Combination of light-driven co-delivery of chemodrugs and plasmonic-induced heat for cancer therapeutics using hybrid protein nanocapsules.

BACKGROUND: Improving the water solubility of hydrophobic drugs, increasing their accumulation in tumor tissue and allowing their simultaneous action by different pathways are essential issues for a successful chemotherapeutic activity in cancer treatment. Considering potential clinical application in the future, it will be promising to achieve such purposes by developing new biocompatible hybrid nanocarriers with multimodal therapeutic activity. RESULTS: We designed and characterised a hybrid nanocarrier based on human serum albumin/chitosan nanoparticles (HSA/chitosan NPs) able to encapsulate free docetaxel (DTX) and doxorubicin-modified gold nanorods (DOXO-GNRs) to simultaneously exploit the complementary chemotherapeutic activities of both antineoplasic compounds together with the plasmonic optical properties of the embedded GNRs for plasmonic-based photothermal therapy (PPTT). DOXO was assembled onto GNR surfaces following a layer-by-layer (LbL) coating strategy, which allowed to partially control its release quasi-independently release regarding DTX under the use of near infrared (NIR)-light laser stimulation of GNRs. In vitro cytotoxicity experiments using triple negative breast MDA-MB-231 cancer cells showed that the developed dual drug encapsulation approach produces a strong synergistic toxic effect to tumoral cells compared to the administration of the combined free drugs; additionally, PPTT enhances the cytostatic efficacy allowing cell toxicities close to 90% after a single low irradiation dose and keeping apoptosis as the main cell death mechanism. CONCLUSIONS: This work demonstrates that by means of a rational design, a single hybrid nanoconstruct can simultaneously supply complementary therapeutic strategies to treat tumors and, in particular, metastatic breast cancers with good results making use of its stimuli-responsiveness as well as its inherent physico-chemical properties.

Fatty acids and TxA(2) generation, in the absence of platelet-COX-1 activity.

BACKGROUND AND AIMS: Omega-3 fatty acids suppress Thromboxane A(2) (TxA(2)) generation via mechanisms independent to that of aspirin therapy. We sought to evaluate whether baseline omega-3 fatty acid levels influence arachidonic acid proven platelet-cyclooxygenase-1 (COX-1) independent TxA(2) generation (TxA(2) generation despite adequate aspirin use). METHODS AND RESULTS: Subjects with acute myocardial infarction, stable CVD or at high risk for CVD, on adequate aspirin therapy were included in this study. Adequate aspirin action was defined as complete inhibition of platelet-COX-1 activity as assessed by <10% change in light transmission aggregometry to ≥1 mmol/L arachidonic acid. TxA(2) production was measured via liquid chromatography-tandem mass spectrometry for the stable TxA(2) metabolite 11-dehydro-thromboxane B2 (UTxB2) in urine. The relationship between baseline fatty acids, demographics and UTxB(2) were evaluated. Baseline omega-3 fatty acid levels were not associated with UTxB(2) concentration. However, smoking was associated with UTxB(2) in this study. CONCLUSION: Baseline omega-3 fatty acid levels do not influence TxA(2) generation in patients with or at high risk for CVD receiving adequate aspirin therapy. The association of smoking and TxA(2) generation, in the absence of platelet COX-1 activity, among aspirin treated patients warrants further study.

Cytocompatibility and P-glycoprotein inhibition of block copolymers: structure-activity relationship.

Amphiphilic polymeric micelles greatly improve the solubilization and sustained release of hydrophobic drugs and provide a protective environment for the cargo molecules in aqueous media, which favors lower drug administration doses, reduces adverse side effects, and increases blood circulation times and passive targeting to specific cells. These capabilities depend, among other variables, on the structure and composition of the polymer chains. Composition and, in particular, block length have been shown to play an important role in the modification of cellular responses such as drug internalization processes or transduction pathways when polymeric unimer/micelles are in close contact with cells. Here we present a detailed study about the role copolymer structure and composition play on cell viability and cellular response of several cell lines. To do that, more than 30 structurally related copolymers with diblock and triblock architectures containing different hydrophobic blocks and poly(ethylene oxide) as the common hydrophilic unit have been analyzed regarding cytocompatibility and potential as "active" cell response modifiers by testing their influence on the P-gp pump efflux mechanism responsible of multidrug resistance in cancerous cells. An empirical threshold for cell viability could be established at a copolymer EO/POeffective value above ca. 1.5 for copolymers with triblock structure, whereas no empirical rule could be observed for diblocks. Moreover, some of the tested copolymers (e.g., BO12EO227BO12 and EO57PO46EO57 that notably increased and C16EO455C16 that decreased the P-gp ATPase activity) were observed to act as efficient inhibitors of the P-gp efflux pump promoting an enhanced doxorubicin (DOXO) accumulation inside multidrug resistant (MDR) NCI-ADR-RES cells.

