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1.
Development ; 149(8)2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35333324

RESUMO

Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.


Assuntos
Leucoencefalopatias , Doenças Neurodegenerativas , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Animais , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Camundongos , Mutação/genética , Doenças Neurodegenerativas/patologia , Neuroglia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética
2.
Semin Immunol ; 54: 101509, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-34742624

RESUMO

Macrophage colony-stimulating factor (CSF1) is the primary growth factor required for the control of monocyte and macrophage differentiation, survival, proliferation and renewal. Although the cDNAs encoding multiple isoforms of human CSF1 were cloned in the 1980s, and recombinant proteins were available for testing in humans, CSF1 has not yet found substantial clinical application. Here we present an overview of CSF1 biology, including evolution, regulation and functions of cell surface and secreted isoforms. CSF1 is widely-expressed, primarily by cells of mesenchymal lineages, in all mouse tissues. Cell-specific deletion of a floxed Csf1 allele in mice indicates that local CSF1 production contributes to the maintenance of tissue-specific macrophage populations but is not saturating. CSF1 in the circulation is controlled primarily by receptor-mediated clearance by macrophages in liver and spleen. Administration of recombinant CSF1 to humans or animals leads to monocytosis and expansion of tissue macrophage populations and growth of the liver and spleen. In a wide variety of tissue injury models, CSF1 administration promotes monocyte infiltration, clearance of damaged cells and repair. We suggest that CSF1 has therapeutic potential in regenerative medicine.


Assuntos
Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos , Animais , Homeostase , Humanos , Fígado/metabolismo , Fator Estimulador de Colônias de Macrófagos/genética , Macrófagos/metabolismo , Camundongos , Proteínas Recombinantes/genética
3.
Am J Physiol Endocrinol Metab ; 326(2): E149-E165, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38117267

RESUMO

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Acute administration of a CSF1-Fc fusion protein to mice led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilization of body fat. The impacts of CSF1 on macrophage abundance, liver size, and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, and control of liver-to-body weight ratio, which in turn controls systemic metabolic homeostasis. This novel macrophage regulatory axis has the potential to promote fat mobilization, without changes in appetence, which may have novel implications for managing metabolic syndrome.NEW & NOTEWORTHY CSF1 administration expands tissue macrophages, which transforms systemic metabolism. CSF1 drives fat mobilization and glucose uptake to support liver growth. The effects of CSF1 are independent of normal hormonal metabolic regulation. The effects of CSF1 are rapidly reversible, restoring homeostatic body composition. CSF1-dependent macrophages and liver size are coupled in a dynamic equilibrium.


Assuntos
Fator Estimulador de Colônias de Macrófagos , Macrófagos , Animais , Camundongos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Metabolismo dos Carboidratos , Glucose/metabolismo , Lipídeos
4.
Eur J Immunol ; 53(8): e2250312, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37059596

RESUMO

Homozygous null mutation of the Csf1r gene (Csf1rko) in rats leads to the loss of most tissue macrophage populations and pleiotropic impacts on postnatal growth and organ maturation, leading to early mortality. The phenotype can be reversed by intraperitoneal transfer of WT BM cells (BMT) at weaning. Here, we used a Csf1r-mApple transgenic reporter to track the fate of donor-derived cells. Following BMT into Csf1rko recipients, mApple+ve cells restored IBA1+ tissue macrophage populations in every tissue. However, monocytes, neutrophils, and B cells in the BM, blood, and lymphoid tissues remained of recipient (mApple-ve ) origin. An mApple+ve cell population expanded in the peritoneal cavity and invaded locally in the mesentery, fat pads, omentum, and diaphragm. One week after BMT, distal organs contained foci of mApple+ve , IBA1-ve immature progenitors that appeared to proliferate, migrate, and differentiate locally. We conclude that rat BM contains progenitor cells that are able to restore, replace, and maintain all tissue macrophage populations in a Csf1rko rat directly without contributing to the BM progenitor or blood monocyte populations.


