A new severe mutation in the SLC5A7 gene related to congenital myasthenic syndrome type 20.

Congenital myasthenic syndromes are a group of genetically determined rare diseases resulting from ultrastructural alterations in synaptic proteins. Up to 32 genes are known to be involved in those syndromes and many mutations have been reported, of which less than 8% affect the presynaptic complex. One of these syndromes is caused by the impairment of the presynaptic sodium-dependent high-affinity choline transporter 1, as a result of a mutation of the SCL5A7 gene associated with congenital myasthenic syndrome type 20 (MIM # 617143). We present a new case of this syndrome, caused by a mutation not previously described. A full term infant presented with acute respiratory failure and generalized weakness. The genetic analysis revealed the patient to be compound heterozygous for a new mutation of the SCL5A7 gene. The genetic analysis of congenital myasthenic syndromes provide information on the ultrastructural underlying mechanisms, which is valuable for differential diagnosis and specific treatments.

Qué debe saber el médico de primaria sobre los nuevos marcadores en el cáncer de próstata / What primary care physicians should know about new markers in prostate cancer

La utilización del antígeno prostático específico como herramienta diagnóstica en el cribado del cáncer de próstata se ve reflejada en un incremento en la incidencia, un incremento en el diagnóstico de cánceres más precoces y un aumento en los tratamientos con intención curativa, aun a costa de un sobretratamiento. Sabemos, por datos recogidos en la literatura, que no todo paciente con antígeno prostático específico elevado necesita biopsia, y que no todo paciente con diagnóstico de cáncer de próstata necesita tratamiento. Con los nuevos marcadores prostáticos emergentes vamos a tratar de mejorar la especificidad del antígeno prostático específico en la zona gris (4-10 ng/ml) evitando biopsias innecesarias, de mejorar la sensibilidad en la detección de cáncer de próstata significante con antígeno prostático específico bajo y a intentar reducir el riesgo de sobretratamiento. Por otro lado, los biomarcadores pronósticos con test genómicos nos van a ayudar a elegir la mejor opción terapéutica para el paciente

The use of prostate-specific antigen as a diagnostic tool in the screening of prostate cancer is reflected in an increase in the incidence, an increase in diagnosis at initial stages, and an increase in radical therapies, even at the expense of over-treatment in some cases. It is known from the data collected in the literature that not every patient with high prostate-specific antigen needs a biopsy, and that not every patient diagnosed with prostate cancer needs treatment. With the new emerging prostate markers, we will try to improve the specificity of prostate-specific antigen in the grey area (4-10 ng/ml) should be improved. This should avoid unnecessary biopsies. The sensitivity in the detection of significant prostate cancer with low prostate-specific antigen should also be improved in an attempt to reduce the risk of over-treatment. On the other hand, prognostic biomarkers with genomic tests will help to choose the best therapeutic option for the patient

[What primary care physicians should know about new markers in prostate cancer]. / Qué debe saber el médico de primaria sobre los nuevos marcadores en el cáncer de próstata.

The use of prostate-specific antigen as a diagnostic tool in the screening of prostate cancer is reflected in an increase in the incidence, an increase in diagnosis at initial stages, and an increase in radical therapies, even at the expense of over-treatment in some cases. It is known from the data collected in the literature that not every patient with high prostate-specific antigen needs a biopsy, and that not every patient diagnosed with prostate cancer needs treatment. With the new emerging prostate markers, we will try to improve the specificity of prostate-specific antigen in the grey area (4-10 ng/ml) should be improved. This should avoid unnecessary biopsies. The sensitivity in the detection of significant prostate cancer with low prostate-specific antigen should also be improved in an attempt to reduce the risk of over-treatment. On the other hand, prognostic biomarkers with genomic tests will help to choose the best therapeutic option for the patient.

OnabotulinumtoxinA in chronic migraine: predictors of response. A prospective multicentre descriptive study.

