Prediction of neonatal respiratory function and pulmonary hypertension in fetuses with isolated congenital diaphragmatic hernia in the fetal endoscopic tracleal occlusion era: a single-center study.

OBJECTIVE: To correlate prenatal indicators of pulmonary hypoplasia with neonatal lung function and pulmonary hypertension (PHT) in isolated congenital diaphragmatic hernia (iCDH). MATERIALS AND METHODS: Prospective single-center study on 40 fetuses with iCDH either expectantly managed (n = 13) or undergoing tracheal occlusion (n = 27). Prenatal predictors included observed/expected lung-head ratio (O/E LHR), observed/expected total fetal lung volume, fetal pulmonary reactivity to maternal O2 administration (Δpulsatility index, ΔPI) and liver-to-thorax ratio (LiTR) as measured in the second and third trimesters. Postnatal outcome measures included survival until discharge, best oxygenation index (OI) and alveolar-arterial oxygen gradient [D(A-a)O2] in the first 24 h of life and the occurrence of PHT in the first 28 days of life. RESULTS: Median gestational age (GA) at evaluations was 27.2 and 34.3 weeks. GA at delivery was 36.0 weeks, and overall survival was 55%. In the second trimester, measurement of lung size, LiTR and pulmonary reactivity were significantly related to survival and the best OI and D(A-a)O2.The occurrence of PHT was better predicted by ΔPI and LiTR. CONCLUSIONS: O/E LHR, LiTR and vascular reactivity correlate with ventilatory parameters in the first 24 h of life. Occurrence of PHT at ≥28 days was best predicted by LiTR and ΔPI, but not by lung size.

From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds.

The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure-activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.

Analysis of the learning process for laparoscopic sacrocolpopexy: identification of challenging steps.

INTRODUCTION AND HYPOTHESIS: We earlier demonstrated that the operation time of laparoscopic sacrocolpopexy (LSCP) by an experienced surgeon drops significantly after 30 cases to reach a steady state after 90. We now aimed to define the learning curve and to identify the most challenging steps for a trainee learning LSCP. METHODS: Prospective consecutive series of 60 patients undergoing LSCP performed by a trainee experienced in operative laparoscopy but not LSCP. Prior to the first case, the trainee primed his endoscopic suturing skills on an endotrainer for 15 h. His operation time and performance score were analysed using moving average analysis (MOA). The former and the occurrence of complications or short-term failures were compared with those of a concurrent control group consisting of patients operated on by a surgeon experienced in LSCP (teacher). The procedure was empirically divided into five consecutive steps (dissection of the promontory, the paracolic gutter and vagina, suturing of the mesh to the vault, stapling to the promontory, and peritonealisation). RESULTS: The MOA of the operation time demonstrated a learning curve for all steps, except for the dissection of and fixation to the promontory. The most time-consuming step is the dissection of the vault, for which it took the trainee 31 procedures to achieve an operation time comparable to that of the teacher. Also, the quality of the dissection improved over time. Suturing of the implant to the vault and peritonealisation took only 10 and 6 procedures respectively. There was no difference in the occurrence of major complications and in one case the trainee asked for assistance. CONCLUSION: Quality of LSCP improves with experience. Operation time falls as well, and the most time-consuming step is the dissection of the paracolic and perivaginal spaces. Prior training in laparoscopic suturing coincided with a short learning process for the phases requiring suturing.

Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission.

OBJECTIVES: Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues. METHODS: From this library, 15 compounds were evaluated in depth using a broad armamentarium of in vitro assays that are part of a preclinical testing algorithm for microbicide development. Antiviral activity was assessed in a cell line, and in primary human cells, against both subtype B and subtype C HIV-1 and against viruses resistant to therapeutic NNRTIs and the candidate NNRTI microbicide dapivirine. Toxicity towards primary blood-derived cells, cell lines originating from the female reproductive tract and female genital microflora was also studied. RESULTS AND CONCLUSIONS: We identified several compounds with highly potent antiviral activity and toxicity profiles that are superior to that of dapivirine. In particular, compound UAMC01398 is an interesting new candidate that warrants further investigation because of its superior toxicity profile and potent activity against dapivirine-resistant viruses.

Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents.

This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains.

Sonographic evaluation of vascular pulmonary reactivity following oxygen administration in fetuses with normal lung development.

OBJECTIVE: This study aimed to establish nomograms for sonographic assessment of fetal pulmonary vascular reactivity following maternal hyperoxygenation. STUDY DESIGN: Sixty-two healthy fetuses were assessed at four weekly intervals from 26 weeks onwards. Pulmonary reactivity was evaluated using Doppler ultrasound in the main pulmonary artery and in the first branch of this main pulmonary artery. The difference in pulsatility index (∆PI) during maternal inhalation of a mixture of room air and oxygen (9 L/min) for at least 10 min was expressed as a percentage. Nomograms were constructed, and Kaplan-Meier curves were used to express the occurrence of a reactive test (∆PI ≥ 20%) with advancing gestation. RESULTS: In the first branch, linear regression analysis revealed a significant correlation of ∆PI (%) with gestational age (r(2) = 0.04, p = 0.0057). Large inter-individual and intra-individual variability was noted. The ∆PI (%) in the main pulmonary artery remained constant throughout gestation (6.62 ± 17.83%). CONCLUSION: Vascular reactivity in the pulmonary circulation increases in the first branch of the pulmonary artery. Large individual variability is limiting its use as a management tool.

Preterm prelabor rupture of membranes and fetal survival after minimally invasive fetal surgery: a systematic review of the literature.

OBJECTIVE: Iatrogenic preterm prelabor rupture of membranes (iPPROM; <37 weeks of gestation) is a major complication of fetal surgery. Little information is available about risk factors and incidence. METHODS: We systematically reviewed reported iPPROM rates, gestational age at delivery and fetal survival after representative minimally invasive antenatal procedures. RESULTS: A total of 1,146, 36 and 194 cases with mean iPPROM rates of 27, 31 and 26% were included for placental laser in twin-twin transfusion syndrome, shunting in lower urinary tract obstruction and interventions for twin-reversed arterial perfusion, respectively. In the statistical analysis, the maximum diameter of the instrument predicted iPPROM rate and was significantly related to gestational age at birth as well as fetal survival. Information on duration of the respective procedures was scarce and did not allow for meaningful analysis. CONCLUSIONS: iPPROM occurs in about 30% of cases treated by minimally invasive fetal surgery. The maximum diameter of the instrument explains iPPROM rate, gestational age at birth and fetal survival. Great variations in the reporting of iPPROM make data analysis difficult.

Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs).

In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A.

Control of viral replication after cessation of HAART.

We describe two patients who did not experience a viral rebound after cessation of HAART which was initiated for progressive disease. CD4 T-cell count remained stable in one patient and progressively declined in the other, despite apparent viral control. We failed to identify any immune activation or genetic markers that could offer an explanation for this unusual "secondary controller" status. But their viruses are clearly less fit compared to viruses from rebounders.

High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations.

TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that is highly effective in treating wild-type and drug-resistant HIV-1 infections in clinical trials at relatively low doses ( approximately 25-75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with TMC278 at 1.8 A resolution, using an RT crystal form engineered by systematic RT mutagenesis. This high-resolution structure reveals that the cyanovinyl group of TMC278 is positioned in a hydrophobic tunnel connecting the NNRTI-binding pocket to the nucleic acid-binding cleft. The crystal structures of TMC278 in complexes with the double mutant K103N/Y181C (2.1 A) and L100I/K103N HIV-1 RTs (2.9 A) demonstrated that TMC278 adapts to bind mutant RTs. In the K103N/Y181C RT/TMC278 structure, loss of the aromatic ring interaction caused by the Y181C mutation is counterbalanced by interactions between the cyanovinyl group of TMC278 and the aromatic side chain of Y183, which is facilitated by an approximately 1.5 A shift of the conserved Y(183)MDD motif. In the L100I/K103N RT/TMC278 structure, the binding mode of TMC278 is significantly altered so that the drug conforms to changes in the binding pocket primarily caused by the L100I mutation. The flexible binding pocket acts as a molecular "shrink wrap" that makes a shape complementary to the optimized TMC278 in wild-type and drug-resistant forms of HIV-1 RT. The crystal structures provide a better understanding of how the flexibility of an inhibitor can compensate for drug-resistance mutations.

