Delphi consensus on the diagnosis and treatment of patients with short stature in Spain: GROW-SENS study.

PURPOSE: To identify consensus aspects related to the diagnosis, monitoring, and treatment of short stature in children to promote excellence in clinical practice. METHODS: Delphi consensus organised in three rounds completed by 36 paediatric endocrinologists. The questionnaire consisted of 26 topics grouped into: (1) diagnosis; (2) monitoring of the small-for-gestational-age (SGA) patient; (3) growth hormone treatment; and (4) treatment adherence. For each topic, different questions or statements were proposed. RESULTS: After three rounds, consensus was reached on 16 of the 26 topics. The main agreements were: (1) diagnosis tests considered as a priority in Primary Care were complete blood count, biochemistry, thyroid profile, and coeliac disease screening. The genetic test with the greatest diagnostic value was karyotyping. The main criterion for initiating a diagnostic study was prediction of adult stature 2 standard deviations below the target height; (2) the main criterion for initiating treatment in SGA patients was the previous growth pattern and mean parental stature; (3) the main criterion for response to treatment was a significant increase in growth velocity and the most important parameter to monitor adverse events was carbohydrate metabolism; (4) the main attitude towards non-responding patients is to check their treatment adherence with recording devices. The most important criterion for choosing the delivery device was its technical characteristics. CONCLUSIONS: This study shows the different degrees of consensus among paediatric endocrinologists in Spain concerning the diagnosis and treatment of short stature, which enables the identification of research areas to optimise the management of such patients.

Seguimiento de mujeres con síndrome de Turner tratadas con hormona de crecimiento en la infancia y que han alcanzado la talla final / Follow-up of women with Turner syndrome treated with growth hormone in childhood and who have reached final height

INTRODUCCIÓN: El síndrome de Turner es un trastorno genético que se caracteriza por la monosomía total o parcial del cromosoma X. La talla baja puede ser la única manifestación de este síndrome, siendo actualmente una de las indicaciones de tratamiento con hormona de crecimiento. El objetivo de este trabajo ha sido realizar un estudio retrospectivo de pacientes con síndrome de Turner tratadas con hormona de crecimiento, con la finalidad de determinar qué variables se relacionan con una buena respuesta al tratamiento. MATERIAL Y MÉTODOS: Estudio de cohortes retrospectivo. Se incluyen 48 pacientes afectas de síndrome de Turner que recibieron tratamiento con hormona de crecimiento en la infancia y que han alcanzado talla final. Se realizó una regresión lineal múltiple para correlacionar qué variables independientes se correlacionan con la variable de resultado principal. RESULTADOS: Se observó una ganancia de talla de 0,56 ± 0,86 DS, siendo la talla final alcanzada de 149,2 ± 6,47 cm (-2,43 ± 1,14 DE). La mayor ganancia de talla se produjo durante el primer año de tratamiento. Los factores asociados, de manera estadísticamente significativa, con una mejor respuesta al tratamiento fueron la edad al inicio del mismo y la edad ósea al inicio del tratamiento estrogénico. CONCLUSIONES: Nuestro trabajo refleja una ganancia media de talla de 0,5 DE en mujeres con síndrome de Turner tratadas con hormona de crecimiento. Los factores implicados en una mayor ganancia de talla en nuestra serie son la edad de inicio del tratamiento con rhGH y la edad ósea al inicio del tratamiento con estrógenos

INTRODUCTION: Turner syndrome is a genetic disorder characterized by the total or partial monosomy of the X chromosome. Short stature may be the only manifestation of this syndrome, being currently one of the initiations of growth hormone treatment. The objective of this work has been carried out in a retrospective study of patients with Turner syndrome treated with growth hormone, with the determination to determine which variables are related to a good response to treatment. MATERIAL AND METHODS: Retrospective cohort study. It includes 48 patients affected by Turner syndrome who received treatment with childhood growth hormone and who have obtained final size. A multiple linear regression was performed to correlate which independent variables correlate with the main outcome variable. RESULTS: A size gain of 0.56 ± 0.86 SD was obtained, the final size being reached of 149.2 ± 6.47 cm (-2.43 ± 1.14 DS). The greatest height gain occurred during the first year of treatment. The associated factors, in a statistically significant way, with a better response to the treatment were the age at the beginning of the treatment and the bone age at the beginning of the estrogenic treatment. CONCLUSIONS: Our work reflects an average height gain of 0.5 SD in women with Turner syndrome treated with growth hormone. The factors involved in a greater height gain in our series are the age of onset of rhGH treatment and the age at the beginning of estrogen treatment

[Prophylactic thyroidectomy in RET proto-oncogen mutation]. / Tiroidectomía profiláctica en mutación del protooncogén RET.

