Improved pharmacokinetic profile of lipophilic anti-cancer drugs using ανβ3-targeted polyurethane-polyurea nanoparticles

Glutathione degradable polyurethane-polyurea nanoparticles (PUUa NP) with a disulfide-rich multiwalled structure and a cyclic RGD peptide as a targeting moiety were synthesized, incorporating a very lipophilic chemotherapeutic drug named Plitidepsin. In vitro studies indicated that encapsulated drug maintained and even improved its cytotoxic activity while in vivo toxicity studies revealed that the maximum tolerated dose (MTD) of Plitidepsin could be increased three-fold after encapsulation. We also found that pharmacokinetic parameters such as maximum concentration (Cmax), area under the curve (AUC) and plasma half-life were significantly improved for Plitidepsin loaded in PUUa NP. Moreover, biodistribution assays in mice showed that RGD-decorated PUUa NP accumulate less in spleen and liver than non-targeted conjugates, suggesting that RGD-decorated nanoparticles avoid sequestration by macrophages from the reticuloendothelial system. Overall, our results indicate that polyurethane-polyurea nanoparticles represent a very valuable nanoplatform for the delivery of lipophilic drugs by improving their toxicological, pharmacokinetic and whole-body biodistribution profiles.     

Multifunctional magnetic-responsive hydrogels to engineer tendon-to-bone interface

Photocrosslinkable magnetic hydrogels are attracting great interest for tissue engineering strategies due to their versatility and multifunctionality, including their remote controllability ex vivo, thus enabling engineering complex tissue interfaces. This study reports the development of a photocrosslinkable magnetic responsive hydrogel made of methacrylated chondroitin sulfate (MA-CS) enriched with platelet lysate (PL) with tunable features, envisioning their application in tendon-to-bone interface. MA-CS coated iron-based magnetic nanoparticles were incorporated to provide magnetic responsiveness to the hydrogel. Osteogenically differentiated adipose-derived stem cells and/or tendon-derived cells were encapsulated within the hydrogel, proliferating and expressing bone- and tendon-related markers. External magnetic field (EMF) application modulated the swelling, degradation and release of PL-derived growth factors, and impacted both cell morphology and the expression and synthesis of tendon- and bone-like matrix with a more evident effect in co-cultures. Overall, the developed magnetic responsive hydrogel represents a potential cell carrier system for interfacial tissue engineering with EMF-controlled properties.     

Plasma troponins as markers of myocardial damage during cardiac surgery with extracorporeal circulation

All types of cardiac surgery involve considerable injury to the myocardium. However, it is difficult to differentiate, in the immediate post-operative state, between ischemic alterations associated with the cardiac surgery itself and the pathological alterations of a peri-operative myocardial infarction. The diagnosis of damaged myocardium, classically performed with the enzymatic markers creatine kinase (CK) and its muscle fraction (CK-MB), has become more precise with the option of measuring cardiac troponins T and I. We measured these markers in 58 patients undergoing elective cardiac surgery with extra-corporeal circulation (ECC). The patients included 37 cases undergoing valve surgery, 14 for coronary revascularization, 6 for mixed procedures, and 1 for closure of an inter-atrial communication. The markers were measured in plasma at baseline (at anesthesia initiation), 5 min post-ECC commencement, following aorta de-clamping, during the surgical closure, and 6, 18 and 42 hrs after surgery. All the markers were increased significantly relative to the baseline values. Troponin I, CK and CK-MB values peaked between 6 and 18 hrs after surgery, troponin T between 18 and 42 hrs, and myoglobin at the surgical closure. The values of all markers were higher in patients undergoing coronary surgery compared to those in patients undergoing valve surgery. In the evaluation of myocardial damage after surgery, the measurement of classical markers such as CK and myoglobin remain valid, but other markers such as troponins provide significant additional diagnostic benefit and, thus, need to be included in the routine biochemical measurements for monitoring myocardial damage associated with the surgical procedure.     