Cross-sectional study of tracheomegaly in children after fetal tracheal occlusion for severe congenital diaphragmatic hernia.

PURPOSE: To measure tracheal dimensions in children with congenital diaphragmatic hernia (CDH) who had undergone fetoscopic endoluminal tracheal occlusion (FETO) or were treated expectantly during gestation. MATERIALS AND METHODS: The study was approved by the local ethics committee. Computed tomography was performed in 23 patients (14 boys and nine girls) aged 1 month to 6.5 years, and the anteroposterior diameter, width, area, and perimeter of the trachea were determined. Seven of the 23 patients had undergone FETO and 16 had been treated expectantly. The relative difference of each parameter between the two most proximal concentric sections of the trachea, just below the larynx, and the two sections on which the trachea was the largest was compared between both groups (Mann-Whitney U test). Regression statistics were applied to maximum and mean tracheal areas as a function of age. Each trachea was divided into quartiles, and mean areas normalized to 3 years of age were analyzed for each quartile as a function of its relative position on the trachea (Student t test). RESULTS: Tracheal width, area, and perimeter were significantly different between both groups. A linear relationship was observed between the maximum and mean tracheal areas and age for both the FETO group (maximum tracheal area: R(2) = 0.83, P = .0045; mean tracheal area: R(2) = 0.92, P = .0005) and the non-FETO group (maximum tracheal area: R(2) = 0.66, P = .0001; mean trachea area: R(2) = 0.66, P = .0001). The maximum tracheal area in both groups tended to decrease toward the age of 5 years. Significantly different mean tracheal areas per tracheal quartile (P < .05) were found for all quartiles except for the proximal one-fourth. CONCLUSION: The relative difference between proximal and largest tracheal width, area, and perimeter was significantly larger in patients who underwent FETO than in those treated expectantly, demonstrating tracheal dilatation in the former. Measurements of tracheal dimensions at different levels indicate a maximum dilatation in the lower half of the trachea, which tends to level off toward the age of 5 years.

Albumin as an adjunct to tracheal occlusion in fetal rats with congenital diaphragmatic hernia: a placebo-controlled study.

OBJECTIVE: We sought to investigate effects of intratracheal albumin injection prior to tracheal occlusion (TO) on lung proliferation in fetal rats with nitrofen-induced congenital diaphragmatic hernia. STUDY DESIGN: On embryonic day 19, nitrofen-exposed fetuses underwent TO, TO and 50 microL of either intratracheal albumin 20% or saline, or remained untouched. Main outcome at embryonic day 21.5 was expression of the proliferation marker Ki-67. Secondary outcomes were lung-to-bodyweight ratio (LBWR), tropoelastin expression, density and spatial distribution of elastin, pulmonary/alveolar morphometry, and fetal survival. RESULTS: TO increased Ki-67 messenger RNA and LBWR. Albumin further increased LBWR and density of Ki-67-positive cells but also fetal mortality. TO with or without adjuncts induced elastin deposits at the tips of arising secondary crests, increased air space size, and decreased septal thickness. CONCLUSION: TO had effects on lung proliferation and advanced the morphologic appearance. Addition of albumin increased density of proliferating cells and LBWR, yet at the expense of additional fetal loss.

Sacrocolpopexy using xenogenic acellular collagen in patients at increased risk for graft-related complications.

