ABSTRACT
Introduction: Frasier syndrome is a genetic disorder produced by a mutation in intron 9 of the WT1 gene, responsible for renal and genital dysfunctions. Clinical findings: It is characterized by discrepancy between the individual karyotype and the individual phenotype and corticosteroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. Patients usually have a female phenotype with a 46 XY karyotype, which increases the risk of gonadoblastoma in 50% of cases. Kidney disease requires kidney transplantation in adulthood. Cardiovascular and bone-derived comorbidities such as hyperlipidaemia and osteopenia/osteoporosis, respectively, are also common. Main diagnoses: Mutations of the WT1 gene can lead to different clinical entities, most notably Denysh-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. We present a clinical case of a woman who debuted in childhood with difficult-to-control nephrotic syndrome, the lack of pubertal development, primary amenorrhoea and the absence of ovaries on imaging tests in adolescence, alerted to an underlying genetic problem that, after cytogenetic studies, allowed a diagnosis of Frasier syndrome. Therapeutic interventions: It is recommended to remove the gonads due to increased risk of developing gonadoblastoma. Treatment of associated dyslipidaemia and osteopenia is also necessary. Conclusion: Frasier syndrome is an unusual cause of infertility due to gonadal dysgenesis and is associated with kidney problems.(AU)
Introducción: El síndrome de Frasier es un trastorno genético producido por una mutación en el intrón 9 del gen WT1, responsable de disfunciones a nivel renal y genital. Principales síntomas: Se caracteriza por disgenesia gonadal con discrepancia entre cariotipo-fenotipo y síndrome nefrótico resistente a corticoides debido a glomeruloesclerosis focal y segmentaria. Las pacientes presentan habitualmente fenotipo femenino con cariotipo 46 XY, lo que aumenta el riesgo de gonadoblastoma en un 50% de los casos. La enfermedad renal obliga a trasplante renal en la edad adulta. Son habituales también las comorbilidades derivadas a nivel cardiovascular y óseo como hiperlipidemia y osteopenia/osteoporosis, respectivamente. Diagnósticos principales: Las mutaciones del gen WT1 pueden conducir en distintas entidades clínicas entre las que destaca el síndrome de Denys-Drash, el síndrome de Frasier o la glomeruloesclerosis focal y segmentaria aislada. Se presenta un caso clínico de una mujer que debutó en la infancia con síndrome nefrótico de difícil control y que, durante la adolescencia, ante la falta de desarrollo puberal, la amenorrea primaria y la ausencia de ovarios en las pruebas de imagen alertaron de un problema genético subyacente que, tras estudios citogenéticos, permitió el diagnóstico de síndrome de Frasier. Intervenciones terapéuticas: Se recomienda la exéresis de las gónadas debido al riesgo incrementado de gonadoblastoma. El tratamiento de la dislipemia y la osteopenia asociadas también es necesario. Conclusión: El síndrome de Frasier es una causa inusual de infertilidad debido a una disgenesia gonadal y se asocia con problemas a nivel renal.(AU)
Subject(s)
Humans , Female , Child , Gonadoblastoma , Glomerulonephritis, Membranous , Frasier Syndrome , Gonadal Dysgenesis , Inpatients , Physical ExaminationABSTRACT
La preeclampsia (PE) constituye una de las principales causas de mortalidad materna y perinatal en el mundo. En los países desarrollados, los estudios apuntan a un importante aumento de la incidencia de PE en la última década, en parte, por el aumento de la prevalencia, en la población general, de enfermedades que afectan a la función vascular, como la diabetes, la hipertensión crónica o la enfermedad renal. En el presente documento se lleva cabo una revisión actualizada de la PE. Se describen los criterios diagnósticos y la fisiopatología de la enfermedad. El objetivo principal del documento es revisar los nuevos marcadores bioquímicos que pueden ser de utilidad en la práctica clínica para la predicción y el diagnóstico de la PE, así como los distintos métodos mediante los cuales se puede llevar a cabo su determinación
