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Introduction: Recent evidence indicates that respiratory distress (RD) in near-term infants is caused by elevated airway liquid (EL) volume at the beginning of air-breathing after birth. While the adverse effects EL volumes on newborn lung function are known, the effects on respiratory control and breathing patterns shortly after birth (<4â h) are unknown. We investigated the effects of EL volumes on cardiorespiratory function and breathing patterns in spontaneously breathing near-term newborn lambs in the first hours after birth. Methods: At 137-8 days gestation (2-3 days prior to delivery; term â¼147 days), sterile surgery was performed on fetal sheep (n = 17) to implant catheters and blood flow probes. At 140 days, lambs were delivered via caesarean section under spinal anaesthesia. Airway liquid volumes were adjusted to mimic the level expected following vaginal delivery (â¼10â ml/kg; Controls; n = 7), or elective caesarean section (â¼30â ml/kg; elevated airway liquid group; EL; n = 10). Spontaneous breathing and cardiorespiratory parameters were recorded over four hours after birth. Non-invasive respiratory support with supplemental oxygen was provided if required. Results: EL lambs required higher inspired oxygen levels (p = 0.0002), were less active (p = 0.026), fed less (p = 0.008) and had higher respiratory morbidity scores than Controls (p < 0.0001). EL lambs also displayed higher rates of breathing patterns associated with RD, such as expiratory braking and tachypnoea. These patterns were particularly evident in male EL lambs who displayed higher levels of severe respiratory morbidity (e.g., expiratory braking) than female EL lambs. Conclusion: The study demonstrates that EL volumes at birth trigger respiratory behaviour and breathing patterns that resemble clinically recognised features of RD in term infants.
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Apolipoprotein E ε4 allele (APOE4) is the predominant genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 mouse models have provided advances in the understanding of disease pathogenesis, but unaccounted variables like rodent housing status may hinder translational outcomes. Non-sterile aspects like food and bedding can be major sources of changes in rodent microflora. Alterations in intestinal microbial ecology can cause mucosal barrier impairment and increase pro-inflammatory signals. The present study examined the role of sterile and non-sterile food and housing on redox indicators and the immune status of humanized-APOE4 knock-in mice (hAPOe4). hAPOE4 mice were housed under sterile conditions until 22 months of age, followed by the transfer of a cohort of mice to non-sterile housing for 2 months. At 24 months of age, the redox/immunologic status was evaluated by flow cytometry/ELISA. hAPOE4 females housed under non-sterile conditions exhibited: (1) higher neuronal and microglial oxygen radical production and (2) lower CD68+ microglia (brain) and CD8+ T cells (periphery) compared to sterile-housed mice. In contrast, hAPOE4 males in non-sterile housing exhibited: (1) higher MHCII+ microglia and CD11b+CD4+ T cells (brain) and (2) higher CD11b+CD4+ T cells and levels of lipopolysaccharide-binding protein and inflammatory cytokines in the periphery relative to sterile-housed mice. This study demonstrated that sterile vs. non-sterile housing conditions are associated with the activation of redox and immune responses in the brain and periphery in a sex-dependent manner. Therefore, housing status may contribute to variable outcomes in both the brain and periphery.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Humanos , Ratones , Animales , Femenino , Masculino , Anciano , Lactante , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Microglía/patología , Enfermedad de Alzheimer/genética , Calidad de la Vivienda , Caracteres Sexuales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Encéfalo/metabolismo , Sistema Inmunológico/metabolismo , Sistema Inmunológico/patología , Ratones TransgénicosRESUMEN
Introduction: The transition to newborn life has typically been studied in intubated and mechanically ventilated newborn lambs delivered via caesarean section (CS) under general anaesthesia. As a result, little is known of the spontaneous breathing patterns in lambs at birth, particularly those at risk of developing respiratory distress (RD). We have developed a method for delivering spontaneously breathing near-term lambs to characterise their breathing patterns in the immediate newborn period. Methods: At 137-8 days gestation (2-3 days prior to delivery; term â¼147 days), fetal lambs (n = 7) were partially exteriorised for instrumentation (insertion of catheters and flow probes) before they were returned to the uterus. At 140 days, lambs were delivered via CS under light maternal sedation and spinal anaesthesia. Lambs were physically stimulated and when continuous breathing was established, the umbilical cord was clamped. Breathing patterns were assessed by measuring intrapleural and upper-tracheal pressures during the first four hours after birth. Results: Newborn lambs display significant heterogeneity in respiratory patterns in the immediate newborn period that change with time after birth. Seven distinct breathing patterns were identified including: (i) quiet (tidal) breathing, (ii) breathing during active periods, (iii) breathing during oral feeding, (iv) tachypnoea, (v) expiratory braking manoeuvres, (vi) expiratory pauses or holding, and (vii) step changes in ventilation. Conclusions: We have described normal respiratory behaviour in newborn lambs, in order to identify respiratory behaviours that are indicative of RD in term newborn infants.
