Hypoglycemia during hyperosmolar hyperglycemic crises is associated with long-term mortality.

BACKGROUND: Previous research has indicated that hypoglycemia during hospitalization is a predictor of unfavorable outcomes in patients with diabetes. However, no studies have examined the long-term impact of hypoglycemia in adults admitted for hyperglycemic crises. The study was aimed to investigate the long-term implications of hypoglycemia during hyperosmolar hyperglycemic crises, particularly in terms of all-cause mortality. METHODS: This retrospective cohort study included 170 patients (82 men [48.2%], median age 72 years) admitted to a university hospital for hyperosmolar hyperglycemic crises, including pure hyperosmolar hyperglycemic states and hyperosmolar diabetic ketoacidoses. We separately investigated the prognostic significance of hypoglycemia on mortality during the initial intravenous insulin therapy phase and during the later subcutaneous insulin therapy phase, both during hospitalization and in the long term (median follow-up, 652 days; range 2-3460 days). RESULTS: Both hypoglycemia during the initial intravenous insulin therapy phase (observed in 26.5% of patients) and hypoglycemia during the later subcutaneous insulin therapy phase (observed in 52.7% of patients) were associated with long-term mortality. After adjusting for potential confounders, hypoglycemia during the initial intravenous insulin therapy phase remained associated with mortality (hazard ratio 2.10, 95% CI 1.27-3.46, p = 0.004). CONCLUSIONS: Hypoglycemia during hyperosmolar hyperglycemic crises is a marker of long-term mortality, especially when it occurs during the initial intravenous insulin therapy phase.

Metformin and Glucose Concentration as Limiting Factors in Retinal Pigment Epithelial Cell Viability and Proliferation.

Metformin is a well-established drug for the treatment of type 2 diabetes; however, the mechanism of action has not been well described and many aspects of how it truly acts are still unknown. Moreover, regarding in vitro experiments, the glycaemic status when metformin is used is generally not considered, which, added to the suprapharmacological drug concentrations that are commonly employed in research, has resulted in gaps of its mechanism of action. The aim of this study was to determine how glucose and metformin concentrations influence cell culture. Considering that diabetic retinopathy is one of the most common complications of diabetes, a retinal pigment epithelial cell line was selected, and cell viability and proliferation rates were measured at different glucose and metformin concentrations. As expected, glucose concentration by itself positively influenced cell proliferation rates. When the metformin was considered, results were conditioned, as well, by metformin concentration. This conditioning resulted in cell death when high concentrations of metformin were used under physiological concentrations of glucose, while this did not happen when clinically relevant concentrations of metformin were used independently of glucose status. Our study shows the importance of in vitro cell growth conditions when drug effects such as metformin's are being analysed.

Social services for the elderly: a multivariate perspective study.

Introduction: Today's society is aware that healthy aging favors quality of life in the future, even more so as life expectancy increases in populations such as Europe. As in countries such as Japan, it is necessary for institutions to provide social services to support the elderly, with the aim of achieving an optimal quality of life for these people. The aim of this study is to analyze the different types of social services and activities that certain institutions provide to the elderly in order to find areas for improvement or to propose relationships between them that will benefit both users and institutions. Methods: Official data from Junta de Castilla y León (Spain) on social services for the elderly in the 9 provinces of the autonomous community of Castilla y León from 2007 to 2021 were analysed using multivariate statistical techniques. Results: Throughout the period under analysis, there is an association between the number of places in public and private non-profit residential centers for the elderly and the number of places in day-care centers or the number of students in the Inter-University Experience Programme. The variables associated with the telecare programme are related to the number of people under guardianship. On the other hand, three well-differentiated clusters of provinces of Castilla y León were observed. Discussion: Our findings have implications for the quality of life of the elderly, as the differences in social services in the areas analysed have a direct impact on the health of the elderly.

Prolonged mechanical muscle loading increases mechanosensor gene and protein levels and causes a moderate fast-to-slow fiber type switch in mice.

