RESUMEN
OBJECTIVE: To examine the trajectory of fatigue experienced by 26 Puerto Rican (PR) men over the course of External Beam Radiation Therapy (EBRT) and to assess gene expression changes from baseline to midpoint of EBRT using microarray technology. Design/Research Approach- Prospective exploratory and comparative design study. Setting- RT facility located in San Juan, PR. Sample/Participants-26 PR men with non-metastatic prostate cancer. METHODS: Participants completed 2 paper forms: demographics and the Spanish version of the 13-item FACT-fatigue at baseline, midpoint, and end of EBRT. Wholeblood samples were collected at baseline and at midpoint of EBRT. Descriptive data was analyzed using t-test, Wilcoxon, and Friedman test for repeated measures. Gene expression data was analyzed using the LIMMA package in R; the functional network analysis was conducted using Ingenuity Pathway analysis. Main Research Variable-Fatigue scores, gene expression. RESULTS: Subjects were of ages 52-81 with fatigue scores that remained unchanged during EBRT (baseline=42.38, SD=9.34; midpoint=42.11, SD=8.93, endpoint=43.04, SD=8.62). Three hundred seventy-three genes (130-up regulated and 243-down regulated) were differentially expressed from baseline to mid-point of EBRT (FDR<0.01). The top distinct canonical pathways of the differentially expressed probesets (p<0.0001) were: "Phospholipase C Signaling," "Role of NFAT in Regulation of the Immune Response," and "Gαq Signaling." CONCLUSION: While fatigue did not worsen over the course of EBRT for this sample as a group, there was variability in fatigue across the sample. It is possible that the over expression of the SESN3 gene, known to suppress oxidative damage, may have contributed to the attenuation of fatigue in this clinical population.
Asunto(s)
Fatiga/epidemiología , Proteínas de Choque Térmico/genética , Hispánicos o Latinos , Neoplasias de la Próstata/radioterapia , Anciano , Anciano de 80 o más Años , Regulación hacia Abajo , Fatiga/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Estudios Prospectivos , Neoplasias de la Próstata/genética , Puerto Rico , Estadísticas no Paramétricas , Regulación hacia ArribaRESUMEN
Endurance training has been shown to increase pancreatic ß-cell function and mass. However, whether exercise modulates ß-cell growth and survival pathways signaling is not completely understood. This study investigated the effects of exercise on growth and apoptotic markers levels in rat pancreatic islets. Male Wistar rats were randomly assigned to 8-wk endurance training or to a sedentary control group. After that, pancreatic islets were isolated; gene expression and the total content and phosphorylation of several proteins related to growth and apoptotic pathways as well as the main antioxidant enzymes were determined by real-time polymerase chain reaction and Western blot analysis, respectively. Reactive oxygen species (ROS) production was measured by fluorescence. Endurance training increased the time to reach fatigue by 50%. Endurance training resulted in increased protein phosphorylation content of AKT (75%), AKT substrate (AS160; 100%), mTOR (60%), p70s6k (90%), and ERK1/2 (50%), compared with islets from control group. Catalase protein content was 50% higher, whereas ROS production was 49 and 77% lower in islets from trained rats under basal and stimulating glucose conditions, respectively. Bcl-2 mRNA and protein levels increased by 46 and 100%, respectively. Bax and cleaved caspase-3 protein contents were reduced by 25 and 50% in islets from trained rats, respectively. In conclusion, these results demonstrate that endurance training favors the ß-cell growth and survival by activating AKT and ERK1/2 pathways, enhancing antioxidant capacity, and reducing ROS production and apoptotic proteins content.
Asunto(s)
Células Secretoras de Insulina/fisiología , Islotes Pancreáticos/fisiología , Resistencia Física/fisiología , Transducción de Señal/fisiología , Animales , Antioxidantes/metabolismo , Apoptosis/fisiología , Peso Corporal , Fatiga/genética , Fatiga/metabolismo , Fatiga/fisiopatología , Expresión Génica , Glucosa/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Oxidación-Reducción , Fosforilación , Condicionamiento Físico Animal , Resistencia Física/genética , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
CONTEXT: Corticosteroid-binding globulin (CBG; SERPIN A6) gene mutations are rare; only four mutations have been described, often in association with fatigue and chronic pain, albeit with incomplete penetrance. PATIENT: We report a kindred with a novel SERPINA6 mutation. The proband, a 9-yr-old male, had excessive postexertional fatigue, weakness, and migraine. MAIN OUTCOME MEASURES AND RESULTS: Investigations revealed low morning and ACTH-stimulated peak cortisol levels. SERPIN A6 sequencing detected a novel exon 2 single base deletion (c.13delC) leading to a frameshift generating a stop codon within the signal peptide coding region (p.Leu5CysfsX26) and 50% reduced CBG levels in heterozygotes. The patient's father and two sisters share the mutation. Symptom expression within the family may have been modified by a polymorphic CBG allele (c.735G>T). Exogenous hydrocortisone had no effect on the fatigue. CONCLUSION: This report documents the fifth CBG gene mutation in humans and the second causing major effects on CBG levels. Individuals with low CBG levels may be misdiagnosed as having secondary hypocortisolism. The association with fatigue and idiopathic pain is again noted and may relate to altered stress system function. Variability of the phenotype may relate to other genetic variations of the CBG gene or environmental factors.
