[Assessment of thyroid hormones and androgens in amniotic fluid: clinical interest]. / Dosage des hormones thyroïdiennes et surrénaliennes dans le liquide amniotique: aide au diagnostic.

Ultrasound scanning is able to detect foetal goiter due either to an hypothyroidy either to an hyperthyroidy, or clitoris hypertrophia resulting from adrenal hyperplasia in female, during the second half of pregnancy. The diagnosis of these rare diseases is of interest because the treatment can be started during pregnancy. An amniotic fluid punction can be discussed and its biochemical analysis may be of interest even though very few commercial assays have been tested on amniotic fluid. Our aim was two investigate the practicability and the value of free thyroxin (FT4), thyrotropin (TSH), 17alpha hydroxyprogesterone (17-OHP) and delta 4 androstenedione (Delta4A) measurement on amniotic fluid using commercially available assays for serum. FT4 and TSH are detectable at low levels in amniotic fluid. FT4 significantly increases from 2.1 pmol/L to 4.2 pmol/L while TSH significantly decreases from 0.27 mU/L to 0.12 mU/L during the second half of pregnancy. An increase in amniotic fluid TSH concentration contributes to the diagnosis of foetal hypothyroidy while the measurement of amniotic fluid FT4 is not informative in case of foetal goiter. 17-OHP and Delta4A are present in amniotic fluid at the same level as in serum. 17-OHP significantly decreases from 1.9 ng/mL to 1 ng/mL during the second half of pregnancy while Delta4A significantly increases from 0.5 ng/mL to 0.8 ng/mL. Absence of increase in their concentrations excludes any severe adrenal hyperplasia.

Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter.

OBJECTIVES: To determine whether sonography can be used to distinguish hyperthyroidism from hypothyroidism in pregnancies with fetal goiter. METHODS: This was a retrospective study of 39 cases of fetal goiter. The majority of the mothers had Graves' disease. Fetuses were scanned for the existence of a hypertrophic thyroid gland (goiter) beginning at 22 gestational weeks. Once a goiter was diagnosed, different echographic features were analyzed and the effect of chosen treatment on fetal thyroid development was monitored. RESULTS: On color Doppler, 68.8% of hypothyroid goiters had a peripheral vascular pattern vs. 20% in cases of fetal hyperthyroidism (P = 0.0574). No hypothyroid goiter presented central vascularization whereas half the hyperthyroid goiters did (P = 0.0013). Fetal tachycardia was a good indicator of hyperthyroidism (57.1% v.s 6.3%; P = 0.0055). Delayed bone maturation was seen in hypothyroid goiters (46.9% vs. 0%; P = 0.0307), while advanced bone maturity was specific to hyperthyroid goiters (85.7% vs. 0%; P < 0.0001). Lastly, an increase in fetal movement was observed in cases of fetal hypothyroidism (43.8% vs. 0%; P = 0.0364). CONCLUSION: Based on the color Doppler pattern of goiter, fetal heart rate, bone maturation and fetal mobility, we established an ultrasound score to predict fetal thyroid function in cases of fetal goiter.

[Biologic tests for the diagnosis of amniotic fluid embolism]. / Dépistage de l'embolie amniotique: vers un test diagnostique ?

Amniotic fluid embolism is a rare, unpredictable and often lethal complication of pregnancy and childbirth. Because of its variable presentation, an early biologic test would help to establish the diagnosis. We investigated in maternal serum 4 components of amniotic fluid, i.e., alpha-fetoprotein (AFP), l'insuline like growth factor binding protein-1 (IGFBP-1), fetal fibronectin (fFN) and placental alpha1-microglobulin (PAMG-1). On the 6 cesareans controls involved, none of the makers increased after membranes section. PAMG-1 is unsuitable because its detection is always positive or doubtful even in the baseline. On the 7 cases suspected of amniotic fluid embolism, no detectable increase in any of those markers was noted in 3 cases, which is not in favour of this diagnosis. In the remaining cases, IGFBP-1 and fFN became detectable, confirming histological evidences of amniotic fluid embolism in 2 cases. The follow up of those markers in maternal blood confirmed the suspicion of amniotic fluid embolism at 21 wg in one case of ongoing pregnancy. These preliminary results point out the potential interest to assay maternal serum AFP, IGFBP-1 and fFN to confirm amniotic fluid embolism using rapid laboratory tests.

