Could We Consider Ultrasound-Guided Minimally Invasive Autopsy as a Part of POCUS?

We present a 3-patient case series that support the use of ultrasound guided minimally invasive autopsy (MIA). This technique has a high diagnostic accuracy in specific clinical settings. It makes easier to diagnose pathologies once the patient has died, avoiding body deformation, with a notable reduction in sample processing time compared to the open autopsy study and, therefore, a shorter overall diagnostic response time. MIA shows some similarities with point of care ultrasound (POCUS), like examination protocols or that they can be performed at the bedside.

Top Chief: A Critical Assessment of a Cross-disciplinary Case Study as Common Intellectual Experience.

Common intellectual experiences (CIEs) are one of the lesser-known modalities that have been identified as a high impact practice (HIP) in higher education. This mixed-methods study assesses the outcomes of a short-term CIE, which took the form of a multi-disciplinary, multi-classroom case study focused on Danny Meyer, CEO of Union Square Hospitality group (the titular Top Chief), and his handling of the challenges faced by the hospitality industry under the conditions of the global pandemic. The findings suggest that such CIEs can be effective in fostering integrative thinking both within and across curricula, though the benefits may not accrue equally across all student populations. The study has implications for how universities develop and diversify their HIP portfolios, how faculty implement CIEs in their classrooms, and how students develop their capabilities as wicked problem solvers.

Genomic Surveillance of Yellow Fever Virus Epizootic in São Paulo, Brazil, 2016 - 2018.

São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHPs in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species.

A molecular signature for the metabolic syndrome by urine metabolomics.

BACKGROUND: Metabolic syndrome (MetS) is a multimorbid long-term condition without consensual medical definition and a diagnostic based on compatible symptomatology. Here we have investigated the molecular signature of MetS in urine. METHODS: We used NMR-based metabolomics to investigate a European cohort including urine samples from 11,754 individuals (18-75 years old, 41% females), designed to populate all the intermediate conditions in MetS, from subjects without any risk factor up to individuals with developed MetS (4-5%, depending on the definition). A set of quantified metabolites were integrated from the urine spectra to obtain metabolic models (one for each definition), to discriminate between individuals with MetS. RESULTS: MetS progression produces a continuous and monotonic variation of the urine metabolome, characterized by up- or down-regulation of the pertinent metabolites (17 in total, including glucose, lipids, aromatic amino acids, salicyluric acid, maltitol, trimethylamine N-oxide, and p-cresol sulfate) with some of the metabolites associated to MetS for the first time. This metabolic signature, based solely on information extracted from the urine spectrum, adds a molecular dimension to MetS definition and it was used to generate models that can identify subjects with MetS (AUROC values between 0.83 and 0.87). This signature is particularly suitable to add meaning to the conditions that are in the interface between healthy subjects and MetS patients. Aging and non-alcoholic fatty liver disease are also risk factors that may enhance MetS probability, but they do not directly interfere with the metabolic discrimination of the syndrome. CONCLUSIONS: Urine metabolomics, studied by NMR spectroscopy, unravelled a set of metabolites that concomitantly evolve with MetS progression, that were used to derive and validate a molecular definition of MetS and to discriminate the conditions that are in the interface between healthy individuals and the metabolic syndrome.

Impact of Caffeine on Ethanol-Induced Stimulation and Sensitization: Changes in ERK and DARPP-32 Phosphorylation in Nucleus Accumbens.

BACKGROUND: Caffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)-related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD-1 mice. METHODS: Acute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol-induced (1.5 to 3.5 g/kg) changes in open-field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor-dependent phosphorylation markers were assessed: extracellular signal-regulated kinase (pERK), and dopamine-and cAMP-regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP-32-Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol-sensitized (1.5 g/kg) mice. RESULTS: Acute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol -induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol-induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol-sensitized mice in an ethanol-free state resulted in blunted stimulant effects compared with those seen in ethanol-naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP-32(Thr75) immunoreactivity. CONCLUSIONS: The present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol-sensitized animals.

Highly Discriminative Physiological Parameters for Thermal Pattern Classification.

