[Nonautonomous effects of oncogenic YAP in hepatocarcinogenesis]. / Nichtautonome Effekte des Onkogens YAP in der Hepatokarzinogenese.

BACKGROUND: The transcriptional coactivator yes-associated protein (YAP) is a strong oncogene in liver cancer development. OBJECTIVES: To investigate if and how YAP-induced paracrine-acting factors are regulated in hepatocytes and liver cancer cells. MATERIAL AND METHODS: Transcriptome analysis and proteomics of murine wildtype and YAP-transgenic hepatocytes were performed to identify paracrine-acting proteins. Molecular and biochemical techniques were used to examine the mechanisms of YAP-dependent gene regulation. Gene expression data from HCC (hepatocellular carcinoma) patients was evaluated. RESULTS: Several YAP-dependent, secreted factors (e. g. CXCL10, GDF15, PDGFB) were identified. YAP regulates these factors through transcription factors of the TEAD (TEA domain) protein family. Moreover, the dysregulation of the YAP-target genes is often associated with poor HCC patient prognosis. CONCLUSIONS: YAP induces the expression of paracrine-acting factors that may affect the tumor microenvironment and therefore support carcinogenesis. This multicellular network could allow the development of novel and specific perturbation approaches.

Experiencia del uso de terapia biológica en pacientes con enfermedad inflamatoria intestinal en un hospital público / Experience in the use of biological therapy in IBD patients in a public hospital

Biological therapy plays an important role in the treatment of inflammatory bowel disease (IBD). However, the use of these drugs is limited due to fears about their side effects. Aim: To report the experience with the use of infliximab/adalimumab in IBD patients in a public hospital. Material and Methods: Descriptive study of a historical cohort of IBD patients treated with infliximab and adalimumab between April 2012 and July 2014. The clinical response was considered favourable when general, intestinal and extra intestinal symptoms subsided after the induction therapy. In addition, endoscopic and/or imaging response was evaluated at three and six months of treatment. Results: Fifteen out of 162 patients, aged 17 to 52 years (7 women) were included. Seven had Crohn´s Disease, 7 had ulcerative colitis and one had non-classifiable IBD. Biological therapy was indicated due to conventional refractory disease in all patients. All patients received combined treatment with immunosuppressive medications. A favorable clinical response was observed in 93 percent after induction therapy and 73 percent showed endoscopic/imagining remission after 3-6 months. Only one patient experienced side effects associated to the biological therapy, which did not result in discontinuation or treatment interruption. Conclusions: In this cohort of IBD patients treated in a public hospital, the use of infliximab/adalimumab was associated with favorable clinical and endoscopic evolution, post induction therapy with no major side effects.

La terapia biológica tiene un papel fundamental en el tratamiento de la enfermedad inflamatoria intestinal (EII). Sin embargo, el uso de estos fármacos es escaso debido a los costos y los temores sobre los efectos secundarios. Objetivo: Dar a conocer la experiencia en el uso de infliximab/adalimumab en pacientes con EII atendidos en un hospital público de nuestro país. Material y Métodos: Estudio descriptivo de una cohorte histórica de pacientes con EII tratados con infliximab y adalimumab entre abril de 2012 y julio de 2014. La respuesta clínica fue considerada favorable cuando los síntomas generales, intestinales y extra-intestinales desaparecieron después de la terapia de inducción. Además se evaluó la respuesta endoscópica/radiológica a los 3 y 6 meses de tratamiento. Resultados: De un total de 162 pacientes con EII, 15 fueron tratados con terapia biológica, con edad entre 17-52 años (7 mujeres). Siete presentaban el diagnóstico de enfermedad de Crohn, siete colitis ulcerosa y uno EII no clasificable. En todos se inició terapia biológica debido a la presencia de refractariedad a la terapia convencional. Todos recibieron terapia combinada con inmunosupresores. Se observó una respuesta clínica favorable en 93 por ciento después de la terapia de inducción y 73 por ciento tuvo una mejoría endoscópica después de 3-6 meses. Sólo un paciente presentó un evento adverso a terapia biológica, el cual no motivó la interrupción del tratamiento. Conclusiones: En esta cohorte de pacientes con EII tratados en un hospital público, el uso de infliximab/adalimumab se asoció con mejoría clínica y endoscópica post terapia de inducción, sin mayores efectos secundarios.

Role of B cells and macrophages in microvascular disease after heart transplantation.

