Local IL-17 Production Exerts a Protective Role in Murine Experimental Glomerulonephritis

IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1β p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases

Three endo-β-mannanase genes expressed in the micropylar endosperm and in the radicle influence germination of Arabidopsis thaliana seeds

Mannans are hemicellulosic polysaccharides in the plant primary cell wall (CW). Mature seeds, specially their endosperm cells, have CWs rich in mannan-based polymers that confer a strong mechanical resistance for the radicle protrusion upon germination. The rupture of the seed coat and endosperm are two sequential events during the germination of Arabidopsis thaliana. Endo-β-mannanases (MAN; EC. 3.2.1.78) are hydrolytic enzymes that catalyze cleavage of β1 → 4 bonds in the mannan-polymer. In the genome of Arabidopsis, the endo-β-mannanase (MAN) family is represented by eight members. The expression of these eight MAN genes has been systematically explored in different organs of this plant and only four of them (AtMAN7, AtMAN6, AtMAN2 and AtMAN5) are expressed in the germinating seeds. Moreover, in situ hybridization analysis shows that their transcript accumulation is restricted to the micropylar endosperm and to the radicle and this expression disappears soon after radicle emergence. T-DNA insertion mutants in these genes (K.O. MAN7, K.O. MAN6, K.O. MAN5), except that corresponding to AtMAN2 (K.O. MAN2), germinate later than the wild type (Wt). K.O. MAN6 is the most affected in the germination time course with a t 50 almost double than that of the Wt. These data suggest that AtMAN7, AtMAN5 and specially AtMAN6 are important for the germination of A. thaliana seeds by facilitating the hydrolysis of the mannan-rich endosperm cell walls

Targeting cancer metabolism: a therapeutic window opens

Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.Burroughs Wellcome FundSmith Family FoundationStarr Cancer ConsortiumDamon Runyon Cancer Research FoundationNational Institutes of Health (U.S.

Genes involved in ethylene and gibberellins metabolism are required for endosperm-limited germiantion of Sisymbrium officinales L. Seeds

The rupture of the seed coat and that of the endosperm were found to be two sequential events in the germination of Sisymbrium officinale L. seeds, and radicle protrusion did not occur exactly in the micropylar area but in the neighboring zone. The germination patterns were similar both in the presence of gibberellins (GA4+7) and in presence of ethrel. The analysis of genes involved in GAs synthesis and breakdown demonstrated that (1) SoGA2ox6 expression peaked just prior to radicle protrusion (20–22 h), while SoGA3ox2 and SoGA20ox2 expression was high at early imbibition (6 h) diminishing sharply thereafter; (2) the accumulation of SoGA20ox2 transcript was strongly inhibited by paclobutrazol (PB) as well as by inhibitors of ET synthesis and signaling (IESS) early after imbibition (6 h), while SoGA3ox2 and SoGA2ox6 expression was slowly depressed as germination progressed; (3) ethrel and GA4+7 positively or negatively affected expression of SoGA3ox2, SoGA20ox2, and SoGA2ox6, depending on the germination period studied. Regarding genes involved in ET synthesis, our results showed that SoACS7 was expressed, just prior to radicle emergence while SoACO2 expression slowly increased as germination progressed. Both genes were strongly inhibited by PB but were almost unaffected by externally added ethrel or GA4+7. These results suggest that GAs are more important than ET during the early stages of imbibition, while ET is more important at the late phases of germination of S. officinale L. seed

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Does lumbar spinal degeneration begin with the anterior structures? A study of the observed epidemiology in a community-based population

<p>Abstract</p> <p>Background-</p> <p>Prior studies that have concluded that disk degeneration uniformly precedes facet degeneration have been based on convenience samples of individuals with low back pain. We conducted a study to examine whether the view that spinal degeneration begins with the anterior spinal structures is supported by epidemiologic observations of degeneration in a community-based population.</p> <p>Methods-</p> <p>361 participants from the Framingham Heart Study were included in this study. The prevalences of anterior vertebral structure degeneration (disk height loss) and posterior vertebral structure degeneration (facet joint osteoarthritis) were characterized by CT imaging. The cohort was divided into the structural subgroups of participants with 1) no degeneration, 2) isolated anterior degeneration (without posterior degeneration), 3) combined anterior and posterior degeneration, and 4) isolated posterior degeneration (without anterior structure degeneration). We determined the prevalence of each degeneration pattern by age group < 45, 45-54, 55-64, ≥65. In multivariate analyses we examined the association between disk height loss and the response variable of facet joint osteoarthritis, while adjusting for age, sex, BMI, and smoking.</p> <p>Results-</p> <p>As the prevalence of the no degeneration and isolated anterior degeneration patterns decreased with increasing age group, the prevalence of the combined anterior/posterior degeneration pattern increased. 22% of individuals demonstrated isolated posterior degeneration, without an increase in prevalence by age group. Isolated posterior degeneration was most common at the L5-S1 and L4-L5 spinal levels. In multivariate analyses, disk height loss was independently associated with facet joint osteoarthritis, as were increased age (years), female sex, and increased BMI (kg/m²), but not smoking.</p> <p>Conclusions-</p> <p>The observed epidemiology of lumbar spinal degeneration in the community-based population is consistent with an ordered progression beginning in the anterior structures, for the majority of individuals. However, some individuals demonstrate atypical patterns of degeneration, beginning in the posterior joints. Increased age and BMI, and female sex may be related to the occurrence of isolated posterior degeneration in these individuals.</p

Prótesis de cuerpo vertebral JR: dispositivo modular, anatómico y expandible, con función de jaula y placa diseñada ad hoc para estabilizar la columna después de corpectomía

