Understanding One Half of the Sex Difference Equation: The Modulatory Effects of Testosterone on Diabetic Cardiomyopathy.

Diabetes is a prevalent disease, primarily characterized by high blood sugar (hyperglycemia). Significantly higher rates of myocardial dysfunction have been noted in individuals with diabetes, even in those without coronary artery disease or high blood pressure (hypertension). Numerous molecular mechanisms have been identified through which diabetes contributes to the pathology of diabetic cardiomyopathy, which presents as cardiac hypertrophy and fibrosis. At the cellular level, oxidative stress and inflammation in cardiomyocytes are triggered by hyperglycemia. Although males are generally more likely to develop cardiovascular disease than females, diabetic males are less likely to develop diabetic cardiomyopathy than are diabetic females. One reason for these differences may be the higher levels of serum testosterone in males compared with females. Although testosterone appears to protect against cardiomyocyte oxidative stress and exacerbate hypertrophy, its role in inflammation and fibrosis is much less clear. Additional preclinical and clinical studies will be required to delineate testosterone's effect on the diabetic heart.

Continuous Glucose Monitoring and Other Wearable Devices to Assess Hypoglycemia among Older Adult Outpatients with Diabetes Mellitus.

BACKGROUND: Hypoglycemia (HG) causes symptoms that can be fatal, and confers risk of dementia. Wearable devices can improve measurement and feedback to patients and clinicians about HG events and risk. OBJECTIVES: The aim of the study is to determine whether vulnerable older adults could use wearables, and explore HG frequency over 2 weeks. METHODS: First, 10 participants with diabetes mellitus piloted a continuous glucometer, physical activity monitor, electronic medication bottles, and smartphones facilitating prompts about medications, behaviors, and symptoms. They reviewed graphs of glucose values, and were asked about the monitoring experience. Next, a larger sample (N = 70) wore glucometers and activity monitors, and used the smartphone and bottles, for 2 weeks. Participants provided feedback about the devices. Descriptive statistics summarized demographics, baseline experiences, behaviors, and HG. RESULTS: In the initial pilot, 10 patients aged 50 to 85 participated. Problems addressed included failure of the glucometer adhesive. Patients sought understanding of graphs, often requiring some assistance with interpretation. Among 70 patients in subsequent testing, 67% were African-American, 59% were women. Nearly one-fourth (23%) indicated that they never check their blood sugars. Previous HG was reported by 67%. In 2 weeks of monitoring, 73% had HG (glucose ≤70 mg/dL), and 42% had serious, clinically significant HG (glucose under 54 mg/dL). Eight patients with HG also had HG by home-based blood glucometry. Nearly a third of daytime prompts were unanswered. In 24% of participants, continuous glucometers became detached. CONCLUSION: Continuous glucometry occurred for 2 weeks in an older vulnerable population, but devices posed wearability challenges. Most patients experienced HG, often serious in magnitude. This suggests important opportunities to improve wearability and decrease HG frequency among this population.

The Effects of Hyperglycemia on Early Endothelial Activation and the Initiation of Atherosclerosis.

It is well established that patients with diabetes have an increased risk of developing atherosclerotic cardiovascular disease. The earliest detectable sign of atherosclerosis initiation is endothelial cell activation. Activated endothelial cells express adhesion proteins, P-selectin, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, which function to recruit monocytes to the subendothelial layer. This study examines the effect of hyperglycemia on endothelial cell activation and the initiation and progression of atherosclerosis. In vitro studies revealed that exposure of human aortic endothelial cells to elevated (30 mmol/L) glucose concentrations significantly increased the expression of P-selectin, E-selectin, and vascular cell adhesion molecule-1. In vivo studies showed that, before lesion development, 5-week-old hyperglycemic ApoE-/-Ins2+/akita mice had significantly increased expression of these adhesion proteins in the aortic sinus and increased macrophage infiltration, compared with normoglycemic ApoE-/- controls. At 25 weeks of age, ApoE-/-Ins2+/akita mice had significantly larger atherosclerotic plaques than ApoE-/- controls (0.022 ± 0.004 versus 0.007± 0.001 mm3; P < 0.05). Similar endothelial activation was observed in heterozygous ApoE+/-Ins2+/akita mice; however, detectable atherosclerotic lesions did not develop in the absence of dyslipidemia. Lowering blood glucose levels (by 55%) using a sodium-glucose cotransporter 2 inhibitor reduced endothelial activation. Together, these findings support a causative role for hyperglycemia in atherogenesis and highlight the importance of blood glucose regulation in preventing atherosclerotic cardiovascular disease.