Pre-eclampsia (PE) is one of the leading causes of maternal and perinatal mortality in the world. In developed countries, studies point to a significant increase in the incidence of PE in the last decade, partly due to the increase in the prevalence in the general population of diseases that affect vascular function, such as diabetes. chronic hypertension, or kidney disease. An updated review of PE is presented in this article. The diagnostic criteria and the pathophysiology of the disease are described. The main objective of the document is to review the new biochemical markers that may be useful in clinical practice for the prediction and diagnosis of PE, as well as the different methods by which yey can be determined
Subject(s)
Humans , Pre-Eclampsia/diagnosis , Placenta Growth Factor/analysis , Proteinuria/diagnosis , Angiogenesis Inhibitors/analysis , Angiogenic Proteins/analysis , Vascular Endothelial Growth Factors/analysis , Biomarkers/analysis , Clinical Chemistry Tests/methods , Predictive Value of Tests , Risk Factors , Mass Screening/methodsABSTRACT
INTRODUCTION: Global developmental delay (GDD) and intellectual disability (ID) are frequent reasons for consultation in paediatric neurology departments. Nowadays, array comparative genomic hybridisation (array-CGH) is one of the most widely used techniques for diagnosing these disorders. Our purpose was to determine the phenotypic features associated with pathological results in this genetic test. METHODS: We conducted a blind study of the epidemiological, clinical, anthropometric, and morphological features of 80 patients with unexplained ID to determine which features were associated with pathological results in array-CGH. RESULTS: Pathological results were found in 27.5% of the patients. Factors associated with pathological results in array-CGH were a family history of GDD/ID (OR = 12.1), congenital malformations (OR = 5.33), having more than 3 facial dysmorphic features (OR = 20.9), and hypotonia (OR = 3.25). CONCLUSIONS: Our findings are consistent with those reported by other published series. We therefore conclude that the probability of having pathological results in array-CGH increases with the presence of any of the features mentioned above in patients with ID/GDD.
Subject(s)
Comparative Genomic Hybridization/methods , Developmental Disabilities/genetics , Intellectual Disability/genetics , Intellectual Disability/pathology , Phenotype , Child , Female , Humans , MaleABSTRACT
The present study aimed to determine whether a whole body vibration training program (WBV) is able to improve static standing balance in adolescents with and without Down syndrome (DS). Thirty adolescents with DS aged 11-20 years (DSG) and 27 adolescent, age/sex matched, without DS (CG) joined the study. Participants of each group were divided into two comparable groups, those who performed WVB (in DSG: VDSG; in CG: VCG) and those who did not perform WVB (in DSG: nVDSG; in CG: nVCG). Static-standing-balance under four conditions (C1: open-eyes/fixed-foot-support; C2: closed-eyes/fixed-foot-support; C3: open-eyes/compliant-foot-support; C4: closed-eyes/compliant-foot-support) was examine, before and after a 20-week WBV training program. For balance study, Postural-Parameters (PPs), based on center of pressure (COP) oscillations (anterior/posterior and medial/lateral COP excursion and COP mean velocity), and PPs ratios among the four conditions were calculated. After WBV training, no significant differences were found in any parameter in the VCG and nVCG and neither in the nVDSG, but there was a decrease of mean values in the analyzed PPs under C4, with significant differences in medial/lateral COP excursion and COP mean velocity, and a significant decrease in the ratio C4/C1 of the mean velocity in VDSG. Therefore, WBV training had positive effects in the balance of DS adolescents although only under specific conditions, with vision and somatosensory input altered. The positive results of this study are encouraging and open a wide field of research, looking for the most efficient program for this population.
