A new LC/MS method for specific determination of human systemic exposure to bisphenol A, F and S through their metabolites: Application to cord blood samples.

Due to restriction of the use of BPA, several structural analogues such as BPS and BPF have been proposed for its replacement in many consumer products. This has increased the prevalence of BPS and BPF in urine from tested cohorts. However, these substitutes have similar endocrine disrupting properties to BPA, particularly on reproductive and metabolic functions, which suggests that fetal exposure to these analogues could be of concern for human health. Bisphenols (BPs) are mainly metabolized to glucuronides (BP-Gs), which are considered as inactive but provide a relevant marker of fetal exposure during pregnancy. In most instances, these metabolites are indirectly quantified after hydrolysis and measurement of the corresponding native BPs, which may lead to bias due to spurious BPs contamination during blood collection and/or analyses. We have developed a new method for direct quantification of BP-Gs, which has the advantage of not being affected by errors related to the presence of BPs. First, BP-Gs were extracted from plasma by anion exchange solid phase extraction. They were then labelled with dansyl chloride, using experimentally-optimized incubation conditions, after which the dansyl derivatives were injected into an on-line SPE-UHPLC/MS/MS system. The performance of the method, in terms of sensitivity, precision and accuracy, was evaluated in plasma over a concentration range of 0.05-5 ng/mL. The intra- and inter-day CV% precision were lower than 20% with accuracies ranging from 93% to 115%. The limit of quantification was set at 0.05 ng/mL. The method was then applied to measure BP-Gs in forty-four cord plasma samples. Although no BPF-G was found, BPA-G and BPS-G was determined in almost half of the cord plasma samples with concentration ranges nd-0.089 ng/mL and nd-0.586 ng/mL, respectively.

Acute steroid myopathy: a highly overlooked entity.

BACKGROUND: Myopathy in patients being treated with corticosteroids is known primarily among chronically treated patients or in critically ill and mechanically ventilated patients receiving corticosteroids, often in high doses. AIM: To highlight the entity of acute, early onset corticosteroid-treatment-associated myopathy and its characteristics. DESIGN AND METHODS: Reporting our experience with four patients and reviewing all published reports of myopathy developing ≤14 days of initiating corticosteroid-treatment. RESULTS: Acute corticosteroid myopathy (ASM) exists, though the syndrome appears to be rare. It is characterized by unpredictability and heterogeneity, sometimes developing within 1-3 days, after a single dose, which may not be high and administered by varied routes. Proximal limb muscle weakness is the most common form, but distal limb, bulbar and respiratory muscles may be involved. Steroid cessation often leads to improvement/resolution, but irreversibility may occur. CONCLUSIONS: A high index of suspicion for the possibility of ASM is necessary to ensure drug discontinuation and recovery. This is particularly true since the entity is not widely recognized and its symptoms are often erroneously interpreted as due to the patient's underlying disease.

[Is rapid intrapartum vaginal screening test of group B streptococci (GBS) during partum useful in identifying infants developing early-onset GBS sepsis in postpartum period?]. / Test de dépistage rapide intra partum du portage vaginal de streptocoque du groupe B (SGB) pour le repérage des nouveau-nés à risque d'infection néonatale précoce à SGB. Étude observationnelle analytique dans une maternité de type III.

