Long-term engrafting multilineage hematopoietic cells differentiated from human induced pluripotent stem cells.

Hematopoietic stem cells (HSCs) derived from human induced pluripotent stem cells (iPS cells) have important biomedical applications. We identified differentiation conditions that generate HSCs defined by robust long-term multilineage engraftment in immune-deficient NOD,B6.Prkdcscid Il2rgtm1Wjl/SzJ KitW41/W41 mice. We guided differentiating iPS cells, as embryoid bodies in a defined culture medium supplemented with retinyl acetate, through HOXA-patterned mesoderm to hemogenic endothelium specified by bone morphogenetic protein 4 and vascular endothelial growth factor (VEGF). Removal of VEGF facilitated an efficient endothelial-to-hematopoietic transition, evidenced by release into the culture medium of CD34+ blood cells, which were cryopreserved. Intravenous transplantation of two million thawed CD34+ cells differentiated from four independent iPS cell lines produced multilineage bone marrow engraftment in 25-50% of immune-deficient recipient mice. These functionally defined, multipotent CD34+ hematopoietic cells, designated iPS cell-derived HSCs (iHSCs), produced levels of engraftment similar to those achieved following umbilical cord blood transplantation. Our study provides a step toward the goal of generating HSCs for clinical translation.

Required number of blastocysts transferred, and oocytes retrieved to optimize live and cumulative live birth rates in the first complete cycle of IVF for autologous and donated oocytes.

PURPOSE: To investigate live birth rate (LBR) and cumulative live birth rate (CLBR) to achieve the first newborn per blastocyst transferred and oocyte retrieved in the first complete IVF cycle of autologous and donated oocytes and identify the possible success factors. METHODS: This was a retrospective cohort study of a private IVF center. There were 1867 cycles, 1241 of which were fresh transfers and 626, their subsequent thawing transfers. RESULTS: We found significant variables by binary logistic regression. For LBR, female infertility and the day of blastocyst transferred were relevant; however, for CLBR, the numbers of blastocysts available for future transfers, oocyte age, and maternal age were more critical. Oocyte age is a negative factor that begins to affect CLBR gradually beyond 36 years; from that age, there are significant worse results in polycystic ovary syndrome and poor responder patients. CONCLUSION: The LBR and CLBR were optimized for oocyte recipients when eight oocytes were retrieved (63.6%; 87.9%); at most, fourteen oocytes should be assigned to avoid freezing surplus blastocysts. Thirteen autologous oocytes (69.2%; 92.3%) were ideal for optimization. CLBR optimized after three blastocysts in donor oocytes (81.8%) and four for autologous oocyte patients (80.9%). Our outcomes are valuable for doctors and infertile couples, and they give us information on what we can expect from a first complete IVF cycle.

Pilot study on the effectiveness of the socialmind program for the rehabilitation of social cognition following acquired brain injury.

Background: People with acquired brain injury (ABI) often have Social Cognition (SC) deficits. Impairment of SC causes the individual to have difficulties in daily functioning and can lead to social isolation. Research aimed at rehabilitation of SC in individuals with ABI is scarce and almost always addresses only one component of this ability. Objective: This pilot study aimed to assess the effectiveness of the new "SocialMind" program in improving all core components of SC in people with ABI. Method: The study included 31 participants with ABI, divided into experimental and control groups. The study spanned 44 weeks, involving an initial meeting, evaluation, training, and final assessment phases. The SocialMind program, structured into four modules, each with a duration of 30 h, targeted each SC component through tailored exercises. The program addressed emotion recognition, social awareness, ToM, and empathy. Results: The SocialMind group demonstrated significant improvements in emotion recognition (p = 0.017), social knowledge (p < 0.001), and empathy (p = 0.001) compared to the control group. ToM also showed a notable improvement that approached significance (p = 0.057). Conclusion: This pilot study suggests that the SocialMind program effectively enhances three of the four core components of SC in individuals with ABI.

Intraoperative closure of large full thickness macular holes with perfluorocarbon liquid.

