Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells.

BACKGROUND: Standard therapy for acute promyelocytic leukaemia (APL) includes retinoic acid (all-trans retinoic acid (ATRA)), which promotes differentiation of promyelocytic blasts. Although co-administration of arsenic trioxide (ATO) with ATRA has emerged as an effective option to treat APL, the molecular basis of this effect remains unclear. METHODS: Four leukaemia cancer human models (HL60, THP-1, NBR4 and NBR4-R2 cells) were treated either with ATO alone or ATO plus ATRA. Cancer cell survival was monitored by trypan blue exclusion and DEVDase activity assays. Gene and protein expression changes were assessed by RT-PCR and western blot. RESULTS: ATO induced an antioxidant response characterised by Nrf2 nuclear translocation and enhanced transcription of downstream target genes (that is, HO-1, NQO1, GCLM, ferritin). In cells exposed to ATO plus ATRA, the Nrf2 nuclear translocation was prevented and cytotoxicity was enhanced. HO-1 overexpression reversed partially the cytotoxicity by ATRA-ATO in HL60 cells. The inhibitory effects of ATRA on ATO-mediated responses were not observed in either the ATRA-resistant NB4-R2 cells or in NB4 cells pre-incubated with the RARα antagonist Ro-41-52-53. CONCLUSIONS: The augmented cytotoxicity observed in leukaemia cells following combined ATO-ATRA treatment is likely due to inhibition of Nrf2 activity, thus explaining the efficacy of combined ATO-ATRA treatment in the APL therapy.

[Development and validation of a clinical predictive model for delirium in hospitalized older people]. / Riesgo de delirium durante la hospitalización en personas mayores: desarrollo y validación de un modelo de predicción clínica.

BACKGROUND: Delirium is a prevalent problem among older patients and it is frequently underdiagnosed. AIM: To develop and validate a clinical predictive model to identify patients at high risk of delirium. MATERIAL AND METHODS: Two consecutive prospective cohort studies were used to develop and validate the model. The development cohort included 542 consecutive medical inpatients, 65 years or older. The validation cohort included 85 comparable patients. A predictive score was constructed with a multivariate analysis, using variables independently associated with delirium and subsequently tested in the new cohort. Patients were assessed within the first 48 hours of admission, and every 48 hours thereafter, using the Confusion Assessment Method to diagnose delirium, evaluating also the severity of underlying disease, comorbidities, functionality, and laboratory data. RESULTS: Delirium occurred in 192 patients (35.4%) of the development cohort and was independently associated with age and functional status assessed using the Barthel Index. With these two variables, the predictive score for delirium was developed and tested rendering an area under the receiver operating characteristic (ROC) of 0.80 (confidence intervals 0.77-0.85). Cut-off points were chosen to establish low, intermediate, and high-risk groups for delirium. According to these cut-off points, delirium frequencies in the development cohort were 8%, 23%, and 69%, and in the validation cohort 5%, 34%, and 66%, respectively (c² p<0.05). CONCLUSIONS: This simple predictive model based on age and functional status may be a useful tool for identifying older patients risking delirium.

Antiproliferative effects of phenylaminonaphthoquinones are increased by ascorbate and associated with the appearance of a senescent phenotype in human bladder cancer cells.

Quinone-containing molecules have been developed against cancer mainly for their redox cycling ability leading to reactive oxygen species (ROS) formation. We have previously shown that donor-acceptor phenylaminonaphthoquinones are biologically active against a panel of cancer cells. In this report, we explored the mechanisms involved in cancer cell growth inhibition caused by two phenylaminonaphthoquinones, namely Q7 and Q9, with or without ascorbate (ASC). The results show that Q7 and Q9 are both redox cyclers able to form ROS, which strongly inhibit the proliferation of T24 cells. Q9 was a better redox cycler than Q7 because of marked stabilization of the semiquinone radical species arising from its reduction by ascorbate. Indeed, ASC dramatically enhances the inhibitory effect of Q9 on cell proliferation. Q9 plus ASC impairs the cell cycle, causing a decrease in the number of cells in the G2/M phase without involving other cell cycle regulating key proteins. Moreover, Q9 plus ASC influences the MAPK signaling pathways, provoking the appearance of a senescent cancer cell phenotype and ultimately leading to necrotic-like cell death. Because cellular senescence limits the replicative capacity of cells, our results suggest that induction of senescence may be exploited as a basis for new approaches to cancer therapy.

Counselling and self-management therapies for temporomandibular disorders: a systematic review.