[Autoimmune and inflammatory pathologies associated with systemic scleroderma: Clinical, serological and prognostic profiles. Bi-centric retrospective series in the PACA region]. / Pathologies auto-immunes et inflammatoires associées à la sclérodermie systémique : profils cliniques, sérologiques et pronostiques. Série rétrospective bi-centrique en région PACA.

INTRODUCTION: Systemic sclerosis (SSc) is a rare auto-immune disease, affecting principally women between 40 and 60 years old. It is caracterised by a cutaneous and visceral fibrosis, an alteration of the microvascular network and the presence of autoantibodies. SSc can be associated with another connectivite tissue disease or to other autoimmune diseases, thus defining the overlap syndrome. The goal of our study is to describe these overlap syndromes. METHODS: We have analysed the data of a retrospective and bicentrique cohort, from the internal medicine unit of Hôpital Nord in Marseille and from the internal medicine unit of the Hôpital Sainte-Anne in Toulon, of patients followed for a SSc between January 1st, 2019 and December 1st, 2021. We have collected clinical, imunological features, associated auto-immune and inflammatory diseases with its morbidity and mortality. RESULTS: The cohort included 151 patients including 134 limited cutaneous SSc. Fifty-two (34.4%) patients presented at least one associated auto-immune or inflammatory disease. The association of two connectivite tissue diseases including SSc was found in 24 patients (15.9%), a third with Sjögren's syndrome and a third with autoimmune myositis. The principal associated disease to SSc was the autoimmune thyroiditis found in 17 patients (11.3%). The occurrence of complications (hospitalization, long-term oxygene therapy, death) was not significantly different depending on the existence or not of an overlap syndrom. CONCLUSION: SSc is often associated with other autoimmune diseases. This interrelation between associated pathologies and SSc, modifying sometimes the evolution of SSc, enhances the need of a personalized follow-up.

[Giant retroperitoneal hydatid cyst in a traveller]. / Kyste hydatique rétropéritonéal géant chez un voyageur.

INTRODUCTION: Giant hydatid cyst located in the retroperitoneal space is rare. The purpose of this report is to present a case cured by surgery in an adult traveller. CASE REPORT: In August 2009, a 67-year-old female who traveled frequently to Lebanon was admitted for assessment of a giant retroperitoneal hydatid cyst discovered coincidentally following palpation of an abdominal mass in 1997. From 1966 to 1975, the patient had undergone several surgical procedures for pulmonary and hepatic hydatidosis, complicated by vomica and anaphylactic shock. In 1997, computed tomography showed that the retroperitoneal cyst measured 100 mm at the widest point. At that time, the patient refused to undergo further surgery and was treated medically using albendazole initially in association with praziquantel. In 2009, the cyst had expanded to 180 mm at the widest point and the patient finally consented to perikystectomy. Excision was total and recovery was uneventful. Histology examination confirmed the viability of the cyst. Follow-up examination at 12 months indicated no relapse. COMMENTS: The retroperitoneal space is a rare location for hydatidosis. Occurrence in this location is generally primary. In case of discovery of a liquid-filled retroperitoneal mass, a history of travel to an endemic area for hydatid disease should be elicited. Diagnosis relies on radiological findings and positive serology. Since retroperitoneal cysts are often giant, they respond poorly to medical treatment. Similarly radiological treatment is difficult due to retroperitoneal location. Surgery, preferably perikystectomy, is the treatment of choice.

[Diagnostic issues of Whipple's disease during chronic inflammatory rheumatism: About three cases]. / Difficultés diagnostiques de la maladie de Whipple au cours des rhumatismes inflammatoires chroniques : trois observations.

