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BACKGROUND: Many patients with X-linked hypophosphataemic rickets (X-LHPR) demonstrate significant lower limb deformity despite optimal medical management. This study evaluates the use of guided growth by means of hemi-epiphysiodesis to address coronal plane deformity in the skeletally immature child. METHODS: Since 2005, 24 patients with X-LHPR have been referred to our orthopaedic unit for evaluation. All patients had standardised long leg radiographs that were analysed sequentially before and after surgery if any was performed. The rate of correction of deformity was calculated based on peri-articular angles and diaphyseal deformity angles measured at regular intervals using Traumacad software. Clinical records were reviewed to obtain relevant clinical and demographic details. Statistical analysis was performed using SPSS 23 (SPSS Inc., Chicago, IL, USA). RESULTS: The indication for surgical intervention was a mechanical axis progressing through Zone 2 or in Zone 3 despite one year of optimised medical treatment. The 15 patients underwent 16 episodes of guided growth (30 limbs, 38 segments) at a mean age of 10.3 years. In four limbs, surgery has only taken place recently; and in three limbs, correction is ongoing. Neutral mechanical axis was restored in 16/23 (70%) limbs: six improved and one limb (one segment) required osteotomy for residual deformity. The mean rate of angular correction per month was 0.3° for the proximal tibia and 0.7° for the distal femur. Patients with ≥ 3 years of growth remaining responded significantly better than older patients (p = 0.004). Guided growth was more successful in correcting valgus than varus deformity (p = 0.007). In younger patients, diaphyseal deformity corrected at a rate of 0.2° and 0.6° per month for the tibia and the femur, respectively. There has been one case of recurrent deformity. Patients with corrected coronal plane alignment did not complain of significant residual torsional malalignment. Serum phosphate and alkaline phosphatase levels did not affect response to surgery. CONCLUSIONS: Guided growth is a successful, minimally invasive method of addressing coronal plane deformity in X-LHPR. If coronal plane deformity is corrected early in patients with good metabolic control, osteotomy can be avoided.
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BACKGROUND: Recently, important discoveries regarding the archaeon that functioned as the "host" in the merger with a bacterium that led to the eukaryotes, its "complex" nature, and its phylogenetic relationship to eukaryotes, have been reported. Based on these new insights proposals have been put forward to get rid of the three-domain Model of life, and replace it with a two-domain model. RESULTS: We present arguments (both regarding timing, complexity, and chemical nature of specific evolutionary processes, as well as regarding genetic structure) to resist such proposals. The three-domain Model represents an accurate description of the differences at the most fundamental level of living organisms, as the eukaryotic lineage that arose from this unique merging event is distinct from both Archaea and Bacteria in a myriad of crucial ways. CONCLUSIONS: We maintain that "a natural system of organisms", as proposed when the three-domain Model of life was introduced, should not be revised when considering the recent discoveries, however exciting they may be.
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Archaea/genética , Bacterias/genética , Evolución Biológica , Eucariontes/genética , Clasificación , FilogeniaRESUMEN
BACKGROUND: Hyperparathyroidism (HPT) in children is rare and surgical management is supported only by limited evidence. METHODS: Retrospective case series of all children under the age of 16 years who underwent parathyroidectomy (PTx) between 1978 and 2012. RESULTS: We identified 29 children who had surgery for HPT. Six were neonates with neonatal severe hyperparathyroidism (NSHPT) and 23 older children (age range 7-16 years) with sporadic (16) or familial (7) HPT and 93% were symptomatic. Accuracy of ultrasound and MIbi in localising solitary parathyroid adenomas was 96%, but less helpful in hyperplasia and neonates. Children with NSHPT underwent 5 curative total and 1 subtotal PTx (no reoperations). Children with familial HPT underwent 3 total and 4 subtotal PTx. One child with subtotal PTx required a reoperation. Children with sporadic HPT underwent subtotal PTx prior to 1980 (2), exploration and removal of enlarged glands 1980-2002 (5) and minimally invasive PTx since 2002 (9) and all cured by the first operation. CONCLUSIONS: Our study documents that HPT in children is predominantly symptomatic on presentation and genetically determined in 46% of cases. Imaging is accurate in localising parathyroid adenomas, but not hyperplasias. Total PTx for familial HPT was curative and minimally invasive PTx is the operation of choice for older children with sporadic HPT.
