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Protein tyrosine phosphatases (PTPs) regulate multiple signaling pathways. Disruption of tyrosine phosphorylation through imbalanced action between protein tyrosine kinases (RTKs) and PTPs is a hallmark of metabolic disorders, including insulin resistance. A representative member of the receptor-type PTP family, PTPRJ (DEP-1), was previously identified as a negative regulator of insulin signaling and possesses post-translational glycosylation sites. In this regard, it seems of great importance to decipher the structure of PTPRJ's glycosylation, particularly in the context of metabolic disturbances, but this has not been done in detail. Thus, here we aimed at characterizing the glycosylation pattern of PTPRJ in liver. We show that N-glycosylation accounts for up to half of PTPRJ's molecular weight. Applying mass spectrometry, we detected increased levels of high-mannose structures in PTPRJ in liver tissue of obese mice compared to lean littermates. In addition, complex neutral structures without fucose were also elevated in PTPRJ of high-fat diet (HFD) mice. Conversely, complex fucosylated N-glycans as well as sialylated bi- and triantennary N-glycans, were significantly reduced in PTPRJ of HFD-derived liver tissue compared to LFD by â¼two fold (P≤.01, P≤.0001 and P≤.001, respectively). In congruence with these findings, the mannosidase MAN2A1, responsible for the conversion of high-mannose to complex N-glycans, was significantly downregulated under HFD conditions. Here we present for the first time that HFD-induced obesity impacts on the glycosylation pattern of the insulin signaling component PTPRJ in liver. These findings may inspire new research on the glycosylation of PTPs in metabolic diseases and may open up new therapeutic approaches.
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Dieta Hiperlipídica , Glicosilação , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Insulina/metabolismo , Fígado/metabolismo , Manose/metabolismo , Polissacarídeos , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismoRESUMO
BACKGROUND: Among health care personnel working regular hours or rotating shifts can affect parameters of general health and nutrition. We have investigated physical activity, sleep quality, metabolic activity and stress levels in health care workers from both groups. METHODS: We prospectively recruited 46 volunteer participants from the workforce of a University Medical Department of which 23 worked in rotating shifts (all nursing) and 21 non-shift regular hours (10 nursing, 13 clerical staff). All were investigated over 7 days by multisensory accelerometer (SenseWear Bodymedia® armband) and kept a detailed food diary. Physical activity and resting energy expenditure (REE) were measured in metabolic equivalents of task (METs). Quality of sleep was assessed as Pittsburgh Sleeping Quality Index and stress load using the Trier Inventory for Chronic Stress questionnaire (TICS). RESULTS: No significant differences were found for overall physical activity, steps per minute, time of exceeding the 3 METs level or sleep quality. A significant difference for physical activity during working hours was found between shift-workers vs. non-shift-workers (p<0.01) and for shift-working nurses (median = 2.1 METs SE = 0.1) vs. non-shift-working clerical personnel (median = 1.5 METs SE = 0.07, p<0.05). Non-shift-working nurses had a significantly lower REE than the other groups (p<0.05). The proportion of fat in the diet was significantly higher (p<0.05) in the office worker group (median = 42% SE = 1.2) whereas shift-working nurses consumed significantly more carbohydrates (median = 46% SE = 1.4) than clerical staff (median = 41% SE = 1.7). Stress assessment by TICS confirmed a significantly higher level of social overload in the shift working group (p<0.05). CONCLUSION: In this prospective cohort study shift-working had no influence on overall physical activity. Lower physical activity during working hours appears to be compensated for during off-hours. Differences in nutritional habits and stress load warrant larger scale trials to determine the effect on implicit health-associated conditions.