Infrared Thermography (IRT) is a non-contact, non-intrusive, and non-ionizing radiation tool used for detecting breast lesions. This paper analyzes the surface temperature distribution (STD) on an optimal Region of Interest (RoI) for extraction of suitable internal heat source parameters. The physiological parameters are estimated through the inverse solution of the bio-heat equation and the STD of suspicious areas related to the hottest spots of the RoI. To reach these values, the STD is analyzed by means: the Depth-Intensity-Radius (D-I-R) measurement model and the fitting method of Lorentz curve. A highly discriminative pattern vector composed of the extracted physiological parameters is proposed to classify normal and abnormal breast thermograms. A well-defined RoI is delimited at a radial distance, determined by the Support Vector Machines (SVM). Nevertheless, this distance is less than or equal to 1.8 cm due to the maximum temperature location close to the boundary image. The methodology is applied to 87 breast thermograms that belong to the Database for Mastology Research with Infrared Image (DMR-IR). This methodology does not apply any image enhancements or normalization of input data. At an optimal position, the three-dimensional scattergrams show a correct separation between normal and abnormal thermograms. In other cases, the feature vectors are highly correlated. According to our experimental results, the proposed pattern vector extracted at optimal position a=1.6 cm reaches the highest sensitivity, specificity, and accuracy. Even more, the proposed technique utilizes a reduced number of physiological parameters to obtain a Correct Rate Classification (CRC) of 100%. The precision assessment confirms the performance superiority of the proposed method compared with other techniques for the breast thermogram classification of the DMR-IR.

Enriched Terpenes Fractions of the Latex of Euphorbia umbellata Promote Apoptosis in Leukemic Cells.

The current study was carried out by a bioguided fractionation of a hexane extract of the latex of Euphorbia umbellata against leukemic cells. Samples were analyzed by NMR, GC/MS, triterpenes quantification, and MTT reduction assay. Morphological, cell cycle, mitochondrial membrane potential and caspases 3/7 analyses were performed for the dichloromethane and ethanol fractions, and selectivity index for the dichloromethane fraction. NMR analysis presented characteristic signals of terpenes and steroids, data were confirmed by the quantification of triterpenes and GC/MS analysis. MTT reduction assay demonstrated that HL-60 was the most sensitive cell lineage against dichloromethane and ethanol fractions. Compounds of these matrices caused morphological changes compatible with apoptosis induction, altered cell cycle, increment of depolarized population cells and activation of caspases 3/7. Selectivity indices were higher than 22.44. Bioguided-fractionation study showed that samples of the latex of E. umbellata raised the activity of the phytocomplex against leukemic cells, and the cytotoxicity can be associated with an apoptosis pathway.

Tumor necrosis factor reduces Plasmodium falciparum growth and activates calcium signaling in human malaria parasites.

BACKGROUND: Plasmodium has a complex biology including the ability to interact with host signals modulating their function through cellular machinery. Tumor necrosis factor (TNF) elicits diverse cellular responses including effects in malarial pathology and increased infected erythrocyte cytoadherence. As TNF levels are raised during Plasmodium falciparum infection we have investigated whether it has an effect on the parasite asexual stage. METHODS: Flow cytometry, spectrofluorimetric determinations, confocal microscopy and PCR real time quantifications were employed for characterizing TNF induced effects and membrane integrity verified by wheat germ agglutinin staining. RESULTS: TNF is able to decrease intracellular parasitemia, involving calcium as a second messenger of the pathway. Parasites incubated for 48 h with TNF showed reduced erythrocyte invasion. Thus, TNF induced rises in intracellular calcium concentration, which were blocked by prior addition of the purinergic receptor agonists KN62 and A438079, or interfering with intra- or extracellular calcium release by thapsigargin or EGTA (ethylene glycol tetraacetic acid). Importantly, expression of PfPCNA1 which encodes the Plasmodium falciparum Proliferating-Cell Nuclear Antigen 1, decreased after P. falciparum treatment of TNF (tumor necrosis factor) or 6-Bnz cAMP (N(6)-benzoyladenosine-3',5'-cyclic monophosphate sodium salt). CONCLUSIONS: This is potentially interesting data showing the relevance of calcium in downregulating a gene involved in cellular proliferation, triggered by TNF. GENERAL SIGNIFICANCE: The data show that Plasmodium may subvert the immunological system and use TNF for the control of its proliferation within the vertebrate host.

Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL.

