[De novo heterozygous mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria]. / Mutación de novo en heterocigosis en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria.

INTRODUCTION: The aetiology of autosomal dominant mental retardation type 1, also known as pseudo-Angelman, MBD5-associated neurodevelopmental disorder or MBD5 haploinsufficiency, lies in a microdeletion of chromosome 2q23.1 or in a specific alteration of the MBD5 gene, which constitutes the minimum region affected in the aforementioned microdeletion. AIM: To report the case of a girl with a heterozygous de novo mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria. CASE REPORT: We report the case of an 8-year-old girl who was submitted to a developmental follow-up from the age of 18 months after presenting the association of severe intellectual disability and motor delay, lack of language development, segmental hypotonia, a wide forehead and kyphoscoliosis. Magnetic resonance imaging of the brain revealed the presence of a bilateral band heterotopia and parietooccipital polymicrogiria predominant on the left side. In the exome the de novo heterozygous variant c.397+1G>C was detected in the MBD5 gene. CONCLUSION: This is the first observation of a heterozygous mutation in the MBD5 gene associated with a neuronal migration disorder.

TITLE: Mutación de novo en heterocigosis en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria.Introducción. La etiología del retraso mental autosómico dominante 1, también conocido como pseudo-Angelman, trastorno del neurodesarrollo asociado a MBD5 o haploinsuficiencia MBD5, radica en una microdeleción del cromosoma 2q23.1 o en una alteración específica del gen MBD5, que constituye la mínima región afectada en la citada microdeleción. Objetivo. Comunicar el caso de una niña con una mutación heterocigota y de novo en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria. Caso clínico. Niña de 8 años, seguida evolutivamente desde los 18 meses por presentar la asociación de discapacidad intelectual y retraso motor graves, ausencia de desarrollo del lenguaje, hipotonía segmentaria, frente ancha y cifoescoliosis. En la resonancia magnética cerebral se observó la presencia de una heterotopía en banda bilateral y polimicrogiria parietooccipital de predominio izquierdo. En el exoma se detectó la variante de novo c.397+1G>C en heterocigosis en el gen MBD5. Conclusión. Constituye la primera observación con una mutación heterocigota en el gen MBD5 asociada a un trastorno en la migración neuronal.

Endotelina-1, proteína C reactiva ultrasensible y actividad antioxidante en pacientes con hipotiroidismo subclínico y en eutiroideos con autoinmunidad tiroidea. Efectos del tratamiento con levotiroxina / Endothelin-1, high sensitivity C reactive protein and antioxidant activity in subclinical hypothyroid patients. Effects of levothyroxine treatment

RESUMEN La Endotelina-1 (ET1) y Proteína C Reactiva ultrasensible (PCRus) como marcadores de disfunción endotelial (DE) e inflamación vascular en hipotiroidismo subclínico (HS) han mostrado resultados controvertidos. El rol del estrés oxidativo y defensa antioxidante (TRAP) es motivo de discusión. Objetivos Establecer si el HS y la autoinmunidad tiroidea (AIT), excluyendo otros factores de riesgo cardiovascular, pueden causar DE e inflamación vascular, evaluadas a través de ET1 y PCRus, respectivamente. Establecer si TRAP juega algún rol. Evaluar cambios en ET1 y PCRus luego del tratamiento con levotiroxina (LT4). Material y métodos Se evaluaron prospectivamente 70 pacientes divididos en 3 grupos: HS: 41 pacientes (T4 normal,TSH >4,2 y <10 mUI/L), AIT: 10 pacientes eutiroideos (TSH <4,2 mUI/L) con aTPO y/o aTg (+) y Control: 19 pacientes eutiroideos sin AIT. Se excluyeron otros factores de riesgo cardiovascular. Se midió basalmente ET1, PCRus y TRAP plasmáticos, y en HS bajo LT4 (n = 24): ET1 y PCRus. Resultados No hubo diferencias significativas en edad, IMC, perfil lipídico y TRAP. ET1 y PCRus fueron significativamente mayores en pacientes con HS (media ± DS 1,77 ± 0,85 pg/ml y 1,5 ± 0,6 mg/l vs. controles (0,8 ± 0,3 pg/ml y 0,5 ± 0,2 mg/l) p <0,0001 y <0,008 respectivamente. Del mismo modo en AIT (1,4 ± 0.4 pg/ml y 2,3 ± 1,3 mg/l) vs controles p <0,0001 y <0,034, respectivamente. La TSH fue mayor en el grupo AIT vs. Control 2,57 ± 0,88 vs. 1,64 ± 0,5 mUI/L; p = 0,002. En HS bajo LT4 (8,7 ± 3,8 meses) se observó descenso de ET1 (p <0,001). ET1 correlacionó con TSH (r = 0,5 p <0,0001). El punto de corte de ET1 mediante curva ROC fue 1,32 pg/ml (Sensibilidad 81,6%-Especificidad 75%). Conclusiones ET1 y PCRus resultaron marcadores útiles para evaluar DE e inflamación vascular asociadas a HS. La defensa antioxidante no ejercería un rol en estos mecanismos. El tratamiento con LT4 produjo una significativa caída de ET1, pudiendo necesitarse un período más largo de eutiroidismo para normalizarla. En AIT, niveles de TSH >2,5 mUI/L podrían sugerir un mínimo grado de hipotiroidismo justificando la elevación en ET1 y PCR, sin descartar el rol de la AIT "per se".

