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1.
Diabet Med ; 38(2): e14376, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32738821

RESUMO

AIM: To assess the prevalence of metabolic syndrome in type 1 diabetes, and its age-related association with diabetes complications. METHODS: Australian National Diabetes Information Audit and Benchmarking (ANDIAB) was a well-established quality audit programme. It provided cross-sectional data on people attending specialist diabetes services across Australia. We determined the prevalence of metabolic syndrome (WHO criteria) in adults with type 1 diabetes and its associations with diabetes complications across age groups. RESULTS: Metabolic syndrome prevalence was 30% in 2120 adults with type 1 diabetes. Prevalence increased with age: 21% in those aged <40 years, 35% in those aged 40-60 years, and 44% in those aged >60 years (P<0.001), which was driven by an increase in hypertension rate. Metabolic syndrome was associated with a higher prevalence of microvascular, macrovascular and foot complications, with the greatest impact at a younger age. The odds ratio for macrovascular complications with metabolic syndrome, compared with without, was 5.9 (95% CI 2.1-16.4) in people aged <40 years, 2.7 (95% CI 1.7-4.2) in those aged 40-60 years, and 1.7 (95% CI 1.1-2.7) in those aged >60 years (all P < 0.05). Metformin use was higher in those with metabolic syndrome (16% vs 4%; P<0.001). CONCLUSIONS: In this large Australian cohort, metabolic syndrome was common in type 1 diabetes and identified people at increased risk of the spectrum of diabetes complications, particularly in young to middle-aged adults. Potential clinical implications are that therapies targeting insulin resistance in this high-risk group may reduce diabetes complications and should be explored.


Assuntos
Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Síndrome Metabólica/epidemiologia , Adulto , Distribuição por Idade , Albuminúria/epidemiologia , Amputação Cirúrgica/estatística & dados numéricos , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 1/complicações , Pé Diabético/epidemiologia , Pé Diabético/etiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Dislipidemias/epidemiologia , Feminino , Humanos , Hipertensão/epidemiologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Revascularização Miocárdica/estatística & dados numéricos , Obesidade/epidemiologia , Doenças Vasculares Periféricas/epidemiologia , Doenças Vasculares Periféricas/etiologia , Prevalência , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia
2.
Diabet Med ; 38(2): e14379, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32740980

RESUMO

AIM: To systematically evaluate research investigating the accuracy of the ankle-brachial index (ABI) for diagnosing peripheral artery disease (PAD) in people with diabetes, as the accuracy is thought to be reduced in this cohort. METHODS: A database search of EBSCO Megafile Premier, Embase and The Cochrane Library was conducted to 28 February 2019. Prospective and retrospective investigations of the diagnostic accuracy of the ABI for PAD in people with diabetes using an imaging reference standard were eligible. Sensitivity and specify of the ABI and bivariate meta-analysis against reference tests, or a standard summary receiver operating curve analysis (SROC) was performed. RESULTS: Thirty-three studies met the inclusion criteria. ABI was compared with angiography in 12 studies and with colour duplex ultrasound (CDUS) in 21 studies. A SROC analysis of studies using angiography as the reference standard found a diagnostic odds ratio (DOR) of 9.06 [95% confidence interval (CI) 3.61 to 22.69], and area under the curve (AUC) of 0.76 (95% CI 0.66 to 0.86). Bivariate analysis of studies using CDUS demonstrated mean sensitivity of 0.60 (95% CI 0.48 to 0.71; P = 0.097) and mean specificity of 0.87 (95% CI 0.78 to 0.92; P < 0.001) with a DOR of 9.76 (95% CI 5.24 to 18.20; P < 0.0001) and AUC 0.72. CONCLUSIONS: These results suggest the ABI has a high specificity but lower sensitivity in detecting imaging diagnosed PAD in people with diabetes. The low probability of the testing being able to rule diagnosis in or out suggest that the ABI has limited effectiveness for early detection of PAD in this cohort.


