Evolving determinants of carotid atherosclerosis vulnerability in asymptomatic patients from the MAGNETIC observational study.

MRI can assess plaque composition and has demonstrated an association between some atherosclerotic risk factors (RF) and markers of plaque vulnerability in naive patients. We aimed at investigating this association in medically treated asymptomatic patients. This is a cross-sectional interim analysis (August 2013-September 2016) of a single center prospective study on carotid plaque vulnerability (MAGNETIC study). We recruited patients with asymptomatic carotid atherosclerosis (US stenosis > 30%, ECST criteria), receiving medical treatments at a tertiary cardiac rehabilitation. Atherosclerotic burden and plaque composition were quantified with 3.0 T MRI. The association between baseline characteristics and extent of lipid-rich necrotic core (LRNC), fibrous cap (CAP) and intraplaque hemorrhage (IPH) was studied with multiple regression analysis. We enrolled 260 patients (198 male, 76%) with median age of 71-y (interquartile range: 65-76). Patients were on antiplatelet therapy, ACE-inhibitors/angiotensin receptor blockers and statins (196-229, 75-88%). Median LDL-cholesterol was 78 mg/dl (59-106), blood pressure 130/70 mmHg (111-140/65-80), glycosylated hemoglobin 46 mmol/mol (39-51) and BMI 25 kg/m2 (23-28); moreover, 125 out of 187 (67%) patients were ex-smokers. Multivariate analysis of a data-set of 487 (94%) carotid arteries showed that a history of hypercholesterolemia, diabetes, hypertension or smoking did not correlate with LRNC, CAP or IPH. Conversely, maximum stenosis was the strongest independent predictor of LRNC, CAP and IPH (p < 0.001). MRI assessment of plaque composition in patients on treatment for asymptomatic carotid atherosclerosis shows no correlation between plaque vulnerability and the most well-controlled modifiable RF. Conversely, maximum stenosis exhibits a strong correlation with vulnerable features despite treatment.

Especies de garrapatas duras en un área urbana protegida de la Ciudad Autónoma de Buenos Aires / Hard Tick Species in a Protected Urban Area of Buenos Aires City

INTRODUCCIÓN: Las garrapatas (Acari, Ixodida) son artrópodos vectores de gran diversidad de patógenos virales, bacterianos y protozoarios, muchos de los cuales son zoonóticos y emergentes. En Argentina se encuentran numerosas especies de garrapatas duras (familia Ixodidae) que también parasitan al hombre. Las áreas urbanas protegidas son ecosistemas naturales que están dentro de grandes urbes o limitan con ellas. En la Reserva Ecológica Costanera Sur (RECS) de la Ciudad Autónoma de Buenos Aires (CABA) circulan especies silvestres que no tienen presencia en otras áreas de la ciudad, con potenciales hospedadores y vectores. OBJETIVOS: Determinar las especies de garrapatas presentes en la RECS (CABA). MÉTODOS: Se realizó un estudio cuantitativo descriptivo transversal mediante muestreos para colectar garrapatas de vegetación y de hospedadores como perros y distintas especies de roedores. RESULTADOS: En total se recolectaron 1090 garrapatas de la vegetación (454 de la especie Amblyomma aureolatum, 635 Ixodes auritulus y 1 Amblyomma triste) y 67 de los perros (64 A. aureolatum, 2 Rhipicephalus sanguineus sensu lato y 1 A. triste). No se detectaron garrapatas en 200 roedores revisados. CONCLUSIONES: Las especies de garrapatas detectadas en este estudio tienen importancia en salud pública, tanto porque parasitan a humanos (A. aureolatum, A. triste y R. sanguineus s. l.) como porque participan en el ciclo y transmisión de distintos patógenos zoonóticos en distintas regiones del mundo, incluso Argentina.

