RESUMO
The present study aimed to use poor quality roughages, such as rice and faba bean straw, treated with or without urea, and their impacts on digestibility, rumen fermentation, some blood parameters, and growth performance of lambs. Twenty crossbred male lambs (1/4 Finland ×¾ Ossimi, 25±1.13kg live body weight) were chosen and divided into four groups. All lambs were fed rations of concentrated feed mixture at 2% of live weight with the following roughages ad libitum: URS (control group, untreated rice straw), TRS (urea-treated rice straw), FBS (faba bean straw), and TRS+FBS (mixture of TRS and FBS, 1:1). Nutrient digestibility and feeding values improved (P<0.05) with TRS+FBS lambs versus FBS, TRS and URS lambs. The highest numerical values of ruminal total volatile fatty acid (VFA) concentration in TRS lambs were recorded 23.9 ml.eq/dl followed by TRS+FBS, URS and FBS. Regarding to the ruminal parameters, there were no differences (P>0.05) among evaluated groups except for NH3-N, the highest concentration (P<0.05) was recorded in TRS lambs at 3 h post-feeding. Lambs of TRS, FBS and TRS+FBS showed faster growth (P<0.05) than those of the control (i.e., URS). Intakes of dry matter, total digestible nutrients, and digestible crude protein were numerically increased for TRS, FBS, and TRS+FBS. Feed conversion, as kg dry matter/kg gain, was improved for TRS, FBS, and TRS+FBS lambs versus URS. Daily gain of lambs increased (P<0.05) with lambs of TRS, FBS, and TRS+FBS but URS lambs showed a decrease (P<0.05) in daily gain. Feed conversion as kg dry matter intake/kg gain was improved (P<0.05) by feeding on TRS, FBS and TRS+FBS rations versus URS. The TRS+FBS lambs tended to have the highest economic efficiency versus URS, TRS and FBS lambs. It was concluded that urea-treated rice straw could be used as sole roughage or mixed with faba bean straw (1:1) in growing lambs' ration to improve their performance and economic efficiency without adversely affecting their health.The present study aimed to use poor quality roughages, such as rice and faba bean straw, treated with or without urea, and their impacts on digestibility, rumen fermentation, some blood parameters, and growth performance of lambs. Twenty crossbred male lambs (1/4 Finland ×¾ Ossimi, 25±1.13kg live body weight) were chosen and divided into four groups. All lambs were fed rations of concentrated feed mixture at 2% of live weight with the following roughages ad libitum: URS (control group, untreated rice straw), TRS (urea-treated rice straw), FBS (faba bean straw), and TRS+FBS (mixture of TRS and FBS, 1:1). Nutrient digestibility and feeding values improved (P<0.05) with TRS+FBS lambs versus FBS, TRS and URS lambs. The highest numerical values of ruminal total volatile fatty acid (VFA) concentration in TRS lambs were recorded 23.9 ml.eq/dl followed by TRS+FBS, URS and FBS. Regarding to the ruminal parameters, there were no differences (P>0.05) among evaluated groups except for NH3-N, the highest concentration (P<0.05) was recorded in TRS lambs at 3 h post-feeding. Lambs of TRS, FBS and TRS+FBS showed faster growth (P<0.05) than those of the control (i.e., URS). Intakes of dry matter, total digestible nutrients, and digestible crude protein were numerically increased for TRS, FBS, and TRS+FBS. Feed conversion, as kg dry matter/kg gain, was improved for TRS, FBS, and TRS+FBS lambs versus URS. Daily gain of lambs increased (P<0.05) with lambs of TRS, FBS, and TRS+FBS but URS lambs showed a decrease (P<0.05) in daily gain. Feed conversion as kg dry matter intake/kg gain was improved (P<0.05) by feeding on TRS, FBS and TRS+FBS rations versus URS. The TRS+FBS lambs tended to have the highest economic efficiency versus URS, TRS and FBS lambs. It was concluded that urea-treated rice straw could be used as sole roughage or mixed with faba bean straw (1:1) in growing lambs' ration to improve their performance and economic efficiency without adversely affecting their health.
