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Eric Fontaine

Publications and source records attributed to Eric Fontaine.

At least 19 recordsLinked to original sources
PubMed2006

Muscle denervation promotes opening of the permeability transition pore and increases the expression of cyclophilin D.

Loss of neural input to skeletal muscle fibres induces atrophy and degeneration with evidence of mitochondria-mediated cell death. However, the effect of denervation on the permeability transition pore (PTP), a mitochondrial protein complex implicated in cell death, is uncertain. In the present study, the impact of 21 days of denervation on the sensitivity of the PTP to Ca2+-induced opening was studied in isolated muscle mitochondria. Muscle denervation increased the sensitivity to Ca2+-induced opening of the PTP, as indicated by a significant decrease in calcium retention capacity (CRC: 111 +/- 12 versus 475 +/- 33 nmol (mg protein)(-1) for denervated and sham, respectively). This phenomenon was partly attributable to in vivo mitochondrial and whole muscle Ca2+ overload. Cyclosporin A, which inhibits PTP opening by binding to cyclophilin D (CypD), was significantly more potent in mitochondria from denervated muscle and restored CRC to the level observed in mitochondria from sham-operated muscles. In contrast, the CypD independent inhibitor trifluoperazine was equally effective at inhibiting PTP opening in sham and denervated animals and did not correct the difference in CRC between groups. This phenomenon was associated with a significant increase in the content of the PTP regulating protein CypD relative to several mitochondrial marker proteins. Together, these results indicate that Ca2+ overload in vivo and an altered expression of CypD could predispose mitochondria to permeability transition in denervated muscles.

Animals↗
PubMed2006

Prospective study of safety margins in partial nephrectomy: intraoperative assessment and contribution of frozen section analysis.

OBJECTIVES: To evaluate prospectively a healthy parenchymal safety margin during conservative surgery for renal cell carcinoma. METHODS: From 1997 to 2001, elective nephron-sparing surgery was performed through a flank incision in 61 consecutive patients (mean age 59.4 years, range 34.2 to 78.5). The mean tumor size was 32 mm (range 12 to 50). The tumor localization was juxtahilar in 10 and distant in 51. Prospective margin assessment used the following protocol. Margins were evaluated macroscopically by the surgeon, controlled by frozen section analysis, and subsequently measured during histologic examination. All patients were monitored with computed tomography scans, with a mean follow-up of 72.5 months (range 46 to 95). RESULTS: The histologic type was clear cell in 42 patients, papillary in 17, and chromophobic cell in 2. Of the 61 patients, 57 had 1997 TNM Stage pT1 and 4 had Stage pT2. The Furhman grade was grade 1 in 16, grade 2 in 35, and grade 3 in 10. No tumor margin was positive. Frozen section analysis and routine histologic examination yielded 53 complete and 8 incomplete margins compared with 51 and 10, respectively, as assessed by the surgeons. The mean peritumoral margin was 7 mm (range 4 to 10) for the cortex and 2 mm (range 0 to 5) for the deep part. No patient developed locoregional or metastatic relapse. CONCLUSIONS: No apparent relationship was observed between peritumoral margin width and the risk of disease progression, even for tumors abutting the hilum, rendering illusory a safety margin greater than 1 cm. Although the surgeons' macroscopic margin evaluations were accurate, frozen section analysis is mandatory when the margin status is in doubt. In all cases, margin negativity remains an oncologic imperative.

Adult↗
PubMed2006

The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin.

Mitochondrial reactive oxygen species (ROS) production was investigated in mitochondria extracted from liver of rats treated with or without metformin, a mild inhibitor of respiratory chain complex 1 used in type 2 diabetes. A high rate of ROS production, fully suppressed by rotenone, was evidenced in non-phosphorylating mitochondria in the presence of succinate as a single complex 2 substrate. This ROS production was substantially lowered by metformin pretreatment and by any decrease in membrane potential (Delta Phi(m)), redox potential (NADH/NAD), or phosphate potential, as induced by malonate, 2,4-dinitrophenol, or ATP synthesis, respectively. ROS production in the presence of glutamate-malate plus succinate was lower than in the presence of succinate alone, but higher than in the presence of glutamate-malate. Moreover, while rotenone both increased and decreased ROS production at complex 1 depending on forward (glutamate-malate) or reverse (succinate) electron flux, no ROS overproduction was evidenced in the forward direction with metformin. Therefore, we propose that reverse electron flux through complex 1 is an alternative pathway, which leads to a specific metformin-sensitive ROS production.

2,4-Dinitrophenol↗
PubMed2005

Cellular uptake of (99m)TcN-NOET in human leukaemic HL-60 cells is related to calcium channel activation and cell proliferation.