Subject(s)
Down Syndrome/physiopathology , Down Syndrome/therapy , Physical Therapy Modalities , Postural Balance/physiology , Vibration/therapeutic use , Adolescent , Child , Female , Humans , Male , Posture/physiology , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: Significant changes in the management of acute pancreatitis have taken place since the 2004 Pamplona Consensus Conference. The objective of this conference has been the revision and updating of the Conference recommendations, in order to unify the integral management of potentially severe acute pancreatitis in an ICU. PARTICIPANTS: Spanish and international intensive medicine physicians, radiologists, surgeons, gastroenterologists, emergency care physicians and other physicians involved in the treatment of acute pancreatitis. LEVELS OF EVIDENCE AND GRADES OF RECOMMENDATION: The GRADE method has been used for drawing them up. DRAWING UP THE RECOMMENDATIONS: The selection of the committee members was performed by means of a public announcement. The bibliography has been revised from 2004 to the present day and 16 blocks of questions on acute pancreatitis in a ICU have been drawn up. Firstly, all the questions according to groups have been drawn up in order to prepare one document. This document has been debated and agreed upon by computer at the SEMICYUC Congress and lastly at the Consensus Conference which was held with the sole objective of drawing up these recommendations. CONCLUSIONS: Eighty two recommendations for acute pancreatitis management in an ICU have been presented. Of these 84 recommendations, we would emphasize the new determinants-based classification of acute pancreatitis severity, new surgical techniques and nutritional recommendations. Note. This summary only lists the 84 recommendations of the 16 questions blocks except blocks greater relevance and impact of its novelty or because they modify the current management.
Subject(s)
Critical Care/standards , Pancreatitis/diagnosis , Pancreatitis/therapy , Acute Disease , Hemodiafiltration , Humans , Pancreatitis/classification , Pancreatitis/surgeryABSTRACT
AIM: To analyse static-standing-balance of adolescents with Down syndrome (DS). METHODS: Thirty-two adolescents with DS aged 10-19 years (DSG); 33 adolescents, age/sex-matched, without DS (CG). Static-standing-balance under four conditions (C1: open-eyes/fixed-foot-support; C2: closed-eyes/fixed-foot-support; C3: open-eyes/compliant-foot-support; closed-eyes/compliant-foot-support) was examined by means of time and frequency Postural-Parameters (PPs). To evaluate the contribution of each sensory system influencing postural control ratios among the four conditions were calculated. Mean values of all PPs were higher in the DSG than in the CG. Mean values of time PPs were higher in both groups on compliant-foot-support (with open and closed eyes) than on fixed-foot-support. Ratios C2/C1 were significantly lower in DSG than in CG; ratios C3/C1 presented higher values in DSG than in CG, with significant differences in length path and RMS-velocity; there were no differences in ratios C4/C1. CONCLUSIONS: In our group of DS adolescents the shift from visual to multimodal control of stance had occurred and they showed similar postural control patterns than non-DS. Even though, they presented worse static balance than their peers without DS and they had more problems with altered somasosensory input. An adequate rehabilitation program insisting on somatosensory input could be a useful measure to improve balance.
Subject(s)
Down Syndrome/physiopathology , Motor Skills/physiology , Perceptual Disorders/physiopathology , Postural Balance/physiology , Adolescent , Child , Disability Evaluation , Down Syndrome/complications , Female , Humans , Male , Perceptual Disorders/etiology , Psychomotor Performance/physiology , Young AdultABSTRACT
Introducción. El síndrome de inversión duplicación del cromosoma 15 se refiere a un conjunto de características clínicas entre las que se encuentran hipotonía central desde el nacimiento, retraso psicomotor, epilepsia o trastorno del espectro autista. Una invdup(15) resulta de la tetrasomía parcial de 15q y generalmente está implicada la región del Síndrome de Prader-Willi (SPW). Se evalúan tres casos remitidos a Genética por hipotonía y retraso psicomotor. Material y métodos. Cultivo de linfocitos de sangre periférica, cariotipo de alta resolución, FISH, extracción de ADN de linfocitos de sangre periférica, MS-MLPA de SPW y estudio de microsatélites. Resultados. El primer caso presentó un cariotipo 47,XY+der(15)(q13;p11.2)(pter->q13::p11.2->pter) y