Assuntos
Medula Óssea , Macrófagos , Ratos , Animais , Monócitos , Receptores Proteína Tirosina Quinases , Células da Medula Óssea
5.
PLoS Pathog ; 18(1): e1010166, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35007292

RESUMO

A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.


Assuntos
Listeria monocytogenes/patogenicidade , Listeriose/microbiologia , Macrófagos/microbiologia , Vacúolos/microbiologia , Virulência/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
6.
PLoS Genet ; 17(6): e1009605, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34081701

RESUMO

Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r-mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43hi non-classical monocytes, absent in the Csf1rko, were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.


Assuntos
Fígado Gorduroso/genética , Macrófagos/metabolismo , Anormalidades Musculoesqueléticas/genética , Desenvolvimento Musculoesquelético/genética , Osteopetrose/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Transplante de Medula Óssea , Modelos Animais de Doenças , Embrião de Mamíferos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/terapia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Genes Reporter , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/deficiência , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/genética , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Macrófagos/patologia , Masculino , Anormalidades Musculoesqueléticas/metabolismo , Anormalidades Musculoesqueléticas/patologia , Anormalidades Musculoesqueléticas/terapia , Osteopetrose/metabolismo , Osteopetrose/patologia , Osteopetrose/terapia , Ratos , Ratos Transgênicos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/deficiência
7.
Dig Dis ; 41(3): 439-446, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36327947

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver as a consequence of metabolic perturbations associated with obesity, type 2 diabetes, dyslipidemia, and insulin resistance. People with NAFLD may develop metabolic and cardiovascular complications and/or liver-related complications, especially fibrosis and hepatocellular carcinoma, associated with high morbidity and mortality. Due to the high and increasing prevalence of NAFLD, there is an urgent need to identify people at risk of developing liver fibrosis and complications. CC-chemokine ligand 2 (CCL2) is chemokine that attracts inflammatory monocytes to stressed or injured tissues. Infiltrating inflammatory monocytes and CCL2 are strongly implicated in the pathogenesis of liver disease in animal models; however, evidence in patient cohorts is conflicting. METHODS: We investigated associations between circulating CCL2 and clinical parameters, including fibrosis assessed by liver stiffness measurement, in a cohort of 250 NAFLD patients. We also measured fatty acid binding protein 2 (FABP2), a putative biomarker of intestinal permeability in patients with liver disease, since pro-inflammatory gut-derived microbial products may induce inflammatory chemokines such as CCL2. RESULTS: Serum CCL2 levels were weakly associated with liver stiffness, but the association was no longer significant after accounting for age, diabetes, and BMI in a multivariable model. Consistent with this, girth and BMI were the strongest predictors of elevated circulating CCL2. Serum FABP2 was weakly, but significantly, correlated with CCL2, and negatively correlated with estimated glomerular filtration rate. CONCLUSION: Circulating CCL2 and FABP2 are associated with NAFLD comorbidities but not liver disease progression in patients with NAFLD.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Adiposidade , Ligantes , Cirrose Hepática/complicações , Quimiocinas/metabolismo
8.
J Immunol ; 206(10): 2251-2263, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965905

RESUMO

The laboratory rat continues to be the model of choice for many studies of physiology, behavior, and complex human diseases. Cells of the mononuclear phagocyte system (MPS; monocytes, macrophages, and dendritic cells) are abundant residents in every tissue in the body and regulate postnatal development, homeostasis, and innate and acquired immunity. Recruitment and proliferation of MPS cells is an essential component of both initiation and resolution of inflammation. The large majority of current knowledge of MPS biology is derived from studies of inbred mice, but advances in technology and resources have eliminated many of the advantages of the mouse as a model. In this article, we review the tools available and the current state of knowledge of development, homeostasis, regulation, and diversity within the MPS of the rat.


