RESUMEN
OBJECTIVES: To compare the ambulatory status of a cohort of children who had undergone prenatal repair of an open neural tube defect (ONTD) using one of two different methods (fetoscopic or open hysterotomy) with that of a cohort who had undergone postnatal repair, and to identify the best predictors of ambulation at 30 months of age. METHODS: This was a retrospective review of a cohort of children who underwent ONTD repair either prenatally (n = 110), by fetoscopic surgery (n = 73) or open hysterotomy surgery (n = 37), or postnatally (n = 51), in a single tertiary hospital between November 2011 and May 2023. The cohort comprised a consecutive sample of cases who had undergone ONTD repair in-utero following Management of Myelomeningocele Study (MOMS) trial criteria and cases who had undergone postnatal repair, meeting the same criteria, which were also followed up after birth at the same institution. Motor function assessment by ultrasound was recorded at referral, 6 weeks after prenatal repair, or after referral in postnatally repaired cases, and at the last ultrasound scan before delivery. Clinical examinations to assess motor function at birth and at 12 months were retrieved from records. Intact motor function was defined as first sacral myotome (S1) motor function. Ambulatory status data at each follow-up visit were collected. The proportion of children who were able to walk independently after 30 months of age was compared between those who had undergone fetoscopic vs open prenatal surgery and between prenatal (by either fetoscopic or open surgery) and postnatal ONTD repair. Logistic regression analyses were performed to identify predictors for independent ambulation. RESULTS: After 30 months, the proportion of infants who were able to walk independently was higher in prenatally vs postnatally repaired cases (51.8% vs 15.7%, P < 0.01), and there was no difference between those with fetoscopic (52.1%) vs open (51.4%) prenatal repair (P = 0.66). In the prenatally repaired group, having intact motor function at 12 months (adjusted odds ratio (aOR), 9.14 (95% CI, 2.64-31.63), P < 0.01) and at birth (aOR, 4.50 (95% CI, 1.21-16.80), P = 0.02) were significant predictors of independent walking at 30 months; an anatomical level of lesion below L2 at referral (aOR, 1.83 (95% CI, 1.30-2.58), P = 0.01) and female gender (aOR, 3.51 (95% CI, 1.43-8.61), P < 0.01) were also predictive for this outcome. CONCLUSIONS: Prenatally repaired cases of ONTD have a better chance of being able to walk independently at 30 months than do those who undergo postnatal repair. In patients with prenatally repaired ONTD, ambulatory status at 30 months can be predicted by observing a low lesion level at referral (below L2) and intact motor function postnatally. These results have implications for parental counseling and planning for supportive therapy in pregnancies affected by ONTD. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.
Asunto(s)
Fetoscopía , Histerotomía , Defectos del Tubo Neural , Caminata , Humanos , Fetoscopía/métodos , Femenino , Estudios Retrospectivos , Embarazo , Histerotomía/métodos , Defectos del Tubo Neural/cirugía , Defectos del Tubo Neural/diagnóstico por imagen , Preescolar , Masculino , Resultado del Tratamiento , Recién NacidoRESUMEN
OBJECTIVE: In-utero repair of an open neural tube defect (ONTD) reduces the risk of developing severe hydrocephalus postnatally. Perforation of the cavum septi pellucidi (CSP) may reflect increased intraventricular pressure in the fetal brain. We sought to evaluate the association of perforated CSP visualized on fetal imaging before and/or after in-utero ONTD repair with the eventual need for hydrocephalus treatment by 1 year of age. METHODS: This was a retrospective cohort study of consecutive patients who underwent laparotomy-assisted fetoscopic ONTD repair between 2014 and 2021 at a single center. Eligibility criteria for surgery were based on those of the Management of Myelomeningocele Study (MOMS), although a maternal prepregnancy body mass index of up to 40 kg/m2 was allowed. Fetal brain imaging was performed with ultrasound and magnetic resonance imaging (MRI) at referral and 6 weeks postoperatively. Stored ultrasound and MRI scans were reviewed retrospectively to assess CSP integrity. Medical records were reviewed to determine whether hydrocephalus treatment was needed within 1 year of