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Background: Optimizing respiratory support after birth requires real-time feedback on lung aeration. We hypothesized that lung ultrasound (LUS) can accurately monitor the extent and progression of lung aeration after birth and is closely associated with oxygenation. Methods: Near-term (140 days gestation, term â¼147 days), spontaneously breathing lambs with normal (controls; n = 10) or elevated lung liquid levels (EL; n= 9) were delivered by Caesarean section and monitored for four hours after birth. LUS (Phillips CX50, L3-12 transducer) images and arterial blood gases were taken every 5-20â min. LUS images were analyzed both qualitatively (grading) and quantitatively (using the coefficient of variation of pixel intensity (CoV) to estimate the degree of lung aeration), which was correlated with the oxygen exchange capacity of the lungs (Alveolar-arterial difference in oxygen; AaDO2). Results: Lung aeration, measured using LUS, and the AaDO2 improved over the first 4â h after birth. The increase in lung aeration measured using CoV of pixel intensity, but not LUS grade, was significantly reduced in EL lambs compared to controls (p = 0.02). The gradual decrease in AaDO2 after birth was significantly correlated with increased lung aeration in both control (grade, r2 = 0.60, p < 0.0001; CoV, r2 = 0.54, p < 0.0001) and EL lambs (grade, r2 = 0.51, p < 0.0001; CoV, r2 = 0.44, p < 0.0001). Conclusions: LUS can monitor lung aeration and liquid clearance after birth in spontaneously breathing near-term lambs. Image analysis techniques (CoV) may be able detect small to moderate differences in lung aeration in conditions with lung liquid retention which are not readily identified using qualitative LUS grading.
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OBJECTIVES: Linear unstable angiotensins stimulate hematopoiesis. Here we address: (1) Is cyclic angiotensin-(1-7) myeloprotective in mice? (2) Is cyclic angiotensin-(1-7) stable in rat? (3) Does LP2, a cyclic angiotensin-(1-7) with an N-terminal d-lysine, exert myeloprotective action in tumor-bearing mice? MATERIALS AND METHODS: Cyclic angiotensin-(1-7)'s capacity to restore levels of blood platelets and white blood cells was studied in gemcitabine-treated mice. The stability of cyclic angiotensin-(1-7) in rat was measured in blood samples taken after injection or infusion. The capacity of LP2 to restore total bone marrow cell levels in mice after treatment with 5-fluoruracil was measured. In addition, the capacity of LP2 to counter anemia in tumor-bearing mice treated with erlotinib was measured. RESULTS: Cyclic angiotensin-(1-7) dose-dependently restored blood platelet levels in gemcitabine-treated mice, whereas its capacity to restore levels of white blood cells was less. In vivo aminoterminal breakdown of cyclic angiotensin-(1-7) yielded cyclic angiotensin-(2-7) and cyclic angiotensin-(3-7). LP2 significantly (p < .0001 at 100 µg/kg/day) restored bone marrow cell counts in mice after treatment with 5-fluoruracil. LP2 also significantly (p < .05) countered anemia in tumor-bearing mice treated with erlotinib. CONCLUSIONS: LP2 exerts myeloprotective action with perspectives for continuation of its clinical development.
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Plaquetas , Hematopoyesis , Ratones , Ratas , Animales , Clorhidrato de Erlotinib , Células de la Médula Ósea , Fluorouracilo/farmacología , Fluorouracilo/uso terapéuticoRESUMEN
OBJECTIVE: Insufflation of the amniotic cavity with carbon dioxide (CO2 ) is used clinically to improve visibility during complex fetoscopic surgery. Insufflation with heated, humidified CO2 has recently been shown to reduce fetal hypercapnia and acidosis in sheep, compared with use of cold and dry CO2 , but the underlying mechanisms are unclear. The aim of this study was to investigate whether differences in placental CO2 and oxygen (O2 ) exchange during insufflation with heated and humidified vs cold and dry CO2 could explain these findings. METHODS: Thirteen fetal lambs at 105 days of gestation (term, 146 days) were exteriorized partially, via a midline laparotomy and hysterotomy, and instrumented with an umbilical artery catheter, an umbilical vein catheter and a common umbilical vein flow probe. Arterial and venous catheters and flow probes were also inserted into the maternal uterine circulation. Six ewes were insufflated with cold, dry CO2 (22°C; 0-5% humidity) and seven with heated, humidified CO2 (40°C; 95-100% humidity) at 15 mmHg for 180 min. Blood-flow recordings and paired arterial and venous blood gases were sampled from uterine and umbilical vessels. Rates of placental CO2 and O2 exchange were calculated. RESULTS: After 180 min of insufflation, fetal survival was 33% (2/6) using cold, dry CO2 and 71% (5/7) using heated, humidified CO2 . By 120 min, fetuses insufflated with heated, humidified CO2 had lower arterial CO2 levels and higher arterial pH compared to those insufflated with cold, dry gas. Insufflation decreased significantly placental gas exchange in both groups, as measured by rates of both (i) fetal CO2 clearance and O2 uptake and (ii) maternal O2 delivery and CO2 uptake from the fetal compartment. CONCLUSIONS: Lower arterial CO2 and higher pH levels in fetuses insufflated with heated and humidified, compared to cold and dry, CO2 could not be explained by differences in placental gas exchange. Instead, heated and humidified insufflation appeared to reduce fetal CO2 absorption from the uterus, supporting its use in preference to cold, dry CO2 . © 2019 International Society of Ultrasound in Obstetrics and Gynecology.
