[Anomalies of the male internal genital organs and their impact on fertility].
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Child↗
Biomedical subjects
E Fontaine
Publications and source records attributed to E Fontaine.
Genotypic correlates of resistance to HIV-1 protease inhibitors on longitudinal data: the role of secondary mutations.
Direct sequencing of the pol gene was assessed retrospectively with protease inhibitor susceptibility in a longitudinal study. A total of 134 samples from 26 patients were analysed at regular intervals up to 2 years. Patients were included in virological failure despite indinavir, ritonavir or saquinavir based triple-drug therapy. Both the type and number of certain secondary protease mutations modulated the effect of primary mutations on phenotypic resistance. This was notably applicable to L101/V, and to lesser extents to A711V/T. However, combinations of primary mutations, including 154V could predict resistance to the drug used and nelfinavir in more than 80%. In contrast, in vitro cross-resistance to amprenavir was rarely encountered. In addition, there was a relationship between a higher number of key mutations and poorer virological and clinical outcomes, respectively, from 6 and 3 months on. The key mutations were the protease mutations independently conferring phenotypic resistance and/or the reverse transcriptase mutations predicting treatment outcome. This relationship was independent from drug history, viral load and CD4 cell count measurements. In summary, even on a small sample size, sequence-based genotyping seems to be a good prognostic marker when performed longitudinally. In the context of primary resistance mutations, including additional secondary mutations, it may be useful in the prediction of phenotypic and clinical resistance. This should be assessed to optimize treatment monitoring before emergence of broadly cross-resistant virus.
Acquired Immunodeficiency Syndrome↗
Exogenous Mg-ATP induces a large inhibition of pyruvate kinase in intact rat hepatocytes.
Mg-ATP infusion in vivo has been reported to be beneficial both to organ function and survival rate in various models of shock. Moreover, a large variety of metabolic effects has been shown to occur in several tissues due to purinergic receptor activation. In the present work we studied the effects of exogenous Mg-ATP in rat liver cells perifused with dihydroxyacetone to investigate simultaneously gluconeogenetic and glycolytic pathways. We found a significant effect on oxidative phosphorylation as characterized by a decrease in oxygen consumption rate and in the cellular ATP-to-ADP ratio associated with an increase in lactate-to-pyruvate ratio. In addition, exogenous Mg-ATP induced rapid and reversible inhibition of both gluconeogenesis and glycolysis. The main effect on gluconeogenesis was located at the level of the fructose cycle, whereas the decrease in glycolysis was due to a strong inhibition of pyruvate kinase. Although pyruvate kinase inhibition induced by exogenous Mg-ATP was allosteric when assessed in vitro after enzyme extraction, we found a large decrease in the apparent maximal velocity when kinetics were assessed in vivo in intact perifused hepatocytes. This newly described short-term regulation of pyruvate kinase occurs only in the intact cell and may open new potentials for the pharmacological regulation of pyruvate kinase in vivo.
Adenosine Diphosphate↗
Three classes of ubiquinone analogs regulate the mitochondrial permeability transition pore through a common site.
To identify the structural features required for regulation of the mitochondrial permeability transition pore (PTP) by ubiquinone analogs (Fontaine, E., Ichas, F., and Bernardi, P. (1998) J. Biol. Chem. 40, 25734-25740), we have carried out an analysis with quinone structural variants. We show that three functional classes can be defined: (i) PTP inhibitors (ubiquinone 0, decylubiquinone, ubiquinone 10, 2,3-dimethyl-6-decyl-1,4-benzoquinone, and 2,3,5-trimethyl-6-geranyl-1,4-benzoquinone); (ii) PTP inducers (2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone and 2,5-dihydroxy-6-undecyl-1,4-benzoquinone); and (iii) PTP-inactive quinones that counteract the effects of both inhibitors and inducers (ubiquinone 5 and 2,3,5-trimethyl-6-(3-hydroxyisoamyl)-1,4-benzoquinone) . The structure-function correlation indicates that minor modifications in the isoprenoid side chain can turn an inhibitor into an activator, and that the methoxy groups are not essential for the effects of quinones on the PTP. Since the ubiquinone analogs used in this study have a similar midpoint potential and decrease mitochondrial production of reactive oxygen species to the same extent, these results support the hypothesis that quinones modulate the PTP through a common binding site rather than through oxidation-reduction reactions. Occupancy of this site can modulate the PTP open-closed transitions, possibly through secondary changes of the PTP Ca(2+) binding affinity.
Animals↗
Chronic ethanol ingestion increases efficiency of oxidative phosphorylation in rat liver mitochondria.