Uterine compression sutures for postpartum bleeding with uterine atony.

OBJECTIVE: To assess the efficacy of a new uterine compression suturing technique in reducing postpartum haemorrhage secondary to severe uterine atony. DESIGN: Retrospective study. SETTING: University hospital between December 2000 and March 2006. POPULATION: Twenty women with uterine atony and postpartum bleeding that did not react to usual medical management. METHODS: All these women underwent compression suturing of the uterus, in which the anterior and posterior walls of the uterus were attached so as to compress the uterus. MAIN OUTCOME MEASURES: Arrest of the bleeding, complications and fertility. RESULTS: Uterine compression suturing was sufficient to stop the bleeding immediately in 95% of the women. None of the women developed complications related to the procedure. All the women recovered normal menstrual cycles. Since uterine compression suturing, eight women have tried to conceive and six (75%) have had a term delivery. CONCLUSION: Uterine compression suturing is a simple conservative procedure to stop postpartum haemorrhage in the case of failure of the usual management. This surgical technique can be performed quickly and does not seem to decrease fertility.

Vaginal mesh erosion after transvaginal repair of cystocele using Gynemesh or Gynemesh-Soft in 138 women: a comparative study.

The objective of this study was to compare mesh erosion after transvaginal repair of cystocele using Gynemesh or Gynemesh-Soft mesh. We retrospectively analyzed 138 consecutive cases of transvaginal repair of cystocele using synthetic mesh. The study endpoint was the pathological evidence of vaginal erosion. Multiple logistic regression was used to determine independent predictors of vaginal erosion. One hundred and thirty eight women (ages 30-83 years) with cystocele between October 1999 and October 2004, from a French University Hospital, participated in this study. Cystocele repair was performed in all patients according to the technique of tension-free polypropylene mesh. The median follow-up was 32.1 months (range 7.5-59.9) in the Gynemesh group and 7.1 months (range 1-21.9) in the Gynemesh-Soft group. Vaginal erosion was reported in 27 (20%) of the patients. Anatomically, the success rate was 95% (131/138). There was no statistically significant difference between the Gynemesh and the Gynemesh-Soft meshes [the rate of vaginal erosion of the mesh was 16% (15/89) vs 24% (12/49), respectively, p=0.39]. Univariate analysis only identified age class as factor significantly associated with the probability of vaginal erosion. Multivariate analysis revealed that age class is an independent predictive factor of vaginal erosion (age > 70 years, odds ratio (OR) 3.6, 95% confidence interval (CI) 1.3-9.7, p=0.010). Furthermore cystocele stage > 2 (Baden and Walker classification) is a protective factor against vaginal erosion (OR 0.3, 95% CI 0.1-0.8, p=0.016). Thirteen symptomatic patients (13/27, 48%) necessitated a partial excision of the mesh, associated with a vaginal mucosal closure. Two patients (2/27, 7%) underwent a complete excision of the mesh. The incidence of de novo dyspareunia was 9% in patients with vaginal erosion and 11% in patient without mesh erosion (p=0.85). There was no occurrence of bladder or urethral erosion and no vaginal or pelvic infection. Isolated vaginal erosion of the mesh did not prove to be problematic. Gynemesh-Soft mesh does not decrease the incidence of vaginal erosion. Age > 70 years is an independent predictive factor of vaginal erosion. We recommend that mesh placement by vaginal route should be avoided by women with moderate cystocele. Where possible, total hysterectomy and vertical incision should also be avoided. Management of vaginal erosion is simple and is associated with a low rate of morbidity. However, patients should be informed that vaginal erosion of the mesh can occur. A multivariate analysis reveals that the incidence of vaginal erosion is not significantly different between Gynemesh and Gynemesh-Soft meshes. Other factors of erosion are analyzed.

