Diagnosis of fetal urinary tract malformations: prenatal management and postnatal outcome.

OBJECTIVE: To evaluate prenatal management and to define the criteria of gravity for accurate assessment of the renal and overall prognosis of fetuses presenting malformations of the urinary tract. METHODS: We carried out a retrospective study of 127 cases of urinary tract malformation. We carried out descriptive statistical and univariate analyses as a function of severity criteria and the outcome of pregnancy. RESULTS: One-third of fetuses presented associated extrarenal malformations and 10% of the karyotypes were abnormal. There were more abortions in case of decrease in amniotic fluid volume (p < 0.001), extent of renal damage (p < 0.05), presence of associated extrarenal malformations (p < 0.05), early diagnosis of the malformation (p < 0.001) and presence of chromosomal syndrome (p = 0.01). In our study, there was an excellent correlation between prenatal data and pathological findings for the fetus following abortions for medical reasons or obtained during the surveillance of live-born children. Fetal biochemistry made very little contribution. CONCLUSION: In cases of urinary tract malformation, this work confirms the need for regular and frequent ultrasound scans, checking for the echographic factors indicative of gravity and for adapted karyotyping. It also demonstrates that pluridisciplinary management is necessary for the prenatal evaluation of renal and overall fetal prognosis.

Integrating a palliative approach into the healthcare provided by the French-African Pediatric Oncology Group's pilot units. Insights from a 3-year training program.

Working alongside local stakeholders, members of the French-African Pediatric Oncology Group developed a 3-year program to train pediatric oncology teams from 15 French-speaking countries in Africa in using analgesics and providing palliative care. This program was rolled out in three phases: initial training, in situ assessment, and advanced training in selected topics. To access this program, multidisciplinary teams had to come up with a project to improve their existing palliative care and pain management practices, and commit themselves to implementing it. All the teams invited agreed to take part in the program, which explicitly broached a subject that is often avoided in oncology teaching. The first phase was rolled out in 2017, with 65 trainees from 19 units attending one of three sessions held in Dakar, Senegal, Abidjan, Côte d'Ivoire, and Rabat, Morocco. The subsequent assessment revealed that only half the teams had started to implement their projects. The advanced training phase was therefore adjusted accordingly. A collective training session held in Marseille was attended by 15 trainees from seven teams whose projects were already underway, while in situ mentoring was provided for six other teams, through French-African twinnings in four cases. The length and openness of the program meant that we were able to identify and share the units' diverse realities, and fine-tune their projects accordingly, as well as plan ways of continuing the training both locally and collectively.

[Acute pancreatitis induced by major hypertriglyceridemia during pregnancy. A case report]. / Pancréatite aiguë secondaire à une hypertriglycéridémie majeure au cours de la grossesse. A propos d'un cas.

A parturient in the 37th week of gestation is referred to the obstetrical emergency ward for an acute abdominal pain with vomiting and fever. Few hours after her admission, a caesarean section is performed for acute fetal distress. It gave birth to a 3940 g healthy newborn. An abundant and milky peritoneal fluid is noted during the C-section related to a major hypertriglyceridemia (84,47 g/L) which induced an acute pancreatitis explaining the early symptoms. The patient is then hospitalized in surgical reanimation: heparin and a low fat diet led to a quick decrease of triglyceridemia and the healing of the acute pancreatitis. We review the most recent literature about acute pancreatitis during pregnancy, especially induced by hypertriglyceridemia, and the different management option: heparin, parenteral nutrition or plasmapheresis.

Insights on protein-DNA recognition by coarse grain modelling.

Coarse grain modelling of macromolecules is a new approach, potentially well adapted to answer numerous issues, ranging from physics to biology. We propose here an original DNA coarse grain model specifically dedicated to protein-DNA docking, a crucial, but still largely unresolved, question in molecular biology. Using a representative set of protein-DNA complexes, we first show that our model is able to predict the interaction surface between the macromolecular partners taken in their bound form. In a second part, the impact of the DNA sequence and electrostatics, together with the DNA and protein conformations on docking is investigated. Our results strongly suggest that the overall DNA structure mainly contributes in discriminating the interaction site on cognate proteins. Direct electrostatic interactions between phosphate groups and amino acid side chains strengthen the binding. Overall, this work demonstrates that coarse grain modeling can reveal itself a precious auxiliary for a general and complete description and understanding of protein-DNA association mechanisms.

[Fetal assessment of the labor admission in low risk pregnancies]. / Evaluation du foetus à l'admission des grossesses "a priori" à bas risque.