Assuntos
Índice Tornozelo-Braço , Complicações do Diabetes/diagnóstico , Diabetes Mellitus/fisiopatologia , Doença Arterial Periférica/diagnóstico , Angiografia , Complicações do Diabetes/etiologia , Complicações do Diabetes/fisiopatologia , Humanos , Doença Arterial Periférica/complicações , Doença Arterial Periférica/fisiopatologia , Sensibilidade e Especificidade , Ultrassonografia Doppler em Cores
3.
Diabet Med ; 37(6): 991-999, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31968129

RESUMO

BACKGROUND: Type 2 diabetes diagnosed during youth and early adulthood is aggressive and associated with a high burden of vascular complications. The increase in complications is often attributed to long disease duration and poor metabolic control. Whether people with young-onset type 2 diabetes are inherently more susceptible to long-term complications than those diagnosed in later adulthood is unclear. METHODS: Prospective data from 3322 individuals, diagnosed between the age of 15 and 70 years and collected 10-25 years after diabetes diagnosis, were analysed. The cross-sectional associations between age at diagnosis and microvascular and macrovascular complications were analysed using logistic regression models, adjusted for duration of diabetes exposure and metabolic risk factors including blood pressure, cholesterol and updated mean HbA1c . RESULTS: The prevalence of retinopathy was highest in those with young-onset type 2 diabetes (diagnosed at age 15 to <40 years). After 10-15 years' diabetes duration, the adjusted odds ratio for retinopathy in this population was 2.8 (95% CI 1.9-4.1; reference group those diagnosed at 60 to <70 years of age). The odds of retinopathy remained higher in people with young-onset type 2 diabetes after longer durations of diabetes exposure; the odds decreased with increasing age at diagnosis. This pattern was not observed in models of other complications: after 10-15 years' diabetes exposure, the adjusted odds ratios for albuminuria, peripheral neuropathy and macrovascular disease in people with young-onset type 2 diabetes were 0.5 (95% CI 0.4-0.8), 0.7 (95% CI 0.5-1.1) and 0.2 (95% CI 0.1-0.3), respectively. CONCLUSION: After accounting for disease duration and other important confounders, people with type 2 diabetes diagnosed in youth and early adulthood (or with a younger current age) appeared to be inherently more susceptible to retinopathy. For other complications, adjusted risk appears highest in the oldest age of diagnosis group. These data have screening and treatment target implications.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/epidemiologia , Adulto , Fatores Etários , Idade de Início , Idoso , Albuminúria/epidemiologia , Albuminúria/etiologia , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/etiologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Retinopatia Diabética/etiologia , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/etiologia , Doenças Vasculares Periféricas/epidemiologia , Doenças Vasculares Periféricas/etiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia
4.
Br J Dermatol ; 182(1): 212-217, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31120550

RESUMO

Happle-Tinschert syndrome (HTS) and Curry-Jones syndrome (CJS; OMIM 601707) are rare, sporadic, multisystem disorders characterized by hypo- and hyperpigmented skin patches following Blaschko's lines, plus acral skeletal and other abnormalities. The blaschkoid pattern implies mosaicism, and indeed CJS was found in 2016 to be caused by a recurrent postzygotic mutation in a gene of the hedgehog signalling pathway, namely SMO, c.1234C>T, p.Leu412Phe. More recently the original case of HTS was found to carry the same somatic mutation. Despite this genetic and phenotypic overlap, two significant differences remained between the two syndromes. The histological hallmark of HTS, basaloid follicular hamartomas, is not a feature of CJS. Meanwhile, the severe gastrointestinal manifestations regularly reported in CJS had not been described in HTS. We report a patient whose phenotype was entirely consistent with HTS apart from intractable constipation, and a second patient with classic features of CJS plus early-onset medulloblastoma, a feature of basal cell naevus syndrome (BCNS). Both had the same recurrent SMO mutation. This prompted a literature review that revealed a case with the same somatic mutation, with basaloid follicular hamartomas and other features of both CJS and BCNS. Segmental BCNS can also be caused by a somatic mutation in PTCH1. We thus demonstrate for the first time phenotypic and genetic overlap between HTS, CJS and segmental BCNS. All of these conditions are caused by somatic mutations in genes of the hedgehog signalling pathway and we therefore propose the unifying term 'mosaic hedgehog spectrum'. What's already known about this topic? Happle-Tinschert syndrome (HTS) and Curry-Jones syndrome (CJS) are rare mosaic multisystem disorders with linear skin lesions. CJS is characterized by severe constipation, which has not previously been reported in HTS. HTS is characterized by basaloid follicular hamartomas, which are not a recognized feature of CJS. The recurrent mosaic SMO mutation found in CJS was recently reported in a patient with HTS. What does this study add? We describe a patient with HTS and intractable constipation, and a case of CJS with medulloblastoma. Both patients had the same recurrent somatic SMO mutation also found in a case reported as segmental basal cell naevus syndrome. SMO functions in the hedgehog pathway, explaining phenotypic overlap between HTS, CJS and mosaic basal cell naevus syndrome. We propose the term 'mosaic hedgehog spectrum' for these overlapping conditions.