Assuntos
Imunidade Adaptativa , Modelos Animais de Doenças , Imunidade Inata , Sistema Fagocitário Mononuclear/imunologia , Ratos , Animais , Genoma , Homeostase/imunologia , Inflamação/imunologia , Fator Estimulador de Colônias de Macrófagos/genética , Camundongos , Mutação , Fenótipo
9.
Ann Hepatol ; 28(6): 101142, 2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37468097

RESUMO

INTRODUCTION AND OBJECTIVES: Among people with type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) is very common and has an increased risk of clinically significant liver disease. The use of sodium-glucose co-transporter 2 (SGLT2i) inhibitors and glucagon-like peptide-1 (GLP-1a) receptor agonists is endorsed to reduce major cardiovascular events and/or progression of chronic kidney disease. Their prevalence of use in people with T2D and co-existent NAFLD remains unclear. We sought to determine the prevalence of use of these medications at two different time periods, and their association with prevalence of clinically significant liver disease. MATERIALS AND METHODS: Consecutive people with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) were recruited from diabetes clinics between Jun-2021 and Jun-2022 ('current' cohort). Liver stiffness measurements (LSM) using FibroScan were performed. Medication data were collected prospectively at recruitment and verified with the dispensing pharmacy or general practitioner medical records. Data for a historical cohort with NAFLD and T2D recruited from the same clinics during 2015-2017 ('historical' cohort) were available. Logistic regression was used to evaluate factors associated with LSM <8.0 or ≥8 kPa (clinically significant fibrosis). RESULTS: There were 292 participants, 177 in the historical cohort and 115 in the current cohort. In the current cohort, 57.4% of patients with T2D and NAFLD were taking a GLP-1a and 42.6% were taking a SGLT2i; a 2.6 to 3.4-fold higher prevalence than in 2015-2017. A lower proportion of the current cohort (23.9% compared to 38.4%) had clinically significant fibrosis (LSM ≥8 kPa; p = 0.012). When the cohorts were pooled and differences adjusted for in multivariable logistic regression analysis, patients taking a GLP-1a or a SGLT2i were 2 times more likely to have a lower LSM (<8 kPa) compared to patients not taking these drugs (OR=2.05, 95%CI 1.07-3.94, p = 0.03 and OR 2.07 95%CI 1.04-4.11, p = 0.04, respectively). CONCLUSIONS: The observation of a lower LSM in people taking SGLT2i and/or GLP-1a following adjustment for other relevant clinico-demographic variables provides support for clinical trials to assess their efficacy in reducing the progression of NAFLD.

10.
Trends Immunol ; 40(2): 98-112, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30579704

RESUMO

The mononuclear phagocyte system (MPS) is defined as a cell lineage in which committed marrow progenitors give rise to blood monocytes and tissue macrophages. Here, we discuss the concept of self-proscribed macrophage territories and homeostatic regulation of tissue macrophage abundance through growth factor availability. Recent studies have questioned the validity of the MPS model and argued that tissue-resident macrophages are a separate lineage seeded during development and maintained by self-renewal. We address this issue; discuss the limitations of inbred mouse models of monocyte-macrophage homeostasis; and summarize the evidence suggesting that during postnatal life, monocytes can replace resident macrophages in all major organs and adopt their tissue-specific gene expression. We conclude that the MPS remains a valid and accurate framework for understanding macrophage development and homeostasis.