The assessment of fetal well-being at the beginning of labor must lead to an appropriate monitoring, adapted to the present risks. Even if some medical events are unforeseeable, three ways of reflexions get clear: abnormal maternofetal signs at the admission indicate the need for an increased monitoring (NP5); the reading of the medical file could reveal a high-risk pregnancy; at least, the realization of electronic fetal heart rate monitoring for any woman at the beginning of the labor is recommended: in case of normality, it remains a good criterion of a fetal good health. In this context of admission, there is no evidence supporting that other techniques (amnioscopy, acoustic test, echography, Doppler, etc.) could be beneficial in low-risk women and be recommended (NP5). Research is to be continued in this field.

[Length of pushing efforts: pushing is not playing. Reply to the article of C. Le Ray and F. Audibert]. / Durée des efforts expulsifs : pousser n'est pas jouer. Réponse à l'article de C. Le Ray et F. Audibert.

The aim of this work is to answer constructively to C. Le Ray and F. Audibert who were surprised that the French guidelines recommended an assisted delivery after 30 min pushing, even if the fetal heart rate is reassuring. We first resumed the definition of "second stage of labor", this word including the first phase with no pushing efforts and the second phase with active pushing of the mother. With that definition, the length of the second stage is around 60 min for the primipara and 20 min for the multipara, this length being modified by the use of peridural. We then specified the physiological mechanisms influencing the acidobasic equilibrium during the pushing time. Those mechanisms are difficult to consider because foetal heart rate monitoring is often "lost" during that phase. Altogether, these factors bring incertitude about progressive foetal acidosis and incapacity to diagnose it. Finally, the literature analysis teaches us that increasing the second stage of labor (inactive plus active phases) during the normal pregnancy seems to be at low risk for the foetus within the primiparas, but display a risk for the mother and so might be limited. Comparing the delayed pushing with the immediate pushing only lead us to conclude that delayed pushing is dangerous, as is prolonged second stage. In conclusion, we think that prolonging the second stage of labor is possible but must be by increasing the inactive first phase of the second stage, especially as long as we will not get a noninvasive and reliable method allowing assessing the well-being of the foetus.

Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.

Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARalpha response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARalpha activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARalpha in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.

Performances of Wang-Landau algorithms for continuous systems.

The relative performances of different implementations of the Wang-Landau method are assessed on two classes of systems with continuous degrees of freedom, namely, two polypeptides and two atomic Lennard-Jones clusters. Parallel tempering Monte Carlo simulations serve as a reference, and we pay particular attention to the variations of the multiplicative factor f during the course of the simulation. For the systems studied, the Wang-Landau method is found to be of comparable accuracy as parallel tempering, but has significant difficulties in reproducing low-temperature transitions exhibited by the Lennard-Jones clusters at low temperature. Using a complementary order parameter and calculating a two-dimensional joint density of states significantly improves the situation, especially for the notoriously difficult LJ(38) system. However, while parallel tempering easily converges for LJ(31), we have not been able to get data of comparable accuracy with Wang-Landau multicanonical sampling.

[Prenatal diagnosis of sirenomelia]. / Diagnostic anténatal d'une sirénomélie.

Sirenomelia sequence associates a fusion of inferior legs with renal anomalies until bilateral agenesis. It is a rare and lethal polymalformation. The purpose of the ultrasonographic study is to identify the sirenomelia as early as possible during pregnancy and to differentiate it from caudal regression syndrome. A case of sirenomelia diagnosed early is reported together with a review of the literature. The ultrasonographic diagnosis, associated defects, the interest of color Doppler study of abdominal vasculature are discussed. Antenatal ultrasonographic diagnosis should be obtained as early as possible, before 20th gestational week at the latest. Color Doppler is helpful to confirm the diagnosis in case of bilateral renal agenesis. The main differences between sirenomelia and caudal regression syndrome (which requires a very different genetic counselling) are summarized in a table.

CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors.

BACKGROUND: The scavenger receptors are cell-surface receptors for native and modified lipoproteins that play a critical role in the accumulation of lipids by macrophages. CLA-1/SR-BI binds HDL with high affinity and is involved in the cholesterol reverse-transport pathway. Peroxisome proliferator-activated receptors (PPARs) are transcription factors regulating the expression of genes implicated in lipid metabolism, cellular differentiation, and inflammation. Here, we investigated the expression of CLA-1/SR-BI in macrophages and its regulation by PPARs. METHODS AND RESULTS: CLA-1 is undetectable in human monocytes and is induced upon differentiation into macrophages. Immunohistological analysis on human atherosclerotic lesions showed high expression of CLA-1 in macrophages of the lipid core colocalizing with PPARalpha and PPARgamma staining. Activation of PPARalpha and PPARgamma resulted in the induction of CLA-1 protein expression in monocytes and in differentiated macrophages. Finally, SR-BI expression is increased in atherosclerotic lesions of apoE-null mice treated with either PPARgamma or PPARalpha ligands. CONCLUSIONS: Our data demonstrate that CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and induced by PPAR activation, identifying a potential role for PPARs in cholesterol homeostasis in atherosclerotic lesion macrophages.