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Hiperparatiroidismo/cirugía , Adenoma/cirugía , Adolescente , Niño , Femenino , Humanos , Hiperparatiroidismo Primario/cirugía , Hiperplasia/diagnóstico , Lactante , Recién Nacido , Enfermedades del Recién Nacido/cirugía , Masculino , Glándulas Paratiroides/diagnóstico por imagen , Glándulas Paratiroides/patología , Neoplasias de las Paratiroides/cirugía , Paratiroidectomía/métodos , Cintigrafía , Reoperación , Estudios Retrospectivos , Resultado del Tratamiento , UltrasonografíaRESUMEN
The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.
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Investigación Biomédica/métodos , Atención a la Salud/métodos , Investigación Biomédica/organización & administración , Investigación Biomédica/normas , Atención a la Salud/organización & administración , Atención a la Salud/normas , Humanos , Medicina Estatal/organización & administración , Medicina Estatal/normas , Reino UnidoRESUMEN
BACKGROUND/AIMS: Nephrogenic diabetes insipidus (NDI) is a serious condition with large water losses in the urine and the risk of hypernatremic dehydration. Unrecognized, repeated episodes of hypernatremic dehydration can lead to permanent brain damage. Primary NDI is due to mutations in either AVPR2 or AQP2. NDI can also occur as a secondary complication, most commonly from obstructive uropathy or chronic lithium therapy. We observed NDI in patients with inherited tubulopathies and aimed to define the clinical and molecular phenotype. METHODS: We reviewed the medical notes of 4 patients with clinical NDI and an underlying molecularly confirmed diagnosis of nephropathic cystinosis, Bartter syndrome, nephronophthisis and apparent mineralocorticoid excess, respectively. RESULTS: The patients all failed to concentrate their urine after administration of 1-desamino[8-D-arginine] vasopressin. None had an identifiable mutation in AVPR2 or AQP2, consistent with secondary NDI. Patients experienced repeated episodes of hypernatremic dehydration, and in 2 cases, NDI was initially thought to be the primary diagnosis, delaying recognition of the underlying problem. CONCLUSION: The recognition of this potential complication is important as it has direct implications for clinical management. The occurrence of NDI in association with these conditions provides clues for the etiology of aquaporin deficiency.
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Síndrome de Bartter/diagnóstico , Cistinosis/diagnóstico , Diabetes Insípida Nefrogénica/diagnóstico , Enfermedades Renales Quísticas/diagnóstico , Síndrome de Exceso Aparente de Mineralocorticoides/diagnóstico , Síndrome de Bartter/complicaciones , Síndrome de Bartter/genética , Niño , Preescolar , Cistinosis/complicaciones , Cistinosis/genética , Diabetes Insípida Nefrogénica/etiología , Diabetes Insípida Nefrogénica/genética , Femenino , Humanos , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/congénito , Masculino , Síndrome de Exceso Aparente de Mineralocorticoides/complicaciones , Síndrome de Exceso Aparente de Mineralocorticoides/genética , Mutación/genéticaRESUMEN
BACKGROUND/AIMS: Mutations in the type 2 vasopressin receptor gene (AVPR2) underlie X-linked recessive nephrogenic diabetes insipidus (NDI). Here, we report on a family with a mutation in AVPR2, c.262G>A (p.V88M). This recurrently identified mutation was previously shown to abolish AVPR2 function, yet in some affected members, urine osmolalities of up to 570 mosm/kg were observed. We detail the variable clinical phenotype and investigate its molecular basis. METHODS: Retrospective analysis of clinical data and in vitro assessment of wild-type and V88M-mutant receptors. RESULTS: Clinical data were available on 6 patients. Four of these demonstrated a substantial increase in urinary concentration after 1-desamino[8-D-arginine] vasopressin, consistent with partial NDI, while 2 did not respond. In vitro analysis revealed a reduced cell surface expression and decreased binding affinity for arginine-vasopressin of the mutant receptor, leading to blunted signaling activity. Treatment with the pharmacological chaperone SR121463 enhanced cell surface expression. CONCLUSION: The V88M mutation is associated with phenotypical diversity, which may be explained by the fact that both the expression level and the hormone-binding affinity are affected by the mutation. Our results provide a rational basis for treatment trials with vasopressin analogues in combination with pharmacologic chaperones in patients with this recurrently identified mutation.
