[Partial breast irradiation technique with external beam radiation therapy and brachytherapy]. / Technique d'irradiation partielle du sein : radiothérapie externe et curiethérapie.

Accelerated Partial Breast Irradiation (APBI) appears to be an efficient therapeutic modality provided that it uses strict selection criteria and a reliable and well-managed technique. The techniques that enable to deliver postoperative APBI are interstitial brachytherapy, endocavitary brachytherapy and external beam radiation therapy. Once an appropriate selection of the candidates is made, each radiation technique needs an exact target volume definition and a strict compliance with its own dosimetric constraints. Results of ongoing randomized trials should increase our knowledge of all these parameters, and give us responses about the comparison of the different techniques.

[State of the art and perspectives of accelerated partial breast irradiation in 2014]. / État de l'art et perspectives de l'irradiation partielle et accélérée du sein en 2014.

In the frame of treatment de-escalation and personalization, accelerated partial breast irradiation is taking its place in the breast cancer therapeutic options. This study analyzed the results of phase III randomized trials having compared accelerated partial breast irradiation versus whole breast irradiation. Currently, among those trails, six proposed some results regarding efficacy and/or toxicity. Globally, the non-randomized studies confirmed the expected results showing a low rate of local recurrence and toxicity. The first results of the phase III randomized trials showed encouraging data in terms of local control while the toxicity varied mainly according to the accelerated partial breast irradiation technique used. However, the follow-up of the majority of these studies remains insufficient. The strict respect of accelerated partial breast irradiation indications likely represents one of the key factors of the therapeutic success. The next results could allow proposing a better definition of the accelerated partial breast irradiation selection criteria.

Seroepidemiologic survey of epidemic cholera in Haiti to assess spectrum of illness and risk factors for severe disease.

To assess the spectrum of illness from toxigenic Vibrio cholerae O1 and risk factors for severe cholera in Haiti, we conducted a cross-sectional survey in a rural commune with more than 21,000 residents. During March 22-April 6, 2011, we interviewed 2,622 residents ≥ 2 years of age and tested serum specimens from 2,527 (96%) participants for vibriocidal and antibodies against cholera toxin; 18% of participants reported a cholera diagnosis, 39% had vibriocidal titers ≥ 320, and 64% had vibriocidal titers ≥ 80, suggesting widespread infection. Among seropositive participants (vibriocidal titers ≥ 320), 74.5% reported no diarrhea and 9.0% had severe cholera (reported receiving intravenous fluids and overnight hospitalization). This high burden of severe cholera is likely explained by the lack of pre-existing immunity in this population, although the virulence of the atypical El Tor strain causing the epidemic and other factors might also play a role.

[Pituitary adenomas: multimodal management and modern irradiation techniques]. / Adénomes hypophysaires: mise au point sur la pathologie et les techniques d'irradiation modernes.

Pituitary adenomas represent 10 to 20% of all primary brain tumours. The main classifications consider their size, micro- and macroadenomas, and their properties, secreting or non-functioning. These characteristics determine the choice of treatment, surgery and medical therapy on first line in many cases. Conventional radiotherapy, whose efficiency has been demonstrated, is indicated in the post-operative setting for lesions at high risk of relapse, recurrences, contra-indications to surgery and intolerance or resistance to medical therapies. Optimal target volume delineation is critical, owing to the proximity of organs at risk and a risk of late toxicity for these patients who have normal life expectancy. Technological, computering and imaging advances have led to conformal radiotherapy, intensity-modulated treatment and stereotaxy. These new techniques are reviewed through a recent literature search. Local control rates are high, although follow-up is still short. Indications for radiosurgery are restricted by the size of the lesions. Fractionated stereotactic radiotherapy potentially reduces late toxicity, but longer follow-up is necessary.

[Biochemistry of fetal membranes rupture]. / Biochimie de la rupture des membranes fœtales.

