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Hereditary hemochromatosis (HH) is a genetic disease associated with progressive iron overload, eventually leading in some cases to damage of parenchymal organs, such as the liver, pancreas, and heart. Although the gene had been identified (HFE), HH pathogenesis remains to be fully elucidated. We report here, for the first time, a case of inadvertent transplantation of a liver from a donor with C282Y/H63D compound heterozygosity into a nonhemochromatotic 19-year-old Caucasian male recipient with primary sclerosing cholangitis. Progressive iron overload occurred over 1.5 years, as observed in liver biopsies and iron studies, after ruling out secondary causes of iron overload. This case strengthens the hypothesis that the liver, rather than the small intestine, plays a primary role in the maintenance of iron homeostasis.
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OBJECTIVES: Treatment associated fractures (TAFs) are known severe side effects after surgery and radiotherapy for soft tissue sarcoma (STS). There is no literature about TAF after multimodality treatment with isolated limb perfusion (ILP) for locally advanced STS. This study aimed to analyze predictive factors, treatment and outcome for TAF after multimodality treatment with ILP. METHOD: Out of 126 consecutive patients undergoing ILP after 1991 till now, 25 patients were excluded due to no surgery or direct amputation at initial surgery. Therefore, 101 patients were at risk and 12 developed a TAF (12%). RESULTS: The majority of tumors was located at the upper leg and knee (N = 60), and 11 patients developed a TAF (18%) after median 28 (5-237) months. Twenty-five tumors were located at the lower leg, and 1 patient developed a TAF after 12 months (4%). No patients with a tumor at the upper extremities (N = 16) developed a TAF. Ten out of 12 patients with a fracture received adjuvant RT with a dose of 50 Gy, and a median boost dose of 18 (10-20) Gy. Predictive factors were periosteal stripping, age over 65 years at time of treatment and tumor size after ILP ≥10 cm. Multivariate analysis showed periosteal stripping and tumor size after ILP ≥10 cm as significant predictive factors. The majority of the fractures were treated with intramedullary nailing. Only one of 12 patients without radiotherapy reached bone union (8%). The median survival after developing TAF was 18 (1-195) months. CONCLUSION: The overall risk of TAF after multimodality treatment with ILP was relatively high with 15% at ten years. The incidence of TAF for patients with tumors located at the thigh and knee after resection with periosteal stripping and radiotherapy was even >50%. The treatment of these fractures is challenging due to the high non-union rate, requiring an extensive orthopedic oncological TAF experience.
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Extremidades , Curación de Fractura , Fracturas Espontáneas/epidemiología , Sarcoma/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia del Cáncer por Perfusión Regional , Femenino , Estudios de Seguimiento , Fracturas Espontáneas/diagnóstico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Países Bajos/epidemiología , Radioterapia Adyuvante , Estudios Retrospectivos , Sarcoma/complicaciones , Sarcoma/diagnóstico , Tasa de Supervivencia/tendencias , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. METHODS: For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. RESULTS: Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. CONCLUSION: AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.
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Factor Inductor de la Apoptosis/genética , Ataxia Cerebelosa/tratamiento farmacológico , Ataxia Cerebelosa/genética , Riboflavina/uso terapéutico , Complejo Vitamínico B/uso terapéutico , Adolescente , Niño , Humanos , Masculino , Mutación Missense , FenotipoRESUMEN
BACKGROUND: Walker-Warburg phenotype is a severe and lethal autosomal recessive disorder, belonging to a group of congenital malformations defined as abnormal pial basement membrane formation. So far, prenatal diagnosis was considered possible only during late pregnancy. METHODS: First trimester assessment of a pregnancy suspected to be affected by Walker-Warburg phenotype, using a high-resolution transvaginal ultrasound probe (6-12 MHz), T2 MR imaging (1.5T), molecular genetics and histopathology. RESULTS: Very early diagnosis of the Walker-Warburg phenotype at 11 weeks of gestation proved possible by depicting the classic signs of this entity, confirmed by molecular genetics, post-abortion MR imaging and histopathology. CONCLUSION: Advancements in ultrasound equipment and technology, molecular genetics and histopathology have made very early detection of this syndrome possible, thus shedding new light on the natural history of this malformation.