Beneficial effects of fibrates on apolipoprotein A-I metabolism occur independently of any peroxisome proliferative response.

BACKGROUND: In humans, fibrates are frequently used normolipidemic drugs. Fibrates act by regulating genes involved in lipoprotein metabolism via activation of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in liver. In rodents, however, fibrates induce a peroxisome proliferation, leading to hepatomegaly and possibly hepatocarcinogenesis. Although this peroxisome proliferative response appears not to occur in humans, it remains controversial whether the beneficial effects of fibrates on lipoprotein metabolism can occur dissociated from such undesirable peroxisomal response. Here, we assessed the influence of fenofibrate on lipoprotein metabolism and peroxisome proliferation in the rabbit, an animal that, contrary to rodents and similar to humans, is less sensitive to peroxisome proliferators. METHODS AND RESULTS: First, we demonstrate that in normal rabbits, fenofibrate given at a high dose for 2 weeks does not influence serum concentrations or intestinal mRNA levels of the HDL apolipoprotein apoA-I. Therefore, the study was continued with human apoA-I transgenic rabbits that overexpress the human apoA-I gene under control of its homologous promoter, including its PPAR-response elements. In these animals, fenofibrate increases serum human apoA-I concentrations via an increased expression of the human apoA-I gene in liver. Interestingly, liver weight or mRNA levels and activity of fatty acyl-CoA oxidase, a rate-limiting and marker enzyme of peroxisomal beta-oxidation, remain unchanged after fenofibrate. CONCLUSIONS: Expression of the human apoA-I transgene in rabbit liver suffices to confer fibrate-mediated induction of serum apoA-I. Furthermore, these data provide in vivo evidence that the beneficial effects of fibrates on lipoprotein metabolism occur mechanistically dissociated from any deleterious activity on peroxisome proliferation and possibly hepatocarcinogenesis.

PPAR-alpha-null mice are protected from high-fat diet-induced insulin resistance.

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the expression of genes involved in lipid metabolism. PPAR-alpha furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-alpha-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-alpha in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-alpha-null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-alpha-null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-alpha-null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat-fed wild-type mice, whereas it remained unchanged in PPAR-alpha-null mice. In contrast, PPAR-alpha deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-alpha dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-alpha deficiency on glucose homeostasis seem not to occur via the pancreas, because glucose-stimulated insulin secretion of islets was not influenced by the PPAR-alpha genotype. These data suggest that PPAR-alpha plays a role for the development of IR in response to a Western-type high-fat diet.

Decreased susceptibility to diet-induced atherosclerosis in human apolipoprotein A-II transgenic mice.

Studies performed in vivo have been controversial regarding the implication of human apolipoprotein (apo)A-II in the atherogenic process. Expression of human apoA-II in transgenic mice fed a chow diet leads to (1) a bimodal distribution of high density lipoprotein (HDL) size as in humans, (2) a reduction in total cholesterol concentration that is mainly due to a reduction in non-HDL cholesterol level, and (3) a dramatic reduction in mouse endogenous apoA-I and apoA-II. After 20 weeks on an atherogenic diet, transgenic mice had reduced total cholesterol concentrations because of a reduction in cholesterol associated with all lipoprotein classes. Endogenous apoA-I and apoA-II were also dramatically decreased in transgenic mice. The mean area of atherosclerotic lesions was drastically decreased in transgenic mice (-44%, P=0.0027) compared with control mice. The amount of aortic surface covered by lesions was positively correlated with very low density lipoprotein cholesterol (P<0.01) and intermediate density lipoprotein cholesterol levels (P<0.05). Transgenic mice were protected against the development of atherosclerosis despite a marked decrease in HDL cholesterol and apoA-I concentrations. This protection may be related to the marked reduction in circulating low density lipoprotein (very low density and intermediate density lipoprotein) levels in transgenic mice.

Size distribution of fat globules in human colostrum, breast milk, and infant formula.