Fetal membranes, amnion and chorion, line up the amniotic cavity and are essential for its integrity towards normal term of pregnancy. They consist of a pluristratified structure whose composition assures their cohesion and elasticity. They firstly function in retaining the fluctuant amniotic fluid in a half-rigid cavity. Their elastic limit depends on the organization of the extracellular matrix and firstly on the collagen type it contains. The compact layer of the amnion, responsible for the elastic limit, contains mainly type I collagen, organized in lattice; this allows elongation or spreading. Underneath, the spongy layer, principally of collagen III, is organized in a loose mesh, enriched in hydrated proteoglycans, which allows the absorption of the shocks and the sliding of the amnion on the chorion. The cascade of events leading to the membrane rupture displays: (i) membranes distension with elasticity loss, (ii) separation of the chorion from the amnion, (iii) chorion fracture, (iv) amnion distension which produces an hernia, (v) amnion rupture. The rupture mechanism was long thought to be a consequence of uterine contractions. However, the observation before labour of a zone of altered morphology, with biochemical variations (modifications of metalloprotease activity and of proteoglycans, apoptosis...) associated with focal physical weakness in the region overlying the cervix suggests programming of the rupture before parturition. A better understanding of the biochemical mechanisms of membranes rupture will provide new insights into how to anticipate and to intervene in the case of risk of premature rupture.

Photon regeneration experiment for axion search using x-rays.

In this Letter we describe our novel photon regeneration experiment for the axionlike particle search using an x-ray beam with a photon energy of 50.2 and 90.7 keV, two superconducting magnets of 3 T, and a Ge detector with a high quantum efficiency. A counting rate of regenerated photons compatible with zero has been measured. The corresponding limits on the pseudoscalar axionlike particle-two-photon coupling constant is obtained as a function of the particle mass. Our setup widens the energy window of purely terrestrial experiments devoted to the axionlike particle search by coupling to two photons. It also opens a new domain of experimental investigation of photon propagation in magnetic fields.

New limits on coupling of fundamental constants to gravity using 87Sr optical lattice clocks.

The 1S0-3P0 clock transition frequency nuSr in neutral 87Sr has been measured relative to the Cs standard by three independent laboratories in Boulder, Paris, and Tokyo over the last three years. The agreement on the 1 x 10(-15) level makes nuSr the best agreed-upon optical atomic frequency. We combine periodic variations in the 87Sr clock frequency with 199Hg+ and H-maser data to test local position invariance by obtaining the strongest limits to date on gravitational-coupling coefficients for the fine-structure constant alpha, electron-proton mass ratio mu, and light quark mass. Furthermore, after 199Hg+, 171Yb+, and H, we add 87Sr as the fourth optical atomic clock species to enhance constraints on yearly drifts of alpha and mu.

No "light shining through a wall": results from a photoregeneration experiment.

Recently, axionlike particle search has received renewed interest. In particular, several groups have started "light shining through a wall" experiments based on magnetic field and laser both continuous, which is very demanding in terms of detector background. We present here the 2sigma limits obtained so far with our novel setup consisting of a pulsed magnetic field and a pulsed laser. In particular, we have found that the axionlike particle two photons inverse coupling constant M is >8 x 10{5} GeV provided that the particle mass m{a} approximately 1 meV. Our results definitively invalidate the axion interpretation of the original PVLAS optical measurements with a confidence level greater than 99.9%.

Stimulation of the ADRB3 adrenergic receptor induces relaxation of human placental arteries: influence of preeclampsia.

