Treatment of a Severe Form of Euglycemic Ketoacidosis in a Patient Treated with SGLT-2 Inhibitors with the Aid of Somatostatin.

Currently, the use of SGLT2 inhibitors is becoming more widespread, both for their role in controlling diabetes, and for their pleiotropic effects on glomerular hyperfiltration and heart failure. Along with their positive effects, these drugs can lead to various complications, the most severe being euglycemic ketoacidosis. The clinical case we have reported precisely describes this potentially serious complication which occurred in a 47-year-old patient who had been on SGLT2 inhibitor therapy for 5 years. In the resolution of this case we used, in addition to standard therapy, the continuous infusion of somatostatin, resulting in a rapid resolution of ketoacidosis and an improvement in the clinical condition.

Insomnia Impairs Both the Pro-BDNF and the BDNF Levels Similarly to Older Adults with Cognitive Decline: An Exploratory Study.

Sleep disorders, including insomnia, are common during aging, and these conditions have been associated with cognitive decline in older adults. Moreover, during the aging process, neurotransmitters, neurohormones, and neurotrophins decrease significantly, leading to the impairment of cognitive functions. In this sense, BDNF, the most abundant neurotrophic factor in the human brain, has been suggested as a potential target for the prevention and improvement of cognitive decline during aging; however, the current evidence demonstrates that the exogenous administration of BDNF does not improve cognitive function. Hence, in the present study, we quantified pro-BDNF (inactive) and BDNF (active) concentrations in serum samples derived from older individuals with insomnia and/or cognitive decline. We used linear regression to analyze whether clinical or sociodemographic variables impacted the levels of BNDF concentration. We observed that insomnia, rather than cognitive decline, is significantly associated with BDNF concentration, and these effects are independent of other variables. To our knowledge, this is the first study that points to the impact of insomnia on improving the levels of BDNF during aging and suggests that opportune treatment of insomnia may be more beneficial to prevent cognitive decline during aging.

Tibolone Improves Memory and Decreases the Content of Amyloid-ß Peptides and Tau Protein in the Hippocampus of a Murine Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) affects women more than men and consequently has been associated with menopause. Tibolone (TIB) has been used as a hormone replacement therapy to alleviate climacteric symptoms. Neuroprotective effects of TIB have also been reported in some animal models. OBJECTIVE: This study aimed to assess the effect of TIB on memory and Aß peptides and tau protein content in the hippocampus and cerebellum of transgenic 3xTgAD ovariectomized mice. METHODS: Three-month-old female mice were ovariectomized. Ten days after surgery, animals were divided into four groups: wild-type (WT)+vehicle; WT+TIB (1 mg/kg); 3xTgAD+vehicle; and 3xTgAD+TIB (1 mg/kg). TIB was administered for three months, and memory was evaluated using the object-in-context recognition task. Subsequently, animals were decapitated, and the hippocampus and cerebellum were dissected. Using commercial ELISA kits, these brain structures were homogenized in a PBS buffer for quantifying Aß40 and Aß42 and phosphorylated and total tau.ResultsA long-term memory deficit was observed in the 3xTgAD+vehicle group. In contrast, TIB treatment improved long-term memory in the 3xTgAD+TIB group than those treated with vehicle (p < 0.05). Furthermore, TIB treatment decreased Aß and tau content in the hippocampus of 3xTgAD mice compared to vehicle-treated groups (p < 0.05). No significant changes were observed in the cerebellum. CONCLUSION: Chronic treatment with TIB showed neuroprotective effects and delayed AD neuropathology in the 3xTgAD mice. Our results support hormone replacement therapy with TIB in menopausal women for neuroprotection.

Structural and Pharmacological Network Analysis of miRNAs Involved in Acute Ischemic Stroke: A Systematic Review.

