"Arterial stiffness is not associated with changes in the circadian pattern of blood pressure in patients with type 1 diabetes mellitus and cardiovascular autonomic dysfunction".

INTRODUCTION: Cardiovascular autonomic neuropathy (CAN) associates an abnormal circadian pattern in blood pressure (BP) regulation that might be aggravated by the coexistence of arterial stiffness. We aimed to evaluate the effect of arterial stiffness in the circadian rhythm of BP in patients with type 1 diabetes and CAN. METHODS: Cross-sectional study including 56 consecutive patients with type 1 diabetes and CAN, with (n = 28) or without (n = 24) arterial stiffness as defined by an ankle-brachial index above 1.2. CAN was diagnosed by BP and heart rate responses to active standing and cardiovascular autonomic reflex tests. Absence of nocturnal decrease in BP-"non-dipping" pattern- was defined by a daytime to nighttime decrease in mean BP smaller than 10%. RESULTS: The study's subjects mean age was 40 ± 11 years-old, their mean duration of diabetes was 22 ± 10 years, and their mean A1c was 7.9 ± 1.5%. A "non-dipping" pattern was observed in 28 patients (54%) regardless of the presence or absence of arterial stiffness. Age, waist circumference, body mass index, and A1c, were introduced as independent variables into a multiple regression analysis. The stepwise model (R2: 0.113, p = 0.016) retained only A1c levels (ß: ‒ 0.333, 95% confidence interval [CI]: -3.10 to -0.33) as significant predictor of the percentage of nighttime decrease in mean BP. CONCLUSIONS: A non-dipping pattern in BP is very common in patients with type 1 diabetes presenting with subclinical CAN and is associated with a poorer metabolic control. On the contrary, coexistence of arterial stiffness is not associated with abnormalities in circadian BP regulation.

Sex differences and sex steroids influence on the presentation and severity of cardiovascular autonomic neuropathy of patients with type 1 diabetes.

BACKGROUND: Sex differences characterize cardiovascular outcomes in patients with type 1 diabetes. Cardioautonomic neuropathy is a common complication of type 1 diabetes that associates increased morbi-mortality. Data regarding the interplay between sex and cardiovascular autonomic neuropathy are scarce and controversial in these patients. We aimed to address sex-related differences in the prevalence of seemingly asymptomatic cardioautonomic neuropathy in type 1 diabetes, and their associations with sex steroids. METHODS: We conducted a cross-sectional study including 322 consecutively recruited patients with type 1 diabetes. Cardioautonomic neuropathy was diagnosed using Ewing's score and power spectral heart rate data. We assessed sex hormones by liquid chromatography/tandem mass spectrometry. RESULTS: When considering all subjects as a whole, asymptomatic cardioautonomic neuropathy prevalence was not significantly different between women and men. When age was taken into account, the prevalence of cardioautonomic neuropathy was similar among young men and those > 50 years. However, in women > 50 years, the prevalence of cardioautonomic neuropathy doubled that of young women [45.8% (32.6; 59.7) vs. 20.4% (13.7; 29.2), respectively]. The OR of having cardioautonomic neuropathy was 3.3 higher in women > 50 years than in their younger counterparts. Furthermore, women presented more severe cardioautonomic neuropathy than men. These differences were even more marked when women were classified according their menopausal status instead of age. Peri- and menopausal women had an OR 3.5 (1.7; 7.2) of having CAN compared with their reproductive-aged counterparts [CAN prevalence: 51% (37; 65) vs. 23% (16; 32), respectively]. A binary logistic regression model (R2: 0.161; P = 0.001) displayed age > 50 years as a significant determinant of cardioautonomic neuropathy only in women. Androgens were positively associated with heart rate variability in men, and negatively in women. Accordingly, cardioautonomic neuropathy was associated with increased testosterone/estradiol ratio in women but to decreased testosterone concentrations in men. CONCLUSIONS: Menopause in women with type 1 diabetes is accompanied by an increase in the prevalence of asymptomatic cardioautonomic neuropathy. This age-related excess risk of cardioautonomic neuropathy is not observed in men. Men and women with type 1 diabetes have opposite associations between circulating androgens and indexes of cardioautonomic function. Trial registration ClinicalTrials.gov Identifier: NCT04950634.

Point-of-care sural nerve conduction could predict the presence of cardiovascular autonomic neuropathy in type 1 diabetes mellitus.