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Metabolismo Energético , Exercício Físico , Pessoal de Saúde/psicologia , Pessoal de Saúde/estatística & dados numéricos , Estado Nutricional , Sono/fisiologia , Estresse Psicológico , Acelerometria , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Admissão e Escalonamento de Pessoal , Estudos Prospectivos , Inquéritos e Questionários , Tolerância ao Trabalho ProgramadoRESUMO
Continuous measurement of resting energy expenditure (REE) in critically ill patients remains challenging but is required to prevent malnutrition. SenseWear Pro 3 Armband (SWA) is a research grade accelerometer for assessment of REE with the advantage of easy handling. In a prospective study we compared SWA with indirect calorimetry (IC) and predictive equations in critically ill, ventilated patients. REE was measured by SWA, IC and calculated by predictive formulas. Potential confounding factors that influence REE were also recorded. Results of SenseWear Armband and indirect calorimetry were compared using the Bland-Altman method. 34 ICU patients were investigated. SWA underestimated resting energy expenditure compared to IC with a mean bias of ΔREE = -253.6 ± 333.2 kcal, equivalent to -11.7 % (p = 0.025). This underestimation was seen in both, medical (-14.9 %) and surgical (-12.9 %) patients and the bias was greater in patients with fever (-19.0 %), tachycardia (-18.7 %) or tachypnea (-26.2 %). Differences were also noted when SWA was compared to predictive formulas. At present, SWA cannot be regarded as an alternative to indirect calorimetry. Individual measurements are often inaccurate and should be used with caution until improved algorithms, based on the results of this study, have been implemented.
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Acelerometria/métodos , Calorimetria Indireta/métodos , Cuidados Críticos , Estado Terminal , Metabolismo Energético , Monitorização Ambulatorial/métodos , Idoso , Algoritmos , Antropometria , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Descanso , Ventiladores MecânicosRESUMO
BACKGROUND & AIMS: Malnutrition is a prevalent condition in older inpatients and has been shown to increase morbidity and direct medical costs. A number of established tools to assess malnutrition are available but malnourished patients rarely receive adequate nutritional assessment and treatment. The medical and economic consequences of malnutrition in hospitalized patients are therefore often underestimated. This study investigates whether the Geriatric Nutritional Risk Index (GNRI) predicts hospital mortality, correlates with length of hospital stay (LOS) and inflammatory markers in older inpatients. METHODS: We conducted a prospective monocentric study in 500 hospital patients over 65 years of age (female: 248; male: 252; age: 76.3 ± 0.31 years). GNRI was correlated to C-reactive protein (CRP), lymphocyte count, LOS and all-cause mortality, adjusted for potential confounders. RESULTS: The median body mass index was 24.1 (25th percentile: 21.1; 75th percentile: 27.8) kg/m2 and the mean GNRI 82.2 ± 0.56. A higher risk GNRI was associated with increased CRP levels (p < 0.05) and low lymphocyte counts (p < 0.05) after multivariable adjustment. Moreover, we found positive correlation between a higher risk GNRI and length of hospital stay, whereas, the association with in-hospital mortality was not significant. CONCLUSIONS: The GNRI correlates well with indicators of inflammation and the length of hospital stay. The routine implementation of the GNRI for the nutritional assessment of older patients could have a significant medical and socio-economic impact.
