Immunometric and functional measurement of endogenous vasoinhibin in human sera.

Introduction: Circulating levels of the antiangiogenic protein vasoinhibin, a fragment of prolactin, are of interest in vasoproliferative retinopathies, preeclampsia, and peripartum cardiomyopathy; however, it is difficult to determine the circulating levels of vasoinhibin due to the lack of quantitative assays. Methods: This study used human serum samples to assess the concentration and bioactivity of vasoinhibin using a novel enzyme-linked immunosorbent assay (ELISA) for human vasoinhibin, which employs an anti-vasoinhibin monoclonal antibody, a human umbilical vein endothelial cell (HUVEC) proliferation assay, and a chick chorioallantoic membrane (CAM) angiogenesis assay. Results: Serum samples from 17 pregnant women without (one group) and with preeclampsia and pregnancy induced hypertension (another group) demonstrated endogenous vasoinhibin concentrations in the range of 5-340 ng/ml. Immunoactive vasoinhibin levels were significantly higher in preeclampsia serum compared to healthy pregnancy serum (mean 63.09 ± 22.15 SD vs. 19.67 ± 13.34 ng/ml, p = 0.0003), as was the bioactive vasoinhibin level as determined by the HUVEC proliferation assay (56.12 ± 19.83 vs. 13.38 ± 4.88 ng/ml, p < 0.0001). There was a correlation between the concentration of vasoinhibin measured by ELISA and the HUVEC proliferation assay (Pearson r = 0.95, p < 0.0001). Healthy serum demonstrated a proangiogenic effect in the CAM assay (p < 0.05, compared to control), while serum from preeclamptic patients demonstrated an antiangiogenic effect (p < 0.05 vs. control), as did recombinant human vasoinhibin and a synthetic circular retro-inverse vasoinhibin analogue (CRIVi45-51). The antiangiogenic effects in the CAM assay and the inhibition of HUVEC proliferation were abolished by addition of the ELISA anti-vasoinhibin monoclonal antibody, but not by mouse IgG. Discussion: These results demonstrate the first quantitation of endogenous vasoinhibin in human sera and the elevation of it levels and antiangiogenic activity in sera from women with preeclampsia. The development and implementation of a quantitative assay for vasoinhibin overcomes a long-standing barrier and suggests the thorough clinical verification of vasoinhibin as a relevant biomarker.

Physiological Responses of a Grapefruit Orchard to Irrigation with Desalinated Seawater.

Desalinated seawater (DSW) has emerged as a promising solution for irrigation in regions facing water scarcity. However, adopting DSW may impact the existing cultivation model, given the presence of potentially harmful elements, among other factors. A three-year experiment was carried out to assess the short-term effects of four irrigation waters-freshwater (FW), DSW, a mix 1:1 of FW and DSW (MW), and DSW with low boron (B) concentration (DSW-B)-on a 'Rio Red' grapefruit orchard. These irrigation waters exhibited varying levels of phytotoxic elements, some potentially harmful to citrus trees. Sodium (Na+) and chloride (Cl-) concentrations exceeded citrus thresholds in all treatments, except in DSW-B, whilst B exceeded toxicity levels in DSW and MW treatments. Leaf concentrations of Cl- and Na+ remained low in all treatments, whereas B approached toxic levels only in DSW and MW-irrigated trees. The rapid growth of the trees, preventing excessive accumulation through a dilution effect, protected the plants from significant impacts on nutrition and physiology, such as gas exchange and chlorophyll levels, due to phytotoxic elements accumulation. Minor reductions in photosynthesis in DSW-irrigated trees were attributed to high B in leaves, since Cl- and Na+ remained below toxic levels. The accelerated tree growth effectively prevented the substantial accumulation of phytotoxic elements, thereby limiting adverse effects on tree development and yield. When the maturation of trees reaches maximal growth, the potential accumulation of phytotoxic elements is expected to increase, potentially influencing tree behavior differently. Further study until the trees reach maturity is imperative for comprehensive understanding of the long-term effects of desalinated seawater irrigation.