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Sustitución de Aminoácidos , Diabetes Insípida Nefrogénica/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación , Receptores de Vasopresinas/genética , Adolescente , Adulto , Niño , AMP Cíclico/metabolismo , Desamino Arginina Vasopresina , Diabetes Insípida Nefrogénica/orina , Femenino , Regulación de la Expresión Génica , Enfermedades Genéticas Ligadas al Cromosoma X/orina , Células HEK293/efectos de los fármacos , Células HEK293/metabolismo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Morfolinas/farmacología , Natriuresis , Linaje , Fenotipo , Poliuria/etiología , Unión Proteica/genética , Receptores de Vasopresinas/química , Receptores de Vasopresinas/fisiología , Proteínas Recombinantes de Fusión/fisiología , Estudios Retrospectivos , Sistemas de Mensajero Secundario , Compuestos de Espiro/farmacología , Transfección , Orina/química , Inactivación del Cromosoma X , Adulto JovenRESUMEN
We describe five babies, who were exclusively breast fed, with life-threatening complications of hypernatraemic dehydration secondary to inadequate breast feeding. An increased awareness among health professionals is required so that this potentially devastating condition can be prevented.
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Lactancia Materna/efectos adversos , Deshidratación/etiología , Hipernatremia/etiología , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Renal venous thrombosis (RVT) is the most common form of venous thrombosis in neonates, causing both acute and long term kidney dysfunction. Historical predisposing factors include dehydration, maternal diabetes, and umbilical catheters, but recent reports highlight associations with prothrombotic abnormalities. STUDY: Twenty three patients with neonatal RVT were analysed over 15 years. Predisposing factors, presentation, and procoagulant status were compared with renal outcome using multilevel modelling. RESULTS: Median presentation was on day 1: 19/23 (83%) had pre/perinatal problems, including fetal distress (14), intrauterine growth retardation (five), and pre-identified renal abnormalities (two); 8/18 (44%) had procoagulant abnormalities, particularly factor V Leiden mutations (4/18). Long term abnormalities were detected in 28/34 (82%) affected kidneys; mean glomerular filtration rate was 93.6 versus 70.2 ml/min/1.73 m2 in unilateral versus bilateral cases (difference 23.4; 95% confidence interval 6.4 to 40.4; p = 0.01). No correlation was observed between procoagulant tendencies and outcome, but presenting renal length had a significant negative correlation: mean fall in estimated single kidney glomerular filtration rate was 3 ml/min/1.73 m2 (95% confidence interval 3.7 to -2.2; p = 0.001) per 1 mm increase, and kidneys larger than 6 cm at presentation never had a normal outcome. CONCLUSIONS: This subgroup of neonatal RVT would be better termed perinatal RVT to reflect antenatal and birth related antecedents. Prothrombotic defects should be considered in all patients with perinatal RVT. Kidney length at presentation correlated negatively with renal outcome. The latter, novel observation raises the question of whether larger organs should be treated more aggressively in future.
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Riñón/patología , Venas Renales , Trombosis de la Vena/etiología , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Femenino , Sufrimiento Fetal/complicaciones , Retardo del Crecimiento Fetal , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Recién Nacido , Riñón/anomalías , Masculino , Pronóstico , Factores de Riesgo , Trombofilia/complicaciones , Trombosis de la Vena/embriología , Trombosis de la Vena/patologíaRESUMEN
BACKGROUND AND OBJECTIVE: Long-acting beta(2)-agonists have acquired an indispensable position in the management of bronchial symptoms in patients with asthma. The objective of this study was to compare onset-of-action and clinical effectiveness of formoterol and salmeterol during 2 weeks of treatment. We also investigated the association between bronchodilator effects and perceived relieve of dyspnoea. METHODS: A multi-centre randomized double-blind placebo-controlled cross-over trial was performed in 35 subjects with moderate persistent asthma. Treatment periods existed of 2 weeks formoterol (12 microg bid), salmeterol (50 microg bid) and placebo, all administered by pressurized metered dose inhaler. FEV(1) and Visual Analogue Scale (VAS) scores were repeatedly measured until 180 min post-bronchodilation (post-BD), before as well as after each treatment period. Onset-of-action was defined as a >/=15% increase in FEV(1). Subjects kept diaries of morning and evening PEFR values and use of rescue bronchodilator. RESULTS: Formoterol and salmeterol both caused a significant increase in FEV(1) (0.45L [95% CI 0.01, 0.80] and 0.27L [95% CI 0.08, 0.62] respectively). At 3' post-BD, three times as many subjects demonstrated onset-of-action on formoterol compared to salmeterol (36% versus 13%, P = 0.063), at 6' post-BD 42% versus 27% (P = 0.063). VAS scores were similar for formoterol and salmeterol at pre-treatment assessment, but tended to be higher for formoterol after 2weeks treatment. No differences between formoterol and salmeterol were observed for PEFR values or use of rescue medication. 50% of the subjects preferred formoterol, 29% salmeterol (P < 0.001). Significant associations between FEV(1) and VAS ratings existed only at 10', 15' and 30' post-BD, not before or after these time points. CONCLUSION: The earlier described faster onset-of-action of formoterol as compared to a equipotent dosage of salmeterol was confirmed in this study. Perception of decreasing airflow obstruction may be delayed after acute bronchodilation.