PURPOSE: A major goal of nuclear oncology is the development of new radiolabelled tracers as proliferation markers. Intracellular calcium waves play a fundamental role in the course of the cell cycle. These waves occur in non-excitable tumour cells via store-operated calcium channels (SOCCs). Bis(N-ethoxy, N-ethyldithiocarbamato) nitrido technetium (V)-99m ((99m)TcN-NOET) has been shown to interact with L-type voltage-operated calcium channels (VOCCs) in cultured cardiomyocytes. Considering the analogy between VOCCs and SOCCs, we sought to determine whether (99m)TcN-NOET also binds to activated SOCCs in tumour cells in order to clarify the potential value of this tracer as a proliferation marker. METHODS: Uptake kinetics of (99m)TcN-NOET were measured in human leukaemic HL-60 cells over 60 min and the effect of several calcium channel modulators on 1-min tracer uptake was studied. The uptake kinetics of (99m)TcN-NOET were compared both with the variations of cytosolic free calcium concentration measured by indo-1/AM and with the variations in the SG2M cellular proliferation index. RESULTS: All calcium channel inhibitors significantly decreased the cellular uptake of (99m)TcN-NOET whereas the activator thapsigargin induced a significant 10% increase. In parallel, SOCC activation by thapsigargin, as measured using the indo-1/AM probe, was inhibited by nicardipine. These results indicate that the uptake of (99m)TcN-NOET is related to the activation of SOCCs. Finally, a correlation was observed between the tracer uptake and variations in the proliferation index SG2M. CONCLUSION: The uptake of (99m)TcN-NOET seems to be related to SOCC activation and to cell proliferation in HL-60 cells. These results indicate that (99m)TcN-NOET might be a marker of cell proliferation.

Calcium↗
PubMed2005

Effects of decreasing mitochondrial volume on the regulation of the permeability transition pore.

The permeability transition pore (PTP) is a Ca(2+)-sensitive mitochondrial inner membrane channel involved in several models of cell death. Because the matrix concentration of PTP regulatory factors depends on matrix volume, we have investigated the role of the mitochondrial volume in PTP regulation. By incubating rat liver mitochondria in media of different osmolarity, we found that the Ca(2+) threshold required for PTP opening dramatically increased when mitochondrial volume decreased relative to the standard condition. This shrinkage-induced PTP inhibition was not related to the observed changes in protonmotive force, or pyridine nucleotide redox state and persisted when mitochondria were depleted of adenine nucleotides. On the other hand, mitochondrial volume did not affect PTP regulation when mitochondria were depleted of Mg(2+). By studying the effects of Mg(2+), cyclosporin A (CsA) and ubiquinone 0 (Ub(0)) on PTP regulation, we found that mitochondrial shrinkage increased the efficacy of Mg(2+) and Ub(0) at PTP inhibition, whereas it decreased that of CsA. The ability of mitochondrial volume to alter the activity of several PTP regulators represents a hitherto unrecognized characteristic of the pore that might lead to a new approach for its pharmacological modulation.

Animals↗
PubMed2005

Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process.

Hyperglycemia-induced oxidative stress is detrimental for endothelial cells, contributing to the vascular complications of diabetes. The mitochondrial permeability transition pore (PTP) is an oxidative stress-sensitive channel involved in cell death; therefore, we have examined its potential role in endothelial cells exposed to oxidative stress or high glucose level. Metformin, an antihyperglycemic agent used in type 2 diabetes, was also investigated because it inhibits PTP opening in transformed cell lines. Cyclosporin A (CsA), the reference PTP inhibitor, and a therapeutic dose of metformin (100 micromol/l) led to PTP inhibition in permeabilized human microvascular endothelial cells (HMEC-1). Furthermore, exposure of intact HMEC-1 or primary endothelial cells from either human umbilical vein or bovine aorta to the oxidizing agent tert-butylhydroperoxide or to 30 mmol/l glucose triggered PTP opening, cytochrome c decompartmentalization, and cell death. CsA or metformin prevented all of these effects. The antioxidant N-acetyl-l-cysteine also prevented hyperglycemia-induced apoptosis. We conclude that 1) elevated glucose concentration leads to an oxidative stress that favors PTP opening and subsequent cell death in several endothelial cell types and 2) metformin prevents this PTP opening-related cell death. We propose that metformin improves diabetes-associated vascular disease both by lowering blood glucose and by its effect on PTP regulation.

Cell Death↗
PubMed2004

Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study.

Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.