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Congenital general anosmia (CGA) is a neurological disorder entailing a complete innate inability to sense odors. While the mechanisms underlying vertebrate olfaction have been studied in detail, there are still gaps in our understanding of the molecular genetic basis of innate olfactory disorders. Applying whole-exome sequencing to a family multiply affected with CGA, we identified three members with a rare X-linked missense mutation in the TENM1 (teneurin 1) gene (ENST00000422452:c.C4829T). In Drosophila melanogaster, TENM1 functions in synaptic-partner-matching between axons of olfactory sensory neurons and target projection neurons and is involved in synapse organization in the olfactory system. We used CRISPR-Cas9 system to generate a Tenm1 disrupted mouse model. Tenm1(-/-) and point-mutated Tenm1(A) (/A) adult mice were shown to have an altered ability to locate a buried food pellet. Tenm1(A) (/A) mice also displayed an altered ability to sense aversive odors. Results of our study, that describes a new Tenm1 mouse, agree with the hypothesis that TENM1 has a role in olfaction. However, additional studies should be done in larger CGA cohorts, to provide statistical evidence that loss-of-function mutations in TENM1 can solely cause the disease in our and other CGA cases.
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Proteínas del Tejido Nervioso/genética , Trastornos del Olfato/congénito , Olfato/genética , Tenascina/genética , Adulto , Animales , Sistemas CRISPR-Cas , Modelos Animales de Enfermedad , Exoma/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Ratones , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Neuronas/patología , Trastornos del Olfato/genética , Trastornos del Olfato/fisiopatología , LinajeRESUMEN
Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.
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Agenesia del Cuerpo Calloso/genética , Sistema de Transporte de Aminoácidos ASC/genética , Exoma , Discapacidad Intelectual/genética , Microcefalia/genética , Espasticidad Muscular/genética , Agenesia del Cuerpo Calloso/complicaciones , Agenesia del Cuerpo Calloso/patología , Secuencia de Aminoácidos , Sistema de Transporte de Aminoácidos ASC/química , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Microcefalia/complicaciones , Microcefalia/patología , Datos de Secuencia Molecular , Mutación Missense , Linaje , Alineación de SecuenciaRESUMEN
Huntington disease (HD), an autosomal dominant disorder involving HTT, is characterized by chorea, psychiatric illness and cognitive decline. Diagnosis and age of onset depend on the degree of expansion of the trinucleotide CAG repeat within the gene. The prevalence of HD is known for Europeans but has not been studied in the Israeli population. Between 2006 and 2011 we diagnosed in our adult genetics clinic ten HD probands, nine of whom were Caucasus Jews (CJ) (Azerbaijani), and one Ashkenazi Jewish. We performed haplotype analysis to look for evidence of a founder mutation, and found that of the nine CJ, eight shared the same haplotype that was compatible with the A1 haplogroup. We calculated the coalescence age of the mutation to be between 80 and 150 years. Ninety percent of our HD patients are CJ, as are 27% of the HD patients in Israel, although the CJ comprise only 1.4% of the Israeli population. Our findings suggest a higher prevalence of HD among CJ compared to the general Israeli population and are consistent with a recent founder mutation. We recommend a higher degree of suspicion for HD in CJ with subtle clinical findings.