Effect of Amine, Carboxyl, or Thiol Functionalization of Mesoporous Silica Particles on Their Efficiency as a Quercetin Delivery System in Simulated Gastrointestinal Conditions.

Quercetin (Q) dietary supplements exhibit poor oral bioavailability because of degradation throughout gastrointestinal digestion (GD), which may be overcome using mesoporous silica particles (MSPs) as an oral delivery system (ODS). This study aimed to elucidate the effect of the functionalization of MSPs with amine-(A-MSP), carboxyl-(C-MSP), or thiol-(T-MSP) groups on their efficiency as a quercetin ODS (QODS). The type and degree of functionalization (DF) were used as factors in an experimental design. The Q-loaded F-MSP (F-MSP/Q) was characterized by gas physisorption analysis, loading capacity (LC), and dynamic light scattering and kinetics of Q release at gastric and intestinal pHs. Antioxidant capacity and Q concentration of media containing F-MSP/Q were evaluated after simulated GD. A-MSP showed the highest LC (19.79 ± 2.42%). C-MSP showed the lowest particle size at pH 1.5 or 7.4 (≈200 nm). T-MSP exhibited the maximum Q release at pH 7.4 (11.43%). High DF of A-MSP increased Q retention, regardless of pH. A-MSP preserved antioxidant capacity of Q-released gastric media (58.95 ± 3.34%). Nonetheless, MSP and F-MSP did not protect antioxidant properties of Q released in intestinal conditions. C-MSP and T-MSP showed essential features for cellular uptake and Q release within cells that need to be assessed.

Assessing Outcomes of Patients Subject to Intensive Care to Facilitate Organ Donation: A Spanish Multicenter Prospective Study.

Intensive Care to facilitate Organ Donation (ICOD) consists of the initiation or continuation of intensive care measures in patients with a devastating brain injury (DBI) in whom curative treatment is deemed futile and death by neurological criteria (DNC) is foreseen, to incorporate organ donation into their end-of-life plans. In this study we evaluate the outcomes of patients subject to ICOD and identify radiological and clinical factors associated with progression to DNC. In this first prospective multicenter study we tested by multivariate regression the association of clinical and radiological severity features with progression to DNC. Of the 194 patients, 144 (74.2%) patients fulfilled DNC after a median of 25 h (95% IQR: 17-44) from ICOD onset. Two patients (1%) shifted from ICOD to curative treatment, both were alive at discharge. Factors associated with progression to DNC included: age below 70 years, clinical score consistent with severe brain injury, instability, intracranial hemorrhage, midline shift ≥5 mm and certain types of brain herniation. Overall 151 (77.8%) patients progressed to organ donation. Based on these results, we conclude that ICOD is a beneficial and efficient practice that can contribute to the pool of deceased donors.

Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

Prediabetes and Cardiometabolic Risk: The Need for Improved Diagnostic Strategies and Treatment to Prevent Diabetes and Cardiovascular Disease.

The progression from prediabetes to type-2 diabetes depends on multiple pathophysiological, clinical, and epidemiological factors that generally overlap. Both insulin resistance and decreased insulin secretion are considered to be the main causes. The diagnosis and approach to the prediabetic patient are heterogeneous. There is no agreement on the diagnostic criteria to identify prediabetic subjects or the approach to those with insufficient responses to treatment, with respect to regression to normal glycemic values or the prevention of complications. The stratification of prediabetic patients, considering the indicators of impaired fasting glucose, impaired glucose tolerance, or HbA1c, can help to identify the sub-phenotypes of subjects at risk for T2DM. However, considering other associated risk factors, such as impaired lipid profiles, or risk scores, such as the Finnish Diabetes Risk Score, may improve classification. Nevertheless, we still do not have enough information regarding cardiovascular risk reduction. The sub-phenotyping of subjects with prediabetes may provide an opportunity to improve the screening and management of cardiometabolic risk in subjects with prediabetes.

