Transition-Metal-Catalyzed Transformations for the Synthesis of Marine Drugs.

Transition metal catalysis has contributed to the discovery of novel methodologies and the preparation of natural products, as well as new chances to increase the chemical space in drug discovery programs. In the case of marine drugs, this strategy has been used to achieve selective, sustainable and efficient transformations, which cannot be obtained otherwise. In this perspective, we aim to showcase how a variety of transition metals have provided fruitful couplings in a wide variety of marine drug-like scaffolds over the past few years, by accelerating the production of these valuable molecules.

Identification of Olives Using In-Field Hyperspectral Imaging with Lightweight Models.

During the growing season, olives progress through nine different phenological stages, starting with bud development and ending with senescence. During their lifespan, olives undergo changes in their external color and chemical properties. To tackle these properties, we used hyperspectral imaging during the growing season of the olives. The objective of this study was to develop a lightweight model capable of identifying olives in the hyperspectral images using their spectral information. To achieve this goal, we utilized the hyperspectral imaging of olives while they were still on the tree and conducted this process throughout the entire growing season directly in the field without artificial light sources. The images were taken on-site every week from 9:00 to 11:00 a.m. UTC to avoid light saturation and glitters. The data were analyzed using training and testing classifiers, including Decision Tree, Logistic Regression, Random Forest, and Support Vector Machine on labeled datasets. The Logistic Regression model showed the best balance between classification success rate, size, and inference time, achieving a 98% F1-score with less than 1 KB in parameters. A reduction in size was achieved by analyzing the wavelengths that were critical in the decision making, reducing the dimensionality of the hypercube. So, with this novel model, olives in a hyperspectral image can be identified during the season, providing data to enhance a farmer's decision-making process through further automatic applications.

Continuous Flow Chemistry: A Novel Technology for the Synthesis of Marine Drugs.

In this perspective, we showcase the benefits of continuous flow chemistry and photochemistry and how these valuable tools have contributed to the synthesis of organic scaffolds from the marine environment. These technologies have not only facilitated previously described synthetic pathways, but also opened new opportunities in the preparation of novel organic molecules with remarkable pharmacological properties which can be used in drug discovery programs.

Acute hepatitis secondary to febuxostat.

Febuxostat is a drug from the group of xanthine dehydrogenase inhibitors and is used in the treatment of hyperuricemia and gouty arthritis. However, it is not free of adverse effects, including alteration of liver profile tests. This is why we must pay attention to this type of adverse events in case it is necessary to suspend treatment. We present a clinical case of acute hepatitis secondary to Febuxostat.

DRESS syndrome secondary to carbamazepine.

DRESS syndrome is a multisystem disorder that appears in the context of an adverse drug reaction, characterized by fever, rash and peripheral eosinophilia with involvement of other organs such as the liver. The typical liver involvement is acute toxic hepatitis (DILI), showing improvement and a tendency to resolution when corticotherapy is started. We must not forget this manifestation in the clinical context of a DRESS syndrome.

Design and Evaluation of a Heterogeneous Lightweight Blockchain-Based Marketplace.

The proposal of this paper is to introduce a low-level blockchain marketplace, which is a blockchain where participants could share its power generation and demand. To achieve this implementation in a secure way for each actor in the network, we proposed to deploy it over efficient and generic low-performance devices. Thus, they are installed as IoT devices, registering measurements each fifteen minutes, and also acting as blockchain nodes for the marketplace. Nevertheless, it is necessary that blockchain is lightweight, so it is implemented as a specific consensus protocol that allows each node to have enough time and computer requirements to act both as an IoT device and a blockchain node. This marketplace will be ruled by Smart Contracts deployed inside the blockchain. With them, it is possible to make registers for power generation and demand. This low-level marketplace could be connected to other services to execute matching algorithms from the data stored in the blockchain. Finally, a real test-bed implementation of the marketplace was tested, to confirm that it is technically feasible.

Adrenal insufficiency and hepatic cirrhosis: a relationship to discover.

Liver cirrhosis is an entity that predisposes to adrenal insufficiency. Adequate screening for this condition in patients with liver cirrhosis, since several studies have shown increased survival with the use of corticosteroids in cirrhotic patients with septic shock, it seems reasonable to identify patients with adrenal insufficiency in the context of liver cirrhosis and individualize your treatment.