Assuntos
Macrófagos/imunologia , Monócitos/imunologia , Sistema Fagocitário Mononuclear/imunologia , Animais , Homeostase , Humanos , Camundongos
11.
J Immunol ; 205(11): 3154-3166, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33139489

RESUMO

The proliferation, differentiation, and survival of cells of the mononuclear phagocyte system (MPS; progenitors, monocytes, macrophages, and classical dendritic cells) are controlled by signals from the M-CSF receptor (CSF1R). Cells of the MPS lineage have been identified using numerous surface markers and transgenic reporters, but none is both universal and lineage restricted. In this article, we report the development and characterization of a CSF1R reporter mouse. A FusionRed (FRed) cassette was inserted in-frame with the C terminus of CSF1R, separated by a T2A-cleavable linker. The insertion had no effect of CSF1R expression or function. CSF1R-FRed was expressed in monocytes and macrophages and absent from granulocytes and lymphocytes. In bone marrow, CSF1R-FRed was absent in lineage-negative hematopoietic stem cells, arguing against a direct role for CSF1R in myeloid lineage commitment. It was highly expressed in marrow monocytes and common myeloid progenitors but significantly lower in granulocyte-macrophage progenitors. In sections of bone marrow, CSF1R-FRed was also detected in osteoclasts, CD169+ resident macrophages, and, consistent with previous mRNA analysis, in megakaryocytes. In lymphoid tissues, CSF1R-FRed highlighted diverse MPS populations, including classical dendritic cells. Whole mount imaging of nonlymphoid tissues in mice with combined CSF1R-FRed/Csf1r-EGFP confirmed the restriction of CSF1R expression to MPS cells. The two markers highlight the remarkable abundance and regular distribution of tissue MPS cells, including novel macrophage populations within tendon and skeletal muscle and underlying the mesothelial/serosal/capsular surfaces of every major organ. The CSF1R-FRed mouse provides a novel reporter with exquisite specificity for cells of the MPS.


Assuntos
Biomarcadores/metabolismo , Sistema Fagocitário Mononuclear/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Animais , Diferenciação Celular/fisiologia , Células Dendríticas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Músculo Esquelético/metabolismo , RNA Mensageiro/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Tendões/metabolismo
12.
Curr Osteoporos Rep ; 20(6): 516-531, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36197652

RESUMO

PURPOSE OF REVIEW: The purpose of the review is to summarize the expression and function of CSF1R and its ligands in bone homeostasis and constraints on therapeutic targeting of this axis. RECENT FINDINGS: Bone development and homeostasis depends upon interactions between mesenchymal cells and cells of the mononuclear phagocyte lineage (MPS), macrophages, and osteoclasts (OCL). The homeostatic interaction is mediated in part by the systemic and local production of growth factors, macrophage colony-stimulating factor (CSF1), and interleukin 34 (IL34) that interact with a receptor (CSF1R) expressed exclusively by MPS cells and their progenitors. Loss-of-function mutations in CSF1 or CSF1R lead to loss of OCL and macrophages and dysregulation of postnatal bone development. MPS cells continuously degrade CSF1R ligands via receptor-mediated endocytosis. As a consequence, any local or systemic increase or decrease in macrophage or OCL abundance is rapidly reversible. In principle, both CSF1R agonists and antagonists have potential in bone regenerative medicine but their evaluation in disease models and therapeutic application needs to carefully consider the intrinsic feedback control of MPS biology.


Assuntos
Doenças Ósseas , Receptor de Fator Estimulador de Colônias de Macrófagos , Humanos , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Imunoterapia , Homeostase/genética , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/metabolismo
13.
Intern Med J ; 52(10): 1749-1758, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-34139066