Investigating the protective effects of estrogen on ß-cell health and the progression of hyperglycemia-induced atherosclerosis.

Sex differences in the prevalence and development of diabetes and associated cardiometabolic complications are well established. The objective of this study was to analyze the effects of estrogen on the maintenance of ß-cell health/function and atherosclerosis progression, using a mouse model of hyperglycemia-induced atherosclerosis, the ApoE-/-:Ins2+/Akita mouse. ApoE-/-:Ins2+/Akita mice exhibit sexual dimorphism in the control of blood glucose levels. Male ApoE-/-:Ins2+/Akita mice are chronically hyperglycemic due to a significant reduction in pancreatic ß-cell mass. Female mice are only transiently hyperglycemic, maintain ß-cell mass, and blood glucose levels normalize at 35 ± 1 days of age. To determine the effects of estrogen on pancreatic ß-cell health and function, ovariectomies and estrogen supplementation experiments were performed, and pancreatic health and atherosclerosis were assessed at various time points. Ovariectomized ApoE-/-:Ins2+/Akita mice developed chronic hyperglycemia with significantly reduced ß-cell mass. To determine whether the observed effects on ovariectomized ApoE-/-:Ins2+/Akita mice were due to a lack of estrogens, slow-releasing estradiol pellets were inserted subcutaneously. Ovariectomized ApoE-/-:Ins2+/Akita mice treated with exogenous estradiol showed normalized blood glucose levels and maintained ß-cell mass. Exogenous estradiol significantly reduced atherosclerosis in both ovariectomized female and male ApoE-/-:Ins2+/Akita mice relative to controls. Together, these findings suggest that estradiol confers significant protection to pancreatic ß-cell health and can directly and indirectly slow the progression of atherosclerosis.NEW & NOTEWORTHY This study examines the effect(s) of estrogen on ß cell and cardiometabolic health/function in a novel mouse model of hyperglycemia-induced atherosclerosis (ApoE-/-:Ins2+/Akita). Using a combination of estrogen deprivation (ovariectomy) and supplementation strategies, we quantify effects on glucose homeostasis and atherogenesis. Our results clearly show a protective role for estrogen on pancreatic ß-cell health and function and glucose homeostasis. Furthermore, estrogen supplementation dramatically reduces atherosclerosis progression in both male and female mice.

Characterization of the Elastoplastic Response of Low Zn-Cu-Ti Alloy Sheets Using the CPB-06 Criterion.

Unlike other HCP metals such as titanium and magnesium, the behavior of zinc alloys has only been modeled in the literature. For the low Zn-Cu-Ti alloy sheet studied in this work, the anisotropy is clearly seen on the stress-strain curves and Lankford coefficients. These features impose a rigorous characterization and an adequate selection of the constitutive model to obtain an accurate representation of the material behavior in metal forming simulations. To describe the elastoplastic behavior of the alloy, this paper focuses on the material characterization through the application of the advanced Cazacu-Plunket-Barlat 2006 (CPB-06 for short) yield function combined with the well-known Hollomon hardening law. To this end, a two-stage methodology is proposed. Firstly, the material characterization is performed via tensile test measurements on sheet samples cut along the rolling, diagonal and transverse directions in order to fit the parameters involved in the associate CPB-06/Hollomon constitutive model. Secondly, these material parameters are assessed and validated in the simulation of the bulge test using different dies. The results obtained with the CPB-06/Hollomon model show a good agreement with the experimental data reported in the literature. Therefore, it is concluded that this model represents a consistent approach to estimate the behavior of Zn-Cu-Ti sheets under different forming conditions.

Condromatosis Sinovial Primaria de la Articulación Temporomandibular con Extensión a Hueso Temporal. Reporte de un Caso y Revisión de la Literatura / Primary Synovial Chondromatosis of the Temporomandibular Joint with Temporal Bone Extension. Case Report and Literature Review

RESUMEN: La condromatosis sinovial (CS), es una lesión benigna poco frecuente y de clínica bastante inespecífica. Suele afectar articulaciones de huesos largos como la rodilla, el codo y la cadera, presentándose generalmente de manera unilateral. Se cree que solo un 3 % de los casos de CS afecta la articulación temporomandibular. Esta condición se caracteriza por ser un trastorno metaplásico del tejido conectivo sinovial que suele manifestarse con la formación de pequeños y múltiples nódulos de cartílago que posteriormente pueden desprenderse, calcificarse y formar cuerpos libres dentro del espacio articular. Presentamos el caso de una mujer de 55 años con condromatosis sinovial de la articulación temporomandibular, tratada desde hace 3 años bajo el diagnóstico de desórdenes temporomandibulares. A pesar de ser considerada una lesión de tipo benigna, esta puede llegar a ser localmente agresiva, extendiéndose como en nuestro reporte hacia la fosa craneal media, adelgazando parte del hueso temporal.