Acute ischemic stroke (AIS) is among the main causes of mortality worldwide. A rapid and opportune diagnosis is crucial to improve a patient's outcomes; despite the current advanced image technologies for diagnosis, their implementation is challenging. MicroRNAs have been recognized as useful as biomarkers since they are specific and stable for characterization of AIS. However, there is still a lack of consensus over the primary miRNAs implicated in AIS. Here, we performed a systematic review of the literature covering from 2015-2021 regarding miRNAs expression during AIS and built structural networks to analyze and identify the most common miRNAs expressed during AIS and shared pathways, genes, and compounds that seem to influence their expression. We identified two sets of miRNAs: on one side, a set that was independent of geographical location and tissue (miR-124, miR-107, miR-221, miR-223, miR-140, miR-151a, miR-181a, miR-320b, and miR-484); and on the other side, a set that was connected (hubs) in biological networks (miR-27b-3p, miR-26b-5p, miR-124-3p, miR-570-3p, miR-19a-3p, miR-101-3p and miR-25-3p), which altered FOXO3, FOXO4, and EP300 genes. Interestingly, such genes are involved in cell death, FOXO-mediated transcription, and brain-derived neurotrophic factor signaling pathways. Finally, our pharmacological network analysis depicted a set of toxicants and drugs related to AIS for the first time.

Macrophage Cx43 Is Necessary for Fibroblast Cytosolic Calcium and Lung Fibrosis After Injury.

Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (MacΔCx43) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages. Furthermore, MacΔCx43 mice had decreased lung fibrosis after bleomycin-induced injury. Interrogating single cell data for human and mouse, we found that P2rx4 was the most highly expressed ATP receptor and calcium channel in lung fibroblasts and that its expression was increased in the setting of fibrosis. Fibroblast-specific deletion of P2rx4 in mice decreased lung fibrosis and collagen expression in lung fibroblasts in the bleomycin model. Taken together, these studies reveal a Cx43-dependent profibrotic effect of lung macrophages and support development of fibroblast P2rx4 as a therapeutic target for lung fibrosis.

IL10 trains macrophage profibrotic function after lung injury.

Cx3cr1+ monocyte-derived macrophages (moMacs) are recruited to tissues after injury and are known to have profibrotic effects, but the cell-cell interactions and specific pathways that regulate this polarization and function are incompletely understood. Here we investigate the role of moMac-derived Pdgfa in bleomycin-induced lung fibrosis in mice. Deletion of Pdgfa with Cx3cr1-CreERT2 decreased bleomycin-induced lung fibrosis. Among a panel of in vitro macrophage polarizing stimuli, robust induction of Pdgfa was noted with IL10 in both mouse and human moMacs. Likewise, analysis of single-cell data revealed high expression of the receptor IL10RA in moMacs from human fibrotic lungs. Studies with IL10-GFP mice revealed that IL10-expressing cells were increased after injury in mice and colocalized with moMacs. Notably, deletion of IL10ra with Csf1r-Cre: IL10ra fl/fl mice decreased both Pdgfa expression in moMacs and lung fibrosis. Taken together, these findings reveal a novel, IL10-dependent mechanism of macrophage polarization leading to fibroblast activation after injury.

Direct Visualization of Vesicle Disassembly and Reassembly Using Photocleavable Dendrimers Elucidates Cargo Release Mechanisms.

Release of cargo molecules from cell-like nanocarriers can be achieved by chemical perturbations, including changes to pH and redox state and via optical modulation of membrane properties. However, little is known about the kinetics or products of vesicle breakdown due to limitations in real-time imaging at nanometer length scales. Using a library of 12 single-single type photocleavable amphiphilic Janus dendrimers, we developed a self-assembling light-responsive dendrimersome vesicle platform. A photocleavable ortho-nitrobenzyl inserted between the hydrophobic and hydrophilic dendrons of amphiphilic Janus dendrimers allowed for photocleavage and disassembly of their supramolecular assemblies. Distinct methods used to self-assemble amphiphilic Janus dendrimers produced either nanometer size small unilamellar vesicles or micron size giant multilamellar and onion-like dendrimersomes. In situ observation of giant photosensitive dendrimersomes via confocal microscopy elucidated rapid morphological transitions that accompany vesicle breakdown upon 405 nm laser illumination. Giant dendrimersomes displayed light-induced cleavage, disassembling and reassembling into much smaller vesicles at millisecond time scales. Additionally, photocleavable vesicles demonstrated rapid release of molecular and macromolecular cargos. These results guided our design of multilamellar particles to photorelease surface-attached proteins, photoinduce cargo recruitment, and photoconvert vesicle morphology. Real-time characterization of the breakdown and reassembly of lamellar structures provides insights on partial cargo retention and informs the design of versatile, optically regulated carriers for applications in nanoscience and synthetic biology.