Mechanosensing and subsequent mechanotransduction are indispensable for muscle plasticity. Nevertheless, a scarcity of literature exists regarding an all-encompassing understanding of the muscle mechanosensing machinery's response to prolonged loading, especially in conditions that resemble a natural physiological state of skeletal muscle. This study aimed to comprehensively explore the effects of prolonged mechanical loading on mechanosensitive components, skeletal muscle characteristics, and metabolism-related gene clusters. Twenty male C57BL/6J mice were randomly divided into two groups: control and prolonged mechanical loading. To induce prolonged mechanical loading on the triceps brachii (TRI) and biceps brachii (BIC) muscles, a 14-day period of tail suspension was implemented. In TRI only, prolonged mechanical loading caused a mild fast-to-slow fiber type shift together with increased mechanosensor gene and protein levels. It also increased transcription factors associated with slow muscle fibers while decreasing those related to fast-type muscle gene expression. Succinate dehydrogenase activity, a marker of muscle oxidative capacity, and genes involved in oxidative and mitochondrial turnover increased, whereas glycolytic-related genes decreased. Moreover, prolonged mechanical loading stimulated markers of muscle protein synthesis. Taken together, our data show a collective muscle-specific increase in mechanosensor gene and protein levels upon a period of prolonged mechanical loading in conditions that reflect a more natural physiological state of skeletal muscle in mice. We provide additional proof-of-concept that prolonged tail suspension-induced loading of the forelimbs triggers a muscle-specific fast-to-slow fiber type switch, and this coincides with increased protein synthesis-related signaling.NEW & NOTEWORTHY This study provides a comprehensive overview of the effects of prolonged loading on mechanosensitive components in conditions that better reflect the natural physiological state of skeletal muscle. Although the muscle mechanosensing machinery has been widely acknowledged for its responsiveness to altered loading, an inclusive understanding of its response to prolonged loading remains scarce. Our results show a fast-to-slow fiber type shift and an upregulation of mechanosensor gene and protein levels following prolonged loading.

Circulating miRNA expression in long-standing type 1 diabetes mellitus.

Type 1 diabetes is a chronic autoimmune disease which results in inefficient regulation of glucose homeostasis and can lead to different vascular comorbidities through life. In this study we aimed to analyse the circulating miRNA expression profile of patients with type 1 diabetes, and with no other associated pathology. For this, fasting plasma was obtained from 85 subjects. Next generation sequencing analysis was firstly performed to identify miRNAs that were differentially expressed between groups (20 patients vs. 10 controls). hsa-miR-1-3p, hsa-miR-200b-3p, hsa-miR-9-5p, and hsa-miR-1200 expression was also measured by Taqman RT-PCR to validate the observed changes (34 patients vs. 21 controls). Finally, through a bioinformatic approach, the main pathways affected by the target genes of these miRNAs were studied. Among the studied miRNAs, hsa-miR-1-3p expression was found significantly increased in patients with type 1 diabetes compared to controls, and positively correlated with glycated haemoglobin levels. Additionally, by using a bioinformatic approach, we could observe that changes in hsa-miR-1-3p directly affect genes involved in vascular development and cardiovascular pathologies. Our results suggest that, circulating hsa-miR-1-3p in plasma, together with glycaemic control, could be used as prognostic biomarkers in type 1 diabetes, helping to prevent the development of vascular complications in these patients.

Physical inactivity by tail suspension alters markers of metabolism, structure, and autophagy of the mouse heart.

Sedentary behavior has become ingrained in our society and has been linked to cardiovascular diseases. Physical inactivity is the main characteristic of sedentary behavior. However, its impact on cardiovascular disease is not clear. Therefore, we investigated the effect of physical inactivity in an established mouse model on gene clusters associated with cardiac fibrosis, electrophysiology, cell regeneration, and tissue degradation/turnover. We investigated a sedentary group (CTR, n = 10) versus a tail suspension group (TS, n = 11) that caused hindlimb unloading and consequently physical inactivity. Through histological, protein content, and transcript analysis approaches, we found that cardiac fibrosis-related genes partly change, with significant TS-associated increases in Tgfb1, but without changes in Col1a1 and Fn1. These changes are not translated into fibrosis at tissue level. We further detected TS-mediated increases in protein degradation- (Trim63, p < 0.001; Fbxo32, p = 0.0947 as well as in biosynthesis-related [P70s6kb1, p < 0.01]). Corroborating these results, we found increased expression of autophagy markers such as Atg7 (p < 0.01) and ULK1 (p < 0.05). Two cardiomyocyte regeneration- and sarcomerogenesis-related genes, Yap (p = 0.0535) and Srf (p < 0.001), increased upon TS compared to CTR conditions. Finally, we found significant upregulation of Gja1 (p < 0.05) and a significant downregulation of Aqp1 (p < 0.05). Our data demonstrate that merely 2 weeks of reduced physical activity induce changes in genes associated with cardiac structure and electrophysiology. Hence, these data should find the basis for novel research directed to evaluate the interplay of cardiac functioning and physical inactivity.

Mechanosensors control skeletal muscle mass, molecular clocks, and metabolism.