AIMS: Assessment for cardiovascular autonomic neuropathy (CAN) in patients with type 1 diabetes mellitus remains time-consuming in the clinical setting. We aimed to examine the diagnostic performance of a portable point-of-care diagnostic tool (POCD) for assessing sural nerve conduction during the screening of CAN. METHODS: Nerve amplitude (AMPPOCD ) and conduction velocity (CVPOCD ) were measured in a cross-sectional study including 198 asymptomatic patients with type 1 diabetes. CAN was diagnosed by the Ewing score and power spectral heart rate [low-frequency (LF) and high-frequency (HF) activity]. Diagnostic accuracy was determined by ROC curves. RESULTS: CVPOCD and AMPPOCD showed positive correlations with LF and HF, and a negative correlation with age. Overall, AMPPOCD had an 81.7% accuracy in identifying CAN [AUC = 0.817 (95% CI 0.692-0.942)] with an AMPPOCD ≤6 µV showing 90% sensitivity and 73% specificity. In a stepwise binary logistic regression analysis, the model (R2 : 0.297; P < 0.001) retained the duration of type 1 diabetes [ß: 1.131 (95% CI: 1.051-1.216); P = 0.001) and A1c [ß: 2.131 (95% CI: 1.060-4.283); P = 0.034) as significant predictors of CAN. The combination of AMPPOCD ≤6 µV + a type 1 diabetes duration of ≥8 years maximized the sensitivity, showing a diagnostic performance of 87% [AUC = 0.867 (95% CI 0.769-0.965)] with 90%, 76%, and 99%, sensitivity, specificity, and NPV, respectively. Adding A1c ≥ 7% to this model maintained accuracy [AUC = 0.867 (95% CI: 0.788-0.963) and NPV (99%), while increasing specificity to 84%. CONCLUSIONS: The combination of AMPPOCD with A1c and the duration of type 1 diabetes mellitus showed a good performance for the detection of asymptomatic CAN, making POCD an easy and rapid test for its routine screening in the clinical setting.

Impact of excluding hyperglycemia from international diabetes federation metabolic syndrome diagnostic criteria on prevalence of the syndrome and its association with microvascular complications, in adult patients with type 1 diabetes.

BACKGROUND: We aimed to determine, in patients with type 1 diabetes (T1DM), the impact of excluding hyperglycemia as a criterion from the International Diabetes Federation (IDF) definition of the metabolic syndrome (MetS), both on its prevalence and on its association with micro and macrovascular complications and markers of subclinical inflammation. METHODS: A cross-sectional design, including 280 patients with T1DM. We defined MetS by three different models: (i) the standard IDF criteria, (ii) a modification consisting of excluding of hyperglycemia as a criterion (modified IDF criteria) and (iii) a modification consisting in changing the hyperglycemia by insulin resistance (MetS + IR model) defined by the estimated glucose disposal rate. Microvascular complications and cardioautonomic neuropathy were assessed. We measured an inflammatory panel including high sensitivity C reactive protein, erythrocyte sedimentation rate, homocysteine, and fibrinogen concentrations. RESULTS: After excluding hyperglycemia, the prevalence of MetS was 6.4% (95%CI: 4.1 to 9.9) compared with 20.7% (95%CI: 16.3 to 25.8) using standard IDF criteria. After adjusting for duration of diabetes, all three MetS definitions increased the odds for having microvascular complications [OR: 6.012 (2.208-16.307) for modified definition; OR: 5.176 (2.555-10.486) for standard definition and [OR: 3.374 (1.649-8.456) for MetS+IR model]. However, the both modified IDF models for MetS showed better predictive performance than standard criteria for suffering from neuropathy, nephropathy, cardiovascular disease and were associated with markers of subclinical inflammation. CONCLUSIONS: The prevalence of MetS significantly varies as a function whether or not hyperglycemia is included as a diagnostic criterion. The subset of patients fulfilling the modified MetS definitions may reflect better the concept of metabolic syndrome in T1DM. These modified definitions were accompanied by a poorer metabolic control and lipid profile, showing the worse inflammatory biomarker profiles and higher odds for micro- and macrovascular complications. In patients with T1DM, the inclusion of insulin resistance instead of hyperglycemia as a criterion of MetS may be of interest in routine clinical practice.

High serum copeptin may be a marker of an increased carotid intima-media thickness in asymptomatic patients with type 1 diabetes.

