Assessment of disease severity in late infantile neuronal ceroid lipofuscinosis using multiparametric MR imaging.

BACKGROUND AND PURPOSE: LINCL is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene that encodes for tripeptidyl peptidase 1, a lysosomal enzyme necessary for the degradation of products of cellular metabolism. With the goal of developing quantitative noninvasive imaging biomarkers sensitive to disease progression, we evaluated a 5-component MR imaging metric and tested its correlation with a clinically derived disease-severity score. MATERIALS AND METHODS: MR imaging parameters were measured across the brain, including quantitative measures of the ADC, FA, nuclear spin-spin relaxation times (T2), volume percentage of CSF (%CSF), and NAA/Cr ratios. Thirty MR imaging datasets were prospectively acquired from 23 subjects with LINCL (2.5-8.4 years of age; 8 male/15 female). Whole-brain histograms were created, and the mode and mean values of the histograms were used to characterize disease severity. RESULTS: Correlation of single MR imaging parameters against the clinical disease-severity scale yielded linear regressions with R2 ranging from 0.25 to 0.70. Combinations of the 5 biomarkers were evaluated by using PCA. The best combination included ADC, %CSF, and NAA/Cr (R2=0.76, P<.001). CONCLUSIONS: The multiparametric disease-severity score obtained from the combination of ADC, %CSF, and NAA/Cr whole-brain MR imaging techniques provided a robust measure of disease severity, which may be useful in clinical therapeutic trials of LINCL in which an objective assessment of therapeutic response is desired.

Treatment of transplant renal artery stenosis by percutaneous transluminal angioplasty and/or stenting: study in 63 patients in a single institution.

OBJECTIVE: Our aim was a retrospective evaluation of technical procedures, clinical success, and follow-up of renal transplant patients with stenosis in the transplant renal artery (TRAS) after endovascular treatment. METHODS: From January 1981 to September 2009, 2,150 allograft renal transplants included 62 patients who underwent endovascular procedures for TRAS >75%. Parameters included technical success, arterial blood pressure, antihypertensive drugs, and creatinine level before and after the intervention. RESULTS: Percutaneous transluminal angioplasty (PTA)/stent placement success was 90.3%. Seventy-nine PTAs with 11 stents were primary interventions with 6 PTAs and 4 stent procedures subsequently performed due to restenosis (mean time to event, 1.5 months). The median follow-up was 39 months (range, 1-236). The mean preprocedure creatinine level was 2.8 ± 1.7 mg/dL, and the 1-month postprocedure value was decreased to 2.1 ± 1.2 mg/dL (P < .001). Systolic arterial blood pressure fell from 147.2 ± 18.7 mm Hg to 131.6 ± 14.2 mm Hg (P < .001) and diastolic blood pressure from 84.4 ± 9.8 mm Hg to 76 ± 9.4 mm Hg (P < .001). Postprocedure number of antihypertensive drugs was reduced from 2.3 ± 1.1 to 1.6 ± 1 (P < .0001). The patency rates were: 95 ± 2.8% at 1 month, 87.9 ± 4.3% at 3 months, and 85 ± 4.7% at 12 months. Secondary patency was 100% with no restenosis on follow-up. Allograft survival after primary and secondary PTA/stenting was 97% at 1, 93% at 3.89% at 5, and 85% at 10 years. The complication included 2 renal artery thromboses, a dissection treated with stents, and a late arterial graft pseudoaneurysm. CONCLUSIONS: TRAS, a problem after kidney transplantation, is detected to be a significant stenosis through the use of Doppler ultrasound. Revascularization is recommended to improve hypertension and graft function. PTA should be primarily planned with stenting for patients with a restenosis or after a lack of response to PTA.

Interventional radiologist treatment for inferior vena caval thrombosis in a liver transplant recipient.

Vascular complications remain an important cause of postoperative morbidity and mortality in liver transplant patients. There is no elective treatment and the need for retransplantation is common. Herein, we have reported an unusual case of nonanastomotic inferior vena cava thrombosis in a patient with a piggyback caval anastomosis. The conditions was successfully treated with catheter-directed thrombolytic therapy and endovascular stent placement.

[Biochemical characterization of the optic nerve in mice overexpressing the P53 gen. Oxidative stress assays]. / Caracterización bioquímica del nervio óptico en el ratón que sobreexpresa el gen P53. Análisis de estrés oxidativo.