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Dióxido de Carbono/administración & dosificación , Insuflación , Placenta/metabolismo , Animales , Análisis de los Gases de la Sangre , Dióxido de Carbono/metabolismo , Femenino , Modelos Animales , Embarazo , OvinosRESUMEN
INTRODUCTION: The COVID-19 pandemic has been characterised by significant in-hospital virus transmission and deaths among healthcare workers. Sources of in-hospital transmission are not fully understood, with special precautions currently reserved for procedures previously shown to generate aerosols (particles <5 µm). Pleural procedures are not currently considered AGPs (Aerosol Generating Procedures), reflecting a lack of data in this area. METHODS: An underwater seal chest drain bottle (R54500, Rocket Medical UK) was set up inside a 60-litre plastic box and connected via an airtight conduit to a medical air supply. A multichannel particle counter (TSI Aerotrak 9310 Aerosol Monitor) was placed inside the box, allowing measurement of particle count/cubic foot (pc/ft3) within six channel sizes: 0.3-0.5, 0.5-1, 1-3, 3-5, 5-10 and >10 µm. Stabilised particle counts at 1, 3 and 5 L/min were compared by Wilcoxon signed rank test; p values were Bonferroni-adjusted. Measurements were repeated with a simple anti-viral filter, designed using repurposed materials by the study team, attached to the drain bottle. The pressure within the bottle was measured to assess any effect of the filter on bottle function. RESULTS: Aerosol emissions increased with increasing air flow, with the largest increase observed in smaller particles (0.3-3 µm). Concentration of the smallest particles (0.3-0.5 µm) increased from background levels by 700, 1400 and 2500 pc/ft3 at 1, 3 and 5 L/min, respectively. However, dispersion of particles of all sizes was effectively prevented by use of the viral filter at all flow rates. Use of the filter was associated with a maximum pressure rise of 0.3 cm H2O after 24 hours of flow at 5 L/min, suggesting minimal impact on drain function. CONCLUSION: A bubbling chest drain is a source of aerosolised particles, but emission can be prevented using a simple anti-viral filter. These data should be considered when designing measures to reduce in-hospital spread of SARS-CoV-2.
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Betacoronavirus , Tubos Torácicos , Infecciones por Coronavirus/transmisión , Personal de Salud , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Exposición Profesional/prevención & control , Neumonía Viral/transmisión , Aerosoles , COVID-19 , Drenaje , Filtración/instrumentación , Humanos , Pandemias , Tamaño de la Partícula , Material Particulado , SARS-CoV-2RESUMEN
BACKGROUND: Despite progress made over the past twenty years, child mortality remains high, with 5.3 million children under five years having died in 2018 globally. Pneumonia, diarrhoea, and malaria remain among the commonest causes of under-five mortality; contributing 15%, 8%, and 5% of global mortality respectively. Recent evidence shows that integrated community case management (iCCM) of pneumonia, diarrhoea, and malaria can reduce under-five mortality. However, despite growing evidence of the effectiveness of iCCM, there are implementation challenges, especially stock out of iCCM commodities and inadequate supportive supervision of community health workers (CHWs). This study aimed to address these two key challenges to successful iCCM implementation by using mobile health (mHealth) technology. METHODS: This cluster randomised controlled trial compared health centre catchment areas (clusters) where CHWs and their supervisors implemented mHealth-enhanced iCCM supportive supervision and supply chain management vs clusters implementing iCCM as per current Zambian guidelines. CHWs in intervention clusters used community DHIS2 platform on mobile phones to report on a weekly basis children with iCCM conditions and make requisitions for iCCM commodities. Their supervisors received electronic reports on disease caseloads and monthly automated supervision reminders. The supervisors on receipt of requisitions, organized the medical supplies and notified CHWs for collection. Intention-to-treat analysis on the primary outcome, the percentage of children aged 2-59 months receiving appropriate treatment for malaria, pneumonia, or diarrhoea from an iCCM trained CHW, was performed using a generalized linear model. Prevalence ratios and 95% confidence intervals comparing the prevalence of appropriate treatment in the intervention and control groups were calculated using log binomial regression with an exchangeable correlation matrix, adjusted for clustering by health facility. RESULTS: In the intervention clusters, 61.3% (98/160) of expected monthly supervision visits took place vs 52.0% (78/150) in the