un cariotipo molecular arr 15q12.1q13(18,432,358-26,658,490)x3∼4 con ganancia de 8,23Mb implicando a genes sometidos a imprinting de la región causante de los síndromes de PWS y Angelman (SA). En el segundo caso se obtuvo una fórmula cromosómica 47, XX, + mar.ish idic (15)(q13)(Acro p-arm ++, D15Z1 ++, D15S10 ++, PML-) y cariotipo molecular arr 15q11.2q13.3(18,432,358-30,230,511)x3, con duplicación de aproximadamente 12Mb. En el tercer caso la paciente resultó ser portadora de una doble línea celular en mosaico 47,XX+ der (15) inv (15)(q11;p11.2) [40%] / 46,XX [60%]. En los tres casos se analizó mediante MLPA la región del SPW encontrándose un patrón de metilación alterado y la causa genética resultó ser un síndrome invdup(15) «de novo». Discusión. A pesar de la dificultad para establecer una correlación fenotipo-genotipo en los casos con invdup(15) las técnicas genéticas más recientes pueden aportar información para el diagnóstico clínico de estos pacientes (AU)
Introduction. The chromosome 15 inversion duplication syndrome refers to distinctive clinical findings, such as, early central hypotonia, developmental delay, epilepsy and autistic behaviour. Invdup(15) results from partial 15q tetrasomy and the Prader-Willi syndrome(PWS) region is generally involved. We have analyzed three clinical cases in a Genetics Unit diagnosed with hypotonia and developmental delay. Material and methods. Lymphocyte cultures from peripheral blood samples, high resolution karyotype, FISH, DNA isolation from peripheral blood leukocytes, PWS MS-MLPA and microsatellites study. Results. The first case showed a karyotype 47,XY+der(15)(q13;p11.2)(pter->q13::p11.2->pter) and a molecular karyotype arr 15q12.1q13(18,432,358-26,658,490)x3 ∼ 4 with an extra 8.23Mb genetic material involving imprinted genes from SPW and Angelman (SA) syndromes region. In the second case there was a karyotype 47, XX, + mar.ish idic (15)(q13)(Acro p-arm ++, D15Z1 ++, D15S10 ++, PML-) and a molecular karyotype arr 15q11.2q13.3(18,432,358-30,230,511)x3 with an approximately 12Mb duplication. The third patient was a carrier of a mosaic double line cell with karyotype 47,XX+ der (15) inv (15)(q11;p11.2) [40%] / 46,XX [60%]. In the three cases the SPW region was analysed using a modified methylation pattern and all resulted from a invdup(15) «de novo» genetic defect. Discussion. Although it is difficult to establish a phenotype-genotype correlation in invdup (15) cases, most recent genetic techniques should provide information for the clinical diagnosis in these patients (AU)
Subject(s)
Humans , Male , Female , Chromosomes, Human, Pair 15/microbiology , Chromosomes, Human, Pair 15/ultrastructure , Muscle Hypotonia/diagnosis , Tetrasomy/diagnosis , Epilepsy/complications , Epilepsy/diagnosis , Tetrasomy/physiopathology , Prader-Willi Syndrome/pathologyABSTRACT
Forefoot varus is a static deformity not easy to assess clinically. If left uncorrected, it is thought to affect both the posture of the patient and the kinematics of their lower limbs, and even the spine. Three-dimensional gait assessment could help to confirm forefoot varus diagnosis and provide objective evidence of the functional adaptive mechanisms postulated in the literature. The recently available Oxford Foot Model was used, simultaneously with a conventional lower limb model, to compare the kinematics of 10 forefoot varus children (aged 8-13) and 11 healthy controls (aged 7-13) during gait. Data acquisition was performed using a six-camera motion capture system, with a total of 27 reflective markers. A patient-by-patient comparison with the controls suggested several compensation patterns, although statistically significant differences were found only for the mean values of hip adduction/abduction during load response and midstance and hip flexion/extension during pre-swing. A multivariate statistical technique was used to determine which of the measured variables better separated both groups. The best discriminant model presented here includes hip adduction/abduction during load response, hindfoot/tibia inversion/eversion during pre-swing, hindfoot/tibia dorsiflexion/plantar flexion during load response and arch height during midstance, providing a rate of correct classification of 81%. The results could not fully confirm the kinematic relationships suggested in the literature. The small degree of forefoot varus deformity present in the patient group could have prevented other variables from becoming discriminant. A larger patient sample would help determine the possible different compensatory patterns to different degrees of forefoot varus.