We aimed to study the association of copeptin with carotid intima-media thickness in 60 patients with type 1 diabetes (T1DM-patients). Our results suggest that copeptin might improve the stratification of cardiovascular risk in T1DM-patients. Further research is needed to determine the value in identifying carotid disease of this biochemical marker.

Fasting serum copeptin and asymptomatic peripheral artery disease: No association in patients with type 1 diabetes mellitus.

OBJECTIVE: As copeptin is associated with lower-extremity amputation in patients with type 1 diabetes mellitus (T1DM), our study aimed to address the putative association between copeptin and asymptomatic peripheral artery disease (aPAD) in those patients. DESIGN AND METHODS: This observational cross-sectional study included 112 patients with T1DM from a larger cohort (ClinicalTrials.gov: NCT02910271), selected (1:2) as per the presence of aPAD (n = 37) or not (n = 75). aPAD was evaluated by ankle-brachial index (ABI), toe-brachial index (TBI), and peripheral Doppler ultrasound. The two groups of patients were matched by age, gender distribution and duration of T1DM. Fasting serum copeptin was measured by high-sensitivity ELISA, and its relationships with clinical and biochemical variables as well as aPAD were evaluated too. RESULTS: The study population was aged 42 ± 8 years, duration of T1DM was 27 ± 7 years, and mean HbA1c was 7.7 ± 1.1%. No significant differences in copeptin concentrations were found between patients with or without aPAD (16.9 ± 10.8 vs 17.3 ± 14.7 pmol/L, respectively; P = 0.462). Considering all patients as a whole, copeptin correlated with systolic blood pressure (SBP; ρ = -0.209, P = 0.027), eGFR ρ = -0.271, P = 0.004), and serum sodium (ρ = -0.208, P = 0.027), but not with ABI (ρ = -0.068, P = 0.476). Stepwise multiple linear regression analysis (R2: 0.059; P = 0.035) retained SBP (ß: -0.219, 95% CI: -1.391; -0.089) as the only significant predictor of copeptin concentration. CONCLUSION: As serum copeptin does not appear to be associated with aPAD in patients with T1DM, further studies are now needed to elucidate whether it has any other potential role to play in the subclinical vascular disease of this patient population.

Valor nutricional del almuerzo ofrecido por una organización no gubernamental a niños(as) de 4 a 12 años de edad en zonas urbano marginales de San José, Costa Rica, 2017-2018 / Nutritional value of the lunch offered by a non-governmental organization to children between 4 and 12 years of age in marginal urban areas of San José, Costa Rica, 2017-2018

RESUMEN Propósito: La inexistencia de datos a nivel nacional y regional sobre el valor nutricional (VN) de la alimentación ofrecida en comedores comunitarios dirigidos por Organizaciones No Gubernamentales (ONG), que atienden población infantil de zonas urbano marginales, junto con el incremento en la prevalencia de exceso de peso reportada por el Ministerio de Educación Pública de Costa Rica (MEP) en el 2016, justifican el estudio del VN del almuerzo servido a niños(as), que participan en programas de alimentación complementaria en zonas urbano marginales de San José, Costa Rica. Método: Se analizaron mediante muestreo aleatorio 321 platos de almuerzo, durante 12 días en dos comedores. Se reconstruyeron recetas y se determinaron tamaños de porción mediante pesaje directo y se calculó el VN promedio por plato. Resultados: El valor energético fue cercano a la recomendación nutricional. Sin embargo, valores de proteína, grasa total, grasa insaturada, fibra dietética, calcio y potasio fueron inferiores a las recomendaciones y por el contrario, carbohidratos totales, azúcar agregada, grasa saturada y sodio fueron superiores a la recomendación nacional. Conclusión: No es suficiente ofrecer un aporte adecuado de energía. Los excesos y deficiencias de nutrientes reflejan un patrón alimentario obesogénico que suma vulnerabilidad a la condición de pobreza y pobreza extrema de la población infantil de zonas urbano-marginales.