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3.

AIMS: Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. METHODS AND RESULTS: We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to a lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. CONCLUSION: The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.

Vasoinhibin's Apoptotic, Inflammatory, and Fibrinolytic Actions Are in a Motif Different From Its Antiangiogenic HGR Motif.

Vasoinhibin, a proteolytic fragment of the hormone prolactin, inhibits blood vessel growth (angiogenesis) and permeability, stimulates the apoptosis and inflammation of endothelial cells, and promotes fibrinolysis. The antiangiogenic and antivasopermeability properties of vasoinhibin were recently traced to the HGR motif located in residues 46 to 48 (H46-G47-R48), allowing the development of potent, orally active, HGR-containing vasoinhibin analogues for therapeutic use against angiogenesis-dependent diseases. However, whether the HGR motif is also responsible for the apoptotic, inflammatory, and fibrinolytic properties of vasoinhibin has not been addressed. Here, we report that HGR-containing analogues are devoid of these properties. Instead, the incubation of human umbilical vein endothelial cells with oligopeptides containing the sequence HNLSSEM, corresponding to residues 30 to 36 of vasoinhibin, induced apoptosis, nuclear translocation of NF-κB, expression of genes encoding leukocyte adhesion molecules (VCAM1 and ICAM1) and proinflammatory cytokines (IL1B, IL6, and TNF), and adhesion of peripheral blood leukocytes. Also, intravenous or intra-articular injection of HNLSSEM-containing oligopeptides induced the expression of Vcam1, Icam1, Il1b, Il6, and Tnf in the lung, liver, kidney, eye, and joints of mice and, like vasoinhibin, these oligopeptides promoted the lysis of plasma fibrin clots by binding to plasminogen activator inhibitor-1 (PAI-1). Moreover, the inhibition of PAI-1, urokinase plasminogen activator receptor, or NF-κB prevented the apoptotic and inflammatory actions. In conclusion, the functional properties of vasoinhibin are segregated into 2 different structural determinants. Because apoptotic, inflammatory, and fibrinolytic actions may be undesirable for antiangiogenic therapy, HGR-containing vasoinhibin analogues stand as selective and safe agents for targeting pathological angiogenesis.

Clopidogrel-loaded vascular grafts prepared using digital light processing 3D printing.

The leading cause of death worldwide and a significant factor in decreased quality of life are the cardiovascular diseases. Endovascular operations like angioplasty, stent placement, or atherectomy are often used in vascular surgery to either dilate a narrowed blood artery or remove a blockage. As an alternative, a vascular transplant may be utilised to replace or bypass a dysfunctional or blocked blood vessel. Despite the advancements in endovascular surgery and its popularisation over the past few decades, vascular bypass grafting remains prevalent and is considered the best option for patients in need of long-term revascularisation treatments. Consequently, the demand for synthetic vascular grafts composed of biocompatible materials persists. To address this need, biodegradable clopidogrel (CLOP)-loaded vascular grafts have been fabricated using the digital light processing (DLP) 3D printing technique. A mixture of polylactic acid-polyurethane acrylate (PLA-PUA), low molecular weight polycaprolactone (L-PCL), and CLOP was used to achieve the required mechanical and biological properties for vascular grafts. The 3D printing technology provides precise detail in terms of shape and size, which lead to the fabrication of customised vascular grafts. The fabricated vascular grafts were fully characterised using different techniques, and finally, the drug release was evaluated. Results suggested that the performed 3D-printed small-diameter vascular grafts containing the highest CLOP cargo (20% w/w) were able to provide a sustained drug release for up to 27 days. Furthermore, all the CLOP-loaded 3D-printed materials resulted in a substantial reduction of the platelet deposition across their surface compared to the blank materials containing no drug. Haemolysis percentage for all the 3D-printed samples was lower than 5%. Moreover, 3D-printed materials were able to provide a supportive environment for cellular attachment, viability, and growth. A substantial increase in cell growth was detected between the blank and drug-loaded grafts.