Differentiation of memory cells involves DNA-sequence changes in B lymphocytes but is less clearly defined in T cells. RNA rearrangement is identified here as a key event in memory T cell differentiation by analysis of a mouse mutation that altered the proportions of naive and memory T cells and crippled the process of Ptprc exon silencing needed to generate CD45RO in memory T cells. A single substitution in a memory-induced RNA-binding protein, hnRNPLL, destabilized an RNA-recognition domain that bound with micromolar affinity to RNA containing the Ptprc exon-silencing sequence. Hnrpll mutation selectively diminished T cell accumulation in peripheral lymphoid tissues but not proliferation. Exon-array analysis of Hnrpll mutant naive and memory T cells revealed an extensive program of alternative mRNA splicing in memory T cells, coordinated by hnRNPLL. A remarkable overlap with alternative splicing in neural tissues may reflect a co-opted strategy for diversifying memory T cells.

Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology.

Motivation has been defined as the process that allows organisms to regulate their internal and external environment, and control the probability, proximity and availability of stimuli. As such, motivation is a complex process that is critical for survival, which involves multiple behavioural functions mediated by a number of interacting neural circuits. Classical theories of motivation suggest that there are both directional and activational aspects of motivation, and activational aspects (i.e. speed and vigour of both the instigation and persistence of behaviour) are critical for enabling organisms to overcome work-related obstacles or constraints that separate them from significant stimuli. The present review discusses the role of brain dopamine and related circuits in behavioural activation, exertion of effort in instrumental behaviour, and effort-related decision-making, based upon both animal and human studies. Impairments in behavioural activation and effort-related aspects of motivation are associated with psychiatric symptoms such as anergia, fatigue, lassitude and psychomotor retardation, which cross multiple pathologies, including depression, schizophrenia, and Parkinson's disease. Therefore, this review also attempts to provide an interdisciplinary approach that integrates findings from basic behavioural neuroscience, behavioural economics, clinical neuropsychology, psychiatry, and neurology, to provide a coherent framework for future research and theory in this critical field. Although dopamine systems are a critical part of the brain circuitry regulating behavioural activation, exertion of effort, and effort-related decision-making, mesolimbic dopamine is only one part of a distributed circuitry that includes multiple neurotransmitters and brain areas. Overall, there is a striking similarity between the brain areas involved in behavioural activation and effort-related processes in rodents and in humans. Animal models of effort-related decision-making are highly translatable to humans, and an emerging body of evidence indicates that alterations in effort-based decision-making are evident in several psychiatric and neurological disorders. People with major depression, schizophrenia, and Parkinson's disease show evidence of decision-making biases towards a lower exertion of effort. Translational studies linking research with animal models, human volunteers, and clinical populations are greatly expanding our knowledge about the neural basis of effort-related motivational dysfunction, and it is hoped that this research will ultimately lead to improved treatment for motivational and psychomotor symptoms in psychiatry and neurology.

Shiga Toxin 1-Producing Shigella sonnei Infections, California, United States, 2014-2015.

Shiga toxins (Stx) are primarily associated with Shiga toxin-producing Escherichia coli and Shigella dysenteriae serotype 1. Stx production by other shigellae is uncommon, but in 2014, Stx1-producing S. sonnei infections were detected in California. Surveillance was enhanced to test S. sonnei isolates for the presence and expression of stx genes, perform DNA subtyping, describe clinical and epidemiologic characteristics of case-patients, and investigate for sources of infection. During June 2014-April 2015, we identified 56 cases of Stx1-producing S. sonnei, in 2 clusters. All isolates encoded stx1 and produced active Stx1. Multiple pulsed-field gel electrophoresis patterns were identified. Bloody diarrhea was reported by 71% of case-patients; none had hemolytic uremic syndrome. Some initial cases were epidemiologically linked to travel to Mexico, but subsequent infections were transmitted domestically. Continued surveillance of Stx1-producing S. sonnei in California is necessary to characterize its features and plan for reduction of its spread in the United States.

An external sensing system in Plasmodium falciparum-infected erythrocytes.