Cefditoren-induced hepatitis.

There are many daily antibiotic prescriptions, especially beta-lactams in trivial infections such as cystitis in young women. Many of these drugs carry an implicit probability of producing hepatotoxicity, manifested by a nonspecific general picture and elevated analytical transaminases. We must take it into account when making the differential diagnosis in the hepatotoxicity study and suspend it as soon as we recognize it.

Meta-analysis of intravascular volume expansion strategies to prevent contrast-associated acute kidney injury following invasive angiography.

OBJECTIVE: To perform a detailed analysis of published data regarding intravascular volume expansion to prevent contrast-associated acute kidney injury (CA-AKI) and to determine if an ideal dose of IV fluids can be recommended. BACKGROUND: Administration of contrast media during invasive angiography is associated with CA-AKI. Intravascular volume expansion is the most effective intervention to prevent CA-AKI, yet evidenced based protocols are lacking. METHODS: Literature review and meta-analysis of randomized controlled trials (RCT) of patients receiving IV volume expansion as prophylaxis for CA-AKI was performed. Normal saline, Lactated Ringer's and sodium bicarbonate were included. The primary outcome was incidence of CA-AKI. RESULTS: 37 RCTs studying 12,166 patients were included. Mean age was 67 ± 5 years, 70% of the patients were male. 68% had chronic kidney disease, 41% diabetes, and 30% heart failure. The incidence of CA-AKI was 9.5% (95% CI: 8-12%). IV expansion versus no volume administration was associated with a lower risk of CA-AKI (RR:0.62; 95% CI: 0.49-0.77, p < .001). Intensive IV volume expansion was associated with a reduced risk of CA-AKI(RR: 0.66; 95%CI: 0.52-0.85, p < .01). The intensive IV volume expansion arm received significantly more fluids than the standard protocols: 1,574(1,123 - 1,913) ml versus 849(558-1,067) ml (p = .03) without significant difference in the duration of infusion (median of 12 vs. 17 hr, p = .1) or pulmonary edema (1.7% vs 1.3%, p = .7). CONCLUSIONS: Despite high variability in protocols used, IV volume expansion is effective in preventing CA-AKI. Intensive IVF expansion (median 1.6 L over 17 hr) was associated with decreased risk of CA-AKI.

COVID-19 and the cardiovascular system: A review of current data, summary of best practices, outline of controversies, and illustrative case reports.

As the severe acute respiratory syndrome coronavirus 2 virus pandemic continues to grow globally, an association is apparent between patients with underlying cardiovascular disease comorbidities and the risk of developing severe COVID-19. Furthermore, there are potential cardiac manifestations of severe acute respiratory syndrome coronavirus 2 including myocyte injury, ventricular dysfunction, coagulopathy, and electrophysiologic abnormalities. Balancing management of the infection and treatment of underlying cardiovascular disease requires further study. Addressing the increasing reports of health care worker exposure and deaths remains paramount. This review summarizes the most contemporary literature on the relationship of the cardiovascular system and COVID-19 and society statements with relevance to protection of health care workers, and provides illustrative case reports in this context.

Programme for Harmonization to the International Scale in Latin America for BCR-ABL1 quantification in CML patients: findings and recommendations.

Objectives The quantitation of BCR-ABL1 mRNA is mandatory for chronic myeloid leukemia (CML) patients, and RT-qPCR is the most extensively used method in testing laboratories worldwide. Nevertheless, substantial variation in RT-qPCR results makes inter-laboratory comparability hard. To facilitate inter-laboratory comparative assessment, an international scale (IS) for BCR-ABL1 was proposed. Methods The laboratory-specific conversion factor (CF) to the IS can be derived from the World Health Organization (WHO) genetic reference panel; however, this material is limited to the manufacturers to produce and calibrate secondary reference reagents. Therefore, we developed secondary reference calibrators, as lyophilized cellular material, aligned to the IS. Our purpose was both to re-evaluate the CF in 18 previously harmonized laboratories and to propagate the IS to new laboratories. Results Our field trial including 30 laboratories across Latin America showed that, after correction of raw BCR-ABL1/ABL1 ratios using CF, the relative mean bias was significantly reduced. We also performed a follow-up of participating laboratories by annually revalidating the process; our results support the need for continuous revalidation of CFs. All participating laboratories also received a calibrator to determine the limit of quantification (LOQ); 90% of them could reproducibly detect BCR-ABL1, indicating that these laboratories can report a consistent deep molecular response. In addition, aiming to investigate the variability of BCR-ABL1 measurements across different RNA inputs, we calculated PCR efficiency for each individual assay by using different amounts of RNA. Conclusions In conclusion, for the first time in Latin America, we have successfully organized a harmonization platform for BCR-ABL1 measurement that could be of immediate clinical benefit for monitoring the molecular response of patients in low-resource regions.