The aim of this review was to investigate the effectiveness of counselling and other self-management-based therapies on muscle and temporomandibular joint (TMJ) pain relief and increasing the functional abilities of patients with temporomandibular disorders (TMD). A systematic literature review was conducted by three independent reviewers and included articles published up to 2012. PubMed and Cochrane Library electronic databases were used in addition to hand-searching to assess clinical outcomes for counselling and self-management approaches for TMD treatment. The review yielded 581 records that were narrowed down to 7. All included studies were classified as blind-randomized controlled clinical trials. The selected articles analysed revealed that counselling was able to improve tenderness upon masticatory muscle palpation and maximum mouth opening with and without pain in patients with TMD, with similar results to those of interocclusal appliances approaches. Thus, counselling- and self-management-based therapies could be considered a conservative low-cost and beneficial treatment alternative for treating TMD to potentially improve psychological domains and remove harmful behaviours for the control of the signs and symptoms of TMD.

Gut microbiota-derived propionate reduces cancer cell proliferation in the liver.

BACKGROUND: Metabolites released by the gut microbiota may influence host metabolism and immunity. We have tested the hypothesis that inulin-type fructans (ITF), by promoting microbial production of short-chain fatty acids (SCFA), influence cancer cell proliferation outside the gut. METHODS: Mice transplanted with Bcr-Abl-transfected BaF3 cells, received ITF in their drinking water. Gut microbiota was analysed by 16S rDNA polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and qPCR. Serum Short-chain fatty acids were quantified by UHPLC-MS. Cell proliferation was evaluated in vivo, by molecular biology and histology, and in vitro. RESULTS: Inulin-type fructans treatment reduces hepatic BaF3 cell infiltration, lessens inflammation and increases portal propionate concentration. In vitro, propionate reduces BaF3 cell growth through a cAMP level-dependent pathway. Furthermore, the activation of free fatty acid receptor 2 (FFA2), a Gi/Gq-protein-coupled receptor also known as GPR43 and that binds propionate, lessens the proliferation of BaF3 and other human cancer cell lines. CONCLUSION: We show for the first time that the fermentation of nutrients such as ITF into propionate can counteract malignant cell proliferation in the liver tissue. Our results support the interest of FFA2 activation as a new strategy for cancer therapeutics. This study highlights the importance of research focusing on gut microbes-host interactions for managing systemic and severe diseases such as leukaemia.

Inhibition of cell proliferation and migration by oxidative stress from ascorbate-driven juglone redox cycling in human bladder-derived T24 cells.

The effects of juglone on T24 cells were assessed in the presence and absence of ascorbate. The EC(50) value for juglone at 24 h decreased from 28.5 µM to 6.3 µM in the presence of ascorbate. In juglone-treated cells, ascorbate increased ROS formation (4-fold) and depleted GSH (65%). N-acetylcysteine or catalase restricted the juglone/ascorbate-mediated effects, highlighting the role of oxidative stress in juglone cytotoxicity. Juglone alone or associated with ascorbate did not cause caspase-3 activation or PARP cleavage, suggesting necrosis-like cell death. DNA damage and the mild ER stress caused by juglone were both enhanced by ascorbate. In cells treated with juglone (1-5 µM), a concentration-dependent decrease in cell proliferation was observed. Ascorbate did not impair cell proliferation but its association with juglone led to a clonogenic death state. The motility of ascorbate-treated cells was not affected. Juglone slightly restricted motility, but cells lost their ability to migrate most noticeably when treated with juglone plus ascorbate. We postulate that juglone kills cells by a necrosis-like mechanism inhibiting cell proliferation and the motility of T24 cells. These effects are enhanced in the presence of ascorbate.

Finger retronychias detected early by 3D ultrasound examination.

BACKGROUND: A new pattern of ingrown nail, called retronychia is involved in the posterior translation of the whole nail unit producing paronychia. OBJECTIVE: To demonstrate an unusual case of paronychia that affected three of the fingers on the right hand. METHODS: We used 3D ultrasound to study the whole nail unit in the fingers of both the affected (right) and non affected (left) hand. RESULTS: Backward motion of the nail unit with decreased distance between the origin of the nail plates and the distal interphalangeal joint was clearly demonstrated by 3D ultrasound in the affected fingers. CONCLUSION: 3D ultrasound provides non invasive and more understandable information about the physiopathological changes in retronychia.

A structural study of the self-association of different starches in presence of bacterial cellulose fibrils.