OXIDATIVE STRESS, TELOMERE LENGTH, AND FRAILTY IN AN OLD AGE POPULATION.

Background: A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. In this field, oxidative stress and telomere length have been suggested as biomarkers of aging. Objective: The objective of the study was to study the association of oxidative stress, telomere length, and frailty in an old age population. Methods: We conducted a cross-sectional study based on 2015 data from 202 members of a cohort of older adults (n = 202; F/M gender ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species were measured by dichlorofluorescein diacetate and lipid peroxidation by malondialdehyde. Telomere length was determined using quantitative polymerase chain reaction with SYBR Green Master Mix. Results: Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress and telomere length or frailty. Conclusions: Telomere length could eventually be used as a marker to differentiate between healthy and unhealthy aging as expressed by frailty phenotype; oxidative stress seemed merely a biological process of aging.

Oxidative stress, telomere length, and frailty in an old age population

Abstract Background A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. In this field, oxidative stress and telomere length have been suggested as biomarkers of aging Objective The objective of the study was to study the association of oxidative stress, telomere length, and frailty in an old age population Methods We conducted a cross-sectional study based on 2015 data from 202 members of a cohort of older adults (n = 202; F/M gender ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species were measured by dichlorofluorescein diacetate and lipid peroxidation by malondialdehyde. Telomere length was determined using quantitative polymerase chain reaction with SYBR Green Master Mix Results Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress and telomere length or frailty Conclusions Telomere length could eventually be used as a marker to differentiate between healthy and unhealthy aging as expressed by frailty phenotype; oxidative stress seemed merely a biological process of aging.

El perímetro de cuello y su relación con los factores de riesgo cardiometabólico en las mujeres / Neck´s perimeter and its relation with the cardiometabolic risk factors in women

RESUMEN Introducción: El perímetro de cuello en la actualidad es una medida útil asociada de manera significativa a la resistencia a la insulina y al riesgo cardiometabólico. Objetivo: Determinar la relación entre el perímetro de cuello y los factores de riesgo cardiometabólico en mujeres de 45 a 60 años de edad. Métodos: Se realizó un estudio en 270 mujeres aparentemente sanas, de 45 a 60 años de edad. Se tomaron medidas antropométricas como peso corporal, índice de masa corporal, perímetro de cintura, perímetro de cuello y el tejido adiposo visceral por bioimpedancia. Se determinaron niveles séricos de glucosa, perfil lipídico (colesterol, triglicéridos, HDL-colesterol, LDL-colesterol), HbA1c, insulina y proteína C reactiva. Resultados: El índice de masa corporal de las participantes fue de 28,2 ± 4,2. Se encontró que 38,1 por ciento de las mujeres presentaban síndrome metabólico y mayor perímetro de cuello, en comparación con las participantes sin síndrome (36,8 + 2,1 vs 35,1 + 1,6 cm, respectivamente, p< 0,0001). El perímetro de cuello se asoció positivamente con índice de masa corporal (r= 0,690, p= 0,0001), tejido adiposo visceral (r= 0,548, p= 0,0001), circunferencia de Cintura (r= 0,640, p< 0,0001), glucosa (r= 0,251, p= 0,0001), triglicéridos (r= 0,143, p= 0,019), HbA1c (r= 0,160, p= 0,010) y proteína C reactiva (r= 0,342, p= 0,001). Conclusiones: Las mujeres con incremento en el perímetro de cuello presentan un perfil de riesgo cardiometabólico aumentado. La medición del perímetro de cuello representa un método útil y práctico en la predicción del riesgo cardiometabólico(AU)

