Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Comparative study on nutraceutical and sensorial characteristics of saffron (Crocus sativus L.) cultivated in Iran, Spain, and Türkiye.

BACKGROUND: Quality properties of 14 saffron samples from Iran, Spain, and Türkiye were compared. RESULTS: Significant differences were observed between anthocyanins, volatile compounds, fatty acids, total phenolic content, and antioxidant activity of saffron samples (P < 0.05). Besides, significant differences in color parameters were observed. Moreover, a total of 13 volatile compounds were identified in the saffron samples using. headspace-solid-phase microextraction-gas chromatography-mass spectrometry, safranal and α-isophorone being the two predominant aroma compounds. Regarding fatty acids, significant differences were seen in the fatty acid profiles of saffron samples (P < 0.05), while linoleic acid was the most concentrated fatty acid. In terms of sensory properties, different concentrations of safranal, α-isophorone and 4-ketoisophorone may lead to significant differences in the odor and taste attributes of saffron samples (P < 0.05). CONCLUSION: Changes in corm origin along with climate and agricultural conditions may affect the quality characteristics of saffron cultivated in different geographical areas to a significant degree. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Influence of non-osteoporotic treatments in patients on active anti-osteoporotic therapy: evidence from the OSTEOMED registry.

PURPOSE: To evaluate the effect of different non-osteoporotic drugs on the increase or decrease in the risk of incident fragility fractures (vertebral, humerus or hip) in a cohort of patients diagnosed with osteoporosis on active anti-osteoporotic therapy. METHODS: For this retrospective longitudinal study, baseline and follow-up data on prescribed non-osteoporotic treatments and the occurrence of vertebral, humerus or hip fractures in 993 patients from the OSTEOMED registry were analyzed using logistic regression models. The drugs evaluated with a possible beneficial effect were thiazides and statins, while the drugs evaluated with a possible harmful effect were antiandrogens, aromatase inhibitors, proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, GnRH agonists, thyroid hormones, and oral and inhaled corticosteroids. RESULTS: Logistic regression analyses indicated that no treatment significantly improved fracture risk, with the only treatments that significantly worsened fracture risk being letrozole (OR = 0.18, p-value = 0.03) and oral corticosteroids at doses ≤ 5 mg/day (OR = 0.16, p-value = 0.03) and > 5 mg/day (OR = 0.27, p-value = 0.04). CONCLUSION: The potential beneficial or detrimental effects of the different drugs evaluated on fracture risk are masked by treatment with anabolic or antiresorptive drugs that have a more potent action on bone metabolism, with two exceptions: letrozole and oral corticosteroids. These findings may have important clinical implications, as patients receiving these treatments are not fully protected by bisphosphonates, which may imply the need for more potent anti-osteoporotic drugs such as denosumab or teriparatide.

Functional regeneration of the murine neuromuscular synapse relies on long-lasting morphological adaptations.

BACKGROUND: In a broad variety of species, muscle contraction is controlled at the neuromuscular junction (NMJ), the peripheral synapse composed of a motor nerve terminal, a muscle specialization, and non-myelinating terminal Schwann cells. While peripheral nerve damage leads to successful NMJ reinnervation in animal models, muscle fiber reinnervation in human patients is largely inefficient. Interestingly, some hallmarks of NMJ denervation and early reinnervation in murine species, such as fragmentation and poly-innervation, are also phenotypes of aged NMJs or even of unaltered conditions in other species, including humans. We have reasoned that rather than features of NMJ decline, such cellular responses could represent synaptic adaptations to accomplish proper functional recovery. Here, we have experimentally tackled this idea through a detailed comparative study of the short- and long-term consequences of irreversible (chronic) and reversible (partial) NMJ denervation in the convenient cranial levator auris longus muscle. RESULTS: Our findings reveal that irreversible muscle denervation results in highly fragmented postsynaptic domains and marked ectopic acetylcholine receptor clustering along with significant terminal Schwann cells sprouting and progressive detachment from the NMJ. Remarkably, even though reversible nerve damage led to complete reinnervation after 11 days, we found that more than 30% of NMJs are poly-innervated and around 65% of postsynaptic domains are fragmented even 3 months after injury, whereas synaptic transmission is fully recovered two months after nerve injury. While postsynaptic stability was irreversibly decreased after chronic denervation, this parameter was only transiently affected by partial NMJ denervation. In addition, we found that a combination of morphometric analyses and postsynaptic stability determinations allows discriminating two distinct forms of NMJ fragmentation, stable-smooth and unstable-blurred, which correlate with their regeneration potential. CONCLUSIONS: Together, our data unveil that reversible nerve damage imprints a long-lasting reminiscence in the NMJ that results in the rearrangement of its cellular components. Instead of being predictive of NMJ decline, these traits may represent an efficient adaptive response for proper functional recovery. As such, these features are relevant targets to be considered in strategies aimed to restore motor function in detrimental conditions for peripheral innervation.