controls. A total of 3690 children 2-59 months old presented with malaria, diarrhoea, or pneumonia. In the intervention group, 65.9% (1,252/1,899) of children received appropriate care for iCCM conditions, compared to 63.3% (1,134/1,791) in the control group. The mHealth intervention was associated with 18.0% improvement in supportive supervision and 21.0% increase in appropriate treatment for pneumonia; these changes were not statistically significant. There was a 2-3-fold increase in the proportion of CHWs receiving supplies ordered: prevalence ratios ranged from 2.82 (confidence interval (CI) = 1.50, 5.30) to 3.01 (95% CI = 1.29, 7.00) depending on the particular commodity. CONCLUSION: This study was unable to determine whether using mHealth technology would strengthen supervision and supply chain management of iCCM commodities for community-level workers. There was no statistically significant effect of mHealth enhanced iCCM on appropriate diagnosis and treatment for children with malaria, pneumonia, and diarrhoea in rural Zambia. Longer term longitudinal studies are required to determine the impact of mHealth enhanced iCCM on health outputs and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02866097.
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Manejo de Caso/organización & administración , Agentes Comunitarios de Salud , Equipos y Suministros , Organización y Administración , Proyectos de Investigación , Telemedicina , Preescolar , Servicios de Salud Comunitaria/organización & administración , Diarrea/tratamiento farmacológico , Femenino , Humanos , Lactante , Recién Nacido , Malaria/tratamiento farmacológico , Masculino , Neumonía/tratamiento farmacológico , Población Rural , ZambiaRESUMEN
OBJECTIVES: Infants with congenital diaphragmatic hernia (CDH) are predisposed to pulmonary hypertension after birth, owing to lung hypoplasia that impairs fetal pulmonary vascular development. Antenatal sildenafil treatment attenuates abnormal pulmonary vascular and alveolar development in rabbit and rodent CDH models, but whether this translates to functional improvements after birth remains unknown. We aimed to evaluate the effect of antenatal sildenafil on neonatal pulmonary hemodynamics and lung function in lambs with diaphragmatic hernia (DH). METHODS: DH was surgically induced at approximately 80 days' gestation in 16 lamb fetuses (term in lambs is approximately 147 days). From 105 days' gestation, ewes received either sildenafil (0.21 mg/kg/h intravenously) or saline infusion until delivery (n = 8 fetuses in each group). At approximately 138 days' gestation, all lambs were instrumented and then delivered via Cesarean section. The lambs were ventilated for 120 min with continuous recording of physiological (pulmonary and carotid artery blood flow and pressure; cerebral oxygenation) and ventilatory parameters, and regular assessment of arterial blood gas tensions. Only lambs that survived until delivery and with a confirmed diaphragmatic defect at postmortem examination were included in the analysis; these comprised six DH-sildenafil lambs and six DH-saline control lambs. RESULTS: Lung-to-body-weight ratio (0.016 ± 0.001 vs 0.013 ± 0.001; P = 0.06) and dynamic lung compliance (0.8 ± 0.2 vs 0.7 ± 0.2 mL/cmH2 O; P = 0.72) were similar in DH-sildenafil lambs and controls. Pulmonary vascular resistance decreased following lung aeration to a greater degree in DH-sildenafil lambs, and was 4-fold lower by 120 min after cord clamping than in controls (0.6 ± 0.1 vs 2.2 ± 0.6 mmHg/(mL/min); P = 0.002). Pulmonary arterial pressure was also lower (46 ± 2 vs 59 ± 2 mmHg; P = 0.048) and pulmonary blood flow higher (25 ± 3 vs 8 ± 2 mL/min/kg; P = 0.02) in DH-sildenafil than in DH-saline lambs at 120 min. Throughout the 120-min ventilation period, the partial pressure of arterial carbon dioxide tended to be lower in DH-sildenafil lambs than in controls (63 ± 8 vs 87 ± 8 mmHg; P = 0.057), and there was no significant difference in partial pressure of arterial oxygen between the two groups. CONCLUSIONS: Sustained maternal antenatal sildenafil infusion reduced pulmonary arterial pressure and increased pulmonary blood flow in DH lambs for the first 120 min after birth. These findings of improved pulmonary vascular function are consistent with improved pulmonary vascular structure seen in two previous animal models. The data support the rationale for a clinical trial investigating the effect of antenatal sildenafil in reducing the risk of neonatal pulmonary hypertension in infants with CDH. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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Hemodinámica/efectos de los fármacos , Hernias Diafragmáticas Congénitas/tratamiento farmacológico , Pulmón/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Citrato de Sildenafil/farmacología , Animales , Autopsia/métodos , Análisis de los Gases de la Sangre/métodos , Femenino , Terapias Fetales/métodos , Feto , Hernias Diafragmáticas Congénitas/fisiopatología , Pulmón/irrigación sanguínea , Pulmón/fisiopatología , Modelos Animales , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Inhibidores de Fosfodiesterasa 5/sangre , Embarazo , Atención Prenatal , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Ovinos , Citrato de Sildenafil/administración & dosificación , Citrato de Sildenafil/sangreRESUMEN
