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1.
Biochim Biophys Acta Mol Basis Dis ; 1866(10): 165853, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32502648

RESUMO

Phosphatidylethanolamine N-methyltransferase (PEMT) is a small integral membrane protein that converts phosphatidylethanolamine (PE) into phosphatidylcholine (PC). It has been previously reported that, unexpectedly, PEMT deficiency protected from high-fat diet (HFD)-induced obesity and insulin resistance, pointing to a possible role of this enzyme in the regulation of adipose cell metabolism. Using mouse 3T3-L1 preadipocytes as a biological system, we demonstrate that PEMT expression is strongly increased during the differentiation of preadipocytes into mature adipose cells. Knockdown of PEMT reduced the expression of early and late adipogenic markers, inhibited lipid droplet formation, reduced triacylglycerol content and decreased the levels of leptin release from the adipocytes, suggesting that PEMT is a novel and relevant regulator of adipogenesis. Investigation into the mechanisms whereby PEMT regulates adipocyte differentiation revealed that extracellularly regulated kinases (ERK1/2) and AKT are essential factors in this process. Specifically, the activities of ERK1/2 and AKT, which are decreased during adipocyte differentiation, were elevated upon Pemt knockdown. Moreover, treatment of cells with exogenous ceramide 1-phosphate (C1P), which we reported to be a negative regulator of adipogenesis, decreased PEMT expression, suggesting that PEMT is also a relevant factor in the anti-adipogenic action of C1P. Altogether, the data presented here identify PEMT as a novel regulator of adipogenesis and a mediator of the anti-adipogenic action of C1P.

2.
Sensors (Basel) ; 20(11)2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32498271

RESUMO

The electrocardiogram records the heart's electrical activity and generates a significant amount of data. The analysis of these data helps us to detect diseases and disorders via heart bio-signal abnormality classification. In unbalanced-data contexts, where the classes are not equally represented, the optimization and configuration of the classification models are highly complex, reflecting on the use of computational resources. Moreover, the performance of electrocardiogram classification depends on the approach and parameter estimation to generate the model with high accuracy, sensitivity, and precision. Previous works have proposed hybrid approaches and only a few implemented parameter optimization. Instead, they generally applied an empirical tuning of parameters at a data level or an algorithm level. Hence, a scheme, including metrics of sensitivity in a higher precision and accuracy scale, deserves special attention. In this article, a metaheuristic optimization approach for parameter estimations in arrhythmia classification from unbalanced data is presented. We selected an unbalanced subset of those databases to classify eight types of arrhythmia. It is important to highlight that we combined undersampling based on the clustering method (data level) and feature selection method (algorithmic level) to tackle the unbalanced class problem. To explore parameter estimation and improve the classification for our model, we compared two metaheuristic approaches based on differential evolution and particle swarm optimization. The final results showed an accuracy of 99.95%, a F1 score of 99.88%, a sensitivity of 99.87%, a precision of 99.89%, and a specificity of 99.99%, which are high, even in the presence of unbalanced data.

3.
Essays Biochem ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32579188

RESUMO

Sphingolipids are a class of complex lipids containing a backbone of sphingoid bases, namely the organic aliphatic amino alcohol sphingosine (Sph), that are essential constituents of eukaryotic cells. They were first described as major components of cell membrane architecture, but it is now well established that some sphingolipids are bioactive and can regulate key biological functions. These include cell growth and survival, cell differentiation, angiogenesis, autophagy, cell migration, or organogenesis. Furthermore, some bioactive sphingolipids are implicated in pathological processes including inflammation-associated illnesses such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease (namely Crohn's disease and ulcerative colitis), type II diabetes, obesity, and cancer. A major sphingolipid metabolite is ceramide, which is the core of sphingolipid metabolism and can act as second messenger, especially when it is produced at the plasma membrane of cells. Ceramides promote cell cycle arrest and apoptosis. However, ceramide 1-phosphate (C1P), the product of ceramide kinase (CerK), and Sph 1-phosphate (S1P), which is generated by the action of Sph kinases (SphK), stimulate cell proliferation and inhibit apoptosis. Recently, C1P has been implicated in the spontaneous migration of cells from some types of cancer, and can enhance cell migration/invasion of malignant cells through interaction with a Gi protein-coupled receptor. In addition, CerK and SphK are implicated in inflammatory responses, some of which are associated with cancer progression and metastasis. Hence, targeting these sphingolipid kinases to inhibit C1P or S1P production, or blockade of their receptors might contribute to the development of novel therapeutic strategies to reduce metabolic alterations and disease.

