Location, speciation, and quantification of carbon in silica phytoliths using synchrotron scanning transmission X-ray microspectroscopy.

Phytoliths of biogenic silica play a vital role in the silicon biogeochemical cycle and occlude a fraction of organic carbon. The location, chemical speciation, and quantification of this carbon within phytoliths have remained elusive due to limited direct experimental evidence. In this work, phytoliths (bilobate morphotype) from the sugarcane stalk epidermis are sectioned with a focused ion beam to produce lamellas (≈10 × 10 µm2 size, <500 nm thickness) and probed by synchrotron scanning transmission X-ray microspectroscopy (≈100-200 nm pixel size; energies near the silicon and carbon K-absorption edges). Analysis of the spectral image stacks reveals the complementarity of the silica and carbon spatial distributions, with carbon found at the borders of the lamellas, in islands within the silica, and dispersed in extended regions that can be described as a mixed silica-carbonaceous matrix. Carbon spectra are assigned mainly to lignin-like compounds as well as to proteins. Carbon contents of 3-14 wt.% are estimated from the spectral maps of four distinct phytolith lamellas. The results provide unprecedented spatial and chemical information on the carbon in phytoliths obtained without interference from wet-chemical digestion.

Predicting value for incomplete recovery in Bell's palsy of facial nerve ultrasound versus nerve conduction study.

OBJECTIVE: This longitudinal study aims at assessing the predictive value of facial nerve high-resolution ultrasound (HRUS) for incomplete clinical recovery in patients with Bell's palsy, the most common facial nerve disease. METHODS: We prospectively enrolled 34 consecutive patients with Bell's palsy. All patients underwent neurophysiological testing (including facial nerve conduction study) and HRUS evaluations 10-15 days (T1), one month (T2), and three months (T3) after the onset of Bell's palsy. Patients who did not experience complete recovery within three months were also evaluated after six months (T4). We have then compared the accuracy of HRUS with that of the facial nerve conduction study in predicting incomplete clinical recovery at three and six months. RESULTS: At T1, the facial nerve diameter, as assessed with HRUS, was larger on the affected side than on the normal side, particularly in patients with incomplete recovery at T2, T3 and T4. ROC curve analysis, however, showed that the facial nerve diameter at T1 had a lower predictive value than the facial nerve conduction study for an incomplete clinical recovery at three (T3) and six (T4) months. Still, the facial nerve diameter asymmetry, as assessed with HRUS, had a relatively high negative predictive value (thus indicating a strong association between normal HRUS examination and a good prognosis). CONCLUSIONS: Although HRUS shows abnormally increased facial nerve diameter in patients in the acute phase of Bell's palsy, the predictive value of this technique for incomplete clinical recovery at three and six months is lower than that of the nerve conduction study. SIGNIFICANCE: Nerve ultrasound has a low predictive value for incomplete clinical recovery in patients with Bell's Palsy.

Adenoid cystic carcinoma of Bartholin's gland, a case report with genomic data and literature review.

Adenoid cystic carcinoma of the Bartholin's gland (ACCBG) is a rare, slowly but aggressive malignancy. We reported the case of a 31-year-old woman who was treated by local excision and then hemi-vulvectomy, with positive margins and perineural invasion. Radiation therapy (RT) was then performed delivering 45Gy in 25 fractions in bilateral inguinal lymph nodes and 64.8Gy in 36 fractions on the vulvar area. After 30 months, there was no local relapse (LR) but the patient presented a histologically documented lung recurrence. Genomic profiling of the tumor showed a MYB-NFIB fusion transcript and a somatic mutation of PLCG1. A treatment by Lenvatinib was started. We conducted a literature review of 100 published cases. Patients were mainly treated by radical vulvectomy (30%), hemi-vulvectomy (17%), wide or local excision (21% and 24%, respectively) or other. Forty-four percent of patients received postoperative RT, more frequently in case of positive margin (71.9% versus 29.5%). RT may reduce the risk of LR regardless of margin status, with 15.4% vs. 41.9% of LR with or without RT, respectively, in patients with negative margins, and 13% vs. 33.3% of LR with or without RT, respectively, in patients with positive margins. The risk of relapse of any type was 40.9% in patients who received adjuvant RT vs. 48.2% in patients who did not. Median time to relapse was 24 months (range 6-156 months). The most frequent metastatic sites were lung (76.7%) and bone (26.7%). Optimal treatment for ACCBG is still not clearly defined but pooling the data from published case report help us better understand this rare disease and help in the therapeutic decision.