Assuntos
Oryza , Vicia faba , Masculino , Ovinos , Animais , Carneiro Doméstico , Nutrientes , Fibras na Dieta , Ureia , Ácidos Graxos Voláteis , Peso CorporalRESUMO
This study was conducted to investigate the effect of dried cafeteria leftover food (DCLF) incorporation in growing APRI rabbit diets on nutrient digestibility, live body weight, body weight gain, carcass traits, meat quality, blood parameters, and economic efficiency. Thirty-six APRI rabbits (6 weeks of age), after weaning, were randomly divided into three groups (12 rabbits/group, 613 ± 5 g). During the experiment, rabbits aged 6-14 weeks participated in the experiment. An approximate isocaloric and isonitrogenous composition was achieved in three pelleted experimental diets. For the rabbit groups D1 (as the control), D2, and D3, DCLF was added at doses of 0%, 17.5%, and 35%, respectively. Digestibility trails were carried out at the end of the feeding experiment to evaluate the nutritional and feeding values of the experimental diets. To examine the characteristics of the carcasses, the quality of the meat, the histopathological analysis, and the blood plasma parameters, three rabbits were slaughtered from each group. The results showed that the feeding values (TDN and DE), which had the greatest values, as well as the digesting coefficients for dry matter, organic matter, crude fiber, and ether extract between the D1 and D3 groups were significantly different (p < 0.05). On the contrary, the curde protein, nitrogen-free extract, and digestible crude protein of the examined diets showed no signifcant differences compared with the control diet. The level of DCLF incorporation in diets significantly (p < 0.05) increased the live body weight at 14 weeks; with D3 recording the highest values (2130.9 g) when compared to the D1 and D2 groups. A similar pattern was observed for both daily increase and total body gain (6-14 weeks). Feed conversion recorded insignificant differences among the experimental diets respecting the period 6-14 weeks of age. DCLF levels had a significant effect on dressing and giblet percentages. The chemical composition and color parameters of rabbit meat were similar (p > 0.05), except for fat%, which had the highest value in the D3 group (p < 0.05) compared to the D1 and D2 groups. Economic efficiency was improved by using DLCF up to 35% in terms of gross margin and feed cost/kg gain. In conclusion, using DCLF in the feeding system of rabbits could enhance productive performance, carcass traits, meat quality, and physiological function, as well as improve economic efficiency.
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Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Dieta , Carne , Animais , Coelhos/fisiologia , Ração Animal/análise , Carne/normas , Dieta/veterinária , MasculinoRESUMO
This experiment was carried out to study the effect of acetic acid addition to rice straws that had been already treated with urea on chemical composition, digestibility, nutritive value, and productive performance of ewes. Thirty ewes with an initial body weight of 44 ± 0.41 kg were chosen 7 days after parturition and divided into 3 groups (10 of each) for 3 months. Each group was assigned randomly to receive one of the three experimental rations composed of concentrate feed mixture and untreated rice straw as a control group (G1), urea-treated rice straw (G2), and urea-acetic acid-treated rice straw (G3). Digestibility coefficients and nutritive value were determined using fifteen mature rams and blood samples were obtained at the end of the collecting period. Findings indicated that the crude protein of rice straw was increased, and crude fiber content was decreased by either urea or urea-acetic acid rations (i.e., G2 and G3). Digestibility of most nutrients was increased (P < 0.05) for animals fed either G2 or G3 rations. There were no significant differences in nutritive value as total digestible nutrients (TDN) among tested groups; however, digestible crude protein (DCP) increased (P < 0.05) for G2 and G3 rations. Plasma total protein, AST, creatinine, and urea were increased (P < 0.05) by feeding on G2 or G3 ration; however, plasma ALT was not affected. The average daily intake of dry matter (DM), TDN, and DCP was higher for G2 and G3 rations. Actual milk yield, fat-corrected milk (FCM), percentages of fat, and total solids and constituents yield were increased (P < 0.05) by feeding on treated rice straw rations (i.e., G2 and G3); however, the percentages of protein, lactose, solids not fat, and ash were not affected. In the 1st month after parturition, the changes in ewes body weight were less (P < 0.05) when they fed on G2 and G3 rations than the control one (G1)). Dams' production and offspring performance were improved (P < 0.05) by feeding on G2 and G3 rations. Feed conversion as kg DMI/kg FCM, kg TDN/kg FCM, and economic efficiency was improved for G2 and G3. In concluded, adding acetic acid to urea-treated rice straw may improve the performance of ewes fed on it and increase their milk production and profitability. The same trend was observed with (G2) which received urea-treated rice straw ration.