INTRODUCTION: Whipple's disease (WD) can mimic chronic inflammatory rheumatism leading to incorrect prescription of tumor necrosis factor inhibitors (TNFI). Several complicated cases of WD have been reported during TNFI treatment which is strongly suspected to modify the host-pathogen relationship. Tropheryma whipplei asymptomatic carriage is high in the general population, making the diagnosis of WD more difficult face to unexplained arthritis. OBSERVATIONS: We report three observations that illustrate situations for which the detection of T. whipplei might be valuable to investigate the differential diagnosis of inflammatory rheumatism. CONCLUSION: The decision to check for T. whipplei infection should rely on individual clinical assessment. It should be considered in the absence of clinical response or in case of worsening of an inflammatory rheumatism under TNFI treatment, especially in front of atypical features. A systematic screening for T. whipplei before anti-TNF treatment seems unjustified since asymptomatic carriers are frequent.

[Ebola virus disease: Clinical presentation, prognosis and treatment]. / Maladie à virus Ebola : présentation clinique, aspects pronostiques et principes thérapeutiques.

The clinical spectrum of Ebola virus disease (EVD) ranges from very serious forms with organ failure and death within days to paucisymptomatic forms and perhaps even asymptomatic. The authors propose a focus on the clinical manifestations of EVD, on prognosis and on therapeutic aspects (excluding resuscitation). This work extracts from the literature the main data gathered during the 2014-2015 epidemic that raged in Guinea Conakry and Sierra Leone. These two countries, even if they are separated by a border, are one and the same population base. The characteristics of the epidemic in Liberia have not been analyzed. The authors have treated EVD patients in the health workers treatment center of Conakry and enrich this work about their personal experience.

Restoration of elbow and hand function in total brachial plexus palsy with intercostal nerves and C5 root neurotization. Results in 21 patients.

Consensus opinion is that active movement of the elbow is a priority in the surgical treatment of total brachial plexus injuries. But the indications and neurotization techniques used to restore motor function of the hand are the subject of discussion. The aim of this retrospective study was to evaluate, in adult patients with complete post-traumatic paralysis of the brachial plexus, the functional results of neurotization of four intercostal nerves on the musculocutaneous nerve and grafting of the C5 root by one strand on the nerve to the long head of triceps and three strands on the medial component of the median nerve. The cohort included 21 patients (mean age 21years). The average time between the trauma and surgical treatment was 4.8months. At a mean follow-up of 22months, 67% of patients achieved≥M3 elbow flexion, and 62% achieved≥M3 active elbow extension. Of the patients who had the required follow-up of 2years to assess motor recovery of the median nerve, 40% achieved function≥M3. Based on our results, use of the C5 root is suitable for surgically restoring elbow extension and finger flexion.

[Biphasic low-energy internal cardioversion in atrial fibrillation induced during electrophysiologic study]. / Cardioversión eléctrica interna con baja energía y curva bifásica en fibrilación auricular inducida durante el estudio electrofisiológico.

INTRODUCTION: Atrial fibrillation is observed in 10% of electrophysiological studies. Previous studies have shown the efficacy of biphasic low energy internal cardioversion to restore sinus rhythm. We studied the efficacy and safety of low-energy internal cardioversion and the biphasic curve, in sustained atrial fibrillation (>15 min) during electrophysiologic procedures. MATERIALS AND METHODS: From January 1997 to August 1998, 320 patients underwent an electrophysiological study. An internal cardioversion was done on those patients who developed sustained atrial fibrillation. We delivered biphasic shocks between electrodes-catheters positioned in the right atrium and the coronary sinus. Increasing energy was applied until restoration of sinus rhythm or a maximum of 10 joules were achieved with no result. A right ventricle electrode was used to synchronize the V wave and for temporary pacing. RESULTS: Thirty one episodes of sustained atrial fibrillation were observed in 26 patients (1,23 episodes/patient) and a mean of 2,58 internal cardioversions were applied per every patient. Sinus rhythm was restored in twenty three patients. The mean energy delivered was 4.1 joules. The mean time for the recovery was 3,200 ms. Temporary pacing was used in 16% of the patients for up to 1 minute. No AV blocks were observed. CONCLUSIONS: Internal cardioversion successfully restored sinus rhythm in 88.5% of the patients who presented sustained atrial fibrillation (88.5%). Temporary pacing was necessary for the treatment of postsinus shock pauses.