Role of radiotherapy in the management of bladder cancer: Recommendations of the French society for radiation oncology.

We present the recommendations of the French society of oncological radiotherapy on the indications and techniques for external beam radiotherapy for bladder cancer.

Genomics and transcriptomics insights into luteolin effects on the beta-rhizobial strain Cupriavidus necator UYPR2.512.

Cupriavidus necator UYPR2.512 is a rhizobial strain that belongs to the Beta-subclass of proteobacteria, able to establish successful symbiosis with Mimosoid legumes. The initial steps of rhizobium-legumes symbioses involve the reciprocal recognition by chemical signals, being luteolin one of the molecules involved. However, there is a lack of information on the effect of luteolin in beta-rhizobia. In this work, we used long-read sequencing to complete the genome of UYPR2.512 providing evidence for the existence of four closed circular replicons. We used an RNA-Seq approach to analyse the response of UYPR2.512 to luteolin. One hundred and forty-five genes were differentially expressed, with similar numbers of downregulated and upregulated genes. Most repressed genes were mapped to the main chromosome, while the upregulated genes were overrepresented among pCne512e, containing the symbiotic genes. Induced genes included the nod operon and genes implicated in exopolysaccharides and flagellar biosynthesis. We identified many genes involved in iron, copper and other heavy metals metabolism. Among repressed genes, we identified genes involved in basal carbon and nitrogen metabolism. Our results suggest that in response to luteolin, C. necator strain UYPR2.512 reshapes its metabolism in order to be prepared for the forthcoming symbiotic interaction.

[Impact of neck dissection in N2-3 oropharyngeal squamous cell carcinomas treated with definitive chemoradiotherapy: An observational real-life study]. / Impact du curage ganglionnaire cervical dans la prise en charge par chimioradiothérapie exclusive des cancers de l'oropharynx de stade N2-3 : étude observationnelle en vie réelle.

PURPOSE: The purpose of this study was to assess the efficacy in terms of neck failure of an initial neck dissection before definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinomas, as well as the dosimetric impact and the acute and delayed morbidity of this approach. MATERIALS AND METHODS: All patients consecutively treated between 2009 and 2018 with definitive chemoradiotherapy using intensity-modulated conformal radiotherapy (IMRT) for a histologically proven N2-3 oropharyngeal squamous cell carcinomas were retrospectively included. The therapeutic approach consisted of induction chemotherapy, followed by cisplatine-based chemoradiotherapy preceded or not by neck dissection. Neck dissection was discussed on a case-by-case basis in a dedicated multidisciplinary tumour board for patients with a dissociated response to induction chemotherapy, defined as a better response on the primary than on the node. Chemoradiotherapy without neck dissection was systematically performed in case of a major lymph node response to induction chemotherapy (decrease in size of 90% or more). Intensity-modulated radiotherapy using a simultaneous-integrated boost delivered 70Gy in 35 fractions on macroscopic tumour volumes, 63Gy on intermediate-risk levels or extra-nodal extension and 54Gy on prophylactic lymph node areas. RESULTS: Two groups were constituted: 47 patients without an initial neck dissection (62.7%), and 28 patients with a neck dissection prior to definitive chemoradiotherapy (37.3%). Initial patient characteristics were not statistically different between the two groups. The median follow-up was 60.1months (range: 3.2-119months). Incidence of neck failure was higher in patients without neck dissection (P=0.015). The neck failure rate at 5years was 19.8% (95% confidence interval: 7.4-30.6%; P=0.015) without neck dissection versus 0% following neck dissection. All lymph node failures occurred in the planned target volume at 70Gy. Upfront neck dissection suggested a decrease in the mean dose received by the homolateral parotid gland (P=0.01), mandible (P=0.02), and thyroid gland (P=0.02). Acute toxicity of chemoradiotherapy after neck dissection suggested a reduction in grade≥3 adverse events (P=0.04), early discontinuation of concomitant chemotherapy (P=0.009) and feeding tube-dependence (P=0.008) in univariate analysis. During follow-up, there was no difference between the two groups in terms of xerostomia, dysgeusia, dysphagia or gastrostomy dependence in univariate analysis. CONCLUSION: Neck dissection prior to definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinoma was associated with high neck control without additional mid and long-term morbidity.