BACKGROUND AND PURPOSE: OnabotulinumtoxinA is a treatment specifically approved for the prophylaxis of chronic migraine in adults. The aim of this study was to assess the effectiveness of OnabotulinumtoxinA in chronic migraine after 1 year of treatment in a real-life setting and to identify clinical predictors of outcome. METHODS: We designed a prospective multicentre study performed in 13 hospitals in Spain. Patients underwent a complete medical history and examination. They were treated with OnabotulinumtoxinA every 12 weeks for 1 year. Data about outcome, adverse events, abortive medication use, emergency room use and disability were collected at 3 and 12 months. RESULTS: A total of 725 subjects completed the study. At 12 months, 79.3% showed >50% reduction in number of headaches per month and 94.9% reported no adverse events. Unilaterality of pain, fewer days of disability per month and milder headache at baseline were correlated with good outcome. Duration of disease <12 months increased the chances of response to treatment with OnabotulinumtoxinA (odds ratio, 1.470; 95% confidence interval, 1.123-2.174; P = 0.045). CONCLUSIONS: This study confirmed the effectiveness of treatment with OnabotulinumtoxinA after 1 year of treatment. The chances of a good outcome may be increased by starting treatment in the first 12 months after chronic migraine diagnosis.

Aspectos actuales sobre el cribado en el cáncer de próstata / Current aspects of prostate cancer screening

Los programas de cribado de cáncer de próstata basados en la determinación sérica del antígeno específico de próstata han llevado a un sobrediagnóstico y, como consecuencia, a un sobretratamiento. Un porcentaje de varones diagnosticados de cáncer de próstata tienen un tumor que no progresará o lo hará lentamente (sobrediagnóstico o pseudoenfermedad). Esta tasa de sobrediagnóstico oscila entre el 17-50%. El cribado poblacional se define como la exploración sistemática de hombres asintomáticos. La detección precoz o cribado oportunista conlleva la búsqueda de casos individuales, siendo iniciada por el médico o el propio paciente. Ante un paciente que acuda a consulta solicitando un antígeno específico de próstata se le deben explicar una serie de cuestiones relativas al sobrediagnóstico, el sobretratamiento y los posibles daños derivados de la biopsia. Con los datos de los estudios aleatorizados sobre el antígeno específico de próstata y el cribado de cáncer de próstata, ninguna sociedad urológica recomienda realizar cribado poblacional (AU)

Screening programs for prostate cancer based on the determination of serum prostate specific antigen has led to overdiagnosis, and consequently overtreatment. A percentage of men diagnosed with prostate cancer have a tumour that will not progress, or do so slowly (overdiagnosis or pseudo-disease). This overdiagnosis rate ranges from 17-50%. Mass screening is defined as the systematic examination of asymptomatic men. Early detection or opportunistic screening involves the pursuit of individual cases being initiated by the doctor or the patient. In the case of a patient who requests a prostate specific antigen from their general practitioner, a number of issues on overdiagnosis, over-treatment and possible damage from the biopsy, should be explained to him. With data from randomised studies on prostate specific antigen and prostate cancer screening, population screening is not recommended by any urological society (AU)

[Current aspects of prostate cancer screening]. / Aspectos actuales sobre el cribado en el cáncer de próstata.

Screening programs for prostate cancer based on the determination of serum prostate specific antigen has led to overdiagnosis, and consequently overtreatment. A percentage of men diagnosed with prostate cancer have a tumour that will not progress, or do so slowly (overdiagnosis or pseudo-disease). This overdiagnosis rate ranges from 17-50%. Mass screening is defined as the systematic examination of asymptomatic men. Early detection or opportunistic screening involves the pursuit of individual cases being initiated by the doctor or the patient. In the case of a patient who requests a prostate specific antigen from their general practitioner, a number of issues on overdiagnosis, over-treatment and possible damage from the biopsy, should be explained to him. With data from randomised studies on prostate specific antigen and prostate cancer screening, population screening is not recommended by any urological society.

Actitud terapéutica ante los terceros molares: ¿exodoncia o vigilancia? / Therapeutic approach to third molars ¿Extraction or surveillance?