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Agonistas Adrenérgicos beta/uso terapéutico , Albuterol/análogos & derivados , Albuterol/uso terapéutico , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Etanolaminas/uso terapéutico , Agonistas Adrenérgicos beta/administración & dosificación , Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Etanolaminas/administración & dosificación , Femenino , Fumarato de Formoterol , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Xinafoato de Salmeterol , Factores de TiempoRESUMEN
The early diagnosis of Lowe's syndrome can be difficult. Urinary excretion of retinol binding protein (RBP) and the lysosomal enzyme N-acetyl-glucosaminidase (NAG) were significantly increased in boys with Lowe's syndrome. Measurement of these urine parameters is recommended in suspected cases.
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Enfermedades Renales/fisiopatología , Túbulos Renales/fisiopatología , Síndrome Oculocerebrorrenal/fisiopatología , Acetilglucosaminidasa/orina , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Humanos , Lactante , Recién Nacido , Enfermedades Renales/orina , Síndrome Oculocerebrorrenal/orina , Proteínas de Unión al Retinol/orinaRESUMEN
BACKGROUND: The previous epidemiological study of paediatric nephrolithiasis in Britain was conducted more than 30 years ago. AIMS: To examine the presenting features, predisposing factors, and treatment strategies used in paediatric stones presenting to a British centre over the past five years. METHODS: A total of 121 children presented with a urinary tract renal stone, to one adult and one paediatric centre, over a five year period (1997-2001). All children were reviewed in a dedicated stone clinic and had a full infective and metabolic stone investigative work up. Treatment was assessed by retrospective hospital note review. RESULTS: A metabolic abnormality was found in 44% of children, 30% were classified as infective, and 26% idiopathic. Bilateral stones on presentation occurred in 26% of the metabolic group compared to 12% in the infective/idiopathic group (odds ratio 2.7, 95% CI 1.03 to 7.02). Coexisting urinary tract infection was common (49%) in the metabolic group. Surgically, minimally invasive techniques (lithotripsy, percutaneous nephrolithotomy, and endoscopy) were used in 68% of patients. CONCLUSIONS: There has been a shift in the epidemiology of paediatric renal stone disease in the UK over the past 30 years. Underlying metabolic causes are now the most common but can be masked by coexisting urinary tract infection. Treatment has progressed, especially surgically, with sophisticated minimally invasive techniques now employed. All children with renal stones should have a metabolic screen.