INTRODUCTION: Ticks (Acari, Ixodida) are arthropod vectors of great diversity of viral, bacterial and protozoan pathogens, many of which are zoonotic and emerging. In Argentina, there are numerous hard tick species (Ixodidae family) which also parasitize humans. Protected urban areas are natural ecosystems located within or near large urban centers. The Costanera Sur Ecological Reserve (RECS) of Buenos Aires city shows a circulation of wild species that have no presence in other areas of the city. There are potential hosts and vectors. OBJECTIVES: A quantitative cross sectional study was carried to detect the species of ticks present in the RECS of Buenos Aires city. METHODS: A quantitative cross - sectional study was carried out by sampling to collect ticks from vegetation and hosts (rodents and dogs). RESULTS: In total, 1090 ticks were collected from the vegetation (454 of the species Amblyomma aureolatum, 635 Ixodes auritulus and 1 Amblyomma triste) and 67 from dogs (64 A. aureolatum, 2 Rhipicephalus sanguineus sensu lato and 1 A. triste). No ticks were detected in 200 examined rodents. CONCLUSIONS: Ticks species detected in this study are important for public health, because they are parasites of humans (A. aureolatum, A. triste and R. sanguineus s. l.) and participate in the cycle and transmission of different zoonotic pathogens in different regions of the world, including Argentina.

C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines.

C-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by pro-caspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines.

Hyper-activation of Notch3 amplifies the proliferative potential of rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells.

Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS.

BACKGROUND: Embryonal Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma derived from myogenic precursors that is characterized by a good prognosis in patients with localized disease. Conversely, metastatic tumors often relapse, leading to a dismal outcome. The histone methyltransferase EZH2 epigenetically suppresses skeletal muscle differentiation by repressing the transcription of myogenic genes. Moreover, de-regulated EZH2 expression has been extensively implied in human cancers. We have previously shown that EZH2 is aberrantly over-expressed in RMS primary tumors and cell lines. Moreover, it has been recently reported that EZH2 silencing in RD cells, a recurrence-derived embryonal RMS cell line, favors myofiber-like structures formation in a pro-differentiation context. Here we evaluate whether similar effects can be obtained also in the presence of growth factor-supplemented medium (GM), that mimics a pro-proliferative microenvironment, and by pharmacological targeting of EZH2 in RD cells and in RD tumor xenografts. METHODS: Embryonal RMS RD cells were cultured in GM and silenced for EZH2 or treated with either the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) that induces EZH2 degradation, or with a new class of catalytic EZH2 inhibitors, MC1948 and MC1945, which block the catalytic activity of EZH2. RD cell proliferation and myogenic differentiation were evaluated both in vitro and in vivo. RESULTS: Here we show that EZH2 protein was abnormally expressed in 19 out of 19 (100%) embryonal RMS primary tumors and cell lines compared to their normal counterparts. Genetic down-regulation of EZH2 by silencing in GM condition reduced RD cell proliferation up-regulating p21Cip1. It also resulted in myogenic-like differentiation testified by the up-regulation of myogenic markers Myogenin, MCK and MHC. These effects were reverted by enforced over-expression of a murine Ezh2, highlighting an EZH2-specific effect. Pharmacological inhibition of EZH2 using either DZNep or MC inhibitors phenocopied the genetic knockdown of EZH2 preventing cell proliferation and restoring myogenic differentiation both in vitro and in vivo. CONCLUSIONS: These results provide evidence that EZH2 function can be counteracted by pharmacological inhibition in embryonal RMS blocking proliferation even in a pro-proliferative context. They also suggest that this approach could be exploited as a differentiation therapy in adjuvant therapeutic intervention for embryonal RMS.

Traqueobroncopatía osteocondroplástica: presentación simulando asma / Tracheobronchopathia osteochondroplastica. Clinical presentation mimicking asthma

La traqueobroncopatía osteocondroplástica (TO) (o traqueopatía osteocondroplástica otraqueopatía osteoplástica)1 es una entidad rara de etiopatogenia desconocida caracterizada por múltiples nódulos de cartílago o hueso originados en el tejido cartilaginoso de la vía aérea, que se proyectan dentro de la luz traqueobronquial. Generalmente decurso crónico y benigno, es casi siempre un hallazgo; cuando presenta síntomas estos son inespecíficos y se deben al estrechamiento de la vía aérea, al engrosamiento de la pared traqueobronquial, o a alguna complicación. Al ser poco reconocida favorece los errores diagnósticos. Reportamos un caso sintomático de TO, confundida con asma, que además presentaba rinosinusitis crónica e infecciones recurrentes de la vía aérea alta y baja. Además de presentar este caso con gran afectación y progresión hasta bronquios distales, mostramos otros 2 presuntos casos sin confirmación endoscópica.