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Mutación Missense , Transcortina/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Chile , Análisis Mutacional de ADN , Fatiga/complicaciones , Fatiga/genética , Humanos , Masculino , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/genética , Debilidad Muscular/complicaciones , Debilidad Muscular/genética , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: Abnormal corticosteroid-binding globulin (CBG) is an extremely rare condition and only three mutations have been described in four families. The molecular basis of an abnormal CBG in a Brazilian family was studied and correlations between genotype and serum cortisol, cortisol binding capacity (CBC) and CBG levels were determined. SUBJECTS: All 10 family members, comprising three generations, and nine healthy volunteers were studied. MEASUREMENTS: Genomic DNA was extracted from white blood cells from all family members. The human cbg exons 2-5 were amplified by PCR, submitted to automatic sequencing. Cortisol and CBG levels in serum were measured by radioimmunoassay (RIA). CBC in serum was determined using tritiated cortisol and other cortisol binding parameters were calculated through Scatchard analysis. RESULTS: A missense mutation in exon 5 of cbg (1254G --> A; Asp367Asn), recently described as CBG Lyon, was found in all family members. The proband and one sister were homozygous whereas all other family members, including parents, were heterozygous for this mutation. Cortisol levels in the only two homozygotes were lower than in heterozygotes and both were significantly lower as compared to controls (69 and 182 nmol/l vs. 267 +/- 129 nmol/l vs. 459 +/- 195 nmol/l, respectively, P < 0.05). CBC was decreased in the two homozygotes as compared to heterozygotes and in both groups as compared to controls (< 90 and 114 nmol/l vs. 305.0 +/- 81.4 nmol/l vs. 594.8 +/- 59.5 nmol/l, respectively, P < 0.05). CBG levels were lower in homozygotes as compared to heterozygotes and in both as compared to controls (325 and 375 nmol/l vs. 496.75 +/- 50.75 nmol/l vs. 647.25 +/- 87.50 nmol/l, respectively, P < 0.05). CONCLUSIONS: An abnormal CBG resulting from a missense mutation and known as CBG Lyon was found in this Brazilian kindred. This abnormal CBG has decreased affinity for cortisol and results in low or low normal serum cortisol levels in homozygous and heterozygous subjects. Although relative hypotension and fatigue have recently been associated with CBG deficiency in a family with two CBG mutations (null and Lyon), the two homozygous subjects in this kindred were both normotensive and only the proband presented with fatigue.
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Hidrocortisona/sangre , Mutación Missense , Transcortina/deficiencia , Adulto , Análisis de Varianza , Brasil , Estudios de Casos y Controles , Fatiga/genética , Femenino , Genotipo , Heterocigoto , Homocigoto , Humanos , Linaje , Análisis de Secuencia de ADN , Estadísticas no ParamétricasRESUMEN
We herein present 10 patients with the childhood onset form of centronuclear myopathy. All patients underwent a clinical and neurologic examination, and EMG/NVC. A series of ancillary examinations, consisting of muscle enzymes, EEG, EKG, echocardiogram, pulmonary function tests and head CT scan was done in most. The mean age was 16.3 years (3-25). Seven were female. There was no family history in seven and in two it was suggestive of an autosomal recessive inheritance. One patient was adopted and no history was available. Frequent gestational and neonatal abnormalities were present, namely poor fetal movements, maternal polyhydramnios, perinatal hypoxia, hypotonia at birth, and weak crying and feeding. In seven patients there was delayed motor milestones. In most patients the motor involvement was stable or slowly progressive. Upon examination the facies were myopathic and there was a global skeletal muscle involvement in all patients, with muscular hypotonia, atrophy, and areflexia. Characteristically, patients presented with ophthalmoparesis, and weakness of masticatory and facial muscles. We frequently found osteoskeletal abnormalities, namely kyphoscoliosis, tendon retractions and high-arched palate. A restrictive pulmonary function pattern was found in five patients, but only one had a cor pulmonale. CK was abnormally high in one patient, and normal in all others. EMG/NVC disclosed a myopathic pattern in nine; in three there was a mixed neurogenic picture; and in one we found myotonic discharges. A long follow-up (median 8.1 years) showed that only the patient with cor pulmonale had an unfavorable prognosis.