Uno de los desafíos a los que se enfrenta a diario un cirujano bucal o maxilofacial es el manejo terapéutico de los terceros molares asintomáticos y libres de patología. Hasta la fecha existe una falta de información concluyente, problemas en la interpretación de la bibliografía reciente, así como diferentes puntos de vista entre profesionales a la horade responder si es mejor realizar la exodoncia a tiempo o mantener una actitud expectante. El objetivo de este trabajo es revisar la bibliografía reciente referente a la toma de decisiones terapéuticas en estos casos y discutir sobre los aspectos de consenso y las controversias. Además, buscar evidencia científica que justifique la exodoncia profiláctica del tercer molar. A día de hoy continúala controversia sobre el manejo terapéutico óptimo de un tercer molar asintomático y libre de patología. En la presente revisión no se ha encontrado evidencia científica que justifique la exodoncia profiláctica del tercermolar. Se necesita mucha más evidencia científica, así como el diseño de estudios clínicos aleatorizados que permitan compararlas consecuencias a corto y largo plazo de la vigilancia activa y de la exodoncia de los terceros molares

The therapeutic management of asymptomatic and disease free third molars is one of the challenges faced daily by an oral and maxillofacial surgeon. To date there is a lack of conclusive information, problems in the interpretation of the recent literature, as well as different views among professionals when asked if it is better to perform a prophylacticor maintain an expectant attitude. The objective is to review the recent literature on the therapeutic decisions in these cases and discuss aspects of consensus and controversies. Search scientific evidence to support prophylactic third molar extraction. At present controversy continues regarding the optimal therapeutic management of an asymptomatic and disease free third molar. Conclusive evidence has not been found to justify prophylactic third molar extraction in the present review. Much more scientific evidence as well as the design of randomized clinical studies comparing the short-and long-term active surveillance and the extraction of third molars is needed

ESX-1-induced apoptosis is involved in cell-to-cell spread of Mycobacterium tuberculosis.

Apoptosis modulation is a procedure amply utilized by intracellular pathogens to favour the outcome of the infection. Nevertheless, the role of apoptosis during infection with Mycobacterium tuberculosis, the causative agent of human tuberculosis, is subject of an intense debate and still remains unclear. In this work, we describe that apoptosis induction in host cells is clearly restricted to virulent M. tuberculosis strains, and is associated with the capacity of the mycobacteria to secrete the 6 kDa early secreted antigenic target ESAT-6 bothunder in vitro and in vivo conditions. Remarkably, only apoptosis-inducing strains are able to propagate infection into new cells, suggesting that apoptosis is used by M. tuberculosis as a colonization mechanism. Finally, we demonstrate that in vitro modulation of apoptosis affects mycobacterial cell-to-cell spread capacity, establishing an unambiguous relationship between apoptosis and propagation of M. tuberculosis. Our data further indicate that BCG and MTBVAC vaccines are inefficient in inducing apoptosis and colonizing new cells, correlating with the strong attenuation profile of these strains previously observed in vitro and in vivo.

Deshidratación hiponatrémica-hipoclorémica de repetición: inicio clínico de fibrosis quística en un lactante con genotipo R334W/1812(-1)G->A / Recurrent episodes of hyponatremic-hypochloremic dehydration as a presentation of cystic fibrosis in an infant with R334W/1812(-1)G->A mutation

La fibrosis quística (FQ) es una enfermedad exocrina autosómica recesiva de afectación multisistémica. El defecto asociado a la FQ se encuentra en un regulador transmembrana que actúa principalmente como canal de cloro. Los pacientes suelen presentar clínica respiratoria o digestiva. La severidad de la enfermedades multifactorial, y uno de sus determinantes es el nivel de actividad de la proteína CTFR y el tipo de mutación del paciente. El paciente de este caso desarrolló episodios recurrentes de anorexia, pérdida de peso, deshidratación y anomalías hidroelectrolíticas. A pesar de estas manifestaciones poco descritas en la bibliografía, se llegó al diagnóstico de FQ. Se encontraron las mutaciones R334W y 1812-1G-4. La FQ se debe considerar particularmente en los lactantes que presentan la clínica descrita de deshidrataciones recurrentes con alcalosis metabólica, hiponatremia e hipocloremia inexplicada por otras causas, incluso en ausencia de síntomas respiratorios, digestivos o fallo de medro(AU)