The efficiency of oxidative phosphorylation was compared between rats chronically fed with ethanol and controls. (i) Results showed that the liver mitochondria state 4 respiratory rate was strongly inhibited, while the corresponding proton-motive force was not affected; (ii) the cytochrome oxidase content and activity were decreased and (iii) the oxidative-phosphorylation yield was increased in the ethanol exposed group. Furthermore, oxidative phosphorylation at coupling site II was not affected by ethanol. Cytochrome oxidase inhibition by sodium-azide mimicked the effects of ethanol intoxication in control mitochondria. This indicates that the decrease in cytochrome oxidase activity induced by ethanol intoxication directly increases the efficiency of oxidative phosphorylation.
Alcohol Drinking↗
Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.
We report here a new mitochondrial regulation occurring only in intact cells. We have investigated the effects of dimethylbiguanide on isolated rat hepatocytes, permeabilized hepatocytes, and isolated liver mitochondria. Addition of dimethylbiguanide decreased oxygen consumption and mitochondrial membrane potential only in intact cells but not in permeabilized hepatocytes or isolated mitochondria. Permeabilized hepatocytes after dimethylbiguanide exposure and mitochondria isolated from dimethylbiguanide pretreated livers or animals were characterized by a significant inhibition of oxygen consumption with complex I substrates (glutamate and malate) but not with complex II (succinate) or complex IV (N,N,N',N'-tetramethyl-1, 4-phenylenediamine dihydrochloride (TMPD)/ascorbate) substrates. Studies using functionally isolated complex I obtained from mitochondria isolated from dimethylbiguanide-pretreated livers or rats further confirmed that dimethylbiguanide action was located on the respiratory chain complex I. The dimethylbiguanide effect was temperature-dependent, oxygen consumption decreasing by 50, 20, and 0% at 37, 25, and 15 degrees C, respectively. This effect was not affected by insulin-signaling pathway inhibitors, nitric oxide precursor or inhibitors, oxygen radical scavengers, ceramide synthesis inhibitors, or chelation of intra- or extracellular Ca(2+). Because it is established that dimethylbiguanide is not metabolized, these results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.
Animals↗
Diagnosis and prediction of recurrence and progression in superficial bladder cancers with DNA image cytometry and urinary cytology.
OBJECTIVE: To investigate the roles of urinary cytology and image cytometric analysis of nuclear DNA ploidy pattern in the diagnosis and prediction of recurrence and/or progression of superficial bladder cancers. PATIENTS AND METHODS: Aliquots of catheterized urine from 92 patients with primary (23) or previous (69) superficial bladder cancers were assessed using urine cytology and image-analysis cytometry independently. RESULTS: Of the 23 primary superficial transitional cell carcinomas (TCCs), 11 (48%) were detected by urinary cytology while 12 (52%) were detected by image-analysis cytometry (P>0.05) and 13 (57%) were revealed by combined cytology and cytometry. Of 42 recurrent superficial TCCs, 29 (69%) were detected by urinary cytology, whilst 19 (45%) were diagnosed by cytometry (P<0.05) and 29 (69%) by combined cytology and cytometry. The degree of ploidy in relation to pathological stage and/or grade showed an increasing frequency of aneuploid pattern in more invasive and undifferentiated tumours, but with no statistical significance (P>0.05). The positivity of DNA image cytometry had no significant association (P>0.05) with tumour recurrence and/or progression. CONCLUSIONS: DNA image cytometry can provide a limited but not significant advantage over urinary cytology in the detection of primary superficial TCCs, but it does not seem to be indicated for the prediction of tumour recurrence and/or progression.
Aneuploidy↗
The effect of intestinal urinary reservoirs on renal function: a 10-year follow-up.
OBJECTIVE: To study the effect of the storage of urine in intestinal reservoirs on long-term renal function and the possible causes of deterioration. PATIENTS AND METHODS: Eighty-seven patients (aged 4-35 years) with bladder exstrophy who underwent reconstruction of the lower urinary tract using a bowel segment were enrolled in a prospective protocol. The glomerular filtration rate (GFR) was measured before and after surgery at 1, 2, 5 and 10 years using 51Cr-ethylenediamine tetra-acetic acid. Patients with a decline in GFR of > 5% were investigated to identify the cause. RESULTS: Of 58 patients with a follow-up of > or = 10 years, 53 were evaluable, four having been lost to follow-up and one refusing to accept the protocol. In these 53 patients, the mean (SD) GFR decreased from 97. 9 (20.4) to 92.9 (23.6) mL/min/1.73 m2 (P = 0.24). However, this decrease was accounted for by 10 patients (19%) whose GFR fell by > or = 20% over the 10 years. The causes of renal deterioration in these 10 patients were; chronic retention and/or infection caused by inadequate catheterization in poorly compliant patients (five), uretero-ileal stenosis (one), a high-pressure reservoir (one) and uncertain causes (three). CONCLUSIONS: For 80% of the patients, the storage of urine in intestinal reservoirs did not change renal function for at least 10 years. However, approximately 20% of patients had some deterioration in renal function during the 10-year follow-up, usually from identifiable and remediable causes. The storage of urine in bowel does not appear to be inherently damaging to kidney function. Patients with an enterocystoplasty need regular monitoring of renal function; when deterioration is detected the urinary tract must be functionally assessed.