Cell Death↗
PubMed2004

Opening of the mitochondrial permeability transition pore induces reactive oxygen species production at the level of the respiratory chain complex I.

We have investigated the consequences of permeability transition pore (PTP) opening on the rate of production of reactive oxygen species in isolated rat liver mitochondria. We found that PTP opening fully inhibited H(2)O(2) production when mitochondria were energized both with complex I or II substrates. Because PTP opening led to mitochondrial pyridine nucleotide depletion, H(2)O(2) production was measured again in the presence of various amounts of NADH. PTP opening-induced H(2)O(2) production began when NADH concentration was higher than 50 microm and reached a maximum at over 300 microm. At such concentrations of NADH, the maximal H(2)O(2) production was 4-fold higher than that observed when mitochondria were permeabilized with the channel-forming antibiotic alamethicin, indicating that the PTP opening-induced H(2)O(2) production was not due to antioxidant depletion. Moreover, PTP opening decreased rotenone-sensitive NADH ubiquinone reductase activity, whereas it did not affect the NADH FeCN reductase activity. We conclude that PTP opening induces a specific conformational change of complex I that (i) dramatically increases H(2)O(2) production so long as electrons are provided to complex I, and (ii) inhibits the physiological pathway of electrons inside complex I. These data allowed the identification of a novel consequence of permeability transition that may partly account for the mechanism by which PTP opening induces cell death.

Animals↗
PubMed2004

Urinary continence after salvage radiation therapy following radical prostatectomy, assessed by a self-administered questionnaire: a prospective study.

OBJECTIVE: To evaluate urinary continence after salvage radiotherapy following radical prostatectomy (RP) for clinically localized prostate cancer. PATIENTS AND METHODS: In all, 145 men had a retropubic RP in our department between 1992 and 2000. From this group, salvage radiotherapy with the dose of 65 Gy was given to 18 patients for a rising prostatic specific antigen (PSA) level. The mean (range) age at RP was 63 (50-72) years and the initial PSA level 14.95 (4.8-34) ng/mL. The radiotherapy was given at 46 (6-96) months after RP. A self-administered questionnaire about their urinary status was mailed to the patients before and 18 months after radiotherapy. The mean follow-up after radiotherapy was 34 (20-70) months. RESULTS: Before radiotherapy, 17 patients were continent (defining continence as no regular use of pads). After salvage radiotherapy, 16 men had had no change in their urinary status, even for the one patient using pads. One patient with stress urinary incontinence showed a slight worsening of his urinary status after radiotherapy. Another patient who was continent before radiotherapy developed urgency with no urinary leakage. Fourteen men stated that they were very satisfied or satisfied about their urinary status after radiotherapy and four were mildly satisfied. Nine would undergo radiotherapy again even with their present continence status and nine probably would. CONCLUSION: Using an anonymous self-administered questionnaire, salvage radiotherapy for a rising PSA level seems to be safe and does not worsen the continence achieved after RP in most patients.

Aged↗
PubMed2004

[Perirenal extension of a pelvic lymphocele after radical prostatectomy].

Lymphocele is a rare symptomatic complication of iliopelvic lymph node dissection during radical prostatectomy. The authors report a case of pelvic lymphocele with perirenal extension diagnosed 6 months after the operation and successfully treated by laparoscopic marsupialisation. The possibility of lymphocele must be considered in any patient presenting with abdominopelvic symptoms after iliopelvic lymph node dissection, even several months after the operation. The treatment of choice is laparoscopic marsupialisation, in the absence of infection.

Aged↗
PubMed2004

[Endocrine therapy for localized or locally advanced prostate cancer].

The place of endocrine therapy, either alone or in combination with radiotherapy and surgery, remains highly controversial in the treatment of non-metastatic prostate cancer. The authors review the results of isolated endocrine therapy or associated with local therapy. At the present time, there are few arguments in favour of the use of endocrine therapy in the following situations: isolated treatment of localized or locally advanced cancer prior to radical prostatectomy, after radical prostatectomy. Current data suggest a benefit of endocrine therapy in combination with radiotherapy in patients with high-grade localized or locally advanced cancer.

Androgen Antagonists↗
PubMed2004

[Prostatic cancer].

Explore the source record for details and available documents.

Antineoplastic Agents↗
PubMed2003

Diagnosis of perforated enterocystoplasty.