BACKGROUND: Skeletal muscles (SkM) are mechanosensitive, with mechanical unloading resulting in muscle-devastating conditions and altered metabolic properties. However, it remains unexplored whether these atrophic conditions affect SkM mechanosensors and molecular clocks, both crucial for their homeostasis and consequent physiological metabolism. METHODS: We induced SkM atrophy through 14 days of hindlimb suspension (HS) in 10 male C57BL/6J mice and 10 controls (CTR). SkM histology, gene expressions and protein levels of mechanosensors, molecular clocks and metabolism-related players were examined in the m. Gastrocnemius and m. Soleus. Furthermore, we genetically reduced the expression of mechanosensors integrin-linked kinase (Ilk1) and kindlin-2 (Fermt2) in myogenic C2C12 cells and analyzed the gene expression of mechanosensors, clock components and metabolism-controlling genes. RESULTS: Upon hindlimb suspension, gene expression levels of both core molecular clocks and mechanosensors were moderately upregulated in m. Gastrocnemius but strongly downregulated in m. Soleus. Upon unloading, metabolism- and protein biosynthesis-related genes were moderately upregulated in m. Gastrocnemius but downregulated in m. Soleus. Furthermore, we identified very strong correlations between mechanosensors, metabolism- and circadian clock-regulating genes. Finally, genetically induced downregulations of mechanosensors Ilk1 and Fermt2 caused a downregulated mechanosensor, molecular clock and metabolism-related gene expression in the C2C12 model. CONCLUSIONS: Collectively, these data shed new lights on mechanisms that control muscle loss. Mechanosensors are identified to crucially control these processes, specifically through commanding molecular clock components and metabolism.

Mental Health in Women Victims of Gender Violence: Descriptive and Multivariate Analysis of Neuropsychological Functions and Depressive Symptomatology.

Female victims of abuse, as well as suffering from psychopathological disorders such as depression, can have neuropsychological sequelae affecting memory and attention, with serious consequences, both physical and psychological, in their daily lives. Therefore, the objective of this study is to analyse these sequelae that affect attention and memory, as well as the possible association of these sequelae to depression. A total of 68 women, victims of gender-based violence, between the ages of 15 and 62 participated in this study. The Luria DNA Battery (Neuropsychological Diagnosis of Adults) by Manga and Ramos (2000); and the Beck Depression Inventory (2011) were applied. It is shown that female victims of gender-based violence present poor short-term memory, attentional control, and score low on the Luria-DNA battery. Of these women, 60% suffer from some relevant type of depression. Through HJ-Biplot analysis, a direct relationship was found between memory and attentional control with the total score of the Luria battery. However, an inverse relationship was found between short-term memory and depression. In addition, three well-differentiated clusters of female victims of gender-based violence were identified. It is concluded that a lower rate of depression is observed in female victims of abuse when they have a more intact short-term memory.

Functional analysis of Arabidopsis immune-related MAPKs uncovers a role for MPK3 as negative regulator of inducible defences.

BACKGROUND: Mitogen-activated protein kinases (MAPKs) are key regulators of immune responses in animals and plants. In Arabidopsis, perception of microbe-associated molecular patterns (MAMPs) activates the MAPKs MPK3, MPK4 and MPK6. Increasing information depicts the molecular events activated by MAMPs in plants, but the specific and cooperative contributions of the MAPKs in these signalling events are largely unclear. RESULTS: In this work, we analyse the behaviour of MPK3, MPK4 and MPK6 mutants in early and late immune responses triggered by the MAMP flg22 from bacterial flagellin. A genome-wide transcriptome analysis reveals that 36% of the flg22-upregulated genes and 68% of the flg22-downregulated genes are affected in at least one MAPK mutant. So far MPK4 was considered as a negative regulator of immunity, whereas MPK3 and MPK6 were believed to play partially redundant positive functions in defence. Our work reveals that MPK4 is required for the regulation of approximately 50% of flg22-induced genes and we identify a negative role for MPK3 in regulating defence gene expression, flg22-induced salicylic acid accumulation and disease resistance to Pseudomonas syringae. Among the MAPK-dependent genes, 27% of flg22-upregulated genes and 76% of flg22-downregulated genes require two or three MAPKs for their regulation. The flg22-induced MAPK activities are differentially regulated in MPK3 and MPK6 mutants, both in amplitude and duration, revealing a highly interdependent network. CONCLUSIONS: These data reveal a new set of distinct functions for MPK3, MPK4 and MPK6 and indicate that the plant immune signalling network is choreographed through the interplay of these three interwoven MAPK pathways.

Salmonella enterica flagellin is recognized via FLS2 and activates PAMP-triggered immunity in Arabidopsis thaliana.