Recent Advances in Polymers as Matrices for Drug Delivery Applications.

Polymeric-based drug delivery systems have become versatile and valuable candidates in sectors such as pharmaceuticals, health, medicine, etc [...].

Solid Dispersion Incorporated into Dissolving Microneedles for Improved Antifungal Activity of Amphotericin B: In Vivo Study in a Fungal Keratitis Model.

Fungal keratitis (FK) is a fungal infection of the cornea, which is part of the eye and causes corneal ulcers and an increased risk of permanent blindness, which is often found in Candida albicans species. Amphotericin B (AMB), which is a group of polyenes as the first-line treatment of FK, is effective in annihilating C. albicans. However, AMB preparations such as eye drops and ointments have major drawbacks, for instance, requiring more frequent administrations, loss of the drug by the drainage process, and rapid elimination in the precornea, which result in low bioavailability of the drug. An ocular dissolving microneedle containing the solid dispersion amphotericin B (DMN-SD-AMB) had been developed using a mixture of poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP) polymers, while the solid dispersion AMB (SD-AMB) was contained in the needle as a drug. This study aims to determine the most optimal and safest DMN-SD-AMB formula for the treatment of FK in the eye as well as a solution to overcome the low bioavailability of AMB eye drops and ointment preparations. SD-AMB had been successfully developed, which was characterized by increased antifungal activity and drug release in vitro compared to other treatments. Furthermore, DMN-SD-AMB studies had also been successfully performed with the best formulation, which exhibited the best ex vivo corneal permeation profile and antifungal activity as well as being safe from eye irritation. In addition, an in vivo antifungal activity using a rabbit infection model shows that the number of fungal colonies was 0.98 ± 0.11 log10 CFU/mL (F3), 5.76 ± 0.32 log10 CFU/mL (AMB eye drops), 4.01 ± 0.28 log10 CFU/mL (AMB ointments), and 9.09 ± 0.65 log10 CFU/mL (control), which differed significantly (p < 0.05). All of these results evidence that DMN-SD-AMB is a new approach to developing intraocular preparations for the treatment of FK.

Wearable Microneedle-Based Array Patches for Continuous Electrochemical Monitoring and Drug Delivery: Toward a Closed-Loop System for Methotrexate Treatment.

Wearable devices based on microneedle (MN) technology have recently emerged as tools for in situ transdermal sensing or delivery in interstitial fluid (ISF). Particularly, MN-based electrochemical sensors allow the continuous monitoring of analytes in a minimally invasive manner through ISF. Exogenous small molecules found in ISF such as therapeutic drugs are ideal candidates for MN sensors due to their correlation with blood levels and their relevance for the optimal management of personalized therapies. Herein, a hollow MN array patch is modified with conductive pastes and functionalized with cross-linked chitosan to develop an MN-based voltammetric sensor for continuous monitoring of methotrexate (MTX). Interestingly, the chitosan coating avoids biofouling while enabling the adsorption of MTX at the electrode's surface for sensitive analysis. The MN sensor exhibits excellent analytical performance in vitro with protein-enriched artificial ISF and ex vivo under a Franz diffusion cell configuration. The MN sensor shows a linear range from 25 to 400 µM, which fits within the therapeutic range of high-dose MTX treatment for cancer patients and an excellent continuous operation for more than two days. Moreover, an iontophoretic hollow MN array patch is developed with the integration of both the anode and cathode in the single MN array patch. The ex vivo characterization demonstrates the transdermal on-demand drug delivery of MTX. Overall, the combination of both MN patches represents impactful progress in closed-loop systems for therapeutic drug management in disorders such as cancer, rheumatoid arthritis, or psoriasis.

Extrusion-based technologies for 3D printing: a comparative study of the processability of thermoplastic polyurethane-based formulations.