Multiple Sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by autoimmune and neurodegenerative pathologies for which there is no cure and no defined etiology. Although several, modestly effective, disease modifying drugs are available to treat MS, there are presently no treatments that offer neuroprotection and prevent clinical progression. Therapies are needed that control immune homeostasis, prevent disease progression, and stimulate regeneration in the CNS. Components of the renin-angiotensin-system (RAS) have recently been identified as chemical mediators in the CNS and in neurological disease. Here we show the beneficial effect of therapeutic treatment with the Mas receptor agonist and metabolite of the protective arm of RAS, angiotensin 1-7 (A(1-7)), in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Therapeutic treatment with A(1-7) caused a dose-dependent reduction both in clinical disease severity and progression, and was dependent on Mas receptor activation. Further analysis of the most optimal dose of A(1-7) treatment revealed that the reductions in clinical disease course were associated with decreased immune infiltration and demyelination, axonal loss and oxidative stress in the spinal cord. In addition A(1-7) treatment was also associated with increases in circulating alternatively activated monocytes/macrophages.
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Angiotensina I/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Angiotensina I/administración & dosificación , Animales , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/diagnóstico , Encefalomielitis Autoinmune Experimental/metabolismo , Masculino , Ratones , Fármacos Neuroprotectores/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: Partial amniotic carbon dioxide (CO2 ) insufflation (PACI) is used to improve visualization and facilitate complex fetoscopic surgery. However, there are concerns about fetal hypercapnic acidosis and postoperative fetal membrane inflammation. We assessed whether using heated and humidified, rather than cold and dry, CO2 might reduce the impact of PACI on the fetus and fetal membranes in sheep. METHODS: Twelve fetal lambs of 105 days' gestational age (term = 145 days) were exteriorized partially, via a midline laparotomy and hysterotomy, and arterial catheters and flow probes were inserted surgically. The 10 surviving fetuses were returned to the uterus, which was then closed and insufflated with cold, dry (22 °C at 0-5% humidity, n = 5) or heated, humidified (40 °C at 100% humidity, n = 5) CO2 at 15 mmHg for 180 min. Fetal membranes were collected immediately after insufflation for histological analysis. Physiological data and membrane leukocyte counts, suggestive of membrane inflammation, were compared between the two groups. RESULTS: After 180 min of insufflation, fetal survival was 0% in the group which underwent PACI with cold, dry CO2 , and 60% (n = 3) in the group which received heated, humidified gas. While all insufflated fetuses became progressively hypercapnic (PaCO2 > 68 mmHg), this was considerably less pronounced in those in which heated, humidified gas was used: after 120 min of insufflation, compared with those receiving cold, dry gas (n = 3), fetuses undergoing heated, humidified PACI (n = 5) had lower arterial partial pressure of CO2 (mean ± standard error of the mean, 82.7 ± 9.1 mmHg for heated, humidified CO2 vs 170.5 ± 28.5 for cold, dry CO2 during PACI, P < 0.01), lower lactate levels (1.4 ± 0.4 vs 8.5 ± 0.9 mmol/L, P < 0.01) and higher pH (pH, 7.10 ± 0.04 vs 6.75 ± 0.04, P < 0.01). There was also a non-significant trend for fetal carotid artery pressure to be higher following PACI with heated, humidified compared with cold, dry CO2 (30.5 ± 1.3 vs 8.7 ± 5.5 mmHg, P = 0.22). Additionally, the median (interquartile range) number of leukocytes in the chorion was significantly lower in the group undergoing PACI with heated, humidified CO2 compared with the group receiving cold, dry CO2 (0.7 × 10-5 (0.5 × 10-5 ) vs 3.2 × 10-5 (1.8 × 10-5 ) cells per square micron, P = 0.02). CONCLUSIONS: PACI with cold, dry CO2 causes hypercapnia, acidosis, hypotension and fetal membrane inflammation in fetal sheep, raising potential concerns for its use in humans. It seems that using heated, humidified CO2 for insufflation partially mitigates these effects and this may be a suitable alternative for reducing the risk of fetal acid-base disturbances during, and fetal membrane inflammation following, complex fetoscopic surgery. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