PURPOSE: To report the role of perfluorocarbon liquid (PFCL) and passive extrusion for management of large full thickness macular holes (FTMHs). METHODS: A standard pars plana vitrectomy with induction of posterior vitreous detachment was performed for all patients. After internal limiting membrane (ILM) peel, a bubble of perfluorocarbon liquid (PFCL) was injected over the posterior pole and passive extrusion of fluid was performed with a backflush instrument below the PFCL bubble, without touching the FTMH edges, until the FTMH centre was reached. Intraoperative optical coherence tomography (OCT) showed formation of an inner retina roof in all cases and confirmed intraoperative FTMH closure. Complete PFCL removal was performed after fluid-air exchange and gas tamponade was utilised in all cases. RESULTS: Preoperative FTMH mean aperture size was 761um and standard deviation (SD) 100um (range 682-918um). FTMH closure was achieved in all eyes and visualised intraoperatively with OCT. After an average follow-up of 2 months, there was improvement in the mean BCVA and central scotoma. CONCLUSION: FTMH closure can be achieved intraoperatively with the use of PFCL and passive extrusion. The described surgical technique could be a valid alternative for repair of large FTMHs.

The components of an electrical synapse as revealed by expansion microscopy of a single synaptic contact.

Most nervous systems combine both transmitter-mediated and direct cell-cell communication, known as 'chemical' and 'electrical' synapses, respectively. Chemical synapses can be identified by their multiple structural components. Electrical synapses are, on the other hand, generally defined by the presence of a 'gap junction' (a cluster of intercellular channels) between two neuronal processes. However, while gap junctions provide the communicating mechanism, it is unknown whether electrical transmission requires the contribution of additional cellular structures. We investigated this question at identifiable single synaptic contacts on the zebrafish Mauthner cells, at which gap junctions coexist with specializations for neurotransmitter release and where the contact unequivocally defines the anatomical limits of a synapse. Expansion microscopy of these single contacts revealed a detailed map of the incidence and spatial distribution of proteins pertaining to various synaptic structures. Multiple gap junctions of variable size were identified by the presence of their molecular components. Remarkably, most of the synaptic contact's surface was occupied by interleaving gap junctions and components of adherens junctions, suggesting a close functional association between these two structures. In contrast, glutamate receptors were confined to small peripheral portions of the contact, indicating that most of the synaptic area functions as an electrical synapse. Thus, our results revealed the overarching organization of an electrical synapse that operates with not one, but multiple gap junctions, in close association with structural and signaling molecules known to be components of adherens junctions. The relationship between these intercellular structures will aid in establishing the boundaries of electrical synapses found throughout animal connectomes and provide insight into the structural organization and functional diversity of electrical synapses.

Neurons communicate with each other through specialized structures known as synapses. At chemical synapses, the cells do not physically interact as they rely instead on molecules called neurotransmitters to pass along signals. At electrical synapses, however, neurons are directly connected via gap junctions, which are clusters of intercellular channels that allow ions and other small compounds to move from one cell to another. Both electrical and chemical synapses play critical roles in neural circuits, and both exhibit some amount of plasticity ­ they weaken or strengthen depending on how often they are used, an important feature for the brain to adapt to the needs of the environment. Yet the structure and molecular organization of electrical synapses have remained poorly understood compared to their chemical counterparts. In response, Cárdenas-García, Ijaz and Pereda took advantage of a new approach known as expansion microscopy to examine the electrical synapse that connects neurons bringing sound information to a pair of unusually large neurons in the brain of most bony fish. With this method, a biological sample is prepared in such a way that its size increases, but the relative position of its components is preserved. This allows scientists to better observe structures that would otherwise be too difficult to capture using traditional microscopy techniques. Experiments in larval zebrafish revealed that contrary to previous assumptions, the electrical synapse was formed of not one but multiple gap junctions of various sizes closely associated with a range of structural and signaling molecules typically found in adherens junctions (a type of structure that physically links cells together). The team suggests that these molecular actors could work to ensure that the multiple gap junctions act in concert at the synapse. Overall, these findings offer a new perspective on how electrical synapses are organized and regulated, which refines our understanding of how the nervous system functions both in health and in disease.