RESUMO

BACKGROUND: The optimal strategy to support primary care practitioners (PCP) to assess fibrosis severity in non-alcoholic fatty liver disease (NAFLD) and thereby make appropriate management decisions remains unclear. AIMS: To examine the feasibility of using a two-step pathway that combined simple scores (NAFLD Fibrosis Score and Fibrosis-4 Index) with transient elastography (FibroScan) to streamline NAFLD referrals from a 'routine' primary care population to specialist hepatology management clinics (HMC). METHODS: The two-step 'Towards Collaborative Management of NAFLD' (TCM-NAFLD) fibrosis risk assessment pathway was implemented at two outer metropolitan primary healthcare practices in Brisbane. Patients aged ≥18 years with a new or established PCP-diagnosis of NAFLD were eligible for assessment. The pathway triaged patients at 'high risk' of clinically significant fibrosis to HMC for specialist review, and 'low risk' patients to receive ongoing management and longitudinal follow up in primary care. RESULTS: A total of 162 patient assessments between June 2019 and December 2020 were included. Mean age was 58.7 ± 11.7 years, 30.9% were male, 54.3% had type 2 diabetes or impaired fasting glucose, and mean body mass index was 34.2 ± 6.9 kg/m2 . A total 122 patients was considered 'low risk' for clinically significant fibrosis, two patients had incomplete assessments and 38 (23.5%) were triaged to HMC. Among 31 completed HMC assessments to date, 45.2% were considered to have clinically significant (or more advanced) fibrosis, representing 9.2% of 153 completed assessments. CONCLUSION: Implementation of the two-step TCM-NAFLD pathway streamlined hepatology referrals for NAFLD and may facilitate a more cost-effective and targeted use of specialist hepatology resources.


Assuntos
Diabetes Mellitus Tipo 2 , Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Fibrose , Glucose , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/terapia , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Atenção Primária à Saúde , Medição de Risco
14.
BMC Health Serv Res ; 22(1): 487, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35413987

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic that affects approximately half of all people with type 2 diabetes. Those with type 2 diabetes are a high-risk NAFLD subgroup because of their increased risk of clinically significant liver-related outcomes from NAFLD which include hepatocellular carcinoma, cirrhosis-related complications and liver disease mortality. They may benefit from early detection of disease as this would allow at risk patients to access hepatocellular carcinoma surveillance, emerging drug trials for NAFLD and specialist hepatology care prior to emergence of liver-related complications. METHODS: This is a prospective cohort study aimed at incorporating and assessing a community care pathway for liver fibrosis screening into routine care for type 2 diabetes. Patients undergo a point of care assessment of hepatic steatosis and stiffness using FibroScan at the time of the routine diabetes appointment or when attending the clinic for blood tests in preparation for this appointment. DISCUSSION: We propose that implementation of a community-based NAFLD diagnosis, risk-stratification, and referral pathway for people with type 2 diabetes is feasible, will provide earlier, targeted detection of advanced fibrosis, and reduce unnecessary referrals to hepatology outpatients for fibrosis risk assessment. Our study will provide important information about the feasibility of establishing a NAFLD pathway for people with type 2 diabetes in primary care. Ultimately, our findings will help direct spending and resource allocation for NAFLD in a high-risk population. Regular evaluation by stakeholders during implementation will help to create a reliable and sustainable community care pathway and establish a perpetual cycle of learning in primary care. TRIAL REGISTRATION: ANZCTR, ACTRN12621000330842 . Registered 23 March 2021.


Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Carcinoma Hepatocelular/complicações , Procedimentos Clínicos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Fibrose , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/terapia , Neoplasias Hepáticas/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Estudos Prospectivos
15.
Neurobiol Dis ; 151: 105268, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33450391

RESUMO

Mutations in the human CSF1R gene have been associated with dominant and recessive forms of neurodegenerative disease. Here we describe the impacts of Csf1r mutation in the rat on development of the brain. Diffusion imaging indicated small reductions in major fiber tracts that may be associated in part with ventricular enlargement. RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats. There was no evidence of region or sex-specific expression of microglia-associated transcripts. Other than the microglial signature, Csf1rko had no effect on any neuronal or region-specific transcript cluster. Expression of markers of oligodendrocytes, astrocytes, dopaminergic neurons and Purkinje cells was minimally affected. However, there were defects in dendritic arborization of doublecortin-positive neurogenic precursors and expression of poly-sialylated neural cell adhesion molecule (PS-NCAM) in the dentate gyrus of the hippocampus. Heterozygous Csf1rko rats had no detectable brain phenotype. We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy.


