coefficient of sural nerve hydration was elevated to 30 +/- 6% (p < 0.05) in 79 symptomatic neuropathic diabetic subjects with an average of 15 years of diabetes mellitus, compared to a value of 25 +/- 3% in 72 non-diabetic control subjects. In contrast, in 75 asymptomatic diabetic subjects with an average of 6 additional years of diabetes, the mean hydration coefficient was only 28 +/- 5% (p < 0.05). A nerve hyperhydration state was identified with a prevalence of 25% within the asymptomatic group characterized by nerve hydration greater than the 95th percentile, early changes in nerve electrophysiology and neurological examination, but with no symptomatology of neuropathy. Stratification of the symptomatic neuropathic group by worsening nerve electrophysiology, demonstrates a coincident deterioration in neurological examination (RR = 5.39 at maximum NCV-score), and neuropathy symptomatology (RR = 4.80 at maximum NE-score). The present data are consistent with the hypothesis that endoneurial oedema initiates deterioration sequentially in nerve electrophysiology, followed by abnormal findings on neurological examination, preceding the patient's final perception of symptomatic stocking glove peripheral diabetic neuropathy.
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Diabetes Mellitus/fisiopatología , Neuropatías Diabéticas/fisiopatología , Modelos Neurológicos , Nervios Periféricos/fisiología , Nervios Periféricos/fisiopatología , Nervio Sural/fisiopatología , Equilibrio Hidroelectrolítico , Adulto , Edema , Electromiografía , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Conducción Nerviosa , Examen Neurológico , Valores de Referencia , Nervio Sural/fisiología , Factores de TiempoRESUMEN
OBJECTIVE: To evaluate the extent of decreased insulin sensitivity in relation to body mass index and its relationship to serum androgens in women with polycystic ovarian syndrome (PCOS). DESIGN: Comparative study of endogenous glucose disposal and serum insulin responses to oral glucose load with endocrine parameters in PCOS. SETTING: Fertility and Endocrine Clinics, North Staffordshire Hospital Centre. PATIENTS: Forty-nine obese and 16 nonobese women with PCOS were compared with 18 obese and 16 nonobese control women with regular ovulatory cycles and no features of PCOS. MAIN OUTCOME MEASURES: Basal concentrations of serum LH, FSH, T, androstenedione, sex hormone-binding globulin (SHBG), and free T index. Measurements of insulin sensitivity by rate of endogenous glucose disposal after i.v. bolus injection of insulin and glucose mediated insulin responses. RESULTS: Obese women with PCOS showed decreased insulin sensitivity and hyperinsulinemia to an extent greater than can be explained by obesity alone. Serum insulin showed inverse correlation with SHBG, and therefore hyperinsulinemia increased the bioavailability of androgens in obese PCOS. In nonobese PCOS, this method of assessment failed to reveal insulin resistance. CONCLUSION: Hyperandrogenemia and insulin resistance are independent features of PCOS. Hyperinsulinemia enhances expression of hyperandrogenemia by increasing bioavailability of androgens.
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Andrógenos/sangre , Resistencia a la Insulina , Síndrome del Ovario Poliquístico/fisiopatología , 17-alfa-Hidroxiprogesterona , Adolescente , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hidroxiprogesteronas/sangre , Insulina/sangre , Hormona Luteinizante/sangre , Obesidad/sangre , Obesidad/complicaciones , Síndrome del Ovario Poliquístico/complicaciones , Progesterona/sangre , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangreRESUMEN
To enable the quantitative assessment of peripheral nerve structure and function, we determined the normal values for sural nerve hydration structure as measured by magnetic resonance proton imaging, and for neurological function with scores for neuropathic symptoms, signs, and nerve conduction properties. Normal human sural nerves contain 24.8 +/- 3.4% water. The structural water content of the nerves did not vary systematically in relation to age, height, gender, sural nerve conduction, neurologic symptoms, or examination deficits. In contrast, the neurological function scores were significantly influenced by age and selectively by height. Both nerve structure and function were stable over a 1-year interval. Measurement of human sural nerve water content in vivo by magnetic resonance proton imaging, and quantitation of the neurological profile of symptoms, signs, and conduction velocity are useful, noninvasive tools for the investigation of diseases in which changes in nerve structure may be related to alterations in nerve function.
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Agua Corporal , Conducción Nerviosa/fisiología , Nervio Sural/química , Adulto , Anciano , Envejecimiento , Estatura , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Examen Neurológico , Caracteres Sexuales , Nervio Sural/fisiologíaRESUMEN
A gene encoding or controlling the expression of the H-Y transplantation antigen was previously mapped to the human Y chromosome. We now report the sublocalization of this gene on the long arm of the human Y chromosome. Eight patients with Y-chromosomal abnormalities were examined with a series of existing and new DNA markers for the Y chromosome. The resulting deletion map was correlated with H-Y antigen expression. We conclude that the H-Y antigen gene maps to a portion of deletion interval 6 that is identified by specific DNA markers.
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Deleción Cromosómica , Antígeno H-Y/genética , Cromosoma Y , Adolescente , Secuencia de Bases , Southern Blotting , Mapeo Cromosómico , ADN , Marcadores Genéticos , Humanos , Lactante , Recién Nacido , Datos de Secuencia MolecularRESUMEN
3,4-diaminopyridine was evaluated for its ability to improve muscle strength, respiratory function and electromyographic compound muscle action potentials in human botulism. In a double blind, placebo controlled study, 3,4-diaminopyridine failed to improve these parameters in a 31-year old patient with severe food-borne type A botulism. The addition of an anti-cholinesterase medication to the 3,4-diaminopyridine did not add any benefit. Lack of clinical improvement from 3,4-diaminopyridine in this patient differed from some reports of benefit in animals experimentally poisoned with type A botulinum toxin.
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4-Aminopiridina/análogos & derivados , Botulismo/tratamiento farmacológico , Unión Neuromuscular/efectos de los fármacos , 4-Aminopiridina/uso terapéutico , Potenciales de Acción/fisiología , Adulto , Amifampridina , Botulismo/fisiopatología , Método Doble Ciego , Electromiografía , Humanos , Masculino , Músculos/fisiopatologíaRESUMEN
Nine patients with unrecognized incomplete cervical spinal cord injury are discussed. Four were sent home as normal, three were called hysterical, and two went undiagnosed during stupor or coma. A literature search revealed 28 additional cases. Eighty percent of these were males, two thirds were over 50 years old, and most had central or posterior cord syndromes. Falls with hyperextension, spondylosis, or disc disease, and motor vehicle accidents were the most common causes. Only one of the 37 had a cervical fracture. In some the neurologic problem was missed altogether; in others it was attributed to hysteria, intoxication, or to other neurologic or systemic diseases. Minor injuries without cervical fracture or dislocation, advanced age, unusual or changeable neurologic deficits, intoxication, and psychiatric problems all contributed to the confusion.