Cell Culture Differentiation and Proliferation Conditions Influence the In Vitro Regeneration of the Human Airway Epithelium.

The human airway mucociliary epithelium can be recapitulated in vitro using primary cells cultured in an air-liquid interface (ALI), a reliable surrogate to perform pathophysiological studies. As tremendous variations exist among media used for ALI-cultured human airway epithelial cells, the aim of our study was to evaluate the impact of several media (BEGM, PneumaCult, Half & Half, and Clancy) on cell type distribution using single-cell RNA sequencing and imaging. Our work revealed the impact of these media on cell composition, gene expression profile, cell signaling, and epithelial morphology. We found higher proportions of multiciliated cells in PneumaCult-ALI and Half & Half, stronger EGF signaling from basal cells in BEGM-ALI, differential expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry factor ACE2, and distinct secretome transcripts depending on the media used. We also established that proliferation in PneumaCult-Ex Plus favored secretory cell fate, showing the key influence of proliferation media on late differentiation epithelial characteristics. Altogether, our data offer a comprehensive repertoire for evaluating the effects of culture conditions on airway epithelial differentiation and will aid in choosing the most relevant medium according to the processes to be investigated, such as cilia, mucus biology, or viral infection. We detail useful parameters that should be explored to document airway epithelial cell fate and morphology.

Adaptation and Psychometric Properties of an Attitude toward Artificial Intelligence Scale (AIAS-4) among Peruvian Nurses.

BACKGROUND: The integration of Artificial Intelligence (AI) into various aspects of daily life has sparked growing interest in understanding public attitudes toward this technology. Despite advancements in tools to assess these perceptions, there remains a need for culturally adapted instruments, particularly in specific contexts like that of Peruvian nurses. OBJECTIVE: To evaluate the psychometric properties of the AIAS-4 in a sample of Peruvian nurses. METHODS: An instrumental design was employed, recruiting 200 Peruvian nurses. The Attitude toward Artificial Intelligence in Spanish (AIAS-S), a cultural and linguistic adaptation of the AIAS-4, involved data analysis using descriptive statistics, confirmatory factor analysis (CFA), and invariance tests. RESULTS: The Confirmatory Factor Analysis (CFA) confirmed a unidimensional factor structure with an excellent model fit (χ2 = 0.410, df = 1, p = 0.522, CFI = 1.00, TLI = 1.00, RMSEA = 0.00, SRMR = 0.00). The scale demonstrated high internal consistency (α = 0.94, ω = 0.91). Tests of invariance from configural to strict confirmed that the scale is stable across different demographic subgroups. CONCLUSIONS: The AIAS-S proved to be a psychometrically solid tool for assessing attitudes toward AI in the context of Peruvian nurses, providing evidence of validity, reliability, and gender invariance. This study highlights the importance of having culturally adapted instruments to explore attitudes toward emerging technologies in specific groups.

Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p <0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p =0.12; D90: 78% vs. 68%, p =0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p <0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Developing and validating a prediction model of live birth following single vitrified-warmed blastocyst transfer.

RESEARCH QUESTION: Can the developed clinical prediction model offer an accurate estimate of the likelihood of live birth, involving blastocyst morphology and vitrification day after single vitrified-warmed blastocyst transfer (SVBT), and therefore assist clinicians and patients? STUDY DESIGN: Retrospective cohort study conducted at a Spanish university-based reproductive medicine unit (2017-2021) including consecutive vitrified-warmed blastocysts from IVF cycles. A multivariable logistic regression incorporated key live birth predictors: vitrification day, embryo score, embryo ploidy status and clinically relevant variables, i.e. maternal age. RESULTS: The training set involved 1653 SVBT cycles carried out between 2017 and 2020; 592 SVBT cycles from 2021 constituted the external validation dataset. The model revealed that female age and embryo characteristics, including overall quality and blastulation day, is linked to live birth rate in SVBT cycles. Stratification by vitrification day and quality (from day-5A to day-6 C blastocysts) applied to genetically tested and untested embryos. The model's area under the curve was 0.66 (95% CI 0.64 to 0.69) during development and 0.65 (95% CI 0.61 to 0.70) in validation, denoting moderate discrimination. Calibration plots showed strong agreement between predicted and observed probabilities. CONCLUSION: By incorporating essential predictors such as vitrification day, embryo morphology grade, age and preimplantation genetic testing for aneuploidy usage, this predictive model offers valuable guidance to clinicians and patients, enabling accurate forecasts of live birth rates for any given vitrified blastocyst within SVBT cycles. Additionally, it serves as a potentially indispensable laboratory tool, aiding in selecting the most promising blastocysts for optimal outcomes.

