Cow Milk and Intestinal Epithelial Cell-derived Extracellular Vesicles as Systems for Enhancing Oral Drug Delivery

Ingestion is the preferred way for drug administration. However, many drugs have poor oral bioavailability, warranting the use of injections. Extracellular vesicles (EVs) from cow milk have shown potential utility in improving oral drug bioavailability. However, EVs produced by intestinal epithelial cells have not been investigated for this application. We compared the capacity of cow milk EVs and intestinal epithelial cell-derived counterparts to enhance oral drug bioavailability. EVs were isolated, fluorescently labelled, and loaded with curcumin (CUR) as a model poorly absorbable drug. These were then characterised before testing in an intestinal model (Caco-2). Epithelial cell-derived EVs showed notably higher cell uptake compared to cow milk EVs. Cell uptake was significantly higher in differentiated compared to undifferentiated cells for both types of EVs. While both milk- and cell-derived EVs improved the cell uptake and intestinal permeability of CUR (confirming oral drug bioavailability enhancement potential), epithelial cell EVs demonstrated a superior effect

Nanoparticle modification in biological media:implications for oral nanomedicines

Nanomedicine has shown potential in enabling oral administration of poorly absorbable drugs, such as biologics. As part of the process related to optimisation of the safety and efficacy of nanomedicines, it is imperative that the interaction of nanoparticles with the biological systems – including the gut – is fully characterised. In this article, we provide an overview of the major mechanisms by which nanoparticles may transform upon introduction in biological media. Specifically, the phenomena of association, dissolution and biomolecule adsorption are discussed, together with factors which influence the occurrence of each phenomenon. The implications of these phenomena within the context of therapeutic action of nanomedicines, which includes reduced targeting efficiency, are also explored. Finally, we will comment on nanoparticle modification within the gut environment, including the currently available gastrointestinal models for the study of nano-bio interactions, with implications in the area of nanomedicines for oral administration

Continuous subcutaneous insulin infusion reduces neonatal risk in pregnant women with type 1 diabetes mellitus

Objectives: An attempt was made to demonstrate the superiority of the treatment model using continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) of insulin in achieving a successful pregnancy outcome and good newborn’s condition in patients with type 1 diabetes.  Material and methods: The study included 297 infants born to type 1 diabetic patients; 175 patients were treated with MDI and 122 with CSII.  Maternal metabolic control during pregnancy, gestational weight gain, insulin requirements, pregnancy outcome and neonatal status were compared between MDI and CSII arm.  The composite adverse neonatal outcome was diagnosed if at least one of the following was found: abnormal birth weight (LGA or SGA), congenital malformation, miscarriage, intrauterine fetal death, emergency CS due to fetal risk, iatrogenic prematurity, RDS, hypoglycemia, hyperbilirubinemia, and the postpartum pH in the umbilical artery ≤ 7.1.  Results: The studied groups did not differ regarding gestational week at delivery, a proportion of births at full term, preterm births, miscarriages, or late pregnancy losses (intrauterine fetal death > 22 weeks). Newborns of mothers treated with CSII showed lower incidence of neonatal complications (composite adverse neonatal outcome) compared to those of mothers treated with MDI (60% vs 74%, respectively; p = 0.01). We did not find any association between the mode of treatment and composite adverse maternal outcome.  Conclusions: The use of CSII in the treatment of pregnant women with type 1 diabetes was associated with reduced number of neonatal complications presented as neonatal composite outcome but had no influence on maternal outcome

Endometriosis is associated with an increased whole-blood thrombogenicity detected by a novel automated microchip flow-chamber system (T-TAS®)

