[How far can we go to oocyte donation? Debates on the risks of late pregnancies]. / Jusqu'où peut-on aller en don d'ovocytes? Réflexions sur les risques des grossesses tardives.

In France, there is a decline in first-time motherhood influenced by many sociocultural factors thus leading to a reproductive age where fertility decreases and which increase the risks associated with late pregnancy. The oocyte donation in France is subject to The Bioethic law granting no support in infertility beyond past 43 years. Thus, to satisfy their need for maternity, the French use a gift abroad. Then we will report the case of a pregnancy obtained by an oocyte donation, after 42 years, which was complicated. We will discuss the importance of taking into account the risk factors before a support to ART, and the ethical issues raised by this case. After a brief review of French legislative framework governing the practice of oocyte donation, we will evoke ways to improve the coverage needs of it in France.

Pharmacological characterization of 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a high-affinity antagonist selective for κ-opioid receptors.

2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242) is a novel κ-opioid receptor (KOR) antagonist with high affinity for human (3 nM), rat (21 nM), and mouse (22 nM) KOR, a ∼ 20-fold reduced affinity for human µ-opioid receptors (MORs; K(i) = 64 nM), and negligible affinity for δ-opioid receptors (K(i) > 4 µM). PF-04455242 also showed selectivity for KORs in vivo. In rats, PF-04455242 blocked KOR and MOR agonist-induced analgesia with ID(50) values of 1.5 and 9.8 mg/kg, respectively, and inhibited ex vivo [(3)H](2-(benzofuran-4-yl)-N-methyl-N-((5S,7R,8R)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]decan-8-yl)acetamide ([(3)H]CI977) and [(3)H](2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl) propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3-phenylpropanamide ([(3)H]DAMGO) binding to KOR and MOR receptors with ID(50) values of 2.0 and 8.6 mg/kg, respectively. An in vivo binding assay was developed using (-)-4-[(3)H]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(3)H]PF-04767135), a tritiated version of the KOR positron emission tomography ligand (-)-4-[(11)C]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(11)C]GR103545) in which PF-04455242 had an ID(50) of 5.2 mg/kg. PF-04455242 demonstrated antidepressant-like efficacy (mouse forced-swim test), attenuated the behavioral effects of stress (mouse social defeat stress assay), and showed therapeutic potential in treating reinstatement of extinguished cocaine-seeking behavior (mouse conditioned place preference). KOR agonist-induced plasma prolactin was investigated as a translatable mechanism biomarker. Spiradoline (0.32 mg/kg) significantly increased rat plasma prolactin levels from 1.9 ± 0.4 to 41.9 ± 4.9 ng/ml. PF-04455242 dose-dependently reduced the elevation of spiradoline-induced plasma prolactin with an ID(50) of 2.3 ± 0.1 mg/kg, which aligned well with the ED(50) values obtained from the rat in vivo binding and efficacy assays. These data provide further evidence that KOR antagonists have potential for the treatment of depression and addiction disorders.

Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

[Gynecological and breast cancer in the department of Somme]. / Cancers gynécologiques et mammaires dans le département de la Somme.

BACKGROUND: Breast and gynecological tumors are the most common cancers in women. The aim of this study was to show the epidemiologic features of gynecological and breast cancers in the French administrative district of La Somme. METHODS: This study focused on the 1982-1999 period. Incidence, mortality and survival rates were calculated. RESULTS: In 1997-1999, the world standardized breast incidence and mortality rates were 81.6 and 20.2 per 100,000 females per year. Breast and genital tract cancers accounted for 47% of all cancers in women. The incidence and mortality of uterine cervix cancers showed a clear decline over the past 10 years, whereas the trend of breast cancers was dominated by continuing increase. However, mortality was stable for breast cancers. Five year relative survival rates were respectively 80% for breast cancers, and 68%, 76%, 38%, for uterine cervix, uterine body and ovary cancers respectively. Incidence and mortality rates in Somme were in the middle risk range of other cancer French registries. CONCLUSION: The results of this study indicate that genital tract and breast cancers constitute a serious public health problem pointing out the importance of screening activities in the Somme area.

Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement.

A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.

Treatment of CIN after menopause.

OBJECTIVES: To characterise cervical neoplasia after the menopause. MATERIAL AND METHODS: We studied our computerized files of CIN from 1993-1999. Of the 738 cases, 78 were after menopause (11%). RESULTS: We made a report of the specificities of cytological and colposcopical diagnosis and the treatment given. Cytological results are the same after and before menopause. On the other hand, colposcopical patterns are significantly different because of a particular topography of the lesion. The majority of CIN after menopause are localized in the canal and are 44% versus 12. Incomplete conization is no more frequent after menopause than before. However, stenosis is higher: 73% unseen junction against 15%. Therefore, at this age, a total hysterectomy could possibly be preferable. In this study, we will outline the positive and the negative aspects of this form of treatment.

(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine receptor.

Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.