OBJECTIVE: Analysis of prophylactic thyroidectomy cases carried out in our Center in patients with RET gene mutations. MATERIAL AND METHODS: Retrospective study of 25 patients with RET proto-oncogene mutations subjected to prophylactic thyroidectomy between January 2000 and January 2016. Epidemiologic variables, surgical technique, histological results and follow-up were studied. RESULTS: Our sample consists of 25 patients, 15 males and 10 females. The range of age was from 7 months to 12 years old, with a median of 5 years old. We obtained 21 cases with NEM2A, from which 19 (76%) presented 634 mutation and 2 (8%) presented 611 mutation. Four cases were NEM2B, all with 918 mutation. Microscopical findings showed microcarcinoma, in situ carcinoma or medullary thyroid carcinoma in 16 patients (64%). Eight of them showed hyperplasia (32%) and 1 presented fibrosis (4%). The presence of elevated calcitonin was correlated with histologic alterations in 7 cases (43.7%), without significant differences (χ2 0.3; p 0.6). From 16 patients with carcinoma (13 NEM2A and 3 NEM2B), 10 were 5 years old or less at the moment of the surgery. A total thyroidectomy was performed in all patients. There were no intra or post-surgical complications. During the follow-up of the patients, levels of calcitonin, calcium, parathormone, catecholamines and metanephrines were normal, except from one case. CONCLUSIONS: The study of RET proto-oncogene allows the identification of patients susceptible of performing a prophylactic thyroidectomy, which have to be carried out early, in an experienced centers.

OBJETIVO: Analizar los casos de tiroidectomía profiláctica realizados en nuestro centro en pacientes con mutaciones del gen RET. MATERIAL Y METODOS: Estudio retrospectivo de 25 pacientes con mutación del protooncogén RET a los que se les realizó tiroidectomía profiláctica entre enero del 2000 y enero de 2016. Se estudiaron variables epidemiológicas, técnica quirúrgica, resultados anatomopatológicos y seguimiento. RESULTADOS: Nuestra serie consta de 25 pacientes, 15 varones y 10 mujeres. La mediana de la edad fue de 5 años con un rango de 7 meses a 12 años. Obtuvimos 21 casos con MEN2A de los que 19 (76%) presentaban la mutación 634 y 2 (8%) la mutación 611. Cuatro casos fueron MEN2B, todos con la mutación 918. Los hallazgos microscópicos revelaron microcarcimona, carcinoma in situ o carcinoma medular de tiroides en 16 casos (64%). 8 presentaron hiperplasia (32%) y 1 (4%) fibrosis. La presencia de calcitonina elevada se correlacionó con alteraciones anatomopatológicas en 7 casos (43,7%), pero no mostró diferencias significativas (χ² 0,3; p 0,6). De los 16 pacientes con carcinoma, (13 MEN2A, 3 MEN2B), 10 de ellos (62,5%) tenían 5 años o menos en el momento de la intervención. En todos los casos se realizó tiroidectomía total. No existieron complicaciones intra ni postoperatorias. Durante el seguimiento, los valores de calcitonina, calcio, paratohormona, catecolaminas y metanefrinas se han mantenido normales, excepto en 1 paciente. CONCLUSIONES: El estudio del protooncogén RET permite identificar pacientes susceptibles de realizar tiroidectomía profiláctica, la cual debe ser realizada de forma precoz, y en centros con experiencia.

