[Analysis of the impact on the overall survival of laparoscopic Vs open nephroureterectomy in locally advanced upper tract urinary tumors (pT3-pT4).] / Análisis del impacto en la supervivencia global de la nefroureterectomía laparoscópica vs abierta en los tumores del tracto urinario superior localmente avanzados (pT3-pT4).

OBJECTIVE: To compare the impact onoverall survival (OS) of laparoscopic nephroureterectomy (LNU) vs open nephroureterectomy (ONU) in patients with locally advanced upper tract transitional cell carcinoma (UTTCC) (pT3-pT4). MATERIAL AND METHODS: Sixty-six patients underwent LNU/ONU at our institution between March 2001 and August 2016 (36 ONU and 30 LNU) with confirmed UTTCC diagnosis. Demographic, histological and survival variables were extracted. The statistical analysis was performed using Chi-square test, Exact Ficher test,log-rank test and Cox regression analysis. RESULTS: The median time of follow-up was 14.3 months (Q1-Q3 6.6, 38.8). No differences were found between both groups in terms of demographic or pathology variables. The median survival time was 11.6 months (IQR 5.0- 18.2) in the ONU group and 33.8 months (IQR 2.5-65.2) in the LNU group. The 5y OS rate was 14% in the ONU group and 37% in the LNUgroup. Surgical approach, ASA or pT and the multifocality showed a statistically significant association with OS. CONCLUSION: Our study shows an association between the surgical approach and OS, with increased mortality associated to the ONU.

OBJETIVO: Comparar el impacto en la supervivencia global (SG) de la nefroureterectomía laparoscópica (NUL) Vs Nefroureterectomía abierta (NUA) en pacientes afectados de carcinoma urotelial del tracto urinario superior (CUTUS) localmente avanzado (pT3-pT4).MATERIAL Y MÉTODOS: Se estudiaron 66 pacientes intervenidos en nuestro centro entre marzo de 2001 y agosto de 2016 (36 NUA y 30 NUL) y con diagnóstico anatomopatológico de CUTUS. Se recogieron variables demográficas, histológicas y de supervivencia. El análisis estadístico se realizó empleando los test chi-cuadrado, test exacto de Ficher, log-rank test y análisis de regresión de Cox. RESULTADOS: El tiempo mediano de seguimiento fuede 14,3 meses (Q1-Q3: 6,6-38,8). No se encontraron diferencias entre ambos grupos en cuanto a las variables demográficas ni anatomopatológicas. El tiempo mediano de supervivencia fue de 11,6 meses (Q1-Q3:5,0-18,2) en el grupo NUA y de 33,8 meses (Q1-Q3:2,5-65,2) en el grupo NUL. La tasa de supervivencia global estimada a 5 años fue de 14% en el grupo NUA y de 37% en el grupo NUL. El tipo de abordaje quirúrgico,la clasificación de riesgo anestésico de la American Society of Anesthesiologists (ASA), el estadío local (pT) y la multifocalidad mostraron una asociación estadísticamente significativa con la SG.CONCLUSIÓN: Nuestro estudio muestra una asociación entre el abordaje quirúrgico y la SG, con una mayor mortalidad asociada al abordaje convencional.

Kaposi sarcoma of th e penis in anHIV-negative patient.

Kaposi sarcoma is an angioproliferative disorder that ranges from a single indolent skin lesion to respiratory and gastrointestinal/visceral involvement. Kaposi sarcoma is rare in non-immunosuppressed patients. Nineteen cases of penile Kaposi sarcoma in HIV-negative patients were reported in 2012. We present the case report of a 48-year-old male patient with no previous medical history, who came to our urology clinic presenting a purple-color papule on the penis glans. Lab tests revealed negative serology for HIV, but tissue PCR was positive for human herpesvirus 8. Histopathology examination after lesion excision was compatible with Kaposi sarcoma. No other cutaneous or mucosal lesions were present. Primary Kaposi sarcoma of the penis is rare, but may occur in non-immunosuppressed patients.

Impact of an osteoporosis specialized unit on bone health in breast cancer survivals treated with aromatase inhibitors.

