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Human African trypanosomiasis (HAT), also known as sleeping sickness is a parasitic disease transmitted by the bite of the 'Glossina' insect, commonly known as the tsetse fly. This disease affects mostly poor populations living in remote rural areas of Africa. Untreated, it is usually fatal. Currently, safe and effective treatments against this disease are lacking. Phenotypic screening of triazine non-nucleoside HIV-1 reverse transcriptase inhibitors (monomers) resulted in potent and selective antitrypanosomal compounds. This serendipitous discovery and the presence of dimers in many compounds active against these neglected tropical diseases prompted us to investigate antitrypanosomal activity of triazine dimers. Optimization of the triazine dimers resulted in 3,3'-(((ethane-1,2-diylbis(azanediyl))bis(4-(mesityloxy)-1,3,5-triazine-6,2-diyl))bis(azanediyl))dibenzonitrile (compound 38), a compound with very potent in vitro and moderate in vivo antitrypanosomal activity.

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New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.

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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.

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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.

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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.

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Diaryltriazines (DATAs) constitute a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are being investigated for use as anti-HIV microbicides. The aim of the present study was (1) to assess the biopharmaceutical properties of the DATA series, (2) to select the lead candidate as vaginal microbicide and (3) to develop and evaluate gel formulations of the lead candidate. First, the vaginal tissue permeation potential of the different DATAs was screened by performing permeability and solubility measurements. To obtain a suitable formulation of the lead microbicide candidate, several hydroxyethylcellulose-based gels were assessed for their cellular toxicity, stability and ability to enable UAMC01398 epithelial permeation. Also, attention was given to appropriate preservative selection. Because of its favourable in vitro activity, safety and biopharmaceutical profile, UAMC01398 was chosen as the lead microbicide candidate among the DATA series. Formulating UAMC01398 as a vaginal gel did not affect its anti-HIV activity. Safe and chemically stable gel formulations of UAMC01398 (0.02%) included a non-solubilizing gel and a gel containing sulfobutyl ether-ß-cyclodextrin (SBE-ßCD, 5%) as solubilizing excipient. Inclusion of SBE-ßCD in the gel formulation resulted in enhanced microbicide flux across HEC-1A epithelial cell layers, to an extent that could not be achieved by simply increasing the dose of UAMC01398. The applied rational (pre)formulation approach resulted in the development of aqueous-based gel formulations that are appropriate for further in vivo investigation of the anti-HIV microbicide potential of the novel NNRTI UAMC01398.

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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.

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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.

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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.

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The CAPRISA 004 study in South Africa has accelerated the development of vaginal and rectal microbicides containing antiretrovirals that target specific enzymes in the reproduction cycle of HIV, especially reverse transcriptase inhibitors (RTI). In this review we discuss the potential relevance of HIV-1 RTIs as microbicides, focusing in the nucleotide RTI tenofovir and six classes of nonnucleoside RTIs (including dapivirine, UC781, urea and thiourea PETTs, DABOs and a pyrimidinedione). Although tenofovir and dapivirine appear to be most advanced in clinical trials as potential microbicides, several issues remain unresolved, e.g., the importance of nonhuman primates as a "gatekeeper" for clinical trials, the emergence and spread of drug-resistant mutants, the combination of microbicides that target different phases of viral reproduction and the accessibility to microbicides in low-income countries. Thus, here we discuss the latest research on RTI as microbicides in the light of the continuing spread of the HIV pandemic from the point of view of medicinal chemistry, virological, and pharmaceutical studies.

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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.

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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.

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In isolated congenital diaphragmatic hernia, lung size and/or the position of the liver are predictive of neonatal outcome. Percutaneous Fetal Endoscopic Tracheal Occlusion (FETO) by a balloon can be undertaken to prompt lung growth in the worst cases. The feasibility and safety of FETO is no longer at stake, and it is associated with an apparent increase in neonatal survival. The gestational age at birth, the pre-existing lung size, the ability to remove the balloon prior to birth, and the lung response are predicting outcome. The most frequent complication is preterm premature rupture of the membranes, and as a consequence preterm delivery, which also complicates balloon removal. We have set up a randomized trial for the formal evaluation of FETO in Europe, including criteria for fetoscopy centers. Training of European as well as North American centers is taking place, so that the procedure could be safely and more widely offered.

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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.

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In isolated congenital diaphragmatic hernia, prenatal prediction is made based on measurements of lung size and the presence of liver herniation into the thorax. A subset of fetuses likely to die in the postnatal period is eligible for fetal intervention that can promote lung growth. Rather than anatomical repair, this is now attempted by temporary fetal endoscopic tracheal occlusion (FETO). Herein we describe purpose-designed instruments that were developed thanks to a grant from the European Commission. The feasibility and safety of FETO have now been demonstrated in several active fetal surgery programs. The most frequent complication of the procedure is preterm premature rupture of the membranes, which is probably iatrogenic in nature. It does have an impact on gestational age at delivery and complicates balloon removal. FETO is associated with an apparent increase in survival compared with same severity controls, although this needs to be evaluated in a formal trial. The time has come to do so.

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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.

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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.

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AIM: Describe lung tissue and central airway mechanics using forced oscillation in preterm rabbits at different gestational ages and after maternal administration of betamethasone (BM). METHODS: One hundred twelve fetuses from 54 does were studied. Ventilation was done using a Flexivent (Scireq, Montreal, Canada). Resistance (Rrs), compliance/bodyweight (Crs/bw), Newtonian resistance (Rn), tissue damping (G(L)), and elastance (H(L)) were assessed. Maturational changes were studied in normal controls at days 27-31. The effect of BM (0.05 mg/kg on days 25 and 26) or placebo was studied in preterm fetuses at days 27, 28, and 29. RESULTS: In unmanipulated control fetuses, Rrs decreased and Crs/bw increased with advancing gestation. Rn remained stable while G(L) and H(L) decreased. After day 29 no differences in pulmonary mechanics were observed. At 28 days Rrs and Crs/bw in BM and placebo fetuses were better compared to controls. At 29 days, Crs/bw and Rrs were higher, respectively, lower in control fetuses than BM or placebo exposed pups. CONCLUSION: Maturational changes in preterm rabbits occur mainly up to day 29 of gestation and are largely due to changes in tissue mechanics. Maternal BM injection improves lung mechanics at 28 days but placebo has equal effects.

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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.

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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 (

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