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Oryza , Animais , Feminino , Masculino , Ácido Acético/metabolismo , Ração Animal/análise , Peso Corporal , Dieta/veterinária , Digestão , Lactação , Leite/química , Ovinos , Carneiro Doméstico , Ureia/metabolismoRESUMO
This study aimed to evaluate the effects of rations containing restaurant food waste (RFW) on nutrient digestibility, milk yield and its composition, and some blood parameters of lactating Zaraibi goats. In the last month of pregnancy, 30 goats (32.8 + 0.91 kg body weight and aged 3-4 years) were chosen and divided into three similar groups (10 goats per group). Each group was randomly assigned to be fed one of the experimental rations. The control group (R1) fed on a ration comprising concentrate feed mixture (CFM1) and berseem as a fresh roughage whereas the second (R2) and the third groups (R3) fed on CFM partially substituted by 15 and 30% of RFW (CFM2 and CFM3, respectively). Nutrient digestibility and feeding values were improved with R3 goats, which had the highest level of RFW (30%) versus R2 and R1 goats. The total volatile fatty acid (TVFA) concentration in the in-rumen liquor was elevated by increasing the level of RFW up to 30% in CFM3 of R3 goats. Actual daily milk yields were significantly (P < 0.05) higher (1269.30 g/h/d) for R3 goats versus R1 and R2 (1037.57 and 1180.70 g/h/d, respectively). The inclusion of RFW in rations had a significant effect on the yield of milk constituents, without significant different among experimental rations regarding some blood constituents and offspring performance. Economic feed efficiency (relative feed cost and relative daily profit) was improved by including RFW in the CFM. Therefore, it can be concluded that the inclusion of up to 30% RFW improved productive performance and economic efficiency in lactating Zaraibi goat rations.
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Leite , Eliminação de Resíduos , Ração Animal/análise , Animais , Dieta/veterinária , Digestão , Feminino , Fermentação , Cabras/metabolismo , Lactação , Leite/metabolismo , Nutrientes , Restaurantes , Rúmen/metabolismoRESUMO
OBJECTIVE: To explore the pattern of fetal cortical development in pregnancies complicated by pre-eclampsia (PE), with and without a small-for-gestational-age (SGA) fetus, compared to uncomplicated pregnancies. METHODS: This was a prospective observational study including singleton pregnancies complicated by normotensive SGA (birth weight < 10th centile) (n = 77), PE with an appropriate-for-gestational-age (AGA) fetus (n = 76) or PE with a SGA fetus (n = 67), and 128 uncomplicated pregnancies (normotensive AGA) matched by gestational age at ultrasound. All pregnancies underwent detailed neurosonography, using a transabdominal and transvaginal approach, at 31-35 weeks' gestation to assess the depth of the insula, Sylvian fissure, parieto-occipital sulcus, cingulate sulcus and calcarine sulcus. All measurements were adjusted for biparietal diameter (BPD). In addition, a grading score of cortical development was assigned to each brain structure, ranging from Grade 0 (no development) to Grade 5 (maximum development). Univariate and multiple regression analyses were conducted. RESULTS: Similar to findings in previous studies, normotensive pregnancies with a SGA fetus showed significant differences in cortical development compared with controls, with reduced Sylvian fissure depth adjusted for BPD (14.5 ± 2.4 vs 16.6 ± 2.3; P < 0.001) and increased insula depth adjusted for BPD (33.2 ± 2.0 vs 31.8 ± 2.0; P < 0.001). Interestingly, a similar cortical development pattern was observed in PE pregnancies with a SGA fetus and in PE pregnancies with an AGA fetus, manifested by reduced Sylvian fissure depth adjusted for BPD (14.2 ± 2.3 and 14.3 ± 2.3 vs 16.6 ± 2.3; P < 0.001 for both) and greater insula depth adjusted for BPD (33.2 ± 2.1 and 32.8 ± 1.7 vs 31.8 ± 2.0; P < 0.001 for both) compared with controls. No significant differences were observed in parieto-occipital, cingulate sulcus or calcarine sulcus depth across the study groups. The Sylvian fissure was scored as Grade 4 in significantly