OBJECTIVE: Considering the increased fracture risk in early breast cancer patients treated with aromatase inhibitors (AI), we assessed the impact of a preventive intervention conducted by a specialized osteoporosis unit on bone health at AI treatment start. MATERIAL AND METHODS: Retrospective cohort of postmenopausal women who started treatment with AI after breast cancer surgical/chemotherapy treatment and were referred to the osteoporosis unit for a comprehensive assessment of bone health. Bone densitometry and fracture screening by plain X-ray were performed at the baseline visit and once a year for 5 years. RESULTS: The final record included 130 patients. At AI treatment start, 49% had at least one high-risk factor for fractures, 55% had osteopenia, and 39% osteoporosis. Based on the baseline assessment, 79% of patients initiated treatment with bisphosphonates, 88% with calcium, and 79% with vitamin D. After a median of 65 (50-77) months, 4% developed osteopenia or osteoporosis, and 14% improved their densitometric diagnosis. Fifteen fractures were recorded in 11 (8.5%) patients, all of them receiving preventive treatment (10 with bisphosphonates). During the follow-up period, patients with one or more high-risk factors for fracture showed a greater frequency of fractures (15% vs. 3%) and experienced the first fracture earlier than those without high-risk factors (mean of 99 and 102 months, respectively; P=0.023). CONCLUSIONS: The preventive intervention of a specialized unit at the start of AI treatment in breast cancer survivors allows the identification of patients with high fracture risk and may contribute to preventing bone events in these patients.

Kaposi sarcoma of th e penis in anHIV-negative patient / Sarcoma de Kaposi de pênis em paciente HIV negativo

ABSTRACT Kaposi sarcoma is an angioproliferative disorder that ranges from a single indolent skin lesion to respiratory and gastrointestinal/visceral involvement. Kaposi sarcoma is rare in non-immunosuppressed patients. Nineteen cases of penile Kaposi sarcoma in HIV-negative patients were reported in 2012. We present the case report of a 48-year-old male patient with no previous medical history, who came to our urology clinic presenting a purple-color papule on the penis glans. Lab tests revealed negative serology for HIV, but tissue PCR was positive for human herpesvirus 8. Histopathology examination after lesion excision was compatible with Kaposi sarcoma. No other cutaneous or mucosal lesions were present. Primary Kaposi sarcoma of the penis is rare, but may occur in non-immunosuppressed patients.

RESUMO O sarcoma de Kaposi é uma doença angioproliferativa que varia de uma lesão cutânea indolente isolada ao envolvimento visceral respiratório e gastrintestinal. É raro em pacientes não imunossuprimidos. Dezenove casos de sarcoma de Kaposi de pênis em pacientes HIV negativos foram relatados em 2012. Descrevemos o caso de um paciente do sexo masculino, 48 anos, sem história pregressa, que se apresentou em nossa clínica urológica com pápula violeta na glande. Os testes de laboratório revelaram sorologia negativa para HIV, mas o PCR em tecido foi positivo para o herpesvírus humano 8. A histopatologia após a excisão da lesão foi compatível com sarcoma de Kaposi. Não existia outra lesão cutânea ou de mucosa. O sarcoma de Kaposi primário de pênis é raro, mas pode ocorrer em pacientes não imunossuprimidos.

Hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function.

Loss of brain glutathione has been associated with cognitive decline and neuronal death during aging and neurodegenerative diseases. However, whether decreased glutathione precedes or follows neuronal dysfunction has not been unambiguously elucidated. Previous attempts to address this issue were approached by fully eliminating glutathione, a strategy causing abrupt lethality or premature neuronal death that led to multiple interpretations. To overcome this drawback, here we aimed to moderately decrease glutathione content by genetically knocking down the rate-limiting enzyme of glutathione biosynthesis in mouse neurons in vivo. Biochemical and morphological analyses of the brain revealed a modest glutathione decrease and redox stress throughout the hippocampus, although neuronal dendrite disruption and glial activation was confined to the hippocampal CA1 layer. Furthermore, the behavioral characterization exhibited signs consistent with cognitive impairment. These results indicate that the hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function.

Regulation of BDNF Release by ARMS/Kidins220 through Modulation of Synaptotagmin-IV Levels.

BDNF is a growth factor with important roles in the nervous system in both physiological and pathological conditions, but the mechanisms controlling its secretion are not completely understood. Here, we show that ARMS/Kidins220 negatively regulates BDNF secretion in neurons from the CNS and PNS. Downregulation of the ARMS/Kidins220 protein in the adult mouse brain increases regulated BDNF secretion, leading to its accumulation in the striatum. Interestingly, two mouse models of Huntington's disease (HD) showed increased levels of ARMS/Kidins220 in the hippocampus and regulated BDNF secretion deficits. Importantly, reduction of ARMS/Kidins220 in hippocampal slices from HD mice reversed the impaired regulated BDNF release. Moreover, there are increased levels of ARMS/Kidins220 in the hippocampus and PFC of patients with HD. ARMS/Kidins220 regulates Synaptotagmin-IV levels, which has been previously observed to modulate BDNF secretion. These data indicate that ARMS/Kidins220 controls the regulated secretion of BDNF and might play a crucial role in the pathogenesis of HD.SIGNIFICANCE STATEMENT BDNF is an important growth factor that plays a fundamental role in the correct functioning of the CNS. The secretion of BDNF must be properly controlled to exert its functions, but the proteins regulating its release are not completely known. Using neuronal cultures and a new conditional mouse to modulate ARMS/Kidins220 protein, we report that ARMS/Kidins220 negatively regulates BDNF secretion. Moreover, ARMS/Kidins220 is overexpressed in two mouse models of Huntington's disease (HD), causing an impaired regulation of BDNF secretion. Furthermore, ARMS/Kidins220 levels are increased in brain samples from HD patients. Future studies should address whether ARMS/Kidins220 has any function on the pathophysiology of HD.