ABSTRACT Purpose: The lack of data at a national and regional level regarding the nutritional value (NV) of the food offered in community feeding programs run by Non-Governmental Organizations, which serve the population of marginal urban areas (an important indicator of infant health), along with the increase in the prevalence of excess weight reported in 2016 by the Ministry of Public Education of Costa Rica, justifies the study of the NV of the lunch served to preschool and school-aged children, who participate in complementary feeding programs in marginal urban areas of San José, Costa Rica. Method: 321 meals served were analyzed over 12 days, in 2 food services. Recipes were reconstructed, and portion sizes were determined by direct weighing of food served and the average NV per dish was calculated. Results: The energy value of the lunch served was similar to the nutritional recommendation. However, for the values of protein, total fat, unsaturated fat, dietary fiber, calcium and potassium which were lower than the nutritional recommendation and on the contrary, the content of total carbohydrates, added sugar, saturated fat and sodium was excessive. Conclusion: It is not enough to offer minors an adequate energy amount. Nutrient excesses and deficiencies reflect an obesogenic food pattern, which adds vulnerability to the condition of poverty and extreme poverty of the child population of marginalized urban areas.

The Opening of Connexin 43 Hemichannels Alters Hippocampal Astrocyte Function and Neuronal Survival in Prenatally LPS-Exposed Adult Offspring.

Clinical evidence has revealed that children born from mothers exposed to viral and bacterial pathogens during pregnancy are more likely to suffer various neurological disorders including schizophrenia, autism bipolar disorder, major depression, epilepsy, and cerebral palsy. Despite that most research has centered on the impact of prenatal inflammation in neurons and microglia, the potential modifications of astrocytes and neuron-astrocyte communication have received less scrutiny. Here, we evaluated whether prenatally LPS-exposed offspring display alterations in the opening of astrocyte hemichannels and pannexons in the hippocampus, together with changes in neuroinflammation, intracellular Ca2+ and nitric oxide (NO) signaling, gliotransmitter release, cell arborization, and neuronal survival. Ethidium uptake recordings revealed that prenatal LPS exposure enhances the opening of astrocyte Cx43 hemichannels and Panx1 channels in the hippocampus of adult offspring mice. This enhanced channel activity occurred by a mechanism involving a microglia-dependent production of IL-1ß/TNF-α and the stimulation of p38 MAP kinase/iNOS/[Ca2+]i-mediated signaling and purinergic/glutamatergic pathways. Noteworthy, the activity of Cx43 hemichannels affected the release of glutamate, [Ca2+]i handling, and morphology of astrocytes, whereas also disturbed neuronal function, including the dendritic arbor and spine density, as well as survival. We speculate that excitotoxic levels of glutamate triggered by the activation of Cx43 hemichannels may contribute to hippocampal neurotoxicity and damage in prenatally LPS-exposed offspring. Therefore, the understanding of how astrocyte-neuron crosstalk is an auspicious avenue toward the development of broad treatments for several neurological disorders observed in children born to women who had a severe infection during gestation.

Factores asociados a la sobrecarga en el cuidador primario. Medellín, 2017 / Factors associated with overloading in the primary caregiver. Medellin, 2017

Resumen Introducción: El aumento de personas dependientes conlleva a la necesidad de cuidadores que asuman tareas básicas de cuidado; la responsabilidad de cuidar es asumida principalmente por familiares y el cuidado constante repercute en cambios de índole personal, familiar, laboral y social. Objetivo: Identificar los principales factores sociodemográficos y del cuidado, asociados a la sobrecarga en el cuidador primario de la ciudad de Medellín para el año 2017. Materiales y métodos: Estudio transversal, cuantitativo, de fuente de información primaria obtenida por encuestas telefónicas. La muestra fue de 340 cuidadores. El consentimiento fue verbal. Resultados: El 92,6% de los cuidadores eran mujeres, la edad promedio fue de 57 años; el 53,8% percibía su salud como regular o mala. La prevalencia de sobrecarga fue 39,7% y las características asociadas fueron la mala percepción de salud, el abandono de actividades y el no recibir capacitación previa al cuidado. Conclusiones: El cuidador es un sujeto con derechos que requiere atención en programas de prevención de riesgos que se derivan del cuidado. Es necesario brindar educación y acompañamiento a las personas encargadas del cuidado para que se empoderen de su salud.

Abstract Introduction: The increase in dependent people leads to the need for caregivers who assume basic tasks of care. The responsibility to care is assumed mainly by family members and the constant care impacts on changes of personal, family, labor and social nature. Objective: To identify the main sociodemographic and care factors associated with the overload in the primary caregiver in the city of Medellín during 2017. Materials and methods: A cross-sectional, quantitative study was made, which primary information source was obtained by telephone surveys. The sample was 340 caregivers and the consent was verbal. Results: 92.6% of the caregivers were women whose average age was 57; 53.8% perceived their health as regular or bad. The prevalence of overload was 39.7% and the associated characteristics were poor perception of health, abandonment of activities and not receiving pre-care training. Conclusions: The caregiver is a subject with rights that requires care in risk prevention programs that derive from care. It is necessary to provide education and accompaniment to caregivers so they are empowered of their health.