Adolescent↗
Urinary continence following radical prostatectomy assessed by a self-administered questionnaire.
OBJECTIVES: A total aim of this study was to assess the incidence of urinary incontinence in patients following radical prostatectomy and determine the factors that may influence this incidence. METHODS: A total of 135 men underwent radical retropubic prostatectomy at our center between 1987 and 1997. 120 patients were sent a questionnaire regarding preoperative and postoperative voiding habits. Data collected included preoperative and postoperative continence status, interval to postoperative continence status, associated urinary symptoms, willingness to undergo radical prostatectomy again if need be and additional postoperative procedures. Patient age, date of surgery, number of neurovascular bundles resected at prostatectomy and duration of follow-up were also noted. RESULTS: Of the 120 patients, 116 (96.7%), a mean of 65.2 (range 48-76) years old, responded to the questionnaire. Mean follow-up was 4.3 years (range 1-10.8). Continence was defined as no regular use of pads. Our overall urinary incontinence rate was 14.4%. Of the respondents, 88. 8% (103/116) had achieved final continence status by 6 months postoperatively, and 95% (110/116) would undergo surgery again if need be. Of the patients considered incontinent postoperatively, 66. 6% had associated urgency. Age, year of surgery, number of neurovascular bundles resected at prostatectomy, preoperative urinary leakage of postvoiding dribbling, postoperative pelvic floor exercises, and anastomotic stricture had no significant impact on postoperative continence status. CONCLUSIONS: Using an anonymous self-administered questionnaire, we found a 14.4% incontinence rate after radical prostatectomy. These results allow patients to have realistic expectations when counseled prior to this operation.
Aged↗
Diagnosis and prediction of recurrence and progression in superficial bladder cancers with DNA image cytometry and urinary cytology
OBJECTIVE: To investigate the roles of urinary cytology and image cytometric analysis of nuclear DNA ploidy pattern in the diagnosis and prediction of recurrence and/or progression of superficial bladder cancers. PATIENTS AND METHODS: Aliquots of catheterized urine from 92 patients with primary (23) or previous (69) superficial bladder cancers were assessed using urine cytology and image-analysis cytometry independently. RESULTS: Of the 23 primary superficial transitional cell carcinomas (TCCs), 11 (48%) were detected by urinary cytology while 12 (52%) were detected by image-analysis cytometry (P > 0.05) and 13 (57%) were revealed by combined cytology and cytometry. Of 42 recurrent superficial TCCs, 29 (69%) were detected by urinary cytology, whilst 19 (45%) were diagnosed by cytometry (P < 0.05) and 29 (69%) by combined cytology and cytometry. The degree of ploidy in relation to pathological stage and/or grade showed an increasing frequency of aneuploid pattern in more invasive and undifferentiated tumours, but with no statistical significance (P > 0.05). The positivity of DNA image cytometry had no significant association (P > 0.05) with tumour recurrence and/or progression. CONCLUSIONS: DNA image cytometry can provide a limited but not significant advantage over urinary cytology in the detection of primary superficial TCCs, but it does not seem to be indicated for the prediction of tumour recurrence and/or progression.
Journal Article↗
Role of the bladder in delayed failure of kidney transplants in boys with posterior urethral valves.