Preeclampsia, which complicates 3-8% of pregnancies, is one of the leading causes of neonatal morbidity and mortality. Its pathophysiology remains unclear. The aim of the present study was to investigate the presence and the role of beta2- and beta2-adrenergic receptors (ADRB2 and ADRB3, respectively) in human placental arteries and to assess the influence of preeclampsia on ADRB responsiveness. SR 59119A, salbutamol, and isoproterenol (ADRB3, ADRB2, and nonselective ADRB agonists, respectively) induced a concentration-dependent relaxation of placental artery rings obtained from women with uncomplicated or preeclamptic pregnancies. SR 59119A-induced relaxation was unaffected by the blockade of ADRB1 and ADRB2 by 0.1 microM propranolol but was significantly decreased by the blockade of ADRB1, ADRB2, and ADRB3 by 10 microM propranolol. Both SR 59119A and salbutamol were associated with a significant increase in cAMP production that was significantly inhibited by pretreatment with 0.1 microM propranolol only for salbutamol. SR 59119A-induced relaxation (E(max) = 28% +/- 5% vs. 45% +/- 4%, respectively) and cAMP production (2.7 +/- 0.5 vs. 4.9 +/- 0.4 pmol/mg of protein, respectively; P < 0.01) were decreased in arteries obtained from preeclamptic compared to normotensive women. Both ADRB2 and ADRB3 transcripts were expressed at the same level between arteries from normotensive and preeclamptic women. Western blot analysis, however, revealed a decreased expression of the ADRB3 immunoreactive protein in arteries from preeclamptic compared to normotensive women. We suggest the presence of functional ADRB2 and ADRB3 in human placental arteries. Even if preeclampsia is associated with an impairment of the ADRB3 responsiveness, ADRB3 agonists may have future pharmaceutical implications in the management of pregnancy-related disorders.

[Treatment of heterotopic ossification by extracorporeal shock wave: 26 patients]. / Traitement des paraostéoarthropathies par ondes de choc. Etude sur 26 patients.

OBJECTIVES: To evaluate the effects of extracorporeal shockwave therapy (ESWT) on heterotopic ossification leading to functional limitations in the short and medium term. METHODS: Twenty-six patients with heterotopic ossification received sessions of ESTW (4000 shocks, 3/s), with an energy ranging from 0.54 to 1.06 mJ/mm2, once a week for 4 consecutive weeks. Intermediary assessments performed 1 month after the last session related to pain (on a visual analog scale [VAS]), range of motion, functional independence (FIM), walking distance (whenever possible), radiology, and blood calcium and alkaline phosphatase levels. Eighteen patients with total hip arthroplasty (THA) were followed up by quiz, at 11 months, on average. RESULTS: Heterotopic ossification was neurogenic in 5 patients and nonneurogenic in 21. The length of evolution of ossification was 32+/-21 months. The measurements showing significant improvement in the short term were pain, with a mean decrease of 4.32 to 1.14 on a VAS; joint flexion, with an mean increase of 8.18+/-11.9 degrees; and walking distance, with a mean increase from 1126 to 2776 m. The treatment was tolerated for the most part. THA cases showed a decline in factors initially shown to be improved. However, the long-term results were superior to clinical status before treatment. CONCLUSION: ESWT might be an interesting treatment for heterotopic ossification and can be a complement to usual medical treatment, physiotherapy, and before surgery.

Beta3-adrenoceptor is the predominant beta-adrenoceptor subtype in human myometrium and its expression is up-regulated in pregnancy.

To assess whether pregnancy might influence the functionality and expression of human myometrial beta(2)- and beta(3)-adrenoceptors (beta(2)- and beta(3)-AR), we performed functional, binding, Western blot, and molecular biology experiments in human nonpregnant and near-term pregnant myometrium. Inhibition of spontaneous contractions induced by a beta(3)-AR agonist, SR 59119A, was significantly greater in pregnant, compared with nonpregnant, myometrial strips (E'(max) = 61 +/- 5% vs. 44 +/- 5% for pregnant and nonpregnant myometrium, respectively), whereas salbutamol, a beta(2)-AR agonist, was significantly less efficient in pregnant, compared with nonpregnant, myometrium (E(max) = 29 +/- 4 vs. 54 +/- 8%). Although two populations of binding sites corresponding to beta(2)- and beta(3)-AR were identified in both nonpregnant and pregnant myometrium, we found a clear predominance of the beta(3)-AR subtype. Moreover, beta(3)-AR binding sites were up-regulated 2-fold in myometrium at the end of pregnancy. Both beta(2)- and beta(3)-AR mRNA were expressed in human nonpregnant and pregnant myometrium. Contrary to beta(2)-AR, the expression of the beta(3)-AR transcripts and immunoreactive proteins was increased in pregnant, compared with nonpregnant, myometrium. Such compelling data suggest a predominant role for beta(3)-AR in the regulation of human myometrium contractility, especially at the end of pregnancy, which might have important consequences for the clinical management of preterm labor.