Poly(styrene oxide)-poly(ethylene oxide) block copolymers: From "classical" chemotherapeutic nanocarriers to active cell-response inducers.

Two poly(styrene oxide)-poly(ethylene oxide) (PSO-PEO) triblock copolymers with different chain lengths were analyzed as potential chemotherapeutic nanocarriers, and their ability to inhibit the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line were measured in order to establish possible cell-responses induced by the presence of the copolymer molecules. Thus, EO33SO14EO33 and EO38SO10EO38 polymeric micelles were tested regarding doxorubicin (DOXO) entrapment efficiency (solubilization test), physical stability (DLS), cytocompatibility (fibroblasts), release profiles at various pHs (in vitro tests), as well as P-gp inhibition and evasion and cytotoxicity of the DOXO-loaded micelles in an ovarian MDR NCI-ADR/RES cell line and in DOXO-sensitive MCF-7 cells. EO33SO14EO33 and EO38SO10EO38 formed spherical micelles (~13nm) at lower concentration than other copolymers under clinical evaluation (e.g. Pluronic®), exhibited 0.2% to 1.8% loading capacity, enhancing more than 60 times drug apparent solubility, and retained the cargo for long time. The copolymer unimers inhibited P-gp ATPase activity in a similar way as Pluronic P85, favoring DOXO accumulation in the resistant cell line, but not in the sensitive cell line. DOXO loaded in the micelles accumulated more slowly inside the cells, but caused greater cytotoxicity than free drug solutions in the NCI-ADR-RES cell line, which overexpressed P-gp. Hence, PSO-PEO block copolymers offer interesting features as new biological response modifiers to be used in the design of efficient nanocarriers for cancer chemotherapy.

Doxorubicin-loaded micelles of reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers as efficient "active" chemotherapeutic agents.

Five reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers, BOnEOmBOn, with BO ranging from 8 to 21 units and EO from 90 to 411 were synthesized and evaluated as efficient chemotherapeutic drug delivery nanocarriers and inhibitors of the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line. The copolymers were obtained by reverse polymerization of poly(butylene oxide), which avoids transfer reaction and widening of the EO block distribution, commonly found in commercial poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamers). BOnEOmBOn copolymers formed spherical micelles of 10-40 nm diameter at lower concentrations (one order of magnitude) than those of equivalent poloxamers. The influence of copolymer block lengths and BO/EO ratios on the solubilization capacity and protective environment for doxorubicin (DOXO) was investigated. Micelles showed drug loading capacity ranging from ca. 0.04% to 1.5%, more than 150 times the aqueous solubility of DOXO, and protected the cargo from hydrolysis for more than a month due to their greater colloidal stability in solution. Drug release profiles at various pHs, and the cytocompatibility and cytotoxicity of the DOXO-loaded micelles were assessed in vitro. DOXO loaded in the polymeric micelles accumulated more slowly inside the cells than free DOXO due to its sustained release. All copolymers were found to be cytocompatible, with viability extents larger than 95%. In addition, the cytotoxicity of DOXO-loaded micelles was higher than that observed for free drug solutions in a MDR ovarian NCI-ADR-RES cell line which overexpressed P-gp. The inhibition of the P-gp efflux pump by some BOnEOmBOn copolymers, similar to that measured for the common P-gp inhibitor verapamil, favored the retention of DOXO inside the cell increasing its cytotoxic activity. Therefore, poly(butylene oxide)-poly(ethylene oxide) block copolymers offer interesting features as cell response modifiers to complement their role as efficient nanocarriers for cancer chemotherapy.

[Tropical sprue in an expatriate]. / Sprue tropicale chez un expatrié.

INTRODUCTION: Tropical sprue is a postinfective malabsorption syndrome that occurs in some tropical endemic areas. CASE REPORT: A 65-year-old Caucasian patient, with no significant past medical history, living in Cambodia for 10 years, presented with a 23 kg weight loss and chronic diarrhea. Clinical examination was unremarkable. Laboratory tests showed a moderate nutritional deficiency syndrome. The upper gastrointestinal endoscopy showed duodenal villous atrophy and histological analysis confirmed subtotal villous atrophy with important intraepithelial lymphocytosis. The diagnosis of tropical sprue was considered on the epidemiological, clinical and biological context, and the absence of other cause of villous atrophy. A three-month duration treatment with antibiotics, folic acid and vitamin B12 was initiated. The clinical course was favorable with disappearance of diarrhea in 15 days. One year later, the patient had resumed his usual weight, and laboratory tests and duodenal biopsies were normal. CONCLUSION: The diagnosis of tropical sprue should be systematically discussed in any malabsorption syndrome with villous atrophy in a patient living or having lived in the tropics.