Usability evaluation of the educational website "understanding my diabetes" for Mexican patients with type 2 diabetes.

Background: Diabetes education is an integral part of the treatment for the metabolic control of patients with diabetes. The use of the Internet as a tool for diabetes education, as well as its acceptance, is still under study. Aim: To assess the usability of the educational website "I understand my diabetes" designed for patients with type 2 diabetes attending primary care clinics. Material and method: A cross-sectional study was done in 110 patients with type 2 diabetes from two family medicine clinics, each of whom was assigned a user account on the educational website "Entiendo mi diabetes." The web site assigned a user name and password to each patient. They were able to access the educational website at home. After a 15-day review period, participants were asked to evaluate usability using the Computer System Usability Questionnaire. Additionally, we developed an eight-item questionnaire usability focusing on diabetes care. Sociodemographic data, blood pressure, and anthropometric measurements were recorded. Glucose levels and lipid profiles were also measured. Results: The patients with diabetes had a mean age of 52.7 years and a median of 5 years since they were diagnosed with diabetes. The website received a good usability rating from 89.1% of participants, with favorable assessments in all three dimensions: 87.3% for information, 85.5% for quality, and 88.2% for interface. Regarding usability specifically for diabetes care, 98.2% rated it as having good usability. Conclusion: The website for education about the disease in patients "I understand my diabetes" had an adequate usability evaluation by patients, so they also considered it very useful for diabetes care. The diabetes care instrument had adequate usability and reliability.

Psychometric Properties of a Short Academic Motivation Scale (SAMS) in Medical Students.

Background: Medical education represents a complex field of study, influenced by various psychological, demographic, and contextual factors. Academic motivation, essential for educational success, has been linked to critical decisions in medical careers and can be modulated by contextual elements such as socioeconomic and geographical environments. The theory of self-determination has provided a solid framework for understanding the multidimensional nature of motivation. Objective: To evaluate the psychometric properties of a Spanish version of the Short Scale of Academic Motivation among Peruvian medical students. Methods: Using an instrumental design, the factorial structure, reliability, and gender invariance of the SAMS-S were assessed. A confirmatory factor analysis (CFA) was conducted to validate the scale's structure based on seven dimensions. Additionally, reliability was assessed through Cronbach's alpha coefficient and omega coefficient, and gender invariance was determined through multi-group confirmatory factor analysis. Results: The Peruvian version of the SAMS-S showed a good fit in the CFA with satisfactory goodness-of-fit indices. However, challenges in discriminant validity among certain dimensions were detected, suggesting the presence of a second-order factor. The proposed second-order model yielded an adequate fit (χ2 = 198.26, df = 70, CFI = 0.92, TLI = 0.90, RMSEA = 0.08 [90% CI: 0.07-0.1], SRMR = 0.07), validating the factorial structure of the SAMS-S. The scale's reliability and its subscales were within acceptable ranges. Furthermore, the gender invariance of the SAMS-S was confirmed at all levels, from configural to strict. Conclusions: The second-order model of the SAMS-S presents as a valid and reliable tool for measuring academic motivation among medical students in Peru. Its robustness and adaptability make it relevant for future research in similar educational contexts and can serve as a basis for interventions aimed at improving academic motivation in this specific group.

Association between cardiovascular risk and maternal perception of BMI in Peruvian schoolchildren.