Infections with Salmonella enterica belong to the most prominent causes of food poisoning and infected fruits and vegetables represent important vectors for salmonellosis. Recent evidence indicates that plants recognize S. enterica and raise defense responses. Nonetheless, the molecular mechanisms controlling the interaction of S. enterica with plants are still largely unclear. Here, we show that flagellin from S. enterica represents a prominent pathogen-associated molecular pattern (PAMP) in Arabidopsis thaliana, which induces PAMP-triggered immunity (PTI) via the recognition of the flg22 domain by the receptor kinase FLS2. The Arabidopsis fls2 mutant shows reduced though not abolished PTI activation, indicating that plants rely also on recognition of other S. enterica PAMPs. Interestingly, the S. enterica type III secretion system (T3SS) mutant prgH- induced stronger defense gene expression than wild-type bacteria in Arabidopsis, suggesting that T3SS effectors are involved in defense suppression. Furthermore, we observe that S. enterica strains show variation in the flg22 epitope, which results in proteins with reduced PTI-inducing activity. Altogether, these results show that S. enterica activates PTI in Arabidopsis and suggest that, in order to accomplish plant colonization, S. enterica evolved strategies to avoid or suppress PTI.

An abscisic acid-independent oxylipin pathway controls stomatal closure and immune defense in Arabidopsis.

Plant stomata function in innate immunity against bacterial invasion and abscisic acid (ABA) has been suggested to regulate this process. Using genetic, biochemical, and pharmacological approaches, we demonstrate that (i) the Arabidopsis thaliana nine-specific-lipoxygenase encoding gene, LOX1, which is expressed in guard cells, is required to trigger stomatal closure in response to both bacteria and the pathogen-associated molecular pattern flagellin peptide flg22; (ii) LOX1 participates in stomatal defense; (iii) polyunsaturated fatty acids, the LOX substrates, trigger stomatal closure; (iv) the LOX products, fatty acid hydroperoxides, or reactive electrophile oxylipins induce stomatal closure; and (v) the flg22-mediated stomatal closure is conveyed by both LOX1 and the mitogen-activated protein kinases MPK3 and MPK6 and involves salicylic acid whereas the ABA-induced process depends on the protein kinases OST1, MPK9, or MPK12. Finally, we show that the oxylipin and the ABA pathways converge at the level of the anion channel SLAC1 to regulate stomatal closure. Collectively, our results demonstrate that early biotic signaling in guard cells is an ABA-independent process revealing a novel function of LOX1-dependent stomatal pathway in plant immunity.

Constitutively active mitogen-activated protein kinase versions reveal functions of Arabidopsis MPK4 in pathogen defense signaling.

Plant mitogen-activated protein kinases (MAPKs) are involved in important processes, including stress signaling and development. In a functional yeast screen, we identified mutations that render Arabidopsis thaliana MAPKs constitutively active (CA). Importantly, CA-MAPKs maintain their specificity toward known activators and substrates. As a proof-of-concept, Arabidopsis MAPK4 (MPK4) function in plant immunity was investigated. In agreement with the phenotype of mpk4 mutants, CA-MPK4 plants were compromised in pathogen-induced salicylic acid accumulation and disease resistance. MPK4 activity was found to negatively regulate pathogen-associated molecular pattern-induced reactive oxygen species production but had no impact on callose deposition, indicating that CA-MPK4 allows discriminating between processes regulated by MPK4 activity from processes indirectly affected by mpk4 mutation. Finally, MPK4 activity was also found to compromise effector-triggered immunity conditioned by the Toll Interleukin-1 Receptor-nucleotide binding (NB)-Leu-rich repeat (LRR) receptors RPS4 and RPP4 but not by the coiled coil-NB-LRR receptors RPM1 and RPS2. Overall, these data reveal important insights on how MPK4 regulates plant defenses and establishes that CA-MAPKs offer a powerful tool to analyze the function of plant MAPK pathways.

Role of AGC kinases in plant growth and stress responses.

AGC kinases are important regulators of cell growth, metabolism, division, and survival in mammalian systems. Mutation or deregulation of members of this family of protein kinases contribute to the pathogenesis of many human diseases, including cancer and diabetes. Although AGC kinases are conserved in the plant kingdom, little is known about their molecular functions and targets. Some of the best-studied plant AGC kinases mediate auxin signaling and are thereby involved in the regulation of growth and morphogenesis. Furthermore, certain members are regulated by lipid-derived signals via the 3-phosphoinositide-dependent kinase 1 (PDK1) and the kinase target of rapamycin (TOR), similar to its animal counterparts. In this review, we discuss recent findings on plant AGC kinases that unravel important roles in the regulation of plant growth, immunity and cell death, and connections to stress-induced mitogen-activated protein kinase signaling cascades.