Phorboxazole synthetic studies. 1. Construction of a C(3-19) subtarget exploiting an extension of the Petasis-Ferrier rearrangement.

[formula: see text] In this, the first of two letters, we outline our overall strategy for the total synthesis of phorboxazoles A (1) and B (2), rare oxazole-containing macrolides possessing extraordinary antimitotic activity, and describe the assembly of a C(3-19) subtarget (-)-5 for the total synthesis of phorboxazole A. The synthesis of (-)-5 was achieved in 15 linear steps (12% overall yield), exploiting a modification of the Petasis-Ferrier rearrangement to construct the C(11-15) cis-tetrahydropyran. Dimethylaluminum chloride (Me2AlCl) proved to be the Lewis acid of choice for the Petasis-Ferrier rearrangement.

Phorboxazole synthetic studies. 2. Construction of a C(20-28) subtarget, a further extension of the Petasis-Ferrier rearrangement.

[formula: see text] In this, the second of two Letters, we describe the efficient assembly of (+)-4, a C(20-28) subtarget for the total synthesis of phorboxazoles A (1) and B (2). The synthesis was achieved in 12 linear steps (20% overall yield) via Petasis-Ferrier rearrangement of an E/Z mixture of trisubstituted enol ethers (15) to assemble the C(22-26) cis-tetrahydropyran. A mechanism for the observed diastereoconvergence of 15 is proposed. In addition, a new tactic for the synthesis of enol ethers (e.g., 15) based on the elegant work of Julia is described.

Use of an experimental model of chlamydial salpingitis in mice for the evaluation of activity of antibiotics and anti-inflammatory drugs on fertility.

An experimental animal model has been used to study the separate and combined use of antibiotics and anti-inflammatories in the treatment of salpingitis. The addition of an anti-inflammatory did not seem to help preserve fertility.

[Use of an experimental Chlamydia trachomatis salpingitis model for evaluating the effectiveness of antibiotics and anti-inflammatory agents on fertility]. / Utilisation d'un modèle de salpingite expérimentale à Chlamydia trachomatis pour l'évaluation de l'efficacité des antibiotiques et des anti-inflammatoires sur la fertilité.

OBJECTIVES: An experimental model of Chlamydia trachomatis salpingitis was developed in mice to study the effect of combination antibiotic and antiinflammatory therapy on restoring fertility after tubal infection. METHODS: The mice were infected by injection via the ovarian bursa with a suspension containing a human strain of Chlamydia trachomatis sevar F. After treatment with antibiotics alone or in combination with antiinflammatory agents, fertility was studied at 4 months. RESULTS: With doxycycline and ofloxacine, there was not a significant difference in fertility between animals treated with antibiotics alone and those treated with antibiotics and antiinflammatory agents. However, a piroxicam and azythromycin combination improved fertility with a longer delay than with azythromycin alone. The most important factor appeared to be the antibiotic treatment. CONCLUSION: Associating an antiinflammatory agent was not shown to have a beneficial effect in reducing infertility after Chlamydia trachomatis salpingitis.

[Tuberculosis of the breast]. / Tuberculose mammaire.

The authors report a case of tuberculosis of the breast in a patient aged 71. The case described is an example of a rare form of extra pulmonary tuberculosis whose diagnosis can pose problems. In view of the recent increase in the incidence of tuberculosis in certain developed countries and the growth in the proportion of cases of extra pulmonary tuberculosis especially in HIV sero-positive individuals an observation such as this is useful in that it recalls for clinicians the fact that tuberculosis may present in very unusual forms which are easily forgotten.

Detection of benzo[a]pyrene-DNA adducts in human placenta and umbilical cord blood.

Placenta constitutes a vital organ of exchange between mother and foetus. In addition to this favourable effect for foetal development, placenta indirectly may allow transfer of several maternal blood xenobiotics. Human placenta and umbilical cord blood are interesting models for investigating maternal environment and the metabolism, the bioactivation and the transfer of carcinogens such as polycyclic aromatic hydrocarbons. We used them to assess the effect of a woman's smoking on the foetus. Few studies cover this subject. In pregnant women who have continued to smoke, benzo[a]pyrene compound of cigarette smoke is metabolically activated to diol-epoxide derivative: benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide, ultimate carcinogen (BPDE-I). This derivative is covalently fixed on DNA and gives BPDE-I-DNA adducts. By a competitive immunoassay technique, we determined BDPE-I-DNA adducts in 20 samples of placenta and umbilical cord blood from women who smoked (n = 15) and who did not (n = 10). Tobacco consumption was checked by urinary cotinine determination. In the group of smokers levels of adducts were found in 13 specimens of placenta (from 10 to 60 fmol/50 micrograms of DNA) and 12 umbilical cord blood (from 10 to 22.15 fmol/50 micrograms of DNA) samples. These results indicate that a mother's tobacco consumption is linked to the accumulation of BPDE-I-DNA adducts in the placenta, which are seen in smaller quantities in the umbilical cord blood, probably because of the metabolic capacity of the placenta and the transfer of B[a]P from the mother to the foetus.