The tracheobronchopathia osteochondroplastica (TO) is a rare disease of unknown pathogenesis. It is characterized by multiple osteocartilaginous nodules protrudinginto the tracheobronchial airway lumen. Generally it is an incidental finding because its evolution is chronic and benign; when symptoms are present, they are non specific and result from the obstruction of the airway, the thickening of the tracheobronchial wall or some complication. Since it is an uncommon condition the diagnostic errors arefrequent. We report a symptomatic TO case, that was misdiagnosed as asthma, and in addition the patient had chronic sinusitis and recurrent upper and lower respiratory tract infections. This case had progressive invasion of distal bronchi. We also report two other suspected cases without endoscopic confirmation.

Temozolomide induced c-Myc-mediated apoptosis via Akt signalling in MGMT expressing glioblastoma cells.

PURPOSE: We investigated the molecular mechanisms underlying the cytotoxic effect of Temozolomide (TMZ) in both O(6)-methylguanine-DNA methyl transferase (MGMT) depleted as well as undepleted glioblastoma cell lines. Since TMZ is used in clinics in combination with radiotherapy, we also studied the effects of TMZ in combination with ionising radiation (IR). METHODS: Cell colony-forming ability was measured using a clonogenic assay. Cell cycle analysis and apoptosis were evaluated by Flow Cytometry (FCM). Proteins involved in cell cycle control were detected by Western blot and co-immunoprecipitation assays. RESULTS: Our data showed that TMZ, independent of MGMT expression, inhibited glioblastoma cell growth via an irreversible G(2) block in MGMT depleted cells or the induction of apoptosis in MGMT normal expressing cells. When TMZ was administered in combination with IR, apoptosis was greater than observed with either agent separately. This TMZ-induced apoptosis in the MGMT expressing cells occurred through Akt/Glycogen-Synthase-Kinase-3ß (GSK3ß) signalling and was mediated by Myelocytomatosis (c-Myc) oncoprotein. Indeed, TMZ phosphorylated/activated Akt led to phosphorylation/inactivation of GSK3ß which resulted in the stabilisation of c-Myc protein and subsequent modulation of the c-Myc target genes involved in the apoptotic processes. CONCLUSION: C-Myc expression could be considered a good indicator of TMZ effectiveness.

Ruptura bronquial: Manejo inicial con la colocación de un stent endobronquial / The bronchial rupture: Initial management with the placement of an endobronchial stent

La ruptura bronquial es una condición rara y grave, secundaria a un traumatismo severo del tórax. Presenta una alta morbimortalidad y la mayoría de las veces requiere resolución quirúrgica. Presentamos un caso que, no habiendo sido diagnosticado inicialmente como tal, padeció complicaciones que dilataron el tratamiento correspondiente. Se realizó la colocación de stent endobronquial y sucesivas fibrobroncoscopías de control y aspiración, además de kinesia respiratoria y drenaje postural, evolucionando favorablemente.

The bronchial rupture is a rare and serious condition, secondary to a severe thoracic trauma. It often requires surgical treatment and the case fatality is high. In the case presented here the treatment was delayed because of late diagnosis and complications. The therapeutic measures included endobronchial stenting, successive control and aspiration fiberbronchoscopies, kinetic respiratory assistance and postural drainage. The evolution was favorable.

Complicaciones respiratorias en los infectados por el Virus de Inmunodeficiencia Humano (VIH) en Buenos Aires / Respiratory complications in the infected by human immunodeficiency virus (HIV) in Buenos Aires