Only a few results are available on the size of human milk fat globules (MFG), despite its significance regarding fat digestion in the infant, and no data are available at <24 h postpartum (PP). We measured the MFG size distribution in colostrum and transitional human milk in comparison with fat globules of mature milk and infant formula. Colostrum and transitional milk samples from 18 mothers were collected regularly during 4 d PP and compared with mature milk samples of 17 different mothers and 4 infant formulas. The size distribution was measured by laser light scattering. For further characterization, the zeta-potential of some mature MFG was measured by laser Doppler electrophoresis. The MFG diameter decreased sigmoidally in the first days. At <12 h PP, the mode diameter was 8.9 +/- 1.0 microm vs 2.8 +/-0.3 microm at 96 h PP. Thus, the surface area of MFG increased from 1.1 +/-0.3 to 5.4 +/-0.7 m2/g between colostrum and transitional milk. In mature milk, the MFG diameter was 4 microm on average and increased with advancing lactation, whereas the droplets in infant formula measured 0.4 microm. The zeta potential of mature MFG was -7.8 +/- 0.1 mV. The fat globules are larger in early colostrum than in transitional and mature human milk and in contrast with the small-sized fat droplets in infant formula. Human MFG also have a low negative surface charge compared with bovine globules. These structural differences can be of nutritional significance for the infant.

[Tolerance of copper intrauterine device in nulliparous patients: a single-center prospective study]. / Tolérance du dispositif intra-utérin au cuivre chez les patientes nullipares : étude prospective unicentrique.

INTRODUCTION: The purpose of this work was to study the continuation rate of intrauterine device (IUD) copper in a nulliparous population. PATIENTS AND METHOD: A prospective study in a family planning centre including nulliparous patients between January and December 2012. RESULTS: A total of 83 nulliparous patients had IUD copper insertion and 11 patients were excluded because they were lost to follow-up. Finally, 72 nulliparous patients were included in the study. Continuation rate after one-year follow-up was 90.3% (65/72). Satisfaction rate of patient was high (93.8%). Menstruation amount was increased for 84% (55/65) patients, but 75% (41/55) did not report any inconvenience about this. Dysmenorrhea were increased for 80% (52/65) patients, but 58% (30/52) were not troubled by this. CONCLUSION: Continuation rate of IUD copper was high (90%) after one-year follow-up in nulliparous women. Tolerance was also good for evaluated patients.

Pan-European, open-label dose titration study of fentanyl buccal tablet in patients with breakthrough cancer pain.

BACKGROUND: Fentanyl buccal tablet (FBT), a rapid onset opioid used to treat breakthrough cancer pain, must be titrated to an effective dose that provides adequate analgesia and minimizes undesirable events. This open-label, randomized study compared the percentage of patients achieving an effective dose of FBT when starting titration at 100 or 200 µg. METHODS: Opioid-tolerant patients with chronic cancer-related pain who experienced up to four breakthrough pain episodes daily were randomized to a starting dose of 100 or 200 µg for the titration period. The dose was increased until an effective dose (100, 200, 400, 600 or 800 µg) providing adequate analgesia with acceptable adverse events was achieved. Patients achieving an effective dose entered a treatment period during which they treated up to eight breakthrough pain episodes with their effective dose. RESULTS: A total of 442 patients from 135 sites in seven European countries were screened. Non-inferiority was established with the percentage of patients achieving an effective dose starting titration at 200 µg (81.4%) compared with the 100-µg (75.2%) starting dose. The most common effective doses of FBT were 200 µg (39.6%) and 400 µg (26.9%). No new safety concerns were identified with use of FBT at doses up to 800 µg per episode. CONCLUSIONS: This study involving a real clinical practice setting showed a similar percentage of patients safely achieving an effective dose by titration starting with 100 versus 200 µg of FBT.

[Reproductive health care for women with spina bifida]. / Suivi gynécologique des patientes atteintes d'un spina bifida.

OBJECTIVES: Few studies have focused on reproductive health care for women with spina bifida. This subject is rarely discussed, whether in patient groups or in the medical community. However, these patients need advice and a care that is appropriate to their condition. METHODS: In association with the spina bifida reference center of the University Hospital of Rennes, we have conducted a four-year retrospective, observational study. Its aim was to analyze the characteristics of the patients' gynecological care and to adapt our practice to their needs. RESULTS: Forty-eight patients were included. We demonstrated an increased risk of precocious puberty, labia minora hypertrophy and genital prolapse. CONCLUSION: Some specific characteristics of the reproductive health care of patients with spina bifida are interesting to know. A study on a larger series of patients is needed to further analyze the obstetric, gynecological and sexological issues of these women.