A multi-analytical study was performed to analyse the effect of bacterial cellulose (BCF) on the self-association of starches with different amylose content (wheat, waxy-maize), assessing macrostructural properties (rheology, gel strength) and some nano and sub-nano level features (small and wide-angle X-ray scattering). Although pasting viscosities and G' were significantly increased by BCF in both starches, cellulose did not seem to promote the self-association of amylose in short-range retrogradation. A less elastic structure was reflected by a 2-3-fold increase in loss factor (G″/G') at the highest BCF concentration tested. This behavior agreed with the nano and sub-nano characterisation of the samples, which showed loss of starch lamellarity and incomplete full recovery of an ordered structure after storage at 4 °C for 24 h. The gel strength data could be explained by the contribution of BCF to the mechanical response of the sample. The information gained in this work is relevant for tuning the structure of tailored starch-cellulose composites.

[Management of communication between inpatients isolated due to COVID-19 and their families]. / Gestión de la comunicación de los pacientes hospitalizados, aislados con sus familias por la COVID-19.

BACKGROUND AND GOAL: Quality of healthcare has been affected by the current dimensions of the COVID-19 pandemic and the strict hospital isolation to which some inpatients have been subjected. Therefore, we propose to describe the process designed to facilitate the communication of inpatients with their families to detect their needs and perform individualized treatments in each case. METHOD: Qualitative study with action research methodology, responding to the following algorithm: plan the action, diagnosis of the need and hypothesis-action; apply the action, creation of the group of case managers and training of the members; observe the action, collect and analyse the information. During the month of April 2020. RESULTS: 1,754 interactions were undertaken, that affected 490 inpatients. Case Managers made 767 calls, to provide information about admissions (71.45%), changes in inpatient location or operation of units (18.84%), among others. One thousand and ninety-eight calls from family members were received requesting medical information (43.8%), to talk to inpatients (18.48%), to deliver personal articles or manage lost objects (12.84%), and seeking information about patient location or medical discharge (10.20%). Sixty-six percent of the requests were solved by Case Managers, 30% were referred on and 4% could not be solved. CONCLUSIONS: Implementation of the Case Manager Group contributed to encourage communication of inpatients isolated due to COVID-19 with their families, responding to needs raised, improving quality of care and promoting humanization of care.

Evaluation of minimum interdental threshold ability in dentate female temporomandibular disorder patients.

Minimum interdental threshold is the smallest thickness that can be detected between teeth during an occlusion and has an influence on the occlusal force and on the control of mandibular movements. The aim of this study was to assess the possible association of the signs and symptoms of temporomandibular disorders (TMD) with the ability to detect a minimum interdental threshold. Two hundred women were equally divided into four groups: asymptomatic (control), subjects with masticatory muscle pain, with articular [temporomandibular joint (TMJ)] pain and mixed (muscular and articular pain). Evaluation of the ability to detect a minimum interdental threshold was performed using aluminium foils with 0.010, 0.024, 0.030, 0.050, 0.080 and 0.094 mm of thickness in the premolar region. A total of 20 tests with each thickness for each patient were performed, starting with the thickest foil (0.094 mm) and ending with the thinnest one. The myogenic pain and articular groups presented significantly higher threshold values (0.020 and 0.022 mm, respectively), when compared to the control. Both groups reached the level of certain perceptiveness only at 0.030 mm. No significant correlation was found between minimum interdental threshold and age. These results suggest that discrimination of thicknesses can be disturbed as a consequence of TMD manifestations and not the cause of it. Clinicians should, therefore, be aware that changes on muscles and TMJ can secondarily lead to occlusion changes. The mechanisms involved in this process, however, are not well understood and warrant further investigation.

In situ modulation of oxidative stress: a novel and efficient strategy to kill cancer cells.

Cancer cells show an up-regulation of glycolysis, they readily take up vitamin C, and they appear more susceptible to an oxidative stress than the surrounding normal cells. Here we compare, analyse and discuss these particular hallmarks by performing experiments in murine hepatomas (TLT cells) and freshly isolated mouse hepatocytes. The results show that rates of lactate formation are higher in TLT cells as compared to mouse hepatocytes, but their ATP content represents less than 25% of that in normal cells. The uptake of vitamin C is more important in hepatoma cells as compared to normal hepatocytes. This uptake mainly occurs through GLUT1 transporters. Hepatoma cells have less than 10% of antioxidant enzyme activities as compared to normal hepatocytes. This decrease includes not only the major antioxidant enzymes, namely catalase, superoxide dismutase and glutathione peroxidase, but also the GSH content. Moreover, catalase is almost not expressed in hepatoma cells as shown by western blot analysis. We explored therefore a selective exposure of cancer cells to an oxidative stress induced by pro-oxidant mixtures containing pharmacological doses of vitamin C and a redox active compound such as menadione (vitamin K(3)). Indeed, the combination of vitamin C (which accumulates in hepatoma cells) and a quinone undergoing a redox cycling (vitamin K(3)) leads to an oxidative stress that kills cancer cells in a selective manner. This differential sensitivity between cancer cells and normal cells may have important clinical applications, as it has been observed with other pro-oxidants like Arsenic trioxide, isothiocyanates, Adaphostin.