Cystic fibrosis (CF) is an autosomal recessive exocrine disease affecting multiple organ systems. The defect associated with CF is in the cystic fibrosis transmembrane regulator (CFTR), which acts primarily as a chloride channel. Patients with CF usually present with respiratory and/or gastrointestinal abnormalities. The severity of the disease is multifactorial, one of the factors depends on the level of activity of the CFTR protein, which is related with the mutation type that affects the patient. An infant is presented who developed recurrent episodes of anorexia, weight loss, dehydration and electrolyte abnormalities. CF was diagnosed showing an unusual and not very publicized presentation of the disease. Mutations R334W and 1812-1G-A were found. CF should be considered in patients of any age, but particularly in infants, presenting with recurrent episodes of hyponatremic hypochloremic dehydration with metabolic alkalosis unexplained by other causes, even in the absence of respiratory or gastrointestinal symptoms or failure to thrive(AU)

Consequences of dietary manganese and copper imbalance on neuronal apoptosis in a murine model of scrapie.

AIMS: Copper and manganese levels are altered in mice both lacking PrPc and prion-infected brains. The aim of this study was to analyse the effects of manganese and copper imbalance on neuronal apoptosis in a scrapie-infected Tga20 mouse model. METHODS: Immunoreactivities for the apoptotic proteins Bax and active caspase-3 were evaluated in nine regions of the brain of scrapie-infected and control Tga20 mice treated with one of several diets: depleted cooper (-Cu), loaded manganese (+Mn), depleted copper/loaded manganese (-Cu+Mn) and regular diet. Immunohistochemical determination of NeuN was used to detect possible neuronal loss. RESULTS: Intracellular Bax detection was significantly decreased in animals fed with modified diets, particularly in those treated with copper-depleted diets. A decrease in active caspase-3 was primarily observed in animals fed with enhanced manganese diets. Our results show that the -Cu, -Cu+Mn and +Mn diets protected against apoptosis in scrapie-infected mice. However, NeuN immunolabelling quantification revealed that no diet was sufficient to arrest neuronal death. CONCLUSIONS: With regard to apoptosis induction, the response of Tga20 mice to prion infection was similar to that reported for other mice models. Our results demonstrate the neuroprotective effects of -Cu, -Cu+Mn and +Mn diets in a murine model of scrapie. However, neuronal death induced by infection with prions seems to be independent of apoptosis marker signalling. Moreover, copper-modified diets were neuroprotective against the possible toxicity of the prion transgene in Tga20 control and infected mice even though manganese supplementation could not counteract this toxicity.

The effect of metal imbalances on scrapie neurodegeneration.

Environmental exposure to metal appears to enhance susceptibility to Transmissible Spongiform Encephalopathies (TSEs); however, published data are not conclusive. The current study focuses on assessing the effects of copper depletion and/or manganese enhancement in the diet on susceptibility to Scrapie and this disease progression. The degree of spongiosis was the highest in the animals that received a copper- depleted diet. These observations suggest that this diet contributes to the Scrapie lesions and to the worsening of the condition in animals that have been inoculated with Scrapie. The highest intensities of GFAP immunostaining were also associated with the copper- depleted diet. Dietary supplementation with manganese had a negative effect on neuronal counts. In conclusion, this study demonstrates that certain environmental factors may aggravate neuropathological Scrapie lesions. This is consistent with reports from other neurodegenerative diseases where some metalloenzymes play a pivotal protector role against the oxidative stress associated with pathogenesis.

Immunohistochemical characterisation of classical scrapie neuropathology in sheep.

Neuroinflammation elicited by PrP(res) (resistant prion protein [PrP]) deposits in the central nervous system (CNS) has been shown to involve cellular and oxidative stress responses in bovine spongiform encephalopathy (BSE) as well as in several murine models of transmissible spongiform encephalopathy (TSE). Additionally, deregulation of water homeostasis has been suggested to be a further component of the spongiform changes observed in TSEs. The aim of the present study was to characterize the pathogenic events occurring in the CNS of sheep with spontaneously arising classical scrapie. Brains from seven affected animals and two controls were subject to immunohistochemical and histochemical examinations. Semi-quantitative evaluation of PrP(res) deposits and spongiform changes throughout the encephalon confirmed that PrP(res) deposition elicits significant astroglial and microglial reactions, as evidenced by an increase in the number of glial cells and changes in glial cell morphology involving increased expression of vimentin. The altered expression of metallothionein and heat shock protein 25 (HSP25) suggested that this neuroinflammatory reaction entails cellular and oxidative stress responses. In contrast, there was no change in expression of the membrane-associated water channel aquaporin 1 when PrP(res) accumulated in the brain.