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Enfermedad de Huntington/genética , Judíos/genética , Mutación , Proteínas del Tejido Nervioso/genética , Adulto , Anciano , Alelos , Femenino , Tamización de Portadores Genéticos , Haplotipos , Humanos , Proteína Huntingtina , Israel , Masculino , Persona de Mediana Edad , Linaje , Repeticiones de Trinucleótidos , Población BlancaAsunto(s)
Diarrea Infantil/diagnóstico , Diarrea Infantil/genética , Exoma , Retardo del Crecimiento Fetal/diagnóstico , Retardo del Crecimiento Fetal/genética , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/genética , Análisis de Secuencia de ADN , Proteínas Portadoras/genética , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Diagnóstico Diferencial , Facies , Femenino , Genotipo , Humanos , Mutación , LinajeAsunto(s)
Síndrome de Loeys-Dietz/diagnóstico por imagen , Ultrasonografía Prenatal , Aborto Eugénico , Adulto , Amniocentesis , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/embriología , Diagnóstico Diferencial , Ecocardiografía Tetradimensional , Femenino , Asesoramiento Genético , Humanos , Recién Nacido , Síndrome de Loeys-Dietz/embriología , Síndrome de Loeys-Dietz/genética , Embarazo , Segundo Trimestre del EmbarazoRESUMEN
OBJECTIVE: To evaluate the long-term results of 20 years of experience with isolated limb perfusion (ILP) with tumour necrosis factor α (TNF-α) and melphalan, followed by surgical resection and adjuvant radiotherapy, for the treatment of advanced soft tissue sarcomas of the extremities. DESIGN: Retrospective cohort study. METHOD: From 1991 to 2011, 113 patients with primary irresectable soft tissue sarcomas underwent 117 ILPs at the University Medical Centre Groningen. 96 ILPs (82%) were performed in the lower limb, and 21 (18%) in the upper limb. The dosages used were 1-4 mg TNF-α and 10-13 mg/l melphalan. RESULTS: After a median follow up of 8 (range 2-15) weeks after ILP, 107 tumours were resected: 81 (76%) of the resection margins were tumor-free. After the resection, 69 patients (61%) received adjuvant radiotherapy. In total, 85 ILPs resulted in a tumoural response; 16 patients (14%) developed a local recurrence and after 46 treatments (39%), distant metastases had developed. After a median follow-up of 51 months, the limb had been spared in 88 patients (78%). The 10- year disease-specific survival was 53.8%. There was a median follow-up period of 76 months (range: 7-234); still alive at the end of this period were 56 patients (50%). A total of 83 perfusion- or resection-related complications occurred from 58 ILPs (50%): 55 (66%) early and 28 (34%) late treatment-related complications. None of the patients died as a result of the treatment. CONCLUSION: ILP is a safe and effective procedure in the treatment of advanced primary irresectable soft tissue sarcoma that can prevent amputation in many cases. It is however associated with significant morbidity and is burdensome for the patient.
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Antineoplásicos Alquilantes/uso terapéutico , Recuperación del Miembro , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Antineoplásicos Alquilantes/administración & dosificación , Quimioterapia del Cáncer por Perfusión Regional , Estudios de Cohortes , Extremidades/patología , Extremidades/cirugía , Femenino , Humanos , Masculino , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/cirugía , Radioterapia Adyuvante , Estudios Retrospectivos , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/administración & dosificación , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
Low doses of sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of portal hypertension. The aim of our study was to explore whether the combination of propranolol and sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and sham-operated control rats were treated by gavage with vehicle, propranolol (30 mg·kg(-1)·day(-1)), sorafenib (1 mg·kg(-1)·day(-1)), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats, propranolol and sorafenib produced a significant (P < 0.001) and similar reduction in PP (-19 and -15%, respectively). This was achieved through different mechanisms: whereas propranolol decreased PP by reducing portal blood flow (-35%; P = 0.03), sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (-30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (-39%) under combined therapy was not significantly greater than after propranolol alone. Sorafenib, alone or in combination with propranolol, produced significant reduction in portal-systemic shunting (-25 and -33%, respectively), splanchnic vascularization (-37 and -41%, respectively), liver fibrosis (38%), and hepatic neovascularization (-42 and -51%, respectively). These effects were not observed after propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and liver fibrosis, suggesting that this drug combination is a potentially useful strategy in the treatment of portal hypertension.