Assuntos
Síndrome do Nevo Basocelular , Neoplasias Cutâneas , Síndrome do Nevo Basocelular/genética , Proteínas Hedgehog/genética , Humanos , Mutação/genética , Receptor Patched-1 , Neoplasias Cutâneas/genética
5.
Clin Genet ; 90(3): 270-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26706854

RESUMO

Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Deformidades Congênitas dos Membros/genética , Disostose Mandibulofacial/genética , Anormalidades Múltiplas/fisiopatologia , Feminino , Humanos , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Disostose Mandibulofacial/fisiopatologia , Mosaicismo , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Gravidez
6.
Diabet Med ; 33(3): 356-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26433207

RESUMO

AIMS: To determine whether alanine aminotransferase or gamma-glutamyltransferase levels, as markers of liver health and non-alcoholic fatty liver disease, might predict cardiovascular events in people with Type 2 diabetes. METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (non-fatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years. RESULTS: Alanine aminotransferase measure had a linear inverse relationship with the first cardiovascular event occurring in participants during the study period. After adjustment, for every 1 sd higher baseline alanine aminotransferase measure (13.2 U/l), the risk of a cardiovascular event was 7% lower (95% CI 4-13; P = 0.02). Participants with alanine aminotransferase levels below and above the reference range 8-41 U/l for women and 9-59 U/l for men, had hazard ratios for a cardiovascular event of 1.86 (95% CI 1.12-3.09) and 0.65 (95% CI 0.49-0.87), respectively (P = 0.001). No relationship was found for gamma-glutamyltransferase. CONCLUSIONS: The data may indicate that in people with Type 2 diabetes, which is associated with higher alanine aminotransferase levels because of prevalent non-alcoholic fatty liver disease, a low alanine aminotransferase level is a marker of hepatic or systemic frailty rather than health.


Assuntos
Alanina Transaminase/sangue , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Fenofibrato/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , gama-Glutamiltransferase/sangue
7.
Diabet Med ; 31(2): 126-35, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24103027

RESUMO

AIMS: To review the incidence and evidence for screening for thyroid autoimmunity and thyroid dysfunction in Type 1 diabetes. METHODS: Systematic review and meta-analysis. Inclusion criteria were prospective cohort studies screening for thyroid autoimmunity and/or dysfunction (defined as an abnormal thyroid-stimulating hormone level) in Type 1 diabetes. Exclusion criteria included pregnancy and thyroid dysfunction before diabetes onset. Outcomes examined were: incidence of thyroid autoimmunity and/or dysfunction; association between thyroid autoimmunity and dysfunction; and cost-effectiveness. Data sources were MEDLINE, EMBASE, the Cochrane Library, manual searching and contact with authors, with limitations to English language and human studies. Meta-analysis was performed using random effects models. RESULTS: We identified 14 eligible studies, involving 2972 young people and 789 adults with Type 1 diabetes. Follow-up ranged from 1-18 years. None of the studies were of good methodological quality (Newcastle Ottowa Scale score > 7). The incidence of thyroid dysfunction (11 studies) ranged from 27 (95% CI 15-45) to 246 (95% CI 118-453) per 10 000 patient-years and thyroid autoimmunity (four studies) from 13 (95% CI 0.3-71) to 326 (95% CI 194-510). The risk of thyroid dysfunction was higher in those with thyroid autoimmunity: summary risk ratio 25 (95% CI 9-71) and was higher in children (49, 95% CI 16-150) compared with adults (7, 95% CI 3-13). No studies examined cost-effectiveness of screening. CONCLUSIONS: There is a markedly increased risk of thyroid dysfunction in people with Type 1 diabetes and thyroid autoimmunity. The optimal method or frequency of screening could not be determined from available data. Future studies should examine whether screening improves clinical outcomes in this population.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Tireoidite Autoimune/complicações , Adulto , Autoimunidade , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Humanos , Incidência , Gravidez , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/epidemiologia , Glândula Tireoide/imunologia , Glândula Tireoide/fisiopatologia , Tireoidite Autoimune/diagnóstico , Tireoidite Autoimune/epidemiologia
8.
Diabet Med ; 30(7): 818-24, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23330615