Production of cadmium sulfide quantum dots by the lithobiontic Antarctic strain Pedobacter sp. UYP1 and their application as photosensitizer in solar cells.

BACKGROUND: Microbes are present in almost every environment on Earth, even in those with extreme environmental conditions such as Antarctica, where rocks may represent the main refuge for life. Lithobiontic communities are composed of microorganisms capable of colonizing rocks and, as it is a not so well studied bacterial community, they may represent a very interesting source of diversity and functional traits with potential for biotechnological applications. In this work we analyzed the ability of Antarctic lithobiontic bacterium to synthesize cadmium sulfide quantum dots (CdS QDs) and their potential application in solar cells. RESULTS: A basaltic andesite rock sample was collected from Fildes Peninsula, King George Island, Antarctica, and processed in order to isolate lithobiontic bacterial strains. Out of the 11 selected isolates, strain UYP1, identified as Pedobacter, was chosen for further characterization and analysis due to its high cadmium tolerance. A protocol for the biosynthesis of CdS QDs was developed and optimized for this strain. After 20 and 80 min of synthesis, yellow-green and orange-red fluorescent emissions were observed under UV light, respectively. QDs were characterized through spectroscopic techniques, dynamic light scattering analysis, high-resolution transmission electron microscopy and energy dispersive x-ray spectroscopy. Nanostructures of 3.07 nm, composed of 51.1% cadmium and 48.9% sulfide were obtained and further used as photosensitizer material in solar cells. These solar cells were able to conduct electrons and displayed an open circuit voltage of 162 mV, a short circuit current density of 0.0110 mA cm-2, and had an efficiency of conversion up to 0.0016%, which is comparable with data previously reported for solar cells sensitized with biologically produced quantum dots. CONCLUSIONS: We report a cheap, rapid and eco-friendly protocol for the production of CdS QDs by an Antarctic lithobiontic bacterium, Pedobacter, a genus that was not previously reported as a quantum dot producer. The application of the biosynthesized QDs as sensitizer material in solar cells was validated.

[New concepts of medical consultation in oncology]. / Nouveaux concepts de consultations médicales en oncologie.

New concepts of medical consultations are currently disrupting the practice of medicine. The use of standardized questionnaires, or patient-reported outcome (PRO and ePRO) has already significantly changed the relationship between the physician and the patient. Telemedicine, or even automatic conversational agents, such as chatbots, are also providing more convenient access to care and medical information for many patients. These tools have a major impact in oncology, precisely because of the rising chronicity of the diseases the radiation oncologists treat. In this article, we provide a detailed analysis of these new concepts.

Implementation of image-guided brachytherapy as part of non-surgical treatment in inoperable endometrial cancer patients.

