Synthesis, antibiofilm activity and molecular docking of N-acylhomoserine lactones containing cinammic moieties.

We prepared a series of cinnamoyl-containing furanones by an affordable and short synthesis. The nineteen compounds hold a variety of substituents including electron-donating, electron-withdrawing, bulky and meta-substituted phenyls, as well as heterocyclic rings. Compounds showed antibiofilm activity in S. aureus, K. pneumoniae and, more pronounced, against P. aeruginosa. The disruption of quorum sensing (QS) was tested using the violacein test and molecular docking predicted the antagonism of LasR as a plausible mechanism of action. The trimethoxylated and diene derivatives showed the best antibiofilm and anti-QS properties, thus becoming candidates for further modifications.

A regioselective synthesis of 3,4-diaryl-1H-pyrazoles through a 1,3-dipolar cycloaddition of tosylhydrazones and nitroalkenes.

A procedure for the selective synthesis of 3,4-diaryl-1H-pyrazoles through a 1,3-dipolar cycloaddition is reported. The transformation occurred under mild conditions using affordable tosylhydrazones and nitroalkenes commencing from benzaldehydes/heteroaromatic aldehydes as starting materials. Due to the versatility of this protocol, we prepared a vast collection of 3,4-diaryl-1H-pyrazoles, which included the incorporation of heterocyclic rings at the pyrazole core. Two-dimensional NMR techniques (2D-NOESY and HMBC) confirmed the regioselectivity of the transformation and correlated well with DFT calculations. Accordingly, the analysis of the transition states indicated that the 3,4-diaryl product corresponded to the product with the lowest activation energy and led to the most stable product. Finally, the series was evaluated against three cancer cell lines, with compound 8f being the most remarkable analog in terms of activity and extraordinary selectivity towards PC-3 compared to the other cell lines (including COS-7).

Methemoglobinemia in Hemodialysis Patients due to Acute Chlorine Intoxication: A Case Series Calling Attention on an Old Problem.

INTRODUCTION: Hemodialysis uses municipal water that must be strictly purified and sterilized to be used for that procedure. Large amounts of decontaminants are often used, such as chlorine, and if these compounds are not subsequently removed they can be transferred to the blood of patients causing complications including methemoglobinemia. METHODS: In this case series study, dialysis patients in one unit were evaluated. We reviewed clinical characteristics and laboratory findings obtained on the day when the water supply was disinfected with chlorine, with the aim to quantify methemoglobin concentrations. Our objective was to characterize the clinical presentation and management of patients who presented with methemoglobinemia on a specific index day. We also reviewed reported cases in the literature regarding this underreported complication. RESULTS: Eight patients who presented with chlorine intoxication were evaluated. The methemoglobin concentrations were between 1.3% and 7.9% (reference value 0-1%). We believe this to be caused by water containing 0.78 mg/L of total chlorine. Seven patients presented with cyanosis, 4 with dizziness, 6 with dark brown blood, 4 with dyspnea, and 4 with headache and hemolytic anemia. Subjects were treated with supplemental oxygen, methylene blue, intravenous vitamin C, blood transfusions, and increased doses of erythropoietin. No patient died, and all continued with their usual hemodialysis sessions. CONCLUSION: Acute chlorine intoxication transferred by the water used during hemodialysis sessions can present with methemoglobinemia accompanied by cyanosis, oxygen desaturation, and hemolytic anemia. Chlorine levels should be carefully monitored in the water used for hemodialysis treatment.

EEG effective connectivity during the first year of life mirrors brain synaptogenesis, myelination, and early right hemisphere predominance.

INTRODUCTION: The maturation of electroencephalogram (EEG) effective connectivity in healthy infants during the first year of life is described. METHODS: Participants: A cross-sectional sample of 125 healthy at-term infants, from 0 to 12 months of age, underwent EEG in a state of quiet sleep. PROCEDURES: The EEG primary currents at the source were described with the sLoreta method. An unmixing algorithm was applied to reduce the leakage, and the isolated effective coherence, a direct and directed measurement of information flow, was calculated. RESULTS AND DISCUSSION: Initially, the highest indices of connectivity are at the subcortical nuclei, continuing to the parietal lobe, predominantly the right hemisphere, then expanding to temporal, occipital, and finally the frontal areas, which is consistent with the myelination process. Age-related connectivity changes were mostly long-range and bilateral. Connections increased with age, mainly in the right hemisphere, while they mainly decreased in the left hemisphere. Increased connectivity from 20 to 30 Hz, mostly at the right hemisphere. These findings were consistent with right hemisphere predominance during the first three years of life. Theta and alpha connections showed the greatest changes with age. Strong connectivity was found between the parietal, temporal, and occipital regions to the frontal lobes, responsible for executive functions and consistent with behavioral development during the first year. The thalamus exchanges information bidirectionally with all cortical regions and frequency bands. CONCLUSIONS: The maturation of EEG connectivity during the first year in healthy infants is very consistent with synaptogenesis, reductions in synaptogenesis, myelination, and functional and behavioral development.

Harmonized-Multinational qEEG norms (HarMNqEEG).

This paper extends frequency domain quantitative electroencephalography (qEEG) methods pursuing higher sensitivity to detect Brain Developmental Disorders. Prior qEEG work lacked integration of cross-spectral information omitting important functional connectivity descriptors. Lack of geographical diversity precluded accounting for site-specific variance, increasing qEEG nuisance variance. We ameliorate these weaknesses. (i) Create lifespan Riemannian multinational qEEG norms for cross-spectral tensors. These norms result from the HarMNqEEG project fostered by the Global Brain Consortium. We calculate the norms with data from 9 countries, 12 devices, and 14 studies, including 1564 subjects. Instead of raw data, only anonymized metadata and EEG cross-spectral tensors were shared. After visual and automatic quality control, developmental equations for the mean and standard deviation of qEEG traditional and Riemannian DPs were calculated using additive mixed-effects models. We demonstrate qEEG "batch effects" and provide methods to calculate harmonized z-scores. (ii) We also show that harmonized Riemannian norms produce z-scores with increased diagnostic accuracy predicting brain dysfunction produced by malnutrition in the first year of life and detecting COVID induced brain dysfunction. (iii) We offer open code and data to calculate different individual z-scores from the HarMNqEEG dataset. These results contribute to developing bias-free, low-cost neuroimaging technologies applicable in various health settings.

Expanding the structure-activity relationship of cytotoxic diphenyl macrocycles.

Twenty-four biaryl tetrapeptide macrocycles were synthesized as an extension of our previous work. Two groups of compounds were constructed for establishing a structure-activity relationship: one having an aromatic substituent at α-position of one exo-peptide and the other group with a variation in the size of the lipophilic chain. Compound 13t had the best cytotoxicity from all the compounds tested (in a panel of six human cancer cell lines) and low toxicity on one healthy cell line. The study identified the lipophilic chain as the main structural moiety for improving the biological activity, being the seven-carbon chain the optimal length. On the other hand, the aromatic rings at α-position did not enhance the cytotoxicity.

Greenhouse gas emissions from cattle dung depositions in two Urochloa forage fields with contrasting biological nitrification inhibition (BNI) capacity.

Grazing-based production systems are a source of soil greenhouse gas (GHG) emissions triggered by excreta depositions. The adoption of Urochloa forages (formerly known as Brachiaria) with biological nitrification inhibition (BNI) capacity is a promising alternative to reduce nitrous oxide (N2O) emissions from excreta patches. However, how this forage affects methane (CH4) or carbon dioxide (CO2) emissions from excreta patches remains unclear. This study investigated the potential effect of soils under two Urochloa forages with contrasting BNI capacity on GHG emissions from cattle dung deposits. Additionally, the N2O and CH4 emission factors (EF) for cattle dung under tropical conditions were determined. Dung from cattle grazing star grass (without BNI) was deposited on both forage plots: Urochloa hybrid cv. Mulato and Urochloa humidicola cv. Tully, with a respectively low and high BNI capacity. Two trials were conducted for GHG monitoring using the static chamber technique. Soil and dung properties and GHG emissions were monitored in trial 1. In trial 2, water was added to simulate rainfall and evaluate GHG emissions under wetter conditions. Our results showed that beneath dung patches, the forage genotype influenced daily CO2 and cumulative CH4 emissions during the driest conditions. However, no significant effect of the forage genotype was found on mitigating N2O emissions from dung. We attribute the absence of a significant BNI effect on N2O emissions to the limited incorporation of dung-N into the soil and rhizosphere where the BNI effect occurs. The average N2O EFs was 0.14%, close to the IPCC 2019 uncertainty range (0.01-0.13% at 95% confidence level). Moreover, CH4 EFs per unit of volatile solid (VS) averaged 0.31 g CH4 kgVS-1, slightly lower than the 0.6 g CH4 kgVS-1 developed by the IPCC. This implies the need to invest in studies to develop more region-specific Tier 2 EFs, including farm-level studies with animals consuming Urochloa forages to consider the complete implications of forage selection on animal excreta based GHG emissions.

Multicomponent synthesis and preliminary anti-inflammatory activity of lipophilic diphenylamines.

Non-Steroidal Anti-inflammatory Drugs (NSAIDs) are some of the most prescribed medications for pain but the incidence of adverse effects -especially during chronic treatment- points out the requirement of new analgesics. In this study, we showed an efficient two-steps synthesis of diphenylamine-containing dipeptides consisting of a multicomponent process followed by a Buchwald-Hartwig cross-coupling reaction. We prepared 16 diphenylamine derivatives and evaluated their in vivo anti-inflammatory activity through an ear edema model using 12-O-tetradecanoylpholbol-13-acetate. Furthermore, the toxicity of the more potent compounds in the Artemia salina model and their cell viability using murine RAW 264.7 cells is reported. The fluorinated compound 10k becomes a reliable candidate since it reduced the TPA-induced edema to 92%, lacked cytotoxicity against murine macrophages, and had minimal toxicity in Artemia salina.

Multicomponent synthesis and anti-proliferative screening of biaryl triazole-containing cyclophanes.

We report a practical two-step approach involving a Ugi 4-CR/ azide-alkyne cycloaddition for the synthesis of biaryl-containing cyclophanes. The series represents an extension of our previously reported macrocycles as an effort to enhance the anti-proliferative activity of this scaffold. In this variant, we incorporate a biphenyl moiety in the framework, thus enhancing the macrocycle size, lipophilicity, and structural diversity. Macrocycles were tested against different cell lines, being more cytotoxic against prostate (PC-3 and DU-145) and breast (MCF-7) tumor cells. Gratifyingly, the most active compound showed a significative enhancement of PC-3 growth inhibition with respect to our previous series, reaffirming the potential anti-proliferative activity of this kind of cyclophanes.

Neurofeedback Training Based on Motor Imagery Strategies Increases EEG Complexity in Elderly Population.

Neurofeedback training (NFT) has shown promising results in recent years as a tool to address the effects of age-related cognitive decline in the elderly. Since previous studies have linked reduced complexity of electroencephalography (EEG) signal to the process of cognitive decline, we propose the use of non-linear methods to characterise changes in EEG complexity induced by NFT. In this study, we analyse the pre- and post-training EEG from 11 elderly subjects who performed an NFT based on motor imagery (MI-NFT). Spectral changes were studied using relative power (RP) from classical frequency bands (delta, theta, alpha, and beta), whilst multiscale entropy (MSE) was applied to assess EEG-induced complexity changes. Furthermore, we analysed the subject's scores from Luria tests performed before and after MI-NFT. We found that MI-NFT induced a power shift towards rapid frequencies, as well as an increase of EEG complexity in all channels, except for C3. These improvements were most evident in frontal channels. Moreover, results from cognitive tests showed significant enhancement in intellectual and memory functions. Therefore, our findings suggest the usefulness of MI-NFT to improve cognitive functions in the elderly and encourage future studies to use MSE as a metric to characterise EEG changes induced by MI-NFT.

Novel coronavirus, novel faculty development programs: rapid transition to eLearning during the pandemic.

The novel coronavirus disease 2019 (COVID-19) has caused a rapid and massive transition to online education. We describe the response of our Office of Faculty Development at Texas Tech University Health Sciences Center El Paso (TTUHSC EP) to this unprecedented challenge during and after this post-pandemic crisis. The initiatives for emergency transition to eLearning and faculty development described in this paper may serve as a model for other academic health centers, schools, colleges and universities.

Diarrheagenic Escherichia coli pathotypes isolated from a swine farm in a region of Morelos state, Mexico.

OBJECTIVE: Determine the frequency of diarrheagenic Escherichia coli pathotypes colonizing swine. MATERIALS AND METHODS: E. coli strains isolated of fecal samples from 280 swine, produced for local consumption, in a semi-technical farm of Morelos state, (central Mexico) were tested to identify the diarrheagenic E. coli pathotypes by multiplex PCR. RESULTS: Of the 521-diarrheagenic E. coli isolates examined, 50 (9.6%) were positive for at least one virulence gene in 42 different animals. Thus, 15% (42/280) of the swine in this farm were colonized with pathogenic E. coli. Among the E. coli isolates, the pathotype EPEC (6.5%) was the most frequently, followed by EHEC (2.3%), ETEC and EIEC (0.4%). CONCLUSIONS: In this study, four different E. coli pathotypes were found among swine colonized by E. coli in this farm. Thus, these swine are reservoirs for these virulent bacteria and there is potential risk of causing diarrhea in swine and in the population consuming the meat.

Correction: Martínez-Cagigal, V.; Santamaría-Vázquez, E.; Hornero, R. Asynchronous Control of P300-Based Brain-Computer Interfaces Using Sample Entropy. Entropy 2019, 21, 230.

Figure 5 of the original paper contains errors [...].

Synthesis of diphenylamine macrocycles and their anti-inflammatory effects.

A collection of fourteen diphenylamine macrocyclic derivatives containing a peptide chain with different substituents was synthesized using a protocol of two Ugi four component reactions (Ugi-4CR) and a Buchwald-Hartwig macrocyclization. Their anti-inflammatory effects were assayed with an ear edema model using 12-O-tetradecanoylphorbol-13-acetate, while the activity of myeloperoxidase was determined to evaluate the index of leukocyte infiltration. Compound 5e had an ID50 of 0.18 µM per ear with a potency higher than that of the reference drugs indomethacin and celecoxib (0.24 and 0.91 µM per ear, respectively). Moreover, the cytotoxicity of the macrocycles was determined in two healthy cell lines, showing a low percentage of toxicity.

Validating Non-invasive EEG Source Imaging Using Optimal Electrode Configurations on a Representative Rat Head Model.

The curtain of technical limitations impeding rat multichannel non-invasive electroencephalography (EEG) has risen. Given the importance of this preclinical model, development and validation of EEG source imaging (ESI) is essential. We investigate the validity of well-known human ESI methodologies in rats which individual tissue geometries have been approximated by those extracted from an MRI template, leading also to imprecision in electrode localizations. With the half and fifth sensitivity volumes we determine both the theoretical minimum electrode separation for non-redundant scalp EEG measurements and the electrode sensitivity resolution, which vary over the scalp because of the head geometry. According to our results, electrodes should be at least ~3 to 3.5 mm apart for an optimal configuration. The sensitivity resolution is generally worse for electrodes at the boundaries of the scalp measured region, though, by analogy with human montages, concentrates the sensitivity enough to localize sources. Cramér-Rao lower bounds of source localization errors indicate it is theoretically possible to achieve ESI accuracy at the level of anatomical structures, such as the stimulus-specific somatosensory areas, using the template. More validation for this approximation is provided through the comparison between the template and the individual lead field matrices, for several rats. Finally, using well-accepted inverse methods, we demonstrate that somatosensory ESI is not only expected but also allows exploring unknown phenomena related to global sensory integration. Inheriting the advantages and pitfalls of human ESI, rat ESI will boost the understanding of brain pathophysiological mechanisms and the evaluation of ESI methodologies, new pharmacological treatments and ESI-based biomarkers.

Asynchronous Control of P300-Based Brain-Computer Interfaces Using Sample Entropy.

Brain-computer interfaces (BCI) have traditionally worked using synchronous paradigms. In recent years, much effort has been put into reaching asynchronous management, providing users with the ability to decide when a command should be selected. However, to the best of our knowledge, entropy metrics have not yet been explored. The present study has a twofold purpose: (i) to characterize both control and non-control states by examining the regularity of electroencephalography (EEG) signals; and (ii) to assess the efficacy of a scaled version of the sample entropy algorithm to provide asynchronous control for BCI systems. Ten healthy subjects participated in the study, who were asked to spell words through a visual oddball-based paradigm, attending (i.e., control) and ignoring (i.e., non-control) the stimuli. An optimization stage was performed for determining a common combination of hyperparameters for all subjects. Afterwards, these values were used to discern between both states using a linear classifier. Results show that control signals are more complex and irregular than non-control ones, reaching an average accuracy of 94 . 40 % in classification. In conclusion, the present study demonstrates that the proposed framework is useful in monitoring the attention of a user, and granting the asynchrony of the BCI system.

Oral acyclovir induced hypokalemia and acute tubular necrosis a case report.

BACKGROUND: Acyclovir is one of the most common prescribed antiviral drugs. Acyclovir nephrotoxicity occurs in approximately 12-48% of cases. It can present in clinical practice as acute kidney injury (AKI), crystal-induced nephropathy, acute tubulointerstitial nephritis, and rarely, as tubular dysfunction. Electrolytes abnormalities like hypokalemia, were previously described only when given intravenously. CASE PRESENTATION: A 54 year-old female presented with weakness and lower extremities paresis, nausea and vomiting after receiving oral acyclovir. Physical examination disclosed a decrease in the patellar osteotendinous reflexes (++ / ++++). Laboratory data showed a serum creatinine level of 2.1 mg/dL; serum potassium 2.1 mmol/L. Kidney biopsy was obtained; histological findings were consistent with acute tubular necrosis and acute tubulointerstitial nephritis. The patient was advised to stop the medications and to start with oral and intravenous potassium supplement, symptoms improved and continued until serum potassium levels were > 3.5 meq/L. CONCLUSIONS: The case reported in this vignette is unique since it is the first one to describe hypokalemia associated to acute tubular necrosis induced by oral acyclovir.

Ácido úrico sérico como marcador de gravedad clínica y comorbilidad en psoriasis en placas.

INTRODUCCIÓN: La hiperuricemia es común en pacientes con psoriasis. Se ha sugerido que la elevación de ácido úrico en psoriasis está fuertemente asociada con morbilidad cardiovascular. OBJETIVO: Determinar la relación entre niveles de ácido úrico, gravedad clínica medida por Psoriasis Area Severity Index (PASI), Body Surface Area (BSA) y static Physician's Global Assessment (sPGA) en pacientes con psoriasis en placas y comorbilidades ungueales y artritis psoriásica. MÉTODO: Determinación de ácido úrico sérico en 45 pacientes con psoriasis en placas y 45 controles pareados por sexo, edad e índice de masa corporal; medición de índices de gravedad clínica en pacientes y presencia de manifestaciones ungueales y articulares. RESULTADOS: Los pacientes con psoriasis presentaron niveles más elevados de ácido úrico (7.03 ± 1.47 versus 5.32 ± 1.17, p < 0.01) y mayor prevalencia de hiperuricemia asintomática (68 versus 17.8 %, p < 0.01) que los controles. Existió correlación proporcional significativa entre gravedad determinada por PASI y ácido úrico (r2 = 0.70) y entre manifestaciones articulares e hiperuricemia en pacientes con psoriasis en placas (p < 0.01; RM = 2.85, IC 95 % = 1.52-5.33). CONCLUSIONES: Los niveles séricos de ácido úrico tuvieron correlación proporcional con PASI y se asociaron con manifestaciones articulares en pacientes con psoriasis en placas. INTRODUCTION: Hyperuricemia is common in patients with psoriasis. Uric acid elevation in psoriasis has been suggested to be strongly associated with cardiovascular morbidity. OBJECTIVE: To determine the relationship between uric acid levels and clinical severity as measured by the Psoriasis Area Severity Index (PASI), body surface area (BSA) and static Physician's Global Assessment (sPGA) in patients with plaque psoriasis and nail comorbidities and psoriatic arthritis. METHOD: Determination of serum uric acid in 45 patients with plaque psoriasis and 45 controls matched by gender, age and body mass index; measurement of patient clinical severity indices and presence of nail and joint manifestations. RESULTS: Patients with psoriasis had higher levels of uric acid (7.03 ± 1.47 versus 5.32 ± 1.17, p < 0.01), and higher prevalence of asymptomatic hyperuricemia than controls (68% versus 17.8%, p < 0.01). There was significant proportional correlation between PASI-determined severity and uric acid (r2 = 0.70), and between joint manifestations and hyperuricemia in patients with plaque psoriasis (p < 0.01; OR = 2.85, 95% CI = 1.52-5.33). CONCLUSIONS: Serum uric acid levels had a proportional correlation with PASI and were associated with joint manifestations in patients with plaque psoriasis.

Bleeding Risk of Antithrombotic Treatment in Patients on Hemodialysis.

BACKGROUND: The risk-benefit of antithrombotic treatment (ATT) has not been established in patients on dialysis. Our objective was to determine the influence of ATT on the risk of hemorrhage in patients on hemodialysis. METHODS: We included patients who began dialysis between 2003 and 2007. We determined the rates of fatal bleeding or bleeding leading to hospitalization or transfusion. RESULTS: Two hundred twenty-one patients were included. Over the follow-up period (45.5 ± 34 months), there were 76 hemorrhages in 52 patients. There were 10 fatal bleedings. The annual incidence of patients presenting with hemorrhagia was 6.2%. Bleeding occurred in 5.2% of those being treated with aspirin, 7% with acenocumarol, 12.3% with clopidogrel, 15.2% with aspirin + clopidogrel, 45.9% with anticoagulants + antiplatelets, 49.6% with low-molecular-weight heparin, and 3.9% without ATT. On multivariate analysis, masculine gender [hazard ratio (HR): 2.421; 95% confidence interval (CI), 1.261-4.650; P = 0.003], treatment with dicumarins (HR: 2.406; 95% CI, 1.013-5.718; P = 0.047), treatment with clopidogrel (HR: 2.697; 95% CI, 1.440-5.051; P = 0.002), and treatment with low-molecular-weight heparin (HR: 21.463; 95% CI, 9.067-50.806; P = 0.001) were independent predictors of bleeding. CONCLUSIONS: ATT increases the risk of bleeding in patients on hemodialysis. The incidence of hemorrhage varies with the type of antithrombotics used.