Identification of novel regulatory partners of the glutamate transporter GLT-1.

We used proximity-dependent biotin identification (BioID) to find proteins that potentially interact with the major glial glutamate transporter, GLT-1, and we studied how these interactions might affect its activity. GTPase Rac1 was one protein identified, and interfering with its GTP/GDP cycle in mixed primary rat brain cultures affected both the clustering of GLT-1 at the astrocytic processes and the transport kinetics, increasing its uptake activity at low micromolar glutamate concentrations in a manner that was dependent on the effector kinase PAK1 and the actin cytoskeleton. Interestingly, the same manipulations had a different effect on another glial glutamate transporter, GLAST, inhibiting its activity. Importantly, glutamate acts through metabotropic receptors to stimulate the activity of Rac1 in astrocytes, supporting the existence of cross-talk between extracellular glutamate and the astrocytic form of the GLT-1 regulated by Rac1. CDC42EP4/BORG4 (a CDC42 effector) was also identified in the BioID screen, and it is a protein that regulates the assembly of septins and actin fibers, influencing the organization of the cytoskeleton. We found that GLT-1 interacts with septins, which reduces its lateral mobility at the cell surface. Finally, the G-protein subunit GNB4 dampens the activity of GLT-1, as revealed by its response to the activator peptide mSIRK, both in heterologous systems and in primary brain cultures. This effect occurs rapidly and thus, it is unlikely to depend on cytoskeletal dynamics. These novel interactions shed new light on the events controlling GLT-1 activity, thereby helping us to better understand how glutamate homeostasis is maintained in the brain.

HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a deadly chronic lung disease. Extracellular accumulation of adenosine and subsequent activation of the ADORA2B receptor play important roles in regulating inflammation and fibrosis in IPF. Additionally, alternatively activated macrophages (AAMs) expressing ADORA2B have been implicated in mediating adenosine's effects in IPF. Although hypoxic conditions are present in IPF, hypoxia's role as a direct modulator of macrophage phenotype and identification of factors that regulate ADORA2B expression on AAMs in IPF is not well understood. In this study, an experimental mouse model of pulmonary fibrosis and lung samples from patients with IPF were used to examine the effects and interactions of macrophage differentiation and hypoxia on fibrosis. We demonstrate that hypoxia-inducible factor 1-α (HIF1A) inhibition in late stages of bleomycin-induced injury attenuates pulmonary fibrosis in association, with reductions in ADORA2B expression in AAMs. Additionally, ADORA2B deletion or pharmacological antagonism along with HIF1A inhibition disrupts AAM differentiation and subsequent IL-6 production in cultured macrophages. These findings suggest that hypoxia, through HIF1A, contributes to the development and progression of pulmonary fibrosis through its regulation of ADORA2B expression on AAMs, cell differentiation, and production of profibrotic mediators. These studies support a potential role for HIF1A or ADORA2B antagonists in the treatment of IPF.-Philip, K., Mills, T. W., Davies, J., Chen, N.-Y., Karmouty-Quintana, H., Luo, F., Molina, J. G., Amione-Guerra, J., Sinha, N., Guha, A., Eltzschig, H. K., Blackburn, M. R. HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis.

Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors.