OBJECTIVE: This study assessed outcomes of inoperable endometrial cancer (IEC) patients treated with definitive external beam radiation therapy (EBRT) followed by a 3D image-guided brachytherapy boost. METHODS: All consecutive patients treated with EBRT followed by 3D image-guided brachytherapy for IEC were retrospectively included. EBRT delivered a dose of 45Gy. Then, patients had an uterovaginal brachytherapy guided by 3D imaging. Clinical target volume (CTVBT) included the whole uterus and the initial disease extent. Gross tumour volume (GTVres) included the residual disease at time of brachytherapy. RESULTS: Twenty-seven patients were identified. Causes of inoperability were comorbidities (37%) or tumour loco regional extent (63%). Including EBRT and brachytherapy, the median D90 (minimal dose delivered to 90% of the volume) was 60.7 GyEQD2 (IQR = 56.4-64.2) for the CTVBT, and was 73.6 GyEQD2 (IQR = 64.1-83.7) for the GTVres. The median overall treatment time was 50 days (IQR = 46-54). The mean follow-up was 36.5 months (SD = 30.2). The cumulative incidence of local, pelvic and distant failures was 19% (n = 5), 7% (n = 2) and 26% (n = 7), respectively. Five-year overall survival was 63% (95% CI = 43-91). Late urinary and gastro intestinal toxicities ≥ grade 2 were reported in four (15%) and two patients (7%) respectively. No vaginal toxicity ≥ grade 2 was reported. CONCLUSIONS: EBRT followed by intracavitary brachytherapy seems to be an effective option for IEC. The implementation of 3D concepts at time of brachytherapy may contribute to high local control probability and low toxicity profile. Large scale retrospective or prospective data are needed to confirm these early data.

Nitrergic perivascular innervation in health and diseases: Focus on vascular tone regulation.

For a long time, the vascular tone was considered to be regulated exclusively by tonic innervation of vasoconstrictor adrenergic nerves. However, accumulating experimental evidence has revealed the existence of nerves mediating vasodilatation, including perivascular nitrergic nerves (PNN), in a wide variety of mammalian species. Functioning of nitrergic vasodilator nerves is evidenced in several territories, including cerebral, mesenteric, pulmonary, renal, penile, uterine and cutaneous arteries. Nitric oxide (NO) is the main neurogenic vasodilator in cerebral arteries and acts as a counter-regulatory mechanism for adrenergic vasoconstriction in other vascular territories. In the penis, NO relaxes the vascular and cavernous smooth muscles leading to penile erection. Furthermore, when interacting with other perivascular nerves, NO can act as a neuromodulator. PNN dysfunction is involved in the genesis and maintenance of vascular disorders associated with arterial and portal hypertension, diabetes, ageing, obesity, cirrhosis and hormonal changes. For example defective nitrergic function contributes to enhanced sympathetic neurotransmission, vasoconstriction and blood pressure in some animal models of hypertension. In diabetic animals and humans, dysfunctional nitrergic neurotransmission in the corpus cavernosum is associated with erectile dysfunction. However, in some vascular beds of hypertensive and diabetic animals, an increased PNN function has been described as a compensatory mechanism to the increased vascular resistance. The present review summarizes current understanding on the role of PNN in control of vascular tone, its alterations under different conditions and the associated mechanisms. The knowledge of these changes can serve to better understand the mechanisms involved in these disorders and help in planning new treatments.

Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases.

Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

[Stereotactic body radiotherapy of oligometastases: Main pending trials and to come in France]. / Radiothérapie des oligométastases : principaux essais en cours et à venir en France.

Stereotactic radiotherapy of oligometastases, mono- or hypofractionated, represents a fundamental change in the practice of the specialty as it was developed for a century. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Four main phase II and III trials are underway in France. Future research concerns the association of stereotactic radiotherapy with immunotherapy or different conventional chemotherapy protocols, the identification of the best clinical presentations, and optimization of fractionation and biological dose for poor prognosis localizations.

[Stereotactic pulmonary radiotherapy: Which machine?] / Radiothérapie stéréotaxique pulmonaire : quelle machine ?

Stereotactic radiotherapy represents a fundamental change in the practice of radiotherapy of lung cancers. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Stereotactic radiotherapy can be realized either by a dedicated accelerator (CyberKnife®) or by a conventional accelerator associated with specific systems. The two modalities deliver a very precise irradiation whose very good results published to date are similar. Some technical characteristics specific to each type of linear accelerator could guide the choice according to the target volume treated.

[Organ preservation by chemoradiation for bladder cancer]. / Préservation par chimioradiothérapie des cancers de vessie.