Subject(s)
Foot Deformities/physiopathology , Forefoot, Human/physiopathology , Adolescent , Anthropometry , Biomechanical Phenomena , Child , Discriminant Analysis , Female , Heel/physiopathology , Humans , MaleABSTRACT
The purpose of this study was to evaluate foot arch types of obese children and adolescents aged 9-16.5 years using both indirect and direct measures. Fifty-eight obese children/adolescents attending the paediatric endocrinology unit of the University Hospital "Lozano Blesa" in Zaragoza were selected as experimental subjects. Fifty-eight gender and age matched, normal-weight children/adolescents were selected as control subjects. To assess the medial longitudinal arch (MLA) height, which is used as a main reference for the diagnosis of flatfoot, footprints from both feet were collected (in both groups) and lateral weight-bearing radiographs of both feet were taken (of 49 of the 58 obese children). Footprint angle (FA) and the Chippaux-Smirak index (CSI) were calculated from the footprints. Talus-first metatarsal (TFMA) and calcaneal inclination angles (CIA) were obtained from lateral feet radiographs. In the normal-weight group, mean values of FA and CSI indicated a normal MLA. In the obese group, morphological flatfoot was identified. Comparison between both groups, by side and gender, showed a decrease of FA (p<0.001) and an increase of CSI (p<0.001) in obese subjects. Mean values of TFMA and CIA in the obese group indicated a lowering of the MLA. Obese children/adolescents between 9 and 16.5 years of age had significantly lower values of FA and higher CSI, related to a lower MLA. Radiographic parameters supported these findings and mean values were associated with a fall of this arch.
Subject(s)
Flatfoot/diagnostic imaging , Flatfoot/epidemiology , Obesity/epidemiology , Adolescent , Anthropometry , Body Mass Index , Body Weights and Measures/methods , Child , Female , Flatfoot/rehabilitation , Humans , Male , RadiographyABSTRACT
La localización ovárica es una forma poco frecuente de embarazo ectópico y supone el 3,3% de todos ellos. Se presenta un caso en una mujer 28 años que consultó por metrorragia y dolor hipogástrico a los 14 días de la retirada de un DIU, con la sospecha diagnóstica de embarazo ectópico. Tras empeorar clínicamente se realiza una laparoscopia en la que se aprecia un embarazo ectópico ovárico izquierdo que confirma la anatomía patológica. Se ha revisado la literatura médica respecto a esta infrecuente localización de la gestación, sobre todo desde el punto de vista del diagnóstico diferencial (AU)
Ovarian pregnancy is an infrequent form of ectopic pregnancy, constituting 3.3% of all ectopic pregnancies. We report the case of a 28-year-old woman who presented with metrorrhagia and hypogastric pain 14 days after removal of an intrauterine device. The initial diagnosis was ectopic pregnancy. Clinical deterioration indicated the need for surgical management. Laparoscopic findings revealed a left ovarian ectopic pregnancy, which was confirmed by pathological study of the specimen. We review the literature on this uncommon localization, with special emphasis on its differential diagnosis (AU)
Subject(s)
Humans , Female , Adult , Pregnancy, Ectopic/complications , Pregnancy, Ectopic/diagnosis , Abdominal Pain/complications , Abdominal Pain/diagnosis , Diagnosis, Differential , Pregnancy Complications/diagnosis , Pregnancy Complications/epidemiology , Metrorrhagia/complications , Metrorrhagia/diagnosis , Abdominal Pain/etiology , Prospective Studies , Predictive Value of TestsABSTRACT
OBJECTIVE. To analyse the association between overweight and obesity and foot structure in children older than 9 years of age, whose longitudinal medial arch (MLA) should be practically established. DESIGN, SETTING AND SUBJECT. A cross-sectional study of 245 children (age: 13.22±1.8 years) from four randomly selected schools (Zaragoza, Spain). Body mass index (BMI) was calculated and normal-weight, overweight and obese groups were defined. Footprints for both feet were collected. MEASUREMENTS. Foot angle (FA) and Chippaux-Smirak index (CSI) were calculated from the footprints. Height and body mass were measured to calculate the BMI. RESULTS. Mean values of FA and CSI in the normal-weight group indicated the presence of a normal MLA; however, in the overweight they indicated an intermediary MLA and in the obese group, a low MLA. Comparison among the groups showed a decrease of FA (p<0.01) and an increase of CSI (p<0.01) with increasing weight associated with a lower MLA. A low but significant correlation (p<0.0001) was found between the z-score BMI and footprint parameters. CONCLUSIONS. In children aged 9 to 16.5 years, the increase of body mass is related to a lower MLA. The MLA is lower in these obese children than in the younger ones studied in previous works probably due to the continuous bearing of excessive mass from childhood. A lower MLA could cause health problems. An assessment of foot structure in these children is recommended as the classification of the foot arch type can help decide if treatment to avoid these problems is necessary.