RESUMO

AIM: Diabetic ketoacidosis is a life-threatening complication of Type 1 diabetes. Blood ß-hydroxybutyrate testing is now widely available as an alternative to urine acetoacetate testing for detecting ketosis. The aim of this study was to review the effectiveness of capillary or serum ß-hydroxybutyrate compared with urine acetoacetate testing in prevention and management of diabetic ketoacidosis. METHODS: MEDLINE, EMBASE, EBM Reviews, The Cochrane Library and CINAHL (until April 2012, no language restrictions, studies in humans) were searched for experimental and observational studies comparing the effectiveness of blood ß-hydroxybutyrate and urine acetoacetate testing. Outcomes examined were prevention of diabetic ketoacidosis, time to recovery from diabetic ketoacidosis, healthcare costs and patient or caregiver satisfaction. Additional sources included reference lists, conference proceedings and contact with experts in the field. RESULTS: Four studies (two randomized controlled trials and two cohort studies) met eligibility criteria, including 299 participants across 11 centres. Risk of bias was low to moderate. Blood ketone testing compared with urine testing was associated with reduced frequency of hospitalization (one study), reduced time to recovery from diabetic ketoacidosis (three studies), cost benefits (one study) and greater satisfaction (one study, intervention group only). No study assessed prevention of diabetic ketoacidosis. Meta-analysis could not be performed because of heterogeneity in study design and published data. CONCLUSIONS: There is evidence suggesting that blood ß-hydroxybutyrate testing is more effective than urine acetoacetate testing in reducing emergency department assessment, hospitalization and time to recovery from diabetic ketoacidosis, as well as potentially lowering healthcare expenditure. Further research in both young people and adults is needed.


Assuntos
Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/urina , Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/prevenção & controle , Cetoacidose Diabética/terapia , Cuidados Críticos/economia , Estatura Cabeça-Cóccix , Cetoacidose Diabética/economia , Gastos em Saúde , Hospitalização/economia , Humanos , MEDLINE , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Nat Genet ; 24(4): 387-90, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10742103

RESUMO

The genetic analysis of congenital skull malformations provides insight into normal mechanisms of calvarial osteogenesis. Enlarged parietal foramina (PFM) are oval defects of the parietal bones caused by deficient ossification around the parietal notch, which is normally obliterated during the fifth fetal month. PFM are usually asymptomatic, but may be associated with headache, scalp defects and structural or vascular malformations of the brain. Inheritance is frequently autosomal dominant, but no causative mutations have been identified in non-syndromic cases. We describe here heterozygous mutations of the homeobox gene MSX2 (located on 5q34-q35) in three unrelated families with PFM. One is a deletion of approximately 206 kb including the entire gene and the others are intragenic mutations of the DNA-binding homeodomain (RK159-160del and R172H) that predict disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal Msx2 DNA-binding site. Our findings contrast with the only described MSX2 homeodomain mutation (P148H), associated with craniosynostosis, that binds with enhanced affinity to the same target. This demonstrates that MSX2 dosage is critical for human skull development and suggests that PFM and craniosynostosis result, respectively, from loss and gain of activity in an MSX2-mediated pathway of calvarial osteogenic differentiation.