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Insuflación , Meningomielocele , Animales , Dióxido de Carbono , Femenino , Fetoscopía , Humanos , Modelos Animales , Embarazo , Ovinos , ÚteroRESUMEN
INTRODUCTION: Effective community health management information systems (C-HMIS) are important in low-resource countries that rely heavily on community-based health care providers. Zambia currently lacks a functioning C-HMIS to provide real-time, community-based health information from community health workers (CHWs) to health center staff and higher levels of the health system. PROGRAM DESCRIPTION: We developed a C-HMIS mobile platform for use by CHWs providing integrated community case management (iCCM) services and their supervisors to address challenges of frequent stock-outs and inadequate supportive supervision of iCCM-trained CHWs. The platform used simple feature mobile phones on which were loaded the District Health Information System version 2 (DHIS2) software and Java 2 platform micro edition (J2ME) aggregation and tracker applications. This project was implemented in Chipata and Chadiza districts, which supported previous mHealth programs and had cellular coverage from all 3 major network carriers in Zambia. A total of 40 CHWs and 20 CHW supervisors received mobile phones with data bundles and training in the mobile application, after which they implemented the program over a period of 5.5 months, from February to mid-July 2016. CHWs used the mobile phones to submit data on iCCM cases seen, managed, and referred, as well as iCCM medical and diagnostic supplies received and dispensed. Using their mobile phones, the supervisors tracked CHWs' reported cases with medicine consumption, sent CHWs feedback on their referrals, and received SMS reminders to set up mentorship sessions. OBSERVATIONS: CHWs were able to use the mobile application to send weekly reports to health center supervisors on disease caseloads and medical commodities consumed, to make drug and supply requisitions, and to send pre-referral notices to health centers. Health center staff used the mobile system to provide feedback to CHWs on the case outcomes of referred patients and to receive automated monthly SMS reminders to invite CHWs to the facility for mentorship. District- and central-level staff were able to access community-level health data in real time using passwords. LESSONS LEARNED: C-HMIS, using simple feature phones, was feasible and viable for the provision of real-time community-based health information to all levels of the health care system in Zambia, but smartphones, laptops, or desktop computers are needed to perform data analysis and visualization. Ongoing technical support is needed to address the hardware and software challenges CHWs face in their day-to-day interaction with the application on their mobile phones.
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Servicios de Salud Comunitaria , Agentes Comunitarios de Salud , Sistemas de Información en Salud , Aplicaciones Móviles , Atención a la Salud/organización & administración , Humanos , Derivación y Consulta , ZambiaRESUMEN
BACKGROUND AND AIMS: Apolipoprotein (apo) A-IV, the third most abundant HDL-associated protein, is atheroprotective and shares similar properties as apoA-I. We have reported previously that apoA-I, the most abundant apolipoprotein in HDL, inhibits plaque disruption in a mouse model. We aimed at examining the effects of apoA-IV on markers of plaque stability in vivo. METHODS: Plaques within brachiocephalic arteries of 16-week old apoE-knockout C57BL/6 mice were examined for changes in composition after 10 weeks on a high-fat diet (HFD). The animals received twice-weekly injections of human lipid-free apoA-IV (1 mg/kg, n = 31) or PBS (n = 32) during the 9th and 10th weeks of the HFD. RESULTS: In the apoA-IV treated mice, there were significantly fewer hemorrhagic plaque disruptions (9/31 vs. 18/32, p < 0.05), thicker fibrous caps, smaller lipid cores, a lower macrophage:SMC ratio, less MMP-9 protein, more collagen, and fewer proliferating cells. In the plaques of mice given apoA-IV, MCP-1, VCAM-1, and inducible NOS were also significantly lower. Based on the percentage of cleaved PARP-positive and TUNEL-positive plaque nuclei, apoA-IV reduced apoptosis. in HMDMs, apoA-IV reduced MMP-9 mRNA expression by half, doubled mRNA levels of TIMP1 and decreased MMP-9 activity. CONCLUSIONS: ApoA-IV treatment is associated with a more stable plaque phenotype and a reduced incidence of acute disruptions in this mouse model.