PURPOSE: The tumour inhibitor p53 gene has the ability of triggering proliferation arrest and cellular death by apoptosis subsequent to several factors, among them oxidative stress. The p53 protein is a major regulator of gene expression. Using genetically manipulated mice carrying an extra copy of gene p53 (transgenic mice super p53) versus control mice, we have investigated the generation of reactive oxygen species and antioxidant activity in the optic nerve of mice in relation to p53 availability. METHODS: We studied two groups of 12-month-old mice of the strain C57BL/6: 1) super p53 group (Sp53) and 2) wild-type control group (CG). Mice were anesthetized in ether atmosphere and the eyeball and retrobulbar optic nerves were excised, washed, soaked in PBS, and stored in liquid nitrogen at -85 degrees C until processing. Three-four optic nerves from the same group were placed in an eppendorf tube, homogenized and enzymatic-colorimetric methods used to determine oxidative and antioxidant activities and the nitric oxide synthesis. RESULTS: A significant increase in free radical formation (via lipid peroxidation; p<0.001), antioxidant activity (p<0.001) and nitric oxide synthesis (p<0.001) was found in the optic nerves from transgenic super p53 mice compared to respective controls. CONCLUSION: The presence of an extra copy of the p53 gene correlated with redox status in the mouse optic nerve. This transgenic mouse could be useful as an experimental model to study cell resistance to neurodegenerative processes in relation to oxidative stress and to apoptosis induction, such as glaucomatous optic neuropathy or age-related macular degeneration.

Caracterización bioquímica del nervio óptico en el ratón que sobreexpresa el gen p53. Análisis de estrés oxidativo / Biochemical characterization of the optic nerve in mice overexpressing the P53 gen. Oxidative stress assays

Objetivos: El gen supresor tumoral p53 detiene la proliferación y la muerte celular por apoptosis subsecuente a la acción de diversos factores, entre ellos el estrés oxidativo. La proteína p53 es fundamentalmente un regulador de la expresión génica. Utilizando ratones genéticamente manipulados para presentar una copia extra del gen p53 (transgénicos super p53) frente a ratones controles, hemos investigado el estado oxidativo y antioxidante en los nervios ópticos, en relación a p53. Método: Se han utilizado ratones de la cepa C57BL/6 de 12 meses de edad en dos grupos: 1) grupo super p53 (Sp53) y 2) grupo de controles wild-type (GC). Los ratones fueron anestesiados en atmósfera de éter, extrayendo los globos oculares y nervios ópticos que se lavaron en PBS, manteniendo las muestras en nitrógeno líquido y en congelador de –85ºC hasta su procesamiento. Se homogeneizaron 3-4 nervios ópticos por cada eppendorf, clasificando por grupos y determinando mediante métodos enzimático-colorimétricos la actividad traperoxidativa y actividad antioxidante total y la concentración de oxido nítrico. Resultados: Existe aumento significativo en la formación de radicales libres via peroxidación lipídica (p<0,001), de la actividad antioxidante (p<0,001) y síntesis de óxido nítrico (p<0,05) en los nervios ópticos de los ratones transgénicos super p53, frente a los ratones controles. Conclusiones: La presencia de una copia extra del gen p53 está ligada a modificaciones de la actividad redox en el nervio óptico del ratón, sugiriendo que p53 otorga una mayor resistencia a la agresión oxidativa. Valoramos la utilización de este modelo de ratón transgénico en procesos neurodegenerativos relacionados con el estrés oxidativo y la inducción de la apoptosis, como la neuropatía óptica glaucomatosa o la degeneración macular asociada a la edad

Purpose: The tumour inhibitor p53 gene has the ability of triggering proliferation arrest and cellular death by apoptosis subsequent to several factors, among them oxidative stress. The p53 protein is a major regulator of gene expression. Using genetically manipulated mice carrying an extra copy of gene p53 (transgenic mice super p53) versus control mice, we have investigated the generation of reactive oxygen species and antioxidant activity in the optic nerve of mice in relation to p53 availability. Methods: We studied two groups of 12-month-old mice of the strain C57BL/6: 1) super p53 group (Sp53) and 2) wild-type control group (CG). Mice were anesthetized in ether atmosphere and the eyeball and retrobulbar optic nerves were excised, washed, soaked in PBS, and stored in liquid nitrogen at –85ºC until processing. Three-four optic nerves from the same group were placed in an eppendorf tube, homogenized and enzymatic-colorimetric methods used to determine oxidative and antioxidant activities and the nitric oxide synthesis. Results: A significant increase in free radical formation (via lipid peroxidation; p<0.001), antioxidant activity (p<0.001) and nitric oxide synthesis (p<0.001) was found in the optic nerves from transgenic super p53 mice compared to respective controls. Conclusion: The presence of an extra copy of the p53 gene correlated with redox status in the mouse optic nerve. This transgenic mouse could be useful as an experimental model to study cell resistance to neurodegenerative processes in relation to oxidative stress and to apoptosis induction, such as glaucomatous optic neuropathy or age-related macular degeneration