Assuntos
Suturas Cranianas/anormalidades , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Mutação , Crânio/anormalidades , Adulto , Animais , Sequência de Bases , Southern Blotting , Criança , Pré-Escolar , Cromossomos Humanos Par 5/genética , Suturas Cranianas/diagnóstico por imagem , Suturas Cranianas/crescimento & desenvolvimento , Análise Mutacional de DNA , Proteínas de Ligação a DNA/deficiência , Feminino , Humanos , Lactente , Masculino , Camundongos , Repetições de Microssatélites , Dados de Sequência Molecular , Osteogênese/genética , Osso Parietal/anormalidades , Osso Parietal/crescimento & desenvolvimento , Linhagem , Radiografia , Deleção de Sequência , Crânio/diagnóstico por imagem , Crânio/crescimento & desenvolvimento
10.
Diabet Med ; 28(10): 1272-6, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21679233

RESUMO

AIMS: Icodextrin is a glucose polymer used to maintain an osmotic gradient in peritoneal dialysis. Metabolites of icodextrin are known to cause overestimation of blood glucose in glucose meters using glucose dehydrogenase/pyrroloquinolinequinone systems. The aim of this study is to determine the extent of icodextrin interference in glucose meters using the newer glucose dehydrogenase/NAD or glucose oxidase systems. This has not been established previously. METHODS: Fasting blood samples (n = 4) were spiked with either one icodextrin metabolite (maltose, maltotriose or maltotetraose) or a combination, at various blood concentrations expected during dialysis. Samples were tested in triplicate on: five glucose-meters, a Radiometer® (glucose oxidase/hydrogen peroxide) and laboratory (hexokinase) analysers. Each meter was also tested on blood from six patients undergoing dialysis. Accuracy was evaluated as % Bias = [(meter glucose - laboratory glucose)/laboratory glucose] × 100. RESULTS: A single icodextrin metabolite affected glucose measurements and, in combination, the interferences were additive in the two Accu-Chek® and Optium® Xceed meters by > 10%. Amongst these meters, the Optium Xceed 5-s machine was less affected. Meters using glucose oxidase were least affected by interference. A similar trend in interference was observed in vivo. CONCLUSION: While meters using glucose dehydrogenase/NAD are less affected by icodextrin metabolites, interference can still be demonstrated. The degree of interference can vary in different glucose meters using this enzyme/cofactor system, as seen in the Optium Xceed machines. Icodextrin is an important source of interference that sometimes even experienced professionals are unaware of and which leads to clinically significant errors in insulin dose adjustment. Awareness of this interference and selection of the most appropriate glucose meters are crucial to minimize this hazard.


Assuntos
Autoanálise/instrumentação , Glicemia/efeitos dos fármacos , Soluções para Diálise/efeitos adversos , Glucanos/efeitos adversos , Glucose/efeitos adversos , Diálise Peritoneal Ambulatorial Contínua , Glucanos/sangue , Humanos , Icodextrina , Valor Preditivo dos Testes , Padrões de Referência
11.
Am J Physiol Cell Physiol ; 299(5): C1212-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20810913

RESUMO

CD147 is a highly glycosylated transmembrane protein that is known to play a role in regulation of many protein families. It has the unique ability to maintain functional activity in both the membrane bound state and in the soluble form. CD147 is known to play a role in regulation of matrix metalloproteinase (MMP) expression, but whether its expression is affected by the diabetic milieu is not known, and its role in regulation of monocyte MMPs in this environment has not been investigated. Therefore, in this study we investigated the effect of advanced glycation end products (AGEs) and high glucose (HG; 25 mM), on monocyte CD147 expression. Culture of THP-1 monocytes in the presence of AGEs or HG significantly increased CD147 at the gene and protein level. THP-1 cell results were confirmed using freshly isolated monocytes from human volunteers. The effect of AGEs and HG on CD147 expression was also mimicked by addition of proinflammatory cytokines. Addition of AGEs or HG also increased expression of monocyte MMP-1 and MMP-9 but not MMP-2. This increase in MMPs was significantly attenuated by inhibition of CD147 using either a small interfering RNA or an anti-CD147 antibody. Inhibition of NF-κB or addition of antibodies to either TNF-α or the receptor for AGE (RAGE) each significantly prevented in a dose-dependent manner the induction of CD147 gene and protein by AGE and also decreased MMP-1 and MMP-9. This novel result shows that AGEs can induce monocyte CD147 expression, an effect mediated by inflammatory pathways and RAGE. Because MMPs play a role in monocyte migration, inhibition of their regulator CD147 may assist in the prevention of diabetic complications, particularly those where monocyte infiltration is an early initiating event.