INTRODUCTION: Group B streptococcus (GBS) is the most common infectious agent responsible for early-onset bacterial sepsis (EOS) in term newborns. French prevention of perinatal GBS disease guidelines recommend screening for maternal vaginal GBS colonization at the 9th month of pregnancy, and use of intrapartum antibiotic prophylaxis (IAP) in case of detected GBS vaginal colonization. Peripheral bacterial sampling (gastric aspiration, ear, or meconium) and measurement of C-reactive protein (CRP) are performed in asymptomatic newborns in case of infectious risk factors and/or incomplete IAP. OBJECTIVE: The aim of this study was to investigate the relation between a rapid intrapartum screening test for GBS during labor in term parturients and infants developing GBS EOS and in comparison to current recommendations. METHODS: We conducted an observational analytic single-center study, with use of a rapid intrapartum GBS screening test, at Toulouse University Hospital. RESULTS: A total of 1416 mother-newborn dyads were prospectively included between 31/01/2012 and 17/08/2012. Vaginal GBS colonization was found at the 9th month of pregnancy in 148 mothers (10.6 %), and 176 mothers (12.5 %) were screened positively at delivery using intrapartum GBS rapid polymerase chain reaction assay (GBS PCR) (P=0.025). No confirmed neonatal GBS EOS was found. Nine infants had suspected GBS EOS because of a positive peripheral bacterial finding and elevated CRP. In these infants, seven pregnant mothers were GBS-positive with GBS PCR assay during labor, and four women were positive on prenatal culture at the 9th month of pregnancy. The diagnostic values of the two tests highlighted a nonsignificant superiority of intrapartum GBS PCR assay (AUC=0.83 [0.68-0.97] vs. 0.67 [0.50-0.84]), (P=0.057). The negative predictive value was improved with intrapartum PCR assay (negative likelihood ratio [LR]: 0.3 [0.1-0.9] vs. 0.6 [0.4-1.1]). Intrapartum GBS PCR assay provided its best positive predictive value in the absence of complete AIP and without other infectious factors (positive LR: 21.3 [15.4-29.5]). CONCLUSION: These results suggest that the intrapartum GBS PCR assay offers a better predictive value of GBS EOS than the usual vaginal culture swab at the 9th month but requires confirmation by large studies.

[Reproductive options for people living with HIV: 2013 guidelines from the French expert working group]. / Désir d'enfant chez les personnes vivant avec le VIH : nouvelles recommandations 2013 du groupe d'experts français.

The desire for children is a legitimate aspiration that should be part of multidisciplinary care for all men, women or couples living with HIV. The use of effective antiretroviral therapy has revolutionized the prevention of sexual, as well as mother-to-child HIV transmission. When the HIV plasma viral load is undetectable on long-term antiretroviral therapy, the risk of mother-to-child transmission is <1% and the risk of heterosexual HIV transmission without condom use in a stable relationship is very low (estimated at less than 1/10,000) in the absence of inflammation of the genital tract. In a man with a long-term undetectable viral load, viral shedding in semen is uncommon, but may occur persistently or intermittently. The same appears true of viral shedding in the vaginal tract of women. Reproductive options are: natural conception, self-insemination when the woman is HIV-infected, assisted reproduction. Natural conception is now considered to be an acceptable option when the conditions are met, after exploring four aspects: (1) virological (viral load undetectable sustained for at least 6 months on therapy), (2) genital (absence of genital infections or lesions), (3) fertility (after appropriate evaluation) and (4) detecting the ovulation period to limit intercourse without condoms. Assisted reproduction has two objectives in the context of HIV, to allow the couple to conceive without abandoning condom use and/or to treat infertility.

[HIV and pregnancy: 2013 guidelines from the French expert working group]. / Infection par le VIH et grossesse: nouvelles recommandations 2013 du groupe d'experts français.

With effective antiretroviral therapy, the risk of mother to child transmission (MTCT) is now under 1%. The 2013 French guidelines emphasize early antiretroviral lifelong antiretroviral therapy. Thus, the current trend for women living with HIV is to take antiretroviral therapy before, during and after their pregnancies. A major issue today is the choice of antiretroviral drugs, to maximize the benefits and minimize the risks of fetal exposure. This requires interdisciplinary care. The use of effective therapies permits gradual but profound changes in obstetric practice. When maternal plasma viral load is controlled (<50 copies/ml), obstetrical care can be more similar to standards in HIV-negative women. Prophylactic cesarean section is recommended when the viral load in late pregnancy is above 400 copies/mL. Intravenous zidovudine during labor is recommended only if the last maternal viral load is>400 copies/mL or in case of complications such as preterm delivery, bleeding or chorio-amnionitis during labor. In case of premature rupture of membranes before 34 weeks, a multidisciplinary decision should be made, based on gestational age and control of maternal viral load; if the woman is under antiretroviral therapy and especially if her viral load is undetectable, steroids and antibiotics should be offered and pregnancy can be continued except in case of signs or symptoms of chorio-amnionitis. Breastfeeding is not recommended in women living with HIV in France, as in industrialized countries. Prophylaxis in the newborn is usually zidovudine for 1 month. In case of significant exposure to HIV perinatally, in particular when, maternal viral load is>1000 copies/mL, prophylactic combination therapy is recommended. Monitoring of the child is necessary to determine whether or not it is free of HIV infection and to monitor possible adverse effects of perinatal exposure to antiretroviral drugs.