age. Parametric and non-parametric tests were used as appropriate to compare outcomes between cases with perforated CSP and those with intact CSP as determined on ultrasound at referral. Logistic regression analysis was performed to assess the predictive performance of various imaging markers for the need for hydrocephalus treatment. RESULTS: A total of 110 patients were included. Perforated CSP was identified in 20.6% and 22.6% of cases on preoperative ultrasound and MRI, respectively, and in 26.6% and 24.2% on postoperative ultrasound and MRI, respectively. Ventricular size increased between referral and after surgery (median, 11.00 (range, 5.89-21.45) mm vs 16.00 (range, 7.00-43.5) mm; P < 0.01), as did the proportion of cases with severe ventriculomegaly (ventricular width ≥ 15 mm) (12.7% vs 57.8%; P < 0.01). Complete CSP evaluation was achieved on preoperative ultrasound in 107 cases, of which 22 had a perforated CSP and 85 had an intact CSP. The perforated-CSP group presented with larger ventricles (mean, 14.32 ± 3.45 mm vs 10.37 ± 2.37 mm; P < 0.01) and a higher rate of severe ventriculomegaly (40.9% vs 5.9%; P < 0.01) compared to those with an intact CSP. The same trends were observed at 6 weeks postoperatively for mean ventricular size (median, 21.0 (range, 13.0-43.5) mm vs 14.3 (range, 7.0-29.0) mm; P < 0.01) and severe ventriculomegaly (95.0% vs 46.8%; P < 0.01). Cases with a perforated CSP at referral had a lower rate of hindbrain herniation (HBH) reversal postoperatively (65.0% vs 88.6%; P = 0.01) and were more likely to require treatment for hydrocephalus (89.5% vs 22.7%; P < 0.01). The strongest predictor of the need for hydrocephalus treatment within 1 year of age was lack of HBH reversal on MRI (odds ratio (OR), 36.20 (95% CI, 5.96-219.12); P < 0.01) followed by perforated CSP on ultrasound at referral (OR, 23.40 (95% CI, 5.42-100.98); P < 0.01) and by perforated CSP at 6-week postoperative ultrasound (OR, 19.48 (95% CI, 5.68-66.68); P < 0.01). CONCLUSIONS: The detection of a perforated CSP in fetuses with ONTD can reliably identify those cases at highest risk for needing hydrocephalus treatment by 1 year of age. Evaluation of this brain structure can improve counseling of families considering fetal surgery for ONTD, in order to set appropriate expectations about postnatal outcome. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Asunto(s)
Hidrocefalia , Meningomielocele , Espina Bífida Quística , Embarazo , Femenino , Humanos , Espina Bífida Quística/complicaciones , Espina Bífida Quística/diagnóstico por imagen , Espina Bífida Quística/cirugía , Estudios Retrospectivos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/etiología , Hidrocefalia/cirugía , Encéfalo , Meningomielocele/cirugíaRESUMEN
OBJECTIVE: In-utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcome for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in-utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in-utero ONTD repair. METHODS: This was a retrospective cohort study of pregnancies complicated by ONTD that underwent laparotomy-assisted fetoscopic repair or open-hysterotomy fetal surgery at a single tertiary center between September 2011 and July 2021. All patients met the MOMS eligibility criteria and had a normal karyotype. In a subset of the pregnancies (n = 77), CMA testing was also conducted. We reviewed the CMA results and divided the cohort into two groups according to whether clinically reportable copy-number variants (CNV) were detected (reportable-CNV group) or not (normal-CMA group). Surgical characteristics, complications, and maternal and early neonatal outcomes were compared between the two groups. The primary outcomes were fetal or neonatal death, hydrocephalus, motor function at 12 months of age and walking status at 30 months of age. Standard parametric and non-parametric statistical tests were employed as appropriate. RESULTS: During the study period, 146 fetuses with ONTD were eligible for and underwent in-utero repair. CMA results were available for 77 (52.7%) patients. Of those, 65 (84%) had a normal CMA and 12 (16%) had a reportable CNV, two of which were classified as pathogenic. The first case with a pathogenic CNV was diagnosed with a 749-kb central 22q11.21 deletion spanning low-copy-repeat regions B-D of chromosome 22; the second case was diagnosed with a 1.3-Mb interstitial deletion at 1q21.1q21.2. Maternal