Thermoplastic polyurethanes (TPU) offer excellent properties for a wide range of dosage forms. These polymers have been successfully utilized in personalized medicine production using fused deposition modeling (FDM) 3D printing (3DP). However, direct powder extrusion (DPE) has been introduced recently as a challenging technique since it eliminates filament production before 3DP, reducing thermal stress, production time, and costs. This study compares DPE and single-screw extrusion for binary (drug-TPU) and ternary (drug-TPU-magnesium stearate [MS]) mixtures containing from 20 to 60% w/w of theophylline. Powder flow, mechanical properties, fractal analysis, and percolation theory were utilized to analyze critical properties of the extrudates. All the mixtures could be processed at a temperature range between 130 and 160 °C. Extrudates containing up to 50% w/w of drug (up to 30% w/w of drug in the case of single-screw extrusion binary filaments) showed toughness values above the critical threshold of 80 kg/mm2. MS improved flow in mixtures where the drug is the only percolating component, reduced until 25 °C the DPE temperature and decreased the extrudate roughness in high drug content systems. The potential of DPE as an efficient one-step additive manufacturing technique in healthcare environments to produce TPU-based tailored on-demand medicines has been demonstrated.

Liposome-loaded polymeric microneedles for enhanced skin deposition of rifampicin.

Methicillin-resistant Staphylococcus aureus (MRSA) is a prevailing bacterial pathogen linked to superficial skin and soft tissue infections (SSTIs). Rifampicin (RIF), a potent antibiotic against systemic and localised staphylococcal infections, faces limitations due to its low solubility. This constraint hampers its therapeutic potential for MRSA-induced SSTIs. To address this, an advanced liposomal system was designed for efficient dermal RIF delivery. Rifampicin-loaded liposomes (LipoRIF) were embedded within polymeric dissolving microneedles (DMNs) to enable targeted intradermal drug delivery. A robust Design of Experiment (DoE) methodology guided the systematic preparation and optimisation of LipoRIF formulations. The optimal LipoRIF formulation integrated within polymeric DMNs. These LipoRIF-DMNs exhibited favourable mechanical properties and effective skin insertion characteristics. Notably, in vitro assays on skin deposition unveiled a transformative result - the DMN platform significantly enhanced LipoRIF deposition within the skin, surpassing LipoRIF dispersion alone. Moreover, LipoRIF-DMNs displayed minimal cytotoxicity toward cells. Encouragingly, rigorous in vitro antimicrobial evaluations demonstrated LipoRIF-DMNs' capacity to inhibit MRSA growth compared to the control group. LipoRIF-DMNs propose a potentially enhanced, minimally invasive approach to effectively manage SSTIs and superficial skin ailments stemming from MRSA infections.

Fabrication and characterisation of poly(sulfonated) and poly(sulfonic acid) dissolving microneedles for delivery of antibiotic and antifungal agents.

Skin and soft tissue infections (SSTIs) arise from microbial ingress into the skin. In this study, poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (polyAMPS), which has been reported to exhibit antimicrobial properties was synthesised for the manufacture of microarray patches (MAPs). The free acid and sodium salt of polyAMPS with controlled molar masses and narrow dispersity were synthesised via reversible addition - fragmentation chain-transfer (RAFT) polymerisation reaction with a monomer conversion of over 99%, as determined by 1H NMR. The polymers were shown to be biocompatible when evaluated using a fibroblast dermal cell line while agar plating assay using cultures of C. albican demonstrated that the acid form of polyAMPS exhibited antimicrobial inhibition, which is potentiated in the presence of antimicrobial agents. The synthesised polymers were then used to fabricate dissolving MAPs, which were loaded with either ITRA or levofloxacin (LEV). The MAPs displayed acceptable mechanical resistance and punctured ex vivo skin to a depth of 600 µm. Skin deposition studies revealed that the MAPs were able to administer up to âˆ¼ 1.9 mg of LEV (delivery efficiency: 94.7%) and âˆ¼ 0.2 mg of ITRA (delivery efficiency: 45.9%), respectively. Collectively, the synthesis and development of this novel pharmaceutical system may offer a strategy to manage SSTIs.