more (93.2% vs 59.5%) and as Grade 5 in significantly fewer (2.7% vs 37.3%) PE pregnancies with an AGA fetus compared with controls (P < 0.05 for both). These differences remained significant even after statistical adjustment for potential confounders, including ethnicity, low socioeconomic status, nulliparity, chronic hypertension, pregestational diabetes, assisted reproductive technologies, smoking and fetal gender, with the application of Benjamini-Hochberg procedure for multiple comparisons. CONCLUSIONS: PE with or without SGA is associated with a differential fetal cortical development pattern which is similar to that described previously in small fetuses. Future research is warranted to elucidate better the mechanism(s) underlying these changes. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
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Doenças do Recém-Nascido , Pré-Eclâmpsia , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/diagnóstico por imagem , Feto , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Pré-Eclâmpsia/diagnóstico por imagem , Gravidez , Ultrassonografia Pré-Natal/métodosRESUMO
OBJECTIVE: To explore whether neurosonography can detect differences in cortical development and corpus callosal length in late-onset small fetuses subclassified into small-for-gestational age (SGA) or growth restricted (FGR). METHODS: This was a prospective cohort study in singleton pregnancies, including normally grown fetuses (birth weight between the 10th and 90th centiles) and late-onset small fetuses (estimated fetal weight < 10th centile, diagnosed after 32 weeks of gestation and confirmed by birth weight < 10th centile). Small fetuses were subclassified into SGA (birth weight between the 3rd and 9th centiles and normal fetoplacental Doppler) and FGR (birth weight < 3rd centile and/or abnormal cerebroplacental ratio and/or abnormal uterine artery Doppler). Neurosonography was performed at 33 ± 1 weeks of gestation to assess the depth of the insula, Sylvian fissure and parieto-occipital sulcus in the axial views and corpus callosal length in the midsagittal plane. Measurements were performed offline using Alma Workstation software and were adjusted by biparietal diameter or cephalic index. Linear regression analysis was used to assess the association between the neurosonographic variables and study group, adjusting for confounding factors such as gender, gestational age at neurosonography, nulliparity and pre-eclampsia. RESULTS: In total, 318 fetuses were included, of which 97 were normally grown and 221 were late-onset small fetuses that were further subdivided into late-onset SGA (n = 67) or late-onset FGR (n = 154). Compared to controls, both SGA and FGR cases showed significantly increased insular depth adjusted for biparietal diameter (median (interquartile range), controls 0.329 (0.312-0.342) vs SGA 0.339 (0.321-0.347) vs FGR 0.336 (0.325-0.349); P = 0.006). A linear tendency to reduced Sylvian fissure depth adjusted for biparietal diameter was also observed across the study groups (mean ± SD, controls 0.148 ± 0.021 vs SGA 0.142 ± 0.025 vs FGR 0.139 ± 0.022; P = 0.003). However, differences were significant only between the FGR and control groups. Corpus callosal length adjusted for cephalic index was significantly reduced in FGR cases compared with both controls and SGA cases, while there was no difference between SGA cases and controls (median (interquartile range), controls 0.500 (0.478-0.531) vs SGA 0.502 (0.487-0.526) vs FGR 0.475 (0.447-0.508); P = 0.005). No differences were found in parieto-occipital sulcus depth between the three study groups. CONCLUSION: Neurosonography seems to be a sensitive tool to detect subtle structural differences in brain development in late-onset small fetuses. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
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Córtex Cerebral/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Neuroimagem/métodos , Ultrassonografia Pré-Natal/métodos , Peso ao Nascer , Córtex Cerebral/embriologia , Corpo Caloso/embriologia , Feminino , Desenvolvimento Fetal , Retardo do Crescimento Fetal/diagnóstico por imagem , Peso Fetal , Idade Gestacional , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Gravidez , Estudos Prospectivos , Sensibilidade e Especificidade , Ultrassonografia Doppler/métodosRESUMO