Subject(s)
Flatfoot/etiology , Foot/pathology , Obesity/complications , Overweight/complications , Adolescent , Age Factors , Body Mass Index , Case-Control Studies , Child , Cross-Sectional Studies , Female , Flatfoot/pathology , Humans , Male , Obesity/diagnosis , Obesity/pathology , Overweight/diagnosis , Overweight/pathology , Risk Assessment , Risk Factors , SpainABSTRACT
This study presents a bioassay procedure, based on the root and shoot growth parameters, for the determination of the herbicide sulfosulfuron (1-(4,6 dimethoxypyrimidin-2-yl)-3-(2-ethylsulfonylimidazo[1,2-a]pyridin-3-ylsulfonil)urea) sensitivity on seven vegetal species. Plant response to sulfosulfuron was calculated with the equations fitted to the root growth data as a function of the logarithm of the herbicide concentration by non-linear regression and was used to calculate the doses for 10, 30 and 50% inhibition of root growth (EC10, EC30 and EC50). The results indicate that the phytotoxic effect of sulfosulfuron in all the species assayed followed the order: flax > maize > onion > vetch > lepidium sativum > tomato > barley. These species showed phytotoxicity at low levels of sulfosulfuron and flax appeared to be the most susceptible species to sulfosulfuron (0.001 mg/L).
Subject(s)
Herbicides/toxicity , Plants/drug effects , Pyrimidines/toxicity , Sulfonamides/toxicity , Biological Assay , Dose-Response Relationship, Drug , Flax/drug effects , Flax/growth & development , Hordeum/drug effects , Hordeum/growth & development , Lepidium sativum/drug effects , Lepidium sativum/growth & development , Solanum lycopersicum/drug effects , Solanum lycopersicum/growth & development , Onions/drug effects , Onions/growth & development , Plant Development , Solubility , Species Specificity , Vicia/drug effects , Vicia/growth & development , Zea mays/drug effects , Zea mays/growth & developmentABSTRACT
The dissipation of residue levels of captan and trichlorfon in field-treated kaki crops was studied according to good laboratory practices to propose maximum residue limits (MRLs). Residue levels of captan and trichlorfon were analysed by GC/MS and LC-MS/MS, respectively. Residue levels of captan and trichlorfon permitted one to propose MRLs in kaki of 3 and 5 mg kg(-1), respectively. The behaviour of these residues was also studied after peeling and cooking, and in individual fruits versus composite samples. Residue levels of these compounds for individual fruits suggested that a variability factor up to three could be set for the acute risk assessment. Levels of captan decreased by more than 90% after peeling and completely after cooking. Trichlorfon penetrates into the flesh in a proportion of 70% of the residue at the pre-harvest interval. Cooking resulted in a decrease of 27% of residue levels of trichlorfon.
Subject(s)
Captan/analysis , Diospyros/chemistry , Fruit/chemistry , Pesticide Residues/analysis , Trichlorfon/analysis , Chromatography, Liquid/methods , Dichlorvos/analysis , Food Contamination/analysis , Food Handling/methods , Fungicides, Industrial/analysis , Gas Chromatography-Mass Spectrometry/methods , Insecticides/analysis , Phthalimides/analysis , Vegetables/chemistryABSTRACT
Alzheimer's disease (AD) is associated to a gradual loss of attention and memory that have been associated to impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons in the nucleus basalis of Meynert. Thus, it is not surprising that the first therapeutic target that has demonstrated therapeutic efficacy on cognition, behaviour and functional daily activities has been the inhibitors of acetylcholinesterase (AChE), i.e. tacrine, donepezil, rivastigmine and galanthamine. But not all inhibitors of AChE have the same potency to block the enzyme and have a different pharmacological profile. For instance, rivastigmine is a dual inhibitor of AChE and butyrylcholinesterase (BuChE), and galanthamine is a mild inhibitor of AChE and an allosteric potentiating ligand of neuronal nicotinic receptors for acetylcholine (nAChRs). In addition, we have recently found that galanthamine has neuroprotective effects by inducing calcium signals and the induction of the antiapoptotic protein Bcl-2. In this frame, we have been synthesizing new tacrine derivatives that keep their ability to inhibit AChE but that interfere with neuronal calcium overloading and prevent apoptosis. Some of these compounds exhibit neuroprotecting properties and thus, could be useful in the treatment of neurodegenerative and ischaemic brain diseases.
