Rad51c- and Trp53-double-mutant mouse model reveals common features of homologous recombination-deficient breast cancers.

Almost half of all hereditary breast cancers (BCs) are associated with germ-line mutations in homologous recombination (HR) genes. However, the tumor phenotypes associated with different HR genes vary, making it difficult to define the role of HR in BC predisposition. To distinguish between HR-dependent and -independent features of BCs, we generated a mouse model in which an essential HR gene, Rad51c, is knocked-out specifically in epidermal tissues. Rad51c is one of the key mediators of HR and a well-known BC predisposition gene. Here, we demonstrate that deletion of Rad51c invariably requires inactivation of the Trp53 tumor suppressor (TP53 in humans) to produce mammary carcinomas in 63% of female mice. Nonetheless, loss of Rad51c shortens the latency of Trp53-deficient mouse tumors from 11 to 6 months. Remarkably, the histopathological features of Rad51c-deficient mammary carcinomas, such as expression of hormone receptors and luminal epithelial markers, faithfully recapitulate the histopathology of human RAD51C-mutated BCs. Similar to other BC models, Rad51c/p53 double-mutant mouse mammary tumors also reveal a propensity for genomic instability, but lack the focal amplification of the Met locus or distinct mutational signatures reported for other HR genes. Using the human mammary epithelial cell line MCF10A, we show that deletion of TP53 can rescue RAD51C-deficient cells from radiation-induced cellular senescence, whereas it exacerbates their centrosome amplification and nuclear abnormalities. Altogether, our data indicate that a trend for genomic instability and inactivation of Trp53 are common features of HR-mediated BCs, whereas histopathology and somatic mutation patterns are specific for different HR genes.

[Emergent drugs (II): the Pharming phenomenon]. / Drogas emergentes (II): el pharming.

The use of medicines, with or without medical prescription, for recreational ends by the young population has received little attention from doctors. In the USA, one in five adolescents has used medicines for recreational purposes, and consultations in Emergency Departments for medicine abuse have exceeded those for illegal drugs. Although few data are available in Spain, such consumption is situated between 3.1 and 8.6% according to surveys. The medicines most used are dextromethorphan and methylphenidate. The former, on sale without prescription, presents a varied symptomatology, dosage and dependent metabolic action, ranging from euphoria to hallucinations. Methylphenidate, taken orally, nasally or intravenously, is used as a stimulant in substitution for cocaine and is one of the medicines most diverted onto the illicit market at the world level. In principle, other substances like modafinil and propofol present a limited incidence of non-medical use, but they have a probable abuse potential that should be borne in mind, above all in the health context. Finally, opiates like fentanyl, oxycodone and buprenorphine, with new pharmaceutical presentations, have recently become generalized in the therapeutic arsenal of many medical specialities; they are giving rise to phenomena of abuse, dependence and diversion towards the illicit market. Demands for detoxification treatment, their mixture with illegal substances, and cases of death should alert us to the abuse of these medicines.

Drogas emergentes (II): el pharming / Emergent drugs (II): the Pharming phenomenon

El uso por la población joven de fármacos con y sin receta médica con fines recreativos, ha tenido escasa atención por los médicos. En USA, uno de cada cinco adolescentes han usado fármacos con finalidad recreativa, y en el servicio de Urgencias, las consultas por abuso de fármacos han superado a las de drogas ilegales. Aunque es España existen pocos datos, este consumo se sitúa, según las encuestas, entre el 3,1 y el 8,6%.Los fármacos más utilizados son el dextrometorfán y el metilfenidato. El primero, de venta sin receta, presenta una sintomatología variable, dosis y acción metabólica dependiente, el cual varía desde la euforia a las alucinaciones. El metilfenidato se utiliza como estimulante sustituto de la cocaína, tanto por vía oral como nasal e intravenosa, siendo uno de los fármacos con más desvío hacia el mercado ilícito a nivel mundial. Otras sustancias como el modafinilo y el propofol presentan un uso no médico en principio de escasa incidencia, pero con un potencial de abuso a tener en cuenta, sobre todo en el ámbito sanitario. Finalmente, opiáceos como el fentanilo, la oxicodona y la buprenorfina, de reciente generalización en el arsenal terapéutico de muchas especialidades médicas y con nuevas presentaciones farmacéuticas, están produciendo fenómenos de abuso, dependencia y comercio ilícito. Las demandas de tratamiento de desintoxicación, la mezcla con sustancias ilegales y los casos de muerte, alertan sobre el abuso de estos fármacos (AU)