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Apolipoproteínas A/sangre , Macrófagos/metabolismo , Placa Aterosclerótica/patología , Animales , Apoptosis , Arterias/patología , Aterosclerosis/metabolismo , Dieta Alta en Grasa , Humanos , Inflamación , Lipoproteínas HDL/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Estrés Oxidativo , Fenotipo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Diabetic patients are at an increased risk of cardiovascular disease, in part due to inflammation and oxidative stress. These two pathological mechanisms also affect other organs and cells including the kidneys and progenitor cells. Angiotensin-(1-7) [Ang-(1-7)] has previously been shown to counterbalance pathological effects of angiotensin II, including inflammation and oxidative stress. The aim of this study was to investigate the effects of short-term (2 weeks) Ang-(1-7) treatment on cardiovascular and renal function in a mouse model of type 2 diabetes (db/db). EXPERIMENTAL APPROACH: Eight- to nine-week-old db/db mice were administered either vehicle, Ang-(1-7) alone, or Ang-(1-7) combined with an inhibitor (losartan, PD123319, A-779, L-NAME or icatibant) daily for 14 days. KEY RESULTS: An improvement in physiological heart function was observed in Ang-(1-7)-treated mice. Ang-(1-7) also reduced cardiomyocyte hypertrophy, fibrosis and inflammatory cell infiltration of the heart tissue and increased blood vessel number. These changes were blocked by antagonists of the MAS1, AT2 and bradykinin receptors and inhibition of NO formation. Treatment with Ang-(1-7) reduced glomerular damage and oxidative stress in kidney tissue. Bone marrow and circulating endothelial progenitors, as well as bone marrow mesenchymal stem cells, were increased in mice treated with Ang-(1-7). CONCLUSIONS AND IMPLICATIONS: Short-term Ang-(1-7) treatment of young db/db mice improved heart function and reduced kidney damage. Treatment also improved bone marrow and circulating levels of endothelial and mesenchymal stem cells. All of this may contribute to improved cardiovascular and renal function.
RESUMEN
CNS immune signaling contributes to deleterious opioid effects including hyperalgesia, tolerance, reward, and dependence/withdrawal. Such effects are mediated by opioid signaling at toll-like receptor 4 (TLR4), presumptively of glial origin. Whether CNS endothelial cells express TLR4 is controversial. If so, they would be well positioned for activation by blood-borne opioids, contributing to opioid-induced pro-inflammatory responses. These studies examined adult primary rat CNS endothelial cell responses to (-)-morphine or its mu opioid receptor (MOR)-inactive metabolite morphine-3-glucuronide (M3G), both known TLR4 agonists. We demonstrate that adult rat CNS endothelial cells express functional TLR4. M3G activated nuclear factor kappaB (NF-κB), increased tumor necrosis factor-α (TNFα) and cyclooxygenase-2 (COX2) mRNAs, and released prostaglandin E2 (PGE2) from these cells. (-)-Morphine-induced upregulation of TNFα mRNA and PGE2 release were unmasked by pre-treatment with nalmefene, a MOR antagonist without TLR4 activity (unlike CTAP, shown to have both MOR- and TLR4-activity), suggestive of an interplay between MOR and TLR4 co-activation by (-)-morphine. In support, MOR-dependent Protein Kinase A (PKA) opposed TLR4 signaling, as PKA inhibition (H-89) also unmasked (-)-morphine-induced TNFα and COX2 mRNA upregulation. Intrathecal injection of CNS endothelial cells, stimulated in vitro with M3G, produced TLR4-dependent tactile allodynia. Further, cortical suffusion with M3G in vivo induced TLR4-dependent vasodilation. Finally, endothelial cell TLR4 activation by lipopolysaccharide and/or M3G was blocked by the glial inhibitors AV1013 and propentofylline, demonstrating endothelial cells as a new target of such drugs. These data indicate that (-)-morphine and M3G can activate CNS endothelial cells via TLR4, inducing proinflammatory, biochemical, morphological, and behavioral sequelae. CNS endothelial cells may have previously unanticipated roles in opioid-induced effects, in phenomena blocked by presumptive glial inhibitors, as well as TLR4-mediated phenomena more broadly.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Derivados de la Morfina/farmacología , Morfina/farmacología , Narcóticos/farmacología , Receptor Toll-Like 4/metabolismo , Animales , Sistema Nervioso Central/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Células Endoteliales/fisiología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Masculino , FN-kappa B/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/fisiología , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Receptor Toll-Like 4/agonistas , Factor de Necrosis Tumoral alfa/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
Diabetics have an increased risk of developing cardiovascular disease, in part due to oxidative stress, resulting in endothelial nitric oxide synthase (eNOS) dysfunction. Studies have demonstrated that angiotensin-(1-7) [Ang-(1-7)] can activate eNOS activity. Because the bone marrow is a primary source of a number of progenitors important in physiological homeostasis and healing, the goal of this study was to evaluate the in vivo effects of Ang-(1-7) treatment on oxidative stress and the ensuing nitrative stress in diabetic bone marrow and its potential pathways. BKS.Cg-Dock7(m) +/+ Lepr(db)/J mice and their heterozygous controls were administered Ang-(1-7) alone or combined with A-779, losartan, PD123,319, nitro-l-arginine methyl ester, or icatibant sc for 14 d. The bone marrow was then collected to measure nitric oxide levels, eNOS phosphorylation, and expression of nitric oxide synthase, superoxide dismutase, and p22-phox. Nitric oxide levels in the bone marrow were significantly decreased in diabetic mice, and Ang-(1-7) treatment was able to significantly increase these measures (P < 0.01). This effect was blocked by the coadministration of PD123,319, A-779, nitro-l-arginine methyl ester, and icatibant. In addition, Ang-(1-7) treatment reversed the paradoxical increase in eNOS and neuronal nitric oxide synthase expression and decreased the phosphorylation of eNOS at Thr495 seen in diabetic mice. Ang-(1-7) also reversed diabetes-induced production of reactive oxygen species by decreasing p22-phox expression and increasing superoxide dismutase 3 expression, leading to a significant reduction in 3-nitrotyrosine formation in diabetic bone marrow (P < 0.05). Our findings demonstrate that Ang-(1-7) administration decreases diabetes-induced oxidative stress in the bone marrow and modifies pathways involved in eNOS dysfunction.