Introduction: In the modern era, the maternal perception of children's nutritional status has emerged as a critical area of study, given its potential influence on nutritional interventions and long-term child health. The relationship between this perception and children's Body Mass Index (BMI) by age is particularly intriguing, as it may reveal discrepancies between perception and reality. Objective: The aim of this study was to evaluate Peruvian mothers' perception of their children's Body Mass Index (BMI) in relation to age and to determine how this perception associates with the children's cardiovascular risk. The study also analyzed sociodemographic factors that might influence this perception. Methods: The study included 130 mothers of schoolchildren aged 5 to 11 from a school in Lima. Mothers' perceptions of their children's weight were assessed using pictograms, and sociodemographic characteristics were collected through a questionnaire. Weight and height measurements were taken to calculate BMI, and waist circumference was measured to classify cardiovascular risk. Results: A total of 57.4% of the schoolchildren presented with excess malnutrition, and 51.5% of the mothers incorrectly classified the actual BMI/Age of their children (kappa 0.11; p ≤ 0.05). Additionally, it was found that the schoolchild's age is associated with the mother's failure to accurately perceive her child's weight (OR 1.59). Lastly, there was a significant association between maternal perception and cardiovascular risk (p ≤ 0.05). Conclusion: There is a significant discrepancy between maternal perception and the actual nutritional status of children, which can increase cardiovascular risk. It is necessary to implement intervention and education strategies targeted at parents to enhance the recognition and management of childhood overweight and obesity.

Epidemiology, clinical features, and classification of 3,404 patients with uveitis: Colombian Uveitis Multicenter Study (COL-UVEA).

PURPOSE: To describe the epidemiology, clinical features, and classification of uveitis in a large cohort of Colombian patients. METHODS: Data were collected from seven ophthalmological referral centers in the four main cities in Colombia. The study included patients with a confirmed diagnosis of uveitis from January 2010 to December 2022. Information on demographics, ophthalmic examination findings, uveitis classification, and etiology was recorded. RESULTS: The study reviewed 3,404 clinical records of patients with uveitis. The mean age at diagnosis was 41.1 (SD 19.0) years, and 54.2% of the patients were female. Overall, 1,341(39.4%) were infectious, 626 (18.4%) non-infectious, and four masquerade syndromes (0.1%). The most common types of uveitis were unilateral (66.7%), acute (48.3%), and non-granulomatous (83%). Anterior uveitis was the most common anatomical localization (49.5%), followed by posterior uveitis (22.9%), panuveitis (22.3%), and intermediate uveitis (5.2%). A diagnosis was established in 3,252 (95.5%) cases; idiopathic was the most common cause (27.7%), followed by toxoplasmosis (25.3%) and virus-associated uveitis (6.4%). The age group between 30 and 50 exhibited the highest frequency of uveitis. CONCLUSION: This multicenter study comprehensively describes uveitis characteristics in Colombian patients, providing valuable insights into its demographic and clinical features. The study findings emphasize the need to continue updating the changing patterns of uveitis to improve diagnosis and treatment strategies for diseases associated with intraocular inflammation.

Depression, professional self-efficacy, and job performance as predictors of life satisfaction: the mediating role of work engagement in nurses.

Background: The life satisfaction and job performance of nursing professionals are affected by a multitude of factors, including work engagement, self-efficacy, and depression. The Job Demands-Resources (JD-R) model provides a theoretical framework to explore these relationships. Objective: Our study aimed to analyze the primary goal of this research, which is to examine the mediating role of work engagement in the relationship between depression, professional self-efficacy, job performance, and their impact on life satisfaction in nurses, using the JD-R theory as a guide. Methods: This cross-sectional study involved 579 participants aged between 21 to 57 years (M = 39, SD = 9.95). Mediation analysis was used to examine the influence of depression, self-efficacy, and job performance on work engagement, and in turn, its effect on life satisfaction. Results: Findings indicated that work engagement plays a crucial mediating role between depression, self-efficacy, job performance, and life satisfaction. Interventions to increase work engagement could assist nurses in better managing depression and improving their performance and life satisfaction. Conclusions: Our study highlights the need for workplace policies and strategies that foster work engagement and self-efficacy among nurses while effectively managing job demands to prevent depression. Moreover, these findings underscore the importance of the JD-R theory to understand and improve nurses' job satisfaction and performance, and suggest areas for future research, including exploring other potential factors and applying these findings across different contexts and cultures.