4.
Br J Pharmacol ; 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32562276

RESUMO

COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has overwhelmed Healthcare Systems requiring the rapid development of treatments, at least, to reduce COVID-19 severity. Drug repurposing offers a fast track. Here, we discuss the potential beneficial effects of statins in COVID-19 patients based on evidence that they may target virus receptors, replication, degradation and downstream responses in infected cells, addressing both basic research and epidemiological information. Briefly, statins could act modulating virus entry, acting on the SARS-CoV-2 receptors, ACE2 and CD147, and/or lipid rafts engagement. Statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects. The well-known anti-inflammatory properties of statins, by blocking several molecular mechanisms, including NF-κB and NLRP3 inflammasome, could limit the "cytokine storm" in severe COVID-19 patients which is linked to fatal outcome. Finally, statin moderation of coagulation response activation may also contribute to improve COVID-19 outcomes.

5.
Antioxidants (Basel) ; 9(6)2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32503213

RESUMO

Aging is one of the major risk factors for suffering cardiovascular and metabolic diseases. Due to the increase in life expectancy, there is a strong interest in the search for anti-aging strategies to treat and prevent these aging-induced disorders. Both omega 3 polyunsaturated fatty acids (ω-3 PUFA) and extra virgin olive oil (EVOO) exert numerous metabolic and cardiovascular benefits in the elderly. In addition, EVOO constitutes an interesting ingredient to stabilize ω-3 PUFA and decrease their oxidation process due to its high content in antioxidant compounds. ω-3 PUFA are commonly obtained from fish. However, more ecological and sustainable sources, such as algae oil (AO) can also be used. In this study, we aimed to study the possible beneficial effect of an oil mixture composed by EVOO (75%) and AO (25%) rich in ω-3 PUFA (35% docosahexaenoic acid (DHA) and 20% eicosapentaenoic acid (EPA)) on the cardiometabolic alterations associated with aging. For this purpose; young (three months old) and old (24 months old) male Wistar rats were treated with vehicle or with the oil mixture (2.5 mL/kg) for 21 days. Treatment with the oil mixture prevented the aging-induced increase in the serum levels of saturated fatty acids (SFA) and the aging-induced decrease in the serum concentrations of mono-unsaturated fatty acids (MUFA). Old treated rats showed increased serum concentrations of EPA and DHA and decreased HOMA-IR index and circulating levels of total cholesterol, insulin and IL-6. Treatment with the oil mixture increased the mRNA levels of antioxidant and insulin sensitivity-related enzymes, as well as reduced the gene expression of pro-inflammatory markers in the liver and in cardiac and aortic tissues. In addition, the treatment also prevented the aging-induced endothelial dysfunction and vascular insulin resistance through activation of the PI3K/Akt pathway. Moreover, aortic rings from old rats treated with the oil mixture showed a decreased response to the vasoconstrictor AngII. In conclusion, treatment with a mixture of EVOO and AO improves the lipid profile, insulin sensitivity and vascular function in aged rats and decreases aging-induced inflammation and oxidative stress in the liver, and in the cardiovascular system. Thus, it could be an interesting strategy to deal with cardiometabolic alterations associated with aging.

6.
Food Chem ; 329: 127153, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512392

RESUMO

Olive leaves are an under valorized residue of olive tree pruning and olive fruit harvesting and that are usually removed by either burning or grinding and scattering them on fields. However, as plant material easily available, they may be used as raw material in biorefineries, or for the industrial manufacture of many diverse products, given their lignocellulosic composition. Like other lignocellulosic biomasses, the composition of olive leaves depends on cultivar and to know it is essential for an adequate use. Therefore, this work tackles a characterization analysis of the lignocellulosic fraction of some olive leaf cultivars, both commercial and wild. In general, the cultivars studied did not show large differences in their quantitative composition, except for the content of ethanolic extractives and cellulose of the commercial and wild cultivars. In addition, the high lignin content (around 15%) is remarkable.