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Fenômenos Fisiológicos da Nutrição do Idoso , Mediadores da Inflamação/sangue , Desnutrição/diagnóstico , Estado Nutricional , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Coortes , Feminino , Avaliação Geriátrica , Alemanha/epidemiologia , Mortalidade Hospitalar , Humanos , Tempo de Internação , Contagem de Linfócitos , Masculino , Desnutrição/sangue , Desnutrição/epidemiologia , Desnutrição/imunologia , Avaliação Nutricional , Estudos Prospectivos , Risco , Índice de Gravidade de Doença , Centros de Atenção TerciáriaRESUMO
PURPOSE: Patients with biliopancreatic tumors frequently suffer from weight loss and cachexia. The in-hospital work-up to differentiate between benign and malignant biliopancreatic lesions requires repeated pre-interventional fasting periods that can aggravate this problem. We conducted a randomized intervention study to test whether routine in-hospital peripheral intravenous nutrition on fasting days (1000 ml/24 h, 700 kcal) has a beneficial effect on body weight and body composition. MATERIAL AND METHODS: 168 patients were screened and 100 enrolled in the trial, all undergoing in-hospital work-up for biliopancreatic mass lesions and randomized to either intravenous nutrition or control. Primary endpoint was weight loss at time of hospital discharge; secondary endpoints were parameters determined by bioelectric impedance analysis and quality of life recorded by the EORTC questionnaire. RESULTS: Within three months prior to hospital admission patients had a median self-reported loss of 4.0 kg (25*th: -10.0 kg and 75*th* percentile: 0.0kg) of body weight. On a multivariate analysis nutritional intervention increased body weight by 1.7 kg (95% CI: 0.204; 3.210, p = 0.027), particularly in patients with malignant lesions (2.7 kg (95% CI: 0.71; 4.76, p < 0.01). CONCLUSIONS: In a hospital setting, patients with suspected biliopancreatic mass lesions stabilized their body weight when receiving parenteral nutrition in fasting periods even when no total parenteral nutrition was required. Analysis showed that this effect was greatest in patients with malignant tumors. Further studies will be necessary to see whether patient outcome is affected as well. TRIAL REGISTRATION: ClinicalTrials.gov NCT02670265.
Assuntos
Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Nutrição Parenteral , Idoso , Composição Corporal , Pesos e Medidas Corporais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nutrição Parenteral/efeitos adversos , Nutrição Parenteral/métodos , Qualidade de Vida , Tempo para o Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer-related mortality in both genders. More than 80% of patients suffer from significant weight loss at diagnosis and over time develop severe cachexia. Early nutritional support is therefore essential. SUMMARY: This review evaluates the different nutritional therapies, such as enteral nutrition, parenteral nutrition and special nutritional supplements, on nutritional status, quality of life and survival. KEY MESSAGE: Due to the high prevalence of malnutrition and the rapid development of anorexia-cachexia-syndrome, early nutritional intervention is crucial and supported by clinical data. PRACTICAL IMPLICATIONS: Enteral nutrition should be preferred over parenteral nutrition. Omega-3 fatty acids and l-carnitine are promising substances for the prevention of severe cachexia, but further randomized controlled trials are needed to establish generally accepted guidelines on nutrition in pancreatic cancer.
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OBJECTIVES: To investigate changes in the fat content of abdominal compartments and muscle area during weight loss using confounder-adjusted chemical-shift-encoded magnetic resonance imaging (MRI) in overweight diabetics. METHODS: Twenty-nine obese diabetics (10/19 men/women, median age: 59.0 years, median body mass index (BMI): 34.0 kg/m2) prospectively joined a standardized 15-week weight-loss program (six weeks of formula diet exclusively, followed by reintroduction of regular food with gradually increasing energy content over nine weeks) over 15 weeks. All subjects underwent a standardized MRI protocol including a confounder-adjusted chemical-shift-encoded MR sequence with water/fat separation before the program as well at the end of the six weeks of formula diet and at the end of the program at 15 weeks. Fat fractions of abdominal organs and vertebral bone marrow as well as volumes of visceral and subcutaneous fat were determined. Furthermore, muscle area was evaluated using the L4/L5 method. Data were compared using the Wilcoxon signed-rank test for paired samples. RESULTS: Median BMI decreased significantly from 34.0 kg/m2 to 29.9 kg/m2 (p < 0.001) at 15 weeks. Liver fat content was normalized (14.2% to 4.1%, p < 0.001) and vertebral bone marrow fat (57.5% to 53.6%, p = 0.018) decreased significantly throughout the program, while fat content of pancreas (9.0%), spleen (0.0%), and psoas muscle (0.0%) did not (p > 0.15). Visceral fat volume (3.2 L to 1.6 L, p < 0.001) and subcutaneous fat diameter (3.0 cm to 2.2 cm, p < 0.001) also decreased significantly. Muscle area declined by 6.8% from 243.9 cm2 to 226.8 cm2. CONCLUSION: MRI allows noninvasive monitoring of changes in abdominal compartments during weight loss. In overweight diabetics, weight loss leads to fat reduction in abdominal compartments, such as visceral fat, as well as liver fat and vertebral bone marrow fat while pancreas fat remains unchanged.