demographics, clinical characteristics, operative data and postoperative complications were similar between those with normal CMA results and those with reportable CNVs. There were no significant differences in gestational age at delivery or any obstetric and early neonatal outcome between the study groups. Motor function at birth and at 12 months of age, and walking status at 30 months of age, were similar between the two groups. CONCLUSIONS: Standard diagnostic testing with CMA should be offered when an ONTD is detected prenatally, as this approach has implications for counseling regarding prognosis and recurrence risk. Our results indicate that the presence of a clinically reportable CNV should not a priori affect eligibility for in-utero repair, as overall pregnancy outcome is similar in these cases to that of cases with normal CMA. Nevertheless, significant CMA results will require a case-by-case multidisciplinary discussion to evaluate eligibility. To generalize the conclusion of this single-center series, a larger, multicenter long-term study should be considered. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
Asunto(s)
Meningomielocele , Atención Prenatal , Recién Nacido , Femenino , Embarazo , Humanos , Preescolar , Estudios Retrospectivos , Atención Prenatal/métodos , Feto , Meningomielocele/cirugía , Análisis por Micromatrices/métodos , Diagnóstico Prenatal/métodos , Estudios Multicéntricos como AsuntoRESUMEN
OBJECTIVES: To assess brain white matter using diffusion tensor imaging (DTI) at 1 year of age in infants diagnosed with open neural tube defect (ONTD) and explore the association of DTI parameters with ambulatory skills at 30 months of age. METHODS: Magnetic resonance imaging (MRI) was performed at an average of 12 months of age and included an echo planar axial DTI sequence with diffusion gradients along 20 non-collinear directions. TORTOISE software was used to correct DTI raw data for motion artifacts, and DtiStudio, DiffeoMap and RoiEditor were used for further postprocessing. DTI data were analyzed in terms of fractional anisotropy (FA), trace, radial diffusivity and axial diffusivity. These parameters reflect the integrity and maturation of white-matter motor pathways. At 30 months of age, ambulation status was evaluated by a developmental pediatrician, and infants were classified as ambulatory if they were able to walk independently with or without orthoses or as non-ambulatory if they could not. Linear mixed-effects method was used to examine the association between study outcomes and study group. Possible confounders were sought, and analyses were adjusted for age at MRI scan and ventricular size by including them in the regression model as covariates. RESULTS: Twenty patients with ONTD were included in this study, including three cases that underwent postnatal repair and 17 cases that underwent prenatal repair. There were five ambulatory and 15 non-ambulatory infants evaluated at a mean age of 31.5 ± 5.7 months. MRI was performed at 50.3 (2-132.4) weeks postpartum. When DTI analysis results were compared between ambulatory and non-ambulatory infants, significant differences were observed in the corpus callosum (CC). Compared with non-ambulatory infants, ambulatory infants had increased FA in the splenium (0.62 (0.48-0.75) vs 0.41 (0.34-0.49); P = 0.01, adjusted P = 0.02), genu (0.64 (0.47-0.80) vs 0.47 (0.35-0.61); P = 0.03, adjusted P = 0.004) and body (0.55 (0.45-0.65) vs 0.40 (0.35-0.46), P = 0.01, adjusted P = 0.01). Reduced trace was observed in the CC of ambulatory children at the level of the splenium (0.0027 (0.0018-0.0037) vs 0.0039 (0.0034-0.0044) mm2 /s; P = 0.04, adjusted P = 0.03) and genu (0.0029 (0.0020-0.0038) vs 0.0039 (0.0033-0.0045) mm2 /s; P = 0.04, adjusted P = 0.01). In addition, radial diffusivity was reduced in the CC of the ambulatory children at the level of the splenium (0.00057 (0.00025-0.00089) vs 0.0010 (0.00084-0.00120) mm2 /s; P = 0.02, adjusted P = 0.02) and the genu (0.00058 (0.00028-0.00088) vs 0.0010 (0.00085-0.00118) mm2 /s; P = 0.02, adjusted P = 0.02). There were no differences in axial diffusivity between ambulatory and non-ambulatory children. CONCLUSION: This study demonstrates a significant association between white matter integrity of connecting fibers of the corpus callosum, as assessed by DTI, and ambulatory skills at 30 months of age in infants with ONTD. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
Asunto(s)
Cuerpo Calloso , Disrafia Espinal , Caminata , Sustancia Blanca , Preescolar , Humanos , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Imagen de Difusión Tensora , Disrafia Espinal/diagnóstico por imagen , Disrafia Espinal/fisiopatología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Caminata/fisiologíaRESUMEN
OBJECTIVE: To identify predictors for intact motor function (MF) at birth and at 12 months of life in babies with prenatally versus postnatally repaired open spina bifida (OSB). DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital, 2011-2018. POPULATION: Patients who underwent either prenatal or postnatal OSB repair. METHODS: Prenatal MF of the lower extremities was evaluated by ultrasound following a metameric distribution at the time of diagnosis (US1), 6 weeks postoperatively (or 6 weeks after initial evaluation in postnatally repaired cases) (US2) and at the last ultrasound before delivery (US3). At birth and at 12 months, MF was assessed clinically. Intact MF (S1) was defined as the observation of plantar flexion of the ankle. Results from logistic regression analysis are expressed as odds ratios (95% confidence intervals, P values). RESULTS: A total of 127 patients were included: 93 with prenatal repair (51 fetoscopic; 42 open hysterotomy repair) and 34 with postnatal repair. In the prenatal repair group, predictors for intact MF at birth and at 12 months included: absence of clubfeet (OR 11.3, 95% CI 3.2-39.1, P < 0.01; OR 10.8 95% CI 2.4-47.6, P < 0.01); intact MF at US1 (OR 19.7, 95% CI 5.0-76.9, P < 0.01; OR 8.7, 95% CI 2.0-38.7, P < 0.01); intact MF at US2 (OR 22, 95% CI 6.5-74.2, P < 0.01; OR 13.5, 95% 3.0-61.4, P < 0.01); intact MF at US3 (OR 13.7, 95% CI 3.4-55.9, P < 0.01; OR 12.6, 95% CI 2.5-64.3, P < 0.01); and having a flat lesion (OR 11.2, 95% CI 2.4-51.1, P < 0.01; OR 4.1, 95% CI 1.1-16.5, P = 0.04). In the postnatal repair group, the only predictor of intact MF at 12 months was having intact MF at birth (OR 15.2, 95% CI 2.0-113.3, P = 0.03). CONCLUSIONS: The detection of intact MF in utero from mid-gestation to delivery predicts intact MF at birth and at 12 months in babies who undergo prenatal OSB repair. TWEETABLE ABSTRACT: Detection of intact motor function in utero predicts intact motor function at birth and at 1 year in fetuses who undergo prenatal OSB repair.
Asunto(s)
Enfermedades Fetales/cirugía , Fetoscopía , Histerotomía , Actividad Motora/fisiología , Espina Bífida Quística/fisiopatología , Espina Bífida Quística/cirugía , Femenino , Enfermedades Fetales/diagnóstico por imagen , Enfermedades Fetales/fisiopatología , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Estudios Retrospectivos , Factores de Riesgo , Espina Bífida Quística/diagnóstico por imagen , Resultado del Tratamiento , Ultrasonografía PrenatalRESUMEN
The sugarcane borer, Diatraea saccharalis (F.) (Lepidoptera: Crambidae), is the primary pest of sugarcane, Saccharum spp., in Louisiana. Spring populations are not considered economically damaging, but quantifying infestations can provide an indication of the spatial and temporal character of the damaging summer populations. Statewide surveys quantified the density of sugarcane tillers killed by D. saccharalis (deadhearts) from sugarcane fields across the state in spring from 2003 to 2020. Deadheart density varied greatly among years with a high of 1,318/ha in 2003 to a low of 0/ha in 2018. Linear regressions of the 3-yr rolling average showed declines in spring D. saccharalis populations and the percentage of acreage treated with insecticides over 17 yr. Weather factors including minimum winter temperatures and average spring temperatures were poor predictors of D. saccharalis populations. Only total precipitation in the month of April was positively correlated with numbers of deadhearts per hectare. Results suggest overwintering mortality is not a key factor influencing populations of the first generation of D. saccharalis in Louisiana. Total precipitation in the month of July was positively associated with percentage of treated acreage. Spring deadheart density was directly related to percentage of acreage treated with insecticides during the summer. Quantifying first-generation D. saccharalis populations by recording deadheart density can aid in predicting pest pressure later in the growing season.
Asunto(s)
Insecticidas , Mariposas Nocturnas , Saccharum , Animales , LouisianaRESUMEN
The West Indian canefly, Saccharosydne saccharivora (Westwood) (Hemiptera: Delphacidae), is a sporadic pest of sugarcane in Louisiana which has recently emerged as a more consistent threat with outbreaks occurring in 2012, 2016, 2017, and 2019. Surveys of commercial fields in 2016 revealed that S. saccharivora infestations were present throughout Louisiana sugarcane and populations peaked in mid-June before declining. High minimum winter temperatures are generally associated with S. saccharivora outbreaks. Six insecticide evaluations demonstrated effective control with several insecticides including λ-cyhalothrin, flupyradifurone, acetamiprid, and imidacloprid. In five of the six insecticide trials, S. saccharivora infestations had substantially declined by 21 d after treatment. Effects of insecticidal control of S. saccharivora on sugar yields were detected in one of four small plot trials in which yield data were collected. Linear regression revealed S. saccharivora cumulative insect days in a grid sampling study were inversely associated with sugar yields. Results from these collective experiments suggest impacts on sugar yields are influenced by pest density and infestation duration. Differences were detected in numbers of S. saccharivora nymphs and adults as well as sooty mold coverage among commercial sugarcane cultivars with more than twofold increases in the most susceptible compared to resistant cultivars. The research presented herein documents the impact of S. saccharivora to Louisiana sugarcane and provides important ground work for developing effective pest management strategies. Future research efforts should aim to identify ecological factors influencing population dynamics, varietal preferences, and economic thresholds.
Asunto(s)
Hemípteros , Insecticidas , Saccharum , Animales , Louisiana , NinfaRESUMEN
Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.
Asunto(s)
Pólipos Adenomatosos/genética , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Neoplasias Gástricas/genética , Linfocitos T/inmunología , Proteínas Quinasas Activadas por AMP , Pólipos Adenomatosos/inmunología , Pólipos Adenomatosos/patología , Animales , Quimiocina CXCL2/genética , Eliminación de Gen , Expresión Génica , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-11/genética , Interleucina-6/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Síndrome de Peutz-Jeghers/inmunología , Síndrome de Peutz-Jeghers/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Parasite diseases are a huge burden on human health causing significant morbidity and mortality. However, parasite structure based drug discovery programmes have been hindered by a lack of high resolution structural information from parasite derived proteins and have often relied upon homology models from mammalian systems. The recent renaissance in electron microscopy (EM) has caused a dramatic rise in the number of structures being determined at high resolution and subsequently enabled it to be thought of as a tool in drug discovery. RESULTS: In this review, we discuss the challenges associated with the structural determination of parasite proteins including the difficulties in obtaining sufficient quantities of protein. We then discuss the reasons behind the resurgence in EM, how it may overcome some of these challenges and provide examples of EM derived parasite protein structures. Finally, we discuss the challenges which EM needs to overcome before it is used as a mainstream technique in anti-parasite drug discovery. CONCLUSIONS: This review reports the progress that has been made in obtaining sufficient quantities of proteins for structural studies and the role EM may play in future structure based drug design programs. The outlook for future structure based drug design programs against some of the most devastating parasite diseases looks promising.
Asunto(s)
Antiparasitarios/química , Diseño de Fármacos , Microscopía Electrónica , Proteínas Protozoarias/antagonistas & inhibidores , Sitios de Unión , Cristalografía por Rayos X , Humanos , Estructura Terciaria de Proteína , Proteínas Protozoarias/metabolismoRESUMEN
Recent developments in electron microscopy (EM) have led to a step change in our ability to solve the structures of previously intractable systems, especially membrane proteins and large protein complexes. This has provided new opportunities in the field of structure-based drug design, with a number of high-profile publications resolving the binding sites of small molecules and peptide inhibitors. There are a number of advantages of EM over the more traditional X-ray crystallographic approach, such as resolving different conformational states and permitting the dynamics of a system to be better resolved when not constrained by a crystal lattice. There are still significant challenges to be overcome using an EM approach, not least the speed of structure determination, difficulties with low-occupancy ligands and the modest resolution that is available. However, with the anticipated developments in the field of EM, the potential of EM to become a key tool for structure-based drug design, often complementing X-ray and NMR studies, seems promising.
Asunto(s)
Diseño de Fármacos , Microscopía Electrónica/métodos , Animales , Ligandos , Modelos Moleculares , Plasmodium falciparum/enzimología , Plasmodium falciparum/ultraestructura , Complejo de la Endopetidasa Proteasomal/metabolismo , Complejo de la Endopetidasa Proteasomal/ultraestructura , Ratas , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/ultraestructura , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/ultraestructura , ATPasas de Translocación de Protón Vacuolares/metabolismo , ATPasas de Translocación de Protón Vacuolares/ultraestructuraRESUMEN
Foraging honey bees (Apis mellifera L.) can routinely travel as far as several kilometers from their hive in the process of collecting nectar and pollen from floral patches within the surrounding landscape. Since the availability of floral resources at the landscape scale is a function of landscape composition, apiculturists have long recognized that landscape composition is a critical determinant of honey bee colony success. Nevertheless, very few studies present quantitative data relating colony success metrics to local landscape composition. We employed a beekeeper survey in conjunction with GIS-based landscape analysis to model colony success as a function of landscape composition in the State of Ohio, USA, a region characterized by intensive cropland, urban development, deciduous forest, and grassland. We found that colony food accumulation and wax production were positively related to cropland and negatively related to forest and grassland, a pattern that may be driven by the abundance of dandelion and clovers in agricultural areas compared to forest or mature grassland. Colony food accumulation was also negatively correlated with urban land cover in sites dominated by urban and agricultural land use, which does not support the popular opinion that the urban environment is more favorable to honey bees than cropland.
RESUMEN
The numbers of glutathione S-transferase, cytochrome P450 and esterase genes in the genome of the hymenopteran parasitoid Nasonia vitripennis are about twice those found in the genome of another hymenopteran, the honeybee Apis mellifera. Some of the difference is associated with clades of these families implicated in xenobiotic resistance in other insects and some is in clades implicated in hormone and pheromone metabolism. The data support the hypothesis that the eusocial behaviour of the honeybee and the concomitant homeostasis of the nest environment may obviate the need for as many gene/enzyme systems associated with xenobiotic metabolism as are found in other species, including N. vitripennis, that are thought to encounter a wider range of potentially toxic xenobiotics in their diet and habitat.
Asunto(s)
Hidrolasas de Éster Carboxílico/genética , Sistema Enzimático del Citocromo P-450/genética , Variación Genética , Glutatión Transferasa/genética , Filogenia , Avispas/enzimología , Animales , Hidrolasas de Éster Carboxílico/metabolismo , Mapeo Cromosómico , Análisis por Conglomerados , Biología Computacional , Sistema Enzimático del Citocromo P-450/metabolismo , Genómica , Glutatión Transferasa/metabolismo , Modelos Genéticos , Receptores Odorantes/metabolismo , Especificidad de la Especie , Xenobióticos/metabolismoRESUMEN
BACKGROUND: This randomized, open-label study evaluated Aquacel Ag Hydrofiber dressing with silver (HDS; ConvaTec, Skillman, NJ, USA) with an adherent or gelled protocol in the management of split-thickness donor sites. METHODS: HDS was the primary dressing in the adherent group (gauze as secondary covering) and gelled group (transparent film as secondary covering). Dressings were changed on study day 1 or 2 and study days 5 (optional), 10 (optional), and 14. The primary outcome was healing (>or=90% re-epithelialization) at study day 14. RESULTS: Seventy subjects were treated (36 adherent, 34 gelled). By study day 14, 77% of donor sites had healed (67% adherent, 88% gelled). Pain scores decreased over time in both treatment groups. Investigators were "very satisfied" or "satisfied" with (adherent, gelled) time required to manage dressing change (89%, 79% of subjects), minimization of donor-site pain (64%, 82%), ease of application (97%, 94%), management of drainage (92%, 82%), ease of removal (77%, 85%), and ability of dressing to remain in place (69%, 76%). Thirty-nine (56%) subjects had adverse events, most commonly non-donor-site infection (11%) and gastrointestinal events (11%). CONCLUSION: In this randomized, open-label study, HDS was well-tolerated, versatile, and effective in the management of split-thickness donor sites.
Asunto(s)
Vendajes , Carboximetilcelulosa de Sodio/uso terapéutico , Portadores de Fármacos , Compuestos de Plata/uso terapéutico , Trasplante de Piel , Heridas y Lesiones/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Epitelio/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor Postoperatorio , Cicatrización de Heridas , Adulto JovenRESUMEN
PURPOSE: PG11047 is a polyamine analog currently in Phase I trials for advanced cancer as a monotherapy and in combination with a number of approved anti-cancer agents. The use of polyamines as a target for antiproliferative therapy is based on findings that cells synthesize polyamines excessively when induced to grow and that polyamine metabolism is frequently dysregulated in cancer. A selective polyamine transport system provides access for PG11047 into rapidly dividing cells to inhibit polyamine biosynthetic enzymes, to induce the polyamine catabolic enzymes spermidine/spermine N(1)-acetyltransferase (SSAT) and spermine oxidase (SMO) which could subsequently induce reactive oxygen species that contribute to tumor cell responses to PG11047, and to function as a polyamine with altered function when it binds to natural polyamine binding sites. The objective of the present study was to assess the antitumor effects of PG11047 alone and in combination with approved anti-cancer agents. METHODS: The antitumor efficacy of PG11047 as a single agent, and in combination with cisplatin and bevacizumab, was tested in models of lung (A549) and prostate (DU-145) cancer, respectively. RESULTS: PG11047 significantly inhibited tumor development in both lung and prostate cancer models when administered as a single agent. In the lung cancer model, PG11047 potentiated the antitumor effect of cisplatin. Although potent activity was observed with PG11047 and bevacizumab when administered as single agents in the prostate cancer model, the combination arm significantly enhanced antitumor activity compared with either agent alone. In all experiments, PG11047 was well tolerated with no adverse effects on bodyweight gain. CONCLUSIONS: The preclinical data support the rationale for the current Phase I trials which are assessing PG11047 as a monotherapy and in combination with a number of approved anti-cancer agents including cisplatin and bevacizumab.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/administración & dosificación , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Desnudos , Poliaminas/administración & dosificación , Neoplasias de la Próstata/patologíaAsunto(s)
Contaminación de Medicamentos/prevención & control , Esterilización , Tecnología Farmacéutica/métodos , Microbiología del Agua , Purificación del Agua , Agua/administración & dosificación , Agua/análisis , Biopelículas , Seguridad de Productos para el Consumidor , Formas de Dosificación , Europa (Continente) , Agencias Gubernamentales , Guías como Asunto , Humanos , Inyecciones , Concesión de Licencias , Ósmosis , Gestión de Riesgos , Esterilización/legislación & jurisprudencia , Esterilización/normas , Tecnología Farmacéutica/legislación & jurisprudencia , Tecnología Farmacéutica/normas , Purificación del Agua/legislación & jurisprudencia , Purificación del Agua/normasRESUMEN
Muscle regeneration involves the coordination of myogenesis and revascularization to restore proper muscle function. Myogenesis is driven by resident stem cells termed satellite cells (SC), whereas angiogenesis arises from endothelial cells and perivascular cells of preexisting vascular segments and the collateral vasculature. Communication between myogenic and angiogenic cells seems plausible, especially given the number of growth factors produced by SC. To characterize these interactions, we developed an in vitro coculture model composed of rat skeletal muscle SC and microvascular fragments (MVF). In this system, isolated epididymal MVF suspended in collagen gel are cultured over a rat SC monolayer culture. In the presence of SC, MVF exhibit greater indices of angiogenesis than MVF cultured alone. A positive dose-dependent effect of SC conditioned medium (CM) on MVF growth was observed, suggesting that SC secrete soluble-acting growth factor(s). Next, we specifically blocked VEGF action in SC CM, and this was sufficient to abolish satellite cell-induced angiogenesis. Finally, hypoxia-inducible factor-1alpha (HIF-1alpha), a transcriptional regulator of VEGF gene expression, was found to be expressed in cultured SC and in putative SC in sections of in vivo stretch-injured rat muscle. Hypoxic culture conditions increased SC HIF-1alpha activity, which was positively associated with SC VEGF gene expression and protein levels. Collectively, these initial observations suggest that a heretofore unexplored aspect of satellite cell physiology is the initiation of a proangiogenic program.
Asunto(s)
Tejido Adiposo/irrigación sanguínea , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neovascularización Fisiológica , Células Satélite del Músculo Esquelético/metabolismo , Animales , Hipoxia de la Célula , Células Cultivadas , Medios de Cultivo Condicionados/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Microvasos/metabolismo , Comunicación Paracrina , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factores de Tiempo , Técnicas de Cultivo de Tejidos , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Although safe firearm storage is a promising injury prevention strategy, many parents do not keep their firearms unloaded and locked up. Using the theory of planned behavior as a guiding conceptual framework, this study examines factors associated with safe storage among married women with children and who have firearms in their homes. Data come from a national telephone survey (n=185). We examined beliefs about defensive firearm use, subjective norms, perceived behavioral control and firearm storage practices. A Wilcoxon-Mann-Whitney test was conducted to assess associations between psychosocial factors and firearm storage practices. Women were highly motivated to keep firearms stored safely. Those reporting safe storage practices had more favorable attitudes, more supportive subjective norms and higher perceptions of behavioral control than those without safe storage. One-fourth believed a firearm would prevent a family member from being hurt in case of a break-in, 58% believed a firearm could scare off a burglar. Some 63% said they leave decisions about firearm storage to their husbands. Women were highly motivated to store firearms safely as evidenced by favorable attitudes, supportive subjective norms and high perceptions of behavioral control. This was especially true for those reporting safer storage practices.
Asunto(s)
Armas de Fuego , Conocimientos, Actitudes y Práctica en Salud , Madres/psicología , Seguridad , Adulto , Femenino , Humanos , Persona de Mediana Edad , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Chronic hepatitis B virus infections are a major cause of morbidity and mortality in HIV co-infected patients. The standard of care for treating HCV co-infection has been guided by major clinical trials, but the treatment of HBV co-infection has not been as thoroughly studied and the standard of care remains largely untested. The single pill formulation of tenofovir with emtricitabine has become a standard treatment approach in HBV co-infected patients. WU114 was a phase 1 clinical trial that examined the safety and tolerability of sequential treatment of HBV with pegylated interferon-alpha2a plus delayed-initiation tenofovir in HIV co-infected individuals. We postulated that initial HBV viral load reduction with pegylated interferon prior to initiation of nucleoside/nucleotide therapy would increase seroconversion events and durability of HBV virologic suppression. No severe pegylated IFN-alpha2a drug toxicities were seen in either the monotherapy or delayed tenofovir arms. Sequential pegylated interferon and tenofovir-based therapy was tolerable and should be compared with dual nucleoside/nucleotide suppression to determine relative frequencies of seroconversion and durability of HBV suppression in co-infected patients.
Asunto(s)
Adenina/análogos & derivados , Infecciones por VIH/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Organofosfonatos/efectos adversos , Organofosfonatos/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Antivirales/efectos adversos , Antivirales/uso terapéutico , Femenino , Hepatitis B Crónica/complicaciones , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , TenofovirRESUMEN
Induced triploidy (3N) in salmon results from a blockage of maternal meiosis II, and hence provides a unique opportunity to study dosage effects on phenotypic variance. Chinook salmon families were bred using a paternal half-sib breeding design (62 females and 31 males) and half of each resulting family was treated to induce triploidy. The paired families were used to test for dosage effects (resulting from triploidy) on (1) the distribution and magnitude of phenotypic variation, (2) narrow-sense heritability and (3) maternal effects in fitness-related traits (i.e., survival, size-at-age, relative growth rate and serum lysozyme activity). Quantitative genetic analyses were performed separately for diploid and triploid family groups. Triploidization resulted in significantly higher levels of phenotypic variance and substantial differences in patterns of variance distribution for growth and survival-related traits, although the patterns were reversed for lysozyme activity. Triploids exhibited higher narrow sense heritability values relative to diploid Chinook salmon. However, maternal effects estimates were generally lower in triploids than in diploids. Thus, the dosage effects resulting from adding an extra set of chromosomes to the Chinook salmon genome are primarily additive. Somewhat counterintuitively, however, the relative magnitude of the combined effects of dominance, epistasis and maternal effects is not affected by dosage. Our results indicate that inheritance of fitness-related quantitative traits is profoundly affected by dosage effects associated with induced triploidy, and that triploidization can result in unpredictable performance and fitness outcomes.