Translational medicine in hereditary hemorrhagic telangiectasia.

Scientific community have gained lots of new insights in the genetic and biochemical background of different conditions, rare diseases included, settling the basis for preclinical models that are helping to identify new biomarkers and therapeutic targets. Translational Medicine (TM) is an interdisciplinary area of biomedicine with an essential role in bench-to-bedside transition enhancement, generating a circular flow of knowledge transference between research environment and clinical setting, always centered in patient needs. Here, we present different tools used in TM and an overview of what is being done related to hereditary hemorrhagic telangiectasia (HHT), as a disease's model. This work is focused on how this combination of basic and clinical research impacts in HHT patient's daily clinical management and also looking into the future. Further randomized clinical trials with HHT patients should assess the findings of this bench-to-bedside transition. The benefits of this basic and clinical research combination, may not only be important for HHT patients but for patients with other vascular diseases sharing angiogenic disturbances.

The Genetic Basis of Moyamoya Disease.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive spontaneous bilateral occlusion of the intracranial internal cerebral arteries (ICA) and their major branches with compensatory capillary collaterals resembling a "puff of smoke" (Japanese: Moyamoya) on cerebral angiography. These pathological alterations of the vessels are called Moyamoya arteriopathy or vasculopathy and a further distinction is made between primary and secondary MMD. Clinical presentation depends on age and population, with hemorrhage and ischemic infarcts in particular leading to severe neurological dysfunction or even death. Although the diagnostic suspicion can be posed by MRA or CTA, cerebral angiography is mandatory for diagnostic confirmation. Since no therapy to limit the stenotic lesions or the development of a collateral network is available, the only treatment established so far is surgical revascularization. The pathophysiology still remains unknown. Due to the early age of onset, familial cases and the variable incidence rate between different ethnic groups, the focus was put on genetic aspects early on. Several genetic risk loci as well as individual risk genes have been reported; however, few of them could be replicated in independent series. Linkage studies revealed linkage to the 17q25 locus. Multiple studies on the association of SNPs and MMD have been conducted, mainly focussing on the endothelium, smooth muscle cells, cytokines and growth factors. A variant of the RNF213 gene was shown to be strongly associated with MMD with a founder effect in the East Asian population. Although it is unknown how mutations in the RNF213 gene, encoding for a ubiquitously expressed 591 kDa cytosolic protein, lead to clinical features of MMD, RNF213 has been confirmed as a susceptibility gene in several studies with a gene dosage-dependent clinical phenotype, allowing preventive screening and possibly the  development of new therapeutic approaches. This review focuses on the genetic basis of primary MMD only.

Implicación en Cataluña de los Servicios de Anestesiología y Reanimación en la pandemia por SARS-CoV-2. Una solución real coste-efectiva para una crisis sanitaria sin precedentes / Involvement in Catalonia of the Anaesthesiology and Resuscitation Services in the SARS-CoV-2 pandemic. A real, cost-effective solution to an unprecedented health crisis

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Estudios comparativos en la gestión clínica: ¿están justificadas las técnicas espinales en cirugía ambulatoria? / Comparative studies in the clinical management: are spinal anaesthesic techniques in ambulatory surgery justified?

Introducción: La técnica anestésica adecuada es imprescindible en Cirugía Mayor Ambulatoria (CMA) para disminuir la estancia de los pacientes en la unidad y los efectos no deseados. Existe controversia en cuanto a la utilización de las técnicas neuro-axiales en los centros de CMA. Material y métodos: Revisión en la base de datos PubMed entre los años 2000 y 2015, con las palabras clave ‘spinal anesthesia’ y ‘ambulatory surgery’. Estudios comparativos entre técnicas anestésicas, anestésicos locales y dosis, adición de fentanilo. Experiencia en nuestra unidad entre los años 2010 a 2014. Resultados: Estudios comparativos entre técnicas (anestesia intradural [Al] vs. general, bloqueo periférico, con sedación). Favorecen la anestesia intradural, de ser posible. Diferente dosificación de anestésico local: mejores resultados a menores dosis. Adición de fentanilo: resultados no concluyentes. Diferentes anestésicos locales: prilocaína con menores efectos no deseados, alta más precoz con lidocaína. Conclusiones: La Al es una opción válida en CMA, adecuando la técnica a los pacientes y los procedimientos. La situación ideal sería utilizar preferentemente prilocaína a la menor dosis posible y asociando fentanilo (AU)