Objectives: Potential thrombotic and antifibrinolytic influence of endometriosis on haemostasis has been recently reported in the literature, as well as increased cardiovascular morbidity in women suffering from the disease. We performed a pilot study to assess the influence of endometriosis on the thrombus formation process under in vitro flow conditions. Material and methods: This study compared women with confirmed endometriosis (n = 23) surgically and control healthy subjects (n = 10). In both groups, the same exclusion criteria were used: a prior episode of thrombosis diagnosed as acquired or inherited thrombophilia, neoplasm, and an uncertain family history of thrombosis. We evaluated the whole blood thrombogenicity using T-TAS® at a shear rate of 240 s-1 (Total-Thrombus Analysis System, Zacros, Japan).  Results: The blood clot formation initiation time (T10) and occlusion time (OT) were significantly shortened in the endometriosis group (p < 0.05). The area under the curve (AUC30) of blood clot time formation values (BCTF) was substantially higher in the patients suffering from a disease (p = 0.03). An increase in AUC (TTAS) values by 100 increases the risk of developing endometriosis by 1.56-fold [adjusted OR = 1.56 (p = 0.01);(95% CI: 1.10–2.18)]. Inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), and the leucocyte, neutrophil, basophil, and neutrophil concentrations) were also substantially higher in the endometriosis group (p < 0.05).  Conclusions: The alteration of the T-TAS and NLR values supports the thesis of a shift of the equilibrium towards thrombosis in women who have endometriosis. This phenomenon links to a state of chronic inflammation. It is detectable using a novel system for the quantitative assessment of the platelet thrombus formation process under flow conditions in vitro

Maternal body mass index and gestational weight gain and their association with perinatal outcome in women with gestational diabetes

Abstract Objectives: Maternal overweight and obesity constitute the most important factors causing perinatal complications. The purpose of the study was to analyze obstetrical results in overweight/obese pregnant women with gestational diabetes in relation to Institute of Health recommendations concerning gestational weight gain and assessment of the role of prepregnancy BMI in prediction of macrosomia, pregnancy induced hypertension and cesarean deliveries. Material and methods: Retrospective analysis of 209 overweight and obese pregnant women with gestational diabetes divided into 4 subgroups according to The National Institute of Health (USA) recommendations. The following data were included in the analysis: gestational week in which GDM was diagnosed; HbA1c level in the first and third trimester just before delivery; incidence of pregnancy induced hypertension; incidence of cesarean deliveries; incidence of macrosomia. The following data of II, III, IV subgroups were compared to these found in I subgroup which was classified as the control group. Selected obstetric parameters were also compared between subgroups II, III, IV. Results: The selected parameters of subgroups II, III, IV were not significantly different from these of subgroup I. Pregnancy induced hypertension was diagnosed more frequently among subgroup II in comparison to subgroup III. Using ROC curves analysis, the role of pre-pregnancy BMI was found in the prognosis of: birth weight greater than 4300g, pregnancy induced hypertension, cesarean delivery. Conclusions: 1. The application of the National Institute of Health recommendations on gestational weight gain is limited in case of overweight or obese pregnant women with gestational diabetes mellitus. 2. Excessive weight gain during pregnancy according to National Health Institute recommendations may increase the risk of developing pregnancy induced hypertension in comparison to a pregnant women with weight gain less than recommended, but greater than zero. 3. Increased prepregnancy BMI has a role in prediction of birth weight greater than 4300g, pregnancy induced hypertension, cesarean delivery

Recent Advances in Transition-Metal Catalyzed Oxidative Annulations to Benzazepines and Benzodiazepines

NOTICE: This is the peer reviewed version of the following article: Velasco-Rubio, A., Varela J. A., Saá C. (2020). Recent Advances in Transition-Metal Catalyzed Oxidative Annulations to Benzazepines and Benzodiazepines. Adv. Synth. Catal., 362, 22, 4861-4875. [doi: 10.1002/adsc.202000808]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for self-archivingBenzazepines and benzodiazepines, benzofused seven-membered N-heterocycles, compose an important family of natural products and pharmaceuticals. Although certainly important and effectives, classical synthetic methods of these cyclic compounds involve methodologies that often require multistep procedures, with generation of waste materials and lack of sustainability. By contrast, cycloadditions based on transition metal catalyzed C-H bond activations (oxidative annulations) have emerged as appealing strategies for more sustainable synthetic processes. In this review, we focus our attention to describe the state-of-the-art transition-metal catalyzed annulations via C-H activations to benzazepines and benzodiazepines.This work has received financial support from MINECO (project CTQ2017-87939R and ORFEO-CINQA network RED2018- 102387-T), the Xunta de Galicia (project ED431C 2018/04 and Centro singular de investigación de Galicia accreditation 2019- 2022, ED431G 2019/03) and the European Union (European Regional Development Fund – ERDF)S