BACKGROUND: A number of experiments have previously indicated that Plasmodium falciparum-infected erythrocytes (pRBC) were able to sense host environment. The basis of this ability to detect external cues is not known but in screening signalling molecules from pRBC using commercial antibodies, a 34 kDa phosphorylated molecule that possesses such ability was identified. METHODS: The pRBC were exposed to different culture conditions and proteins were extracted for 1D or 2D gel electrophoresis followed by Western blot. The localization of 34 kDa protein was examined by biochemical fractionation followed by Western blot. High-resolution mass spectrometric analysis of immune precipitants was used to identify this protein and real-time quantitative reverse transcriptase polymerase chain reaction was used for detecting mRNA expression level. RESULTS: The 34 kDa protein was called PfAB4 has immediate responses (dephosphorylation and rapid turnover) to host environmental stimuli such as serum depletion, osmolality change and cytokine addition. PfAB4 is expressed constitutively throughout the erythrocytic lifecycle with dominant expression in trophozoites 30 h post-infection. Tumour necrosis factor (TNF) treatment induced a transient detectable dephosphorylation of PfAB4 in the ItG strain (2 min after addition) and the level of expression and phosphorylation returned to normal within 1-2 h. PfAB4 localized dominantly in pRBC cytoplasm, with a transient shift to the nucleus under TNF stimulation as shown by biochemical fractionation. High-resolution mass spectrometric analysis of immune precipitants of AB4 antibodies revealed a 34 kDa PfAB4 component as a mixture of proliferating cellular nuclear antigen-1 (PCNA1) and exported protein-2 (EXP2), along with a small number of other inconsistently identified peptides. Different parasite strains have different PfAB4 expression levels, but no significant association between mRNA and PfAB4 levels was seen, indicating that the differences may be at the post-transcriptional, presumably phosphorylation, level. A triple serine phosphorylated PCNA1 peptide was identified from the PfAB4 high expression strain only, providing further evidence that the identity of PfAB4 is PCNA1 in P. falciparum. CONCLUSION: A protein element in the human malaria parasite that responds to external cues, including the pro-inflammatory cytokine TNF have been discovered. Treatment results in a transient change in phosphorylation status of the response element, which also migrates from the parasite cytoplasm to the nucleus. The response element has been identified as PfPCNA1. This sensing response could be regulated by a parasite checkpoint system and be analogous to bacterial two-component signal transduction systems.

[Psoas abscess caused by Staphylococcus lugdunensis]. / Absceso de psoas por Staphylococcus lugdunensis.

Staphylococcus lugdunensis is a coagulase-negative staphylococcus of growing importance and atypical behavior. The infections caused by this microorganism are becoming more frequent, having a broader spectrum. Psoas abscesses caused by this germ are rare, with few cases reported in the literature. In this work, we present a case of a psoas abscess caused by S. lugdunensis in a patient suffering from diabetes mellitus and rheumatoid arthritis, which was treated with intravenous cloxacillin with a good outcome.

Investigation of antimalarial activity, cytotoxicity and action mechanism of piperazine derivatives of betulinic acid.

OBJECTIVES: To semisynthesise piperazine derivatives of betulinic acid to evaluate antimalarial activity, cytotoxicity and action mechanism. METHODS: The new derivatives were evaluated against the CQ-sensitive Plasmodium falciparum 3D7 strain by flow cytometry (FC) using YOYO-1 as stain. Cytotoxicity of 4a and 4b was performed with HEK293T cells for 24 and 48 h by MTT assay. The capability of compound 4a to modulate Ca(2+) in the trophozoite stage was investigated. The trophozoites were stained with Fluo4-AM and analysed by spectrofluorimetry. Effect on mitochondrial membrane potential (ΔΨm) was tested for 4a by FC with DiOC6 (3) as stain. For ß-haematin assay, 4a was incubated for 24 h with reagents such as haemin, and the fluorescence was measured by FlexStation at an absorbance of 405 nm. RESULTS: Antimalarial activity of 4a and 4b was IC50 = 1 and 4 µm, respectively. Compound 4a displayed cytotoxicity with IC50 = 69 and 29 µm for 24 and 48 h, respectively, and 4b was not cytotoxic at the tested concentrations. Addition of 4a leads to an increase in cytosolic Ca(2+) . We have measured ΔΨm after treating parasites with the compound. Data on Figure 4a show that mitochondria were not affected. The action mechanism for 4a, inhibition of ß-haematin formation (17%), was lower than CQ treatment (83%; IC50 = 3 mm). CONCLUSION: Compound 4a showed excellent antimalarial activity, and its action mechanism is involved in Ca(2+) pathway(s).

Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: implications for animal models of the motivational symptoms of depression.

Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.

Bupropion increases selection of high effort activity in rats tested on a progressive ratio/chow feeding choice procedure: implications for treatment of effort-related motivational symptoms.

BACKGROUND: Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology. METHODS: Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber. RESULTS: Bupropion (10.0-40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation. CONCLUSION: The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans.

Diagnostic criteria in proliferative verrucous leukoplakia: evaluation.