Introduction: An adequate anaesthetic technique is essential in Ambulatory Surgery (AS) to decrease patients stay in the Unit and unwanted effects.There is controversy in relation to neuro-axial techniques practice in AS centers. Material and methods: PubMed database review between 2000 and 2015, with keywords ‘spinal anaesthesia’ and ‘ambulatory surgery’. Comparative studies between anaesthetic techniques, local anaesthetics and doses, fentanyl addition. Our own Unit experience between 2010 and 2014. Results: Comparative studies between techniques (spinal anaesthesia ISA] vs. general, peripheral block with sedation. If possible, SA is favoured. Different local anesthetic doses. Better results with lower doses. Fentanyl addition: inconclusive results. Different local anaesthetics: prilocaine has less unwanted effects, earlier discharge with lidocaine. Conclusions: SA is a good option in AS, but technique have to be adapted to the patient and procedures. Ideal situation would be to use mainly prilocaine at lower doses associated to fentanyl (AU)

Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action.

Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis. Promotion of angiogenesis is in part due to the activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway. Inhibition of this pathway decreases protein translation and inhibits both angiogenesis and tumour cell proliferation. Although tyrosine kinase inhibitors (TKIs) stand as the main first-line treatment option for advanced RCC, eventually all patients will become resistant to TKIs. Resistance can be overcome by using second-line treatments with different mechanisms of action, such as inhibitors of mTOR, c-MET, programmed death 1 (PD-1) receptor, or the combination of an mTOR inhibitor (mTORi) with a TKI. In this article, we briefly review current evidence regarding mechanisms of resistance in RCC and treatment strategies to overcome resistance with a special focus on the PI3K/AKT/mTOR pathway.

The PDGFRß-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors.

PURPOSE: We examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells. EXPERIMENTAL DESIGN: We compared AKT and ERK activation levels in CDDP-sensitive testicular tumor cells and in their corresponding CDDP-resistant-derived cells. We also analyzed these pathways in orthotopic testicular tumors and human patient samples. RESULTS: Our results indicated that there was overactivation of AKT in CDDP-resistant cells compared with sensitive cells, but no effect on activated ERK levels. We observed an increase in mRNA and protein levels for platelet-derived growth factor (PDGF) receptor ß and PDGF-B ligand. These were responsible for AKT overactivation in CDDP-resistant cells. When PDGFRß levels were decreased by short hairpin RNA (shRNA) treatment or its activation was blocked by pazopanib, CDDP-resistant cells behaved like sensitive cells. Moreover, CDDP-resistant cells were more sensitive to incubation with PDGFRß inhibitors such as pazopanib or sunitinib than sensitive cells, a finding consistent with these cells being dependent on this signaling pathway. We also found overexpression of PDGFRß and pAKT in CDDP-resistant choriocarcinoma orthotopic tumor versus their CDDP-sensitive counterparts. Finally, we found high PDGFRß levels in human testicular tumors, and overexpression in CDDP-resistant testicular choriocarcinomas compared with the CDDP-sensitive and nontreated tumors. CONCLUSIONS: The PDGFRß-AKT pathway plays a critical role in the development of CDDP resistance in testicular tumoral cells.

ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.

Glaucoma agudo unilateral en el postoperatorio de cirugía abdominal / Postoperative unilateral acute glaucoma after abdominal surgery

El diagnóstico correcto y precoz mejora sustancialmente el pronóstico en el glaucoma agudo de ángulo cerrado postoperatorio. Mujer de 90 años de edad a la que se practicó laparotomía para hemicolectomía derecha por neoplasia de colon derecho bajo anestesia combinada y sin incidencias intraoperatorias. La paciente presentó un cuadro de dolor periorbitario en ojo derecho a las 12 horas de la intervención, reiterativo y acompañado de enrojecimiento marcado de la mucosa del globo ocular, visión borrosa y midriasis arreactiva unilateral. Se realizó diagnóstico de glaucoma agudo de ángulo cerrado y se inició tratamiento conservador, precisando iridotomías con láser YAG. En el glaucoma agudo de ángulo cerrado postoperatorio, sobre un globo ocular predispuesto por diversos factores locales como la predisposición genética, género femenino, hipermetropía, aumento del grosor del cristalino y diámetro corneal pequeño, se añaden el bloqueo pupilar secundario a la utilización de fármacos simpaticomiméticos y parasimpaticolíticos en el procedimiento anestésico. Un cuadro de dolor ocular o periorbitario agudo e intenso, con o sin alteración visual, debe alertar al médico responsable. Debe plantearse el diagnóstico diferencial con otras afecciones oculares y causas de dolor craneal postoperatorias(AU)