Subject(s)
Chemistry, Pharmaceutical/methods , Cholinesterase Inhibitors/therapeutic use , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Brain/drug effects , Brain/metabolism , Chemistry, Pharmaceutical/trends , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Humans , Reactive Oxygen Species/metabolismABSTRACT
INTRODUCTION: The syndrome of chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by ptosis and ophthalmoplegia has that has been associated to the presence of large deletion, single or multiple, in the mitochondrial DNA of skeletal muscle. CASE REPORT: We report a familiar case of chronic progressive external ophthalmoplegia of maternal inheritance that began at birth, and developed with slow progression but with no multisystemic involvement. Non of the affected individuals had ragged-red fibers in skeletal muscle. Genetic analysis of mitochondrial DNA revealed the presence of a single deletion of 4,977 bp that encompasses the nucleotide positions 8,482 to 13,460, flanked by a direct repeat sequence. CONCLUSIONS: The amount of deleted mitochondrial DNA (15%) in this patient's muscle suggests, even if the percentage of the mutation is low, that this deletion is the molecular cause of the phenotypic presentation of this patient. This is one of the few cases described in the literature of CPEO maternally inherited.
Subject(s)
DNA, Mitochondrial , Mitochondria, Muscle , Ophthalmoplegia, Chronic Progressive External/physiopathology , Adolescent , Adult , Child , Child, Preschool , Disease Progression , Humans , Infant , Infant, Newborn , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Mutation , Ophthalmoplegia, Chronic Progressive External/diagnosis , Sequence DeletionABSTRACT
Mitochondria play an important role in the homeostasis of intracellular Ca(2+) and regulate its availability for exocytosis. Inhibitors of mitochondria Ca(2+) uptake such as protonophore CCCP potentiate the secretory response to a depolarizing pulse of K(+). Exposure of cells to agents that directly (cytochalasin D, latrunculin B) or indirectly (PMA) disrupt cortical F-actin networks also potentiate the secretory response to high K(+). The effects of cytochalasin D and CCCP on secretion were additive whereas those of PMA and CCCP were not; this suggests different mechanisms for cytochalasin D and CCCP and a similar mechanism for PMA and CCCP. Mitochondria were the site of action of CCCP, because the potentiation of secretion by CCCP was observed even after depletion of Ca(2+) from the endoplasmic reticulum. CCCP induced a small increase in the cytosolic Ca(2+) concentration ([Ca(2+)](c)) that was not modified by the protein kinase C (PKC) inhibitor chelerythrine. Both CCCP and PMA induced cortical F-actin disassembly, an effect abolished by chelerythrine. In addition, rotenone and oligomycin A, two other mitochondrial inhibitors, also evoked cortical F-actin disassembly and potentiated secretion; again, these effects were blocked by chelerythrine. CCCP also enhanced the phosphorylation of PKC and myristoylated alanine-rich C kinase substance (MARCKS), and these were also inhibited by chelerythrine. The results suggest that the rapid sequestration of Ca(2+) by mitochondria would protect the cell from an enhanced PKC activation and cortical F-actin disassembly, thereby limiting the magnitude of the secretory response.