BACKGROUND: The role of B cells and macrophages in microvascular disease after heart transplantation remains controversial. METHODS: Out of a total of 809 endomyocardial biopsies without evidence of acute cellular rejection (n = 422, 72 females and 350 males, median age 46 years), 393 without evidence of the quilty phenomenon were investigated zero to ten years after heart transplantation. Vascular reaction (endothelial cell swelling and vessel wall thickening) was graded by H&E staining, and immunohistochemistry was performed for T cells (clone UCHL1), B cells (clone L26) and macrophages (clone KP1) and evaluated semi-quantitatively (light microscopy x 200). RESULTS: Positive reaction for T cells and macrophages as well as evidence of endothelial cell swelling decreased with time after heart transplantation. Positive reactions for B cells were less frequent and increased slightly during the observation time, while vessel wall thickening dominated the last observation interval between the fourth and tenth years. Severity of vascular reaction was independent of immunohistochemical evidence of B cells or macrophages. CONCLUSIONS: While activation of the humoral and the non-specific immunological system is common after heart transplantation, microvascular alterations seem to develop independently of these findings.

Magnetic resonance imaging following fat obliteration of the frontal sinus.

The paper describes the evaluation of magnetic resonance imaging (MRI) following osteoplastic flap procedure with fat obliteration. MRI scans performed in patients after surgery between 1st January 1986 and 31st December 1997 were evaluated. Outcome parameters were time-dependent changes in the distribution of adipose or connective tissue, development of necroses or oil cysts, recurrences, inflammatory complications, or mucocoeles. Eighty-six postoperative MRI scans from 51 operations were evaluated. In 19 cases between two and five MRI scans were available. Time between surgery and the last MRI scan was 24.1 months on average. We found five mucocoeles. The amount of adipose tissue depictable on the last scan was less than 20% in the majority of cases (53%) and more than 60% in only 18% of cases. Statistical tests and modelling showed a significant decrease of adipose tissue with time, with a median half-life of 15.4 months in a subgroup with at least two MRIs. MRI is at times the most valuable diagnostic tool after frontal sinus obliteration using adipose tissue. The method has some limitations with regard to detection of small (recurrences of) mucocoeles and differentiation between vital adipose tissue and fat necroses in the form of oil cysts. In difficult cases long-term MRI follow-up is necessary for definitive evaluation.

No stress--no whiplash? Prevalence of "whiplash" symptoms following exposure to a placebo rear-end collision.

Volunteer studies of experimental, low-velocity rear-end collisions have shown a percentage of subjects to report short-lived symptoms, but the cause of these symptoms remains unknown. It is unclear whether the symptoms arise from biomechanical stress causing injury or from psychological stress causing symptom expectation and anxiety. Similarly, the cause of symptoms remains obscure in virtually all "whiplash" patients because it is impossible to identify acute pathology in many cases. In this study subjects were exposed to placebo collisions that almost completely lacked biomechanical stress. It was highly probable that if the symptoms reported following low-velocity collisions were not due to injury but to other factors (including misattribution of symptoms from other sources), then the proportion of subjects reporting symptoms would be similiar to that reported for volunteers in true (experimental) low-velocity, rear-end collisions. A total of 51 volunteers (33 males and 18 females, mean age 32.4 years) were recruited through local newspaper advertisements. An experimental set-up for a placebo collision was constructed using two standard European cars. At time T0, prior to the placebo collision, a history and physical examination was performed, including a psychological analysis (Freiburger Personality Inventory). A symptom history and physical examination were also performed at time T1, immediately after the placebo collision, and the subjects completed symptom questionnaires 3 days (time T2) and 4 weeks (time T3) after the placebo collision. Data analysis included a determination of the predictive value of psychological data for the presence of symptoms following exposure to a placebo collision. At time T1, 9 out 51 participants (17.6%) indicated symptoms. Within 3 days (time T2) after the placebo collision, 10 (19.6%) of the subjects had symptoms, and within 4 weeks (time T3) 5 subjects (9.8%) had symptoms. Of the last group, two of the five did not relate these symptoms to the "collision". Subjects who endorsed symptoms at time T1 had significantly higher scores on the psychological scale of psychosomatic disorders (measured at time T0). Subjects endorsing symptoms at time T2 had significantly higher scores on emotional instability. There was also a tendency to higher scores on this sub-scale for subjects with whiplash-associated disorders (WAD) at time T3. A discriminant analysis using all four psychological scales from time T0 had a power of 87%, 83% and 92% for correct classification of subjects as asymptomatic times T1, T2 and T3, respectively. Approximately 20% of subjects exposed to placebo, low-velocity rear-end collisions will thus indicate WAD, even though no biochemical potential for injury exists. Certain psychological profiles place an individual at higher risk for phenomenon.