OBJECTIVE: To assess in women with early-onset severe pre-eclampsia whether longitudinal changes in angiogenic factors improve the prediction of adverse outcome. DESIGN: Prospective cohort study. SETTING: Maternity units in two Spanish hospitals. POPULATION: Women with diagnosis of early-onset severe pre-eclampsia. METHODS: Levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-) and sFlt-1/PlGF ratio were measured at admission and before delivery, and average daily change calculated. The association of longitudinal changes of angiogenic factors with the time interval to delivery and with complications was evaluated by logistic and Cox regression. MAIN OUTCOME MEASURES: Interval to delivery and composite of adverse outcomes. RESULTS: We included 63 women, of which 26 (41.3%) had a complication. Longitudinal changes of sFlt-1 were more pronounced in complicated pregnancies (median: 1047 versus 342 pg/ml/day; P = 0.04). On the multivariate analysis, the clinical risk score and sFlt-1 at admission explained 6.2% of the uncertainty for complication; the addition of sFlt-1 longitudinal changes improved this to 25.3% (P = 0.002). The median time from admission to delivery was 4 days (95% CI 1.6-6.04) in those in the highest quartile of sFlt-1 longitudinal changes versus 16 days (95% CI 12.4-19.6) in the remaining women (Log-rank test P < 0.001). CONCLUSIONS: Longitudinal changes in sFlt-1 maternal levels from admission for confirmed early-onset severe pre-eclampsia add to baseline characteristics in the prediction of adverse outcome and interval to delivery. TWEETABLE ABSTRACT: In early-onset severe pre-eclampsia, longitudinal changes in sFlt-1 levels improve the prediction of complications and interval to delivery.
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Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Estudos Longitudinais , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal , Prognóstico , Estudos Prospectivos , Curva ROC , Espanha , Fatores de TempoRESUMO
While a simple interrupted sutured anastomosis remains the gold standard in microsurgery, the introduction of the microanastomotic coupler device (MACD) has decreased procedure time and thrombosis risk, and improved the patency of venous anastomoses. The aim of this review is to update the evidence-based advantages of the MACD on arteries, based on clinical and experimental data, and to compare them to the hand-sewn approach in free flap transfer. All relevant articles that appeared in the PubMed and Medline/Ovid databases during the past three decades were reviewed. After exclusions, 11 studies were retained and discussed. The MACD had a generally shorter arterial anastomosis time, with improved flap survival and reduced ischaemia compared with the hand-sewn approach. The use of the MACD in arterial anastomosis is an efficient and less time-consuming alternative to the hand-sewn technique, provided that the selection of vessels is appropriate and the vessel diameter is large enough to do the anastomosis.
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Retalhos de Tecido Biológico , Procedimentos de Cirurgia Plástica , Anastomose Cirúrgica , Artérias/cirurgia , Humanos , Microcirurgia , Estudos RetrospectivosRESUMO
Noscapine is a natural alkaloid that is used as an antitussive medicine. However, it also acts as a weak anticancer agent in certain in vivo models through a mechanism that is largely unknown. Here, we performed structural studies and show that the cytotoxic agent 7A-O-demethoxy-amino-noscapine (7A-aminonoscapine) binds to the colchicine site of tubulin. We suggest that the 7A-methoxy group of noscapine prevents binding to tubulin due to a steric clash of the compound with the T5-loop of α-tubulin. We further propose that the anticancer activity of noscapine arises from a bioactive metabolite that binds to the colchicine site of tubulin to induce mitotic arrest through a microtubule cytoskeleton-based mechanism.
