RESUMEN
PURPOSE: Chronic low-grade periprosthetic joint infection (PJI) of a shoulder replacement can be challenging to diagnose. 18F-FDG PET/CT is suggested as a modality to diagnose lower-limb PJI, but no studies on shoulder replacements exist. The aim of this study was therefore to determine the diagnostic accuracy of 18F-FDG PET/CT in diagnosing chronic PJI of the shoulder. METHODS: Patients evaluated for a failed shoulder replacement during a 3-year period were prospectively included in the study. All patients underwent pre-operative 18F-FDG PET/CT, and were evaluated for signs of infection by three independent reviewers using shoulder-specific criteria. Interrater-agreement was calculated between the reviewers. If the patient had revision surgery, biopsy specimens were obtained and cultured with bacterial growth in the cultures serving as gold standard of infection. RESULTS: A total of 86 patients were included in the study. Nine patients were 18F-FDG PET/CT positive for infection, with only three true positive. Using the gold standard, infection was diagnosed after revision surgery in 22 cases. All infections were chronic and caused by low-virulent microbes. The sensitivity of 18F-FDG PET/CT was 0.14 95% CI (0.03-0.36), specificity 0.91 95% CI (0.81-0.97), positive predictive value was 0.40 95% CI (0.15-0.71) and negative predictive value 0.71 95% CI (0.67-0.75). The inter-observer agreement was 0.56 (Fleiss' kappa), indicating moderate agreement of the visual FDG-PET evaluation using the shoulder-specific criteria. CONCLUSION: 18F-FDG PET/CT has poor diagnostic accuracy in diagnosing low-grade PJI of the shoulder. 18F-FDG PET/CT cannot be recommended as a part of the routine preoperative workup to diagnose low-grade infection of a shoulder replacement.
Asunto(s)
Artropatías/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/normas , Infecciones Relacionadas con Prótesis/diagnóstico por imagen , Articulación del Hombro/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos , Sensibilidad y Especificidad , Prótesis de Hombro/efectos adversosRESUMEN
Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed noninvasive 11 C-metformin positron emission tomography (PET)/computed tomography (CT) to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans.
Asunto(s)
Hipoglucemiantes/administración & dosificación , Hígado/efectos de los fármacos , Metformina/administración & dosificación , Factor 1 de Transcripción de Unión a Octámeros/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Femenino , Humanos , Hipoglucemiantes/metabolismo , Inyecciones Intravenosas , Hígado/diagnóstico por imagen , Hígado/metabolismo , Masculino , Metformina/metabolismo , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodosRESUMEN
BACKGROUND: Psoriasis is associated with cardiovascular disease; it has been proposed that increased cardiovascular risk is caused by low-grade systemic inflammation involving organs and tissues other than the skin and joints. OBJECTIVES: To investigate signs of vascular inflammation in untreated patients with moderate-to-severe psoriasis assessed by 18 F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography. A secondary objective was to assess signs of subcutaneous adipose tissue inflammation. METHODS: This was an observational, controlled clinical study including patients with psoriasis (n = 12, mean ± SD age 61·4 ± 4·1 years, 83% men, mean ± SD Psoriasis Area Severity Index score 14·5 ± 4·3) and matched controls (n = 23, mean ± SD age 60·4 ± 4·5 years, 87% men). Vascular inflammation was measured using aortic maximal standardized uptake values (SUVmax ) and the target-to-background ratio (TBRmax ) of the whole vessel and aortic segments. Subcutaneous adipose tissue inflammation was assessed and compared with regard to SUVmax and TBRmax . RESULTS: Arterial inflammation was increased in patients with psoriasis vs. controls (mean ± SD whole vessel TBRmax 2·46 ± 0·31 vs. 2·09 ± 0·36; P = 0·005). In patients with psoriasis, higher FDG uptake values were observed for all aortic segments except the ascending aorta. Subcutaneous adipose tissue FDG uptake was increased in patients with psoriasis vs. controls (mean ± SD TBRmax 0·49 ± 0·18 vs. 0·31 ± 0·12; P = 0·002). Associations remained significant after adjusting for body mass index and age. CONCLUSIONS: Global arterial inflammation and subcutaneous inflammation were significantly increased in patients with moderate-to-severe psoriasis compared with controls.