Adhesion molecule Amigo2 is involved in the fasciculation process of the fasciculus retroflexus.

BACKGROUND: The fasciculus retroflexus is the prominent efferent pathway from the habenular complex. Medial habenular axons form a core packet whereas lateral habenular axons course in a surrounding shell. Both groups of fibers share the same initial pathway but differ in the final segment of the tract, supposedly regulated by surface molecules. The gene Amigo2 codes for a membrane adhesion molecule with an immunoglobulin-like domain 2 and is selectively expressed in the medial habenula. We present it as a candidate for controlling the fasciculation behavior of medial habenula axons. RESULTS: First, we studied the development of the habenular efferents in an Amigo2 lack of function mouse model. The fasciculus retroflexus showed a variable defasciculation phenotype. Gain of function experiments allowed us to generate a more condensed tract and rescued the Amigo2 knock-out phenotype. Changes in Amigo2 function did not alter the course of habenular fibers. CONCLUSION: We have demonstrated that Amigo2 plays a subtle role in the fasciculation of the fasciculus retroflexus.

[Epidemiological profile of patients with COVID-19 admitted to a tertiary care public hospital]. / Experiencia de la pandemia por SARS-CoV-2 en un centro hospitalario de alta complejidad en Chile.

BACKGROUND: The knowledge about the epidemiological profile of patients admitted to the hospital for severe COVID infection, allows an adequate health care planning and resource allocation. AIM: To describe the epidemiology of patients with COVID-19 admitted to a public hospital between March 2020 and July 2021. MATERIAL AND METHODS: Demographic variables, comorbidities, ventilatory support requirements, and hospital resources were recorded from clinical records and hospital databases of diagnosis related groups. The primary outcomes were overall mortality and need of ventilatory support. RESULTS: In the study period, 4,474 patients (56% males) were hospitalized with a diagnosis of COVID-19. Overall mortality was 25.8% and in-hospital mortality was 18%. Invasive and non-invasive ventilatory support was required in 1349 (30.2%) and 2060 (46%) patients, respectively. The most common comorbidities in admitted patients were diabetes mellitus (29.2%), chronic kidney disease (11.1%), and chronic liver disease (10.4%). The readmission rate was 3.2%. CONCLUSIONS: Mortality associated with COVID-19 in this hospital was similar to the rates reported abroad. Local risk predictors for this infection should be identified.

Personality traits and psychopathology in adolescents with videogame addiction. / Rasgos de personalidad y psicopatología en adolescentes con adicción a videojuegos.

