Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin.

Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-ß (Aß) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aß42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.

Src family kinases and Syk are required for neutrophil extracellular trap formation in response to ß-glucan particles.

We report that particles of ß-glucan, one of the surface components of yeasts, are powerful inducers of neutrophil extracellular trap (NET) formation in human neutrophils. ß-Glucan triggered a prolonged phosphorylation of Src family kinases and Syk that were suppressed by the Src family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3, 4-d] pyrimidine (PP2) and a novel Syk inhibitor, PRT-060318, respectively. PP2 and PRT-060318 also inhibited ß-glucan-induced NET formation and reactive oxygen species (ROS) generation, suggesting that both responses are triggered by a Src/Syk-regulated signaling pathway. Given that the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) markedly inhibited NET formation, our findings suggest that ROS are required for the full-blown formation of NETs in response to ß-glucan particles. Contrary to ß-glucan, ROS generation triggered by phorbol myristate acetate (PMA) was unaffected by PP2 and PRT-060318, but these compounds, as well as DPI, suppressed Src/Syk phosphorylation triggered by PMA. Whereas PP2 had no effect on PMA-induced NET formation, PRT-060318 had a significant, albeit partial, inhibitory effect, thus suggesting that ROS induce NET formation in part via activation of Syk. These findings were substantiated by the evidence that neutrophils from mice with the conditional deletion of Syk were defective in formation of NETs in response to ß-glucan.

IL23R, NOD2/CARD15, ATG16L1 and PHOX2B polymorphisms in a group of patients with Crohn's disease and correlation with sub-phenotypes.

Recent genomic research has identified interleukin-23 receptor (IL23R), nucleotide-binding oligomerization domain containing 2 caspase-activation recruitment domain 15 (NOD2/CARD15), autophagy related 16-like 1 (ATG16L1) and paired-like homeobox 2b (PHOX2B) as susceptibility loci for Crohn's Disease (CD). Our aim was to investigate these gene variants in a group of CD patients and to analyse the correlation to sub-phenotypes such as gender, smoking habits, disease behaviour at diagnosis, severity of disease and extra-intestinal manifestations. Nineteen patients with CD and 20 healthy controls were included in the study. The gene variants IL23R rs7517847 and rs11209026, NOD2/CARD15 rs2066845, PHOX2B rs16853571, ATG16L1 rs2241879 and rs2241880 were genotyped by PCR followed by sequencing. The frequency of the G risk allele of IL23R rs7517847 was found to be increased in patients with CD (42%) compared to that in control subjects (20%) [odds ratio (OR), 2.9; 95% confidence interval [CI], 1.06-7.9; P=0.03]. In addition, the homozygous condition GG was also associated with CD (OR, 8.70; 95% CI, 0.9-81.6; P=0.038). The analysis of correlation of genotype to sub-phenotypes showed an association of ATG16L1 rs2241879 with the lack of extra-intestinal manifestations (OR, 0.03; 95% CI, 0.002-0.45; P=0.006), and the patients defined as non-smokers displayed an increased frequency of the risk allele C (P=0.03). The present study confirms the association of the heterozygous and homozygous IL23R rs7517847 variant with CD and suggests an additive effect of smoking to the ATG16L1 rs2241879 C risk allele SNP, in the context of the multifactorial model established for the development of CD and a protective effect of the same allele against extra-intestinal manifestations.

[Upper urinary tract tumors: our experience]. / Tumores del tracto urinario superior, nuestra experiencia.

OBJECTIVES: To study the clinical, diagnostic, and therapeutic features of upper urinary tract tumors. METHODS: We perform a retrospective study of upper urinary tract tumors treated in our Department at Clinica La Luz Madrid between 1995 and 2008. RESULTS: We treated 42 tumors in 40 patients. Mean age was 64 years; there were 29 males and 11 females. Macroscopic hematuria was the most frequent clinical presentation, in 45% of the cases, and the imaging diagnostic test most frequently used was intravenous urogram (62,5%).There were more tumors on the right side (20 cases( than the left side (18 case), 2 cases were bilateral. Distal ureter was the most frequent site.27,5% of the patients presented associated bladder tumors. The most frequently used therapy was laser endoscopic resection. 5 patients required a second operation due to recurrence and 2 more a programmed second procedure due to incomplete resection; 7 cases presented postoperative complications. 70%of the tumors were superficial. 40%of the cases underwent local chemotherapy with weekly bladder instillations of Mitomycin C for 8 weeks. Recurrence rate was 20% and mortality 10%. CONCLUSIONS: Upper urinary tract tumors keep being a rare entity appearing in mid-advanced ages. Radical nephroureterectomy with excision of bladder cuff has been the treatment of choice for years, but in recent years endoscopic treatment is gaining more importance and is showing good results in selected cases.

