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1.
BMC Pregnancy Childbirth ; 20(1): 271, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375687

RESUMO

BACKGROUND: Visual estimation of blood loss following delivery often under-reports actual bleed volume. To improve accuracy, quantitative blood loss measurement was introduced for all births in the 12 hospitals providing maternity care in Wales. This intervention was incorporated into a quality improvement programme (Obstetric Bleeding Strategy for Wales, OBS Cymru). We report the incidence of postpartum haemorrhage in Wales over a 1-year period using quantitative measurement. METHODS: This prospective, consecutive cohort included all 31,341 women giving birth in Wales in 2017. Standardised training was cascaded to maternity staff in all 12 hospitals in Wales. The training comprised mock-scenarios, a video and team drills. Uptake of quantitative blood loss measurement was audited at each centre. Data on postpartum haemorrhage of > 1000 mL were collected and analysed according to mode of delivery. Data on blood loss for all maternities was from the NHS Wales Informatics Service. RESULTS: Biannual audit data demonstrated an increase in quantitative measurement from 52.1 to 87.8% (P < 0.001). The incidence (95% confidence intervals, CI) of postpartum haemorrhage of > 1000 mL, > 1500 mL and > 2000 mL was 8.6% (8.3 to 8.9), 3.3% (3.1 to 3.5) and 1.3% (1.2 to 1.4), respectively compared to 5%, 2% and 0.8% in the year before OBS Cymru. The incidence (95% CI) of bleeds of > 1000 mL was similar across the 12 hospitals despite widely varied size, staffing levels and case mix, median (25th to 75th centile) 8.6% (7.8-9.6). The incidence of PPH varied with mode of delivery and was mean (95% CI) 4.9% (4.6-5.2) for unassisted vaginal deliveries, 18.4 (17.1-19.8) for instrumental vaginal deliveries, 8.5 (7.7-9.4) for elective caesarean section and 19.8 (18.6-21.0) for non-elective caesarean sections. CONCLUSIONS: Quantitative measurement of blood loss is feasible in all hospitals providing maternity care and is associated with detection of higher rates of postpartum haemorrhage. These results have implications for the definition of abnormal blood loss after childbirth and for management and research of postpartum haemorrhage.


Assuntos
Hemorragia Pós-Parto/epidemiologia , Adulto , Estudos de Coortes , Parto Obstétrico/estatística & dados numéricos , Feminino , Humanos , Incidência , Hemorragia Pós-Parto/patologia , Gravidez , Estudos Prospectivos , País de Gales/epidemiologia
2.
Curr Biol ; 34(15): 3327-3341.e9, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38955177

RESUMO

Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis. Contingent on nutritional stores, adipocytes secrete adipokines, such as the fat hormone leptin, to signal nutrient status to the central brain. Increased leptin secretion underlies metabolic dysregulation during common obesity, but the molecular mechanisms regulating leptin secretion from human adipocytes are poorly understood. Here, we report that Atg8/LC3 family proteins, best known for their role in autophagy during nutrient scarcity, play an evolutionarily conserved role during nutrient surplus by promoting adipokine secretion. We show that in a well-fed state, Atg8/LC3 promotes the secretion of the Drosophila functional leptin ortholog unpaired 2 (Upd2) and leptin from human adipocytes. Proteomic analyses reveal that LC3 directs leptin to a secretory pathway in human cells. We identified LC3-dependent extracellular vesicle (EV) loading and secretion (LDELS) as a required step for leptin release, highlighting a unique secretory route adopted by leptin in human adipocytes. In Drosophila, mutations to Upd2's Atg8 interaction motif (AIM) result in constitutive adipokine retention. Atg8-mediated Upd2 retention alters lipid storage and hunger response and rewires the bulk organismal transcriptome in a manner conducive to starvation survival. Thus, Atg8/LC3's bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively. We posit that decoding how bidirectional molecular switches-such as Atg8/LC3-operate at the nexus of nutritional scarcity and surplus will inform therapeutic strategies to tackle chronic metabolic disorders.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Transdução de Sinais , Animais , Humanos , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Adipócitos/metabolismo , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Família da Proteína 8 Relacionada à Autofagia/genética , Leptina/metabolismo , Leptina/genética , Nutrientes/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Autofagia
3.
Elife ; 112022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36201241