Difficult diagnosis in the clinical evaluation of a patient with squamous cell carcinoma of the sigmoid colon: a case report.

BACKGROUND: Squamous cell carcinoma (SCC) of the sigmoid colon is an exceedingly rare subtype of colorectal cancer (CRC) associated with chronic inflammatory conditions. Due to its variable clinical presentation ranging from subclinical to fully symptomatic and limited available information, it poses a diagnostic challenge. We aim to provide a review of the current literature and raise awareness about the importance of a thorough clinical analysis for an early diagnosis. CASE PRESENTATION: We describe the case of a 59-year-old Peruvian woman with a medical history of diverticular disease and irritable bowel syndrome. The patient presented with nonspecific symptoms such as abdominal discomfort, constipation, and bloating. Diagnostic tests and biopsy revealed a rare case of squamous cell carcinoma of the sigmoid colon. The patient underwent surgical resection and adjuvant chemotherapy. CONCLUSION: Despite the rarity of this type of cancer in the colon, the patient's clinical course highlights the importance of considering it as a potential diagnosis in patients with nonspecific symptoms and a history of gastrointestinal disorders. Surgical treatment followed by radiotherapy is the preferred management. Factors such as lack of postoperative complications and the stage of the neoplasia can augur a positive. PROGNOSIS: A prompt diagnosis is crucial, as detecting a neoplasia in its early stages can make surgery more effective.

Inteligencia artificial en la colonoscopia de tamizaje y la disminución del error.

Artificial Intelligence (AI) has the potential to change many aspects of healthcare practice. Image discrimination and classification has many applications within medicine. Machine learning algorithms and complicated neural networks have been developed to train a computer to differentiate between normal and abnormal areas. Machine learning is a form of AI that allows the platform to improve without being programmed. Computer Assisted Diagnosis (CAD) is based on latency, which is the time between the captured image and when it is displayed on the screen. AI-assisted endoscopy can increase the detection rate by identifying missed lesions. An AI CAD system must be responsive, specific, with easy-to-use interfaces, and provide fast results without substantially prolonging procedures. AI has the potential to help both, trained and trainee endoscopists. Rather than being a substitute for high-quality technique, it should serve as a complement to good practice. AI has been evaluated in three clinical scenarios in colonic neoplasms: the detection of polyps, their characterization (adenomatous vs. non-adenomatous) and the prediction of invasive cancer within a polypoid lesion.

La inteligencia artificial (IA) tiene el potencial de cambiar muchos aspectos de la práctica sanitaria. La discriminación y la clasificación de imágenes tiene muchas aplicaciones dentro de la medicina. Se han desarrollado algoritmos de aprendizaje automático y redes neuronales complicadas para entrenar a una computadora a diferenciar las áreas normales de las anormales. El aprendizaje automático es una forma de IA que permite que la plataforma mejore sin ser programada. El diagnóstico asistido por computadora (CAD) se basa en latencia, que es el tiempo entre la imagen capturada y cuando es mostrada en la pantalla. La endoscopia asistida por IA puede incrementar la tasa de detección al identificar lesiones obviadas. Un sistema CAD de IA debe ser sensible, específico, con interfaces fáciles de usar, y proporcionar resultados rápidos sin prolongar sustancialmente los procedimientos. La IA tiene el potencial de ayudar tanto a endoscopistas entrenados como a los que están en entrenamiento. En vez de ser un sustituto para una técnica de alta calidad, deberá servir como un complemento de las buenas prácticas. La IA ha sido evaluada en tres escenarios clínicos en las neoplasias colónicas: la detección de pólipos, su caracterización (adenomatosos vs. no adenomatosos) y la predicción de cáncer invasor dentro de una lesión polipoide.

Solid implantable devices for sustained drug delivery.