Tiroidectomía profiláctica en mutación del protooncogén RET / Prophylactic thyroidectomy in RET proto-oncogen mutation

Objetivo. Analizar los casos de tiroidectomía profiláctica realizados en nuestro centro en pacientes con mutaciones del gen RET. Material y métodos. Estudio retrospectivo de 25 pacientes con mutación del protooncogén RET a los que se les realizó tiroidectomía profiláctica entre enero del 2000 y enero de 2016. Se estudiaron variables epidemiológicas, técnica quirúrgica, resultados anatomopatológicos y seguimiento. Resultados. Nuestra serie consta de 25 pacientes, 15 varones y 10 mujeres. La mediana de la edad fue de 5 años con un rango de 7 meses a 12 años. Obtuvimos 21 casos con MEN2A de los que 19 (76%) presentaban la mutación 634 y 2 (8%) la mutación 611. Cuatro casos fueron MEN2B, todos con la mutación 918. Los hallazgos microscópicos revelaron microcarcimona, carcinoma in situ o carcinoma medular de tiroides en 16 casos (64%). 8 presentaron hiperplasia (32%) y 1 (4%) fibrosis. La presencia de calcitonina elevada se correlacionó con alteraciones anatomopatológicas en 7 casos (43,7%), pero no mostró diferencias significativas (χ² 0,3; p 0,6). De los 16 pacientes con carcinoma, (13 MEN2A, 3 MEN2B), 10 de ellos (62,5%) tenían 5 años o menos en el momento de la intervención. En todos los casos se realizó tiroidectomía total. No existieron complicaciones intra ni postoperatorias. Durante el seguimiento, los valores de calcitonina, calcio, paratohormona, catecolaminas y metanefrinas se han mantenido normales, excepto en 1 paciente. Conclusiones. El estudio del protooncogén RET permite identificar pacientes susceptibles de realizar tiroidectomía profiláctica, la cual debe ser realizada de forma precoz, y en centros con experiencia (AU)

Objetive. Analysis of prophylactic thyroidectomy cases carried out in our Center in patients with RET gene mutations. Material and methods. Retrospective study of 25 patients with RET proto-oncogene mutations subjected to prophylactic thyroidectomy between January 2000 and January 2016. Epidemiologic variables, surgical technique, histological results and follow-up were studied. Results. Our sample consists of 25 patients, 15 males and 10 females. The range of age was from 7 months to 12 years old, with a median of 5 years old. We obtained 21 cases with NEM2A, from which 19 (76%) presented 634 mutation and 2 (8%) presented 611 mutation. Four cases were NEM2B, all with 918 mutation. Microscopical findings showed microcarcinoma, in situ carcinoma or medullary thyroid carcinoma in 16 patients (64%). Eight of them showed hyperplasia (32%) and 1 presented fibrosis (4%). The presence of elevated calcitonin was correlated with histologic alterations in 7 cases (43.7%), without significant differences (χ2 0.3; p 0.6). From 16 patients with carcinoma (13 NEM2A and 3 NEM2B), 10 were 5 years old or less at the moment of the surgery. A total thyroidectomy was performed in all patients. There were no intra or post-surgical complications. During the follow-up of the patients, levels of calcitonin, calcium, parathormone, catecholamines and metanephrines were normal, except from one case. Conclusions. The study of RET proto-oncogene allows the identification of patients susceptible of performing a prophylactic thyroidectomy, which have to be carried out early, in an experienced centers (AU)

Síndrome de «dumping» en pediatría / Gastric dumping syndrome in pediatrics

El síndrome de dumping (SD) es un conjunto de síntomas gastrointestinales y vasomotores que se produce como consecuencia de la cirugía gástrica. En pediatría se ha descrito fundamentalmente tras la cirugía antirreflujo. El diagnóstico es clínico, pero la sobrecarga oral de glucosa puede ser de utilidad si existen dudas. Se presentan los casos de 8 pacientes afectados de SD, 6 varones y 2 mujeres, con edades comprendidas entre 13 meses y 9 años en el momento del diagnóstico. Cuatro pacientes tenían como enfermedad de base una atresia de esófago intervenida, 2 un reflujo gastroesofágico, 1 una hernia diafragmática congénita y 1 un tumor gástrico. Todos fueron sometidos previamente a algún tipo de cirugía gástrica. En 7 de ellos se realizó una funduplicatura, y en 4 una piloroplastia. Todos los pacientes tenían clínica de SD temprano, y 6 asociaban clínica de SD tardío. En todos ellos se realizó una sobrecarga oral de glucosa, que confirmó el diagnóstico. El tratamiento dietético fue efectivo en 7 pacientes, y 1 paciente precisó además tratamiento con acarbosa. El tratamiento dietético es efectivo en la mayoría de los pacientes con SD (AU)