The effect of ageing on cytochrome p450 enzymes: consequences for drug biotransformation in the elderly.

Ageing is an aggravating factor leading to alterations in the biotransformation of drugs, and therefore their therapeutic efficacy and safety. In this review we discuss the influence of ageing on drug metabolizing enzymes in male Wistar rats. We report that drug metabolizing enzymes can be affected by ageing either by post-translational modifications or by transcriptional modifications. The post-translational modifications could be due to an increase of oxidative stress during ageing. Although it is now well established that transcriptional modifications are due to a change in the GH secretion profile in senescent rats, the intracellular mechanisms underlying these modifications are still unclear. In addition to the strong decrease in the activity of the main CYPs of male rats, we discuss the potential consequences on human drug metabolism in the elderly.

Hospital at home for acute respiratory patients.

BACKGROUND: The issue of "hospital at home" (HAH) for acute respiratory patients is one that is still being debated, partly because economic, cultural and health service differences between locations imply that HAH schemes need to be tailored to local situations. The aim of the present study was to analyze the feasibility and effectiveness of HAH for patients with acute respiratory disease at our institution. METHODS: Of all the patients admitted to our institution via the emergency department during a 34-day subject enrollment period, 25 with diagnoses of respiratory infection, pneumonia, pulmonary insufficiency or exacerbated chronic obstructive pulmonary disease who were living within 25 km of our center and who were willing to receive HAH care were assigned to HAH. Fifty sex-matched controls with the same diagnoses were given conventional hospital care (CHC) as inpatients. The dependent variables evaluated included time to discharge, readmissions within 3 months and deaths within 3 months. RESULTS: There were no significant differences between the HAH and CHC groups with regard to age, diagnoses, physical and analytical findings, or co-morbidity, or with regard to deaths (HAH 16%, CHC 10%) or readmissions (HAH 17%, CHC 24%). Time to final discharge was significantly shorter for HAH patients (7 days) than for CHC patients (12 days). Some 95% of the HAH patients were satisfied and would choose HAH again. CONCLUSIONS: HAH seems feasible for appropriately selected acute respiratory disease patients presenting in our emergency department. It frees hospital beds for other patients, its readmission and mortality rates are no higher than for conventional hospitalization, and, in general, it is favorably evaluated by patients.

Safety assessment of a traditionally used extract from leaves of Boldoa purpurascens.

ETHNOPHARMACOLOGICAL RELEVANCE: Boldoa purpurascens Cav. (Nyctaginaceae) is a plant species used in traditional medicine in Cuba as a diuretic. AIM OF THE STUDY: The aim of the present investigation was to evaluate the safety profile of a hydroalcoholic extract from leaves of Boldoa purpurascens. MATERIALS AND METHODS: First, an experimental study to assess the oral acute toxicity at a dose of 2000mg/kg body weight of the extract was carried out. Potential genotoxicity of the extract was evaluated using the Ames test and the micronucleus induction assay in mouse bone marrow. In the Ames test a concentration range of 50, 100, 150, 300 and 500µg/plate was tested. In the micronucleus induction assay, doses of 500, 1000 and 2000mg/kg of body weight were tested. For completeness, since the extract contains saponins, the evaluation of the hemolytic activity, ocular and skin irritation were included. RESULTS: No signs or symptoms of toxicity were observed in the oral acute toxicity test (body weight at baseline, seven days and end of the experiment of 236.41±20.07, 256.81±30.44 and 240.02±26.16 respectively for the treated group). The hydroalcoholic extract from the leaves was not mutagenic in the Ames test, and no genotoxicity was observed in the micronucleus assay. A hemolysis test at concentration of 1mg/mL confirmed hemolytic activity, which is not a safety concern since saponins are not absorbed after oral administration. In order to evaluate the percentage of protein denaturation, the ocular irritability index was calculated. The extract was found to be irritating. Finally, skin irritability was evaluated and the irritation index was equal to zero. CONCLUSIONS: Based on the toxicological evaluation of a traditionally used hydroalcoholic extract from the leaves of Boldoa purpurascens we can confirm the safety of its oral use.