PRNP haplotype distribution in Moroccan goats.

Susceptibility/resistance to scrapie in sheep and goats is influenced by host prion protein gene (PRNP) genotype. In this study, we report the analysis of prion protein gene polymorphisms in 137 goats of two Moroccan populations: D'man and Chaouni. We found seven previously described amino acid polymorphisms at codons 37, 127, 137, 142, 154, 222 and 240, as well as three known silent mutations. In addition, we identified three new allelic variants: 101R and 139S in D'man goats and 145D in D'man and Chaouni individuals. The high frequency of the resistant allele 154H could offer genetic protection against the disease to the analysed animals. A total of 12 haplotypes and 28 genotypes were found, the distribution of which shows significant differences between both groups. Moreover, haplotype frequencies were compared with bibliographic data showing that the haplotype distribution of PRNP in Moroccan populations is genetically similar to Southern Italian and Greek goats.

Effect of the dimethoate administration on a Scrapie murine model.

Some authors have associated organophosphate compounds with susceptibility to transmissible spongiform encephalopathy (TSE) and even with the origin of this group of diseases. Nevertheless, the actual role played by these compounds still remains unclear. The aim of this study was to assess the effect of oral exposure to dimethoate (DMT) on the development of Scrapie using a genetically modified murine model. A total of 70 C57BL/6 mice over-expressing the PrP gene (Tg20) were included in the present study. A portion of the mice were intraperitoneally inoculated, while the rest were maintained as non-infected controls. Animals from the treated group were exposed to dimethoate dissolved in drinking water from the beginning of the experiment. Variables of incubation period, spongiosis, PrPsc deposits, glial over-expression, neuronal loss, and amyloid plaques were assessed in all animals. According to the results, a treatment consisting of a daily 15 mg/kg dose of DMT for 5 weeks did not show any effect on any of the variables assessed. Although more exhaustive studies for assessing different doses and organic compounds are required, this finding constitutes an empirical study that rules out the possibility that this compound may have a predisposing effect on TSEs.

Infertilidad masculina / Masculine infertility

La infertilidad, entendiendo ésta como la que padece una pareja que, tras un año de relaciones sin tomar medidas de protección, no consigue un embarazo, afecta aproximadamente al 15% de parejas. La importancia del factor masculino como causa de infertilidad puede llegar a suponer el 50% del total de consultas. Entre las múltiples causas de infertilidad masculina se encuentran los problemas obstructivos de la vía seminal, el fallo testicular primario, el varicocele, las infecciones urogenitales o los disturbios endocrinos entre otros. Pero existe también un porcentaje de varones en los que no se encuentra una causa específica de infertilidad, estando en muchos de estos casos implicados un problema genético o inmunológico. En este trabajo revisamos las causas más frecuentes exponiendo de manera esquemática su etiología, anamnesis, exploraciones y tratamiento recomendados

Infertility, understanding this as that suffered by a couple who, after one year of relationships without using any protection measures, does not achieve pregnancy, affects approximately 15% of couples. The importance of the masculine factor as cause of infertility can reach 50% of all the consultations. Among the multiple causes of masculine infertility are the obstructive problems of the seminal duct, primary testicular failure, varicocele, urogenital infections or endocrine disorders, among others. However, there is also a percentage of men in whom no specific cause of infertility is found, a genetic or immunological problem being involved in many of these cases. In this paper, we review the most frequent causes, presenting its etiology, anamnesis, recommended examinations and treatment schematically

Distribution and expression pattern of the nitrergic system in the cerebellum of the sheep.