Bidirectional placental transfer of Bisphenol A and its main metabolite, Bisphenol A-Glucuronide, in the isolated perfused human placenta.

The widespread human exposure to Bisphenol A (BPA), an endocrine disruptor interfering with developmental processes, raises the question of the risk for human health of BPA fetal exposure. In humans, highly variable BPA concentrations have been reported in the feto-placental compartment. However the human fetal exposure to BPA still remains unclear. The aim of the study was to characterize placental exchanges of BPA and its main metabolite, Bisphenol A-Glucuronide (BPA-G) using the non-recirculating dual human placental perfusion. This high placental bidirectional permeability to the lipid soluble BPA strongly suggests a transport by passive diffusion in both materno-to-fetal and feto-to-maternal direction, leading to a calculated ratio between fetal and maternal free BPA concentrations of about 1. In contrast, BPA-G has limited placental permeability, particularly in the materno-to-fetal direction. Thus the fetal exposure to BPA conjugates could be explained mainly by its limited capacity to extrude BPA-G.

Dietary exposure to perfluoroalkyl acids of specific French adult sub-populations: high seafood consumers, high freshwater fish consumers and pregnant women.

Perfluoroalkyl acids (PFAAs) are globally found in various media, including food and especially fishery products. In the present study, the dietary exposure to 15 perfluoroalkyl acids was assessed for 3 French adult populations, namely high seafood consumers, high freshwater fish consumers, and pregnant women. Purified food extracts were analysed by LC-MS/MS and PFBA, PFPA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFTeDA, PFBS, PFHxS, PFHpS, PFOS and PFDS were monitored and quantified according to the isotope dilution principle. Under lower bound (LB) hypothesis (i.e. contamination values

CD84 is a survival receptor for CLL cells.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and bone marrow. The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the signaling lymphocyte activating molecule family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both downmodulation of CD84 expression and its immune-mediated blockade induce cell death in vitro and in vivo. In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 (milatuzumab), shows a decrease in CD84 messenger RNA and protein levels in milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 expression. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.

Effects of ketamine on response properties of neurons in the superior paraolivary nucleus of the mouse.

The superior paraolivary nucleus (SPON; alternative abbreviation: SPN for the same nucleus in certain species) is a prominent brainstem structure that provides strong inhibitory input to the auditory midbrain. Previous studies established that SPON neurons encode temporal sound features with high precision. These earlier characterizations of SPON responses were recorded under the influence of ketamine, a dissociative anesthetic agent and known antagonist of N-methyl-d-aspartate glutamate (NMDA) receptors. Because NMDA alters neural responses from the auditory brainstem, single unit extracellular recordings of SPON neurons were performed in the presence and absence of ketamine. In doing so, this study represents the first in vivo examination of the SPON of the mouse. Herein, independent data sets of SPON neurons are characterized that did or did not receive ketamine, as well as neurons that were recorded both prior to and following ketamine administration. In all conditions, SPON neurons exhibited contralaterally driven spikes triggered by the offset of pure tone stimuli. Ketamine lowered both evoked and spontaneous spiking, decreased the sharpness of frequency tuning, and increased auditory thresholds and first-spike latencies. In addition, ketamine limited the range of modulation frequencies to which neurons phase-locked to sinusoidally amplitude-modulated tones.

Novel model of placental tissue explants infected by cytomegalovirus reveals different permissiveness in early and term placentae and inhibition of indoleamine 2,3-dioxygenase activity.

Human cytomegalovirus (HCMV) is the most common cause of viral intrauterine infection. Placental infection suggests hematogenous spread and permissiveness may vary according to the age of pregnancy. We set up and investigate permissivity of early and term placenta to HCMV with an ex vivo model of placental histocultures and evaluate the activity profile of IDO. Fourteen first trimester placentae were obtained following elective abortion and twelve term placentae after elective caesarean section. Fresh placental chorionic villi were isolated, washed and distributed on collagen sponge gels after overnight incubation with the virus. The culture medium was collected and fresh medium renewed regularly. Histology and immunohistochemistry showed preserved villous integrity in cultured placental histocultures. Infection could be seen in tissue sections of both early and term placentae, although early placentae were more permissive. Indoleamine 2,3-dioxygenase (IDO) is highly expressed in the placenta and is known to prevent maternal immune rejection. Constitutive IDO activity was higher in early, compared to term placentae and HCMV infection inhibited IDO activity in early placentae. IFN-γ-induced IDO activity was suppressed by HCMV in both early and term placentae. Our work shows a novel method of placenta organ culture. Our findings suggest that HCMV infects early placentae more strongly than term placentae. Early placental dysfunction through the inhibition of IDO activity may reveal a possible mechanism for miscarriages.

Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.

BACKGROUND: On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. METHODS: Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. FINDINGS: 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. INTERPRETATION: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche.

Connections of the superior paraolivary nucleus of the rat: projections to the inferior colliculus.

GABAergic neurotransmission contributes to shaping the response properties of inferior colliculus (IC) neurons. In rodents, the superior paraolivary nucleus (SPON) is a prominent and well-defined cell group of the superior olivary complex that sends significant but often neglected GABAergic projections to the IC. To investigate the trajectory, distribution and morphology of these projections, we injected the neuroanatomical tracer biotinylated dextran amine into the SPON of albino rats. Our results demonstrate that: (1) the SPON innervates densely all three subdivisions of the ipsilateral IC: central nucleus (CNIC), dorsal cortex (DCIC) and external cortex (ECIC). The SPON also sends a sparse projection to the contralateral DCIC via the commissure of the IC. (2) SPON axons are relatively thick (diameter >1.2 microm), ascend to the midbrain tectum in the medial aspect of the lateral lemniscus, and, for the most part, do not innervate the nuclei of the lateral lemniscus. (3) SPON fibers ramify profusely within the IC and bear abundant en passant and terminal boutons. (4) The axons of neurons in discrete regions of the SPON form two laminar terminal plexuses in the ipsilateral IC: a medial plexus that spans the CNIC and DCIC parallel to the known fibrodendritic laminae of the CNIC, and a lateral plexus located in the ECIC and oriented more or less parallel to the surface of the IC. (5) The projection from SPON to the ipsilateral IC is topographic: medial SPON neurons innervate the ventromedial region of the CNIC and DCIC and the ventrolateral region of the ECIC, whereas more laterally situated SPON neurons innervate more dorsolateral regions of the CNIC and DCIC and more dorsomedial regions of the ECIC. Thus, SPON fibers follow a pattern of distribution within the IC similar to that previously reported for intracollicular and corticocollicular projections.

Diagnosis of congenital toxoplasmosis: prenatal and neonatal evaluation of methods used in Toulouse University Hospital and incidence of congenital toxoplasmosis.

The aim of this study was to determine the incidence of congenital toxoplasmosis (CT) and to assess the performances of prenatal and neonatal diagnoses. From 1994-2005, in Toulouse University Hospital, France, amniocentesis was performed on 352 pregnant women who were infected during pregnancy. All women were treated with spiramycin and pyrimethamine-sulfadoxine when prenatal diagnosis was positive. Among the 275 foetuses with follow-up, 66 (24%) were infected. The transmission rates of Toxoplasma gondii were 7%, 24% and 59% in the first, second and third trimesters, respectively. The sensitivity and specificity of PCR on amniotic fluid (AF) were 91% and 99.5%, respectively. One case was diagnosed by mouse inoculation with AF and six cases were diagnosed by neonatal or postnatal screening. The sensitivity and specificity of PCR on placentas were 52% and 99%, respectively. The sensitivity of tests for the detection of specific IgA and IgM in cord blood was 53% and 64%, respectively, and specificity values were 91% and 92%. In conclusion, PCR performed on AF had the highest levels of sensitivity and specificity for the diagnosis of CT. This permits an early diagnosis of most cases and should be recommended.

Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database.