ABSTRACT The measurement of endothelin-1 (ET1) and high sensitivity C-reactive protein (hsCRP) as markers of endothelial dysfunction (ED) and vascular inflammation in subclinical hypothyroidism (SH) has shown controversial results. The role of oxidative stress and antioxidant defense (TRAP) is a matter of discussion. Objectives To establish if SH and thyroid autoimmunity (TAI), excluding other cardiovascular risk factors, may cause ED and vascular inflammation, evaluated through the measurement of ET1 and hsCRP respectively. To determine if TRAP could have some role. Additionally, changes in these parameters after treatment with levothyroxine (LT4) will be evaluated. Material and methods: 70 patients were prospectively evaluated. They were classified into: SH Group: 41 patients (normal T4, TSH> 4.2 and <10 mIU/L), TAI Group: 10 euthyroid patients (TSH <4.2 mUI/L) with positive aTPO and/or aTg and Control Group: 19 euthyroid patients without TAI. Other cardiovascular risk factors were excluded in patients and controls. Plasma ET1, hsCRP and TRAP were measured basally, and ET1 and hsCRP under LT4 therapy in the HS Group. Results There were no significant differences between the 3 groups in age, BMI, lipids and TRAP. ET1 and hsCRP were significantly higher in patients with SH (mean ± SD 1.77 ± 0.85 pg/ml and 1.5 ± 0.6 mg/l) vs. controls (0.8 ± 0.3 pg/ml y 0.5 ± 0.2 mg/l) p <0.0001 y <0.008 respectively. Similarly, in TAI patients (1.4 ± 0.4 pg/ml y 2.3 ± 1.3 mg/l) vs controls, p <0.0001 and <0.034, respectively. TSH was higher in the TAI patients versus control group (2.5 ± 0.88 versus 1.64 ± 0.5 mIU/L, p = 0.002). Twenty-four patients with SH showed a significant decrease in ET1 (p <0.001) under treatment with LT4 (8.7 ± 3.8 months). ET1 had a highly significant correlation (p <0.0001) with TSH (r = 0.5). The cut-off level of ET1 established by ROC curve was 1.32 pg/ml (Sensitivity 81.6%-Specificity 75%). Conclusions ET1 and hsCRP were useful markers to evaluate ED and vascular inflammation associated with SH. There were no differences in TRAP levels between patients and controls, so it does not appear that oxidative stress would have played any role. Treatment with LT4 produced a significant drop in ET1. Probably, a longer period of euthyroidism might be necessary to normalize ET1 levels. In TAI Group, TSH levels >2.5 mUI/L could suggest a "minimal degree" of hypothyroidism justifying the elevation in ET1 and hs CRP. The role of the TAI "per se" couldn't be completely ruled out.

Development of an analytical method for the determination of the misuse in sports of boldenone through the analysis of urine by on-line coupling liquid chromatography-gas chromatography-combustion-isotope ratio mass spectrometry.

