Hexyl Aminolevulinate-Guided Fluorescence Cystoscopy in the Diagnosis and Follow-up of Patients with Non-Muscle-invasive Bladder Cancer: A Critical Review of the Current Literature.

CONTEXT: Controversy exists regarding the therapeutic benefit and cost effectiveness of photodynamic diagnosis (PDD) with 5-aminolevulinic acid (5-ALA) or hexyl aminolevulinate (HAL) in addition to white-light cystoscopy (WLC) in the management of non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To systematically evaluate evidence regarding the therapeutic benefits and economic considerations of PDD in NMIBC detection and treatment. EVIDENCE ACQUISITION: We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in October 2012 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) and Standards for the Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forty-four publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports used 5-ALA (in 26 studies), HAL (15 studies), or both (three studies) as photosensitising agents. PDD increased the detection of both papillary tumours (by 7-29%) and flat carcinoma in situ (CIS; by 25-30%) and reduced the rate of residual tumours after transurethral resection of bladder tumour (TURBT; by an average of 20%) compared to WLC alone. Superior recurrence-free survival (RFS) rates and prolonged RFS intervals were reported for PDD, compared to WLC in most studies. PDD did not appear to reduce disease progression. Our findings are limited by tumour heterogeneity and a lack of NMIBC risk stratification in many reports or adjustment for intravesical therapy use in most studies. Although cost effectiveness has been demonstrated for 5-ALA, it has not been studied for HAL. CONCLUSIONS: Moderately strong evidence exists that PDD improves tumour detection and reduces residual disease after TURBT compared with WLC. This has been shown to improve RFS but not progression to more advanced disease. Further work to evaluate cost effectiveness of PDD is required.

Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death.

Mitochondrial fusion and fission is a dynamic process critical for the maintenance of mitochondrial function and cell viability. During excitotoxicity neuronal mitochondria are fragmented, but the mechanism underlying this process is poorly understood. Here, we show that Mfn2 is the only member of the mitochondrial fusion/fission machinery whose expression is reduced in in vitro and in vivo models of excitotoxicity. Whereas in cortical primary cultures, Drp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, Mfn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of Mfn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF2 regulates basal Mfn2 expression in neurons and that excitotoxicity-dependent degradation of MEF2 causes Mfn2 downregulation. Thus, Mfn2 reduction is a late event in excitotoxicity and its targeting may help to reduce excitotoxic damage and increase the currently short therapeutic window in stroke.

Sports-related chronic repetitive head trauma as a cause of pituitary dysfunction.

Traumatic brain injury (TBI) is recognized as a cause of hypopituitarism even after mild TBI. Although over the past decade, a growing body of research has detailed neuroendocrine changes induced by TBI, the mechanisms and risk factors responsible for this pituitary dysfunction are still unclear. Around the world, sports-especially combative sports-are very popular. However, sports are not generally considered as a cause of TBI in most epidemiological studies, and the link between sports-related head trauma and hypopituitarism has not been investigated until recently. Thus, there is a paucity of data regarding this important concern. Because of the large number of young sports participants with near-normal life expectancy, the implications of undiagnosed or untreated postconcussion pituitary dysfunction can be dramatic. Understanding the pathophysiological mechanisms and risk factors of hypopituitarism caused by sports injuries is thus an important issue that concerns both medical staff and sponsors of sports. The aim of this paper was to summarize the best evidence for understanding the pathophysiological mechanisms and to discuss the current data and recommendations on sports-related head trauma as a cause of hypopituitarism.

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-kappa B and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38 alpha) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-alpha, markers of fibrosis (transforming growth factor-beta, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-kappa B activation, and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis. (J Am Coll Cardiol 2010;56:2115-25) (C) 2010 by the American College of Cardiology Foundation.