[Vaginal mesh extrusion after transvaginal repair of cystocele using a prosthetic mesh: Treatment and functional outcomes]. / Exposition prothétique après mise en place d'une prothèse par voie vaginale pour cure de cystocèle: traitement et conséquences fonctionnelles.

OBJECTIVE: To describe management of vaginal mesh erosion following transvaginal repair of acystocele by placement of a polypropylene mesh. MATERIALS AND METHOD: Retrospective analysis of 34 consecutive cases of vaginal mesh erosion following transvaginal repair of cystocele using synthetic mesh (Gynemesh or Gynemesh-Soft). We have analyzed the results of both medical and surgical management of this complication. Furthermore, we also assessed sexual and urinary morbidity in women with mesh erosion (n = 34) and in women who had undergone the same procedure but without mesh erosion (n = 111). RESULTS: Among the 34 patients with vaginal mesh erosion, 23 (68%) have undergone local therapy using Colposeptine (Chlorquinaldol + Promestriène). In 12 (52%) cases no modification of the surface of the erosion was observed. In 6 (26%) cases, a decrease of the surface of the mesh erosion was observed. In 5 (22%) cases the mesh erosion had completely disappeared, with a follow-up of 2 to 9 months. Nineteen symptomatic patients (19/32, 59%) required partial (n = 18) or complete (n = 1) excision of the mesh, associated with vaginal mucosal closure, under general anaesthesia. Duration of operation ranged from 15 to 40 minutes for partial excision of the mesh. This procedure was successful in 14 cases (77%). Four women required repeated resection of the mesh because of recurrence. The incidence of de novo dyspareunia was 12% in patients with vaginal mesh erosion, and 11% in patients without mesh erosion (p = 0.81). The incidence of urge urinary symptoms and voiding dysfunction symptoms was respectively 8% versus 9% (p = 0.95), and 8% versus 10% (p = 0.81) in the 2 groups. CONCLUSION: Management of vaginal mesh erosion is simple and is associated with a low rate of morbidity. However, patients should be informed that vaginal erosion of the mesh can occur.

[Subtotal hysterectomy: evolving concepts with implications for practice]. / Hystérectomie sub-totale: données récentes et implications pratiques.

INTRODUCTION: The advantages and drawbacks of total and sub-total hysterectomy remain a topic of debate. Our study reviews the literature concerning recent comparative and prospective studies regarding the options of total and subtotal hysterectomy. RESULTS: Subtotal hysterectomy may be useful in preventing severe complications when total hysterectomy is technically difficult. Furthermore, conservation of the uterine cervix may decrease vaginal erosion in genital prolapse repair when synthetic meshes are used. The type of technique does not appear to determine the persistence or development of problems related to sexual activity (frequency of intercourse, sexual desire, and achievement of orgasm). There are no apparent advantages to subtotal hysterectomy compared with total hysterectomy with respect to bowel or bladder function. Some women (5-20%) who had the subtotal procedure continued to have genital bleeding, although this can be avoided with endocervical electro-coagulation or resection. Cervical stump prolapse is uncommon (1.5-2%), 12 months after subtotal hysterectomy. The risk of carcinoma of the cervical stump is low, and treatment results are similar in both patients with carcinoma of the cervical stump and in patients with carcinoma of the intact uterus. CONCLUSION: When subtotal hysterectomy is necessary, it can be performed with a low rate of long term complications. Furthermore, for women undergoing hysterectomy for benign disease, it should be reasonable to discuss advantages and drawbacks of both procedures and offer a choice. Nevertheless, sub-total hysterectomy should be avoided in populations with restricted access to screening programs for cancer of the uterine cervix.

Phenylisoserine: a versatile amino acid for the construction of novel beta-peptide structures.