Boldenone (Bo), androsta-1,4-dien-17ß-ol-3-one, is an anabolic androgenic steroid not clinically approved for human application. Despite this, many cases are reported every year of athletes testing positive for Bo or its main metabolite 5ß-androst-1-en-17ß-ol-3-one (BoM). Recently the capability of different human intestinal bacteria to produce enzymes able to modify endogenous steroids in Bo has been demonstrated. When a urinary concentration of Bo and/or BoM between 5 and 30 ng/mL is measured a complementary analysis by gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) must be carried out to discriminate the endogenous or exogenous origin. In the present work, a novel analytical method that couples LC-GC by means of the TOTAD interface with C-IRMS is described. The method is based on a first RPLC separation of unacetyled steroids, followed by acetylation and automated on-line LC-GC-C-IRMS, which includes a second RPLC clean-up of acetyl Bo and BoM, isolation of the two fractions in a fraction collector and their consecutive analysis by GC-C-IRMS. The method has been applied to the analysis of urine samples fortified at 5 and 10 ng/mL, where it has shown a good performance.

Severe and acute loss of visual field in a young patient with optic disc drusen.

CASE REPORT: We describe a case of a young patient with bilateral optic disc drusen, who in the course of 10 months, had a sudden visual field constriction in the right eye accompanied by moderate loss of vision, corresponding to the ophthalmological examination of changing from hidden to visible drusen. DISCUSSION: The optic disk drusen are a fairly common disorder that is mainly considered as a benign disorder due to the low frequency of complications that appear during their course. This case shows how they can become a real problem in a short period of time.

The treatment with an anti-glycosaminoglycan antibody reduces aortic oxidative stress in a rabbit model of atherosclerosis.

Retained low-density lipoproteins (LDL) by arterial glycosaminoglycans (GAG) are more susceptible to reactive oxygen species-mediated oxidation, contributing to oxidative stress and atherosclerosis. Recently, we reported the properties of the chimeric mouse/human monoclonal antibody chP3R99-LALA to bind sulfated GAG, to inhibit LDL-chondroitin sulfate binding, and to avoid LDL oxidation in vitro. Here, we hypothesized that chP3R99-LALA treatment might reduce aortic oxidative stress in a therapeutic setting. Redox biomarkers and serum lipids were determined by spectrophotometric methods. Subcutaneous administration of five doses (100 µg) of chP3R99-LALA, after Lipofundin administration (2 mL/kg/day, i.v.) during 8 days, reduced atherosclerotic lesion development, which was not associated with a serum lipid modulation. In contrast, the treatment with chP3R99-LALA reduced (p < 0.05) malondialdehyde and protein oxidation, induced a restoration of reduced glutathione level, of the superoxide dismutase and catalase activities and of endothelial nitric oxide level. Thus, the antiatherogenic effect of chP3R99-LALA treatment seems to be associated with a reduction of aortic oxidative stress. These results contribute in understanding the molecular mechanisms associated with chP3R99-LALA atheroprotection and support the use of anti-GAG antibody-based immunotherapy as a potential tool to treat the atherosclerosis.

[Paediatric emergency triage in Spanish primary care using mobile phones. Analysis of a model in a health area]. / Triaje de las urgencias pediátricas en Atención Primaria en España mediante telefonía móvil. Análisis de un modelo en una zona de salud.

OBJECTIVES: To conduct a pilot study of telephone consultation in the paediatric population of an urban health centre. To evaluate the telephone consultation as an effective tool when it comes to exercising prior triage of patients requiring urgent attention. MATERIAL AND METHODS: The study was conducted in two phases. In the first, data were collected from all calls received for six months. In a second phase, we conducted a telephone intervention study to analyse what a random sample of users remembered of the care provided. All those who requested a telephone consultation were included in the study. Demographic, social-welfare, epidemiological, and clinical features, of each patient were recorded. Data were processed using a statistical package SPSS version 17.0 for Windows. RESULTS: There were 439 telephone inquiries in our pilot project, of which 35.1% were attended by residents, 36% by paediatricians, and 28.9% by paediatric nurses. There were more telephone calls in the afternoons and on weekends. Patients less than or equal to 2 years accounted for 57.9% of cases handled, and there were no differences between sexes. The most frequent reasons for consultation were gastrointestinal symptoms, fever and respiratory problems. The health problem was resolved in 85.8% of cases, requiring only home care instructions, and only 13.3% of children were referred to emergency services. We obtained a mean score of satisfaction of 9.2. CONCLUSIONS: The pilot project had a high level of satisfaction and resolution, demonstrating cost savings by reducing 55% of face to face visits, with a saving of 35.2 euros per telephone consultation. A teleconsultation model for dealing with emergencies in primary care by telephone would be comparable to a practice staffed by trained paediatric nurses.