INTRODUCCIÓN: debido a los resultados clínicos no satisfactorios con instrumentaciones posteriores en los casos de tumor vertebral y a las carencias económicas de nuestros pacientes para adquirir los sistemas disponibles en el mercado, fue diseñada una prótesis de cuerpo vertebral para estabilizar la columna después de una corpectomía. OBJETIVO: describir las características estructurales y funcionales de la prótesis JR, las pruebas biomecánicas en cadáver y la técnica quirúrgica en el paciente. MÉTODOS: primeramente fue realizado un estudio anatómico detallado de los cuerpos vertebrales. Se obtuvo el diseño de un dispositivo modular, anatómico y expandible. Sus componentes una vez ensamblados hacen un implante con función dual de jaula y placa lateral expandibles. Posteriormente se efectuó un ensayo de propiedades biomecánicas en cadáver y se implantó un dispositivo en un paciente con metástasis en cuerpo vertebral. RESULTADOS: las radiografías que le fueron tomadas al cadáver, posterior a la colocación del implante, no mostraron pérdida de la fijación. Al levantar el cadáver se generaron momentos de flexión en sentido lateral con brazos de palanca de 80 cm de largo, por lo que la prótesis fue demandada en su punto más vulnerable con una fuerza de aproximadamente 588 N. Con la rotación, flexión y extensión forzadas, la estabilidad se conservó y no se visualizó movimiento del implante. Se colocó el dispositivo en una mujer de 50 años con cáncer metastásico de tiroides que afectaba L3. El dolor mejoró en el postoperatorio inmediato, así como su función motora que le permitió caminar con una columna estable e indolora por siete años. No se observó fracaso del implante. CONCLUSIÓN: la función dual de jaula y placa integrada en la prótesis de cuerpo vertebral establece una ventaja mecánica comparada con la función de la jaula y de la placa separadamente, ya que el diseño de la prótesis permite aplicar fuerza axial y fijación lateral al mismo tiempo, a través de solo un implante. Los resultados de la colocación del implante en paciente son satisfactorios.INTRODUÇÃO: devido aos resultados clínicos não satisfatórios com instrumentações posteriores nos casos de tumor vertebral e às carências econômicas dos nossos pacientes para adquirir os sistemas disponíveis no mercado, foi desenhada uma prótese de corpo vertebral para estabilizar a coluna depois de uma corpectomia. OBJETIVO: descrever as características estruturais e funcionais da prótese JR, as provas biomecânicas no cadáver e a técnica cirúrgica no paciente. MÉTODOS: primeiro foi realizado um estudo anatômico detalhado dos corpos vertebrais. Obteve-se o desenho de um dispositivo modular, anatômico e expansível. Seus componentes uma vez ensamblados fazem um implante com função dual de jaula e placa lateral expansível. Posteriormente, realizou-se um ensaio de propriedades biomecânicas em cadáver e se implantou um dispositivo num paciente com metástase no corpo vertebral. RESULTADOS: as radiografias que foram tiradas do cadáver, posterior à colocação do implante não mostraram perda da fixação. Ao levantar o cadáver se geraram momentos de flexão no sentido lateral com braços de palanca de 80 cm de longitude, neste caso a prótese foi desafiada no seu ponto mais vulnerável com uma força de aproximadamente 588 N. Com a rotação, flexão e extensão forçadas, a estabilidade se conservou e não foram visualizados movimentos do implante. Colocou-se o dispositivo numa mulher de 50 anos com câncer metastático de tiroides que afeitava L3. A dor melhorou nos pós-operatório imediato, assim como sua função motora, a qual permitiu que a paciente caminhasse com uma coluna estável e indolor por sete anos. Não se observou fracasso do implante. CONCLUSÃO: a função dual de jaula e placa integrada na prótese de corpo vertebral estabelece uma vantagem mecânica comparada com a função de jaula e placa separadamente, uma vez que o desenho da prótese permite aplicar força axial e fixação lateral ao mesmo tempo, por meio de um só implante. Os resultados da colocação do implante no paciente foram satisfatórios.INTRODUCTION: due to the unsatisfactory results obtained with posterior instrumentations in cases of vertebral tumors and to the economical limitations of our patients for acquiring the systems available in the market, a vertebral body prosthesis to stabilize the spine after corpectomy was designed. OBJECTIVE: to describe the structural and functional characteristics of the JR prosthesis, the biomechanical assays in cadaver and the surgical technique on the patient. METHODS: firstly, it was performed a detailed anatomical study of the vertebral bodies. A design of a modular, anatomical and expandable device was obtained. Its components once assembled make an implant with expandable cage and plate dual function. Afterwards, a biomechanical assay was performed in a cadaver and the device was implanted in a patient with vertebral body metastasis. RESULTS: the radiographs extracted from the cadaver after implant location did not show loss of fixation. When the cadaver was raised, flexion moments were generated laterally with levers 80 cm long; therefore, the prosthesis was demanded in its most vulnerable point with a force of approximately 588 N. With rotation, flexion and extensions forced, stability was preserved and no movement was observed. The device was implanted in a 50-year-old woman with metastatic thyroid cancer affecting L3. Pain improved in the postoperative immediate, as well as its motor function, which allowed her to walk with a stable and painless spine for seven years. No implant failure was observed. CONCLUSION: the dual cage function and plate integrated in a single device offers a mechanical advantage, compared with the cages and plates used separately, since the prosthesis design permits to apply a distraction axial force with lateral fixation at the same time, through one implant. The results of the implant placement in the patient were satisfactory