Assuntos
Antineoplásicos/farmacologia , Noscapina/análogos & derivados , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Colchicina/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Noscapina/química , Noscapina/farmacologia , Ligação Proteica/efeitos dos fármacos , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
OBJECTIVES: To describe placental histopathological findings in a large cohort of pregnancies complicated by pre-eclampsia (PE) and/or small-for-gestational age (SGA), and to investigate their association with fetoplacental Doppler parameters. METHODS: This was a prospective observational study of normotensive pregnancies with SGA (defined as birth weight < 10th centile) (n = 184), PE pregnancies with a normally grown fetus (n = 102), pregnancies with both PE and SGA (n = 120) and uncomplicated pregnancies (n = 202). Uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) artery pulsatility indices (PI) were assessed. The cerebroplacental ratio (CPR) was calculated by dividing MCA-PI by UA-PI. Doppler parameters were considered abnormal when UtA-PI or UA-PI was > 95th centile or MCA-PI or CPR was < 5th centile. Placental lesions were categorized as vascular (maternal or fetal side), immunoinflammatory or other, according to the 2014 Amsterdam Placental Workshop Group Consensus Statement. Comparison between the study groups was performed using univariate and multiple regression analysis, and logistic regression was used to determine the relationship between abnormal Doppler parameters and placental lesions. RESULTS: Maternal-side vascular lesions were significantly more common in PE pregnancies with SGA than in the other groups (PE + SGA, 73% vs PE, 46% vs SGA, 38% vs controls, 31%; P = 0.01) and included mainly two types of lesion: developmental (PE + SGA, 13% vs PE, 5% vs SGA, 3% vs controls, 1.5%; P < 0.001) and malperfusion (PE + SGA, 70% vs PE, 39% vs SGA, 32% vs controls, 25%; P = 0.001). In contrast, the incidence of fetal-side developmental lesions was significantly higher in normotensive SGA pregnancies than in controls and PE pregnancies (PE + SGA, 0% vs PE, 3% vs SGA, 8% vs controls, 2%; P = 0.001). All cases displayed a lower prevalence of infectious lesions than did controls, with the highest prevalence of immune lesions observed in pregnancies with both PE and SGA (PE + SGA, 18% vs PE, 8% vs SGA, 10% vs controls, 9%; P = 0.001). All fetoplacental Doppler parameters evaluated were associated with maternal-side vascular lesions, mainly malperfusion (mean UtA-PI: odds ratio (OR), 2.45 (95% CI, 1.51-3.97); UA-PI: OR, 2.05 (95% CI, 1.02-4.47); MCA-PI: OR, 2.75 (95% CI, 1.40-5.42); CPR: OR, 1.75 (95% CI, 1.04-2.95)). This association was evident mainly in the normotensive SGA group, being non-significant in controls or PE pregnancies without SGA. No significant associations were observed between fetoplacental Doppler parameters and other placental lesions in any of the study groups. CONCLUSIONS: PE and SGA are associated with different patterns of placental histopathological lesions in accordance with the clinical manifestation of the placental disorder (maternal vs fetal). Fetoplacental Doppler findings show an association with placental malperfusion lesions on the maternal side, supporting the use of abnormal Doppler as a surrogate for placental insufficiency. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
Assuntos
Retardo do Crescimento Fetal/diagnóstico , Artéria Cerebral Média/diagnóstico por imagem , Placenta/patologia , Pré-Eclâmpsia/diagnóstico , Artérias Umbilicais/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Artéria Cerebral Média/embriologia , Placenta/diagnóstico por imagem , Insuficiência Placentária/diagnóstico por imagem , Gravidez , Estudos Prospectivos , Fluxo Pulsátil , Ultrassonografia Doppler , Ultrassonografia Pré-NatalRESUMO
The skin is a natural barrier between the interior milieu of the organism and its environment. This barrier has multiple physiological functions and may be affected by an array of pathologies including wounds and burns. The present study aims to determine the effect of the nervous system on wound healing. Specifically, this study tested the effect of denervation by chemical ablation on the burn wound healing process using guanethidine for denervation of the sympathetic postganglionic neurons and resiniferatoxin for denervation of the sensory capsaicin-sensitive fibres. Animals were divided into 8 different groups: (1) control group, (2) sensory denervated and burned, (3) sensory denervated non-burned, (4) sympathetic denervated and burned, (5) sympathetic denervated non-burned, (6) vehicle sensory burned, (7) vehicle sympathetic burned, (8) non-denervated burned. We measured different morphologic and biochemical parameters such as wound surface area, histological alterations and mast cells. In addition, NGF, IL-1ß, IL-6 and IL-8 levels were determined using the ELISA technique. The gross observations, the histological data including mast cell modulation, as well as the molecular data, speak in favour of a significant delay in burn wound healing caused by sensory denervation. On the other hand, results support the positive role of sympathetic denervation in speeding up the healing process. The dual effect of the nervous system on burn wound healing is being documented in an animal model for the first time.