PURPOSE: There is a tendency toward less favorable long-term graft function in patients with posterior urethral valves than in controls. We studied the role of the bladder in boys who underwent transplantation by simultaneously evaluating renal graft and voiding function. MATERIALS AND METHODS: Between 1972 and 1994, 66 boys with posterior urethral valves underwent kidney transplantation. Of these boys 44 with a mean age of 9.7 years who retained a functional renal graft did not undergo any surgery on the lower urinary tract except for the initial treatment of posterior urethral valves. Long-term evaluation included a voiding questionnaire, radiological assessment and serum creatinine measurement. RESULTS: Average followup was 9.01 years (range 2.4 to 19.6). There was no voiding dysfunction symptomatology in 23 boys, while 3 (14.2%) and 8 (38.1%) of the remaining 21 had daytime and nighttime frequency, respectively. Dysuria and incontinence were present in 11 (52.4%) and 12 (57.1%) patients, respectively. Urodynamics in 11 cases revealed a mean bladder compliance plus or minus standard deviation of 11.3+/-2.8 ml./cm. water. In boys with a voiding disorder mean serum creatinine increased after 5 years of followup. At 10 years after kidney transplantation mean serum creatinine was 140.3+/-36.0 and 285.7+/-36.2 micromol./l. in asymptomatic boys and those with a voiding disorder, respectively (p<0.01). CONCLUSIONS: Valve bladder has a role in the deterioration of renal transplants in boys with posterior urethral valves. In those with a voiding disorder closer followup is needed, including urodynamic and radiological studies. Bladder dysfunction, such as hypocompliance and/or hyperreflexia, requires medical or surgical treatment.
Child↗
[Treatment of ureteral calculi: report of 152 calculi].
OBJECTIVE: To define the therapeutic approach to ureteric stones. MATERIAL AND METHODS: 137 patients with 152 ureteric stones were treated between January 1990 and January 1997. Sixty seven stones (44%) were situated in the lumbar ureter, 16 stones (10%) were in the iliac ureter, 69 stones (46%) were in the pelvic ureter. These stones were treated by extracorporeal shock-wave lithotripsy (ESWL), ureteroscopy and, more rarely, ureterotomy. RESULTS: One hundred and three stones were treated in a single session, while 31 required two ESWL sessions. Treatment eliminated 82% of ureteric stones: 89% of lumbar ureteric stones, 31% of iliac stones and 85% of pelvic stones. Ureteroscopy was performed as first- or second-line treatment in 34 cases. It successfully treated 97% of ureteric stones: 100% of pelvic and lumbar stones and 91% of iliac stones. Three patients were successfully treated by ureterolithotomy for a lumbar ureteric stone and two for iliac ureteric stones. CONCLUSION: SWL is the reference treatment for stones of the lumbar ureter. Ureteroscopy is justified after failure of ESWL for stones of the pelvic and iliac ureter, as it gives excellent results.
Adult↗
[Varicocele in adolescents].
Varicocele is a frequent disease in adolescents (15%) and has a harmful effect on growth of the testis and spermatogenesis, which deteriorates with increasing exposure time to varicocele. However, only 15 to 20% of adults with varicocele are infertile. It is currently impossible to predict, among adolescents with a varicocele, those who will subsequently be infertile. Testicular hypotrophy reflects testicular repercussions, but its correlation with subsequent infertility is unknown at the present time. However, treatment of varicocele allows correction of testicular hypotrophy. Although the arguments are still only speculative, testicular hypotrophy, together with symptomatic and/or grade III varicocele, represents a logical indication for treatment of varicocele in adolescents. Many techniques can be used to occlude the varicocele in adolescents. Open retroperitoneal surgery is currently the reference method.
Adolescent↗
[Prostatic biopsies: technical modalities and conditions of the test].
UNLABELLED: Histological examination of prostate biopsies is necessary for the diagnosis of prostate cancer. The technical modalities and examination conditions of prostate biopsies were evaluated in the light of a review of the literature and the conclusions are presented in the form of standards, options and recommendations. STANDARDS: The standard or modified protocol of 6 sextant biopsies, applied as first-line investigation in all cases of stage T1c or T2 prostate cancer is a standard procedure and remains a reproducible, effective and well tolerated method for diagnosis and staging. Rectal preparation by enema and prophylactic antibiotics before the examination decrease the risk of infectious complications. In its usual modality used for the majority of patients, biopsies are performed as an outpatient procedure, with or without local anaesthesia, with ultrasound guidance via a transrectal approach using an 18 Gauge needle (pink colour code), mounted on an automatic biopsy gun and especially sampling the posterior and lateral zone. The patient must be given written information explaining the risks and management of possible complications following this examination. OPTIONS: Local, regional or general anaesthesia may be necessary in a minority of cases, either in the context of a protocol of extensive systematized biopsies (more than 10 biopsies), or in the case of repeated examination, or when preferred by the patient. Modified extensive protocols (sextant plus posterolateral zones or sextant plus anterior zones) applied to all cases as first-line procedure is a useful option, particularly when: 1) a first series of biopsies was negative 2) PSA is < or = 10 ng/ml and digital rectal examination is normal (sextant plus posterolateral zones) 3) the prostate is larger than 50 cm3 (sextant plus anterior zones). The transperineal approach is less reliable for detection and staging, and is used when the transrectal approach is contraindicated. When curative treatment is not considered (life expectancy < 10 years, patient's choice, stage T3, T4), the number of biopsies can be decreased. Transurethral resection of the prostate is not recommended as first-line procedure for the diagnosis of prostate cancer. RECOMMENDATIONS: Written information given to the patient during the visit prior to biopsy to explain the objectives, practical modalities and risks of prostate biopsies facilitates the patient's cooperation during the examination and increases its tolerance.