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Antihipertensivos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Hipertensión Portal/tratamiento farmacológico , Propranolol/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Animales , Quimioterapia Combinada , Hipertensión Portal/fisiopatología , Cirrosis Hepática Experimental/tratamiento farmacológico , Cirrosis Hepática Experimental/fisiopatología , Masculino , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Ratas , Ratas Sprague-Dawley , SorafenibRESUMEN
BACKGROUND: The largest cluster of familial Creutzfeldt-Jakob disease (fCJD) exists in Jews of Libyan origin. Familial Mediterranean fever (FMF) is an inflammatory disease also common in this population. OBJECTIVES: We hypothesized that FMF, as a pro-inflammatory condition, may affect the course of CJD. METHODS: Three hundred and seventy-two consecutive patients diagnosed clinically and genetically as CJD were included in the study. Two hundred and thirty-six had fCJD, and 136 had sporadic disease (sCJD). Review of the patient's records revealed three patients with FMF-CJD co-morbidity. In addition, 50 DNA samples of patients with CJD were genotyped as homozygote, heterozygote, and non-carriers of the FMF mutation. The demographic and clinical variables of the groups were compared. RESULTS: The three patients with FMF had an earlier age of onset and significantly shorter disease duration than the patients without FMF. Heterozygote carriers did not differ in disease onset and duration from patients without FMF. CONCLUSIONS: The shorter disease duration of CJD patients with FMF may indicate the importance of pro-inflammatory factors in the disease.
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Síndrome de Creutzfeldt-Jakob/epidemiología , Fiebre Mediterránea Familiar/epidemiología , Adulto , Edad de Inicio , Comorbilidad , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/fisiopatología , Proteínas del Citoesqueleto/genética , Progresión de la Enfermedad , Fiebre Mediterránea Familiar/genética , Fiebre Mediterránea Familiar/fisiopatología , Femenino , Heterocigoto , Homocigoto , Humanos , Judíos/genética , Libia , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa , PirinaRESUMEN
INTRODUCTION: The aim of the study was to investigate the results of surgical treatment in primary and recurrent dermatofibrosarcoma protuberans (DFSP), with respect to local tumor control. PATIENTS AND METHODS: Thirty-eight patients were treated between 1971 and 2005 at the University Medical Center Groningen (UMCG). Thirty patients presented with primary disease (79%) and 8 patients with locally recurrent disease (21%). The treatment consisted of surgical resection and in case of marginal or positive resection margins (R1 resection) adjuvant radiotherapy. RESULTS: Adequate surgical margins as a single modality was associated with 100% local control in all primary DFSPs. Two patients whose resection specimens had microscopically positive resection margins had withdrawn from adjuvant radiotherapy and developed local recurrence (LF rate 7%). Two of the 8 patients referred with a local recurrence developed a second recurrence (LF rate 25%); one of these patients developed distant disease and ultimately died of systemic disease. None of the five patients with DFSP-FS developed LF after treatment at the UMCG. After a median follow-up of 89 (12-271) months, the 10-year disease-free survival was 85% and the 10-year disease specific survival was 100%. CONCLUSION: After wide surgical resection of a DFSP or DFSP-FS, or an R1 resection combined with adjuvant radiotherapy the risk of local recurrence is extremely low.