Aneurisma de la vena ácigos. A propósito de un caso / No disponible

No disponible

Insuficiencia renal aguda por linfoma de Burkitt renal primario bilateral / Bilateral primary renal Burkitt lymphoma presenting with acute renal failure

Se describe el caso de una niña de 12 años que presenta un cuadro de insuficiencia renal aguda secundaria a infiltración masiva de ambos riñones por un linfoma de Burkitt y que fue diagnosticado por biopsia renal percutánea. Este cuadro cumple los criterios diagnósticos de Malbrain et al para considerarlo un linfoma no Hodgkin primario renal. Se discute el diagnóstico diferencial con otros procesos que se manifiestan con insuficiencia renal aguda y nefromegalia bilateral así como el mecanismo por el cual se produce la insuficiencia renal. En esta paciente es destacable el cuadro clínico de inicio, un cuadro compatible con patología reumática. Se debe tener siempre en cuenta la posibilidad de manifestaciones músculo articulares como patología de inicio en las enfermedades hematopoyéticas (AU)

We report the case of a 12 year-old girl who presented with acute renal failure with massive infiltration in both kidneys due to a Burkitt lymphoma that was diagnosed by percutaneous renal biopsy. This case fulfilled all the diagnostic criteria of Malbrain et al. to be considered as primary renal non-Hodgkin lymphoma. We discuss the differential diagnosis with other processes that present with acute renal failure and bilateral nephromegaly, and the mechanism by which renal failure occurs. It should be emphasised that this patient showed clinical symptoms compatible with rheumatic disease at diagnosis. The possibility of joint and muscle problems should be considered as a sign of onset of hematopoietic disease (AU)

Carcinoma en quiste tirogloso / Carcinoma in thyroglosal duct cyst

El carcinoma diferenciado de tiroides en quiste tirogloso (CaQT) es una rara entidad. En diferentes series de pacientes operados por quistes tiroglosos su incidencia fue del 0.7 al 1.07%. Luego de la extirpación del quiste por el procedimiento de Sistrunk, no hay consenso sobre la indicación de tiroidectomía total, radioablación y/o terapéutica supresiva con levotiroxina. El objetivo del Departamento de tiroides de SAEM, fue evaluar: formas de presentación, evolución clínica, métodos diagnósticos de utilidad y tratamiento para consensuar futuras conductas. Material y Métodos: Estudio multicéntrico, retrospectivo en 22 pacientes entre 10 a 69 años, 15 mujeres y 7 varones. Resultados: El tamaño de los quistes osciló entre 1 y 8 cm (Mediana= 3.0 cm, Χ ± DS= 3.7 ± 2.2 cm). La mitad de los pacientes presentó crecimiento del quiste en los 6 meses previos a la cirugía. La punción resultó sospechosa en 2/5 quistes y positiva en uno. La ecografía tiroidea evidenció nódulos en 4/13 casos (30%). Se realizó tiroidectomía en 17/22 pacientes (total: 15 y subtotal: 2). La histología del CaQT demostró carcinoma papilar en 21 y carcinoma folicular en uno. Hubo coexistencia de cáncer intratiroideo en el 23.5% de los casos, ninguno multicéntrico. Dos pacientes presentaron metástasis ganglionares y otro tuvo compromiso muscular (ninguno de ellos coexistió con cáncer intratiroideo). Se radioablacionó a 13 pacientes. En 9/11 pacientes la tiroglobulina permaneció indetectable durante el seguimiento (1 a 14 años). Conclusiones: 1) Realizar ecografía de cuello y punción ecoguiada a todo paciente con quiste tirogloso. 2) En caso de CaQT combinar simultáneamente tiroidectomía total y procedimiento de Sistrunk. 3) Evaluar radioablación complementaria y tratamiento supresivo con levotiroxina en cada caso. 4) Efectuar el seguimiento tal como en los carcinomas ortotópicos.