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Aortitis/patología , Paniculitis/patología , Psoriasis/patología , Grasa Subcutánea/patología , Anciano , Aortitis/diagnóstico por imagen , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Paniculitis/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Psoriasis/diagnóstico por imagen , Radiofármacos , Grasa Subcutánea/diagnóstico por imagenRESUMEN
BACKGROUND: phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully characterized. OBJECTIVE: to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp. DESIGN: eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition (t = 30) and after 30 min of insulin stimulation (t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1. RESULTS: phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser(341) and Ser(704) 270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr(642) and Ser(588) on AS160 or Ser(237) and Thr(596) on TBC1D1. CONCLUSIONS: AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr(642) and Ser(588). Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle.
Asunto(s)
Ejercicio Físico/fisiología , Proteínas Activadoras de GTPasa/metabolismo , Músculo Esquelético/metabolismo , Fosforilación/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Adulto , Transporte Biológico/fisiología , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Insulina/metabolismo , Masculino , Contracción Muscular/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Descanso/fisiologíaRESUMEN
In a comparative study, we investigated the effects of maximal eccentric or concentric resistance training combined with whey protein or placebo on muscle and tendon hypertrophy. 22 subjects were allocated into either a high-leucine whey protein hydrolysate + carbohydrate group (WHD) or a carbohydrate group (PLA). Subjects completed 12 weeks maximal knee extensor training with one leg using eccentric contractions and the other using concentric contractions. Before and after training cross-sectional area (CSA) of m. quadriceps and patellar tendon CSA was quantified with magnetic resonance imaging and a isometric strength test was used to assess maximal voluntary contraction (MVC) and rate of force development (RFD). Quadriceps CSA increased by 7.3 ± 1.0% (P < 0.001) in WHD and 3.4 ± 0.8% (P < 0.01) in PLA, with a greater increase in WHD compared to PLA (P < 0.01). Proximal patellar tendon CSA increased by 14.9 ± 3.1% (P < 0.001) and 8.1 ± 3.2% (P = 0.054) for WHD and PLA, respectively, with a greater increase in WHD compared to PLA (P < 0.05), with no effect of contraction mode. MVC and RFD increased by 15.6 ± 3.5% (P < 0.001) and 12-63% (P < 0.05), respectively, with no group or contraction mode effects. In conclusion, high-leucine whey protein hydrolysate augments muscle and tendon hypertrophy following 12 weeks of resistance training - irrespective of contraction mode.
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Proteínas de la Leche , Ligamento Rotuliano/anatomía & histología , Hidrolisados de Proteína , Músculo Cuádriceps/anatomía & histología , Entrenamiento de Fuerza/métodos , Carbohidratos de la Dieta , Suplementos Dietéticos , Método Doble Ciego , Electromiografía , Ejercicio Físico/fisiología , Humanos , Hipertrofia , Leucina/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Contracción Muscular/fisiología , Fuerza Muscular , Músculo Cuádriceps/fisiología , Proteína de Suero de Leche , Adulto JovenRESUMEN
AIM: Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting. METHODS: Eight healthy male subjects were studied four times in a randomized, single-blinded parallel design: Control, GH, Fasting (36 h) and GH + Fasting. GH (30 ng × kg(-1) × min(-1)) or saline was infused throughout the metabolic study day. Substrate metabolism and insulin sensitivity were assessed by indirect calorimetry and isotopically determined rates of glucose turnover before and after a hyperinsulinemic euglycemic clamp. PDHa activity, PDH-E1α phosphorylation, PDK4 expression and activation of insulin signalling proteins were assessed in skeletal muscle. RESULTS: Both fasting and GH promoted lipolysis, which was associated with ≈50% reduction in insulin sensitivity compared with the control day. PDHa activity was significantly reduced by GH as well as fasting. This was associated with increased inhibitory PDH-E1α phosphorylation on site 1 (Ser(293)) and 2 (Ser(300)) and up-regulation of PDK4 mRNA, while canonical insulin signalling to glucose transport was unaffected. CONCLUSION: Competition between intermediates of glucose and fatty acids seems to play a causal role in insulin resistance induced by GH in human subjects.