An Optimal Diagnostic Strategy for Tuberculosis in Hospitalized HIV-Infected Patients Using GeneXpert MTB/RIF and Alere Determine TB LAM Ag.

The diagnosis of tuberculosis (TB) in HIV-infected patients is challenging. Both a urinary lipoarabinomannan (LAM) test (Alere TB LAM) and GeneXpert-MTB/RIF (Xpert) are useful for the diagnosis of TB. However, how to optimally integrate Xpert and LAM tests into clinical practice algorithms remain unclear. We performed a post hoc analysis of 561 HIV-infected sputum-expectorating patients (median CD4 count of 130 cells/ml) from a previously published randomized controlled trial evaluating the LAM test in hospitalized HIV-infected patients with suspected TB. We evaluated 5 different diagnostic strategies using sputum culture as a reference standard (Xpert alone, LAM alone, sequential Xpert followed by LAM and vice versa [LAM in Xpert-negative patients and Xpert in LAM-negative patients], and both tests concurrently [LAM + Xpert]). A cost-consequence analysis was performed. Strategy-specific sensitivity and specificity, using culture as a reference, were similar with the Xpert-only and sequential and concurrent strategies. However, when any positive TB-specific test was used as a reference, the incremental yield of LAM over Xpert was 29.6% (45/152) and that of Xpert over LAM was 75% (84/11). The incremental yield of LAM increased with decreasing CD4 count. The costs per TB case diagnosed were similar for the sequential and concurrent strategies ($1,617 to$1,626). In sputum-expectorating hospitalized patients with advanced HIV and access to both tests, concurrent testing with Xpert and LAM may be the best strategy for diagnosing TB. These data inform clinical practice in settings where TB and HIV are endemic

Patients Undergoing Ileoanal Pouch Surgery Experience a Constellation of Symptoms and Consequences Representing a Unique Syndrome: A Report From the Patient-Reported Outcomes After Pouch Surgery (PROPS) Delphi Consensus Study

The primary aim was to create a patient-centered definition of core symptoms that should be included in future studies of pouch function.Functional outcomes after ileoanal pouch creation have been studied; however, there is great variability in how relevant outcomes are defined and reported. More importantly, the perspective of patients has not been represented in deciding which outcomes should be the focus of research.Expert stakeholders were chosen to correlate with the clinical scenario of the multidisciplinary team that cares for pouch patients: patients, colorectal surgeons, gastroenterologists/other clinicians. Three rounds of surveys were employed to select high-priority items. Survey voting was followed by a series of online patient consultation meetings used to clarify voting trends. A final online consensus meeting with representation from all 3 expert panels was held to finalize a consensus statement.One hundred ninety-five patients, 62 colorectal surgeons, and 48 gastroenterologists/nurse specialists completed all 3 Delphi rounds. Fifty-three patients participated in online focus groups. One hundred sixty-one stakeholders participated in the final consensus meeting. On conclusion of the consensus meeting, 7 bowel symptoms and 7 consequences of undergoing ileoanal pouch surgery were included in the final consensus statement.This study is the first to identify key functional outcomes after pouch surgery with direct input from a large panel of ileoanal pouch patients. The inclusion of patients in all stages of the consensus process allowed for a true patient-centered approach in defining the core domains that should be focused on in future studies of pouch function