Tumores del tracto urinario superior. Nuestra experiencia / Upper urinary tract tumours: Our experience

OBJETIVO: Estudiar la clínica, el diagnostico y el tratamiento de los tumores de tracto urinario superior.MÉTODOS: Realizamos un estudio retrospectivo de los tumores de tracto urinario superior tratados en nuestro centro, Clínica La Luz Madrid, entre el 1995 y el 2008.RESULTADOS: Tratamos 42 tumores en 40 pacientes. La edad media fue de 64 años y encontramos 29 varones frente a 11 mujeres.El debut clínico más frecuente fue la hematuria macroscópica en el 45% de los casos y el método diagnostico que más se utilizó fue la urografía intravenosa (62,5%).El lado más afectado fue el derecho (20 casos frente a 18 del lado izquierdo) y en dos casos el tumor se presentó de forma bilateral. La región más afectada fue el uréter distal. El 27,5% de los pacientes presentaron asociado tumor vesical.La terapia más utilizada fue la resección láser endoscópica, 5 pacientes precisaron una segunda intervención por recidiva y dos programada por resección incompleta, siete casos presentaron complicaciones post intervención. El 70% de los tumores fue superficial. El 40% de los casos fue sometido a quimioterapia local con instilaciones endovesicales con Mytomicina C a ritmo semanal por 8 semanas. La tasa de recidiva fue del 20% y la de mortalidad del 10%.CONCLUSIONES: Los tumores del tracto urinario superior siguen siendo una entidad poco frecuente que aparece en la edad media avanzada de la vida. Durante años el tratamiento de elección ha sido la nefroureterectomía radical con resección de rodete vesical, en estos últimos años el tratamiento endoscópico está tomando cada vez más importancia y está dando buenos resultados en casos bien selecionados(AU)

OBJECTIVES: To study the clinical, diagnostic, and therapeutic features of upper urinary tract tumors.METHODS: We perform a retrospective study of upper urinary tract tumors treated in our Department at Clinica La Luz Madrid between 1995 and 2008. RESULTS: We treated 42 tumors in 40 patients. Mean age was 64 years; there were 29 males and 11 females.Macroscopic hematuria was the most frequent clinical presentation, in 45% of the cases, and the imaging diagnostic test most frequently used was intravenous urogram (62,5%).There were more tumors on the right side (20 cases) than the left side (18 cases), 2 cases were bilateral. Distal ureter was the most frequent site.27,5% of the patients presented associated bladder tumors.The most frequently used therapy was laser endoscopic resection. 5 patients required a second operation due to recurrence and 2 more a programmed second procedure due to incomplete resection; 7 cases presented postoperative complications. 70% of the tumors were superficial. 40% of the cases underwent local chemotherapy with weekly bladder instillations of Mitomycin C for 8 weeks. Recurrence rate was 20% and mortality 10%.CONCLUSIONS: Upper urinary tract tumors keep being a rare entity appearing in mid-advanced ages. Radical nephroureterectomy with excision of bladder cuff has been the treatment of choice for years, but in recent years endoscopic treatment is gaining more importance and is showing good results in selected cases(AU)

Aplicación de la tecnología láser en el tratamiento de la litiasis ureteral / Application of laser technology in the treatment of ureteral lithiasis

Objetivo: Valorar las aportaciones del láser, fundamentalmente de holmio, en el tratamiento endourológico de la litiasis ureteral. Método: Analizamos la experiencia acumulada en 154 tratamientos endourológicos con láser holmio de litiasis ubicadas a nivel ureteral, realizado de forma continuada en nuestra Unidad desde junio 2005 a diciembre 2007. Resultados: Se consiguió la fragmentación litiásica en el 100% de los casos. El uso asociado de la pinza de rama larga al láser de holmio, nos permitió alcanzar tasas de ausencia de litiasis residual en el 91% de los pacientes. Conclusiones: El tratamiento de la litiasis ureteral se ha beneficiado de los procedimientos endoscópicos, siendo el láser de holmio la fuente de energía de elección en el momento actual. La tasa de fragmentation alcanzada fue del 100%. Las complicaciones fueron escasas y en ningún momento de importancia (AU)

Objectives: To evaluate the contribution of laser, mainly holmium laser, to the endourological treatment of ureteral lithiasis. Methods: We analyze our experience in 154 endourological treatments of ureteral lithiasis with holmium laser performed in our Unit from June 2005 to December 2007. Results: Stone fragmentation was achieved in 100% of the cases. The use of long jaw forceps associated with the holmium laser enabled us to reach a stone free rate of 91%. Conclusions: The treatment of ureteral lithiasis has benefit from the development of endoscopic procedures, being the holmium laser the energy source of choice nowadays. The fragmentation rate was 100%. Complications were rare and never important (AU)