The human near-term myometrial beta 3-adrenoceptor but not the beta 2-adrenoceptor is resistant to desensitisation after sustained agonist stimulation.

1. In order to compare the beta(2)- and beta(3)-adrenoceptor (beta-AR) desensitisation process in human near-term myometrium, we examined the influence of a pretreatment of myometrial strips with either a beta(2)- or a beta(3)-AR agonist (salbutamol or SR 59119A, respectively, both at 10 microm, for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP) production induced by these agonists. 2. To assess some of the mechanisms potentially implicated in the beta-AR desensitisation process, we studied the influence of such treatment on the number of beta(2)- and beta(3)-AR binding sites, the beta(2)- and beta(3)-AR transcripts expression and the phosphodiesterase 4 (PDE4) activity. 3. Salbutamol, but not SR 59119A, concentration-response curve (CRC) was shifted by a 15 h salbutamol preincubation, with a significant difference in -log EC(20) values (6.31+/-0.13 vs 5.58+/-0.24, for control and 15 h salbutamol pretreatment, respectively, P<0.05). Neither salbutamol nor SR 59119A CRCs were modified after a 15 h preincubation with SR 59119A. 4. A 15 h exposure of myometrial strips to salbutamol significantly reduced the salbutamol-induced (0.60+/-0.26 vs 1.54+/-0.24 pmol mg(-1) protein, P<0.05), but not the SR 59119A-induced, cAMP production. No decrease in cAMP production was observed after a 15 h SR 59119A exposure. 5. A 15 h salbutamol exposure of myometrial strips significantly reduced the beta(2)- but not the beta(3)-AR binding site density, whereas no decrease in the number of beta(2)- and beta(3)-AR binding sites was observed after a 15 h SR 59119A treatment. 6. Neither PDE4 activity nor the beta(2)- and beta(3)-AR mRNA expression levels were affected by salbutamol or SR 59119A treatments. 7. Our results indicate that beta(3)-AR, but not beta(2)-AR, are resistant to the agonist-induced desensitisation. In our model, beta(2)-AR desensitisation is mediated by a decreased number of beta(2)-AR that was not explained by transcriptional regulation of the receptor.

A critical role for PKC zeta in endothelin-1-induced uterine contractions at the end of pregnancy.

We have previously shown that protein kinase C (PKC) zeta and/or PKC delta are necessary for endothelin-1 (ET-1)-induced human myometrial contraction at the end of pregnancy (Eude I, Paris P, Cabrol D, Ferré F, and Breuiller-Fouché M. Biol Reprod 63: 1567-1573, 2000). Here, we report that the selective inhibitor of PKC delta isoform, Rottlerin, does not prevent ET-1-induced contractions, whereas LY-294002, a phosphatidylinositol (PI) 3-kinase inhibitor, affects the contractile response. This study characterized the in vitro contractile response of cultured human pregnant myometrial cells to ET-1 known to induce in vitro contractions of intact uterine smooth muscle strips. Cultured myometrial cells incorporated into collagen lattices have the capacity to reduce the size of these lattices, referred to as lattice contraction. Neither the selective conventional PKC isoform inhibitor, Gö-6976, or rottlerin affected myometrial cell-mediated gel contraction by ET-1, whereas this effect was blocked by LY-294002. We found that treatment of myometrial cell lattices with an inhibitory peptide specific for PKC zeta or with an antisense against PKC zeta resulted in a significant loss of ET-1-induced contraction. Evidence is also presented by using confocal microscopy that ET-1 induced translocation of PKC zeta to a structure coincident with the actin-rich microfilaments of the cytoskeleton. We have shown that PKC zeta has a role in the actin organization in ET-1-stimulated cells. Accordingly, our results suggest that PKC zeta plays a role in myometrial contraction in pregnant women.