Antioxidant and bioenergetic coupling between neurons and astrocytes.

Oxidative and nitrosative stress underlie the pathogenesis of a broad range of human diseases, in particular neurodegenerative disorders. Within the brain, neurons are the cells most vulnerable to excess reactive oxygen and nitrogen species; their survival relies on the antioxidant protection promoted by neighbouring astrocytes. However, neurons are also intrinsically equipped with a biochemical mechanism that links glucose metabolism to antioxidant defence. Neurons actively metabolize glucose through the pentose phosphate pathway, which maintains the antioxidant glutathione in its reduced state, hence exerting neuroprotection. This process is tightly controlled by a key glycolysis-promoting enzyme and is dependent on an appropriate supply of energy substrates from astrocytes. Thus brain bioenergetic and antioxidant defence is coupled between neurons and astrocytes. A better understanding of the regulation of this intercellular coupling should be important for identifying novel targets for future therapeutic interventions.

γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor.

Reactive oxygen species regulate redox-signaling processes, but in excess they can cause cell damage, hence underlying the aetiology of several neurological diseases. Through its ability to down modulate reactive oxygen species, glutathione is considered an essential thiol-antioxidant derivative, yet under certain circumstances it is dispensable for cell growth and redox control. Here we show, by directing the biosynthesis of γ-glutamylcysteine-the immediate glutathione precursor-to mitochondria, that it efficiently detoxifies hydrogen peroxide and superoxide anion, regardless of cellular glutathione concentrations. Knocking down glutathione peroxidase-1 drastically increases superoxide anion in cells synthesizing mitochondrial γ-glutamylcysteine. In vitro, γ-glutamylcysteine is as efficient as glutathione in disposing of hydrogen peroxide by glutathione peroxidase-1. In primary neurons, endogenously synthesized γ-glutamylcysteine fully prevents apoptotic death in several neurotoxic paradigms and, in an in vivo mouse model of neurodegeneration, γ-glutamylcysteine protects against neuronal loss and motor impairment. Thus, γ-glutamylcysteine takes over the antioxidant and neuroprotective functions of glutathione by acting as glutathione peroxidase-1 cofactor.

Group IIA secretory phospholipase A2 (GIIA) mediates apoptotic death during NMDA receptor activation in rat primary cortical neurons.

Phospholipases A(2) (PLA(2)) participate in neuronal death signalling pathways because of their ability to release lipid mediators, although the contribution of each isoform and mechanism of neurotoxicity are still elusive. Using a novel fluorogenic method to assess changes in a PLA(2) activity by flow cytometry, here we show that the group IIA secretory phospholipase A(2) isoform (GIIA) was specifically activated in cortical neurons following stimulation of N-methyl-d-aspartate glutamate receptor subtype (NMDAR). For activation, GIIA required Ca(2+) and reactive oxygen/nitrogen species, and inhibition of its activity fully prevented NMDAR-mediated neuronal apoptotic death. Superoxide, nitric oxide or peroxynitrite donors stimulated GIIA activity, which mediated neuronal death. Intriguingly, we also found that GIIA activity induced mitochondrial superoxide production after NMDAR stimulation. These results reveal a novel role for GIIA in excitotoxicity both as target and producer of superoxide in a positive-loop of activation that may contribute to the propagation of neurodegeneration.

Regulation of glycolysis and pentose-phosphate pathway by nitric oxide: impact on neuronal survival.

Besides its essential role at regulating neural functions through cyclic GMP, nitric oxide is emerging as an endogenous physiological modulator of energy conservation for the brain. Thus, nitric oxide inhibits cytochrome c oxidase activity in neurones and glia, resulting in down-regulation of mitochondrial energy production. The subsequent increase in AMP facilitates the activation of 5'-AMP-dependent protein kinase, which rapidly triggers the activation of 6-phosphofructo-1-kinase--the master regulator of the glycolytic pathway--and Glut1 and Glut3--the main glucose transporters in the brain. In addition, nitric oxide activates glucose-6-phosphate dehydrogenase, the first and rate-limiting step of the pentose-phosphate pathway. Here, we review recent evidences suggesting that nitric oxide exerts a fine control of neuronal energy metabolism by tuning the balance of glucose-6-phosphate consumption between glycolysis and pentose-phosphate pathway. This may have important implications for our understanding of the mechanisms controlling neuronal survival during oxidative stress and bioenergetic crisis.