Assuntos
Complicações do Diabetes/diagnóstico por imagem , Ingestão de Energia , Obesidade/diagnóstico por imagem , Programas de Redução de Peso , Humanos , Imageamento por Ressonância Magnética , Obesidade/complicações , Obesidade/dietoterapia , Estudos ProspectivosRESUMO
Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases.
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OBJECTIVE: Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction. METHODS: Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj (-/-) (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake. RESULTS: High-fat diet fed-Ptprj (-/-) mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj (-/-) mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj (-/-) mice. CONCLUSION: Together, these data establish DEP-1 as novel negative regulator of insulin signaling.
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OBJECTIVE: For hospitalized patients requiring parenteral nutrition (PN), adequate nutritional support has a profound effect on hospital length of stay, morbidity, mortality, and complication rates. Inappropriate or inadequate nutritional therapy may worsen clinical outcome. The aim of this study was to investigate the compliance with nutritional guidelines for PN in a university hospital setting. METHODS: Over a 6-mo period, this monocentric study prospectively recruited 107 (41 women, 66 men) hospitalized medical and surgical patients requiring PN. Data on nutritional support were collected before nutritional counseling. Nutritional requirements were estimated on the basis of the European Society for Clinical Nutrition and Metabolism (ESPEN) Guidelines for Adult Parenteral Nutrition (2009). RESULTS: The mean patient age was 65 ± 1.4 y and the mean body mass index was 23.2 ± 0.5 kg/m². Only 75% of the caloric requirement was met. Multivitamin supplementation was adequate in only 37%, and for vitamin K in only 6% of cases. Trace element supplementation was adequate in only 35%. PN in complete agreement with the ESPEN guidelines was achieved in none of the patients. CONCLUSIONS: In routine hospital practice, PN is generally not provided in compliance with established guidelines. To improve the quality of nutritional therapy, a nutritional support team should be established. Furthermore, there should be periodical training sessions in nutrition for medical and nursing staff, as well as in standard operating procedures.
Assuntos
Fidelidade a Diretrizes/estatística & dados numéricos , Hospitalização , Nutrição Parenteral/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Suplementos Nutricionais , Feminino , Alemanha , Humanos , Masculino , Micronutrientes/administração & dosagem , Pessoa de Meia-Idade , Política Nutricional , Necessidades Nutricionais , Estudos Prospectivos , Controle de Qualidade , Adulto JovemRESUMO
Collateral growth, arteriogenesis, represents a proliferative mechanism involving endothelial cells, smooth muscle cells, and monocytes/macrophages. Here we investigated the role of Density-Enhanced Phosphatase-1 (DEP-1) in arteriogenesis in vivo, a protein-tyrosine-phosphatase that has controversially been discussed with regard to vascular cell biology. Wild-type C57BL/6 mice subjected to permanent left common carotid artery occlusion (CCAO) developed a significant diameter increase in distinct arteries of the circle of Willis, especially in the anterior cerebral artery. Analyzing the impact of loss of DEP-1 function, induction of collateralization was quantified after CCAO and hindlimb femoral artery ligation comparing wild-type and DEP-1(-/-) mice. Both cerebral collateralization assessed by latex perfusion and peripheral vessel growth in the femoral artery determined by microsphere perfusion and micro-CT analysis were not altered in DEP-1(-/-) compared to wild-type mice. Cerebrovascular reserve capacity, however, was significantly impaired in DEP-1(-/-) mice. Cerebrovascular transcriptional analysis of proarteriogenic growth factors and receptors showed specifically reduced transcripts of PDGF-B. SiRNA knockdown of DEP-1 in endothelial cells in vitro also resulted in significant PDGF-B downregulation, providing further evidence for DEP-1 in PDGF-B gene regulation. In summary, our data support the notion of DEP-1 as positive functional regulator in vascular cerebral arteriogenesis, involving differential PDGF-B gene expression.