Gestión de la comunicación de los pacientes hospitalizados, aislados con sus familias por la COVID-19 / Management of communication between inpatients isolated due to COVID-19 and their families

ANTECEDENTES Y OBJETIVO: La calidad asistencial se ha podido ver afectada por las dimensiones de la pandemia de COVID-19 y el estricto aislamiento hospitalario al que han sido sometidos los pacientes. Por ello, se plantea describir el proceso diseñado para facilitar la comunicación de los pacientes aislados con sus familias, detectar sus necesidades y realizar intervenciones individualizadas. MÉTODO: Estudio cualitativo con metodología de investigación acción, respondiendo al siguiente algoritmo: planificar la acción, diagnóstico de la necesidad e hipótesis-acción; aplicar la acción, creación del grupo de gestores de casos y formación de los miembros; observar la acción, recoger y analizar la información. Durante el mes de abril del 2020. RESULTADOS: Se realizaron 1.754 interacciones que afectaron a 490 pacientes. Los gestores de casos realizaron 767 llamadas dirigidas principalmente a facilitar información sobre el ingreso (71,45%) y cambios de ubicación o funcionamiento de las unidades (18,84%). Recibieron un total de 1.098 llamadas de familiares solicitando: información médica (43,8%), comunicación con los pacientes (18,48%), entrega de enseres personales o gestión de objetos extraviados (12,84%) e información sobre la ubicación del paciente o gestión del alta (10,20%). En el 66% de los casos las llamadas fueron resueltas por los gestores, el 30% fueron derivadas y el 4% fallidas. CONCLUSIONES: La puesta en funcionamiento del grupo de gestores de casos ha contribuido a mejorar la comunicación de los pacientes ingresados y aislados por COVID-19 con sus familias, dando respuesta a las necesidades planteadas, mejorando la calidad asistencial y favoreciendo la humanización en los cuidados

BACKGROUND AND GOAL: Quality of healthcare has been affected by the current dimensions of the COVID-19 pandemic and the strict hospital isolation to which some inpatients have been subjected. Therefore, we propose to describe the process designed to facilitate the communication of inpatients with their families to detect their needs and perform individualized treatments in each case. METHOD: Qualitative study with action research methodology, responding to the following algorithm: plan the action, diagnosis of the need and hypothesis-action; apply the action, creation of the group of case managers and training of the members; observe the action, collect and analyse the information. During the month of April 2020. RESULTS: 1,754 interactions were undertaken, that affected 490 inpatients. Case Managers made 767 calls, to provide information about admissions (71.45%), changes in inpatient location or operation of units (18.84%), among others. One thousand and ninety-eight calls from family members were received requesting medical information (43.8%), to talk to inpatients (18.48%), to deliver personal articles or manage lost objects (12.84%), and seeking information about patient location or medical discharge (10.20%). Sixty-six percent of the requests were solved by Case Managers, 30% were referred on and 4% could not be solved. CONCLUSIONS: Implementation of the Case Manager Group contributed to encourage communication of inpatients isolated due to COVID-19 with their families, responding to needs raised, improving quality of care and promoting humanization of care

In vitro lipid metabolism in the rat pancreas. III. Effects of carbamylcholine and pancreozymin on the turnover of phosphatidylinositols, 1,2-diacylglycerols and phosphatidylcholines.

1. The turnover of phosphatidylinositols and other glycerolipids was examined in rat pancreatic fragments incubated in the presence of carbamylcholine and pancreozymin used at a concentration inducing maximal alpha-amylase hypersecretion. 2. In stimulated tissue, [1-14C]acetate-labeled fatty acids were incorporated into phosphatidylinositols, 1,2-diacylglycerols, and phosphatidic acids in preference to phosphatidylcholines, phosphatidylethanolamines, triacylglycerols, monoacylglycerols, and free fatty acids. Variations in the percent distribution of 14C among fatty acids and in specific activity of individual fatty acids in each lipid class suggested that the secretagogues reduced selection of newly synthesized 1,2-diacylglycerols which occurred in the resting state before their incorporation into phosphatidylinositols. Secretagogues also promoted recycling of endogenous 1,2-diacylglycerols (produced from hydrolysis of unlabeled glycerolipids) for the biosynthesis of phosphatidylinositols. 3. Increased rate of incorporation of [1-14C]palmitate, [1-14C]linoleate, [1-14C]arachidonate and [1(3)(n)-3H]glycerol into phosphatidylinositols was detrimental to phosphatidylcholines. 4. The lipolytic effects of carbamylcholine and pancreozymin as illustrated by the release of 1,2-diacylglycerols and free fatty acids, were markedly inhibited in calcium-free medium enriched with 1 mM EGTA but increased turnover of phosphatidylinositols as determined from incorporation of radioactive precursors was only moderately affected.