ABSTRACT: Synovial chondromatosis (CS) is a benign lesion that is rare and clinically quite nonspecific. It usually affects the joints of long bones such as the knee, elbow and hip, usually occurring unilaterally. It is believed that in only 3 % of cases of CS the temporomandibular joint. This is a condition its characterized by being a metaplastic synovial connective tissue that manifests itself with the formation of small and multiple cartridges that detach, calcify and form free bodies within the joint space. We present the case of a 55-year-old woman with synovial chondromatosis of the temporomandibular joint, treated for 3 years under the diagnosis of temporomandibular disorders. Despite being considered a benign lesion, this can become locally aggressive, extending as in our report to the cranial fossa, thinning part of the temporal bone.

Evidence of extensive atherosclerosis, coronary artery disease and myocardial infarction in the ApoE-/-:Ins2+/Akita mouse fed a western diet.

BACKGROUND AND AIMS: Diabetic patients with no history of cardiac infarction have a prevalence of coronary atherosclerosis and a risk of heart attack equivalent to euglycemic patients who have coronary atherosclerosis and have suffered a prior myocardial infarction. Although several murine models of diabetes have been established, none of these show indications of cardiac events. In an attempt to establish a diabetic mouse model with coronary atherosclerosis and myocardial injury, we have fed hyperglycemic ApoE-/-:Ins2+/Akita mice a western diet to enhance the dyslipidemic phenotype. METHODS: Five-week-old ApoE-/-:Ins2+/Akita mice and ApoE-/- controls were fed a diet, 0.15% cholesterol and 21% anhydrous milk lipids, until 25 weeks of age. Changes in lifespan, clinical and metabolic parameters were evaluated as well as atherosclerosis and heart injury. RESULTS: In comparison to male ApoE-/-, male ApoE-/-:Ins2+/Akita mice presented with chronic hyperglycemia (30.8 ±â€¯1.2 mM vs. 9.3 ±â€¯0.5 mM) accompanied by extremely high levels of total plasma cholesterol (49.3 ±â€¯6.3 mM vs. 30.1 ±â€¯1.5 mM) and triglycerides (11.6 ±â€¯1.7 mM vs. 2.36 ±â€¯0.18 mM). These mice have atherosclerosis at multiple vascular sites, including aortic sinus, ascending and descending aorta, brachiocephalic artery and coronary arteries. In addition, myocardial infarcts and a significant reduction of the lifespan (close to 20% of survival vs. other groups) were observed. Distinctively, both strains of female mice presented a parallel increase in plasma lipids, atherosclerosis, and no effects on mortality. CONCLUSIONS: We have established a diabetic mouse model, the western-diet-fed male ApoE-/-:Ins2+/Akita mouse, with profound cardiovascular disease involving extensive atherosclerosis, coronary artery disease and myocardial infarct resulting in shortened lifespan.

Sex-Specific Differences in an ApoE(-/-):Ins2(+/Akita) Mouse Model of Accelerated Atherosclerosis.

Diabetic patients have a twofold to fourfold increased risk of cardiovascular disease. Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of cardiovascular disease are unclear. To further our understanding of how diabetes promotes atherosclerosis, we have established, characterized, and manipulated a new model of hyperglycemia-induced atherosclerosis: the apolipoprotein E-deficient (ApoE(-/-)):Ins2(+/Akita) mouse. All mice were fed a standard chow diet. Male ApoE(-/-):Ins2(+/Akita) mice developed chronic hyperglycemia, which significantly accelerated atherosclerosis. Female ApoE(-/-):Ins2(+/Akita) mice presented hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, advanced atherosclerosis was observed at 15 weeks of age compared with ApoE(-/-) females. To better understand these differences, subsets of mice were castrated or ovariectomized at 5 weeks of age. Castrated ApoE(-/-):Ins2(+/Akita) mice showed a reduction in blood glucose levels that correlated with the amelioration of atherosclerosis. Interestingly, castrated normoglycemic ApoE(-/-) mice developed larger atherosclerotic lesions than sham-operated on controls. Ovariectomized ApoE(-/-):Ins2(+/Akita) mice presented chronic hyperglycemia, and atherosclerosis appeared to be advanced. We have characterized the distinctive sex-specific phenotypes exhibited by the ApoE(-/-):Ins2(+/Akita) mouse model and present evidence for the action of sex hormones on pancreatic ß-cell function and the vasculature that affect the regulation of blood glucose levels and the development of atherosclerosis. This model will provide a test bed to further delineate these effects.