AIMS: We studied the long-term anatomical and functional outcome following sacrocolpopexy for apical vaginal prolapse using xenogenic grafts in a population at increased risk for graft-related complications (GRCs). METHODS: Twenty-two consecutive patients with symptomatic apical prolapse were scheduled for laparoscopic sacrocolpopexy (LSC) with porcine grafts because they were presumed to be at risk for GRC, because of pre-existing vaginal ulcerations (n = 4), concomitant vaginal prolapse repair (n = 15), total hysterectomy (n = 1), or intra-operative abdominal contamination due to accidental laceration of the vagina, bowel perforation (n = 1) or the presence of infection (n = 1). Either small intestinal submucosa (n = 8) or dermal collagen (n = 14) was used. Outcome measures were GRCs, anatomical cure (

Conazoles.

This review provides a historical overview of the analog based drug discovery of miconazole and its congeners, and is focused on marketed azole antifungals bearing the generic suffix "conazole". The antifungal activity of miconazole, one of the first broad-spectrum antimycotic agents has been mainly restricted to topical applications. The attractive in vitro antifungal spectrum was a starting point to design more potent and especially orally active antifungal agents such as ketoconazole, itraconazole, posaconazole, fluconazole and voriconazole. The chemistry, in vitro and in vivo antifungal activity, pharmacology, and clinical applications of these marketed conazoles has been described.

Assessment of fetal cardiac function before and after therapy for twin-to-twin transfusion syndrome.

OBJECTIVE: We sought to assess fetal cardiac function in monochorionic twins before and after therapy for twin-to-twin transfusion syndrome (TTTS) and compare it with control subjects. STUDY DESIGN: We conducted prospective longitudinal assessment of fetal cardiac function in cases undergoing curative fetal therapy for TTTS (n = 39) until 4 weeks postoperatively and in uncomplicated monochorionic twins (n = 23). Fetal cardiac function was assessed by the left and right ventricular myocardial performance index, atrioventricular valve flow pattern, ductus venosus a-wave, and umbilical vein pulsations. RESULTS: Nomograms for the myocardial performance index were constructed. Fetal cardiac function was grossly abnormal in recipient twins of TTTS when compared with control subjects (P < .001 for all indices) but normalized by 4 weeks postoperatively. The donor developed abnormal ductus venosus flow and tricuspid regurgitation postoperatively that regressed within 4 weeks. CONCLUSION: The cardiac dysfunction in the recipient twin of TTTS normalizes within 1 month after laser. The donor develops a transient impairment of cardiac function postoperatively.

The pregnancy and long-term neurodevelopmental outcome of monochorionic diamniotic twin gestations: a multicenter prospective cohort study from the first trimester onward.

OBJECTIVES: We sought to document the pregnancy and neurodevelopmental outcome in monochorionic diamniotic twin pregnancies and to identify risk factors for death and impairment. STUDY DESIGN: We conducted a prospective cohort study of 136 monochorionic twins followed up from the first trimester until infancy. RESULTS: A total of 122 (90%) pregnancies resulted in 2 survivors, 6 (4%) in 1 survivor and 8 (6%) in no survivor. In all, 230 (92%) of 250 surviving infants were assessed at a mean age of 24 months. Neurodevelopmental impairment was present in 22 (10%) infants. Death or impairment of 1 or both infants occurred in 28 (22%) of 126 pregnancies. Twin-to-twin transfusion syndrome and assisted conception increased the risk of both death and impairment, whereas early-onset discordant growth only increased the risk of death. CONCLUSION: The mortality in this prospective series was 8% and neurodevelopmental impairment occurred in 10% of infants.

The effect of maternal betamethasone and fetal tracheal occlusion on pulmonary vascular morphometry in fetal rabbits with surgically induced diaphragmatic hernia: a placebo controlled morphologic study.