Gaming disorder (GD) was recently included in the 11th edition of the International Classification of Diseases. A cross-sectional study was conducted in five secondary schools, with a final sample of 119 students. A diagnosis of GD was made in 6.4% (n = 23) of this sample. Compared with healthy subjects, adolescents with GD showed low levels of conscientiousness (F = 7.82; p = .001) and agreeableness (F = 3.31; p = .041) and scored higher in school maladjustment (SMC; F = 9.23; p < .001). Two discriminating functions were obtained that allowed us to predict patient group allocation with a success rate of 60.5% (Z1 = 0.406 × Sex + 0.560 × Conscientiousness - 0.677 × SMC; Z2 = 0.915 × Sex + 0.191 × Conscientiousness + 0.326 × SMC). Subjects with addiction differed from healthy subjects in presenting school maladjustment and low consciousness, while both groups of subjects with addiction differed in that video game addiction was proportionally higher in boys. The probability of GD was higher if subjects were male (OR [95% CI]) = 4.82 [1.17-19.81]; p = .029) and had school maladjustment (OR [95% CI] = 1.08 [1-1.17]; p = .047); while that of substance use disorder was higher if the subjects had neuroticism (OR [95% CI] = 1.07 [1-1.14]; p < .040), clinical maladjustment (OR [95% CI] = 1.10 [1.01- 1.20]; p = .020), school maladjustment (OR [95% CI] = 1.06 [1-1.13]; p = .048), low personal adjustment (OR [95% CI] = 0.94 [0.88-0.99]; p = .047) and emotional symptoms (OR [95% CI] = 0.86 [0.78-0.96]; p = .006).

El trastorno por uso de videojuegos se incluyó recientemente en la 11ª edición de la Clasificación Internacional de Enfermedades. Se realizó un estudio transversal en cinco institutos, con una muestra final de 119 alumnos. El 6,4% (n = 23) de los sujetos tenía trastorno por uso de videojuegos. Los adolescentes con trastorno por uso de videojuegos mostraron bajos niveles de consciencia (F = 7,82; p = ,001) y amabilidad (F = 3,31; p = ,041); y puntuaron más alto en inadaptación escolar (SMC; F = 9,230; p < ,001) que los sanos. Obtuvimos dos funciones discriminantes que clasificaban correctamente al 60,5% (Z1 = 0,406 × Sexo + 0,560 × Conciencia - 0,677 × SMC; Z2 = 0,915 × Sexo + 0,191 × Conciencia + 0,326 × SMC). Los sujetos con adicción se diferenciaban de los sanos en presentar inadaptación escolar y baja conciencia, mientras que ambos grupos con adicción se diferenciaban en que los alumnos con adicción a videojuegos eran en mayor proporción varones. La probabilidad de trastorno por uso de videojuegos aumentaba si el sujeto era varón (OR [CI 95%] = 4,82 (1,17-19,81); p = ,029) con inadaptación escolar (OR [IC 95%] = 1,08 (1-1,17); p = ,047); mientras que el trastorno por uso de sustancias aumentaba si el sujeto presentaba neuroticismo (OR [IC 95%] =1,07 [1-1,14]; p < ,040), desajuste clínico (OR [IC 95%] = 1,10 [1,01-1,20]; p = ,020), inadaptación escolar (OR [IC 95%] = 1,06 [1-1,13]; p = ,048), bajo ajuste personal (OR [IC 95%] = 0,94 [0,88-0,99]; p = ,047) y síntomas emocionales (OR [IC 95%] = 0,86 [0,78-0,96]; p = ,006).

Perinatal and long-term outcome of endoscopic laser surgery for twin-twin transfusion syndrome with and without selective fetal growth restriction: A retrospective cohort study.

OBJECTIVE: Report survival rates, neonatal mortality and morbidity and long-term outcomes of monochorionic (MC) twin pregnancies complicated by twin-to-twin transfusion syndrome (TTTS) or TTTS plus selective fetal growth restriction (sFGR) treated by endoscopic laser surgery. METHODS: Retrospective cohort study including 149 MC twin pregnancies complicated by TTTS or TTTS plus sFGR.Medical records were reviewed for survival rates, neonatal mortality, neonatal morbidity and long-term outcomes at 2 and 6 years of age. RESULTS: Survival of both babies was higher in the TTTS group than in the TTTS plus sFGR group (72.9%vs.54.8%); survival of at least one baby was similar in the two groups (90.7% and 88.1%). The incidence of severe neurological disability was not significantly different between TTTS and TTTS plus fetal growth restriction group at both stages, 1.9% versus 2.3% (p-value = 1) and 3.4%vs6.1% (p-value = 0.31). Multivariable analysis demonstrated that intact neurological outcome at 2 years of age was related with gestational age (GA) at birth and z score birthweight (Z BW), and at 6 years of age with GA at birth, Z BW and TTTS stage4. sFGR or abnormal brain findings at neonatal ultrasound were not related with impaired neurological outcome at two or 6 years of age. CONCLUSIONS: In pregnancies with TTTS and TTTS plus sFGR survival of at least one baby and long-term neurological outcome are comparable between both groups.