Glycogen synthase kinase 3α deficiency attenuates atherosclerosis and hepatic steatosis in high fat diet-fed low density lipoprotein receptor-deficient mice.

Studies have implicated signaling through glycogen synthase kinase (GSK) 3α/ß in the activation of pro-atherogenic pathways and the accelerated development of atherosclerosis. By using a mouse model, we examined the role of GSK3α in the development and progression of accelerated atherosclerosis. We crossed Gsk3a/GSK3α-knockout mice with low-density lipoprotein receptor (Ldlr) knockout mice. Five-week-old Ldlr(-/-);Gsk3a(+/+), Ldlr(-/-);Gsk3a(+/-), and Ldlr(-/-);Gsk3a(-/-) mice were fed a chow diet or a high-fat diet for 10 weeks and then sacrificed. GSK3α deficiency had no detectible effect on any measured parameters in chow-fed mice. High-fat-diet fed Ldlr(-/-) mice that were deficient for GSK3α had significantly less hepatic lipid accumulation and smaller atherosclerotic lesions (60% smaller in Ldlr(-/-);Gsk3a(+/-) mice, 80% smaller in Ldlr(-/-);Gsk3a(-/-) mice; P < 0.05), compared with Ldlr(-/-);Gsk3a(+/+) controls. GSK3α deficiency was associated with a significant increase in plasma IL-10 concentration and IL-10 expression in isolated macrophages. A twofold to threefold enhancement in endoplasmic reticulum stress-induced IL-10 expression was observed in Thp-1-derived macrophages that were pretreated with the GSK3α/ß inhibitor CT99021. Together, these results suggest that GSK3α plays a pro-atherogenic role, possibly by mediating the effects of endoplasmic reticulum stress in the activation of pro-atherogenic pathways.

Cumplimiento de la normatividad en lapublicidad de medicamentos de ventalibre en Colombia / Fulfillment of the normatividad in the advertising medicine of free sale in Colombia

Introducción: en Colombia la información sobre el cumplimento de la normativa de publicidad de medicamentos de venta libre es limitada.Objetivo: establecer el cumplimiento normativo de la publicidad televisiva de medicamentos de venta libre en Colombia.Métodos: en julio de 2012, la transmisión de 2 canales nacionales (Caracol y RCN)y 1 regional (Teleantioquia) se grabó en forma simultánea entre las 6:00 y 22:00 horas, durante 2 días de semana y 2 días de fin de semana o festivo, seleccionados probabilísticamente con el programa Epi-info V. 6.0.Resultados: en los canales nacionales de 378 anuncios (de 54 medicamentos), 31(8.2 por ciento) de 3 medicamentos no cumplieron con la normatividad. Por su parte en el canal regional, aunque hubo 7 anuncios de 5 productos farmacéuticos, no se identificó publicidad de medicamentos de venta libre.Conclusiones: en un porcentaje pequeño (8 por ciento), los anuncios televisivos de medicamentos de venta libre en los canales nacionales no cumplen con la normativa vigente.

Quantitative analysis and characterization of atherosclerotic lesions in the murine aortic sinus.

Atherosclerosis is a disease of the large arteries and a major underlying cause of myocardial infarction and stroke. Several different mouse models have been developed to facilitate the study of the molecular and cellular pathophysiology of this disease. In this manuscript we describe specific techniques for the quantification and characterization of atherosclerotic lesions in the murine aortic sinus and ascending aorta. The advantage of this procedure is that it provides an accurate measurement of the cross-sectional area and total volume of the lesion, which can be used to compare atherosclerotic progression across different treatment groups. This is possible through the use of the valve leaflets as an anatomical landmark, together with careful adjustment of the sectioning angle. We also describe basic staining methods that can be used to begin to characterize atherosclerotic progression. These can be further modified to investigate antigens of specific interest to the researcher. The described techniques are generally applicable to a wide variety of existing and newly created dietary and genetically-induced models of atherogenesis.