Assuntos
Regulação da Expressão Gênica , Neovascularização Fisiológica/genética , Proteínas Proto-Oncogênicas c-sis/biossíntese , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Animais , Becaplermina , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Artéria Carótida Primitiva/crescimento & desenvolvimento , Artéria Carótida Primitiva/cirurgia , Células Cultivadas , Círculo Arterial do Cérebro/crescimento & desenvolvimento , Círculo Arterial do Cérebro/cirurgia , Humanos , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-sis/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Matrix metalloproteinase (MMP)-dependent extracellular matrix (ECM) remodeling is a key feature in cardiometabolic syndrome-associated adipogenesis and atherosclerosis. Activation of membrane-tethered (MT) 1-MMP depends on furin (PCSK3). However, the regulation and function of the natural furin-inhibitor serpinB8 and thus furin/MT1-MMP-activity in obesity-related tissue inflammation/remodeling is unknown. Here we aimed to determine the role of serpinB8/furin in obesity-associated chronic inflammation. METHODS AND RESULTS: Monocyte â macrophage transformation was characterized by decreases in serpinB8 and increases in furin/MT1-MMP. Rescue of serpinB8 by protein overexpression inhibited furin-dependent pro-MT1-MMP activation in macrophages, supporting its role as a furin-inhibitor. Obese white adipose tissue-facilitated macrophage migration was inhibited by furin- and MMP-inhibition, stressing the importance of the furin-MMP axis in fat tissue inflammation/remodeling. Monocytes from obese patients (body mass index (BMI) >30kg/m(2)) had higher furin, MT1-MMP, and resistin gene expression compared to normal weight individuals (BMI<25kg/m(2)) with significant correlations of BMI/furin and furin/MT1-MMP. In vitro, the adipocytokine resistin induced furin and MT1-MMP in mononuclear cells (MNCs), while MCP-1 had no effect. CONCLUSIONS: Acquisition of the inflammatory macrophage phenotype is characterized by an imbalance in serpinB8/furin, leading to MT1-MMP activation, thereby enhancing migration. Increases in MT1-MMP and furin are present in MNCs from obese patients. Dissecting the regulation of furin and its inhibitor serpinB8 should facilitate targeting inflammation/remodeling in cardiometabolic diseases.
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Tecido Adiposo/patologia , Quimiotaxia , Furina/metabolismo , Macrófagos/patologia , Obesidade/enzimologia , Obesidade/patologia , Animais , Linhagem Celular , Ativação Enzimática , Precursores Enzimáticos/metabolismo , Feminino , Humanos , Hipertensão/complicações , Masculino , Metaloproteinase 14 da Matriz/metabolismo , Camundongos , Pessoa de Meia-Idade , Monócitos/patologia , Obesidade/complicações , Obesidade/metabolismo , Resistina/metabolismo , Serpinas/metabolismoRESUMO
BACKGROUND: Insulin signaling is tightly controlled by tyrosine dephosphorylation of the insulin receptor through protein-tyrosine-phosphatases (PTPs). DEP-1 is a PTP dephosphorylating tyrosine residues in a variety of receptor tyrosine kinases. Here, we analyzed whether DEP-1 activity is differentially regulated in liver, skeletal muscle and adipose tissue under high-fat diet (HFD), examined the role of DEP-1 in insulin resistance in vivo, and its function in insulin signaling. RESULTS: Mice were fed an HFD for 10 weeks to induce obesity-associated insulin resistance. Thereafter, HFD mice were subjected to systemic administration of specific antisense oligonucleotides (ASOs), highly accumulating in hepatic tissue, against DEP-1 or control ASOs. Targeting DEP-1 led to improvement of insulin sensitivity, reduced basal glucose level, and significant reduction of body weight. This was accompanied by lower insulin and leptin serum levels. Suppression of DEP-1 in vivo also induced hyperphosphorylation in the insulin signaling cascade of the liver. Moreover, DEP-1 physically associated with the insulin receptor in situ, and recombinant DEP-1 dephosphorylated the insulin receptor in vitro. CONCLUSIONS: These results indicate that DEP-1 acts as an endogenous antagonist of the insulin receptor, and downregulation of DEP-1 results in an improvement of insulin sensitivity. DEP-1 may therefore represent a novel target for attenuation of metabolic diseases.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Tecido Adiposo/metabolismo , Animais , Linhagem Celular , Insulina/metabolismo , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Obesidade/etiologia , Especificidade de Órgãos , Fenótipo , Fosforilação , Receptor de Insulina/metabolismo , Transdução de Sinais , Tirosina/metabolismoRESUMO
Elderly patients are at high risk of malnutrition and sarcopenia, promoting further morbidity which in turn decreases quality of life and increases the claiming of medical services and associated costs. Early and sustained administration of oral nutritional supplements has been shown to improve the nutritional status with robust clinical benefit. Many patients however, poorly adhere to prescribed supplements, so consistent monitoring is needed. Clinical monitoring usually ends with the discharge rendering the continuation of nutritional supplement therapy in the patient's home problematic. We developed a telemedicine based health care concept for intensive home monitoring. In a first randomized controlled prospective study we analyzed the feasibility of this innovative approach. The intervention group received oral nutritional supplements and telemedical monitoring with daily assessment of body weight, number of taken oral energy supplements and state of health. The control group received usual care. 13 patients were included in each group, eight patients of the intervention group left the study prematurely, five patients were closely monitored and used the devices for a mean 67 ± 63.5 days. Follow up data of body weight and BMI showed no relevant differences between both groups. The results and experiences gained in this pilot study demonstrate that telemedical systems provide encouraging new options to enable an intensive monitoring of malnourished patients. A continuous intensive therapy monitoring of this patient group however, is a particular challenge. Albeit possibilities, limitations and useful parameters were identified, which will be used to improve the conception in an ongoing prospective randomized trial.
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Suplementos Nutricionais , Serviços de Saúde para Idosos/tendências , Desnutrição/dietoterapia , Monitorização Ambulatorial/métodos , Monitorização Fisiológica/métodos , Telemedicina/métodos , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Peso Corporal/fisiologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Desnutrição/epidemiologia , Desnutrição/fisiopatologia , Estado Nutricional/fisiologia , Projetos Piloto , Estudos Prospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
The present study aimed to explore the anti-inflammatory effects and peroxisome proliferator-activated receptor-γ (PPARγ)-activating properties of the angiotensin type 1 receptor blocker telmisartan by analysis of serum interleukin 6 levels and monocytic PPARγ target gene expression in drug-naïve patients with the metabolic syndrome. This was a 14-week, randomized, double-blind, placebo-controlled 2-center study with telmisartan 80 mg/d and telmisartan 160 mg/d in 54 patients with the metabolic syndrome. In addition to clinical laboratory measurements, peripheral monocytes were extracted by negative isolation using a Dynal Monocyte kit to evaluate ligand-activated PPARγ target gene expression (CD36 and CD163) at baseline and study end using quantitative real-time RT-PCR. In this low-risk patient population, telmisartan (80 and 160 mg) treatment did not significantly affect serum interleukin 6 levels. Expression of the PPARγ target gene CD36 in monocytes was markedly induced by telmisartan from baseline to study end (telmisartan 80 mg: 2.3±1.5-fold change versus placebo [P value not significant]; telmisartan 160 mg: 3.5±0.9-fold change versus placebo [P<0.05]). The recently reported PPARγ target gene CD163 was slightly induced by telmisartan (telmisartan 80 mg: 1.1±0.3-fold change versus placebo [P value not significant]; telmisartan 160 mg: 1.4±0.4-fold change versus placebo [P value not significant]), which did not reach statistical significance. This is the first clinical description of monocytic PPARγ target gene regulation with high-dose telmisartan treatment. These data implicate that the angiotensin type 1 receptor blocker telmisartan activates PPARγ in circulating monocytes of patients with the metabolic syndrome.