Connexin 43 Hemichannel Activity Promoted by Pro-Inflammatory Cytokines and High Glucose Alters Endothelial Cell Function.

The present work was done to elucidate whether hemichannels of a cell line derived from endothelial cells are affected by pro-inflammatory conditions (high glucose and IL-1ß/TNF-α) known to lead to vascular dysfunction. We used EAhy 926 cells treated with high glucose and IL-1ß/TNF-α. The hemichannel activity was evaluated with the dye uptake method and was abrogated with selective inhibitors or knocking down of hemichannel protein subunits with siRNA. Western blot analysis, cell surface biotinylation, and confocal microscopy were used to evaluate total and plasma membrane amounts of specific proteins and their cellular distribution, respectively. Changes in intracellular Ca2+ and nitric oxide (NO) signals were estimated by measuring FURA-2 and DAF-FM probes, respectively. High glucose concentration was found to elevate dye uptake, a response that was enhanced by IL-1ß/TNF-α. High glucose plus IL-1ß/TNF-α-induced dye uptake was abrogated by connexin 43 (Cx43) but not pannexin1 knockdown. Furthermore, Cx43 hemichannel activity was associated with enhanced ATP release and activation of p38 MAPK, inducible NO synthase, COX2, PGE2 receptor EP1, and P2X7/P2Y1 receptors. Inhibition of the above pathways prevented completely the increase in Cx43 hemichannel activity of cells treated high glucose and IL-1ß/TNF-α. Both synthetic and endogenous cannabinoids (CBs) also prevented the increment in Cx43 hemichannel opening, as well as the subsequent generation and release of ATP and NO induced by pro-inflammatory conditions. The counteracting action of CBs also was extended to other endothelial alterations evoked by IL-1ß/TNF-α and high glucose, including increased ATP-dependent Ca2+ dynamics and insulin-induced NO production. Finally, inhibition of Cx43 hemichannels also prevented the ATP release from endothelial cells treated with IL-1ß/TNF-α and high glucose. Therefore, we propose that reduction of hemichannel activity could represent a strategy against the activation of deleterious pathways that lead to endothelial dysfunction and possibly cell damage evoked by high glucose and pro-inflammatory conditions during cardiovascular diseases.

Prenatal exposure to inflammatory conditions increases Cx43 and Panx1 unopposed channel opening and activation of astrocytes in the offspring effect on neuronal survival.

Several epidemiological studies indicate that children born from mothers exposed to infections during gestation, have an increased risk to develop neurological disorders, including schizophrenia, autism and cerebral palsy. Given that it is unknown if astrocytes and their crosstalk with neurons participate in the above mentioned brain pathologies, the aim of this work was to address if astroglial paracrine signaling mediated by Cx43 and Panx1 unopposed channels could be affected in the offspring of LPS-exposed dams during pregnancy. Ethidium uptake experiments showed that prenatal LPS-exposure increases the activity of astroglial Cx43 and Panx1 unopposed channels in the offspring. Induction of unopposed channel opening by prenatal LPS exposure depended on intracellular Ca2+ levels, cytokine production and activation of p38 MAP kinase/iNOS pathway. Biochemical assays and Fura-2AM/DAF-FM time-lapse fluorescence images revealed that astrocytes from the offspring of LPS-exposed dams displayed increased spontaneous Ca2+ dynamics and NO production, whereas iNOS levels and release of IL-1ß/TNF-α were also increased. Interestingly, we found that prenatal LPS exposure enhanced the release of ATP through astroglial Cx43 and Panx1 unopposed channels in the offspring, resulting in an increased neuronal death mediated by the activation of neuronal P2X7 receptors and Panx1 channels. Altogether, this evidence suggests that astroglial Cx43 and Panx1 unopposed channel opening induced by prenatal LPS exposure depended on the inflammatory activation profile and the activation pattern of astrocytes. The understanding of the mechanism underlying astrocyte-neuron crosstalk could contribute to the development of new strategies to ameliorate the brain abnormalities induced in the offspring by prenatal inflammation. GLIA 2015;63:2058-2072.