OBJECTIVES: to evaluate the ability of the diagnostic criteria proposed by Cerero et al in 2010 to perform an early diagnose in patients with proliferative verrucous leukoplakia. STUDY DESIGN: retrospective study with patients diagnosed with leukoplakia at Oral Medicine Service at Oral Medicine and Surgery Department at Dentistry Faculty at Universidad Complutense of Madrid. RESULTS: the criteria were applied in 116 patients, turning positive in 40 cases. Out of these, 24 (60%) had been previously diagnosed with PVL. Most frequent criteria were major criteria A and E, concerning lesion's site and histopathology, and minor criteria b and c, concerning sex and smoking habit. CONCLUSIONS: diagnostic criteria developed by Cerero et al can be a useful tool for an early diagnose of PVL, as in 60% of the cases, the criteria would have allowed to make an early diagnose of the disease.

Refining the study of decision-making in animals: differential effects of d-amphetamine and haloperidol in a novel touchscreen-automated Rearing-Effort Discounting (RED) task and the Fixed-Ratio Effort Discounting (FRED) task.

Effort-based decision-making is impaired in multiple psychopathologies leading to significant impacts on the daily life of patients. Preclinical studies of this important transdiagnostic symptom in rodents are hampered, however, by limitations present in currently available decision-making tests, including the presence of delayed reinforcement and off-target cognitive demands. Such possible confounding factors can complicate the interpretation of results in terms of decision-making per se. In this study we addressed this problem using a novel touchscreen Rearing-Effort Discounting (RED) task in which mice choose between two single-touch responses: rearing up to touch an increasingly higher positioned stimulus to obtain a High Reward (HR) or touching a lower stimulus to obtain a Low Reward (LR). To explore the putative advantages of this new approach, RED was compared with a touchscreen version of the well-studied Fixed Ratio-based Effort Discounting (FRED) task, in which multiple touches are required to obtain an HR, and a single response is required to obtain an LR. Results from dopaminergic (haloperidol and d-amphetamine), behavioral (changes in the order of effort demand; fixed-ratio schedule in FRED or response height in RED), and dietary manipulations (reward devaluation by pre-feeding) were consistent with the presence of variables that may complicate interpretation of conventional decision-making tasks, and demonstrate how RED appears to minimize such variables.

Phenolic-rich extracts from toasted white and tannin sorghum flours have distinct profiles influencing their antioxidant, antiproliferative, anti-adhesive, anti-invasive, and antimalarial activities.

Sorghum is a gluten-free cereal commonly used in foods, and its consumption has been associated with the prevention of human chronic conditions such as obesity and cancer, due to the presence of dietary fiber and phenolic compounds. This study aimed to evaluate, for the first time, the antiproliferative, antioxidant, anti-adhesion, anti-invasion, and antimalarial activities of phenolic extracts from toasted white and tannin sorghum flours to understand how different phenolic profiles contribute to sorghum biological activities. Water and 70 % ethanol/water (v/v), eco-friendly solvents, were used to obtain the phenolic extracts of toasted sorghum flours, and their phenolic profile was analyzed by UPLC-MSE. One hundred forty-five (145) phenolic compounds were identified, with 23 compounds common to all extracts. The solvent type affected the phenolic composition, with aqueous extract of both white sorghum (WSA) and tannin sorghum (TSA) containing mainly phenolic acids. White sorghum (WSE) and tannin sorghum (TSE) ethanolic extracts exhibited a higher abundance of flavonoids. WSE demonstrated the lowest IC50 on EA.hy926 (IC50 = 46.6 µg/mL) and A549 cancer cells (IC50 = 33.1 µg/mL), while TSE showed the lowest IC50 (IC50 = 70.8 µg/mL) on HCT-8 cells (human colon carcinoma). Aqueous extracts also demonstrated interesting results, similar to TSE, showing selectivity for cancer cells at higher IC50 concentrations. All sorghum extracts also reduced the adhesion and invasion of HCT-8 cells, suggesting antimetastatic potential. WSE, rich in phenolic acids and flavonoids, exhibited greater toxicity to both the W2 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) strains of Plasmodium falciparum (IC50 = 8 µg GAE/mL and 22.9 µg GAE/mL, respectively). These findings underscore the potential health benefits of toasted sorghum flours, suggesting diverse applications in the food industry as a functional ingredient or even as an antioxidant supplement. Moreover, it is suggested that, besides the phenolic concentration, the phenolic profile is important to understand the health benefits of sorghum flours.

Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer's model mice.

Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer's disease (AD), also known as "type 3 diabetes". Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, ß-amyloid oligomers, plaques, phosphorylated tau, and GSK3ß expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.