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Dermatofibrosarcoma/cirugía , Recurrencia Local de Neoplasia , Neoplasias Cutáneas/cirugía , Adulto , Niño , Dermatofibrosarcoma/radioterapia , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cirugía de Mohs , Recurrencia Local de Neoplasia/cirugía , Radioterapia Adyuvante , Neoplasias Cutáneas/radioterapia , Adulto JovenRESUMEN
BACKGROUND: Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis and an activator of tissue transforming growth factor-beta1 (TGF-beta1). Analyses using genetically modified mice suggested that TSP-1 may play a protective role to prevent infiltration and tissue remodeling responses after myocardial infarction. The expression levels of TSP-1 and their putative role in ventricular remodeling have not been determined in patients with heart failure (HF). MATERIALS AND METHODS: We analyzed the expression of TSP-1 and TGF-beta1 mRNA in myocardial biopsies from 34 subjects with end-stage HF undergoing heart transplantation and 13 healthy controls from heart donors. Among total RNA extracted from the left ventricle, 1 microg was retrotranscribed and mRNA expression levels were quantified by real-time polymerase chain reaction (PCR). RESULTS: The mean age of subjects was 54 +/- 2 years; mean ejection fraction, 21 +/- 5%; end-diastolic diameter and end-systolic diameter, 73 +/- 10 and 61 +/- 11 mm, respectively. TSP-1 mRNA expression in ventricular tissue from HF patients was lower (159.04 +/- 14.55 ng-equivalents [ng-equiv]) than in controls (234 +/- 30.66 ng-equiv; P < .05). Tissue from HF subjects also showed lower levels of TGF-beta1 (68.42 +/- 4.36 vs 80.58 +/- 5.26 ng-equiv; P < .05). TSP-1 mRNA levels correlated positively with TGF-beta1 (P = .001; R(2) = .2), and lower TSP-1 mRNA levels were observed with increasing left ventricular diameters. CONCLUSIONS: Patients with end-stage HF show decreased TSP-1 mRNA levels, which agrees with published results showing lower circulating TSP-1. Ventricular dilatation observed in these patients may be related to lower expression of TSP-1. Surprisingly, TGF-beta1 mRNA levels were lower in failing hearts, which suggested that fibrogenesis takes place in earlier phases of HF.
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Insuficiencia Cardíaca/genética , Trasplante de Corazón/patología , Trombospondina 1/genética , Remodelación Ventricular/genética , Biopsia , Femenino , Regulación de la Expresión Génica , Insuficiencia Cardíaca/patología , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , ARN/genética , ARN Mensajero/genética , Valores de Referencia , Espectrofotometría , Donantes de Tejidos , Transcripción Genética , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
UNLABELLED: The aim of the study was to evaluate long-term toxicity of adjuvant treatment in early stage ovarian cancer survivors. Data from all patients treated in one hospital for early stage ovarian cancer diagnosed between 1980 and 1990 were collected using a structured data form. In 93 FIGO stages I and II patients, cytoreductive and staging surgery was performed; 15 received no adjuvant treatment (controls), 39 whole abdominal radiotherapy (WART) and 39 platin-based chemotherapy. Median age at diagnosis was 54 years (range 21-83 years). During follow-up, 49/93 (53%) patients have died with a median overall survival of 18.4 years (95% CI 12.8-23.9). In both the radiotherapy and the chemotherapy group, 50% of patients reported long-term side-effects (all grades) versus 13% of controls. Two patients in the WART group died from bowel complications. Secondary malignancies were observed in 16 patients. Of all patients alive at the last follow-up, 12/17 (71%) patients treated with radiotherapy and 11/18 (61%) treated with chemotherapy experienced long-term morbidity versus 2/9 (22%) controls (P=0.03). IN CONCLUSION: Long-term follow-up of early stage ovarian cancer patients showed lasting GI morbidity in the survivors treated with adjuvant radiotherapy, which has therefore become obsolete. Cisplatin-based chemotherapy caused peripheral neuropathy versus virtual absence of problems in the survivors of just surgery, emphasising the need for strict criteria before instigating adjuvant treatment.