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Cálculos Renales/epidemiología , Adolescente , Distribución por Edad , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Cálculos Renales/etiología , Cálculos Renales/cirugía , Masculino , Enfermedades Metabólicas/complicaciones , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Estudios Retrospectivos , Factores de Riesgo , Distribución por Sexo , Infecciones Urinarias/complicacionesRESUMEN
BACKGROUND: The efficacy of allopurinol in autosomal dominant familial juvenile hyperuricaemic nephropathy (FJHN) has been disputed. AIM: To address this question, in the absence of controlled trials. DESIGN: Retrospective long-term follow-up study. METHODS: All kindreds were biochemically screened. Measurements included uric acid clearance, creatinine clearance, serum creatinine, and glomerular filtration rate (GFR). We used five siblings who had died or progressed to transplantation, ten other deceased relatives, and two index cases (one untreated, one non-compliant) as controls to assess the effects of allopurinol. RESULTS: Of eight families with FJHN, six had a strong history of renal disease and early parental death (mean age 41 years, n=10). Of 27 patients started immediately on allopurinol and treated uninterruptedly, 21 responded well, including three children born subsequently. Eight siblings (mean age 19 years) with a normal plasma creatinine at start (<120 micromol/l, mean GFR 80 ml/min/1.73 m(2)) retained stable renal function (mean 14.5 years, mean age 34 years, GFR 85 ml/min/1.73 m(2)). Of the 13 other responders, treated for up to 34 years, 10 with a creatinine <200 micromol/l at diagnosis (mean age 28 years, mean creatinine 137 micromol/l at start) now have a mean creatinine of 210 micromol/l. In contrast, five patients (mean age 26 years) with a creatinine >200 micromol/l (GFR <35 ml/min/1.73 m(2)) when allopurinol commenced, plus one untreated index case, all progressed rapidly (mean 6 years) to end-stage renal failure. In two others (one non-compliant, one initially untreated), GFR fell by >50% in 7 years. Introduction of allopurinol in the latter has stabilized GFR. DISCUSSION: Allopurinol reduced the morbidity and mortality from renal failure seen in untreated siblings and previous generations of these families. Early diagnosis of FJHN is important, so that treatment can begin before irreversible renal damage has developed.
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Alopurinol/uso terapéutico , Supresores de la Gota/uso terapéutico , Enfermedades Renales/tratamiento farmacológico , Ácido Úrico/sangre , Uricosúricos/uso terapéutico , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Renales/complicaciones , Enfermedades Renales/genética , Masculino , Linaje , Insuficiencia Renal/etiología , Insuficiencia Renal/prevención & control , Estudios Retrospectivos , Síndrome , Resultado del Tratamiento , Uremia/tratamiento farmacológico , Uremia/genéticaRESUMEN
OBJECTIVE: To explore maternal and child perspectives on children's adjustment in the context of paediatric renal disease, and maternal psychological variables that may account for variance in child and maternal ratings. METHODS: Forty-three children with end stage renal disease and their maternal caregivers completed the Strengths and Difficulties Questionnaire (SDQ). Mothers also reported on their own mental health, and the strategies they used to cope with their child's illness. The severity of the child's condition was rated independently by a renal clinician. RESULTS: Compared with normative data for the SDQ mothers reported their children to be at increased risk of psychological problems. However, the children themselves reported no more problems than a normative sample. Mothers' coping and mental health explained some of the variance in their ratings of the child's adjustment but were not predictive of the children's self-ratings. CONCLUSIONS: The results suggest that maternal factors may not explain the variability in children's adjustment to chronic illness, perhaps especially within the age range studied here. Practical implications of the data are also discussed. In particular, a systemic approach to paediatric liaison by psychologists is emphasized.
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Adaptación Psicológica , Cuidadores/psicología , Niños con Discapacidad/psicología , Fallo Renal Crónico/psicología , Madres/psicología , Estrés Psicológico , Adulto , Niño , Femenino , Hospitales Pediátricos , Humanos , Salud Mental , Relaciones Madre-Hijo , Encuestas y Cuestionarios , Reino UnidoRESUMEN
AIM: To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis. METHODS: The medical records for six patients with ARC syndrome were reviewed, presenting over 10 years to three paediatric referral centres. RESULTS: All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus. Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal. Many of our patients showed dysmorphic features or ichthyosis. All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films revealed abnormally large platelets. CONCLUSIONS: ARC syndrome exhibits notable clinical variability and may not be as rare as previously thought. The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum.
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Acidosis Tubular Renal/diagnóstico , Artrogriposis/diagnóstico , Colestasis/diagnóstico , Síndrome de Fanconi/diagnóstico , Femenino , Humanos , Recién Nacido , Masculino , Linaje , Fenotipo , SíndromeRESUMEN
The blue light receptor photoactive yellow protein (PYP) displays rhodopsin-like photochemistry based on the trans to cis photoisomerization of its p-coumaric acid chromophore. Here, we report that protein refolding from the acid-denatured state of PYP mimics the last photocycle transition in PYP. This implies a direct link between transient protein unfolding and photosensory signal transduction. We utilize this link to study general issues in protein folding. Chromophore trans to cis photoisomerization in the acid-denatured state strongly decelerates refolding, and converts the pH dependence of the barrier for refolding from linear to nonlinear. We propose transition state movement to explain this phenomenon. The cis chromophore significantly stabilizes the acid-denatured state, but acidification of PYP results in the accumulation of the acid-denatured state containing a trans chromophore. This provides a clear example of kinetic control in a protein unfolding reaction. These results demonstrate the power of PYP as a light-triggered model system to study protein folding.