When localized, the reference treatment of urothelial, muscle-invasive bladder tumours relies on radical cystectomy with reconstruction by enterocystoplasty if possible or Bricker bypass. Trimodal therapy combining transurethral resection of the tumour followed by concomitant chemotherapy may be considered as a therapeutic alternative to radical cystectomy in well-selected patients with unifocal tumours, stage T2, non-diverticular location, without in situ carcinoma or hydronephrosis and with macroscopically complete transurethral resection. The functional prognosis of the bladder and quality of life should be discussed with the patient as well as the need for salvage surgery for persistent tumour at a 45-Gy dose level, the latter being a highly unfavourable prognosis factor. On the other hand, this trimodal treatment is the reference in case of surgical contraindication. This article details the methods and results of the main series available in the literature in terms of local control, survival, bladder preservation rates and complications, as well as study prospects.

Maternal high-sodium intake affects the offspring' vascular renin-angiotensin system promoting endothelial dysfunction in rats.

Perinatal sodium overload induces endothelial dysfunction in adult offspring, but the underlying mechanisms are not fully known. The involvement of tissue renin-angiotensin system on high sodium-programmed endothelial dysfunction was examined. Acetylcholine and angiotensin I and II responses were analyzed in aorta and mesenteric resistance arteries from 24-week-old male offspring of normal-salt (O-NS, 1.3% NaCl) and high-salt (O-HS, 8% NaCl) fed dams. COX-2 expression, O2- production and angiotensin converting enzyme (ACE) activity were determined. A separated O-HS was treated with losartan (15 mg kg-1/day) for eight weeks. Compared to O-NS, O-HS were normotensive. Acetylcholine-induced relaxation was impaired in O-HS arteries, which was improved by tempol, apocynin or indomethacin. The angiotensin I-induced contraction was greater in O-HS arteries, whereas the angiotensin II responses were unchanged. ACE activity, O2- production and COX-2 expression were increased in O-HS arteries. In this group, the increased O2- production was inhibited by apocynin or losartan. Chronic losartan decreased COX-2 expression and restored the endothelium-dependent vasodilation in O-HS. Our findings reiterate that perinatal sodium overload programs endothelial dysfunction in adult offspring through a blood pressure-independent mechanism. Our results also suggest that vascular angiotensin II is the main mediator of high sodium-programmed endothelial dysfunction, promoting COX-2 expression and oxidative stress.

Oxidative stress induced by prenatal LPS leads to endothelial dysfunction and renal haemodynamic changes through angiotensin II/NADPH oxidase pathway: Prevention by early treatment with α-tocopherol.

We investigated whether hypertension induced by maternal lipopolysaccharide (LPS) administration during gestation is linked to peripheral vascular and renal hemodynamic regulation, through angiotensin II → NADPH-oxidase signalling, and whether these changes are directly linked to intrauterine oxidative stress. Female Wistar rats were submitted to LPS, in the absence or presence of α-tocopherol during pregnancy. Malondialdehyde in placenta and in livers from dams and foetuses was enhanced by LPS. Tail-cuff systolic blood pressure (tcSBP) was elevated in the 16-week-old LPS offspring. Renal malondialdeyde and protein expression of NADPH oxidase isoform 2 were elevated in these animals at 20 weeks of age. Maternal α-tocopherol treatment prevented the elevation in malondialdehyde induced by LPS on placenta and livers from dams and foetuses, as well as prevented the elevation in tcSBP and the elevation in renal malondialdehyde in adult life. LPS offspring presented impairment of endothelium-dependent relaxation in aorta and mesenteric rings, which was blunted by angiotensin type 1 receptor (AT1R) blockade and NADPH oxidase inhibition. At age of 32 weeks, renal hemodynamic parameters were unchanged in anaesthetised LPS offspring, but angiotensin II infusion led to an increased glomerular filtration rate paralleled by filtration fraction elevation. The renal haemodynamic changes provoked by angiotensin II was prevented by early treatment with α-tocopherol and by late treatment with NADPH oxidase inhibitor. These results point to oxidative stress as a mediator of offspring hypertension programmed by maternal inflammation and to the angiotensin II → NADPH oxidase signalling pathway as accountable for vascular and renal dysfunctions that starts and maintains hypertension.

Phosphodiesterase-3 inhibitor cilostazol reverses endothelial dysfunction with ageing in rat mesenteric resistance arteries.