Implantable drug delivery systems (IDDS) are an attractive alternative to conventional drug administration routes. Oral and injectable drug administration are the most common routes for drug delivery providing peaks of drug concentrations in blood after administration followed by concentration decay after a few hours. Therefore, constant drug administration is required to keep drug levels within the therapeutic window of the drug. Moreover, oral drug delivery presents alternative challenges due to drug degradation within the gastrointestinal tract or first pass metabolism. IDDS can be used to provide sustained drug delivery for prolonged periods of time. The use of this type of systems is especially interesting for the treatment of chronic conditions where patient adherence to conventional treatments can be challenging. These systems are normally used for systemic drug delivery. However, IDDS can be used for localised administration to maximise the amount of drug delivered within the active site while reducing systemic exposure. This review will cover current applications of IDDS focusing on the materials used to prepare this type of systems and the main therapeutic areas of application.

Extracellular cysteine disulfide bond break at Cys122 disrupts PIP2-dependent Kir2.1 channel function and leads to arrhythmias in Andersen-Tawil Syndrome.

Background: Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys122-to-Cys154 disulfide bond in the Kir2.1 channel structure is crucial for proper folding, but has not been associated with correct channel function at the membrane. We tested whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing the open state of the channel. Methods and Results: We identified a Kir2.1 loss-of-function mutation in Cys122 (c.366 A>T; p.Cys122Tyr) in a family with ATS1. To study the consequences of this mutation on Kir2.1 function we generated a cardiac specific mouse model expressing the Kir2.1C122Y mutation. Kir2.1C122Y animals recapitulated the abnormal ECG features of ATS1, like QT prolongation, conduction defects, and increased arrhythmia susceptibility. Kir2.1C122Y mouse cardiomyocytes showed significantly reduced inward rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking ability and localization at the sarcolemma and the sarcoplasmic reticulum. Kir2.1C122Y formed heterotetramers with wildtype (WT) subunits. However, molecular dynamic modeling predicted that the Cys122-to-Cys154 disulfide-bond break induced by the C122Y mutation provoked a conformational change over the 2000 ns simulation, characterized by larger loss of the hydrogen bonds between Kir2.1 and phosphatidylinositol-4,5-bisphosphate (PIP2) than WT. Therefore, consistent with the inability of Kir2.1C122Y channels to bind directly to PIP2 in bioluminescence resonance energy transfer experiments, the PIP2 binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch-clamping the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing PIP2 concentrations. Conclusion: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential to channel function. We demonstrated that ATS1 mutations that break disulfide bonds in the extracellular domain disrupt PIP2-dependent regulation, leading to channel dysfunction and life-threatening arrhythmias.

Deficit Irrigation Applied to Lemon Trees Grafted on Two Rootstocks and Irrigated with Desalinated Seawater.

The use of desalinated seawater (DSW) for irrigation in semi-arid regions is taking hold. Citrus tolerance to ions that predominate in DSW and water stress depends on the rootstock. Deficit irrigation was applied to DSW-irrigated lemon trees and grafted on rootstocks with different tolerance (Citrus macrophylla (CM) and sour orange (SO)). Plants were irrigated with DSW or Control treatment (distilled water), and, 140 days later, irrigation treatments were started: full irrigation (FI) or DI (50% of the volume applied to FI). After 75 days, differences between CM and SO plants irrigated with DSW and under DI were found. The higher concentrations of Cl- and Na+ in CM and B in SO were the main causes of shoot growth reduction. The osmotic adjustment of CM plants was made possible by the accumulation of Na+, Cl-, and proline, but SO failed to adjust osmotically. In CM and SO plants, photosynthesis reduction was due to lower chlorophyll levels, but also to stomatal factors (CM plants) or alterations of the photochemical machinery (SO plants). Finally, unlike CM, SO had a good antioxidant system. In the future, knowing the different responses of CM and SO under these stressful conditions could be useful in citrus-growing areas.