Blastocysts from partial compaction morulae are not defined by their early mistakes.

RESEARCH QUESTION: Is partial compaction during morula formation associated with an embryo's developmental ability and implantation potential? DESIGN: Retrospective analysis of data from 196 preimplantation genetic testing for aneuploidy (PGT-A) cycles. Embryos starting compaction were grouped according to the inclusion or not of all the blastomeres in the forming morula (full compaction or partial compaction). The possible effect of maternal age and ovarian response on compaction was analysed. Morphokinetic characteristics, blastocyst formation rate, morphology and cytogenetic constitution of the obtained blastocysts were compared. Comparisons of reproductive outcomes after the transfer of euploid blastocysts from both groups were established. Finally, in a subset of embryos, the chromosomal constitution concordance of the abandoned cells and the corresponding blastocyst through trophectoderm biopsies was assessed. RESULTS: A total of 430 embryos failed to include at least one cell during compaction (partial compaction group [49.3%]), whereas the 442 remaining embryos formed a fully compacted morula (full compaction group [50.7%]). Neither female age nor the number of oocytes collected affected the prevalence of partial compaction morulae. Morphokinetic parameters were altered in embryos from partial compaction morulae compared with full compaction. Although an impairment in blastocyst formation rate was observed in partial compaction morulae (57.2% versus 70.8%, P < 0.001), both chromosomal constitution (euploidy rate: partial compaction [38.4%] versus full compaction [34.2%]) and reproductive outcomes (live birth rate: partial compaction [51.9%] versus full compaction [46.2%]) of the obtained blastocysts were equivalent between groups. A high ploidy correlation of excluded cells-trophectoderm duos was observed. CONCLUSIONS: Partial compaction morulae show a reduced developmental ability compared with full compaction morulae. Resulting blastocysts from both groups, however, have similar euploidy rates and reproductive outcomes. Cell exclusion might be a consequence of a compromised embryo development regardless of the chromosomal constitution of the excluded cells.

Analytical and functional profiles of paralytic shellfish toxins extracted from Semele proficua and Senilia senilis from Angola.

Paralytic shellfish poisoning is a foodborne illness that typically derive from the consumption of shellfish contaminated with saxitoxin-group of toxins produced by dinoflagellates of the genus Gymnodinium, Alexandrium and Pyrodinium. N-sulfocarbamoyl, carbamate and dicarbamoyl are the most abundant. In 2007 and 2008 some episodes of PSP occurred in Angola where there is not monitoring program for shellfish contamination with marine biotoxins. Therefore, ten samples extracted from Semele proficua from Luanda Bay and Senilia senilis from Mussulo Bay, were analyzed by HPLC finding saxitoxin, decarbamoylsaxitoxin and other three compounds that have an unusual profile different to the known hydrophilic PSP toxins were found in different amounts and combinations. These new compounds were not autofluorescent, and they presented much stronger response after peroxide oxidation than after periodate oxidation. The compounds appear as peaks eluted at 2.5 and 5.6 min after periodate oxidation and 8.2 min after peroxide oxidation. Electrophysiological studies revealed that none of the three unknown compounds had effect at cellular level by decreasing the maximum peak inward sodium currents by blocking voltage-gated sodium channels. Thus, not contributing to PSP intoxication. The presence in all samples of saxitoxin-group compounds poses a risk to human health and remarks the need to further explore the presence of new compounds that contaminate seafood, investigating their activity and developing monitoring programs.

Exosomal Osteoclast-Derived miRNA in Rheumatoid Arthritis: From Their Pathogenesis in Bone Erosion to New Therapeutic Approaches.