An early and correct diagnosis substantially improves the post-operative prognosis of acute angle closure glaucoma (AACG). A 90 year-old woman was operated on for a right colon tumour by laparotomy, under combined anaesthesia without any adverse events. Twelve hours after the operation, the patient described recurrent periorbital pain in her right eye, with ocular hyperaemia, blurred vision, and unresponsive mydriasis. A diagnosis of AACG was made, but although conservative treatment was started YAG laser iridotomies were required to reduce the intraocular pressure. In the AACG postoperative period, as well as with an eye with several predisposed local factors including genetic predisposition, female gender, hypermetropia, increased lens thickness and small corneal diameter, can be added a pupillary block induced by adrenergic and anticholinergic drugs used in anaesthetic procedures. An acute and intensive periorbital or ocular pain, with or without visual disturbance, must aware the doctor. A differential diagnosis with other postoperative ocular diseases and cranial pain causes must be done(AU)

[Postoperative unilateral acute glaucoma after abdominal surgery]. / Glaucoma agudo unilateral en el postoperatorio de cirugía abdominal.

An early and correct diagnosis substantially improves the post-operative prognosis of acute angle closure glaucoma (AACG). A 90 year-old woman was operated on for a right colon tumour by laparotomy, under combined anaesthesia without any adverse events. Twelve hours after the operation, the patient described recurrent periorbital pain in her right eye, with ocular hyperaemia, blurred vision, and unresponsive mydriasis. A diagnosis of AACG was made, but although conservative treatment was started YAG laser iridotomies were required to reduce the intraocular pressure. In the AACG postoperative period, as well as with an eye with several predisposed local factors including genetic predisposition, female gender, hypermetropia, increased lens thickness and small corneal diameter, can be added a pupillary block induced by adrenergic and anticholinergic drugs used in anaesthetic procedures. An acute and intensive periorbital or ocular pain, with or without visual disturbance, must aware the doctor. A differential diagnosis with other postoperative ocular diseases and cranial pain causes must be done.

¿Qué piensan los pacientes de la anestesia? Encuesta de satisfacción postoperatoria en cirugía ambulatoria comparando anestesia general y subaracnoidea / What do patients think about anesthesia? Survey of satisfaction after outpatient surgery under general or spinal anesthesia

OBJETIVOS: Conocer mediante encuesta telefónica postoperatoria, el grado de satisfacción de los pacientes, en función de la técnica anestésica aplicada, en cirugía ambulatoria artroscópica de rodilla. MATERIAL v MÉTODOS: Registramos los rechazos a participar y sus causas. Los pacientes fueron distribuidos aleatoriamente en tres grupos: grupo TIVA, anestesia general endovenosa continua con propofol y remifentanilo a 2 y 0,2-0,4 WKg/h, respectivamente; grupo LIDO, anestesia subaracnoidea con lidocaína y grupo PRILO, anestesia subaracnoidea con prilocaína al 1,5 por ciento. En estos dos últimos grupos se administró una dosis fija de 3 ml del anestésico local. Todos los pacientes fueron entrevistados telefónicamente 48 horas postintervención mediante una encuesta de 8 preguntas que evaluaban: experiencia anestésica previa, grado de satisfacción respecto al tipo de anestesia aplicada, valoración del dolor postoperatorio, calidad de la información recibida sobre el procedimiento anestésico y efectos indeseables. RESULTADOS: Entrevistamos un total de 120 pacientes y otros 32 pacientes rechazaron participar. Todos los pacientes del grupo TIVA frente al 85 por ciento y 82 por ciento en los grupos LIDO y PRILO, respectivamente, permitirían que se les realizara la misma anestesia en futuras intervenciones (p = 0,026). La satisfacción respecto a la anestesia, el dolor postoperatorio y la calidad de la información recibida sobre el procedimiento anestésico no mostraron diferencias entre grupos. No hubo efectos indeseables destacables en ninguno de los grupos de estudio. CONCLUSIONES: La satisfacción global de los pacientes ambulatorios de cirugía artroscópica de rodilla tiene características muy similares en función del tipo de anestesia realizada, por lo que se debe tener más en cuenta la opinión o preferencias del paciente por una u otra técnica (AU)

Acute propranolol administration effectively decreases portal pressure in patients with TIPS dysfunction. Transjugular intrahepatic portosystemic shunt.