Subject(s)
Actins/metabolism , Calcium/metabolism , Carbonyl Cyanide m-Chlorophenyl Hydrazone/analogs & derivatives , Chromaffin Cells/metabolism , Mitochondria/metabolism , Protein Kinase C/metabolism , Animals , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Catecholamines/metabolism , Cattle , Cells, Cultured , Chromaffin Cells/cytology , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Proteins/metabolism , Mitochondria/drug effects , Myristic Acid/metabolism , Myristoylated Alanine-Rich C Kinase Substrate , Phosphorylation , Protein Kinase C/antagonists & inhibitors , ProtonsABSTRACT
Sustained, mild K+ depolarization caused bovine chromaffin cell death through a Ca(2+)-dependent mechanism. During depolarization, Ca(2+) entered preferentially through L-channels to induce necrotic or apoptotic cell death, depending on the duration of the cytosolic Ca(2+) concentration ([Ca(2+)](c)) signal, as proven by the following. (i) The L-type Ca(2+) channel activators Bay K 8644 and FPL64176, more than doubled the cytotoxic effects of 30 mm K+; (ii) the L-type Ca(2+) channel blocker nimodipine suppressed the cytotoxic effects of K+ alone or K+ plus FPL64176; (iii) the potentiation by FPL64176 of the K+ -evoked [Ca(2+)](c) elevation was totally suppressed by nimodipine. Cell exposure to K+ plus the L-type calcium channel agonist FPL64176 caused an initial peak rise followed by a sustained elevation of the [Ca(2+)](c) that, in turn, increased [Ca(2+)](m) and caused mitochondrial membrane depolarization. Cyclosporin A, a blocker of the mitochondrial transition pore, and superoxide dismutase prevented the apoptotic cell death induced by Ca(2+) overload through L-channels. These results suggest that Ca(2+) entry through L-channels causes both calcium overload and mitochondrial disruption that will lead to the release of mediators responsible for the activation of the apoptotic cascade and cell death. This predominant role of L-type Ca(2+) channels is not shared by other subtypes of high threshold voltage-dependent neuronal Ca(2+) channels (i.e. N, P/Q) expressed by bovine chromaffin cells.
Subject(s)
Calcium Channels, L-Type/metabolism , Calcium/metabolism , Chromaffin Cells/physiology , Mitochondria/physiology , Adrenal Medulla/cytology , Adrenal Medulla/physiology , Animals , Apoptosis , Calcium Channel Agonists/pharmacology , Calcium Channel Blockers/pharmacology , Cattle , Chromaffin Cells/cytology , Cytochrome c Group/metabolism , Cytoprotection , Free Radicals/metabolism , Necrosis , Nimodipine/pharmacology , Pyrroles/pharmacologyABSTRACT
The hypothesis that the buffering of Ca(2+) by mitochondria could affect the Ca(2+)-dependent inhibition of voltage-activated Ca(2+) channels, (I(Ca)), was tested in voltage-clamped bovine adrenal chromaffin cells. The protonophore carbonyl cyanide m-chlorophenyl-hydrazone (CCCP), the blocker of the Ca(2+) uniporter ruthenium red (RR), and a combination of oligomycin plus rotenone were used to interfere with mitochondrial Ca(2+) buffering. In cells dialyzed with an EGTA-free solution, peak I(Ca) generated by 20 msec pulses to 0 or +10 mV, applied at 15 sec intervals, from a holding potential of -80 mV, decayed rapidly after superfusion of cells with 2 microm CCCP (tau = 16.7 +/- 3 sec; n = 8). In cells dialyzed with 14 mm EGTA, CCCP did not provoke I(Ca) loss. Cell dialysis with 4 microm ruthenium red or cell superfusion with oligomycin (3 microm) plus rotenone (4 microm) also accelerated the decay of I(Ca). After treatment with CCCP, decay of N- and P/Q-type Ca(2+) channel currents occurred faster than that of L-type Ca(2+) channel currents. These data are compatible with the idea that the elevation of the bulk cytosolic Ca(2+) concentration, [Ca(2+)](c), causes the inhibition of L- and N- as well as P/Q-type Ca(2+) channels expressed by bovine chromaffin cells. This [Ca(2+)](c) signal appears to be tightly regulated by rapid Ca(2+) uptake into mitochondria. Thus, it is plausible that mitochondria might efficiently regulate the activity of L, N, and P/Q Ca(2+) channels under physiological stimulation conditions of the cell.