Dumping syndrome (DS) is a condition where gastrointestinal and vasomotor symptoms happen as a consequence of gastric surgery. In pediatrics it has been described primarily after anti-reflux surgery. The diagnosis is clinical, but the oral glucose tolerance test can be useful if there are doubts. We present the cases of 8 patients with DS, 6 men and 2 women, aged between 13 months and 9 years old. Four patients had atresia of esophagus, 2 gastroesophageal reflux disease, 1 patient a congenital diaphragmatic hernia, and 1 a gastric tumor. All were treated with gastric surgery. In 7 of them fundoplication was performed, and in 4 piloroplastia. All patients had early dumping, and 6 had late dumping. In all patients oral glucose tolerance test confirmed the diagnosis. Dietary treatment was effective in 7 patients; 1 patient also required treatment with acarbose. Dietary treatment is effective in most patients with DS (AU)

Carotid artery stenting in patients with symptomatic carotid stenosis: a single-center series.

OBJECTIVES: Carotid angioplasty with stenting (CAS) in patients with carotid stenosis (CS) has become more restricted in France especially since the disclosure of such studies as EVA-3S and Stent-supported percutaneous angioplasty of the carotid artery versus endarterectomy (SPACE). This report is of a series of CS cases contraindicated for endarterectomy that underwent CAS at a French center of interventional neuroradiology. PATIENTS AND METHODS: Fifty-five patients with symptomatic CS more than 60% consecutively submitted to CAS between September 2008 and February 2011. The primary endpoint was either death or stroke within 30 days of the procedure; a secondary goal was to identify any possible factors that might have influenced the success and outcome of the intervention. RESULTS: The overall periprocedural stroke/death rate at 30 days was 5.4% (three out of 55 patients), with three non-disabling strokes and no deaths. Twenty-seven patients (49.1%) were treated with a cerebral protection device (CPD). Stent placement was achieved in all cases. Open- and closed-cell stents were implanted in 40 (72.7%) and 15 procedures (27.3%), respectively. Neither the use of a CPD, the carotid stent cell design nor any anatomical or technical factors were associated with a lower risk of stroke or death within 30 days of CAS. CONCLUSION: CAS in symptomatic patients with CS contraindicated for endarterectomy in this selected French series proved feasible and safe, with acceptable levels of morbidity. Use of a CPD, type of stent (open- or closed-cell), and anatomical and technical factors had no influence on the success of the procedure or the outcome within 30 days of the operation.

Vital and functional outcomes of the first-ever hemispheric stroke, epidemiological comparative study between Kunming (China) and Limoges (France).

BACKGROUND: Clinical outcomes and socioeconomic consequences after a stroke may differ between regions. METHODS: One cohort was established prospectively in Kunming (China) to compare with a cohort of 156 stroke patients included in Limoges (France). During 1 year, patients hospitalized within 48 hours for a first-ever hemispheric stroke were included. Demographic data and neurocardiovascular risk factors were registered. Hemiplegia was evaluated. Functional outcome was assessed using the Barthel Index (BI) after 3 months. RESULTS: One hundred and eighteen patients were included in Kunming. Patients of Kunming were younger (61.4 ± 13.4 vs 72.3 ± 14.6 years in Limoges, P<0.0001), more involved in professional activity (36.4% vs 12.8%, P<0.0001). Survival analysis indicated that mortality did not differ between cohorts, but independently predicted by coma at the 2nd day (HR=9.33, 95% CI [4.39, 19.78]) and age>70 years (HR=6.29, 95% CI [2.36, 16.59]). Despite a better baseline BI for patients of Kunming (50.0 ± 34.9 vs 37.4 ± 34.2, P=0.0031), after adjustment for confusing, patients in Limoges had a 2.11 OR 95% CI [1.03, 4.31]) to reach a BI>80 at 3 months. CONCLUSIONS: Functional recovery for patients of Kunming was not as good as expected. The socioeconomic consequences of stroke in Kunming are significant as they involved younger subjects who were still in work.

[Management of stroke in sub-Saharan Africa: current issues]. / Prise en charge des accidents vasculaires cérébraux en Afrique subsaharienne.