Assuntos
Microglia , Doenças Neurodegenerativas/genética , Neurogênese/fisiologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/deficiência , Animais , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Mutação , Ratos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética
16.
Int J Equity Health ; 19(1): 27, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066438

RESUMO

BACKGROUND: Indigenous Australians experience greater health disadvantage and have a higher prevalence of many chronic health conditions. Liver diseases leading to cirrhosis are among the most common contributor to the mortality gap between Indigenous and other Australian adults. However, no comparative data exist assessing differences in presentation and patient outcomes between Indigenous and non-Indigenous Australians hospitalised with cirrhosis. METHODS: Using data from the Hospital Admitted Patient Data Collection and the Death Registry, this retrospective, population-based, cohort study including all people hospitalised for cirrhosis in the state of Queensland during 2008-2017 examined rate of readmission (Poisson regression), cumulative survival (Kaplan-Meier), and assessed the differences in survival (Multivariable Cox regression) by Indigenous status. Predictor variables included demographic, health service characteristics and clinical data. RESULTS: We studied 779 Indigenous and 10,642 non-Indigenous patients with cirrhosis. A higher proportion of Indigenous patients were younger than 50 years (346 [44%] vs. 2063 [19%] non-Indigenous patients), lived in most disadvantaged areas (395 [51%) vs. 2728 [26%]), had alcohol-related cirrhosis (547 [70%] vs. 5041 [47%]), had ascites (314 [40%] vs. 3555 [33%), and presented to hospital via the Emergency Department (510 [68%] vs. 4790 [47%]). Indigenous patients had 3.04 times the rate of non-cirrhosis readmissions (95%CI 2.98-3.10), 1.35 times the rate of cirrhosis-related readmissions (95%CI 1.29-1.41), and lower overall survival (17% vs. 27%; unadjusted hazard ratio (HR) = 1.16 95%CI 1.06-1.27), compared to non-Indigenous patients. Most of the survival deficit was explained by Emergency Department presentation (adj-HR = 1.03 95%CI 0.93-1.13), and alcohol-related aetiology (adj-HR = 1.08 95%CI 0.99-1.19). The remaining survival deficit was influenced by the other clinico-demographic and health service factors (final adj-HR = 1.08 95%CI 0.96-1.20). CONCLUSIONS: There was evidence of differential presentation, higher rates of readmissions, and poorer survival for Indigenous Australians with cirrhosis, compared to other Australians. The increased prevalence of Emergency Department presentation among Indigenous patients suggests missed opportunities for early intervention to prevent progressive cirrhosis complications and hospital readmissions.


Assuntos
Disparidades nos Níveis de Saúde , Hospitalização , Cirrose Hepática , Havaiano Nativo ou Outro Ilhéu do Pacífico , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Austrália/epidemiologia , Doença Crônica , Estudos de Coortes , Serviço Hospitalar de Emergência , Feminino , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/mortalidade , Cirrose Hepática/terapia , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Readmissão do Paciente , Modelos de Riscos Proporcionais , Queensland/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
17.
Intern Med J ; 50(9): 1142-1146, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32929822

RESUMO

People with chronic disease often have poor comprehension of their disease and medications, which can negatively affect health outcomes. In a randomised-controlled trial, we found that patients with decompensated cirrhosis who received a pharmacist-led, patient-oriented education and medication management intervention (n = 57) had greater knowledge of cirrhosis and key self-care tasks compared with usual care (n = 59). Intervention patients also experienced improved quality of life. Dedicated resources are needed to support implementation of evidence-based measures at local centres to improve outcomes.