RESUMO

Diet-induced obesity leads to dysfunctional feeding behavior. However, the precise molecular nodes underlying diet-induced feeding motivation dysregulation are poorly understood. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high-sugar regime in Drosophila, we sought to address how diet-induced changes in adipocyte lipid composition regulate feeding behavior. We observed that subjecting adult Drosophila to a prolonged high-sugar diet degrades the hunger-driven feeding response. Lipidomics analysis reveals that longitudinal exposure to high-sugar diets significantly alters whole-body phospholipid profiles. By performing a systematic genetic screen for phospholipid enzymes in adult fly adipocytes, we identify Pect as a critical regulator of hunger-driven feeding. Pect is a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2. We show that disrupting Pect activity only in the Drosophila fat cells causes insulin resistance, dysregulated lipoprotein delivery to the brain, and a loss of hunger-driven feeding. Previously human studies have noted a correlation between PCYT2/Pect levels and clinical obesity. Now, our unbiased studies in Drosophila provide causative evidence for adipocyte Pect function in metabolic homeostasis. Altogether, we have uncovered that PE phospholipid homeostasis regulates hunger response.


Assuntos
Drosophila melanogaster , Fome , Animais , Drosophila , Drosophila melanogaster/genética , Corpo Adiposo/metabolismo , Comportamento Alimentar/fisiologia , Humanos , Fome/fisiologia , Mamíferos , Obesidade/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/metabolismo , Açúcares/metabolismo
4.
ACS Chem Biol ; 17(7): 1658-1664, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35679588

RESUMO

A high-throughput cell-based screen identified redox-active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.


Assuntos
Ritmo Circadiano , Fenazinas , Oxirredução
5.
Open Biol ; 11(10): 210183, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34610264

RESUMO

Time-restricted feeding (TRF) studies underscore that when food is consumed during the daily cycle is important for weight gain/loss because the circadian clock rhythmically modulates metabolism. However, the interpretation of previous TRF studies has been confounded by study designs that introduced an extended period of enforced fasting. We introduce a novel time-optimized feeding (TOF) regimen that disentangles the effects of phase-dependent feeding from the effects of enforced fasting in mice, as well as providing a laboratory feeding protocol that more closely reflects the eating patterns of humans who usually have 24 hour access to food. Moreover, we test whether a sudden switch from ad libitum food access to TRF evokes a corticosterone (stress) response. Our data indicate that the timing of high-fat feeding under TOF allows most of the benefit of TRF without obligatory fasting or evoking a stress response. This benefit occurs through stable temporal coupling of carbohydrate/lipid oxidation with feeding. These results highlight that timing the ingestion of calorically dense foods to optimized daily phases will enhance lipid oxidation and thereby limit fat accumulation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Comportamento Alimentar/fisiologia , Obesidade/prevenção & controle , Animais , Relógios Circadianos , Ritmo Circadiano , Corticosterona/sangue , Metabolismo Energético , Jejum/sangue , Peroxidação de Lipídeos , Masculino , Camundongos , Obesidade/sangue , Obesidade/induzido quimicamente
6.
Toxicol Lett ; 206(2): 166-71, 2011 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-21784140

RESUMO

A number of studies have demonstrated that co-exposure to low levels of melamine and cyanuric acid elicits renal toxicity due to the formation of melamine cyanurate crystals in the kidney nephrons. In this work, we investigated if co-exposure of rats to these compounds leads to alterations in the expression of the genes encoding kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), clusterin, osteopontin, and neutrophil gelatinase-associated lipocalin/lipocalin 2 (NGAL), which have been proposed as urinary biomarkers for nephrotoxicity. Six-week-old male and female F344 rats were fed ad libitum a diet fortified with 0 (control), 7, 23, 69, 229, or 694 ppm melamine and cyanuric acid (co-exposure groups), 1388 ppm melamine, or 1388 ppm cyanuric acid for seven days. Histopathology and clinical chemistry examination indicated marked toxicity only in the animals exposed to the two highest combined doses of melamine and cyanuric acid. Consistent with these observations, quantitative real-time polymerase chain reaction analysis of kidney tissue indicated increased expression of all genes analyzed relative to the control in both male and female rats fed daily with 229 or 694 ppm melamine and cyanuric acid. Exposure to lower levels of both compounds or to the individual compounds did not induce gene expression changes. These data indicate that quantifying the expression levels of the selected biomarker genes constitutes a useful endpoint to assess the combined toxicity of melamine and cyanuric acid in both male and female rats.


Assuntos
Poluentes Ambientais/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Insuficiência Renal/induzido quimicamente , Triazinas/toxicidade , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/metabolismo , Animais , Biomarcadores/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Clusterina/genética , Clusterina/metabolismo , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Feminino , Lipocalina-2 , Lipocalinas/genética , Lipocalinas/metabolismo , Masculino , Nível de Efeito Adverso não Observado , Osteopontina/genética , Osteopontina/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Insuficiência Renal/metabolismo , Caracteres Sexuais , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Triazinas/administração & dosagem
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