Comorbidity and osteoporotic fracture: approach through predictive modeling techniques using the OSTEOMED registry.

PURPOSE: To examine the response to anti-osteoporotic treatment, considered as incident fragility fractures after a minimum follow-up of 1 year, according to sex, age, and number of comorbidities of the patients. METHODS: For this retrospective observational study, data from baseline and follow-up visits on the number of comorbidities, prescribed anti-osteoporotic treatment and vertebral, humerus or hip fractures in 993 patients from the OSTEOMED registry were analyzed using logistic regression and an artificial network model. RESULTS: Logistic regression showed that the probability of reducing fractures for each anti-osteoporotic treatment considered was independent of sex, age, and the number of comorbidities, increasing significantly only in males taking vitamin D (OR = 7.918), patients without comorbidities taking vitamin D (OR = 4.197) and patients with ≥ 3 comorbidities taking calcium (OR = 9.412). Logistic regression correctly classified 96% of patients (Hosmer-Lemeshow = 0.492) compared with the artificial neural network model, which correctly classified 95% of patients (AUC = 0.6). CONCLUSION: In general, sex, age and the number of comorbidities did not influence the likelihood that a given anti-osteoporotic treatment improved the risk of incident fragility fractures after 1 year, but this appeared to increase when patients had been treated with risedronate, strontium or teriparatide. The two models used classified patients similarly, but predicted differently in terms of the probability of improvement, with logistic regression being the better fit.

Impact of metal artefacts on subjective perception of image quality of 13 CBCT devices.

OBJECTIVES: The overall objective of this study was to assess how metal artefacts impact image quality of 13 CBCT devices. As a secondary objective, the influence of scanning protocols and field of view on CBCT image quality with and without metal artefacts was also assessed. MATERIALS AND METHODS: CBCT images were acquired of a dry human skull phantom considering three clinical simulated conditions: one without metal and two with metallic materials (metallic pin and implant). An industrial micro-CT was used as a reference to register the CBCT images. Afterwards, four observers evaluated 306 representative image slices from 13 devices, ranking them from best to worst. Furthermore, within each device, medium FOV and small FOV standard images were compared. General linear mixed models were used to assess subjective perception of examiners on overall image quality in the absence and presence of metal-related artefacts (p < 0.05). RESULTS: Image quality perception significantly differed amongst CBCT devices (p < 0.05). Some devices performed significantly better, independently of scanning protocol and clinical condition. In the presence of metal artefacts, medium FOV standard scanning protocols scored significantly better, while in the absence of metal, small FOV standard yielded the highest performance. CONCLUSIONS: Subjective image quality differs significantly amongst CBCT devices and scanning protocols. Metal-related artefacts may highly impact image quality, with a significant device-dependent variability and only few scanners being more robust against metal artefacts. Often, metal artefact expression may be somewhat reduced by proper protocol selection. CLINICAL RELEVANCE: Metallic objects may severely impact image quality in several CBCT devices.

Changes in temperature alter the relationship between biodiversity and ecosystem functioning.

Global warming and the loss of biodiversity through human activities (e.g., land-use change, pollution, invasive species) are two of the most profound threats to the functional integrity of the Earth's ecosystems. These factors are, however, most frequently investigated separately, ignoring the potential for synergistic effects of biodiversity loss and environmental warming on ecosystem functioning. Here we use high-throughput experiments with microbial communities to investigate how changes in temperature affect the relationship between biodiversity and ecosystem functioning. We found that changes in temperature systematically altered the relationship between biodiversity and ecosystem functioning. As temperatures departed from ambient conditions the exponent of the diversity-functioning relationship increased, meaning that more species were required to maintain ecosystem functioning under thermal stress. This key result was driven by two processes linked to variability in the thermal tolerance curves of taxa. First, more diverse communities had a greater chance of including species with thermal traits that enabled them to maintain productivity as temperatures shifted from ambient conditions. Second, we found a pronounced increase in the contribution of complementarity to the net biodiversity effect at high and low temperatures, indicating that changes in species interactions played a critical role in mediating the impacts of temperature change on the relationship between biodiversity and ecosystem functioning. Our results highlight that if biodiversity loss occurs independently of species' thermal tolerance traits, then the additional impacts of environmental warming will result in sharp declines in ecosystem function.