Assuntos
Basigina/metabolismo , Complicações do Diabetes , Glucose/farmacologia , Produtos Finais de Glicação Avançada/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Animais , Basigina/genética , Células Cultivadas , Citocinas/imunologia , Humanos , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Monócitos/citologia , NF-kappa B/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
12.
Diabetologia ; 53(3): 572-83, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20091023

RESUMO

AIMS/HYPOTHESIS: Chronic non-healing wounds are a common complication of diabetes. Prolonged inflammation and decreased matrix accumulation may contribute. Connective tissue growth factor (CTGF) is induced during normal wound healing, but its regulation in diabetic wounds is unknown. We developed a primate model for the study of in vivo wound healing in baboons with long diabetes duration. METHODS: Drum implants were placed subcutaneously into thighs of diabetic and non-diabetic control baboons. After 2 and 4 weeks the skin incision sites were removed for measurement of breaking strength and epithelial thickness. Drum implants were removed for analysis of granulation tissue and inflammatory cells, CTGF and tissue inhibitor of matrix metalloproteinase (TIMP-1). Degradation of added CTGF by wound fluid was also examined. RESULTS: Healed incision site skin was stiffer (less elastic) in diabetic baboons and epithelial remodelling was slower compared with controls. Granulation tissue from diabetic baboons was reduced at 2 and 4 weeks, with increased vessel lumen areas at 4 weeks. Macrophages were reduced while neutrophils persisted in diabetic tissue. In diabetic wound tissue at 4 weeks there was less CTGF induced, as shown by immunohistochemistry, compared with controls. In contrast, immunoreactive fragments of CTGF were significantly increased in whole tissue lysate in diabetic baboons, suggesting that CTGF is redistributed in diabetes from granulation tissue into wound fluid. When recombinant human CTGF was co-incubated with wound fluid, increased CTGF degradation products were observed in both control and diabetic samples. CONCLUSIONS/INTERPRETATION: This baboon model of wound healing reflects the abnormal microenvironment seen in human diabetic wounds and provides insights into the dysregulation of CTGF in diabetic wounds.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Regulação da Expressão Gênica , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Elasticidade , Epitélio/patologia , Humanos , Imuno-Histoquímica/métodos , Macrófagos/metabolismo , Masculino , Modelos Biológicos , Papio , Proteínas Recombinantes/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo
13.
Diabetes Obes Metab ; 12(12): 1072-8, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20977578