In sub-Saharan Africa, stroke is likely to present an increasingly important public health problem with a larger relative share of overall morbidity and mortality. Overall, sub-Saharan Health Care is characterized by a lack of human resources, lack of facilities for special investigations, and especially an absence of specific programs addressing the prevention of cardiovascular conditions. Current data on the epidemiology of stroke in sub-Saharan Africa, although sparse and fragmentary, indicate a comparatively high incidence of cerebral hemorrhage associated with high blood pressure, while ischemic stroke in black Africans still appears to be related primarily to small artery disease, HIV infection, and sickle cell disease. With urbanization, the role of large-vessel atherosclerosis is increasing. It is thus essential to coordinate government funding, health care professionals and development agencies to address this rising health problem. Access to health care needs to be better structured, and screening programs should be developed in order to identify and treat vascular risk factors. Improved training of health care professionals is also required in the areas of prevention, diagnosis and management of stroke. Implementation of best-practice recommendations for the management of stroke adapted to the specificities and resources of African countries would help rationalize the scarce resources currently available.

Pubertad precoz completa isosexual: hallazgos clínicos, de laboratorio y ecografía pélvica / Complete isosexual precocious puberty: clinical, pelvic ultrasound and laboratory features

Objetivo: El objetivo de este estudio ha sido determinar si la forma de presentación inicial de la pubertad precoz central (PPC) varía en relación con la etiología y permite el diagnóstico diferencial entre formas idiopáticas y orgánicas (neurogénicas), lo que haría innecesarias las pruebas de imagen del sistema nervioso central (SNC) en determinados pacientes. Pacientes y métodos: Los niños con PPC evaluados fueron incluidos de forma consecutiva en un estudio prospectivo observacional. Se recogieron los hallazgos clínicos, de laboratorio y ecográficos. Se compararon los hallazgos de PPC idiopática (3 niños y 49 niñas) y orgánica (2 niños y 8 niñas). Resultados: No hubo diferencias en cuanto al estadio puberal, edad de inicio puberal (7,0 [5,8-7,5] frente a 7,3 [5,1-8,3] años), cociente edad ósea/edad cronológica (1,26 [1,2-1,3] frente a 1,23 [1,1-1,3]) y menarquia materna (11,7 ± 0,2 frente a 11,7 ± 0,6 años) entre PPC idiopática y orgánica, respectivamente. Los pacientes con PPC orgánica presentaron una menor desviación estándar (DE) de la talla (0,35 ± 0,4 frente a 1,6 ± 0,1; p < 0,01), predicción de talla adulta y DE de la velocidad de crecimiento (0,8 ± 0,9 frente a 3,7 ± 0,7). Las niñas con PPC orgánica presentaban de forma significativa unas mayores concentraciones plasmáticas de estradiol (47,5 [25-68] frente a 27 [14-43] pg/ml) que las niñas con PPC idiopática. La ecografía pélvica realizada en el momento del diagnóstico reveló la presencia de cambios puberales en genitales internos en el 43,9 % de las niñas (el 37,2 % en la subpoblación con PPC idiopática frente al 62,5 % en el grupo de PPC orgánica; p = 0,18). Conclusiones: Existe un solapamiento clínico-ecográfico entre PPC idiopática y orgánica. Las pruebas de imagen del SNC siguen siendo necesarias en todos los casos de PPC y los estudios ecográficos no pueden sustituir a otras investigaciones diagnósticas (AU)

Objective: To determine whether initial presentation varies according to aetiology, whether such differences allow differential diagnosis between idiopathic and organic forms, and whether CNS imaging can be avoided in some patients with central precocious puberty (CPP). Patients and methods: Children referred for evaluation of precocious puberty were evaluated, and the subpopulation of children with CPP was enrolled in this prospective observational study. Clinical, laboratory and ultrasound features of 62 consecutive patients with CPP (5 boys and 57 girls) were recorded. We compared the characteristics of idiopathic (3 boys, 49 girls) and organic (2 boys, 8 girls) CPP. Results: There were no differences in pubertal staging, age at puberty onset (7.0 [5.8-7.5] vs. 7.3 [5.1-8.3] years), bone age/chronological age ratio (1.26 [1.2-1.3] vs. 1.23 [1.1-1.3]), maternal menarche (11.7 ± 0.2 vs. 11.7 ± 0.6 years) between idiopathic and organic CPP, respectively. Organic CPP patients had a poorer height SD (0.35 ± 0.4 vs. 1.6 ± 0.1; p < 0.01), predicted adult height, growth rate and growth rate SD (0.8 ± 0.9 vs. 3.7 ± 0.7). Girls with organic CPP had significantly higher oestradiol levels (47.5 [25-68] vs. 27 [14-43] pg/ml) than girls with idiopathic CPP. Pelvic ultrasound at the time of diagnosis revealed the presence of pubertal changes in internal genitalia in 43.9 % of girls (37.2 % idiopathic versus 62.5 % organic CPP subpopulation; p=0.18). Conclusions: There is a clinical-ultrasound overlap between idiopathic and organic CPP. Imaging remains necessary in all cases of central precocious puberty, and ultrasound data should not be replaced by other diagnostic investigations (AU)

[Complete isosexual precocious puberty: clinical, pelvic ultrasound and laboratory features]. / Pubertad precoz completa isosexual: hallazgos clínicos, de laboratorio y ecografía pélvica.