A functional genomic study to identify differential gene expression in the preterm and term human myometrium.

The mechanisms that lead to the onset of human parturition are still unknown, although selected critical factors have been identified. To investigate the changes in myometrial gene expression associated with parturition, we used two macroarrays each containing 1176 different complementary human cDNA clones. Methods involving hierarchical clustering and conventional statistical analysis allowed us to generate a profile of genes expression at three stages of late pregnancy: preterm (29 wk amenorrhea); full term, not in labor (38 wk amenorrhea); and full term in labor (39 wk amenorrhea). Only 4% of the genes investigated were differentially expressed between the preterm and term groups (P < 0.05). These genes could be clustered as groups of either down-regulated or up-regulated transcripts. The changes in transcript abundance were particularly marked between the preterm and term stages of gestation, whereas the differences between term not in labor and term in labor were less pronounced. The parturition was characterized by a massive down-regulation of a large panel of developmental, cell adhesion molecule and proliferation-related genes, along with the up-regulation of inflammatory, contraction and apoptosis associated genes. We propose that the mechanisms of parturition consist primarily in the arrest of the processes of myometrial development, a step that might be essential to allow the uterus to recover appropriate contractile function before delivery.

Interleukin-1beta induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical fibroblasts.

The aim of this study was to identify, in cultured human cervical fibroblasts, the mechanisms by which interleukin (IL)-1beta induces the synthesis of glycosaminoglycans (GAG) and to explore the putative role of prostaglandin E(2) (PGE(2)) in this process. Exposure of the cells for 24 h to IL-1beta induced a significant (P < 0.05) dose-dependent increase in GAG synthesis. IL-1beta (1 ng/ml) induced the expression of cyclooxygenase-2 (COX-2) protein 6 h after treatment, accompanied by a 7.5-fold increase in PGE(2) production. We confirmed that NS398, a selective COX-2 inhibitor, dose-dependently blocked PGE(2) augmentation following IL-1beta treatment. AH23848, the selective EP(4) receptor antagonist, completely abolished IL-1beta-induced GAG synthesis, whereas AH6809, an EP(2) receptor antagonist, had no effect on the stimulatory effects of IL-1beta. Furthermore, we demonstrated that 6 h exposure to IL-1beta induced a notable increase in EP(4) receptor mRNA expression and a decrease in EP(1) receptor mRNA but had no effect on the expression of EP(2) and EP(3) receptor transcripts. In conclusion, these findings indicate that IL-1beta not only induced GAG synthesis by increasing COX-2 protein expression and the subsequent PGE(2) production but also enhanced the responsiveness of cervical fibroblasts to PGE(2) by selectively up-regulating EP(4) receptor mRNA expression. These results suggest that PGE(2) may regulate human cervical ripening in an autocrine/paracrine manner via EP(4) receptors.

Potentiation response of cultured human uterine leiomyoma cells to various growth factors by endothelin-1: role of protein kinase C.

OBJECTIVE: Factors responsible for the abnormal proliferation of myometrial cells that accompanies leiomyoma formation are unknown, although steroid hormones and peptide growth factors have been implicated. We hypothesized that endothelin-1 (ET-1) is a physiological regulator of tumor growth. DESIGN: In this study, we investigated the role of ET-1 on growth of human leiomyoma cells and its synergistic effect with growth factors, as well as the signaling pathway involved in this interaction. METHODS: Leiomyoma cell proliferation was assayed by [H]thymidine incorporation and cell number. Protein kinase C (PKC) isoforms were analyzed by Western blot using specific antibodies. RESULTS: ET-1 on its own was unable to stimulate DNA synthesis but potentiated the leiomyoma cell growth effects of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IGF-I and IGF-II. The failure of a protein tyrosine kinase (PTK) inhibitor, tyrphostin 51, to affect the potentiating effect of ET-1, supports the hypothesis of non-involvement of PTK in this process. The inhibition of PKC by calphostin C or its down-regulation by phorbol 12,13-dibutyrate (PDB) eliminated the potentiating effect of ET-1, but did not block cell proliferation induced by the growth factors alone. Five PKC isoforms (alpha, beta1, epsilon, delta and zeta) were detected in leiomyoma cells, but only phorbol ester-sensitive PKC isoforms (PKCalpha, epsilon and delta) contribute to the potentiating effect of leiomyoma cell growth by ET-1. CONCLUSIONS: We have demonstrated that ET-1 potentiates leiomyoma cell proliferation to growth factors through a PKC-dependent pathway. These findings suggest a possible involvement of ET-1 in the pathogenesis of leiomyomas.