Osteoplastic frontal sinus surgery with fat obliteration: technique and long-term results using magnetic resonance imaging in 82 operations.

OBJECTIVE: To evaluate the intraoperative and late complications of osteoplastic sinus surgery with fat obliteration with long-term magnetic resonance imaging (MRI) follow-up. METHODS: The operative records of all patients who underwent osteoplastic frontal sinus surgery with fat obliteration between January 1, 1986 and December 31, 1997 were reviewed and the postoperative clinical course and magnetic resonance imaging (MRI) scans were analyzed if available. MRI analyses revealed that changes in the distribution of fatty and fibrous tissue, the development of necrosis or oil cysts, recurrences, inflammatory complications, and mucoceles were time-dependent occurrences. RESULTS: Eighty-two operative records were evaluated and 59 patients were followed 1 to 12 years after surgery. Eighty-six MRI scans in 51 patients were available for analysis. The most frequent intraoperative complications were exposure of orbital fat (19.5%), unintentional fracture of the anterior wall (19.5%), incorrect placement of the anterior wall (17%), and dural injury (9.8%). Persistent changes of the frontal contour (embossment, depression) occurred in 10.2% and the esthetic result was unfavorable in 5.1% of the cases. Mucoceles could be detected in 5 of 51 cases (9.8%). The amount of adipose tissue detectable in the last scan was less than 20% in the majority of cases (53%), and more than 60% in only 18% of the cases. The amount of adipose tissue decreased significantly with time (the median half-life was 15.4 mo). CONCLUSIONS: Osteoplastic frontal sinus surgery with fat obliteration is very useful and successful in patients in whom the frontal sinus is not accessible via an endonasal approach or the natural drainage cannot be reestablished. MRI is currently the most valuable diagnostic tool to evaluate the frontal sinus after obliteration with adipose tissue. The method has some limitations with regard to detection of small recurrent mucoceles and differentiating vital adipose tissue from fat necroses in the form of oil cysts. In these difficult cases, long-term MRI follow-up is necessary.

Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study.

The objectives were to determine quantitative liver function prospectively in patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX), to search for risk factors for a loss of quantitative liver function and to assess the relationship between quantitative liver function and histological staging. A total of 117 patients with RA (ACR criteria, 85 women, mean age 59 yr) had measurements of galactose elimination capacity (GEC), aminopyrine breath test (ABT) and liver enzymes [aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (AP), 7-glutamyl transferase (GGT), bile acids, bilirubin, albumin] before treatment with weekly i.m. MTX injections and every year thereafter. In 16 patients, liver biopsies were performed. Before the introduction of MTX, mean GEC was 6.6 mg/min/kg [5th to 95th percentile (5-95 PC) 5.1-8.5; reference range 6.0-9.1] and mean ABT was 0.80% kg/mmol (5-95 PC 0.42-1.30: reference range 0.6-1.0). During treatment with MTX [mean weekly dose 11.8 mg (5-95 PC 5.4-20.2), mean observation period 3.8 yr (5-95 PC 0.4-6.9)], significant declines of GEC (-0.12 mg/min/kg per year. t = 3.30, P < 0.002) and ABT (-0.06% kg/mmol per year, t = 4.81, P < 0.001) were observed. Negative correlations were found between the annual change in GEC and GEC at baseline (Rs = -0.40, P < 0.0001), and the annual change in ABT and ABT at baseline (Rs = -0.43, P < 0.0001). No correlations were found between the annual change in GEC or ABT and weekly MTX dose, age or percentage of increased liver enzymes, and no effect of a history of alcohol consumption > 30 g/week became evident. Two patients with Roenigk grade III had impaired quantitative liver function, while 14 patients with Roenigk grades I and II exhibited a high variability of GEC and ABT from normal to abnormal values. The continuous declines in GEC and ABT observed deserve attention in patients with prolonged treatment. Patients with a low GEC or ABT at baseline seem not to be at increased risk for a further loss of quantitative liver function. An impaired GEC or ABT does not necessarily concur with hepatic fibrosis on histological examination.