OBJECTIVE: To determine whether initial presentation varies according to aetiology, whether such differences allow differential diagnosis between idiopathic and organic forms, and whether CNS imaging can be avoided in some patients with central precocious puberty (CPP). PATIENTS AND METHODS: Children referred for evaluation of precocious puberty were evaluated, and the subpopulation of children with CPP was enrolled in this prospective observational study. Clinical, laboratory and ultrasound features of 62 consecutive patients with CPP (5 boys and 57 girls) were recorded. We compared the characteristics of idiopathic (3 boys, 49 girls) and organic (2 boys, 8 girls) CPP. RESULTS: There were no differences in pubertal staging, age at puberty onset (7.0 [5.8-7.5] vs. 7.3 [5.1-8.3] years), bone age/chronological age ratio (1.26 [1.2-1.3] vs. 1.23 [1.1-1.3]), maternal menarche (11.7+/-0.2 vs. 11.7+/-0.6 years) between idiopathic and organic CPP, respectively. Organic CPP patients had a poorer height SD (0.35+/-0.4 vs. 1.6+/-0.1; p<0.01), predicted adult height, growth rate and growth rate SD (0.8+/-0.9 vs. 3.7+/-0.7). Girls with organic CPP had significantly higher oestradiol levels (47.5 [25-68] vs. 27 [14-43] pg/ml) than girls with idiopathic CPP. Pelvic ultrasound at the time of diagnosis revealed the presence of pubertal changes in internal genitalia in 43.9% of girls (37.2% idiopathic versus 62.5% organic CPP subpopulation; p=0.18). CONCLUSIONS: There is a clinical-ultrasound overlap between idiopathic and organic CPP. Imaging remains necessary in all cases of central precocious puberty, and ultrasound data should not be replaced by other diagnostic investigations.

Pubertad precoz. Actualización en el diagnóstico y tratamiento / Precocious puberty. An update on the diagnosis and treatment

El término pubertad precoz define el inicio del desarrollode los caracteres secundarios antes de los 8años en niñas y antes de los 9 años en niños. Eldiagnóstico precoz es fundamental para conseguiruna talla adulta final adecuada. Es importante distinguirla pubertad precoz verdadera de otras situacionesclínicas conocidas como variantes normales deldesarrollo puberal, que únicamente requieren uncontrol clínico periódico. Tras el diagnóstico de pubertadprecoz hay que individualizar la indicación detratamiento, e identificar a aquellos pacientes que sepuedan beneficiar del mismo. En los casos en losque esté indicado, para el tratamiento de la pubertadprecoz central idiopática disponemos de análogosde GnRH, que usados de forma crónica producenuna desensibilización de la hipófisis al estímulode la GnRH, reduciendo la liberación de gonadotropinas

The term Precocious puberty defines the beginningof the development of secondary sexual characteristicsbefore age of 8 in girls and before 9 inboys. Early diagnosis is fundamental in order toachieve full adequate final adult height. It is importantto distinguish true Precocious puberty from otherclinical situations known as normal variations ofdevelopment, which only need regular clinical control.After the diagnosis of Precocious puberty onemust individualize the treatment indications, andidentify those patients who may benefit from the same.In the cases in which it should be indicated, wehave GnRH agonists available, which when used chronicallyinhibits gonadotripin secretion

Cervical artery dissection: An atypical presentation with Ehlers-Danlos-like collagen pathology?

The authors took skin biopsies of the macroscopically normal skin of seven consecutive patients with spontaneous cervical artery dissection (SCAD). Histologically, alterations of the collagen and elastic fiber networks were found in six patients. In five, the histologic, immunohistochemical, and ultrastructural changes were similar to those usually found in Ehlers-Danlos syndrome (EDS). This suggests that SCAD is frequently associated with the dermal alterations seen in EDS.