Biopsy, Needle↗
Progress on the mitochondrial permeability transition pore: regulation by complex I and ubiquinone analogs.
This review summarizes recent progress on the regulation of the mitochondrial permeability transition pore, an inner membrane channel that may play a role in cell death. We briefly cover its key control points as emerged over the last few years from studies on isolated mitochondria; and describe in some detail our recent results indicating that the pore is modulated by the respiratory chain complex I and can be specifically blocked by selected ubiquinone analogs. We discuss the potential relevance of these findings for the structural definition of the permeability transition pore and illustrate the pharmacological perspectives they offer in diseases where mitochondrial dysfunction is suspected to play a key role.
Animals↗
[Urinary continence after retropubic radical prostatectomy: retrospective study with self-administered questionnaire].
OBJECTIVES: To precisely evaluate the incidence of urinary incontinence after radical prostatectomy and its impact on quality of life. MATERIAL AND METHODS: A self-administered questionnaire was sent to 116 patients operated between 1987 and 1996. Preoperative and postoperative urinary continence, the time until urinary continence was achieved, the presence of urgent micturition, the degree of discomfort caused by urinary incontinence and associated voiding disorders were assessed. RESULTS: The questionnaire response rate was 96.6%. The urinary incontinence rate (continuous use of pads) was 13.4%. No predictive factor for postoperative urinary incontinence was identified. Urge incontinence was present in 31.3% of cases. 85% of patients claimed to be satisfied with the operation and 95.4% declared that they would be willing to undergo radical prostatectomy again. CONCLUSION: The incidence of urinary incontinence after radical prostatectomy is acceptable and the morbidity that it generates is well tolerated and has little impact on quality of life.
Aged↗
A ubiquinone-binding site regulates the mitochondrial permeability transition pore.
We have investigated the regulation of the mitochondrial permeability transition pore (PTP) by ubiquinone analogues. We found that the Ca2+-dependent PTP opening was inhibited by ubiquinone 0 and decylubiquinone, whereas all other tested quinones (ubiquinone 5, 1,4-benzoquinone, 2-methoxy-1,4-benzoquinone, 2,3-dimethoxy-1, 4-benzoquinone, and 2,3-dimethoxy-5,6-dimethyl-1,4-benzoquinone) were ineffective. Pore inhibition was observed irrespective of the method used to induce the permeability transition (addition of Pi or atractylate, membrane depolarization, or dithiol cross-linking). Inhibition of PTP opening by decylubiquinone was comparable with that exerted by cyclosporin A, whereas ubiquinone 0 was more potent. Ubiquinone 5, which did not inhibit the PTP per se, specifically counteracted the inhibitory effect of ubiquinone 0 or decylubiquinone but not that of cyclosporin A. These findings define a ubiquinone-binding site directly involved in PTP regulation and indicate that different quinone structural features are required for binding and for stabilizing the pore in the closed conformation. At variance from all other quinones tested, decylubiquinone did not inhibit respiration. Our results define a new structural class of pore inhibitors and may open new perspectives for the pharmacological modulation of the PTP in vivo.
Animals↗
Flux-force relationships in intact cells: a helpful tool for understanding the mechanism of oxidative phosphorylation alterations?
On isolated mitochondria, numerous studies of the relationships between fluxes and their associated forces have led to the description of some properties of the oxidative phosphorylation pathway. However whether such an approach can be applied to understanding the actual situation in intact living cells needs further consideration. In this study on isolated hepatocytes, we describe the dependence of the respiratory rate on the three thermodynamic forces linked to oxidative phosphorylation (i.e. the redox span over the respiratory chain, the electrical potential difference across the inner mitochondrial membrane and the free energy of ATP synthesis reaction). Even if this description is phenomenological and some objections may be raised regarding the relevance of such a bulk-phase force estimation, we present some results showing that the study of flux-force relationships in intact cells may be a helpful approach for understanding the mechanisms by which oxidative phosphorylation activity is changed.
Adenosine Triphosphate↗