Tumorigenic activity of p21Waf1/Cip1 in thymic lymphoma.

The cell cycle inhibitor p21Waf1/Cip1 is among the most important mediators of the tumor suppressor p53. However, there is increasing evidence indicating that p21 could favor tumorigenesis in specific cell types. In particular, the absence of p21 delays the development of thymic lymphomas induced either by ataxia-telangiectasia mutated deficiency or by ionizing irradiation. Here, we extend these observations to the context of p53-deficient mice. The absence of p21 results in a significant extension of the lifespan of p53-null and p53-haploinsufficient mice, and this effect can be attributed exclusively to a decrease in the incidence of spontaneous thymic lymphomas. Specifically, despite the occurrence of a variety of tumor types in the context of p53 deficiency, the only tumors that were significantly impaired by the absence of p21 were thymic lymphomas. Moreover, the absence of p21 also delays the incidence of radiation-induced thymic lymphomas in p53-deficient mice. Interestingly, p21-deficient lymphomas have a higher apoptotic rate than p21-proficient lymphomas, and this could be on the basis of the delayed incidence of thymic lymphomas in the absence of p21. Together, our results indicate that p21 plays an oncogenic role restricted to thymic lymphomas that is mechanistically independent of p53 and associated to a lower tumor apoptotic rate.

Portal vein thrombosis in patients undergoing orthotopic liver transplantation: intraoperative endovascular radiological procedures.

PURPOSE: To evaluate the usefulness of endovascular procedures for portal vein complications during orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Between May 1994 and November 2004, we performed 504 OLTs in 464 adults. Seventy-eight patients (16.8%) presented with portal vein thrombosis (PVT). This analysis of patients from May 2000 to September 2004 included 10 patients with PVT, who were treated with endovascular techniques due to low portal flow. We compared this group with patients who were treated surgically with attention to rethrombosis and survival rates. If portal vein problems were due to obstruction, a venoplasty and primary stent placement were performed. We also embolized with coils or surgically ligated remaining competitive portosystemic shunts. RESULTS: Perfusion problems in the allograft were solved in all cases. We placed seven stents and embolized six competitive shunts. One anastomotic dysfunction was repaired. None of the patients died or rethrombosed during surgery or follow-up. CONCLUSION: Endovascular techniques during OLT can resolve some liver graft perfusion problems due to PVT and "steal" phenomena, especially with unsatisfactory eversion thromboendovenectomy in patients with grade IV PVT. Although primary permeability of stents has been good, these results need to be confirmed.

Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1.

A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27(Kip1) but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, including p15(INK4b), p16(INK4a), p19( INK4d), and p21(Cip1) as well as other negative cell cycle regulators such as p53 and p19(ARF), implies that this senescence-related growth arrest is independent of the activity of p53, p19(ARF), p16(INK4a), and p21(Cip1), which are associated with replicative senescence. The p27(Kip1) binds to the cyclin/CDK2 complexes and causes a decrease in CDK2 kinase activity. We demonstrated that ectopic expression of p27(Kip1) can induce permanent cell cycle arrest and a senescence-like phenotype in wild-type mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27(Kip1)expression. In summary, these observations taken together suggest that p27(Kip1) is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27(Kip1) is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered cell cycle arrest after treatment with LY294002. We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the loss of p27(Kip1). This is the first description that p130 may have a role in inhibiting CDK activity during senescence.

Re-appraisal of treatment of congenital club foot.

Residual deformity following the treatment of club foot is still very common and in many cases it is the result of the treatment itself. The traditional treatment of this condition is undergoing a critical reappraisal with a swing towards surgery in the earlier stages. The Turco technique is discussed and the results in seventeen patients over one year of age are presented.