La peau est une barrière naturelle entre le milieu intérieur et son environnement. Elle a des fonctions physiologiques multiples et peut être atteinte par de nombreuses pathologies parmi lesquelles plaies et brûlures. Cette étude a pour but d'évaluer les effets du système nerveux sur la cicatrisation et plus particulièrement ceux de la dénervation chimique par guanéthidine des neurones sympathiques post ganglionnaires ainsi que celle des fibres sensitives à capsaïcine par résiniferatoxine. Des animaux ont été répartis en 8 groupes : (1) contrôle, (2) dénervation sensitive + brûlure, (3) dénervation sensitive sans brûlure, (4) dénervation sympathique + brûlure, (5) dénervation sympathique sans brûlure, (6) solvant de résiniferatoxine + brûlure, (7) solvant de guanéthidine + brûlure, (8) pas de dénervation + brûlure. Nous avons mesuré plusieurs paramètres morphologiques et biochimiques parmi lesquels la surface brûlées, les anomalies histologiques et la fonction mastocytaire. NGF, IL1b, IL6 et IL8 ont été mesurés par méthode ELISA. L'observation clinique, les données histologiques dont la modulation mastocytaire ainsi que les données moléculaires orientent vers un ralentissement de la cicatrisation après dénervation sensitive alors que la dénervation sympathique l'accélère. C'est la première fois que ces effets opposés des dénervations sélective est observée chez l'animal.
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Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki ≈ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 µM (1-2 µg/mL) against the H37Ra isolate of M. tuberculosis.
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In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
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While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/química , Janus Quinase 3/antagonistas & inibidores , Valina/análogos & derivados , Animais , Linhagem Celular , Bases de Dados de Compostos Químicos , Cães , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Haplorrinos , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Janus Quinase 2/química , Janus Quinase 3/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Valina/química , Valina/farmacocinética , Valina/farmacologiaRESUMO
Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.
RESUMO
C1q deficiency is related strongly to systemic lupus erythematosus (SLE), but very few and inconsistent studies explored the single nucleotide polymorphisms of the C1q gene in relation to juvenile SLE (jSLE) and lupus nephritis (LN). The objective of this study was to analyse whether C1q rs 292001 polymorphism is associated with SLE and disease phenotype, especially nephritis, and to investigate the relation between this polymorphism and clinical data, treatment outcome, serum level of C1q protein and antibodies. Typing of C1q rs292001 polymorphism using restriction fragment length polymorphism and measuring serum levels of C1q protein and antibodies by enzyme-linked immunosorbent assay (ELISA) were performed for 130 children with SLE and 208 healthy controls. The A allele of C1q rs292001 was associated with jSLE and LN (P = 0·005 and 0·013, respectively) and the AA genotype was associated with jSLE (P = 0·036). Low serum levels of C1q protein were found in jSLE and LN (P < 0·001 and 0·009, respectively), and these levels were increased after treatment in patients with LN (P = 0·009) and active renal disease (P = 0·027). Higher titres of C1q antibodies were found in patients with LN (P = 0·015) and correlated negatively with C1q protein level (P < 0·001) and patient age (P = 0·04). The A allele and AA genotype of C1q rs292001 can be considered a susceptibility risk factor and the GG genotype could be considered protective for jSLE and LN in the studied cohort of Egyptian children. Decreased serum levels of C1q protein and increased titres of C1q antibodies may be involved in the pathogenesis of jSLE, especially LN.
Assuntos
Autoanticorpos/imunologia , Complemento C1q/genética , Complemento C1q/imunologia , Nefrite Lúpica/genética , Criança , Egito , Ensaio de Imunoadsorção Enzimática , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Nefrite Lúpica/imunologia , Masculino , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The discovery of non-symmetric thienoimidazole-containing HCV NS5A inhibitors is described. The inhibitors herein reported display high potencies against both genotype 1a and 1b. In this follow-up manuscript, we discuss the importance of the linker aromaticity to achieve high potency, particularly against genotype 1a.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/efeitos dos fármacos , Animais , Antivirais/química , Genótipo , Hepacivirus/genética , Humanos , Imidazóis/química , RatosRESUMO
The discovery of C2-symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This study revealed the paramount importance of the aromatic character of the linker to achieve high genotype 1a potency.
Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Imidazóis/químicaRESUMO
Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Relação Estrutura-AtividadeRESUMO
The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.