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Hormona de Crecimiento Humana/farmacología , Resistencia a la Insulina/fisiología , Lipólisis/fisiología , Piruvato Deshidrogenasa (Lipoamida)/metabolismo , Western Blotting , Estudios Cruzados , Técnica de Clampeo de la Glucosa , Humanos , Lipólisis/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Músculo Esquelético/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
The influence of adenosine mono phosphate (AMP)-activated protein kinase (AMPK) vs Akt-mammalian target of rapamycin C1 (mTORC1) protein signaling mechanisms on converting differentiated exercise into training specific adaptations is not well-established. To investigate this, human subjects were divided into endurance, strength, and non-exercise control groups. Data were obtained before and during post-exercise recovery from single-bout exercise, conducted with an exercise mode to which the exercise subjects were accustomed through 10 weeks of prior training. Blood and muscle samples were analyzed for plasma substrates and hormones and for muscle markers of AMPK and Akt-mTORC1 protein signaling. Increases in plasma glucose, insulin, growth hormone (GH), and insulin-like growth factor (IGF)-1, and in phosphorylated muscle phospho-Akt substrate (PAS) of 160 kDa, mTOR, 70 kDa ribosomal protein S6 kinase, eukaryotic initiation factor 4E, and glycogen synthase kinase 3a were observed after strength exercise. Increased phosphorylation of AMPK, histone deacetylase5 (HDAC5), cAMP response element-binding protein, and acetyl-CoA carboxylase (ACC) was observed after endurance exercise, but not differently from after strength exercise. No changes in protein phosphorylation were observed in non-exercise controls. Endurance training produced an increase in maximal oxygen uptake and a decrease in submaximal exercise heart rate, while strength training produced increases in muscle cross-sectional area and strength. No changes in basal levels of signaling proteins were observed in response to training. The results support that in training-accustomed individuals, mTORC1 signaling is preferentially activated after hypertrophy-inducing exercise, while AMPK signaling is less specific for differentiated exercise.
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Proteínas Quinasas Activadas por AMP/metabolismo , Ejercicio Físico/fisiología , Complejos Multiproteicos/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/sangre , Acetil-CoA Carboxilasa/metabolismo , Adulto , Glucemia/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Factor 4E Eucariótico de Iniciación/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Hormona del Crecimiento/sangre , Frecuencia Cardíaca , Histona Desacetilasas/metabolismo , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Imagen por Resonancia Magnética , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos/sangre , Fuerza Muscular/fisiología , Músculo Esquelético/anatomía & histología , Consumo de Oxígeno , Fosforilación , Entrenamiento de Fuerza , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Serina-Treonina Quinasas TOR/sangre , Adulto JovenRESUMEN
During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast.
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Ayuno/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Glucógeno/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Músculo Esquelético/metabolismo , Adenilato Quinasa/metabolismo , Adulto , Estudios Cruzados , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Insulina/metabolismo , Masculino , Fosforilación/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Better understanding of the underlying mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing oxidative damage. Reactive oxygen species (ROS) have been proposed to cause deleterious effects on DNA, proteins, and lipids, and generation of these highly reactive molecules takes place in the mitochondria. But ROS is positively implicated in cellular stress defense mechanisms and formation of ROS a highly regulated process controlled by a complex network of intracellular signaling pathways. There are endogenous anti-oxidant defense systems that have the potential to partially counteract ROS impact. In this review, we will describe pathways contributing to the regulation of the age-related decline in mitochondrial function and their impact on longevity. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.