RESUMO

AIM: Following the recent Ongoing Telmistartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) finding of adverse renal outcomes, dual renin-angiotensin blockade has fallen out of favour, despite antihypertensive and antiproteinuric efficacy. However, in high-risk severe hypertension, not studied in ONTARGET, whether combination treatment should be withheld or withdrawn is not clear. We examine the renal effects of angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) monotherapy versus combination therapy in patients with type 2 diabetes and varying degrees of hypertension. METHODS: Subjects attending a hospital diabetes centre were selected as case (combination therapy, n = 120) and control (monotherapy, n = 480). Subjects were matched for age, gender, ethnicity, estimated glomerular filtration rate (eGFR), blood pressure (BP) and study duration. Patients were stratified by BP, hypertension stage 1 (BP < 160/100, n = 506) and stage 2 (≥160/100, n = 94), and by treatment group. Data were analysed for the primary renal outcome of eGFR decline ≥20 ml/min, over a median of 3.7 years. RESULTS: In keeping with the ONTARGET study, for stage 1 hypertension, combination treatment is significantly worse than monotherapy for the primary outcome of eGFR decline ≥20 ml/min (20 vs. 10.7%, p = 0.01). In contrast, for stage 2 hypertension, this endpoint was reached less often for combination versus monotherapy (12.0 vs. 23.2%, p = 0.2). Combination treatment was also not detrimental in patients with proteinuria or eGFR < 60 ml/min and was associated with fewer macrovascular events. CONCLUSION: Given that hypertension control is paramount and in the spirit of primum non nocere, these data are reassuring should clinicians choose to use ACE-I and ARB combination therapy in the very hypertensive diabetic patient.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Quimioterapia Combinada/efeitos adversos , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Estudos de Casos e Controles , Ensaios Clínicos Controlados como Assunto , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Medição de Risco , Fatores de Risco , Resultado do Tratamento
14.
Diabetologia ; 52(9): 1953-61, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19629432

RESUMO

AIMS/HYPOTHESIS: We examined whether age of type 2 diabetes onset is related to mitochondrial DNA content in peripheral blood monocytes (PBMCs). METHODS: PBMCs were isolated from 65 patients with type 2 diabetes. To minimise age as a confounder, only patients aged >or=50 years were studied. Sample mitochondrial DNA (mtDNA) content was determined by amplification of the mitochondrial gene CYT-B (also known as MT-CYB) and adjusted for single-copy nuclear control genes (36B4 [also known as RPLPO] and GAPDH). RESULTS: Age of diabetes onset ranged from 25 to 69 years. There was a significant positive relationship between age of diabetes onset in quartiles and mtDNA content for the whole group (p = 0.02 for trend). When stratified by the presence of diabetes complications, a strong positive relationship was observed between age of diagnosis and mtDNA content for participants without diabetic complications (r = 0.7; p = 0.0002), but not for those with complications (r = -0.04; p = 0.8). Multivariate analysis confirmed age of onset and complication status as independent determinants. There was co-linearity between age of onset and disease duration, with similar relationships also seen between duration and mtDNA content. CONCLUSIONS/INTERPRETATION: An earlier age of type 2 diabetes onset is associated with a lower PBMC mtDNA content, but only in patients without diabetes complications. This may reflect a differing biology of PBMC mtDNA in those with early-onset diabetes and those who are prone to complications. PBMC mtDNA depletion may accelerate diabetes onset; however the independent effect of diabetes duration remains to be evaluated.


Assuntos
Idade de Início , DNA Mitocondrial/sangue , Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 2/sangue , Monócitos/fisiologia , Adulto , Fatores Etários , Idoso , Citocromos b/genética , Primers do DNA , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Clin Radiol ; 64(12): 1146-57, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19913123

RESUMO

Craniocerebral and spinal penetrating trauma, which may be either missile (most typically gun-related) or non-missile (most typically knife-related), is becoming an increasingly common presentation to the urban general and specialized radiology service in the UK. These injuries carry significant morbidity and mortality with a number of criteria for prognosis identifiable on cross-sectional imaging. Potential complications can also be pre-empted by awareness of certain neuroradiological features. Not all of these injuries are criminal in origin, however, a significant proportion will be, requiring, on occasion, provision of both ante-mortem and post-mortem radiological opinion to the criminal investigative procedure. This review aims to highlight certain imaging features of penetrating craniocerebral and spinal trauma including important prognostic, therapeutic, and forensic considerations.