Differential regulation of protein kinase C isoforms in human uterine leiomyoma.

The protein kinase C (PKC) isoenzyme expression pattern in human uterine leiomyoma was compared with that obtained in homologous myometrium distal from the tumor. The six PKC isoforms (PKCalpha, PKCbeta1, PKCbeta2, PKCdelta, PKCepsilon and PKCzeta) evidenced in the myometrium were found to be similarly expressed in leiomyoma. Quantitative immunoblotting revealed that all PKC isoforms were preferentially localized in the particulate fraction. To gain insight into the possible functional consequences of PKC expression patterns, subcellular redistribution in response to the mitogenic peptide endothelin-1 (ET-1) was studied. After stimulation with ET-1, differential redistribution occurred in leiomyoma and myometrium, suggesting a selective role of PKC isoforms in the myometrial growth process.

EP(4) receptors mediate prostaglandin E(2)-stimulated glycosaminoglycan synthesis in human cervical fibroblasts in culture.

The aim of this study was to determine the prostaglandin E (EP) receptors and second messengers implicated in glycosaminoglycan (GAG) synthesis by human cervical fibroblasts in culture. Human cervical fibroblasts were obtained from cervical biopsies in pre-menopausal, cycling women. Cultured cells were incubated with prostaglandin E(2) (PGE(2)) and an array of agonists and antagonists. Glycosaminoglycan synthesis was assayed after extraction by measuring the [(3)H]glucosamine and [(35)S]sulphate incorporated into GAG and cAMP production was determined by radioimmunoassay. PGE(2) significantly stimulated GAG synthesis. Neither 17-phenyl-trinor-PGE(2), the EP(1) selective agonist, nor sulprostone, an EP(3) agonist, had any effect on GAG production. Butaprost, the EP(2) selective agonist, also failed to increase GAG synthesis. AH6809, an EP(2) antagonist, had no effect on PGE(2)-stimulated GAG production. AH23848, an EP(4) antagonist, inhibited the GAG synthesis provoked by PGE(2). PGE(2) and butaprost significantly increased cAMP production. Both AH6809 and AH23848 inhibited the PGE(2)-stimulated cAMP production. H89, a cAMP-dependent protein kinase (PKA) inhibitor, did not inhibit PGE(2)-stimulated GAG synthesis and Sp-cAMPS, a selective PKA activator, failed to increase GAG production. In conclusion, both EP(4) and EP(2) receptors are present and functional in human cervical fibroblasts. Only EP(4) receptors mediate PGE(2) stimulated GAG synthesis in a PKA-independent pathway.

Expression of endothelin receptors in human myometrium during pregnancy and in uterine leiomyomas.

The distribution of mRNAs for endothelinA and B (ET(A) and ET(B)) receptors and their binding properties was studied in human nonpregnant and pregnant term myometrium and in uterine leiomyomas. ET(A)- and ET(B)-receptors functionally coupled to phospholipase C (PLC) coexisted in myometrial tissues, but only the functional ET(A)-receptor subtype was detected in leiomyomas. ET(A)-receptor mRNA and three other spliced variants were distributed in all tissue studied. We reported an increase in the proportion of ET(A)-receptors coupled to PLC in term pregnant myometrium when compared to nonpregnant tissue. These results suggest that upregulation of the myometrial ET(A)-receptors may account for or contribute to the control of normal development and growth of human myometrium during pregnancy. They also support a pathological role for the endothelin-1 (ET-1)/ET(A)-receptor system in leiomyoma development.