Marco de referencia : Un gran hospital público en Buenos Aires, Argentina. Objetivo: Se efectuó un estudio en 155 pacientes VIH positivos ingresados al Hospital de Agudos "Dr. Enrique Tornú" entre 1992 y 1996 para conocer la distribución de las enfermedades respiratorias. Métodos : Se estudiaron los diagnósticos clínicos, los gérmenes causales, la sensibilidad de estos últimos a los antibióticos, el conteo de linfocitos T CD4 y CD8 y la mortalidad intrahospitalaria de 155 pacientes varones con un test VIH positivo en el Servicio de Tisioneumonología. Actuaron como grupo control 130 pacientes varones, VIH negativos, seleccionados al azar. Resultados: Los 155 pacientes VIH positivos tenían una edad media de 32,3ñ8,4 años y los 130 pacientes VIH negativos 37,2ñ13,2 años. Se diagnosticaron en los 155 pacientes VIH positivos las siguientes enfermedades: tuberculosis (TB) en 103 casos (66,4 por ciento), neumonías de la comunidad (NC) en 35 (22,5 por ciento), neumonía por Pneumocystis carinii (PCP) en 19 (12,2 por ciento) candidiasis en 41 (26,4 por ciento) y otras enfermedades en el resto. En el grupo VIH negativo hubo 66 TB (50,7 por ciento), 13 EPOC (10 por ciento), 11 NC (8,4 por ciento) y otros procesos en el resto. De los 155 pacientes VIH positivos murieron en el hospital 45 (29 por ciento) de: TB 31 (39 por ciento), de NC 7 (20 por ciento), de NPC 4 (44,4 por ciento), de criptococcosis 2 (20 por ciento), de Kaposi 1. Conclusión : En Buenos Aires, entre los varones VIH positivos la tuberculosis es la complicación respiratoria más frecuente (66,4 por ciento), seguida por la neumonía de la comunidad (25 por ciento) y la neumonía por Pneumocystis carinii (12,2 por ciento). Implicaciones clínicas : El test de VIH se debe llevar a cabo en todos los pacientes entre 15 y 60 años de edad con una TB confirmada o sospechosa o una neumonía; para los pacientes VIH positivos el conteo de CD4 es importante debido a su valor pronóstico.

Infección por VIH en pacientes tuberculosos / Hiv infection in tuberculosis patients

Entre junio 1992 y junio 1993 a 117 tuberculosos varones internados en el Hospital Tornú, en Buenos Aires se les efectuó el test VIH. Tenían entre 19 y 50 años de edad. Fueron VIH reactivos 25 enfermos (21,3 por ciento). De los 25 positivos, 21 eran tuberculosospulmonares, 3 pleuropulmonares y 1 ganglionar. La reacción de la tuberculínica (PPD) fue positiva en 8 y negativa en 17. Habían enfermedades asociadas en 16 casos; Pneumocistis carinii en 4, candidiasis en, lues en 3, hepatitis C en 4, Criptococosis en 1, micosis en 1, asma en 1, anemia en 1, hepatitis crónica en 1. En el conteo inicial de linfocitos TCD4 en sangre se efectuó en 8 casos, 4 tenían menos 200 por mm3. El tratamiento de la tuberculosis dio el siguiente resultado: curados 5, evolución favorable 11, fallecidos 2, evolución desconocida 7. Las reacciones adversas a las drogas fueron similares a las de los tuberculosos no reactivos. En resumen, nos ha llaamado la atención el elevado porcentaje de VIH reactivos en la población de tuberculosos varones atendidos en el Hospital Tornú en 1 año. En l986-87, el mismo estudio efectuado en 100 tuberculosos varones dio un 5 por ciento de VIH reactivos

Hepatitis fulminante por drogas antituberculosas: Rifampicina o Pirazinamida / Fulminant hepatitis following antituberculosis drugs: Rifampicin or Pyrazinamide

De las drogas empleadas para el tratamiento de la tuberculosis, la isoniacida, la rifampicina y la pirazinamida son capaces de producir hepatitis fulminantes en muy raras ocasiones. Aunque este accidente es excepcional, debe ser tenido en cuenta. Se presenta la observación de un paciente de 30 años de edad, con tuberculosis pulmonar, bebedor de 1 litro de vino diario, con tests funcionales hepáticos normales, que inició su tratamiento con isoniacida, rifampicina, pirazinamida y ethambutol. A los 2 días, una reacción cutáneo mucosa intensa obligó a suspender las drogas. A los 8 días, desaparecida la reacción cutánea, reinició el tratamiento con rifampicina y pirazinamida; como la tolerancia era buena, al cabo de una semana se agregó ethambutol. Una semana mas tarde presentó un cuadro grave con ictericia intensa que lo llevó a una insuficiencia hepática y a la muerte en seis días. La necropsia mostró una necrosis hepática masiva, sin alteraciones en otros órganos. Este paciente había recibido 9 años antes un tratamiento con isoniacida, rifampicina y ethambutol por una pleuresía tuberculosa, y a las 6 semanas de recibir el tratamiento presentó la ictericia. Pasado el episodio ictérico continuó con las mismas drogas, sin inconvenientes, hasta completar 6 meses. Es muy difícil atribuir la hepatitis fulminante a la rifampicina o a la pirazinamida, drogas que recibió durante 2 semanas. Llama también la atención, la multiplicidad de reacciones adversas que tuvo este enfermo, hecho que ha sido observado en otras oportunidades.