The nitrergic system produces nitric oxide as an atypical neurotransmitter in the nervous system. Nitric oxide is produced from l-arginine through specific enzymes known as nitric oxide synthases. Of these, the more abundant form in neurons is the constitutive neuronal nitric oxide synthase, although the inducible isoform can be expressed as well, especially following stress or other injuries. The excessive formation of nitric oxide results in protein nitration, particularly at tyrosine residues, thus the presence of nitrotyrosine can be used as a marker of nitric oxide production. In previous studies we have shown the distribution of the components of the nitrergic system in the cerebellum of rodents, where neuronal nitric oxide synthase immunoreactivity was present in stellate and basket cells, and occasionally in granule cells. Here, we present evidence that in the sheep, as a model of larger mammals, most cerebellar neurons display an intense immunostaining for neuronal nitric oxide synthase, including unipolar brush cells, and Lugaro and Golgi neurons, which are not immunoreactive in rodents. In addition, weak immunoreactivity for inducible nitric oxide synthase and nitrotyrosine was found in particular cell types, indicating a basal expression for these markers. Our results suggest a larger dependence on the nitrergic system for the cerebella of larger mammals. Since this increase happens in both activating and inhibitory neurons of the cerebellar circuitry, we propose that in these animals there is a higher steady-state regulation of the cerebellum based on nitric oxide.

Approaches to Scrapie diagnosis by applying immunohistochemistry and rapid tests on central nervous and lymphoreticular systems.

Comparative studies evaluating the performance of Transmissible Spongiform Encephalopathies (TSE) rapid tests (validated for Bovine Spongiform Encephalopathy samples) on Scrapie samples have not been reported widely, particularly those dealing with lymphoreticular system tissues to a much lesser extent. The main objective of this study was to compare the ability of two current rapid tests (Western blot and Luminiscence Immunoassay Prionics-Check; WB and LIA, respectively) to detect PrPsc using central nervous system as well as lymphoreticular system samples corresponding to naturally infected animals. Thirty-four Scrapie-affected sheep, 26 with clinical signs of the disease, were included in the study. Tonsil, retropharyngeal lymph node and medulla oblongata were assessed by three tests: immunohistochemistry (confirmatory test), WB and LIA (rapid tests). The conclusion which can be drawn from this study is the fact that all animals involved in the study, including those at a preclinical stage, could be diagnosed regardless of the test used (with immunohistochemistry consistently showing higher sensitivity) only when the analyses of both the central nervous system and the lymphoreticular system were considered. The choice of these tissues for routine diagnosis is, therefore, proposed as a valuable tool to highly reduce the number of undetected positive cases.

El uso de metronidazol oral para mejorar los resultados de procedimientos anorectales / The use of oral metronidazole to improve the results of anorectal procedures

Introducción:el tratamiento quirúrgico de enfermedades anorectales como hemorroides, fisuras, abscesos y fístulas, tiene como efecto secundario dolor postoperatorio y estreñimiento que crean dificultad en el manejo de estos pacientes, algunos autores han descrito el uso profiláctico eficaz de metronidazol oral para disminuir el dolor postoperatorio e incrementar la satisfacción de los pacientes, con un retorno al trabajo más pronto luego de hemorroidectomía. Material y métodos: estudio prospectivo que incluyó el análisis de la papeletas médicas de pacientes de práctica privada, tratados quirúrgicamente por enfermedades anorectales entre enero de 1997 y julio de 2003. Los pacientes fueron divididos en dos grupos utilizando el mismo...

Emboli in bulls killed in Spanish traditional bullfighting.

The finding of brain tissue fragments in blood and lungs of cattle stunned in slaughterhouses has raised concerns about food safety in the context of the bovine spongiform encephalopathy epidemic. In the present study, the possible occurrence of brain tissue emboli in animals killed in traditional Spanish bullfighting was investigated. Thorough histological analysis of multiple possible target organs was carried out in 434 bulls. No evidence of brain tissue embolism was obtained, but emboli from diverse sources were detected in pulmonary and hepatic tissue of a significant number of animals. These emboli seem to have been caused by the use of a long sword, which extensively disrupts intra-thoracic and intra-abdominal organs and vascular structures.