Ageing impairs endothelial function, which is considered a hallmark of the development of cardiovascular diseases in elderly. Cilostazol, a phosphodiesterase-3 inhibitor, has antiplatelet, antithrombotic and protective effects on endothelial cells. Here, we hypothesized that cilostazol could improve endothelial function in mesenteric resistance arteries (MRA) from old rats. Using eight-week cilostazol-treated (100mg/kg/day) or untreated 72-week-old Wistar rats, we evaluate the relaxation to acetylcholine, sodium nitroprusside (SNP), forskolin and isoproterenol and the noradrenaline-induced contraction in MRA. Superoxide anion and nitric oxide (NO) was measured by dihydroethidium- and diaminofluorescein-2-emitted fluorescence, respectively. Normotensive old rats had impaired acetylcholine-induced NO- and EDHF-mediated relaxation and increased noradrenaline vasoconstriction than young rats. This age-associated endothelial dysfunction was restored by cilostazol treatment. Relaxation to SNP, forskolin or isoproterenol remained unmodified by cilostazol. Diaminofluorescein-2-emitted fluorescence was increased while dihydroethidium-emitted was decreased by cilostazol, indicating increased NO and reduced superoxide generation, respectively. Cilostazol improves endothelial function in old MRA without affecting blood pressure. This protective effect of cilostazol could be attributed to reduced oxidative stress, increased NO bioavailability and EDHF-type relaxation. Although these results are preliminary, we believe that should stimulate further interest in cilostazol as an alternative for the treatment of age-related vascular disorders.

Orthogonal electronic coupling in multicentre arylamine mixed-valence compounds based on a dibenzofulvene-thiophene conjugated bridge.

Herein we present organic mixed-valence compounds with an innovative H-shape design, where four redox centres are bridged "vertically" via a dibenzofulvene backbone and "horizontally" via a bis-(dibenzofulvene)-thiophene bridge. These compounds are easily oxidized to stable highly charged radical species which show intense intervalence charge transfer transitions in the near infrared region. Interestingly, depending on the position of the arylamine substituents on the bridge, both vertical and horizontal electron transfer pathways can be optically induced.

Biphasic Effect of Diabetes on Neuronal Nitric Oxide Release in Rat Mesenteric Arteries.

INTRODUCTION: We analysed possible time-dependent changes in nitrergic perivascular innervation function from diabetic rats and mechanisms implicated. MATERIALS AND METHODS: In endothelium-denuded mesenteric arteries from control and four- (4W) and eight-week (8W) streptozotocin-induced diabetic rats the vasoconstriction to EFS (electrical field stimulation) was analysed before and after preincubation with L-NAME. Neuronal NO release was analysed in the absence and presence of L-arginine, tetrahydrobiopterine (BH4) and L-arginine plus BH4. Superoxide anion (O2-), peroxynitrite (ONOO-) and superoxide dismutase (SOD) activity were measured. Expressions of Cu-Zn SOD, nNOS, p-nNOS Ser1417, p-nNOS Ser847, and Arginase (Arg) I and II were analysed. RESULTS: EFS response was enhanced at 4W, and to a lesser extent at 8W. L-NAME increased EFS response in control rats and at 8W, but not at 4W. NO release was decreased at 4W and restored at 8W. L-arginine or BH4 increased NO release at 4W, but not 8W. SOD activity and O2- generation were increased at both 4W and 8W. ONOO- decreased at 4W while increased at 8W. Cu-Zn SOD, nNOS and p-NOS Ser1417 expressions remained unmodified at 4W and 8W, whereas p-nNOS Ser847 was increased at 4W. ArgI was overexpressed at 4W, remaining unmodified at 8W. ArgII expression was similar in all groups. CONCLUSIONS: Our results show a time-dependent effect of diabetes on neuronal NO release. At 4W, diabetes induced increased O2- generation, nNOS uncoupling and overexpression of ArgI and p-nNOS Ser847, resulting in decreased NO release. At 8W, NO release was restored, involving normalisation of ArgI and p-nNOS Ser847 expressions.