[A new therapeutic strategy using a ofloxacin-amoxicillin-clavulanic acid combination in the treatment of upper gynecologic infections. Apropos of 123 cases]. / Nouvelle stratégie thérapeutique par l'association ofloxacine-amoxicilline-acide clavulanique dans le traitement des infections gynécologiques hautes. A propos de 123 cas.

OBJECTIVE: To evaluate a new antibiotic strategy with a combination of ofloxacin + co-amoxiclav in the treatment of pelvic infectious diseases. DESIGN: An open-non-comparative multicentre (10) study. SUBJECTS: 123 patients (118 salpingitis and 5 endometritis) were included clinical, laparoscopic and bacteriological assessments were performed before treatment and a laparoscopic control was done in 35% of cases. Among positive bacteriological samples before treatment 48.7% C. trachomatis were isolated; 56.1% of salpingitis were considered as severe (COGIT score > 6). TREATMENT: Patients received at entry oral ofloxacin 200 mg bid in combination with parenteral co-amoxiclav 2 to 4 g following by oral route. Total duration of treatment was 21 days. RESULTS: With respectively 97.2% and 91.6% satisfactory clinical and bacteriological results, this combination should take a major place in the treatment of pelvic infectious diseases.

[Changing management of breech presentation in a primipara]. / Evolution de la conduite à tenir en présentation du siège chez la primipare.

The authors investigate the changing management based on a score including the prognostic items in a primiparous woman with a breach presentation. The study involved two series: one from 1970 to 1975, including 185 breach position primiparous women before the score was established, and the other, dating from 1982 to 1988, consisting of 145 breach position primiparous women after this score came into use. The use of the score has tripled the number of cesareans but reduced neonatal morbidity. In contrast, the authors note a slight increase in maternal morbidity, related to the increased cesarean rate.

[Role of the thyroid in first-trimester miscarriage]. / Rôle de la thyroïde dans les fausse-couches du premier trimestre.

In case of maternal hypothyroidism, the number of miscarriages is higher and reaches 50% in this multicenter study. Several hypotheses are advocated in order to explain this frequent occurrence: the most remarkable is that as substitute treatment is very effective and decreases noticeably the risk of abortion. In case of maternal hypothyroidism, the frequency of abortions in this study reaches 35% before the disease is diagnosed and this figure is not modified (35%) after the diagnosis is made and the treatment initiated. Finally, in case of goiter or euthyroid nodules, there is also a relatively high number of spontaneous abortions. Therefore, there are still a number of unknown factors regarding the role of dysthyroidisms in spontaneous first-trimester abortions.

[Proposal for a new therapeutic strategy in high genital infections]. / Proposition d'une nouvelle stratégie thérapeutique dans les infections génitales hautes.

78 cases of acute salpingitis were treated with the association Oflocet-Augmentin in a multicenter study. An accurate clinical and bacteriological evaluation was carried out prior to the treatment and a control laparoscopy was performed in 31 cases. A Chlamydia infection was responsible in 56 p. cent of the cases; only one bacteria was identified in 56 cases and an association of two or three bacteria in 15 cases; in 7 cases, no bacteria was identified. The antibiotic association was effective in 96 p. cent of the cases, with a good clinical and biological tolerance. Three failure were reported: one in an infection secondary to a non identified bacteria, and two in Chlamydia infections where, despite the clinical cure, a positive culture persisted in the abdomen. The association Oflocet-Augmentation is therefore recommended in the treatment of high genital infections.

[Evaluation of ultrasonography. Apropos of a continuous series of 1,000 pregnancies]. / Evaluation de l'échographie. A propos d'une série en continu de 1,000 grossesses.

2,648 sonograms were performed in a continuous series of 1,000 patients, all of whom had delivered in the department between March 1, 1988 and September 1, 1988; pregnancies resulting in a spontaneous miscarriage, extra-uterine pregnancy, therapeutic abortion as well as invasive sonographies, are excluded. Most patients underwent two or three sonograms during their pregnancy. 74 per cent of the requests come from specialists. The main indications are either systematic (67.7%) or result from early manifestations (25.1%). 12.6 per cent of the sonograms are performed before 12 weeks of amenorrhea, including 36.7 per cent performed systematically, and could be performed at a later date. 90 per cent of the term modifications were correctly indicated, and there were early manifestations in 60 per cent of the cases. 45.1 per cent of intra-uterine growth delays were detected and there were early manifestations in 50 per cent of the cases. 41.6 per cent of the malformations were diagnosed on sonograms. Renal malformations are easily recognized; this is not true of cardiac malformations. 96 per cent of the patients were justifiably reassured or worried. Ultrasonography presents a good sensitivity for term modifications, macrosomia, placental insertion anomalies. The sensitivity is less for intra-uterine growth delays and fetal malformations.