Estradiol coupling to endothelial nitric oxide stimulates gonadotropin-releasing hormone release from rat median eminence via a membrane receptor.

The median eminence (ME), which is the common termination field for adenohypophysiotropic systems, has been shown to produce nitric oxide (NO), a signaling molecule involved in neuroendocrine secretion. Using an ex vivo technique, 17beta-estradiol exposure to ME fragments, including vascular tissues, stimulated NO release within seconds in a concentration-dependent manner, whereas 17alpha-estradiol or testosterone had no effect. 17Beta-estradiol conjugated to BSA (E2-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17beta-estradiol and E2-BSA. Furthermore, estradiol-stimulated NO stimulates GnRH release. This was demonstrated by hemoglobin (a NO scavenger), N(omega)-nitro-L-arginine methyl ester, and L-N5-(1-iminoethyl)ornithine (nitric oxide synthase inhibitors) inhibition of estradiol stimulated NO and GnRH release. In this regard, L-N5-(1-iminoethyl)ornithine, specific for endotheliol constitutive nitric oxide synthase, was significantly more potent, suggesting that the estradiol-stimulated NO release arose from vascular endothelial cells. Additionally, the NO-stimulated GnRH release occurs via guanylyl cyclase activation in GnRH nerve terminals, as ODQ, a potent and selective inhibitor of NO-sensitive guanylyl cyclase, abolished the estradiol-stimulated GnRH release. The results suggest that at physiological concentrations, 17beta-estradiol may have immediate actions on ME endothelial cells via nongenomic signaling pathways leading to NO-stimulated GnRH release.

Is disease progression the major factor in morphine 'tolerance' in cancer pain treatment?

To assess the contribution of pharmacological tolerance to increasing doses of morphine, 29 cancer patients requiring oral morphine to treat pain were studied by two teams working independently. The first team assessed physical impairment, pain intensity and pain treatment. The second team assessed depressive disorders (DSM III criteria), emotional and behavioural depressive patterns (Retardation Depressive Scale, Polydimensional Mood Scale). All patients were seen at the initiation of morphine therapy and followed to the first morphine dose modification. Evaluations were carried out in out-patient clinics except staging investigations which were undertaken at the beginning and at the end of the study. Our results showed that (1) in 24 of the 25 patients for whom morphine doses were increased, progressive disease was recorded; (2) in 4 patients, morphine doses were not increased and in these patients their disease was stable or in remission; and (3) changes in depressed mood were not correlated with pain intensity. These data strongly suggest that, instead of pharmacological tolerance, the main factor resulting in increasing oral morphine requirement in cancer pain management is pain increase due to disease progression.

Interstitial fluid apolipoprotein A-II: an association with the occurrence of myocardial infarction.

A sample of male patients aged 25-64 years, survivors of myocardial infarction (MI) taken from the Lille MONICA register, and age-matched control subjects from the general population were recruited in Lille and its surroundings in the North of France. Diabetics and subjects taking hypolipidemic drugs were excluded from the analysis, so that 73 MI and 144 control subjects were included. Lipids, apolipoprotein (apo) A-I, apo A-II, apo A-IV and apo B, and apo A-I-containing particles such as lipoproteins containing both apo A-I and apo A-II (LpA-I:A-II) and those containing apo A-I but not apo A-II (LpA-I) were measured in interstitial fluid by applying mild suction, and in plasma. Univariate analysis showed that plasma triglycerides, very low density lipoprotein (VLDL)-cholesterol and apo B were significantly higher, while high density lipoprotein (HDL)-cholesterol, apo A-I, LpA-I and LpA-I:A-II were lower in MI survivors compared to controls after adjustment for age, body mass index (BMI), alcohol and tobacco consumption. In interstitial fluid, cholesterol and apo A-II were higher in MI than in controls before adjustment for covariates. However, after adjustment, triglycerides became significant while cholesterol and apo A-II remained significantly higher in MI, at 43.8 and 7.5 mg/dl, respectively, than in control subjects, at 38.6 and 5.9 mg/dl, respectively. Taking into account only the plasma parameters, the multivariate analysis reveals that triglycerides and apo A-I appear to be independent factors indicative of the presence of a MI. When plasma and interstitial fluid parameters were taken together in the multivariate analysis, the measurement of apo A-II in interstitial fluid increased the level of prediction of MI over the information provided by the plasma parameters. These data raise the possibility that interstitial fluid apo A-II levels may be associated with the occurrence of MI.