Abrupt declines in marine phytoplankton production driven by warming and biodiversity loss in a microcosm experiment.

Rising sea surface temperatures are expected to lead to the loss of phytoplankton biodiversity. However, we currently understand very little about the interactions between warming, loss of phytoplankton diversity and its impact on the oceans' primary production. We experimentally manipulated the species richness of marine phytoplankton communities under a range of warming scenarios, and found that ecosystem production declined more abruptly with species loss in communities exposed to higher temperatures. Species contributing positively to ecosystem production in the warmed treatments were those that had the highest optimal temperatures for photosynthesis, implying that the synergistic impacts of warming and biodiversity loss on ecosystem functioning were mediated by thermal trait variability. As species were lost from the communities, the probability of taxa remaining that could tolerate warming diminished, resulting in abrupt declines in ecosystem production. Our results highlight the potential for synergistic effects of warming and biodiversity loss on marine primary production.

Differential thermal tolerance between algae and corals may trigger the proliferation of algae in coral reefs.

Marine heatwaves can lead to rapid changes in entire communities, including in the case of shallow coral reefs the potential overgrowth of algae. Here we tested experimentally the differential thermal tolerance between algae and coral species from the Red Sea through the measurement of thermal performance curves and the assessment of thermal limits. Differences across functional groups (algae vs. corals) were apparent for two key thermal performance metrics. First, two reef-associated algae species (Halimeda tuna and Turbinaria ornata) had higher lethal thermal limits than two coral species (Pocillopora verrucosa and Stylophora pistillata) conferring those species of algae with a clear advantage during heatwaves by surpassing the thermal threshold of coral survival. Second, the coral species had generally greater deactivation energies for net and gross primary production rates compared to the algae species, indicating greater thermal sensitivity in corals once the optimum temperature is exceeded. Our field surveys in the Red Sea reefs before and after the marine heatwave of 2015 show a change in benthic cover mainly in the southern reefs, where there was a decrease in coral cover and a concomitant increase in algae abundance, mainly turf algae. Our laboratory and field observations indicate that a proliferation of algae might be expected on Red Sea coral reefs with future ocean warming.

Impact of clinical features, cytogenetics, genetic mutations, and methylation dynamics of CDKN2B and DLC-1 promoters on treatment response to azacitidine.

Azacitidine (AZA) is a DNA hypomethylation agent administered in myeloid neoplasms; however, there is still a lack of established predictors of response. We studied 113 patients with myelodysplastic syndromes (n = 85) or acute myeloid leukemia (n = 28) who received AZA to assess the predictive value on response of clinical features, cytogenetics, and molecular markers. Overall, 46 patients (41%) responded to AZA. Platelet doubling after the first AZA cycle was associated with a better response (68% vs. 32% responders, P = 0.041). Co-occurrence of chromosome 7 abnormalities and 17p deletion was associated with a worse response (P = 0.039). Pre-treatment genetic mutations were detected in 98 patients (87%) and methylation of CDKN2B and DLC-1 promoters were detected in 50 (44%) and 37 patients (33%), respectively. Patients with SF3B1 mutations showed a better response to AZA (68% vs. 35% responders, P = 0.008). In contrast, subjects with mutations in transcription factors (RUNX1, SETBP1, NPM1) showed a worse response (20% vs. 47% responders, P = 0.014). DLC-1 methylation pre-treatment was associated with poor clinical features and its reduction post-treatment resulted in a better response to AZA in MDS patients (P = 0.037). In conclusion, we have identified several predictors of response to AZA that could help select the best candidates for this treatment.