Assuntos
Conduta do Tratamento Medicamentoso , Qualidade de Vida , Humanos , Cirrose Hepática/tratamento farmacológico , Farmacêuticos , Autocuidado
18.
Am J Physiol Gastrointest Liver Physiol ; 314(3): G388-G398, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351395

RESUMO

Signaling via the colony-stimulating factor 1 receptor (CSF1R) controls the survival, differentiation, and proliferation of macrophages. Mutations in CSF1 or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of pig CSF1-Fc fusion protein as a therapy for low birth weight (LBW) at term, using a model based on maternal dexamethasone treatment in rats. Neonatal CSF1-Fc treatment did not alter somatic growth and did not increase the blood monocyte count. Instead, there was a substantial increase in the size of liver in both control and LBW rats, and the treatment greatly exacerbated lipid droplet accumulation seen in the dexamethasone LBW model. These effects were reversed upon cessation of treatment. Transcriptional profiling of the livers supported histochemical evidence of a large increase in macrophages with a resident Kupffer cell phenotype and revealed increased expression of many genes implicated in lipid droplet formation. There was no further increase in hepatocyte proliferation over the already high rates in neonatal liver. In conclusion, treatment of neonatal rats with CSF1-Fc caused an increase in liver size and hepatic lipid accumulation, due to Kupffer cell expansion and/or activation rather than hepatocyte proliferation. Increased liver macrophage numbers and expression of endocytic receptors could mitigate defective clearance functions in neonates. NEW & NOTEWORTHY This study is based on extensive studies in mice and pigs of the role of CSF1/CSF1R in macrophage development and postnatal growth. We extended the study to neonatal rats as a possible therapy for low birth weight. Unlike our previous studies in mice and pigs, there was no increase in hepatocyte proliferation and no increase in monocyte numbers. Instead, neonatal rats treated with CSF1 displayed reversible hepatic steatosis and Kupffer cell expansion.


Assuntos
Adiposidade/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Retardo do Crescimento Fetal/tratamento farmacológico , Células de Kupffer/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Animais , Animais Recém-Nascidos , Peso ao Nascer , Células Cultivadas , Dexametasona , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Fígado/patologia , Fator Estimulador de Colônias de Macrófagos/toxicidade , Masculino , Gravidez , Ratos Sprague-Dawley , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/agonistas , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Sus scrofa
19.
Intern Med J ; 48(2): 144-151, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29083080

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common cause of incidental liver test abnormalities. General practitioners (GP) have a key role in identifying people with NAFLD at risk of significant liver disease. Recent specialist guidelines emphasise the use of fibrosis algorithms or serum biomarkers rather than routine liver tests, to assess advanced fibrosis. AIM: To evaluate primary care clinicians' current approach to diagnosis, management and referral of NAFLD. METHODS: A cross-sectional survey of primary care clinicians was undertaken through a structured questionnaire about NAFLD. A convenience sample of general practice clinics and general practice conferences in Metropolitan Brisbane and regional south east Queensland was selected. RESULTS: A total of 108 primary care clinicians completed the survey (participation rate 100%). Fifty-one percent of respondents considered the prevalence of NAFLD in the general population to be ≤10%. Twenty-four percent of respondents felt that liver enzymes were sufficiently sensitive to detect underlying NAFLD. Most respondents were unsure whether the Fibrosis 4 score (62.7% unsure) or Enhanced Liver Fibrosis score (63.7% unsure) could help to identify advanced fibrosis or cirrhosis. Although 47% of respondents said they would refer a patient to a Gastroenterologist/Hepatologist if they suspect the patient has NAFLD, 44.1% do not make any referrals. Of concern, 70.6% of clinicians said they were unlikely to refer a patient to Hepatology unless liver function tests are abnormal. CONCLUSION: Our findings demonstrate that many primary care clinicians underestimate the prevalence of NAFLD and under-recognise the clinical spectrum of NAFLD and how this is assessed.


Assuntos
Atitude do Pessoal de Saúde , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Médicos de Atenção Primária , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Cirrose Hepática/sangue , Testes de Função Hepática/tendências , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Médicos de Atenção Primária/tendências , Queensland/epidemiologia , Encaminhamento e Consulta/tendências
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