Novel pharmacological interventions for diabetic kidney disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological interventions from preclinical and early clinical studies with promising findings in the reduction of this condition's burden. RECENT FINDINGS: We will cover the latest evidence on the reduction of proteinuria and kidney function decline in DKD achieved through established renin-angiotensin-aldosterone system (RAAS) system blockade and the more recent addition of SGLT2i, nonsteroidal mineralocorticoid receptor antagonists (MRAs) and GLP1-RA, that combined will most likely integrate the mainstay for current DKD treatment. We also highlight evidence from new mechanisms of action in DKD, including other haemodynamic anti-inflammatory and antifibrotic interventions, oxidative stress modulators and cell identity and epigenetic targets. SUMMARY: Renal specific outcome trials have become more popular and are increasing the available armamentarium to diminish the progression of renal decline in patients at greater risk of end-stage kidney disease (ESKD) such as diabetic individuals. A combined pharmaceutical approach based on available rigorous studies should include RAAS blockade, SGLT2 inhibitors, nonsteroidal MRA and expectedly GLP1-RA on a personalized based-intervention. New specific trials designed to address renal outcomes will be needed for innovative therapies to conclude on their potential benefits in DKD.

Biomonitoring of exposure to multiple metal components in urine, hair and nails of apprentice welders performing shielded metal arc welding (SMAW).

Welding fumes are associated with various diseases. Increased air levels of metals were reported during welding. However, few multielement biomonitoring studies were conducted to assess the actual dose of metal components absorbed in apprentice welders in a learning environment. This research aimed to establish the nature and level of exposure to welding fumes and their metallic components in apprentice welders performing 'Shielded Metal Arc Welding' (SMAW), based on multi-element and multi-matrix analyses. A total of 86 apprentice welders were recruited in three different schools in Montreal, Québec, Canada. Twenty-one elements were measured in urine, hair, fingernail, and toenail samples collected at the beginning of the program and at the end of SMAW practical training. Concentrations of welding fumes and 12 metals were also determined in personal respirable air samples collected over a typical workday in a subgroup of 19 apprentices. Levels of manganese (Mn), iron (Fe) and nickel (Ni) in urine and Mn in hair were higher in samples taken at the end of the SMAW module compared to the beginning of training, while there was no significant difference for the other elements or for nail concentrations. Geometric mean concentrations [5th-95th percentiles] reached 0.31 [0.032-2.84], 9.4 [3.1-51] and 0.87 [0.35-3.1] µg/g creat. in post-shift urine, respectively, for Mn, Fe and Ni, and 0.37 [0.46-6.4] µg Mn/g hair at the end of SWAW. Median concentrations [5th-95th percentiles] were 29 [4.6-1200], 120 [27-3100] and 0.31 [

The Non-Coding RNA Journal Club: Highlights on Recent Papers-10.

We are delighted to share with you our seventh Journal Club and highlight some of the most interesting papers published recently [...].

ApoE and apoC-III-defined HDL subtypes: a descriptive study of their lecithin cholesterol acyl transferase and cholesteryl ester transfer protein content and activity.

BACKGROUND: The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. METHODS: Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E + C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E + C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting. RESULTS: HDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6% of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8, 12.2 and 8.37% of plasma LCAT respectively for E + C-, E-C+ and E + C+). LCAT mass was lower in E + C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL (r = - 0.55, P = 0.017) and E-C- alpha 1 HDL (r = - 0.49, P = 0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL (r = 0.52, P = 0.025). CONCLUSIONS: The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL.

Evaluación de registros Holter durante 19 horas en el contexto de la teoría de la probabilidad / Evaluation of 19-hour Holter recordings in the context of probability theory

Resumen Introducción: Previamente se desarrolló una nueva metodología de ayuda diagnóstica para los registros Holter fundamentada en los sistemas dinámicos y la teoría de probabilidad, a partir de la información registrada en 21 horas. Objetivo: Evaluar la capacidad diagnóstica de esta metodología durante 19 horas, comparándola con los resultados convencionales del Holter y con los resultados del método matemático aplicado en 21 horas. Materiales y Métodos: fueron evaluados 80 casos de pacientes mayores a 20 años, 10 con registro Holter normal y 70 diagnosticados de forma convencional con diferentes patologías cardíacas. Se establecieron los rangos para las frecuencias cardíacas y de número de latidos por hora en 21 y 19 horas; luego, se calculó la probabilidad de ocurrencia de estos, lo que permitió diferenciar estados de normalidad y enfermedad aguda a partir de tres parámetros. Se comparó el diagnóstico físico-matemático con el diagnóstico convencional, tomado como Gold Standard. Resultados: De los casos normales, dos presentaron probabilidad menor o igual a 0,217 y ocho probabilidades mayores o igual a 0,304; ningún caso de enfermedad aguda presentó valores con probabilidad menor o igual a 0,217, mientras que todos presentaron valores mayores o iguales a 0,304, tanto para los registros Holter evaluados en 21 como en 19 horas. Conclusiones: Se confirmó la utilidad clínica de la metodología ante una reducción del tiempo de evaluación a 19 horas, obteniendo diagnósticos objetivos con base en la auto-organización matemática del fenómeno.

Abstract Background: a new method to help evaluate 21-hour holter recordings based on dynamic systems and the theory of probability was previously developed Aim: to evaluate the diagnostic value of this methodology in the analysis of 19 hr compared to conventional holter analysis over a 21-hr recording. Methods: the holter recordings of 80 subjects aged over 20 years old were analyzed. Ten subjects had a normal holter and 70 conventionally diagnosed as abnormal. Ranges for heart rate and number of beats in 21 or 19 hours were determined. The probability of their occurrence was calculated using 3 parameters. The mathematically derived diagnosis was compared to the clinical diagnosis, considered a gold standard. Results: Among normal cases the calculated probability was ≤ 0.217 in 2 cases and ≥0.304 in 8. No case with acute disease presented probability values ≤0.217; all had probability values ≥0.304, both in 21 and 19 hour recordings. Conclusion: the mathematical methodology described was clinically useful allowing a reduction in recording time from 21 to 19 hr. Clinical diagnosis may be inferred from the mathematical organization of a holter recording.

Evaluación del comportamiento cardíaco mediante una metodología diagnóstica basada en sistemas dinámicos en 16 horas / Evaluation of the cardiac behaviour with a diagnostic methodology sustained in dynamical systems in 16 hours

Antecedentes: Con conceptos provenientes de la teoría de sistemas dinámicos y la geometría fractal, se ha logrado caracterizar el comportamiento de la dinámica cardíaca, dando resultados objetivos y estableciendo distinciones entre estados de normalidad y enfermedad. Objetivo: Aplicar una ley matemática exponencial de la dinámica cardíaca, inscrita en el contexto de los sistemas dinámicos y la geometría fractal, para evidenciar su utilidad diagnóstica en 16 horas. Materiales y métodos: Fueron empleados 200 Holters y registros electrocardiográficos continuos, entre normales y con diferentes alteraciones cardíacas. Se simuló una secuencia de frecuencias cardíacas en 16 y 21 horas, con la cual se construyó el atractor de cada dinámica. También se calculó la dimensión fractal y la ocupación de los atractores en el espacio fractal. Se estableció el diagnóstico físico-matemático en 16 y 21 horas y la subsecuente validación estadística. Resultados: Fueron obtenidos valores en la rejilla Kp entre 44 y 198 para estados patológicos y entre 221 y 377 para estados de normalidad en 16 horas, la sensibilidad y especificidad fue del 100% y el coeficiente Kappa de 1. Conclusión: Se logró diferenciar de manera adecuada estados normales de patológicos mediante la ley exponencial aplicada en registros de 16 horas

Background: With concepts derived from dynamical systems theory and fractal geometry, it has been possible to characterize the behavior of the cardiac dynamics, giving objective results and estabishing distinctions between states of normality and disease. Objective: To apply an exponential mathematical law of cardiac dynamics, inscribed in the context of dynamical systems and fractal geometry, to demonstrate its diagnostic utility in the context of a reduction in the evaluation time, originally of 21 hours. Materials and methods: There were used 200 Holters and cotinuous electrocardiographic records, between normal and with different cardiac alterations. A sequence of heart rates was simulated in 16 and 21 hours, with which the attractor of each dynamic was constructed. There were also calculated the fractal dimension and the occupation of the attractors in the fractal space. The physical-mathematical diagnosis was establishd at 16 and 21 hours, and the staqtistical validation was performed. Results: Values obtained in the Kp grid were between 44 y 198 for pathological sttes, and between 221 and 377 for normal states in 16 hours. The sensitivity and specificity was 100% and the Kappa coefficient was 1. Conclusion: It was possible to differentiate adequately normal states of pathological by means fo the exponential law applied in registers of 16 hours

Plasma Levels of Myonectin But Not Myostatin or Fibroblast-Derived Growth Factor 21 Are Associated with Insulin Resistance in Adult Humans without Diabetes Mellitus.

BACKGROUND: Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes. METHODS: We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M-value. RESULTS: Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (p-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) (p-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235, p = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p = 0.091). CONCLUSION: The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

The Phospholipid Linoleoylglycerophosphocholine as a Biomarker of Directly Measured Insulin Resistance.

BACKGROUND: Plasma concentrations of some lysophospholipids correlate with metabolic alterations in humans, but their potential as biomarkers of insulin resistance (IR) is insufficiently known. We aimed to explore the association between plasma linoleoylglycerophosphocholine (LGPC) and objective measures of IR in adults with different metabolic profiles. METHODS: We studied 62 men and women, ages 30 to 69 years, (29% normal weight, 59% overweight, 12% obese). Participants underwent a 5-point oral glucose tolerance test (5p-OGTT) from which we calculated multiple indices of IR and insulin secretion. Fifteen participants additionally underwent a hyperinsulinemic-euglycemic clamp for estimation of insulin-stimulated glucose disposal. Plasma LGPC was determined using high performance liquid chromatography/time-of-flight mass spectrometry. Plasma LGPC was compared across quartiles defined by the IR indices. RESULTS: Mean LGPC was 15.4±7.6 ng/mL in women and 14.1±7.3 ng/mL in men. LGPC did not correlate with body mass in-dex, percent body fat, waist circumference, blood pressure, glycosylated hemoglobin, log-triglycerides, or high density lipoprotein cholesterol. Plasma LGPC concentrations was not systematically associated with any of the studied 5p-OGTT-derived IR indices. However, LGPC exhibited a significant negative correlation with glucose disposal in the clamp (Spearman r=-0.56, P=0.029). Despite not being diabetic, participants with higher plasma LGPC exhibited significantly higher post-challenge plasma glucose excursions in the 5p-OGTT (P trend=0.021 for the increase in glucose area under the curve across quartiles of plasma LGPC). CONCLUSION: In our sample of Latino adults without known diabetes, LGPC showed potential as a biomarker of IR and impaired glucose metabolism.

Effect of diabetes status and hyperglycemia on global DNA methylation and hydroxymethylation.

Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic micro- and macrovascular complications. We hypothesized that some of the target organ damage is mediated by oxidative alterations in epigenetic mechanisms involving DNA methylation (5mC) and DNA hydroxymethylation (5hmC). We analyzed global DNA methylation and hydroxymethylation in peripheral blood cells in well-controlled and poorly controlled patients with T2DM and compared them with healthy controls. We also analyzed microarrays of DNA methylation and gene expression of other important tissues in the context of diabetes from the GEO database repository and then compared these results with our experimental gene expression data. DNA methylation and, more importantly, DNA hydroxymethylation levels were increased in poorly controlled patients compared to well-controlled and healthy individuals. Both 5mC and 5hmC measurements were correlated with the percentage of glycated hemoglobin, indicating a direct impact of hyperglycemia on changes over the epigenome. The analysis of methylation microarrays was concordant, and 5mC levels were increased in the peripheral blood of T2DM patients. However, the DNA methylation levels were the opposite of those in other tissues, such as the pancreas, adipose tissue and skeletal muscle. We hypothesize that a process of DNA oxidation associated with hyperglycemia may explain the DNA demethylation in which the activity of ten-eleven translocation (TET) proteins is not sufficient to complete the process. High levels of glucose lead to cellular oxidation, which triggers the process of DNA demethylation aided by TET enzymes, resulting in epigenetic dysregulation of the damaged tissues.

Antibodies against glutamic acid decarboxylase and indices of insulin resistance and insulin secretion in nondiabetic adults: a cross-sectional study.

BACKGROUND: Autoimmunity against insulin-producing beta cells from pancreatic islets is a common phenomenon in type 1 diabetes and latent autoimmune diabetes in adults. Some reports have also related beta-cell autoimmunity to insulin resistance (IR) in type 2 diabetes. However, the extent to which autoimmunity against components of beta cells is present and relates to IR and insulin secretion in nondiabetic adults is uncertain. AIM: To explore the association between antibodies against glutamic acid decarboxylase (GADA), a major antigen from beta cells, and indices of whole-body IR and beta-cell capacity/insulin secretion in adults who do not have diabetes. METHODS: We studied 81 adults of both sexes aged 30-70, without known diabetes or any autoimmune disease. Participants underwent an oral glucose tolerance test (OGTT) with determination of plasma glucose and insulin at 0, 30, 60, 90, and 120 minutes. From these results we calculated indices of insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] and incremental area under the insulin curve [iAUCins]) and insulin secretion (corrected insulin response at 30 minutes and HOMA beta-cell%). GADAs were measured in fasting plasma using immunoenzymatic methods. RESULTS: We found an overall prevalence of GADA positivity of 21.3%, without differences by sex and no correlation with age. GADA titers did not change monotonically across quartiles of any of the IR or insulin secretion indices studies. GADA did not correlate linearly with fasting IR expressed as HOMA-IR (Spearman's r=-0.18, p=0.10) or postabsorptive IR expressed as iAUCins (r=-0.15, p=0.18), but did show a trend toward a negative correlation with insulin secretory capacity expressed by the HOMA-beta cell% index (r=-0.20, p=0.07). Hemoglobin A1c, body mass index, and waist circumference were not associated with GADA titers. CONCLUSION: GADA positivity is frequent and likely related to impaired beta-cell function among adults without known diabetes.

A blocking-free microfluidic fluorescence heterogeneous immunoassay for point-of-care diagnostics.

In this article, a rapid, sensitive, and disposable microfluidic immunosensor is presented for point-of-care (POC) testing and clinical diagnosis. For the first time, the blocking process is eliminated from a microfluidic heterogeneous immunoassay by using protein A functionalized polydimethylsiloxane microchannels. The nonspecific binding of the assay is maintained around the chip background level by using a pair of antibodies with different affinity to protein A under optimized experimental conditions. C-reactive protein (CRP), a biomarker for inflammation and cardiovascular disease risk assessment, is selected as a model analyte to demonstrate the sensitivity of this blocking-free microfluidic heterogeneous immunoassay. A four parameter logistic function is used to model and assess the data. The limit of detection obtained is 0.54 µg/mL, which is lower than the cut-off value for clinical diagnosis. The overall assay is completed in 5 min. The protein A modified PDMS chips wet-stored at 4°C can maintain biofunctionality up to 14 months. The developed blocking-free microfluidic heterogeneous immunoassay will immediately provide benefits to most immunosensing microdevices targeted for POC diagnostics by shortening analysis time, simplifying fluid transportation, reducing sample consumption, and lowering waste generation.

Intoxicaciones por Talio / Poisonings by Thallium

Aunque no es una intoxicación frecuente, las intoxicaciones por sulfato de Talio en nuestro medio tienen una incidencia que amerita su estudio, máximo cuando muchas de ellas suceden en la población infantil y de manera accidental, y otras tantas son de manera voluntaria y un tercer grupo, bajo en frecuencia, padece la intoxicación por fines delictivos. Queremos entonces presentar la sintomatología aguda y crónica producida por el sulfato de Talio y los diferentes esquemas de manejo.

Medidas generales de atención del intoxicado agudo / General measures of attention of the acute intoxicated

Con este artículo se pretende interesar al médico sobre las diferentes situaciones de emergencia en toxicología y la manera como se deben abordar. Para esto, se hace un análisis de las formas más frecuentes de intoxicación en nuestro medio y presento un esquema de atención al paciente intoxicado agudo, en orden secuencial, enfocándolo en medidas a favor del enfermo y en contra de la sustancia tóxica; haciéndose énfasis en que cada uno de los pasos enumerados se deben realizar simultáneamente, por el personal del servicio de urgencias.