BACKGROUND: Because of the limited data concerning drug risks in pregnancy, health professionals are often deprived of relevant and sufficient information related to prescribing or dispensing during pregnancy. However, previous studies have emphasised the widespread French prescription of several drugs (sometimes "typically French") which have not been assessed in pregnant women. OBJECTIVES: The aim of the present study was to create the first French database of drugs prescribed and dispensed during pregnancy and the outcome of these pregnancies. METHODS: This feasibility study concerns pregnant women who gave birth to a baby between 1 July 2004 to 30 June 2005 in Haute-Garonne and who are registered in the French Health Insurance Service. Data sources include (1) the French Health Insurance Database (drugs prescribed during pregnancy), (2) the Mother and Child Protection Centre Database (newborn health at birth and 9 months after) and (3) the Antenatal Diagnostic Centre Database (medical pregnancy interruptions). RESULTS: The database is composed of 10,174 "mother-outcome" pairs. The prevalence rate of congenital anomalies was 2.2%. Pregnant women were prescribed 11.3 +/- 8.2 different drugs. Among the 20 most frequently prescribed drugs, around half of them have not been evaluated in pregnant women. CONCLUSIONS: The first results of this study show that implementation of a French database on prescription of drugs and pregnancy outcomes is feasible. Compared with several databases available in other countries, EFEMERIS provides exact data on period of exposure to drugs, pregnancy terminations, and follow up of the baby 9 months after birth. Recording these data would make it possible to assess the risk of malformations due to a greater number of drugs and would contribute to international drug evaluation studies.

Diagnosis of congenital toxoplasmosis: prenatal and neonatal evaluation of methods used in Toulouse University Hospital and incidence of congenital toxoplasmosis

The aim of this study was to determine the incidence of congenital toxoplasmosis (CT) and to assess the performances of prenatal and neonatal diagnoses. From 1994-2005, in Toulouse University Hospital, France, amniocentesis was performed on 352 pregnant women who were infected during pregnancy. All women were treated with spiramycin and pyrimethamine-sulfadoxine when prenatal diagnosis was positive. Among the 275 foetuses with follow-up, 66 (24 percent) were infected. The transmission rates of Toxoplasma gondii were 7 percent, 24 percent and 59 percent in the first, second and third trimesters, respectively. The sensitivity and specificity of PCR on amniotic fluid (AF) were 91 percent and 99.5 percent, respectively. One case was diagnosed by mouse inoculation with AF and six cases were diagnosed by neonatal or postnatal screening. The sensitivity and specificity of PCR on placentas were 52 percent and 99 percent, respectively. The sensitivity of tests for the detection of specific IgA and IgM in cord blood was 53 percent and 64 percent, respectively, and specificity values were 91 percent and 92 percent. In conclusion, PCR performed on AF had the highest levels of sensitivity and specificity for the diagnosis of CT. This permits an early diagnosis of most cases and should be recommended.

Novel derivatives of 6-mercaptopurine: synthesis, characterization and antiproliferative activities of S-allylthio-mercaptopurines.

Biologically active S-allylthio derivatives of 6-mercaptopurine (6-MP) and 6-mercaptopurine riboside (6-MPR) were synthesized. The products, S-allylthio-6-mercaptopurine (SA-6MP) and S-allylthio-6-mercaptopurine riboside (SA-6MPR) were characterized. The antiproliferative activity of the new prodrugs was tested on human leukemia and monolayer cell lines, and compared to that of their parent reactants. The new prodrugs acted by a concentration-dependent mechanism. They inhibited cell proliferation and induced-apoptosis more efficiently than the parent molecules. Leukemia cell lines were more sensitive to the new prodrugs than monolayer cell lines. Higher hydrophobicity of the derivatives improves their penetration into cells, where upon reaction with glutathione, S-allylthioglutathione (GSSA) is formed, and 6-MP or 6-MPR is released for further processing.

Direct antiglobulin test reactive with complement only in warm type autoimmune hemolytic anemia.

Direct antiglobulin test (DAT) with only complement detected on red blood cells is a rare laboratory finding, and its significance in the setting of warm autoimmune hemolytic anemia (AIHA) is controversial. During 2 years (2003-2004) 277 patients with positive DAT were recorded in the blood bank registries, 17 of them had DAT reactive with C3 alone with no cold agglutinin or other nonimmune causes for hemolysis diagnosed. Red cell eluate disclosed small amounts of IgG in two patients. In nine patients no signs of clinical hemolysis were found, however, all these patients had underlying conditions that are known to be associated with red cells autoantibodies (autoimmune disorder or malignancy). Eight patients developed AIHA, seven of them with severe hemolysis. Three patients had idiopathic AIHA, and the others have been diagnosed with infectious, lymphoproliferative and autoimmune disorders. In two patients with acute infection the hemolytic process spontaneously resolved, three responded to corticosteroid therapy, while three patients were refractory to two lines of drug therapy and underwent splenectomy. Reticulocytopenia was found in four patients. Our results emphasize that AIHA with DAT reactive with complement alone is a rare disorder and might be accompanied by severe, refractory to conventional treatment and life-threatening hemolysis.