The N-Boc O-tert-butyldimethysilyl-substituted hexa-beta-peptide methyl ester 18 was constructed from the O-TBS ether of (-)-(2R, 3S)-phenylisoserine. By NMR, it was determined that this homo beta-peptide adopts a highly stable beta-strand-type secondary structure in chloroform solution, which is stabilized by both hydrophobic interactions involving the OTBS methyl groups of residues i and i + 2, and inter-(five-membered)/intra (six-membered)-residue H-bonding interactions. These interactions are systematically repeated along the peptide chain and, thereby, operate in concert to stabilize the observed conformation of 18.

Diphenyl quinolines and isoquinolines: synthesis and primary biological evaluation.

The synthesis of a series of 35 substituted 3,4-diphenyl quinolines and isoquinolines is described. The majority of these molecules differ from all other triphenylethylene based antiestrogens by a different spatial location of the aminoalkyl side chain. The binding affinity of the most representative molecules (8, 9, 19, 20, 21, 23 and 25), including analogues 8 and 21 without the side chain, for the estrogen receptor alpha (ER) was determined. The ability of these molecules to induce the progesterone receptor was also studied. Antiproliferative activity was evaluated on MCF-7 human breast cancer cells, while intrinsic cytotoxic/cytostatic properties resulting from interaction with other targets than ER were assayed on L1210 murine leukemia cells. Introduction of an aminoalkylamino side chain at carbon 2 confers strong cytotoxic properties to diphenylquinolines 9 and 10 as well as pure antiestrogenic activities. However, cytotoxicity is so high with respect to antiestrogenicity that the latter was clearly observable only in one case (9b). The structure of compound 9b was determined by X-ray crystallography. Molecular modeling of its docking within the hormone-binding domain of the receptor was subsequently undertaken. According to our results, the design of molecules with the side chain bound to the ethylene part of the triphenyl ethylene skeleton might generate compounds of potential pharmacological interest.

Synthesis and evaluation of 4-amino-substituted 7-methoxy (and 7-hydroxy)- 11-methyl (and 5,11-dimethyl)-10H-pyrido [2,3-b] carbazoles and 4-amino- substituted 11-methyl (and 5,11-dimethyl)-10H-pyrido[3',4':4,5] pyrrolo [3,2-g] quinolines, two new series related to antitumor ellipticine derivatives.

2-Acetyl-4-chloro-3-lithiopyridine ethylene glycol ketal (6b) was reacted with 3-formyl-5-methoxy-1-methyl-indole (9) and 3-formyl-1-methyl-1H-pyrrolo [3,2-c] pyridine (12), giving the corresponding expected alcohols. Reduction of these intermediates with triethylsilane trifluoroacetic acid and subsequent cyclodehydration then led to 4-chloro-7-methoxy-10,11-dimethyl-10H-pyrido [2,3-b] carbazole (8a) and the corresponding 7-aza-analog (8b). The synthesis of 4-chloro-11-methyl (and 5,11-dimethyl)-10-unsubstituted derivatives of these two series was performed through an independent pathway, involving condensation of conveniently substituted 2-amino carbazoles (17) and 7-amino-5H-pyrido [4,3-b] indoles (18) with 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, thermal cyclization of the resulting compounds with concomitant decarboxylation to the corresponding tetracyclic fused-4-quinolone systems and final chlorination with phosphorus oxychloride. Nucleophilic substitution of various 4-chloro derivatives was then easily performed in an excess of the required dialkylamino alkylamines at reflux and 4-amino substituted-7-hydroxy-10H- pyrido [2,3-b] carbazoles (25d-e) were obtained from 7-methoxy precursors (25a-b), by demethylation with boron tribromide in methylene chloride at -65 degrees C or with boiling 47% hydrobromic acid. Cytotoxicity determination of all new aminosubstituted derivatives and in vivo antitumor evaluation of the most active compounds clearly show that these two series of ellipticine analogs closely related to highly active products are devoid of antitumor properties in two experimental models shown to be sensitive to ellipticines. The place of the pyridinic nitrogen atom in these series has thus been demonstrated to play a crucial role in antitumor activity.

Further SAR in the new antitumor 1-amino-substituted gamma-carbolines and 5H-benzo[e]pyrido[4,3-b]indoles series.