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Neoplasias Ováricas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Estudios de Casos y Controles , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/mortalidad , Cisplatino/efectos adversos , Femenino , Estudios de Seguimiento , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/mortalidad , Cardiopatías/complicaciones , Cardiopatías/mortalidad , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Morbilidad , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/mortalidad , Radioterapia Adyuvante/efectos adversos , Radioterapia Adyuvante/mortalidad , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
UNLABELLED: Matrix metalloproteinases (MMPs) are proteolytic enzymes responsible for extracellular matrix protein degradation. They have an important role in tissue remodeling processes. Their activity is regulated at the transcriptional, translational, and posttranslational level and by tissue inhibitors (TIMPs). Our aim was to analyze whether expression changes in MMPs that degrade collagens and their inhibitors in the myocardium have an impact on ventricular remodeling and the fibrogenesis in congestive heart failure. METHODS: We analyzed left ventricle biopsies from 18 patients with idiopathic dilated cardiomyopathy (iCDM) and severe congestive heart failure (HF) and 13 biopsies from organ donors. mRNA expression was quantified by real-time PCR, and fibrosis levels measured with picrosirius red staining. RESULTS: The patients mean age was 53 +/- 3 years. Expression levels of MMP-1, MMP-2, MMP-3, and TIMP1 did not show differences in pathological hearts compared to control hearts. Expression levels of MMP-1 and MMP-3 were low. MMP-9 expression levels were down-regulated in the cardiomyopathic hearts (49.77 +/- 7.6 ng equivalents of cDNA [ng-eq]) compared to controls (91.24 +/- 10.8 ng-eq, P < .005). MMP-2 expression levels correlated with the fibrosis levels (P < .05, R2 = 0.33, n = 18). CONCLUSION: MMP-9 mRNA expression down-regulation suggested that the protein levels were regulated at the posttranscriptional level. The correlation between MMP-2 expression levels and the collagen fraction in the pathological hearts indicated a putative role of MMP-2 in the fibrosis that takes place in congestive heart failure.
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Cardiomiopatía Dilatada/enzimología , Regulación Enzimológica de la Expresión Génica , Insuficiencia Cardíaca/enzimología , Trasplante de Corazón/fisiología , Ventrículos Cardíacos/enzimología , Metaloproteinasa 9 de la Matriz/genética , Cardiomiopatía Dilatada/genética , Colágeno/metabolismo , ADN Complementario/genética , Regulación hacia Abajo , Insuficiencia Cardíaca/genética , Humanos , Metaloproteinasas de la Matriz/genética , Biosíntesis de Proteínas , Transcripción GenéticaRESUMEN
UNLABELLED: Besides the well-established role of mast cells in allergic reactions as an important source of vasoactive and proinflammatory products, they have been related to tissue fibrosis and remodelling processes. In a heart failure (HF) animal model, mast cells were shown to synthesize transforming growth factor beta1 and basic fibroblast growth factor in myocardial tissue and were localized to an area with fibrosis. Our objective was to quantify mast cell density in left ventricles from patients with congestive heart failure who were candidates for transplantation and to analyze whether they showed a correlation with the fibrosis level of the same area. METHODS: We obtained myocardial biopsies from 20 patients with end-stage HF secondary to idiopathic dilated cardiomyopathy (iDCM) undergoing heart transplantation and 15 controls (donors without cardiopathy). Mast cells were detected by immunohistochemistry with a human mast cell chymase antibody and fibrosis levels measured with picrosirius red staining of collagen fibrils with later quantification by morphometry. RESULTS: The patients mean age was 51 +/- 3 years. Fibrosis levels in the myocardial sections from patients with congestive HF was three-fold higher than those in control myocardium (12.41 +/- 1.7% vs 3.98 +/- 0.63%, P < .001). Mast cell density correlated with the collagen fraction and could be fitted to a linear regression curve: collagen fraction = 0.78 + 0.05 mast cell density (n = 33, P < .005, R2 = 0.28). CONCLUSION: The elevated collagen fraction present in failing hearts may be the cause of increased stiffness and loss of elasticity that is detected in patients with end-stage HF. Due to the mast cells capacity to synthesize vasoactive and fibrogenic products and the correlation between their density and fibrosis levels, they probably play a role in the ventricular remodelling in HF.