In the operation of enterocystoplasty, now widely practised, segments of bowel are used to augment or replace the urinary bladder. An occasional complication is perforation, and this may present in non-specialist settings. We investigated the management of spontaneous perforations among 264 patients with enterocystoplasty followed by one surgeon for 2-18 years. Patients' charts were examined for data on presentation, diagnosis and treatment. 10 patients had thirteen perforations; data were available for nine perforations in 9 patients. Mean time from enterocystoplasty to perforation was 45 months. Presentation was shoulder pain in 1 and abdominal pain (with or without fever) in 8. Perforation was diagnosed without delay in 3, but the initial diagnosis was urinary tract infection in 4 and small-bowel obstruction in 2. Ultrasound was the most useful investigation being diagnostic in 6 of 7 cases; contrast cystography showed a leak in only 2 of the 6 patients in whom it was performed. Treatment was successful in 8 cases (surgery 6; percutaneous drainage 2); 1 patient, who remained undiagnosed, was treated medically and died. Patients with enterocystoplasty need to be educated about this potentially lethal complication, so that they can alert non-specialist clinicians to what may have happened. In any patient with enterocystoplasty who reports abdominal pain or shoulder pain, perforation has to be ruled out.

Abdominal Pain↗
PubMed2003

[Hormonal therapy in metastatic prostatic cancer].

For more than sixty years, the treatment of advanced prostate cancer has been based on androgen deprivation. Despite this long follow-up, the optimal treatment regimen is still a subject of controversy. Treatments inducing chemical castration have been greatly improved over recent years with the appearance of LH-RH analogues, non-steroidal antiandrogens and finally, more recently, LH-RH antagonists and Gn-RH agonists. The modalities of endocrine therapy have also evolved: early or late, total, intermittent or even targeted to the prostate by the use of non-steroidal antiandrogens alone. In this article, the authors review the results of each of these various treatment options in order to place them in perspective with the real benefit that can be expected in terms of quality of life and survival in patients with metastatic disease.

Gonadotropin-Releasing Hormone↗
PubMed2002

Mirtazapine, but not fluvoxamine, normalizes the blunted REM sleep response to clonidine in depressed patients: implications for subsensitivity of alpha(2)-adrenergic receptors in depression.

To determine whether alpha(2)-adrenergic receptor (alpha2AR) subsensitivity is a state or a trait marker of depression, we consecutively challenged 32 drug-free depressed patients with a clonidine REM suppression test (CREST). We then treated the patients with fluvoxamine, a selective serotonin reuptake inhibitor, or mirtazapine, a selective alpha(2)-adrenergic receptor antagonist. The first 10 patients from each treatment group who recovered were given a second challenge test. The CREST values of the two treatment groups at each time point were compared, and also compared with the CREST values of a group of 10 normal subjects. Before treatment, the REM sleep response to clonidine in the two groups of patients was significantly blunted compared with the REM sleep response in the healthy subjects. After treatment, there was still an abnormal REM sleep response to clonidine in the fluvoxamine-treated patients, despite clinical recovery, but there was a normalized REM sleep response in the mirtazapine-treated patients. These results are compatible with the hypothesis that alpha2AR subsensitivity is a trait marker of depression and suggest that the effects of these two antidepressants on alpha2AR sensitivity may not be linked to the alleviation of depression.

Adrenergic alpha-Agonists↗
PubMed2002

Bupivacaine myotoxicity is mediated by mitochondria.

We have investigated the effects of the myotoxic local anesthetic bupivacaine on rat skeletal muscle mitochondria and isolated myofibers from flexor digitorum brevis, extensor digitorum longus, soleus, and from the proximal, striated portion of the esophagus. In isolated mitochondria, bupivacaine caused a concentration-dependent mitochondrial depolarization and pyridine nucleotide oxidation, which were matched by an increased oxygen consumption at bupivacaine concentrations of 1.5 mm or less at pH 7.4, whereas respiration was inhibited at higher concentrations. As a consequence of depolarization, bupivacaine caused the opening of the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death. In intact flexor digitorum brevis fibers bupivacaine caused mitochondrial depolarization and pyridine nucleotides oxidation that were matched by increased concentrations of cytosolic free Ca(2+), release of cytochrome c, and eventually, hypercontracture. Both mitochondrial depolarization and cytochrome c release were inhibited by cyclosporin A, indicating that PTP opening rather than bupivacaine as such was responsible for these events. Similar responses to bupivacaine were observed in the soleus, which is highly oxidative. In contrast, fibers from the esophagus (which we show to be more fatigable than flexor digitorum brevis fibers) and from the highly glycolytic extensor digitorum longus didn't undergo pyridine nucleotide oxidation upon the addition of bupivacaine and were resistant to bupivacaine toxicity. These results suggest that active oxidative metabolism is a key determinant in bupivacaine toxicity, that bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the PTP and Ca(2+) dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role.

Anesthetics, Local↗