7.
Med. clín (Ed. impr.) ; 154(8): 289-294, abr. 2020. graf, tab
Artigo em Espanhol | IBECS-Express | ID: ibc-ET2-5796

RESUMO

ANTECEDENTES Y OBJETIVO: El tratamiento con hormona de crecimiento recombinante humana (rhGH) en niños nacidos pequeños para la edad gestacional (PEG) se ha mostrado eficaz, aunque con variedad en la respuesta. Se evalúa la talla adulta y los factores que determinan la respuesta a largo plazo. PACIENTES Y MÉTODOS: Estudio retrospectivo de 80 pacientes PEG tratados con rhGH por baja talla y seguidos hasta la talla adulta (23 varones). RESULTADOS: El grupo que inició el tratamiento antes de la pubertad alcanzó mayor talla adulta (−1,4±0,6 vs. −1,9±0,6 púberes). Existió mayor ganancia de talla en los tratados durante ≥ 2 años en prepubertad (1,32±0,5 SDE). Los factores asociados con una mayor ganancia de talla fueron: a) la menor talla, peso e IMC al inicio; b) la menor edad cronológica, ósea y el menor nivel de IGF-I iniciales; c) la mayor distancia con la talla genética; d) la mayor velocidad de crecimiento el primer y el segundo año y la mayor ganancia de talla previa y durante la pubertad. El porcentaje de buena respuesta en el primer año varió entre el 46,6 y el 81,6% en función del criterio empleado. El incremento de la velocidad de crecimiento≥3cm/año es el que mejor se relaciona con buena respuesta a largo plazo. CONCLUSIONES: El tratamiento con rhGH en niños PEG produce un incremento variable de talla adulta, que les permite alcanzar su rango genético. Los mejores resultados se producen en el grupo con mayor número de años en tratamiento en la prepubertad y no dependen de la respuesta hipofisaria de GH


BACKGROUND AND OBJECTIVE: Recombinant human growth hormone (rhGH) treatment in small for gestational age (SGA) children has been effective, although there is significant variability in the response. Adult height and the factors that determine the long-term response are evaluated. Patients and DESIGN: A retrospective study of 80 patients born SGA with short stature treated with rhGH and followed until adult height (23 males). RESULTS: The group starting treatment pre-puberty reached a higher Adult height (−1.4±0.6 vs. −1.9±.6 in pubertal children), the highest final height gain was achieved in those treated for at least 2years prepuberty (1.32±.5 SDS). Factors associated with greater adult height gain were: a) less height, weight and BMI at start of treatment, b) lower chronological and bone age with lower IGF-I before treatment, c) greater distance to target height, d) higher growth velocity the first and second year of treatment, and higher height gain before and during puberty. The percentage of patients with good response in the first year ranged from 46.6% to 81.6% depending on the criteria. Growth velocity increase ≥3cm/ first year correlated best with long-term response. CONCLUSION: rhGH treatment in children born SGA produced a varying increase in adult height that allowed them to reach their adult height. The best results occurred in the prepubertal group and did not depend on pituitary GH response

9.
Artigo em Inglês | MEDLINE | ID: mdl-32342139

RESUMO

PURPOSE: To investigate the effects of including balance training in a preoperative strengthening intervention on balance and functional outcomes in patients undergoing total knee replacement (TKR) and compare these effects to those induced by preoperative strengthening and no intervention. METHODS: Eighty-two subjects scheduled for TKR were randomly allocated into the strengthening (ST, n = 28) group: a preoperative lower limb strengthening intervention; the strengthening + balance (ST + B, n = 28) group: same intervention augmented with balance training; and the control group (n = 26). The Berg Balance Scale (BBS) and the function in daily living subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS-ADL) were the primary outcomes. The secondary measures included balance and mobility, self-reported status, and knee function. The outcomes were assessed at baseline, 1 week before surgery, and 2, (primary endpoint), 6 and 52 weeks after surgery. RESULTS: Compared with the controls, the participants in the ST and ST + B groups presented significant improvements from baseline to the end of the preoperative intervention in BBS (p = 0.005) and KOOS-ADL (p < 0.001). At 6 weeks post-surgery, the knee extensor strength values were similar in the two treatment groups and significantly higher than that in the controls. Overall, the participant outcomes in all groups stabilized at 1 year after surgery. CONCLUSION: A preoperative strengthening intervention, regardless of whether it is complemented with balance training, enhances strength but not balance or functional outcomes at 6 weeks after surgery. Patients are expected to present similar performance at 1 year postoperatively, but adequately statistically powered trials are needed to confirm the findings. LEVEL OF EVIDENCE: II. TRIAL REGISTRATION: NCT02995668.

11.
Enferm Clin ; 30(3): 155-159, 2020.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32139246

RESUMO

OBJECTIVE: To establish the evolution of the care process after the implementation of the Best Practices Guideline «Assessment and Care of Adults at Risk for Suicidal Ideation and Behaviour¼. METHOD: A descriptive longitudinal study was carried out at the Mental Health Hospitalization Unit in Hospital Universitario Virgen de las Nieves, Granada. All patients admitted to the Unit between 2016 and 2018, 1471 in total, were included. Compliance of care process indicators and suicidal risk were evaluated; in addition, suicide rates per 100,000 inhabitants were obtained. Absolute and relative frequencies of the indicators were calculated, as well as the change during the study period by the chi-square Pearson test, for P<.05. RESULTS: We observed a statistically significant increase in the entire care process. The percentage of patients with suicidal risk assessment improved from 16% in 2016 to 45.25% in 2018. The application of safety measures grew reaching 100% in 2018, and community services referral went from 70.31% to 90.50%. The percentage of patients at risk of suicidal ideation remains stable. Suicide rates per 100,000 inhabitants in Granada decreased by 24.50%. CONCLUSIONS: Improvement in the care process and the decrease in the suicide rate in Granada since the implementation of the guideline are consistent with the results of other research and offer a hopeful vision. Comprehensive strategies for suicide prevention must be promoted, and the evaluation of initiatives undertaken must continue.

12.
Food Chem ; 320: 126626, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32222659

RESUMO

Olive leaves are considered a promising source of bioactives such as phenolic compounds and mannitol. The extraction of high added value products is an issue of great interest and importance from the point of view of their exploitation. However, the content of these compounds can differ between cultivars and extraction methods. In this work, six olive leaves cultivars, including three wild cultivars, and two extraction processes (an innovative and alternative technique, pressurized liquid extraction, and a conventional Soxhlet extraction) were evaluated and compared towards the selective recovery of bioactive compounds. The wild cultivars showed the highest content of phenolic and flavonoid compounds, being oleuropein the compound present in higher amount. Findings also revealed that the highest mannitol content in the extracts was observed with the commercial cultivars, specifically in Arbequina. It is thus possible to decide which cultivars to use in order to obtain the highest yield of each bioproduct.

13.
Orthop Traumatol Surg Res ; 106(2): 325-328, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32192934

RESUMO

Osteochondral injuries of the metacarpal head require anatomical restoration to prevent limitations in range of motion and osteoarthritis. Osteochondral bone grafting is a viable option, especially in younger patients. Central injuries allow for different types of grafting, but when the injured area is on the lateral portion of the metacarpal head, the graft must include both a cortical and a cartilaginous portion. We present here the pearls and pitfalls in the surgical technique of chondrocostal grating from the 6th rib and an example of its use within a case of comminuted fracture of the metacarpal head. This technique provides a graft with cortical bone that allows for a stable fixation, with few complications during its harvesting. The graft is viable in the long-term and shows similar magnetic resonance intensities in comparison to hand cartilage.

14.
J Exp Med ; 217(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32219437

RESUMO

Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.

15.
J Anim Ecol ; 89(6): 1317-1328, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32144757

RESUMO

Large bodies of water represent major obstacles for the migration of soaring birds because thermal updrafts are absent or weak over water. Soaring birds are known to time their water crossings with favourable weather conditions and there are records of birds falling into the water and drowning in large numbers. However, it is still unclear how environmental factors, individual traits and trajectory choices affect their water crossing performance, this being important to understand the fitness consequences of water barriers for this group of birds. We addressed this problem using the black kite Milvus migrans as model species at a major migration bottleneck, the Strait of Gibraltar. We recorded high-resolution GPS and triaxial accelerometer data for 73 birds while crossing the Strait of Gibraltar, allowing the determination of sea crossing duration, length, altitude, speed and tortuosity, the flapping behaviour of birds and their failed crossing attempts. These parameters were modelled against wind speed and direction, time of the day, solar irradiance (proxy of thermal uplift), starting altitude and distance to Morocco, and age and sex of birds. We found that sea crossing performance of black kites is driven by their age, the wind conditions, the starting altitude and distance to Morocco. Young birds made longer sea crossings and reached lower altitude above the sea than adults. Crosswinds promoted longer sea crossings, with birds reaching lower altitudes and with higher flapping effort. Birds starting at lower altitudes were more likely to quit or made higher flapping effort to complete the crossing. The location where birds started the sea crossings impacted crossing distance and duration. We present evidence that explains why migrating soaring birds accumulate at sea passages during adverse weather conditions. Strong crosswinds during sea crossings force birds to extended flap-powered flight at low altitude, which may increase their chances of falling in the water. We also showed that juvenile birds assume more risks than adults. Finally, the way in which birds start the sea crossing is crucial for their success, particularly the starting altitude, which dictates how far birds can reach with reduced flapping effort.