ABSTRACT Introduction: Neck´s perimeter is nowadays a useful measure significantly associated to insulin resistance and to cardiometabolic risk. Objective: To determine the relation between the neck´s perimeter and the cardiometabolic risk factors in women from 45 to 60 years old. Methods: A study was performed in 270 apparently healthy women, aging 45 to 60 years old. Anthropometric measurements were taken such as weight, body mass index, waist circumference, neck´s perimeter and visceral adipose tissue by bioelectrical impedance analysis. There were identified serum levels of glucose, lipid profile (cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol), HbA1c, insulin and C-reactive protein. Results: The body mass index of the participants was 28.2 ± 4.2. It was found that 38.1 percent of the women had a metabolic syndrome and a higher perimeter of neck, in comparison with participants without the syndrome (36.8 + 2.1 vs 35.1 + 1.6 cm, respectively, p< 0.0001). The neck´s perimeter was positively associated with body mass index (r = 0.690, p= 0.0001), visceral adipose tissue (r = 0.548, p= 0.0001), waist circumference (r = 0.640, p< 0.0001), glucose (r = 0.251, p= 0.0001), triglycerides (r = 0.143, p = 0.019), HbA1c (r = 0.160, p = 0.010) and C-reactive protein (r = 0.342, p = 0.001). Conclusions: Women with an increase in the neck´s perimeter have a profile of increased cardiometabolic risk. The measurement of neck´s perimeter represents a useful and practical method for the prediction of cardiometabolic risk(AU)

Soluble Intercellular Adhesion Molecule-1 (sICAM-1) as a Biomarker of Vascular Cognitive Impairment in Older Adults.

BACKGROUND: Endothelial dysfunction and subsequent inflammation contribute to the development of vascular cognitive impairment (VCI). Soluble intercellular adhesion molecule-1 (sICAM-1) is upregulated in endothelial dysfunction and promotes an inflammatory response; however, the relationship between sICAM-1 and VCI remains equivocal. OBJECTIVE: To determine whether sICAM-1 contributes to the prediction of VCI. METHODS: Community-dwelling older adults (n = 172) from the "Cohort of Obesity, Sarcopenia and Frailty of Older Mexican Adults" (COSFOMA) study were identified as VCI or controls using standard neuropsychological evaluations and neuroimaging. sICAM-1 was quantified using ELISA, and multivariate logistic regression determined the association between sICAM-1 and VCI. RESULTS: A total of 31 VCI cases were identified. sICAM-1 was higher in VCI (VCI: 450.7 [241.6] ng/mL vs. controls: 296.9 [140.9] ng/mL). sICAM-1 concentrations above the 90th percentile (464.1 ng/mL) were associated with VCI group membership in all models (OR: 6.9, 95% CI: 1.1-42.2). The final saturated model explained 64% of the variance in VCI group membership. CONCLUSION: High concentrations of sICAM-1 are independently associated with VCI group membership. Efforts to further characterize the relationship between indices of endothelial dysfunction and pathological changes to the aging brain should be further pursued.

Encapsulation of hydrophobic components in dendrimersomes and decoration of their surface with proteins and nucleic acids.

Reconstructing the functions of living cells using nonnatural components is one of the great challenges of natural sciences. Compartmentalization, encapsulation, and surface decoration of globular assemblies, known as vesicles, represent key early steps in the reconstitution of synthetic cells. Here we report that vesicles self-assembled from amphiphilic Janus dendrimers, called dendrimersomes, encapsulate high concentrations of hydrophobic components and do so more efficiently than commercially available stealth liposomes assembled from phospholipid components. Multilayer onion-like dendrimersomes demonstrate a particularly high capacity for loading low-molecular weight compounds and even folded proteins. Coassembly of amphiphilic Janus dendrimers with metal-chelating ligands conjugated to amphiphilic Janus dendrimers generates dendrimersomes that selectively display folded proteins on their periphery in an oriented manner. A modular strategy for tethering nucleic acids to the surface of dendrimersomes is also demonstrated. These findings augment the functional capabilities of dendrimersomes to serve as versatile biological membrane mimics.

Telomere shortening and frailty in Mexican older adults.