[Frequency, persistence and recurrence of HPV lesions of the uterine cervix in HIV-seropositive women]. / Fréquence, persistance et récidive des lésions à HPV du col utérin chez les patientes séropositives pour le VIH.

OBJECTIVE: The aim of this study was to determine the frequency, persistence and risk of recurrence of human papillomavirus (HPV) lesions of the uterine cervix in human immunodeficiency virus (HIV)-infected women. PATIENTS AND METHODS: To determine the frequency of such lesions, we compared 148 HIV-positive patients with 4862 HIV-negative patients who had a cervical smear test in Toulouse university hospital. To determine the persistence and recurrence rate of the lesions, we prospectively followed 63 of the HIV-positive patients. Their follow-up was compared with that of 227 of the HIV-negative patients. RESULTS: Abnormal smears were much more frequent in HIV-positive patients (42 versus 5%, P<0.001). Persistence or aggravation of the lesions was also greater in HIV-positive patients (82 versus 43%, P<0.001). Lastly, the recurrence rate of dysplastic lesions after treatment was significantly higher in HIV-positive patients (64 versus 11%, P<0.001). DISCUSSION AND CONCLUSION: As the frequency, persistence and risk of recurrence of cervical HPV lesions are very high in HIV-positive women, close gynecological surveillance of these patients is indispensable. Surveillance must not be restricted to the uterine cervix because of the frequency of multifocal lesions: vagina, vulva, perineum and anus. It must also be adapted to the severity of immunodeficiency and the patient's history.

Encoding of temporal features of auditory stimuli in the medial nucleus of the trapezoid body and superior paraolivary nucleus of the rat.

Neurons in the superior paraolivary nucleus (SPON) of the rat respond to the offset of pure tones with a brief burst of spikes. Medial nucleus of the trapezoid body (MNTB) neurons, which inhibit the SPON, produce a sustained pure tone response followed by an offset response characterized by a period of suppressed spontaneous activity. This MNTB offset response is duration dependent and critical to the formation of SPON offset spikes [Kadner A, Kulesza RJ Jr, Berrebi AS (2006) Neurons in the medial nucleus of the trapezoid body and superior paraolivary nucleus of the rat may play a role in sound duration coding. J Neurophysiol. 95:1499-1508; Kulesza RJ Jr, Kadner A, Berrebi AS (2007) Distinct roles for glycine and GABA in shaping the response properties of neurons in the superior paraolivary nucleus of the rat. J Neurophysiol 97:1610-1620]. Here we examine the temporal resolution of the rat's MNTB/SPON circuit by assessing its capability to i) detect gaps in tones, and ii) synchronize to sinusoidally amplitude modulated (SAM) tones. Gap detection was tested by presenting two identical pure tone markers interrupted by gaps ranging from 0 to 25 ms duration. SPON neurons responded to the offset of the leading marker even when the two markers were separated only by their ramps (i.e. a 0 ms gap); longer gap durations elicited progressively larger responses. MNTB neurons produced an offset response at gap durations of 2 ms or longer, with a subset of neurons responding to 0 ms gaps. SAM tone stimuli used the unit's characteristic frequency as a carrier, and modulation rates ranged from 40 to 1160 Hz. MNTB neurons synchronized to modulation rates up to approximately 1 kHz, whereas spiking of SPON neurons decreased sharply at modulation rates >or=400 Hz. Modulation transfer functions based on spike count were all-pass for MNTB neurons and low-pass for SPON neurons; the modulation transfer functions based on vector strength were low-pass for both nuclei, with a steeper cutoff for SPON neurons. Thus, the MNTB/SPON circuit encodes episodes of low stimulus energy, such as gaps in pure tones and troughs in amplitude modulated tones. The output of this circuit consists of brief SPON spiking episodes; their potential effects on the auditory midbrain and forebrain are discussed.