16.
Med Clin (Barc) ; 154(12): 512-518, 2020 Jun 26.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32169308

RESUMO

INTRODUCTION: Osteogenesis imperfecta (OI) is a heterogeneous genetic disease manifesting as bone fragility and fractures. PATIENTS AND METHODS: Retrospective descriptive study analysing clinical and genetic features, and treatment of patients with OI. RESULTS: Forty patients were included; 32.5% males, 67.5% females; 29 children, 11 adults. Number of fractures at diagnosis with mild OI was 4.6±6.4 (average age at diagnosis 7.8±12.8years), with moderate OI 1.7±2.4 (age at diagnosis .04±.3years), in severe OI 3.7±2.1 and in extremely severe forms 12.5±7.8, both groups diagnosed at birth. Genetic study in 32 patients, 25 with a positive genetic study (pathogenic/probably pathogenic variant). COL1A1 gene was the most frequently affected. In 7 patients, no pathogenic or probably pathogenic variant was found (5 diagnosed by biochemical study of typeI collagen). Nineteen patients were treated with bisphosphonates; 7 combined with growth hormone. The patients treated with bisphosphonates showed clinical improvement (reduction of bone pain and/or irritability) and reduction of fractures. CONCLUSIONS: The COL1A1 gene is the most frequently affected. OI patients should receive multidisciplinary management and bisphosphonates can improve their quality of life.

17.
Adv Exp Med Biol ; 1227: 81-94, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32072500

RESUMO

Gremlin is a member of the TGF-ß superfamily that can act as a BMP antagonist, and recently, has been described as a ligand of the vascular endothelial growth factor receptor 2 (VEGFR2). Gremlin shares properties with the Notch signaling pathway. Both participate in embryonic development and are reactivated in pathological conditions. Gremlin is emerging as a potential therapeutic target and biomarker of renal diseases. Here we review the role of the Gremlin-VEGFR2 axis in renal damage and downstream signaling mechanisms, such as Notch pathway.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Humanos , Rim/metabolismo , Rim/patologia , Fator de Crescimento Transformador beta/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Clin Sci (Lond) ; 134(5): 513-527, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32104886

RESUMO

An important link exists between hypertension and inflammation. Hypertensive patients present elevated circulating levels of proinflammatory cytokines, including interleukin-17A (IL-17A). This cytokine participates in host defense, autoimmune and chronic inflammatory pathologies, and cardiovascular diseases, mainly through the regulation of proinflammatory factors. Emerging evidence also suggests that IL-17A could play a role in regulating blood pressure and end-organ damage. Here, our preclinical studies in a murine model of systemic IL-17A administration showed that increased levels of circulating IL-17A raised blood pressure induced inward remodeling of small mesenteric arteries (SMAs) and arterial stiffness. In IL-17A-infused mice, treatment with hydralazine and hydrochlorothiazide diminished blood pressure elevation, without modifying mechanical and structural properties of SMA, suggesting a direct vascular effect of IL-17A. The mechanisms of IL-17A seem to involve an induction of vascular smooth muscle cell (VSMC) hypertrophy and phenotype changes, in the absence of extracellular matrix (ECM) proteins accumulation. Accordingly, treatment with an IL-17A neutralizing antibody diminished SMA remodeling in a model of angiotensin II (Ang II) infusion. Moreover, in vitro studies in VSMCs reported here, provide further evidence of the direct effects of IL-17A on cell growth responses. Our experimental data suggest that IL-17A is a key mediator of vascular remodeling of the small arteries, which might contribute, at least in part, to blood pressure elevation.

19.
Nutrients ; 12(2)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093229

RESUMO

Childhood obesity is associated with metabolic and cardiovascular comorbidities. The development of these alterations may have its origin in early life stages such as the lactation period through metabolic programming. Insulin resistance is a common complication in obese patients and may be responsible for the cardiovascular alterations associated with this condition. This study analyzed the development of cardiovascular insulin resistance in a rat model of childhood overweight induced by overfeeding during the lactation period. On birth day, litters were divided into twelve (L12) or three pups per mother (L3). Overfed rats showed a lower increase in myocardial contractility in response to insulin perfusion and a reduced insulin-induced vasodilation, suggesting a state of cardiovascular insulin resistance. Vascular insulin resistance was due to decreased activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, whereas cardiac insulin resistance was associated with mitogen-activated protein kinase (MAPK) hyperactivity. Early overfeeding was also associated with a proinflammatory and pro-oxidant state; endothelial dysfunction; decreased release of nitrites and nitrates; and decreased gene expression of insulin receptor (IR), glucose transporter-4 (GLUT-4), and endothelial nitric oxide synthase (eNOS) in response to insulin. In conclusion, overweight induced by lactational overnutrition in rat pups is associated with cardiovascular insulin resistance that could be related to the cardiovascular alterations associated with this condition.

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