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Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Luz , Fotorreceptores Microbianos , Escherichia coli/metabolismo , Concentración de Iones de Hidrógeno , Cinética , Modelos Químicos , Desnaturalización Proteica , Pliegue de Proteína , Transducción de Señal , Espectrometría de Fluorescencia , Estereoisomerismo , Temperatura , Factores de TiempoRESUMEN
The role of nonoperative management of solid abdominal organ injury from blunt trauma in neurologically impaired patients has been questioned. A statewide trauma registry was reviewed from January 1993 through December 1995 for all adult (age >12 years) patients with blunt trauma and an abdominal solid organ injury (kidney, liver, or spleen) of Abbreviated Injury Scale score > or =2. Patients with initial hypotension (systolic blood pressure <90 mm Hg) were excluded. Patients were stratified by Glasgow Coma Score (GCS) into normal (GCS 15), mild to moderate (GCS 8-14), and severe (GCS < or =7) impairment groups. Management was either operative or nonoperative; failure of nonoperative management was defined as requiring laparotomy for intraabdominal injury more than 24 hours after admission. In the 3-year period 2327 patients sustained solid viscus injuries; 1561 of these patients were managed nonoperatively (66 per cent). The nonoperative approach was initiated less frequently in those patients with greater impairment in mental status: GCS 15, 71 per cent; GCS 8 to 14, 62 per cent; and GCS < or =7, 50 per cent. Mortality, hospital length of stay, and intensive care unit days were greater in operatively managed GCS 15 and 8 to 14 groups but were not different on the basis of management in the GCS < or =7 group. Failure of nonoperative management occurred in 94 patients (6%). There was no difference in the nonoperative failure rate between patients with normal mental status and those with mild to moderate or severe head injuries. Nonoperative management of neurologically impaired hemodynamically stable patients with blunt injuries of liver, spleen, or kidney is commonly practiced and is successful in more than 90 per cent of cases. No differences were noted in the rates of delayed laparotomy or survival between normal, mild to moderately head-injured, and severely head-injured patients.
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Traumatismos Abdominales/complicaciones , Traumatismos Abdominales/terapia , Traumatismos Craneocerebrales/complicaciones , Heridas no Penetrantes/terapia , Traumatismos Abdominales/mortalidad , Adulto , Escala de Coma de Glasgow , Humanos , Riñón/lesiones , Tiempo de Internación , Hígado/lesiones , Sistema de Registros , Estudios Retrospectivos , Medición de Riesgo , Bazo/lesiones , Heridas no Penetrantes/mortalidadRESUMEN
The photoreceptor photoactive yellow protein (PYP) was used as a model system to study receptor activation and protein folding. Refolding was studied by stopped-flow absorbance spectroscopy for PYP with either a trans or a cis chromophore. Chromophore trans to cis isomerization, the mechanism of light detection by PYP, greatly affects the protein folding process. When the cis chromophore is present, refolding from the unfolded state proceeds through the putative signaling state of PYP as an on-pathway intermediate. In addition, moderate denaturant concentrations result in the specific unfolding of the signaling state of PYP. Thus, the signaling state is common to the pathways of folding and signaling. This result provides an avenue for the study of protein folding. We demonstrate how this approach can be used to establish whether a folding intermediate is on-pathway or off-pathway. The results also reveal transient partial unfolding as a molecular mechanism for signaling.
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Células Fotorreceptoras/química , Pliegue de Proteína , Transducción de Señal , Isomerismo , Cinética , Sondas Moleculares , FotoquímicaRESUMEN
Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder involving hearing loss, branchial defects, ear pits and renal abnormalities. Oto-facio-cervical (OFC) syndrome is clinically similar to BOR syndrome, with clinical features in addition to those of BOR syndrome. Mutations in the EYA1 gene (localised to 8q13.3) account for nearly 70% of BOR syndrome cases exhibiting at least three of the major features. Small intragenic deletions of the 3' region of the gene have also been reported in patients with BOR syndrome. We have developed a fluorescent quantitative multiplex polymerase chain reaction for three 3' exons (7, 9 and 13) of the EYA1 gene. This dosage assay, combined with microsatellite marker analysis, has identified de novo deletions of the EYA1 gene and surrounding region in two patients with complex phenotypes involving features of BOR syndrome. One patient with OFC syndrome carried a large deletion of the EYA1 gene region, confirming that OFC syndrome is allelic with BOR syndrome. Microsatellite analysis has shown that comparison of the boundaries of this large deletion with other reported rearrangements of the region reduces the critical region for Duane syndrome (an eye movement disorder) to between markers D8S553 and D8S1797, a genetic distance of approximately 1 cM.