Using previously described techniques, various new 1-amino-substituted 5H-pyrido[4,3-b]indoles (gamma-carbolines, gamma-C) and 5H-benzo[e]pyrido[4,3-b]indoles (BPI) have been synthesized and evaluated. For known compounds containing a 1-[(dimethylamino)propyl] group, 1a and 1b in the gamma-C series and 2 in the BPI series are the most active. Studies with newly synthesized derivatives show that: (i) in the gamma-C series, the 4-unsubstituted-8-hydroxy-compound was inactive, whereas the 4-unsubstituted-9-hydroxy-5H-benzo[e]pyrido[4,3-b]indole is active; (ii) the 4-ethyl-8-hydroxy-5H-pyrido[4,3-b]indole derivative retains antitumor properties, but the 1-amino-substituted 4-ethyl-9-hydroxy-5H-benzo[e]pyrido[4,3-b]indole analog is devoid of biological activity; (iii) in the 5H-benzo[e]pyrido[4,3-b]indole series, the displacement of a hydroxyl group from the 9- to 10-position leads to inactive compounds. Based on the structural analogies, these results were unexpected because the same substituents on the 4-position lead to different biological properties in the two series.

Synthesis and antitumor properties of new 4-methyl-substituted- pyrido[4,3-b]indoles (gamma-carbolines).

A new class of antineoplastic agents, 4-methyl-pyrido[4,3-b]indoles (5) and the related 4-hydroxymethyl derivatives (7), has been synthesized by a new pathway. Key transformations include regiospecific chlorination at the C(4)-position of 3-nitro-4-hydroxy-5-methyl-pyridin-2-(1H)-one (11) and photochemical cyclization of the intermediate triazolopyridones (15). This new synthesis was developed since an attempt to prepare 4-hydrazino-5-ethoxymethyl-pyridin-2-(1H)-one (10b) by the method previously used to obtain 4-hydrazino-5-methyl-pyridin-2-(1H)-one (10a) failed. The biological results obtained in different in vitro and in vivo models indicate that the substitution of the 4-CH3 by a 4-CH2OH group leads to a decrease of the antitumor properties.

Synthesis of new (+-)-3,5-dihydroxypentyl nucleoside analogues from 1-amino-5-(benzyloxy)pentan-3-ol and their antiviral evaluation.

The synthesis and antiviral evaluation of a series of (+-)-3,5- dihydroxypentyl nucleoside analogues related to acyclic nucleoside antiviral agents are reported. All purine and pyrimidine nucleoside analogues described in this paper have been obtained from 1-amino-5-(benzyloxy)pentan-3-ol. A synthesis of this amine is reported from 1-(benzyloxy)but-3-ene after epoxidation and regiospecific diethylaluminum chloride catalyzed opening of the epoxide by trimethylsilyl cyanide. The compounds were tested in vitro in infected MRC5 and CEM cells. None of the compounds exhibited antiviral activity against HSV-1, HCMV, and HIV-1 with the exception of the guanine derivative 7, which inhibited the cytopathic effect of HSV-1 by 50% at 12.5 micrograms/mL.

[Effects of alanine on the metabolism of lactate and glucose in the isolated perfused rat heart (author's transl)]. / Effets de l'alanine sur le métabolisme du lactate et du glucose dans le coeur isolé, perfusé de rat.

Perfused non working isolated rat heart preparations have been used to study whether alanine (0,89 gl-1) could represent an energy source for the myocardium. Its influence on glucose and lactate metabolism in the heart was also studied. The use of 14C labelled compounds permitted the estimation of the oxidation rate of these three metabolites. The results show that: 1) Alanine was not utilized by the heart. 2) Alanine did not alter myocardial glucose metabolism or lactate oxidation. 3) Alanine lowered lactate uptake by the myocardium which may indicate that alanine influences lactate transport through the cell membranes. One may speculate that in vivo, alanine will not interfere with glucose or lactate metabolism by the heart as, even in acute physiological conditions (exercice, hypoxie, fasting) lactate is always present in blood at higher concentration than alanine.