[Chronic inflammatory demyelinating neuropathies and their variants] / Polyradiculonévrites chroniques et leurs frontières.

The Chronic Inflammatory Demyelinating Polyradiculoneuropathies (CIDP) constitute a syndrome whose incidence is difficult to evaluate, and is probably underestimated. In the course of this presentation, we deliberately restricted discussion to issues raised in recent years concerning the extent of this syndrome. We discuss diagnostic criteria, especially electrophysiological ones. As the criteria proposed by the ad hoc committee of the American Academy of Neurology in 1991 have been questioned due to lack of sensitivity, new ones have been proposed recently. We briefly discuss the different types of chronic dysimmune demyelinating neuropathy: not only the CIDP, but also the Lewis and Sumner syndrome or multifocal inflammatory demyelinating neuropathy and the multiple conduction block neuropathies. At last, we point out the consistent finding of axonal involvement in the course of a chronic demyelinating neuropathy; over time, it can become predominant, which may make diagnosis difficult by suggesting a chronic axonal neuropathy that may be assumed to be primary. Consideration of these points may help clinicians recognize more chronic dysimmune neuropathies, for which immunosuppressive therapy has been found to be effective.

[Chronic polyradiculoneuritis and its frontiers]. / Polyradiculonévrites chroniques et leurs frontières.

The Chronic Inflammatory Demyelinating Polyradiculoneuropathies (CIDP) constitute a syndrome whose incidence is difficult to evaluate, and is probably underestimated. In the course of this presentation, we deliberately restricted discussion to issues raised in recent years concerning the extent of this syndrome. We discuss diagnostic criteria, especially electrophysiological ones. As the criteria proposed by the ad hoc committee of the American Academy of Neurology in 1991 have been questioned due to lack of sensitivity, new ones have been proposed recently. We briefly discuss the different types of chronic dysimmune demyelinating neuropathy: not only the CIDP, but also the Lewis and Sumner syndrome or multifocal inflammatory demyelinating neuropathy and the multiple conduction block neuropathies. At last, we point out the consistent finding of axonal involvement in the course of a chronic demyelinating neuropathy; over time, it can become pre-dominant, which may make diagnosis difficult by suggesting a chronic axonal neuropathy that may be assumed to be primary. Consideration of these points may help clinicians recognize more chronic dysimmune neuropathies, for which immunosuppressive therapy has been found to be effective.

Partners in transcription: NFAT and AP-1.

Combinatorial regulation is a powerful mechanism that enables tight control of gene expression, via integration of multiple signaling pathways that induce different transcription factors required for enhanceosome assembly. The four calcium-regulated transcription factors of the NFAT family act synergistically with AP-1 (Fos/Jun) proteins on composite DNA elements which contain adjacent NFAT and AP-1 binding sites, where they form highly stable ternary complexes to regulate the expression of diverse inducible genes. Concomitant induction of NFAT and AP-1 requires concerted activation of two different signaling pathways: calcium/calcineurin, which promotes NFAT dephosphorylation, nuclear translocation and activation; and protein kinase C (PKC)/Ras, which promotes the synthesis, phosphorylation and activation of members of the Fos and Jun families of transcription factors. A fifth member of the NFAT family, NFAT5, controls the cellular response to osmotic stress, by a mechanism that requires dimer formation and is independent of calcineurin or of interaction with AP-1. Pharmacological interference with theNFAT:AP-1 interaction may be useful in selective manipulation of the immune response. Balanced activation of NFAT and AP-1 is known to be required for productive immune responses, but the role of NFAT:AP-1 interactions in other cell types and biological processes remains to be understood.

Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun.

Cooperation between nuclear factor of activated T cells (NFAT) and AP-1 (Fos-Jun) proteins on composite NFAT-AP-1 DNA elements constitutes a powerful mechanism for signal integration of the calcium and protein kinase C/Ras pathways in the regulation of gene expression. Here we report that NFAT can induce expression of certain genes in T cells without the need for cooperative recruitment of Fos and Jun. Using NFAT1 mutant proteins that are unable to interact with Fos-Jun dimers but are unaffected in DNA binding or transcriptional activity, we show that expression of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-4, MIP1alpha and Fas ligand mRNAs is absolutely dependent on cooperation between NFAT and Fos-Jun; in contrast, NFAT induces tumor necrosis factor alpha (TNFalpha) mRNA and IL-13 promoter activity without any necessity to recruit Fos and Jun. Furthermore, we show that NFAT-Fos-Jun cooperation is also essential to elicit the NFAT-dependent program of activation-induced cell death. Our results support the hypothesis that even in a single cell type, NFAT activation can evoke two distinct biological programs of gene expression, dependent or independent of NFAT-AP-1 cooperation.