Imaging spectrum of the operated bladder : P41

Multiple complex procedures involving the bladder have been developed by surgeons in both children and adults, with their own advantages and drawbacks. A greater knowledge of the anatomic changes induced by each category of procedure is mandatory in the follow-up of patients and detection of early and late postoperative complications. A retrospective review of 50 pediatric and adult patients referred or treated in our institution is presented. The combined use of plain films, IVP, MCUG, US, Doppler US, CT, 3DCT and MRI is described. The imaging features are compared with surgical and anatomopathological findings. The purpose of this pictorial essay is to present a wide spectrum of diagnostic imaging findings in children and adult patients with operated bladder. The imaging features of surgical procedures with preserved, partially replaced and totally replaced bladder are described, with emphasis on a systematic multimodality approach. Learning objectives: 1) To provide an in-depth review of bladder surgical procedures with their indications, anatomopathological and imaging features. 2) To describe optimal multimodality imaging techniques for evaluating the operated bladder.

Capillary leak leading to shock in Kawasaki disease without myocardial dysfunction.

Kawasaki disease is an acute vasculitis of childhood. Its clinical presentation is well known, and coronary artery aneurysms are classical complications. Shock and pleural or pericardiac effusion are rare presentations of the disease. In intensive care units, the disease may be mistaken for septic shock or toxic shock syndrome. Owing to the fact that immunoglobulin therapy improves the course of the disease, especially if given early, and thus the diagnosis should not be delayed.

Exaggerated exercise-induced pulmonary hypertension causes lung water accumulation and right ventricular dysfunction in patients with chronic mountain sickness

Background: Chronic mountain sickness (CMS) is characterized by exaggerated exercise-induced pulmonary hypertension. Evidences suggests that exercise may cause lung fluid accumulation at high altitude. We hypothesized that, in patients with CMS, exercise causes lung fluid accumulation.Methods: In 21 male CMS patients and 20 matched healthy controls born and permanently living in La Paz (Bolivia, 3600m) we assessed with echocardiogram, pulmonary artery pressure (PASP), right and left ventricular function and ultrasoundlung comets (ULCs, a marker of lung fluid accumulation) at rest and during mild bicycle exercise (10 min at 50W).Results: CMS patients presented a more than 2-fold greater exercise-induced increase in pulmonary artery pressure than controls (17.1±8.3 vs 7.2±7.9 mmHg, P=0.003). This exaggerated PASP response to exercise was associated with a roughly 3-fold greater increase in UCLs in patients with CMS than in controls (6.3±5.1 vs. 2.1±5.3, p<0.05), and there existed a significant relationship between PASP and UCLs (r=0.44, p<0.001). Finally, TDI on lateral tricuspid annulus decreased during exercise in patients with CMS (from 13.2±3.2 to 11.5±2.1 cm s-1, p=0.03), but increased in controls (from 13.1±2.9 to 14.9±2.6 cm s-1 , p=0.04). Left ventricular function remained unaltered in the 2 groups.Conclusions: we provide the first direct evidence in CMS patients that exaggerated exercise-induced pulmonary hypertension causes rapid lung fluid accumulation and right ventricular dysfunction. We speculate that in patients with CMS these two phenomena contribute to reduced exercise performances and Figure 1 increased cardiovascular morbidity and mortality that characterise these subjects.

Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction.

OBJECTIVE: Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic beta-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation. RESEARCH DESIGN AND METHODS: We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis. RESULTS: Prolonged exposure of the beta-cell line MIN6B1 and pancreatic islets to palmitate causes a time- and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in beta-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion. CONCLUSIONS: Our findings suggest that at least part of the detrimental effects of palmitate on beta-cells is caused by alterations in the level of specific miRNAs.

Effects of thyroid hormones and aldosterone on mineralocorticoid binding sites in the toad bladder.

In the urinary bladder of the toad Bufo marinus triiodothyronine selectively inhibits the late effect of aldosterone on Na+ transport. We have investigated whether T3 might mediate its antimineralocorticoid action by controlling: i) the level of aldosterone binding sites in the soluble (cytosolic) pool isolated from tissues treated with T3 (60 nM) for up to 20 hr of incubation; ii) the kinetics of uptake of 3H-aldosterone into cytoplasmic and nuclear fractions after 2 or 20 hr of exposure to T3. The number and the affinity of Type I (high affinity, low capacity) and Type II (low affinity, high capacity) cytosolic binding sites (measured at 0 degrees C) did not vary significantly after 18 hr of exposure to T3, while aldosterone-dependent Na+ transport was significantly inhibited. In addition, T3 did not modify the kinetics of uptake (90 min) of 3H-aldosterone into cytoplasmic and nuclear fractions of toad bladder incubated in vitro at 25 degrees C. By contrast, aldosterone itself was able to down-regulate its cytosolic and nuclear binding sites after an 18-hr exposure to the steroid hormone (10 or 80 nM). T3 slightly (20%) but significantly potentiated the down regulation of nuclear binding sites. In conclusion, T3 does not appear to have major effects on the regulation of the aldosterone receptor, which could explain in a simple manner its antimineralocorticoid action.