OBJECTIVES: We studied the vascular effects of betamethasone (BM) and/or tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH). METHODS: At day 23 (pseudoglandular phase; term = 31 d), 54 ovarian-end fetuses from 27 does underwent induction of CDH. Thirteen did receive either 0.05 mg/kg BM, on days 28 and 29 with a 24-h interval, or 14 saline [controls (CTR)]. At day 28, one ovarian-end fetus underwent TO and harvesting was at term. In total, we compared (ANOVA) lung-to-body weight ratio (LBWR) and vascular morphometric indices in survivors from the following groups (n - number alive at delivery): CDH (9); CDH + TO (10); unoperated controls (14); CDH + BM (10); CDH + TO (9); controls CTR + BM (13). RESULTS: Maternal BM had no effect on LBWR. LBWR was comparable to normal in CDH fetuses undergoing TO. Both TO and BM have an effect on medial thickening due to CDH which is larger when both interventions are combined. CONCLUSIONS: Both TO and BM lessen peripheric muscularization present in CDH lungs and their effect is cumulative.

Human immunodeficiency virus type 1 (HIV-1) integration: a potential target for microbicides to prevent cell-free or cell-associated HIV-1 infection.

Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4(+) T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for microbicide development.

Antiviral compounds show enhanced activity in HIV-1 single cycle pseudovirus assays as compared to classical PBMC assays.

HIV-1 Env pseudotyped viruses (PV) are an attractive tool for studying the antiviral activities of compounds interfering with virus entry into a target cell. To investigate whether results obtained in PV assays are relevant biologically, the antiviral activity of 6 reference compounds was compared on 5 virus isolates of different clades using three assays: (1) replicating virus in peripheral blood mononuclear cells (PBMCs), (2) PV in CD4 and CCR5- or CXCR4 co-receptor expressing Ghost cells, and (3) PV in PBMCs. A significant linear relationship was found between both single-cycle PV assays (P<0.0001, R2=0.75). Moreover, both assays showed enhanced sensitivity to the antiretrovirals tested (P=0.013 and 0.015, respectively) as compared to the PBMC assay with replication-competent virus. Most importantly, results from the latter assay could be predicted significantly from both PV assays, in which either Ghost target cells (P<0.0001, R2=0.61) or PBMCs (P<0.0001, R2=0.55) were used. The usefulness of the PV assay was demonstrated further by investigating the impact of the HIV-1 Env subtype on the antiviral activity of five new compounds derived from the entry inhibitor BMS806.

The role of ultrasound examination in the first trimester and at 16 weeks' gestation to predict fetal complications in monochorionic diamniotic twin pregnancies.

OBJECTIVE: The purpose of this study was to determine the value of ultrasound examination in the first trimester and at 16 weeks to predict fetal complications in monochorionic diamniotic (MCDA) twin pregnancies, defined as the occurrence of either twin-to-twin transfusion syndrome, severe discordant growth, or intrauterine death. STUDY DESIGN: We identified risk factors to predict a complicated fetal outcome in the first trimester and at 16 weeks in a prospective cohort of 202 twin pregnancies recruited during the first trimester in 2 centers of the EuroTwin2Twin project. RESULTS: Significant predictors in the first trimester were the difference in crown-rump length (odds ratio [OR], 11) and discordant amniotic fluid (OR, 10). At 16 weeks, significant predictors were the difference in abdominal circumference (OR, 29), discordant amniotic fluid (OR, 7), and discordant cord insertions (OR, 3). Risk assessment in the first trimester and at 16 weeks detected 29% and 48% of cases with a complicated fetal outcome, respectively, with a false-positive rate of 3% and 6%, respectively. Combined first-trimester and 16 week assessment identified 58% of fetal complications, with a false-positive rate of 8%. CONCLUSION: Of the MCDA twin pregnancies classified as high risk on the combined first trimester and 16 weeks assessment (n = 41), 73% had a complicated fetal outcome with a survival rate of only 69%. In contrast, of the pregnancies classified as low risk (n = 154), 86% had an uneventful fetal outcome with a survival rate of 95%.