AIM: Telomere shortening has been associated with several age-related diseases, in addition to being considered a hallmark of aging. Frailty is a clinical syndrome characterized by an accentuated physiological and functional decline that might be a predictor of an adverse condition in older age. The present study evaluated the relationship between frailty and telomere shortening in older adults from Mexico City, Mexico. METHODS: This was a cross-sectional study. Data were collected from 323 frail older adults, including physical and environmental factors, such as body mass index, comorbidities, physical activity and tobacco consumption. Telomere length was measured by real-time polymerase chain reaction. The frailty syndrome was diagnosed using the Fried criteria. RESULTS: An association between frailty and telomere shortening was found in both sexes. Telomere length decreased from 6.05 kb (5.54-6.48 kb) to 4.20 kb (3.80-4.54 kb; P < 0.001). It was also observed that tobacco consumption could be a significant modifying factor in the association between these two variables. Previous reports are contradictory, suggesting that there is no relationship between telomere length and frailty; however, it is possible that there are genetic and/or environmental variables to be elucidated, that might influence this association, particularly in the studied population. CONCLUSIONS: Telomere length is inversely related to frailty in Mexican frail older adults, and tobacco consumption is the main environmental modifying factor. Geriatr Gerontol Int 2018; 18: 1286-1292.

Oxidative stress in the elderly with diabetes mellitus or hypertension / Estrés oxidativo en adultos mayores con diabetes mellitus o hipertensión arterial

Background: Mexico City has the highest aging rate in the country, as well as a high prevalence of diabetes mellitus (DM) and hypertension (HT). It is known that each one of these conditions increase oxidative stress (OS) independently. Methods: With this study we described changes in OS of 18 patients without DM or HT (controls), 12 with DM, 23 with HT, and 18 with DM and HT, all of them members of the COSFAMM (Cohorte de Obesidad, Sarcopenia y Fragilidad en Adultos Mayores de México). OS was measured by the quantification of reactive oxygen species (ROS), by the oxidation of diclorofluorosceine, and by determination of lipid peroxidation by product malondialdehyde (MDA). Results: HT patients showed increased ROS levels, as did men with HT compared with the respective DM and HT groups. Also, women of control group showed higher levels of ROS compared with men. Conclusions: Generally, HT turned out to be the most influential factor for the increase of oxidative stress in the elderly while DM has no effect whatsoever.

Introducción: la Ciudad de México tiene el mayor índice de envejecimiento del país, así como una alta prevalencia de diabetes mellitus (DM) e hipertensión arterial (HTA). Se sabe que cada una de estas condiciones incrementa el estrés oxidativo (EO) de forma independiente. Métodos: en este estudio describimos los cambios en el EO de 18 pacientes sin DM ni HTA (controles), 12 con DM, 23 con HTA y 18 con DM y HTA, todos miembros de la Cohorte de Obesidad, Sarcopenia y Fragilidad en Adultos Mayores de México (COSFAMM). El EO fue medido por la cuantificación de especies reactivas de oxígeno (ERO) por la oxidación de la diclorofluorosceína (DCFH) y por determinación de peroxidación de lípidos por producto malondialdehído (MDA). Resultados: los pacientes con HTA mostraron niveles de ERO elevados, así como los hombres con HTA, comparados con los grupos correspondientes de DM y HTA. Asimismo, las mujeres del grupo control mostraron mayor cantidad de ERO que los hombres. Conclusiones: en general, la HTA en el adulto mayor resultó ser el factor que mayor contribución tiene en el incremento del estrés oxidativo, mientras que la DM no tiene efecto alguno.

Ethylene-producing bacteria that ripen fruit.

Ethylene is a plant hormone widely used to ripen fruit. However, the synthesis, handling, and storage of ethylene are environmentally harmful and dangerous. We engineered E. coli to produce ethylene through the activity of the ethylene-forming enzyme (EFE) from Pseudomonas syringae. EFE converts a citric acid cycle intermediate, 2-oxoglutarate, to ethylene in a single step. The production of ethylene was placed under the control of arabinose and blue light responsive regulatory systems. The resulting bacteria were capable of accelerating the ripening of tomatoes, kiwifruit, and apples.