The Escherichia coli trmE (mnmE) gene, involved in tRNA modification, codes for an evolutionarily conserved GTPase with unusual biochemical properties.

The evolutionarily conserved 50K protein of Escherichia coli, encoded by o454, contains a consensus GTP-binding motif. Here we show that 50K is a GTPase that differs extensively from regulatory GTPases such as p21. Thus, 50K exhibits a very high intrinsic GTPase hydrolysis rate, rather low affinity for GTP, and extremely low affinity for GDP. Moreover, it can form self-assemblies. Strikingly, the 17 kDa GTPase domain of 50K conserves the guanine nucleotide-binding and GTPase activities of the intact 50K molecule. Therefore, the structural requirements for GTP binding and GTP hydrolysis by 50K are without precedent and justify a separate classification in the GTPase superfamily. Immunoelectron microscopy reveals that 50K is a cytoplasmic protein partially associated with the inner membrane. We prove that o454 is allelic with trmE, a gene involved in the biosynthesis of the hypermodified nucleoside 5-methylaminomethyl-2-thiouridine, which is found in the wobble position of some tRNAs. Our results demonstrate that 50K is essential for viability depending on the genetic background. We propose that combination of mutations affecting the decoding process, which separately do not reveal an obvious defect in growth, can give rise to lethal phenotypes, most likely due to synergism.

Reciprocal modulatory interaction between human immunodeficiency virus type 1 Tat and transcription factor NFAT1.

Human immunodeficiency virus type 1 (HIV-1) gene expression is regulated by interactions between both viral and host factors. These interactions are also responsible for changes in the expression of many host cell genes, including cytokines and other immune regulators, which may account for the state of immunological dysregulation that characterizes HIV-1 infection. We have investigated the role of a host cell protein, the transcription factor NFAT1, in HIV-1 pathogenesis. We show that NFAT1 interacts with Tat and that this interaction, which involves the major transactivation domain of NFAT1 and the amino-terminal region of Tat, results in a reciprocal modulatory interplay between the proteins: whereas Tat enhances NFAT1-driven transcription in Jurkat T cells, NFAT1 represses Tat-mediated transactivation of the HIV-1 long terminal repeat (LTR). Moreover, NFAT1 binds to the kappaB sites on the viral LTR and negatively regulates NF-kappaB-mediated activation of HIV-1 transcription, by competing with NF-kappaB1 for its binding sites on the HIV-1 LTR. Tat-mediated enhancement of NFAT1 transactivation may explain the upregulation of interleukin 2 and other cytokines that occurs during HIV-1 infection. We discuss the potentially opposing roles of NFAT1 and another family member, NFAT2, in regulating gene transcription of HIV-1 and endogenous cytokine genes.

Stationary phase induction of dnaN and recF, two genes of Escherichia coli involved in DNA replication and repair.

The beta subunit of DNA polymerase III holoenzyme, the Escherichia coli chromosomal replicase, is a sliding DNA clamp responsible for tethering the polymerase to DNA and endowing it with high processivity. The gene encoding beta, dnaN, maps between dnaA and recF, which are involved in initiation of DNA replication at oriC and resumption of DNA replication at disrupted replication forks, respectively. In exponentially growing cells, dnaN and recF are expressed predominantly from the dnaA promoters. However, we have found that stationary phase induction of the dnaN promoters drastically changes the expression pattern of the dnaA operon genes. As a striking consequence, synthesis of the beta subunit and RecF protein increases when cell metabolism is slowing down. Such an induction is dependent on the stationary phase sigma factor, RpoS, although the accumulation of this factor alone is not sufficient to activate the dnaN promoters. These promoters are located in DNA regions without static bending, and the -35 hexamer element is essential for their RpoS-dependent induction. Our results suggest that stationary phase-dependent mechanisms have evolved in order to coordinate expression of dnaN and recF independently of the dnaA regulatory region. These mechanisms might be part of a developmental programme aimed at maintaining DNA integrity under stress conditions.