Assuntos
Diagnóstico por Imagem/métodos , Traumatismos Cranianos Penetrantes/diagnóstico , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Coluna Vertebral/diagnóstico , Ferimentos por Arma de Fogo/diagnóstico , Angiografia Cerebral , Feminino , Patologia Legal , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Prognóstico , Tomografia Computadorizada por Raios X , Ferimentos por Arma de Fogo/etiologia , Ferimentos Perfurantes/diagnóstico
16.
Diabetes Obes Metab ; 10(9): 739-46, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17941867

RESUMO

AIM: Diabetic cardiomyopathy is an increasingly recognized entity. The pathogenic factors that may contribute to its development, especially the earliest changes of diastolic dysfunction (DD), have not been clearly defined. Microvessel dysfunction and upregulation of profibrotic growth factors have been described as possible causes. The aim of this study was therefore to determine whether microvascular dysfunction and/or upregulation of the profibrotic connective tissue growth factor (CTGF) are associated with subclinical DD in subjects with type 2 diabetes. METHODS: Forty subjects with type 2 diabetes and 20 age-matched non-diabetic controls, all of whom had no clinical evidence of ischaemic heart disease, cardiac failure or echo evidence of systolic ventricular dysfunction, were recruited. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in blood flow following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in blood flow in response to the nitric oxide donor sodium nitroprusside (SNP). CTGF levels were determined by Western immunoblotting. RESULTS: DD determined on the basis of traditional echocardiographic criteria was similar in diabetic subjects compared with controls (28 vs. 20%, p = 0.5). Using left ventricular myocardial tissue Doppler-based indices for DD, the E/E' and the E'/A' ratios (where E is the flow related to early ventricular filling and E' and A' are early and late diastolic velocities, respectively) in diabetic subjects revealed evidence of more DD than controls (p = 0.046 and p = 0.007 respectively) . Comparing controls with no DD by conventional echocardiographic criteria (Group I), diabetes and no DD (Group II) and diabetes with DD (Group III), there was a significant trend in reduction of both endothelium-dependent (ACh fold change; p = 0.04) and endothelium-independent (SNP fold change; p = 0.0004) blood flow across the groups. The ACh and SNP responses, however, were not correlated significantly with quartiles of the E/E' ratio or the E'/A' ratio. CTGF plasma levels did not differ across the groups and CTGF did not correlate with parameters of microvascular function. CONCLUSIONS: This study indicates that while there is a significant association between DD and measures of microvascular function, the relationship between endothelial dysfunction, CTGF and subtle measures of DD is not strong. Other factors are therefore likely to play an important role in the early pathogenesis of subclinical cardiac DD in type 2 diabetes.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Diástole/fisiologia , Microcirculação/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Western Blotting , Estudos de Casos e Controles , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ecocardiografia Doppler de Pulso , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Obes Rev ; 18(7): 776-790, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28474421

RESUMO

Skeletal muscle extracellular matrix remodelling has been proposed as a new feature associated with obesity and metabolic dysfunction. Exercise training improves muscle function in obesity, which may be mediated by regulatory effects on the muscle extracellular matrix. This review examined available literature on skeletal muscle extracellular matrix remodelling during obesity and the effects of exercise. A non-systematic literature review was performed on PubMed of publications from 1970 to 2015. A total of 37 studies from humans and animals were retained. Studies reported overall increases in gene and protein expression of different types of collagen, growth factors and enzymatic regulators of the skeletal muscle extracellular matrix in obesity. Only two studies investigated the effects of exercise on skeletal muscle extracellular matrix during obesity, with both suggesting a regulatory effect of exercise. The effects of exercise on muscle extracellular matrix seem to be influenced by the duration and type of exercise training with variable effects from a single session compared with a longer duration of exercise. More studies are needed to elucidate the mechanisms behind skeletal muscle extracellular matrix remodelling during obesity and the effects of exercise.


Assuntos
Exercício Físico/fisiologia , Matriz Extracelular/fisiologia , Músculo Esquelético/fisiopatologia , Obesidade/fisiopatologia , Animais , Humanos
18.
Trends Endocrinol Metab ; 6(8): 273-8, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18406711

RESUMO

Adbances in the identification and localization of the abnormal genes in the multiple endocrine neoplasia syndromes have provided new methods of identifying "at risk" individuals in these families. Genetic testing using linkage analysis in multiple endocrine neoplasia (MEN) 1 and direct mutation analysis of the RET protooncogene in MEN 2 is now available for these disorders. New management issues for these disorders have resulted, and a practical approach to these issues is discussed.

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