Asunto(s)
Anomalías Múltiples/genética , Alelos , Síndrome Branquio Oto Renal/genética , Síndrome de Retracción de Duane/genética , Ligamiento Genético/genética , Eliminación de Secuencia/genética , Transactivadores/genética , Anomalías Múltiples/fisiopatología , Síndrome Branquio Oto Renal/fisiopatología , Análisis Mutacional de ADN , Exones/genética , Femenino , Pruebas Genéticas , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Repeticiones de Microsatélite/genética , Proteínas Nucleares , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Proteínas Tirosina FosfatasasRESUMEN
OBJECTIVE: The objective was to assess the efficacy and safety of growth hormone (GH) treatment in severely growth retarded children with nephropathic cystinosis during conservative treatment and during renal replacement therapy. STUDY DESIGN: The design was an open-labeled prospective trial with a run-in period of 1 year. RESULTS: A total of 74 children with cystinosis (age 3.0 to 18 years) were treated with GH over a mean period of 3.1 years (range 1 to 10 years); 52 patients were receiving conservative treatment (mean age 7.1 years), 7 were receiving dialysis (12.5 years), and 15 had received a renal transplant (14.8 years). The mean standardized height (SD score) was -4.0 in the conservative treatment group, -4.4 in the dialysis group, and -4.9 in the renal transplant group. During the first treatment year, height velocity doubled in the conservative treatment group, increased by 80% in the dialysis group, and increased by 45% in renal transplant group. Within 3 years the height SD score increased by +1.6 (P <.001) in prepubertal patients receiving conservative treatment, and percentile parallel growth was maintained thereafter. These effects of GH were less expressed in peripubertal patients receiving renal replacement therapy. No major side effects were observed. CONCLUSION: Long-term GH treatment is safe and effective in young children with nephropathic cystinosis. GH treatment should be started early in the course of the disease if adequate nutrition and cysteamine treatment do not prevent growth retardation.
Asunto(s)
Cistinosis/terapia , Trastornos del Crecimiento/terapia , Hormona del Crecimiento/uso terapéutico , Enfermedades Renales/terapia , Adolescente , Estatura/efectos de los fármacos , Niño , Preescolar , Femenino , Humanos , Trasplante de Riñón , Cuidados a Largo Plazo , Masculino , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Diálisis RenalRESUMEN
Photoactive yellow protein (PYP) is a eubacterial photoreceptor and a structural prototype of the PAS domain superfamily of receptor and regulatory proteins. We investigate the activation mechanism of PYP using time-resolved Fourier transform infrared (FTIR) spectroscopy. Our data provide structural, kinetic, and energetic evidence that the putative signaling state of PYP is formed during a large-amplitude protein quake that is driven by the formation of a new buried charge, COO(-) of the conserved Glu46, in a highly hydrophobic pocket at the active site. A protein quake is a process consisting of global conformational changes that are triggered and driven by a local structural "fault". We show that large, global structural changes take place after Glu46 ionization via intramolecular proton transfer to the anionic p-coumarate chromophore, and are suppressed by the absence of COO(-) formation in the E46Q mutant. Our results demonstrate the significance of buried charge formation in photoreceptor activation. This mechanism may serve as one of the general themes in activation of a range of receptor proteins. In addition, we report the results of time-resolved FTIR spectroscopy of PYP crystals. The direct comparison of time-resolved FTIR spectroscopic data of PYP in aqueous solution and in crystals reveals that the structure of the putative signaling state is not developed in P6(3) crystals. Therefore, when the structural developments during the functional process of a protein are experimentally determined to be very different in crystals and solutions, one must be cautious in drawing conclusions regarding the functional mechanism of proteins based on time-resolved X-ray crystallography.