Calcium plays an integral role to many cellular processes including contraction, energy metabolism, gene expression, and cell death. The inositol 1, 4, 5-trisphosphate receptor (IP3R) is a calcium channel expressed in cardiac tissue. There are three IP3R isoforms encoded by separate genes. In the heart, the IP3R-2 isoform is reported to being most predominant with regards to expression levels and functional significance. The functional roles of IP3R-1 and IP3R-3 in the heart are essentially unexplored despite measureable expression levels. Here we show that all three IP3Rs isoforms are expressed in both neonatal and adult rat ventricular cardiomyocytes, and in human heart tissue. The three IP3R proteins are expressed throughout the cardiomyocyte sarcoplasmic reticulum. Using isoform specific siRNA, we found that expression of all three IP3R isoforms are required for hypertrophic signaling downstream of endothelin-1 stimulation. Mechanistically, IP3Rs specifically contribute to activation of the hypertrophic program by mediating the positive inotropic effects of endothelin-1 and leading to downstream activation of nuclear factor of activated T-cells. Our findings highlight previously unidentified functions for IP3R isoforms in the heart with specific implications for hypertrophic signaling in animal models and in human disease.

Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension.

Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxia-inducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.

Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-ß activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.

Acquired and Hereditary Hypercoagulable States in Patients with Continuous Flow Left Ventricular Assist Devices: Prevalence and Thrombotic Complications.

BACKGROUND: Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation. METHODS: We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively. RESULTS: A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P < .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005). CONCLUSION: Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.

Design of Assembled Systems Based on Conjugated Polyphenylene Derivatives and Carbon Nanohorns.

Promising materials have been designed and fully characterised by an effective interaction between versatile platforms such as carbon nanohorns (CNHs) and conjugated molecules based on thiophene derivatives. Easy and non-aggressive methods have been described for the synthesis and purification of the final systems. Oligothiophenephenylvinylene (OTP) systems with different geometries and electron density are coupled to the CNHs. A wide range of characterization techniques have been used to confirm the effective interaction between the donor (OTP) and the acceptor (CNH) systems. These hybrid materials show potential for integration into solar cell devices. Importantly, surface-enhanced Raman spectroscopy (SERS) effects are observed without the presence of any metal surface in the system. Theoretical calculations have been performed to study the optimised geometries of the noncovalent interaction between the surface and the organic molecule. The calculations allow information on the monoelectronic energies of HOMO-LUMO orbitals and band gap of different donor systems to be extracted.

High cobalamin levels as a five-year risk predictor for developing hematological cancer.

BACKGROUND: A high cobalamin level has been related to non-malignant diseases (mainly liver diseases, alcoholism, and renal diseases) and cancer (hematological malignancies and solid cancers such as liver and stomach cancer). However, a previous high level of cobalamin and the implications in the possible development of cancer is still unclear. The main aim of this study was to describe if a previous high cobalamin level is a determinant in the future development of cancer in five years of follow-up. The secondary objective was to determine any differences between cancer groups. METHODS: A retrospective study was performed. Two databases were employed. The first one included all patients who had a determination of cobalamin in a routine blood test during the year 2010 (a total of 44,166 patients). The second one showed every patient who was admitted to the reference hospital, Hospital Clinico Universitario de Valladolid, during the following five years. Finally, a number of 6710 patients was included. Both databases belong to the medical records of the Hospital Data Surveillance System and are completely validated. Multivariate logistic regression analyses were employed to evaluate the association between cobalamin levels and the appearance of cancer (total and in each subgroup). All analyses were performed using IBM SPSS 24 software (IBM Corp., Armonk, NY, USA). RESULTS: The sample studied showed a clear association between the risk of hematological cancer and a previous high Cbl level. This relationship was higher among patients with the highest levels (over 779 pmol/L), showing almost two times more risk for development of hematological malignance within 5 years in the multivariate analysis (OR: 1.975, 95% CI: 1.056-3.697, P=0.033). Hematological malignancies were mostly diagnosed within the first three years (86.6%), showing a similar percentage in those three years. There was no association between this previous level and the development of any other type of cancer. CONCLUSIONS: Our study shows that a high cobalamin plasma level (hypervitaminosis) is associated with the development of hematologic cancer within five years after the measurement. The clinical implication of these findings, together with the clinical suspicion, reinforces the necessity of carrying out specific screening hematological tests in patients with not justified elevated plasma cobalamin levels. New prospective and multicenter studies are necessary to validate these results.