Asunto(s)
Angiotensina I/farmacología , Médula Ósea/efectos de los fármacos , Diabetes Mellitus/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Animales , Médula Ósea/metabolismo , Masculino , Ratones , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
While cases of severe kava hepatotoxicity have been reported, studies examining the toxicity of individual kavalactones are limited. The present study examined the in vitro hepatotoxicity of kavain, methysticin and yangonin on human hepatocytes (HepG2) and the possible mechanism(s) involved. Cytotoxicity was assessed using lactate dehydrogenase (LDH) and ethidium bromide (EB) assays. The mode of cell death was analysed with acridine orange/ethidium bromide dual staining with fluorescence microscopy. Glutathione oxidation was measured using the ortho-phthalaldehyde (OPT) fluorescence assay. Kavain had minimal cytotoxicity, methysticin showed moderate concentration-dependent toxicity and yangonin displayed marked toxicity with ~ 40% reduction in viability in the EB assay. Acridine orange/ethidium bromide staining showed the predominant mode of cell death was apoptosis rather than necrosis. No significant changes were observed in glutathione levels, excluding this as the primary mechanism of cell death in this model. Further studies may elucidate the precise apoptotic pathways responsible and whether toxic kavalactone metabolites are involved.
Asunto(s)
Apoptosis/efectos de los fármacos , Lactonas/farmacología , Piranos/farmacología , Pironas/farmacología , Supervivencia Celular , Glutatión/análisis , Células Hep G2 , Hepatocitos/efectos de los fármacos , Humanos , L-Lactato Deshidrogenasa/análisisRESUMEN
The distal biceps brachii tendon is commonly susceptible to traumatic injury. This study aimed to describe the morphology of the distal biceps brachii tendon in relation to the commonly used endobutton repair of tendon rupture. The results suggested that the distal tendon is a series of distinct bands of variable number. These bands are obscured surgically by the tendon sheath. Upon opening this sheath, blunt dissection of the tendon released fibrous connections between the tendon bands. Adjacent bands were variably connected via small oblique bands. The separations between bands were continuous onto the radius. They were therefore considered as separate force-conducting units. This notion is of high relevance to endobutton repairs, as the sutures are typically only passed through the margins of the tendon. Where few connections exist between tendinous bands, this represents a potential weakness, as central bands are therefore free to be pulled proximally. This is of primary concern in the early rehabilitative stages of postoperative care. It may be suggested that sutures that cross the width of the tendon will eliminate the give of central bands, improving postoperative results, reducing revision numbers, and potentially reducing rehabilitation time.
Asunto(s)
Brazo/anatomía & histología , Músculo Esquelético/anatomía & histología , Tendones/anatomía & histología , Anciano , Traumatismos del Brazo/patología , Traumatismos del Brazo/cirugía , Femenino , Humanos , Masculino , Músculo Esquelético/cirugía , Rotura/cirugía , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/cirugíaRESUMEN
Lipoxins (LXs) are endogenously produced eicosanoids that are typically generated by transcellular biosynthesis. These trihydroxytetraene-containing lipid mediators and their stable synthetic analogues possess a wide spectrum of anti-inflammatory and pro-resolution bioactions both in vitro and in vivo. More recently, LXs have emerged as potential anti-fibrotic mediators that may influence pro-fibrotic cytokines and matrix-associated gene expression in response to platelet-derived growth factor (PDGF). Here we review the biosynthesis, metabolism and bioactions of LXs and LX analogues and their therapeutic potential.