Multiphase water-in-oil emulsion droplets for cell-free transcription-translation.

The construction of genetically encoded cellular mimics in compartments containing organized synthetic cytosols is desirable for the development of artificial cells. Phase separated aqueous domains were placed within water-in-oil emulsion droplets in a manner compatible with transcription and translation machinery. Aqueous two-phase and three-phase systems (ATPS and A3PS) were assembled with dextran, poly(ethylene glycol), and Ficoll. Aqueous two-phase systems were capable of supporting the cell-free expression of protein within water droplets, whereas the aqueous three-phase-based system did not give rise to detectable protein synthesis. The expressed protein preferentially partitioned to the dextran-enriched phase. The system could serve as a foundation for building cellular mimics with liquid organelles.

Tolerability and toxicological profile of pixantrone (Pixuvri®) in juvenile mice. Comparative study with doxorubicin.

The tolerability of pixantrone dimaleate (Pixuvri(®)), an aza-anthracenedione for non-Hodgkin lymphoma, was assessed in juvenile mice after intraperitoneal injection. Twenty animals/sex/dose received pixantrone 15 or 27 mg/kg/day on Post-Natal-Days (PND) 10, 13, 17, 20, 35, 39 and 42 in comparison with doxorubicin, 3 mg/kg/day. Animals were sacrificed on PND 42, 73 and 96. All pixantrone animals survived, while doxorubicin induced 52.5% mortality and the surviving animals were sacrificed early due to severe toxicity. Recoverable bone marrow toxicity (pixantrone), and toxicity to thymus and reproductive organs (pixantrone, doxorubicin) were observed without nephro- or hepatotoxicity. Pixantrone was measurable in plasma up to 2h (occasionally 6h) post-dose. At PND 42, mean Cmax and AUC values increased proportionally with dose, without gender difference or accumulation. Pixantrone showed minimal cardiotoxicity in males and negligible in females at PND 96. Doxorubicin induced significant heart weight reduction at PND 42, however early sacrifice impeded further cardiac assessments.

The encapsulation of cell-free transcription and translation machinery in vesicles for the construction of cellular mimics.

As interest shifts from individual molecules to systems of molecules, an increasing number of laboratories have sought to build from the bottom up cellular mimics that better represent the complexity of cellular life. To date there are a number of paths that could be taken to build compartmentalized cellular mimics, including the exploitation of water-in-oil emulsions, microfluidic devices, and vesicles. Each of the available options has specific advantages and disadvantages. For example, water-in-oil emulsions give high encapsulation efficiency but do not mimic well the permeability barrier of living cells. The primary advantage of the methods described herein is that they are all easy and cheap to implement. Transcription-translation machinery is encapsulated inside of phospholipid vesicles through a process that exploits common instrumentation, such as a centrifugal evaporator and an extruder. Reactions are monitored by fluorescence spectroscopy. The protocols can be adapted for recombinant protein expression, the construction of cellular mimics, the exploration of the minimum requirements for cellular life, or the assembly of genetic circuitry.

Apathy: a complex symptom specific to the clinical pattern of presentation of Parkinson's disease?

There is currently no consensus on the nosological position of apathy in clinical practice, although many different articles indicate that apathy is a common, behavioral disturbance in the general Parkinson's disease (PD) population, often related to severe motor symptoms, hypothesizing that the dysfunction of the nigrostriatal pathway may play an important role in its pathophysiology. However, not all patients with PD become apathetic, indicating that apathy should not entirely be considered a dopamine-dependent syndrome in PD. The aim of this study was to examine the prevalence and clinical correlates of apathy in a representative community-based sample of patients within 2 variants of the PD: akinetic-rigid type and tremor-dominant type. Specifically, we wanted to investigate whether these 2 variants of PD would present with apathy as a primary behavioral disorder and whether apathy could be associated with different cognitive and behavioral disorders. Apathy is present in both the groups but significantly more evident in the akinetic-rigid group associated with frontal impairment but not related to motor impairment or depression. We discuss the results, starting with anatomical and physiological brain studies.