Effectiveness of manual lymphatic drainage vs. perineal massage in secundigravida women with gestational oedema: A randomised clinical trial

Perineal trauma (PT) may be considered as a very common injury during the childbirth. The incidence of PT was estimated in 30% to 85%, with 60% to 70% requiring suture. The present study was a prospective, single‐blinded, randomised, clinical trial carried out from January 2015 to January 2016. For this study, 49 secundigravida women diagnosed with gestational oedema were recruited and randomly divided into two groups (A and B). Group A (n = 30) received the conventional treatment plus perineal massage and group B (n = 19) the conventional treatment plus manual lymphatic drainage (MLD). Visual analogue scale (VAS) and King Health's Questionnaire (KHQ) were performed to assess pain intensity and quality of life‐related with urinary incontinence (UI). Pain intensity measurements showed statistically significant differences for a decrease after 30‐weeks (P = .037), after 36‐weeks (P = .000), and at the end of puerperium (P = .014) for MLD with respect to perineal massage group. Moreover, inter‐groups repeated measures ANOVA for the values related statistically significant differences to the interaction of each applied treatment (perineal massage and MLD group, separately) over the pain intensity variable. MLD treatment reduced pain intensity with respect to perineal massage in secundigravida women with gestational oedema from 25‐weeks of gestation to the end of puerperium.     

Revision with plates of humeral nonunions secondary to failed intramedullary nailing

Purpose

The objective of this study was to evaluate the results achieved after revision with plates of humeral nonunions secondary to failed intramedullary nailing.

Methods

We retrospectively evaluated 32 patients with humeral nonunions secondary to failed intramedullary nailing, treated by internal fixation with plates between 1998 and 2012. Nonunions were diaphyseal in 19 cases, they were located in the proximal humeral metaphysis in nine cases, and in the distal humeral metaphysis in four cases. There were 11 atrophic nonunions and 21 oligotrophic nonunions. Initial treatment was performed with static locked nails in 12 cases, nails with expansive locking systems in 11 cases, and using thin elastic nails in nine cases. The nails were placed antegrade in 18 cases and retrograde in 14 cases. Time between initial surgery and revision surgery averaged 14.5 months. In seven diaphyseal nonunions, the intramedullary nail was left in-situ. Bone graft was added in 25 cases.

Results

Follow-up averaged 35 months. Union was achieved in all cases, after an average of 3.8 months. Disabilities of the Arm, Shoulder and Hand (DASH) score at last follow-up averaged 14 points, and Constant’s score averaged 82 points. The analogue scale of pain averaged 0.8 points. Out of seven patients with radial nerve compromise, six recovered completely and one needed tendon transfers.

Conclusions

Revision with plates after failed intramedullary humeral nailing achieved union and good predictable objective and subjective results in all cases. Adequate implant selection and meticulous surgical technique are necessary to achieve successful osteosynthesis and bony union.     

Time course of systemic oxidative stress and inflammatory response induced by an acute exposure to Residual Oil Fly Ash

It is suggested that systemic oxidative stress and inflammation play a central role in the onset and progression of cardiovascular diseases associated with the exposure to particulate matter (PM). The aim of this work was to evaluate the time changes of systemic markers of oxidative stress and inflammation, after an acute exposure to Residual Oil Fly Ash (ROFA). Female Swiss mice were intranasally instilled with a ROFA suspension (1.0 mg/kg body weight) or saline solution, and plasma levels of oxidative damage markers [thiobarbituric acid reactive substances (TBARSs) and protein carbonyls], antioxidant status [reduced (GSH) and oxidized (GSSG) glutathione, ascorbic acid levels, and superoxide dismutase (SOD) activity], cytokines levels, and intravascular leukocyte activation were evaluated after 1, 3 or 5 h of exposure. Oxidative damage to lipids and decreased GSH/GSSG ratio were observed in ROFA-exposed mice as early as 1 h. Afterwards, increased protein oxidation, decreased ascorbic acid content and SOD activity were found in this group at 3 h. The onset of an adaptive response was observed at 5 h after the ROFA exposure, as indicated by decreased TBARS plasma content and increased SOD activity. The observed increase in oxidative damage to plasma macromolecules, together with systemic antioxidants depletion, may be a consequence of a systemic inflammatory response triggered by the ROFA exposure, since increased TNF-α and IL-6 plasma levels and polymorphonuclear leukocytes activation was found at every evaluated time point. These findings contribute to the understanding of the increase in cardiovascular morbidity and mortality, in association with environmental PM inhalation.