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Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Antígenos CD36/metabolismo , Síndrome Metabólica/metabolismo , Monócitos/metabolismo , PPAR gama/metabolismo , Receptores de Superfície Celular/metabolismo , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Interleucina-6/sangue , Masculino , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , PPAR gama/agonistas , Pioglitazona , Telmisartan , Tiazolidinedionas/farmacologiaRESUMO
Integrins link the cytoskeleton to the extracellular matrix, providing outside-in/inside-out signalling essential for vascular smooth muscle cell (VSMC) migration in atherosclerosis. The integrin av subunit is synthesised from its precursor via furin-dependent endoproteolytic cleavage. Furin is a proprotein convertase (PC) highly expressed in VSMCs and in human atherosclerotic lesions. Inhibition of av processing inhibits binding to vitronectin and migration. However, the precise role of furin-dependent av cleavage on integrin bidirectional signalling and subsequent VSMC functions is unknown. Our present study demonstrates that the furin-like PC inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) inhibited av cleavage. This reduced vitronectin-induced (outside-in) focal adhesion kinase (FAK)- and paxillin-phosphorylation, and VSMC motility. Inside-out-stimulated, integrin- mediated VSMC adhesion/migration relied on integrin-adaptor protein activation following protein kinase C (PKC) and ERK1/2 phosphorylation. In contrast to outside-in signalling, PKC-dependent phosphorylation of FAK and paxillin was unaffected by the status of integrin cleavage. Still, cytoskeleton and focal adhesion site rearrangements were modulated by the inhibition of furin-dependent integrin cleavage, thereby lessening inside-out dependent migration. Hence, we find that integrin bidirectional signalling is critically controlled by furin. Furin- dependent integrin processing modulates rapid adaptive integrin/cytoskeleton changes, essential to VSMC motility, which represents a crucial component in atherosclerosis and restenosis.
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Furina/fisiologia , Integrinas/metabolismo , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais , Animais , Aterosclerose/patologia , Adesão Celular , Movimento Celular , Células Cultivadas , Citoesqueleto , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Furina/antagonistas & inibidores , Furina/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , RatosRESUMO
OBJECTIVE.: To determine whether liquid-based cytology improves Pap smear adequacy, as defined by the presence of endocervical cells, compared with conventional cytology during pregnancy. MATERIALS AND METHODS.: A randomized pilot study was conducted between May 2001 and May 2002. Patients presenting for their first prenatal visit were randomized to receive either a conventional Pap smear or a liquid-based smear (ThinPrep). Rates of endocervical cell recovery and cytologic results were compared between the groups. RESULTS.: Eighty-one patients were enrolled in the study. There were no differences between the groups in age (p = .40), parity (p = .62), gestational age (p = .14), history of abnormal pap (p = .08), previous treatment of neoplasia (p = 1.00), and tobacco use (p = .67). Adequacy of the standard pap versus the liquid-based smear was not different between the two groups (90.5% vs 82.1%, respectively;p = .34). CONCLUSIONS.: The results of this pilot study show that rates of endocervical cell recovery in a pregnant population are not statistically different using conventional or liquid-based cytology. Further research is indicated to assess the utility of the more expensive ThinPrep technology in this population.