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.

[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.

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.

[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.

[Acute poisoning caused by hydrogen sulphide: clinical features of 3 cases]. / Intoxicación aguda por sulfuro de hidrógeno: aspectos clínicos en tres casos.

We describe three cases of acute intoxication by hydrogen sulphide which were produced after remaining between 50 and 60 minutes inside a cellulose tank. The three patients had loss of conscience. One of the patients developed a persistent vegetative state; another patient recovered although with neurological post-anoxic sequelas and the third case completely recovered one week after his hospitalization. The patients underwent symptomatic treatment and the environmental concentrations of hydrogen sulphide were measured at the site of the accident. Finally, the application of preventive measures is stressed.

[The radiological findings in poisonings by metals]. / Hallazgos radiológicos en intoxicaciones por metales.

We present four cases of heavy metal poisoning (mercury, lead, bismuth and arsenic) in which plain chest and/or abdominal assisted in the differential diagnosis of the clinical picture manifested upon admission at our Emergency Department. The patients suffering from mercury, lead, and bismuth poisoning recovered some weeks after treatment was started. However, the patient with arsenic trioxide poisoning developed cardio-circulatory collapse leading to death three days after admission.

Acute scopolamine poisoning after sniffing adulterated cocaine.

Five cases of acute poisoning by scopolamine bought as cocaine, are reported. All the cases presented a serious anticholinergic syndrome which needed physostigmine administration. The presence of scopolamine in urine and the specimen sniffed was demonstrated in all the cases.

Acute arsenical myopathy: morphological description.

We describe the histological findings of the muscle in a case of acute voluntary massive arsenic intoxication resulting in severe rhabdomyolysis. The main features on muscle biopsy were perifascicular hypercontracted fibers, myofibrillar disruption, mitochondrial abnormalities and abundant cytoplasmic vacuoles containing lipids.