The use of medicines, with or without medical prescription, for recreational ends by the young population has received little attention from doctors. In the USA, one in five adolescents has used medicines for recreational purposes, and consultations in Emergency Departments for medicine abuse have exceeded those for illegal drugs. Although few data are available in Spain, such consumption is situated between 3.1 and 8.6% according to surveys. The medicines most used are dextromethorphan and methylphenidate. The former, on sale without prescription, presents a varied symptomatology, dosage and dependent metabolic action, ranging from euphoria to hallucinations. Methylphenidate, taken orally, nasally or intravenously, is used as a stimulant in substitution for cocaine and is one of the medicines most diverted onto the illicit market at the world level. In principle, other substances like modafinil and propofol present a limited incidence of non-medical use, but they have a probable abuse potential that should be borne in mind, above all in the health context. Finally, opiates like fentanyl, oxycodone and buprenorphine, with new pharmaceutical presentations, have recently become generalized in the therapeutic arsenal of many medical specialities; they are giving rise to phenomena of abuse, dependence and diversion towards the illicit market. Demands for detoxification treatment, their mixture with illegal substances, and cases of death should alert us to the abuse of these medicines (AU)

Drogas emergentes (I): las «smart drugs» / Emergent drugs (I): smart drugs

En los últimos años han ganado popularidad unaserie de nuevas drogas, conocidas como smart drugs olegal highs, fácilmente accesibles a través de tiendas online.Ello ocurre sobre todo en los segmentos jóvenesde la población, asociado a su consumo lúdico fundamentalmentedurante los fines de semana.En general son derivados sintéticos de productosnaturales, de los que apenas existe investigación clínicay que no son detectables en los laboratorios de loshospitales.Tres de estos productos, el BZP (1-benzilpiperacina),la mefedrona (4-metilcatinona) y el Spice sonprobablemente los más utilizados en Europa. Los dosprimeros se consumen como alternativas al éxtasis y lacocaína, y se caracterizan por producir un cuadro clínicode tipo simpaticomimético, en ocasiones de consecuenciasgraves, con convulsiones e incluso muerte. ElSpice (mezcla de hierbas con cannabinoides sintéticoscomo el JWH-018, el JWH-073 y el CP 47,497-C8) estáocasionando cuadros de dependencia y esquizofrenia.Aunque las drogas emergentes poseen un aurade seguridad, cada vez hay más experiencia sobre susefectos secundarios(AU)

In recent years, a series of new drugs, known assmart drugs or legal highs, have gaining in popularity.They are easily obtainable through online shops. Thisis happening amongst younger segments of the populationand is associated with recreational consumption,at weekends.In general, they are synthetic derivatives of naturalproducts. There has been hardly any clinical researchinto them and they are not detectable in hospital laboratories.Three of these products, BZP (1-benzylpiperazine),mefedrone (4-methylmethcathinone) and Spice are probablythe most widely used in Europe. The first two areconsumed as an alternative to ecstasy and cocaine andare characterized by their producing a clinical profile ofa sympathetic mimetic type; on occasion, they have seriousconsequences, with convulsions and even death.Spice (a mixture of herbs with synthetic cannabinoidssuch as JWH-018, JWH-073 and CP 47497-C8) is givingrise to profiles of dependence and schizophrenia.Although the emergent drugs have an aura of safety,there is an increasing amount of experience on theirsecondary effects(AU)

Intoxicación por sales de hierro en una embarazada / Iron salts overdose in a pregnant patient

La intoxicación por hierro puede causar un fracaso multiorgánico que puede llevar a la muerte y, en algunos países, constituye la segunda causa de fallecimiento en las embarazadas a consecuencia de una intoxicación. Se presenta el caso de una paciente de 27 años y treinta semanas de gestación, que ingirió con ánimo autolítico 30 mg/kg de sulfato de hierro. Tras unas manifestaciones iniciales de gastritis, se constató la presencia de comprimidos radioopacos en una radiografía simple de abdomen, por lo que dada la dosis ingerida, se aplicó un tratamiento descontaminante digestivo a base de polietilenglicol. La concentración de hierro en sangre fue normal, haciendo innecesaria la terapia antidótica con deferoxamina. Tras un período de observación, la paciente fue dada de alta asintomática. El resto del embarazo transcurrió normalmente y la paciente tuvo un parto a término, sin que se detectasen malformaciones en el recién nacido. Se revisa el mecanismo fisiopatológico, las manifestaciones clínicas y el tratamiento de la intoxicación por hierro, haciendo especial énfasis en las características de este tóxico en la embarazada

Iron intoxication may cause a multiorganic failure that may lead to death and, in some countries, it is the second cause of death in pregnants due to intoxication. We show the case of a 27years old patient, thirty weeks pregnant, who ingested 30 mg/kg of ferrous sulfate in a suicide attempt. She had some gastrointestinal symptoms such as gastritis. The presence of radioopaque pills was observed in an abdominal radiography. Therefore, a digestive descontamination treatment with polietilenglicol was initiated. The serum concentratrion of iron was normal, and for this reason, deferoxamine treatment was unecessary. After an observativon period, she was asymtomatic and she was discharged from the hospital. Her pregnancy was normal and she delivered a healthy child without malformations. We review the pathophysiology, clinical manifestations and treatment of iron intoxication with special emphasis on the pregnant patient

Golosinas del siglo XXI, ¿una nueva amenaza toxicológica? / Twenty-first century sweets, a new toxicological threat?

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[General care of the intoxicated patient]. / Asistencia general al paciente intoxicado.

In this chapter we first set out the epidemiology of Clinical Toxicology, with the most frequent poisonings, and the need for making a register at the national level in order to obtain a more exact understanding of the true scale of the problem is emphasised. We next refer to clinical care and we divide patients depending on whether they have symptoms of: reduction in level of consciousness, alterations in their behaviour (agitation, delirium), generalized convulsions, or if they are conscious patients with different clinical manifestations: cardiac, pulmonary, digestive, nephro-urologic. Reference is also made to the neurotoxicological syndromes that can appear with different poisonings, besides the explorations and analyses that must be carried out to obtain an exact diagnosis of the poisoning. Finally, we deal with the treatment of the patient suffering form poisoning; we emphasise digestive decontamination, antidotes, kidney cleansing and the different poisonings that can be effective for extra-renal cleansing.

[Acute pharmacologic poisoning (I). Psychotropic and antiarrhythmic drugs]. / Intoxicaciones medicamentosas (I). Psicofármacos y antiarrítmicos.

In the evaluation of Acute Drug Poisoning (ADP) in patients seriously ill with a potentially non-toxic dose of the drug that is theoretically responsible, it is important to insist on anamnesis in the coingestion of other drugs or toxics. Initially attention is given to life support measures, oxygenation, protection of the airway and expanding the volemia. The ECG is a diagnostic tool of the first order in ADPs, above all for tricyclic antidepressants (TAD) and cardio-vascular drugs. In the majority of cases continuous monitoring is usually necessary during the first 12-24 hours. The benzodiazepines do not usually give rise to serious poisoning. The use of flumazenil will be reserved for cases of respiratory depression, deep coma or where the cause is undetermined. They can give rise to convulsions, above all in the case of mixed poisonings with anti-depressants and abstinence syndrome. The TADs have an enormous potential seriousness, as they can cause mortal arrhythmias. The therapeutic range of lithium is very narrow; it can produce signs of basically digestive and neurological toxicity. In the case of poisoning by digoxin, the use of anti-digital anti-bodies will be considered in cases of serious bradyarrhythmias, AV blocks or PCR. Glucagon is the antidote for serious poisoning by beta-blockers and for refractory hypotension in cases of calcioantagonists.

[Acute pharmacologic poisoning (II). Analgesics and anticonvulsants]. / Intoxicaciones medicamentosas (II). Analgésicos y anticonvulsivantes.

In this second chapter on Acute Drugs Poisoning we deal with two groups of substances of great transcendence from the point of view of their use and morbidity/mortality. Within the group of analgesic-anti-inflammatory drugs we consider paracetamol and the salicylates, which are easily available to the population. With respect to the anticonvulsants, although they are barely involved in the ensemble of acute drug poisonings, their effects can be serious. We concentrate on four drugs: valproic acid, phenobarbitol, carbamacepine, and phenytoin. Finally, a section is dedicated to isoniazid, a drug that, with the renewed incidence of tuberculosis, is of toxicological interest.

Intoxicaciones medicamentosas (II). Analgésicos y anticonvulsivantes / Acute pharmacologic poisoning (II). Analgesics and anticonvulsants

En este segundo capítulo sobre Intoxicaciones Medicamentosas Agudas abordamos dos grupos de sustancias de enorme trascendencia desde el punto de vista de su uso y morbimortalidad. Dentro del grupo de los anagésicos-antiinflamatorios desarrollamos el paracetamol y los salicilatos, de enorme disponibilidad para la población. En cuanto a los anticonvulsivantes, aunque están poco implicados en el conjunto de las intoxicaciones medicamentosas agudas, sus efectos pueden ser graves. Nos ceñimos a cuatro fármacos: ácido valproico, fenobarbital, carbamacepina, y fenitoína. Finalmente dedicamos un apartado a la isoniacida, fármaco que, con el rebrote de la tuberculosis, presenta interés toxicológico. (AU)

Intoxicaciones medicamentosas (I). Psicofármacos y antiarrítmicos / Acute pharmacologic poisoning (I). Psychotropic and antiarrhythmic drugs

En la valoración de la Intoxicación Medicamentosa Aguda (IMA) en pacientes graves con dosis potencialmente no tóxicas del teórico fármaco responsable es importante insistir en la anamnesis en la coingesta de otros fármacos o tóxicos. Inicialmente se prestará atención a las medidas de soporte vital, oxigenando, protegiendo la vía aérea y expandiendo la volemia. El ECG es una herramienta diagnóstica de primer orden en las IMA, sobre todo por antidepresivos tricíclicos (ADT) y medicación cardiovascular. Su monitorización continua durante las primeras 12-24 horas suele ser necesaria en la mayoría de los casos. Las benzodiacepinas no suelen producir intoxicaciones graves. El uso del flumazenilo se reservará a los casos de depresión respiratoria, coma profundo o de causa no filiada. Pueden dar lugar a convulsiones, sobre todo en caso de intoxicación mixta con antidepresivos, y síndrome de abstinencia. Los ADT poseen una potencial gravedad enorme, pudiendo originar arritmias mortales. El rango terapéutico del litio es muy estrecho, pudiendo producirse signos de toxicidad fundamentalmente digestiva y neurológica. En caso de intoxicación por digoxina, se considerará el uso de anticuerpos antidigital en caso de bradiarritmias graves, bloqueos AV o PCR. El glucagón es el antídoto para la intoxicación grave por b-bloqueantes y para la hipotensión refractaria en caso de calcioantagonistas. (AU)

Asistencia general al paciente intoxicado / General care of the intoxicated patient

En este capítulo se expone en primer lugar la epidemiología de la Toxicología Clínica, con las intoxicaciones más frecuentes y se hace hincapié en la necesidad de realizar un registro a nivel nacional para saber con cierta exactitud la verdadera dimensión del problema. Seguidamente hacemos referencia a la clínica y dividimos a los pacientes según el síntoma predominante: disminución del nivel de conciencia, alteraciones de la conducta (agitación, delirio), convulsiones generalizadas, o pacientes con consciencia normal y con clínica predominante cardiovascular, broncopulmonar, digestiva, cutáneo muscular, o nefro-urológica. También se hace referencia a los síndromes neurotoxicológicos que pueden presentarse con las diferentes intoxicaciones, además de las exploraciones y análisis que se deben realizar para llegar al diagnóstico exacto de la intoxicación. Por último se revisa el tratamiento del paciente intoxicado haciendo énfasis en la descontaminación digestiva, antídotos, depuración renal y las diversas intoxicaciones en las que puede estar indicada la depuración extrarrenal (AU)

Hypocalcaemia and hypomagnesaemia due to hydrofluoric acid.

Hydrofluoric acid readily penetrates the skin and mucous membranes, causing deep tissue layer destruction. Dermal exposure can produce hypocalcaemia, hypomagnesaemia, hyperkalaemia, cardiac dysrhythmias and death. We report the case of a 52-year-old man who presented hypocalcaemia and hypomagnesaemia due to occupational dermal contact with hydrofluoric acid. Hypocalcaemia and hypomagnesaemia were corrected by i.v. administration of calcium gluconate and magnesium sulphate.

Coma y alteraciones cardiovasculares: manifestaciones iniciales de una intoxicación mortal por paracetamol / Coma and cardiovascular involvement: initial manifestations of fatal paracetamol poisoning

La afectación hepatocelular es la manifestación más característica de la intoxicación por paracetamol. Otras alteraciones no suelen ser frecuentes ni graves. Se presenta el caso clínico de una mujer con una intoxicación mortal por paracetamol, que desarrolló un coma y un shock cardiogénico como manifestaciones iniciales (AU)

[Availability, use and cost of antidotes in Catalonia]. / Disponibilidad, utilización y coste de los antídotos en Cataluña.

BACKGROUND: To know the availability of antidotes in hospital and extra-hospital emergency services in Catalonia (Spain), their real use, and the cost. PATIENTS AND METHODS: Availability was studied by means of a transversal questionnaire carried out in 24 hospitals and 3 extra-hospital emergency services in Catalonia; the real use of antidotes was investigated using a prospective study carried out for one year in the same 24 hospitals, and the cost was determined using the data obtained over 12 months in one large hospital. RESULTS: Average availability was 35 antidotes in hospital and 13 in extra-hospital emergency services. In no service did the availability coincide exactly with that of another service, nor with the recommendations made by international institutions (World Health Organization and International Programme for Chemical Safety) or the Government of Catalonia. The low incidence of availability of antidotes to cyanide was notable. Antidotes were used in 12.9% of acute intoxications. In 167 cases treated with these drugs, only 9 different antidotes were used. The consumption of these antidotes represents 0.1% of the budget of a pharmacy service in one large hospital. CONCLUSIONS: The availability of antidotes in Catalonia is heterogeneous and some services lack antidotes whose use is considered essential. Antidotes are scarcely used in acute intoxications and their economic cost is low.