Acid-sensing channels in human bladder: expression, function and alterations during bladder pain syndrome.

Purpose: To examine the possible role of H+-activated acid-sensing ion channels (ASICs) in pain perception we characterized their expression in bladder dome biopsies of Bladder Pain Syndrome (BPS) patients and controls, in cultured human urothelium and in urothelial TEU-2 cells.Materials and Methods: Cold cut biopsies from the bladder dome were obtained in 8 asymptomatic controls and 28 patients with symptoms of BPS. ASIC expression was analyzed by QPCR and immunofluorescence. The channel function was measured by electrophysiology.Results: ASIC1a, ASIC2a and ASIC3 mRNAs were detected in human bladder. Similar amounts of ASIC1a and -3 were detected in detrusor smooth muscle, whereas in urothelium ASIC3 levels were higher than -1a. ASIC2a mRNA levels were lower than either -1a or -3 in both layers. ASIC currents were measured in TEU-2 cells and in primary cultures of human urothelium, and ASIC expression was confirmed by QPCR. Differentiation of TEU-2 cells caused an up-regulation of ASIC2a and ASIC3, and a down-regulation of ASIC1a mRNAs. BPS patients showed an up-regulation of ASIC2a and -3 mRNA, whereas ASIC1a remained unchanged. In contrast, the mRNA levels of TRPV1 were down-regulated during BPS. All differences were statistically significant (p<0.05)Conclusions: Several different ASIC subunits are expressed in human bladder and TEU-2 cells, where their levels are regulated during urothelial differentiation. An up-regulation of ASIC2a and -3 in BPS suggests their involvement in increased pain and hyperalgesia. A down-regulation of TRPV1 mRNA levels might indicate a different regulatory mechanism, controlling its expression in human bladder.

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Background Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems. Results Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice. Conclusions These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

Respiratory chain dysfunction associated with multiple mitochondrial DNA deletions in antiretroviral therapy-related lipodystrophy.

Highly-active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome characterized by peripheral fat wasting and central adiposity, usually associated with hyperlipidaemia and insulin resistance [1,2]. Indirect data have led some authors to propose that mitochondrial dysfunction could play a role in this syndrome [3,4].To date, as recently outlined by Kakuda et al. [5] in this journal, HIV-infected patients developing lipodystrophy have not been studied for mitochondrial changes or respiratory chain capacity...

Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.

The paradoxical coexistence of spontaneous tumor antigen-specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8(+) T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1-specific CD8(+) T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1(+) NY-ESO-1-specific CD8(+) T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3(+)PD-1(+) NY-ESO-1-specific CD8(+) T cells are more dysfunctional than Tim-3(-)PD-1(+) and Tim-3(-)PD-1(-) NY-ESO-1-specific CD8(+) T cells, producing less IFN-γ, TNF, and IL-2. Tim-3-Tim-3L blockade enhanced cytokine production by NY-ESO-1-specific CD8(+) T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3-Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8(+) T cells upon prolonged antigen stimulation and acted in synergy with PD-1-PD-L1 blockade. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

Prise en charge des endométriomes et de l'endométriose recto-vaginate et vésicate [Management of endometrioma, recto-vaginal and bladder endometriosis].

Endometriosis is a frequent, benign, chronic disease associated with pain and/or infertility. Classically the lesions are found on the pelvic peritoneum, ovary (endometrioma), rectovaginal septum and bladder. Management of endometrioma has evolved over the last few years to individualised treatment. Indeed endometrioma cystectomy can decrease pain and the risk of recurrence but is also associated with a decrease in ovarian reserve. A multi-disciplinary team should manage recto-vaginal or bladder endometriosis. Surgical resection of these lesions must be as complete as possible and can be complex.