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation, pain, and ultimately, bone erosion of the joints. The causes of this disease are multifactorial, including genetic factors, such as the presence of the human leukocyte antigen (HLA)-DRB1*04 variant, alterations in the microbiota, or immune factors including increased cytotoxic T lymphocytes (CTLs), neutrophils, or elevated M1 macrophages which, taken together, produce high levels of pro-inflammatory cytokines. In this review, we focused on the function exerted by osteoclasts on osteoblasts and other osteoclasts by means of the release of exosomal microRNAs (miRNAs). Based on a thorough revision, we classified these molecules into three categories according to their function: osteoclast inhibitors (miR-23a, miR-29b, and miR-214), osteoblast inhibitors (miR-22-3p, miR-26a, miR-27a, miR-29a, miR-125b, and miR-146a), and osteoblast enhancers (miR-20a, miR-34a, miR-96, miR-106a, miR-142, miR-199a, miR-324, and miR-486b). Finally, we analyzed potential therapeutic targets of these exosomal miRNAs, such as the use of antagomiRs, blockmiRs, agomiRs and competitive endogenous RNAs (ceRNAs), which are already being tested in murine and ex vivo models of RA. These strategies might have an important role in reestablishing the regulation of osteoclast and osteoblast differentiation making progress in the development of personalized medicine.

Surgical Outcomes in Uveitic Glaucoma: Long-Term Evaluation of Trabeculectomy, Non-Penetrating Deep Sclerectomy, Ex-PRESS Shunt and Ahmed Glaucoma Valve. A 3-Year Follow-Up Study.

PURPOSE: Uveitis can lead to secondary glaucoma, a condition with challenging management that can carry irreversible visual loss. Filtering surgery has demonstrated a higher failure rate, increased incidence of postoperative complications and reinterventions in uveitic patients. There is no consensus on the optimal surgical approach for uveitic glaucoma (UG) due to limited data comparing various intraocular pressure (IOP)-lowering surgeries. This retrospective cohort aims to assess the clinical outcomes of trabeculectomy (TBT), non-penetrating deep sclerectomy (NPDS), Ex-PRESS shunt and Ahmed glaucoma valve, providing additional insights into the long-term IOP control and safety of filtering surgeries in UG. METHODS: The filtering surgery was performed on 32 eyes of 27 UG patients. Complete success was defined as IOP ≤ 18 mmHg or a 30% reduction. Qualified success allowed topical hypotensive treatment. RESULTS: Complete success was 40.63% (13/32) at 12 months and 36.67% (11/30) at 36 months. Qualified success was 84.38% (27/32) at 12 months and 63.33% (19/30) at 36 months. In the survival analysis, both NPDS and Ex-PRESS demonstrated decreased failure rates compared to TBT (NPDS vs TBT: HR = 0.20, p = 0.049; Ex-PRESS vs TBT: HR = 0.28, p = 0.13). One or more reinterventions were required in 34.38% (11/32) of the eyes. NPDS had the lowest incidence of hypotony. Secondary cataract was a common complication in all groups. CONCLUSION: Various filtering surgeries are safe and effective procedures for lowering IOP and reducing the requirement of topical antihypertensives in UG at 36 months. However, one-third of the patients will require another IOP-lowering procedure.

Urease-powered nanobots for radionuclide bladder cancer therapy.

Bladder cancer treatment via intravesical drug administration achieves reasonable survival rates but suffers from low therapeutic efficacy. To address the latter, self-propelled nanoparticles or nanobots have been proposed, taking advantage of their enhanced diffusion and mixing capabilities in urine when compared with conventional drugs or passive nanoparticles. However, the translational capabilities of nanobots in treating bladder cancer are underexplored. Here, we tested radiolabelled mesoporous silica-based urease-powered nanobots in an orthotopic mouse model of bladder cancer. In vivo and ex vivo results demonstrated enhanced nanobot accumulation at the tumour site, with an eightfold increase revealed by positron emission tomography in vivo. Label-free optical contrast based on polarization-dependent scattered light-sheet microscopy of cleared bladders confirmed tumour penetration by nanobots ex vivo. Treating tumour-bearing mice with intravesically administered radio-iodinated nanobots for radionuclide therapy resulted in a tumour size reduction of about 90%, positioning nanobots as efficient delivery nanosystems for bladder cancer therapy.

Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. METHODS AND RESULTS: In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O6-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. CONCLUSION: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy.