Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure.

An epidemic of chronic kidney disease of unknown etiology (Mesoamerican nephropathy) has emerged in hot regions of Central America. We have demonstrated that dehydration associated with recurrent heat exposure causes chronic kidney disease in animal models. However, the independent influence of core body temperature on kidney injury has not been explored. In the present study, we tested the hypothesis that kidney injury could be accelerated by increasing body temperature independent of external temperature. Wild-type mice were exposed to heat (39.5°C, 30 min, 2 times daily) with or without the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) for 10 days. Core temperature, renal function, proteinuria, and renal histological and biochemical analyses were performed. Isolated mitochondria markers of oxidative stress were evaluated from kidney tissue. DNP increased body core temperature in response to heat by 1°C (42 vs. 41°C), which was transient. The mild increase in temperature correlated with worsening albuminuria (R = 0.715, P < 001), renal tubular injury, and interstitial infiltration of monocytes/macrophages. Tubular injury was marked in the outer medulla. This was associated with a reduction in kidney tissue ATP levels (nonheated control: 16.71 ± 1.33 nmol/mg and DNP + heat: 13.08 ± 1.12 nmol/mg, P < 0.01), reduced mitochondria, and evidence for mitochondrial oxidative stress. The results of the present study suggest that kidney injury in heat stress is markedly worsened by increasing core temperature. This is consistent with the hypothesis that clinical and subclinical heat stroke may play a role in Mesoamerican nephropathy.

Climate Change and the Kidney.

The worldwide increase in temperature has resulted in a marked increase in heat waves (heat extremes) that carries a markedly increased risk for morbidity and mortality. The kidney has a unique role not only in protecting the host from heat and dehydration but also is an important site of heat-associated disease. Here we review the potential impact of global warming and heat extremes on kidney diseases. High temperatures can result in increased core temperatures, dehydration, and blood hyperosmolality. Heatstroke (both clinical and subclinical whole-body hyperthermia) may have a major role in causing both acute kidney disease, leading to increased risk of acute kidney injury from rhabdomyolysis, or heat-induced inflammatory injury to the kidney. Recurrent heat and dehydration can result in chronic kidney disease (CKD) in animals and theoretically plays a role in epidemics of CKD developing in hot regions of the world where workers are exposed to extreme heat. Heat stress and dehydration also has a role in kidney stone formation, and poor hydration habits may increase the risk for recurrent urinary tract infections. The resultant social and economic consequences include disability and loss of productivity and employment. Given the rise in world temperatures, there is a major need to better understand how heat stress can induce kidney disease, how best to provide adequate hydration, and ways to reduce the negative effects of chronic heat exposure.

Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor.

Interference with DNA damage checkpoints has been demonstrated preclinically to be a highly effective means of increasing the cytotoxicity of a number of DNA-damaging cancer therapies. Cell cycle arrest at these checkpoints protects injured cells from apoptotic cell death until DNA damage can be repaired. In the absence of functioning DNA damage checkpoints, cells with damaged DNA may proceed into premature mitosis followed by cell death. A key protein kinase involved in activating and maintaining the S and G2/M checkpoints is Chk1. Pharmacological inhibition of Chk1 in the absence of p53 functionality leads to abrogation of DNA damage checkpoints and has been shown preclinically to enhance the activity of many standard of care chemotherapeutic agents. LY2603618 is a potent and selective small molecule inhibitor of Chk1 protein kinase activity in vitro (IC(50) = 7 nM) and the first selective Chk1 inhibitor to enter clinical cancer trials. Treatment of cells with LY2603618 produced a cellular phenotype similar to that reported for depletion of Chk1 by RNAi. Inhibition of intracellular Chk1 by LY2603618 results in impaired DNA synthesis, elevated H2A.X phosphorylation indicative of DNA damage and premature entry into mitosis. When HeLa cells were exposed to doxorubicin to induce a G2/M checkpoint arrest, subsequent treatment with LY2603618 released the checkpoint, resulting in cells entering into metaphase with poorly condensed chromosomes. Consistent with abrogation of the Chk1 and p53-dependent G2/M checkpoint, mutant TP53 HT-29 colon cancer cells were more sensitive to gemcitabine when also treated with LY2603618, while wild-type TP53 HCT116 cells were not sensitized by LY2603618 to gemcitabine. Treatment of Calu-6 human mutant TP53 lung cancer cell xenografts with gemcitabine resulted in a stimulation of Chk1 kinase activity that was inhibited by co-administration of LY2603618. By all criteria, LY2603618 is a highly effective inhibitor of multiple aspects of Chk1 biology.

Serotonin 5-HT1A and 5-HT1B receptors co-mediate the RU 24969-induced locomotor activity of male and female preweanling rats.

The serotonin (5-HT) 1A/1B agonist RU 24969 robustly increases the locomotor activity of adult male rats and mice; however, studies using selective antagonists alternately report that 5-HT1A, 5-HT1B, or both receptor types mediate RU 24969's locomotor activating effects. The purpose of the present study was to extend these past findings by administering a selective 5-HT1 agonist and/or antagonists to male and female preweanling rats. This age group was tested because younger rats often exhibit psychopharmacological responses that are quantitatively or qualitatively different from adult rats. In a series of experiments, male and female preweanling rats were pretreated with vehicle, the 5-HT1A antagonist WAY 100635 (0.5, 1, 5, or 10 mg/kg), or the 5-HT1B antagonists NAS-181 (5 or 10 mg/kg) or SB 216641 (5 or 10 mg/kg) 30 min before assessment of locomotor activity. Rats were injected with saline or RU 24969 immediately prior to testing. Results showed that RU 24969 (0.625, 1.25, 2.5, or 5 mg/kg) significantly increased the locomotor activity of both male and female preweanling rats (no sex differences were apparent). Antagonism of either the 5-HT1A or the 5-HT1B receptor was sufficient to significantly reduce the locomotor activity of RU 24969-treated preweanling rats. Unexpectedly, NAS-181 did not act as a silent receptor antagonist, as both doses of NAS-181 significantly increased the locomotor activity of saline-treated preweanling rats. In sum, the present results show that both the 5-HT1A and 5-HT1B receptor systems mediate locomotion during the late preweanling period, and this mediation does not vary according to sex.

Métodos de aprendizaje automático para predecir el comportamiento epidemiológico de enfermedades arbovirales: revisión estructurada de literatura / Machine learning methods to predict epidemiological behavior of arbovirals diseases: structured literature review

Introducción: Los métodos de aprendizaje automático permiten manejar datos estructurados y no estructurados para construir modelos predictivos y apoyar la toma de decisiones. Objetivo: Identificar los métodos de aprendizaje automático aplicados para predecir el comportamiento epidemiológico de enfermedades arbovirales utilizando datos de vigilancia epidemiológica. Metodología: Se realizó búsqueda en EMBASE y PubMed, análisis bibliométrico y síntesis de la información. Resultados: Se seleccionaron 41 documentos, todos publicados en la última década. La palabra clave más frecuente fue dengue. La mayoría de los autores (88,3 %) participó en un artículo de investigación. Se encontraron 16 métodos de aprendizaje automático, el más frecuente fue Red Neuronal Artificial, seguido de Máquinas de Vectores de Soporte. Conclusiones: En la última década se incrementó la publicación de trabajos que pretenden predecir el comportamiento epidemiológico de arbovirosis por medio de diversos métodos de aprendizaje automático que incorporan series de tiempo de los casos, variables climatológicas, y otras fuentes de información de datos abiertos.

Introduction: Machine learning methods allow to manipulate structured and unstructured data to build predictive models and support decision-making. Objective: To identify machine learning methods applied to predict the epidemiological behavior of vector-borne diseases using epidemiological surveillance data. Methodology: A literature search in EMBASE and PubMed, bibliometric analysis, and information synthesis were performed. Results: A total of 41 papers were selected, all of them were published in the last decade. The most frequent keyword was dengue. Most authors (88.3 %) participated in a research article. Sixteen machine learning methods were found, the most frequent being Artificial Neural Network, followed by Support Vector Machines. Conclusions: In the last decade there has been an increase in the number of articles that aim to predict the epidemiological behavior of vector-borne diseases using by means of various machine learning methods that incorporate time series of cases, climatological variables, and other sources of open data information.

Climate Change and the Emergent Epidemic of CKD from Heat Stress in Rural Communities: The Case for Heat Stress Nephropathy.

Climate change has led to significant rise of 0.8°C-0.9°C in global mean temperature over the last century and has been linked with significant increases in the frequency and severity of heat waves (extreme heat events). Climate change has also been increasingly connected to detrimental human health. One of the consequences of climate-related extreme heat exposure is dehydration and volume loss, leading to acute mortality from exacerbations of pre-existing chronic disease, as well as from outright heat exhaustion and heat stroke. Recent studies have also shown that recurrent heat exposure with physical exertion and inadequate hydration can lead to CKD that is distinct from that caused by diabetes, hypertension, or GN. Epidemics of CKD consistent with heat stress nephropathy are now occurring across the world. Here, we describe this disease, discuss the locations where it appears to be manifesting, link it with increasing temperatures, and discuss ongoing attempts to prevent the disease. Heat stress nephropathy may represent one of the first epidemics due to global warming. Government, industry, and health policy makers in the impacted regions should place greater emphasis on occupational and community interventions.

Climate change. Climate in Medieval time.

Many papers have referred to a "Medieval Warm Period." But how well defined is climate in this period, and was it as warm as or warmer than it is today? In their Perspective, Bradley et al. review the evidence and conclude that although the High Medieval (1100 to 1200 A.D.) was warmer than subsequent centuries, it was not warmer than the late 20th century. Moreover, the warmest Medieval temperatures were not synchronous around the globe. Large changes in precipitation patterns are a particular characteristic of "High Medieval" time. The underlying mechanisms for such changes must be elucidated further to inform the ongoing debate on natural climate variability and anthropogenic climate change.