BACKGROUND AND AIMS: Up to 60% of patients treated with transjugular intrahepatic portosystemic shunt (TIPS) require angioplasty or restenting during the first year of follow up because of TIPS dysfunction (stenosis of the intrahepatic shunt increasing the portal pressure gradient above the 12 mm Hg threshold). We hypothesised that in patients with TIPS stenosis, propranolol administration, by decreasing portal inflow, would markedly decrease portal pressure. PATIENTS AND METHODS: Eighteen patients with TIPS dysfunction were investigated by measuring portal pressure gradient before and after acute propranolol administration (0.2 mg/kg intravenously; n=18). RESULTS: Propranolol markedly reduced the portal pressure gradient (from 16.6 (3.5) to 11.9 (4.8) mm Hg; p<0.0001), cardiac index (-26 (7)%), and heart rate (-18 (7)%) (p<0.0001). Portal pressure gradient decreased to less than 12 mm Hg in nine patients, more frequently in those with moderate dysfunction (portal pressure gradient 16 mm Hg) than in patients with severe dysfunction (portal pressure gradient >16 mm Hg) (8/10 v 1/8; p=0.015). CONCLUSIONS: Propranolol therapy may delay the increase in portal pressure and reduce the need for reintervention in patients with TIPS dysfunction.

[What do patients think about anesthesia? Survey on postoperative satisfaction in ambulatory surgery comparing general and subarachnoid anesthesia]. / Qué piensan los pacientes de la anestesia? Encuesta de satisfacción postoperatoria en cirugía ambulatoria comparando anestesia general y subaracnoidea.

OBJECTIVES: To conduct a telephone survey to determine the degree of patient satisfaction with the anesthetic technique applied during outpatient arthroscopic surgery on the knee. MATERIAL AND METHODS: We recorded refusals to respond to the survey and the reasons. The patients were distributed randomly in 3 groups to receive 1) general anesthesia with propofol and remifentanil by continuous intravenous infusion at rates of 2 and 0.2-0.4 microgram/Kg/h, respectively; 2) subarachnoid anesthesia with lidocaine, and 3) subarachnoid anesthesia with 1.5% prilocaine. The second and third group received fixed doses of 3 mL of the local anesthetic. All patients were telephoned 48 hours after surgery and asked to answer 8 questions concerning prior experience of anesthesia, degree of satisfaction with the type of anesthesia used, postoperative pain, quality of information received about the anesthetic procedure, and undesirable side effects. RESULTS: We interviewed 120 patients and 32 refused to participate. All patients in the general anesthesia group would accept the same anesthetic technique again in future operations, whereas 85% and 82% in the lidocaine and prilocaine groups, respectively, would accept the same technique (p = 0.026). Satisfaction with anesthesia, postoperative pain, and quality of information about the anesthetic procedure was similar in all 3 groups. No important undesirable side affects were reported in any of the groups. CONCLUSIONS: The overall satisfaction with various types of anesthesia is similar among outpatients undergoing arthroscopic surgery on the knee; therefore, patient preferences for one technique over another should be taken into more consideration.

The Cuban National Cancer Registry: 1986-1990.

In Cuba, the illness that produces most deaths among 1-64-year-olds is cancer. Over 65, it is the second cause of death after heart diseases. A National Cancer Registry was created 1964. Its main goals are to register all malignant neoplasms diagnosed in the country, to study this disease from the statistical and epidemiological point of view and to aid in the health control and planning of cancer fighting resources. This paper presents the results based on cases registered from 1986 to 1990. More than 50% of incidence and mortality caused by cancer is confined to the five major primary sites: lung, prostate, colon, breast and cervix. World population standardised rates by 100,000 inhabitants for the period 1986-1990 were 218.2 in males and 183.7 in females for incidence and 138.4 in males and 95.1 in females for mortality. Cancer incidence distribution by provinces shows two major regions: western-central, where higher risks of lung, breast, prostate and colon cancers are found, and eastern where very high risk of cervix cancer is observed. Although an improvement of the information quality indexes has been reported by the National Cancer registry in the studied period of time, quality of the data remained very poor according to the international standards. However, the results obtained by the National Cancer Registry seem to be a valuable tool to evaluate the cancer burden and, in particular, to control and eventually modify the tasks of the National Cancer Control Program in Cuba.