Differentiated thyroid carcinoma (DTC) in thyroglosal duct cyst (TGDC) is rare, ranging from 0.7 to 1.07% in different series. After the surgery of choice (Sistrunk procedure) the other alternative treatments such as thyroidectomy (Tx), radioiodine and L-T4 therapy are controversial. OBJECTIVE: to evaluate several and controversial aspects in the largest series of DTC in TGDC reported in the literature. Subjects and methods: retrospective multicentric study: n= 22, aged 10-69 yrs. (15 females and 7 men) who underwent the Sistrunk procedure for TGDC. Results: none of the TGDC was less than 1 cm (median 3.0 cm, Χ±SD= 3.7 ± 2.2cm). In half of them there was an increased cystic size in the last 6 months before surgery. Cyst FNA was suspicious in 2/5 and positive in one, whereas the histological diagnosis of the operated TGCD was papillary cancer in 21 and 1 follicular carcinoma. Thyroid ultrasound (US) (n=13) showed nodules in 30% of the cases. Tx was performed in 17/22 (total: 15, subtotal: 2). Thyroid DTC coexisted in 4/17 (23.5%), and was unilateral in all of them. Lymph node metastases were present in 2 adults and muscle involvement was found in the 10-year old girl. None of these 3 patients had overt thyroid lesions. 131-I therapy was performed in 10 patients. In 9 out of 11 subjects Tg remained undetectable during follow-up (1-14yrs.). Persistent high Tg was present in one case without thyroid DTC. Conclusions: 1) Ultrasonography and FNAB should be performed to every patient with thyroglossal duct cyst 2) In case of TGDC, total Tx and Sistrunk's procedure should be simultaneously combined 3) 131-I therapy and L-T4 suppressive treatment should be evaluated in every case 4) Follow-up as in the DTC.

[Bilateral primary renal Burkitt lymphoma presenting with acute renal failure]. / Insuficiencia renal aguda por linfoma de Burkitt renal primario bilateral.

We report the case of a 12 year-old girl who presented with acute renal failure with massive infiltration in both kidneys due to a Burkitt lymphoma that was diagnosed by percutaneous renal biopsy. This case fulfilled all the diagnostic criteria of Malbrain et al. to be considered as primary renal non-Hodgkin lymphoma. We discuss the differential diagnosis with other processes that present with acute renal failure and bilateral nephromegaly, and the mechanism by which renal failure occurs. It should be emphasised that this patient showed clinical symptoms compatible with rheumatic disease at diagnosis. The possibility of joint and muscle problems should be considered as a sign of onset of hematopoietic disease.

Combined therapeutic effect of a monoclonal anti-idiotype tumor vaccine against NeuGc-containing gangliosides with chemotherapy in a breast carcinoma model.

Anti-idiotypic monoclonal antibodies (mAb) have been evaluated for actively induced immunotherapy with encouraging results. However, rational combination of cancer vaccines with chemotherapy may improve the therapeutic efficacy of these two approaches used separately. The main objective of this study was to evaluate the antitumor effect of the co-administration of 1E10 (Racotumomab), a monoclonal anti-idiotype tumor vaccine against an IgM mAb, named P3 that reacts specifically with NeuGc-containing gangliosides and low-dose Cyclophosphamide in a mammary carcinoma model. F3II tumor-bearing mice were immunized subcutaneously with 100 microg of 1E10 mAb in Alum or with 150 mg/m(2) of Cyclophosphamide intravenously 7 days after the tumor inoculation. While a limited antitumor effect was induced by a single 1E10 mAb immunization; its co-administration with low-dose Cyclophosphamide reduced significantly the F3II mammary carcinoma growth. That response was comparable with the co-administration of the standard high-dose chemotherapy for breast cancer based on 60 mg/m(2) of Doxorubicin and 600 mg/m(2) of Cyclophosphamide, without toxicity signs. Combinatorial chemo-immunotherapy promoted the CD8(+) lymphocytes tumor infiltration and enhanced tumor apoptosis. Furthermore, 1E10 mAb immunization potentiated the antiangiogenic effect of low-dose Cyclophosphamide. Additionally, splenic myeloid cells Gr1(+)/CD11b(+) associated with a suppressor phenotype were significantly reduced in F3II tumor-bearing mice immunized with 1E10 mAb alone or in combination with low-dose Cyclophosphamide. This data may provide a rational for chemo-immunotherapy combinations with potential medical implications in breast cancer.