Proteomic analysis of the inhibitory effect of the butanolic fraction of Jacquinia macrocarpa on Fusarium verticillioides.

Jacquinia macrocarpa, a plant native to northwestern Mexico, has an inhibitory effect against phytopathogenic fungi. Previous studies have shown that the butanolic extract of J. macrocarpa causes retardation and atrophy in mycelial growth of Fusarium verticillioides. However, the action mechanism of this extract is unknown. We used a proteomics approach to understand the inhibitory effect of J. macrocarpa butanolic extract, based on differential protein accumulation in F. verticillioides. Proteins were extracted from F. verticillioides cultured in Czapek broth with and without 202.12 µg/mL (IC50) of butanolic extract of J. macrocarpa. Thirty-eight protein spots showing statistically significant changes (ANOVA, p < 0.01) and at least a 2-fold change in abundance between experimental conditions were analyzed by mass spectrometry. Identified proteins were grouped into different biological processes according to Gene Ontology, among them were amino acid metabolism, protein folding and stabilization, protein degradation, protein transport, carbohydrate metabolism, oxidative stress response, and miscellaneous. This work is the first report of changes in the proteomic profile of F. verticillioides exposed to the J. macrocarpa extract. This information provides new insights into the inhibitory mechanism of the extract and represents a starting point for dissection of the fungal response against the J. macrocarpa extract components.

Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation.

Astaxanthin (ASX) is a carotenoid pigment with strong antioxidant properties. We have reported previously that ASX protects neurons from the noxious effects of amyloid-ß peptide oligomers, which promote excessive mitochondrial reactive oxygen species (mROS) production and induce a sustained increase in cytoplasmic Ca2+ concentration. These properties make ASX a promising therapeutic agent against pathological conditions that entail oxidative and Ca2+ dysregulation. Here, we studied whether ASX protects neurons from N-methyl-D-aspartate (NMDA)-induced excitotoxicity, a noxious process which decreases cellular viability, alters gene expression and promotes excessive mROS production. Incubation of the neuronal cell line SH-SY5Y with NMDA decreased cellular viability and increased mitochondrial superoxide production; pre-incubation with ASX prevented these effects. Additionally, incubation of SH-SY5Y cells with ASX effectively reduced the basal mROS production and prevented hydrogen peroxide-induced cell death. In primary hippocampal neurons, transfected with a genetically encoded cytoplasmic Ca2+ sensor, ASX also prevented the increase in intracellular Ca2+ concentration induced by NMDA. We suggest that, by preventing the noxious mROS and Ca2+ increases that occur under excitotoxic conditions, ASX could be useful as a therapeutic agent in neurodegenerative pathologies that involve alterations in Ca2+ homeostasis and ROS generation.

Diel dynamics and coupling of heterotrophic prokaryotes and dissolved organic matter in epipelagic and mesopelagic waters of the central Red Sea.

The ecological status of an ecosystem can be approached by the taxa present but also by the size of individual organisms. In aquatic ecosystems, flow cytometry (FC) allows to study the individual size spectra and broad community composition through the evaluation of cytometric categories. The Red Sea represents a warm oligotrophic environment with a strong diel signal of vertically migrating mesopelagic fish, which feed at night at the surface and release dissolved organic carbon (DOC) at depth during day-time. However, knowledge about how these conditions affect the dynamics of heterotrophic prokaryotes (HP) and their coupling with DOC is lacking. Here, we analyzed a high frequency sampling over 24 h to identify the community structure and compositional changes of HP in the epipelagic and mesopelagic layers of the central Red Sea. Our results show marked vertical and diel changes in HP communities in both layers. Specifically, the relative contribution of high nucleic acid content cells was remarkably linked to changes in DOC concentration and properties. The patterns observed were likely associated to the diel vertical migration of mesopelagic fish. These findings reveal that the structure of microbial communities in warm oligotrophic environments may be more dynamic than previously thought.

Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H-DNMT3A mutated clone of patient origin.

BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) develops in patients with prior exposure to cytotoxic therapies. Selection of a pre-existing TP53 mutated clone prone to acquire additional mutational events has been suggested as the main pathogenic mechanism of t-AML. Here, we report a unique case of t-AML which developed from a pre-existing DNMT3A mutated clone that persisted in the patient for more than 10 years despite treatment with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT). CASE PRESENTATION: A 42-year-old male was diagnosed with AML harboring a normal karyotype and mutations in the NPM1 (c.863_864ins, p.W288 fs*12), DNMT3A (c.2645G > A, p.R882H), and IDH1 (c.395G > A, p.R132H) genes. He achieved complete remission with intensive chemotherapy and was subsequently submitted to alloHSCT. Eleven years later, he was given chemotherapy and radiotherapy to treat a lung carcinoma. Three years later, t-AML was diagnosed; the disease had arisen from a pre-existing DNMT3A mutated patient-origin clone that had subsequently acquired a TP53 mutation and a complex karyotype. Although a second transplantation was intended, the disease was refractory to induction chemotherapy, and the patient eventually died from disease complications. We retrospectively demonstrated the persistence and post-transplantation latency of the R882H-DNMT3A mutation using a real-time PCR allele-specific analysis at different time-points during the observation period. DISCUSSION AND CONCLUSION: The present case highlights the potential clinical implications of a R882H-DNMT3A mutated clone that persisted after conventional AML treatment, including alloHSCT. It also reinforces the notion of the importance of cell non-intrinsic factors, such as the hematopoietic-stress induced by chemotherapy and radiotherapy, as drivers of clonal expansion.

Murraya paniculata (L.) (Orange Jasmine): Potential Nutraceuticals with Ameliorative Effect in Alloxan-Induced Diabetic Rats.

Orange jasmine, Murraya paniculata (Rutaceae), is a plant from India widely used in folk medicine as antinociceptive, antiinflammatory, and antioxidant. Although oral hypoglycemic agents and insulin are the mainstays of treatment of diabetes mellitus (DM), there is a significant demand for new natural products to reduce the development of diabetic complications. Alloxan-induced diabetic rats were treated for 60 days with a hydroalcoholic extract of M. paniculata (MPE), at doses of 100, 200, and 400 mg/kg. MPE decreased glycemia and also cholesterol and triglyceride levels, starting 1 week after treatments, as compared with the same group before treatments. Glucose values were reduced toward normality after 1 week of treatment. MPE hypoglycemic effects were potentiated by glibenclamide and metformin. MPE also decreased fructosamine and glycated hemoglobin values. MPE reduced diabetes-induced morphological alterations of the kidney, pancreas, and liver. MPE acts similarly to glibenclamide and metformin, and its glucose-lowering action is partly a consequence of ATP-sensitive K+ channel inhibition. MPE may be a potential therapeutic alternative for the treatment of diabetes and its complications. Copyright © 2017 John Wiley & Sons, Ltd.

Antimicrobial activity of pomegranate peel extracts as affected by cultivar.

BACKGROUND: Some studies have reported that different parts of the pomegranate fruit, especially the peel, may act as potential antimicrobial agents and thus might be proposed as a safe natural alternative to synthetic antimicrobial agents. The high tannin content, especially punicalagin, found in pomegranate extracts, has been reported as the main compound responsible for such antimicrobial activity. Because the pomegranate peel chemical composition may vary with the type of cultivar (sweet, sour-sweet and sour), pomegranates may also differ with respect to their antimicrobial capacity. RESULTS: The extract from PTO8 pomegranate cultivar peel had the highest antimicrobial activity, as well as the highest punicalagins (α and ß) and ellagic acid concentrations. In the results obtained from both antibacterial and antifungal activity studies, the sour-sweet pomegranate cultivar PTO8 showed the best antimicrobial activity, and the highest ellagic acid concentrations. CONCLUSION: The results of the present study suggest that ellagic acid content has a significant influence on the antimicrobial activity of the pomegranate extracts investigated. The pomegranate peel of the PTO8 cultivar is a good source of antifungal and antibacterial compounds, and may represent an alternative to antimicrobial agents of synthetic origin. © 2016 Society of Chemical Industry.