[Optical coherence tomography applied to vessels: a bright future]. / L'OCT appliquée aux vaisseaux : un avenir prometteur.

Optical Coherence Tomography (OCT) is a new imaging technique recently applied to coronary and is based on the diffusion and reflection of an infrared spectrum. With a resolution 10 times higher than that of IVUS, it allows an analysis of the atherosclerotic plaque and its components, indicating its possible vulnerable character, and can identify the culprit lesion and the presence of thrombus in the course of acute events. It allows quality control of good apposition of stents to the wall and essentially tracks the downstream dissection. In the longer term, it evaluates the endothelisation and in-stent restenosis. Its scope thus extends to basic research and the pharmaceutical industry where it plays a new reference tool in the monitoring of atherosclerotic plaques and stents with drug treatment. This invasive imaging technique is limited by its cost and artifacts but new generation OCT can better overcome them. The OCT appears as a promising intravascular imaging technique whose feasibility and clinical applications, however, require confirmation by randomized clinical trials to better define its place in the cardiac catheterization lab.

[Use of positron emission tomography in sarcoidosis]. / Apport de la tomographie par émission de positons dans la prise en charge de la sarcoïdose.

FDG-PET, now hybrid positron emission tomography/computed tomography (PET-CT), has become an established diagnostic tool in oncology. Fluorodesoxyglucose ((18)F-FDG) is not specific for malignant lesions, as uptake of the tracer depends on its accumulation in cells with an increased glucose metabolism as it is also the case in infectious and inflammatory lesions, like sarcoidosis. Thus, FDG-PET has been proposed for internal medicine indications, one of whom is sarcoidosis. The main characteristics of FDG-PET are its better sensitivity compared to (67)Ga scintigraphy and its ability to be used as an earlier marker of therapeutic response as compared with anatomy-based and conventional scintigraphic imaging. However, FDG-PET should be used in atypical or advanced stage of the disease. Future prospective studies should be awaited before integrating FDG-PET in clinical routine for treatment outcome and disease activity assessment in sarcoidosis. New radiopharmaceutical probes are under development and will improve the performance of PET.

[Supraventricular paroxysmal tachycardia with ventriculo-atrial dissociation. Report of one case]. / Taquicardia paroxística supraventrictular con disociación ventrículo auricular: a propósito de un caso.

Nodal reentrant supraventricular paroxysmal tachycardia corresponds to a reentry circuit established between fibers with different conduction velocities and refractory periods in the atrioventricular node. These are the slow and fast nodal pathways. That ventricular tissue does not form part of the circuit of this arrhythmia is accepted nowadays, and the involvement of atrial tissue is discussed. We report a 57 years old male with a nodal reentrant tachycardia. In the electrophysiological study he presented an atrial and ventricular dissociation during the tachycardia. These findings allow a better understanding of the electrophysiological substrate of this arrhythmia.

[Late effects of radiofrequency fulguration: report of five cases]. / Efectos tardíos post fulguración con radiofrecuencia: experiencia clínica en 5 casos.

Radiofrequency fulguration is the definitive treatment of several supraventricular and ventricular arrhythmias. During radiofrequency application, the conduction in a specific zone is interrupted as a consequence of cellular necrosis and edema. The disappearance of edema, minutes or hours after the procedure, allows the reappearance of conduction and arrhythmias. On the other hand, the definitive lesion is larger than the one caused acutely, due to the progression of the scar. We report five patients, in whom there was an apparent failure of the fulguration, since at the end of the procedure there was conduction in the fulgurated zone, the tachycardia was inducible or pre excitation and arrhythmias reappeared during the follow up. All five were subjected to a new electrophysiological study and in all, fulguration had been effective. We conclude that these late effects of fulguration are due to the slow progression of fibrosis, that continues days or weeks after the procedure.

[Multiple pathway tachycardias: electrophysiological properties and fulguration of accessory pathways in 2 cases]. / Taquicardias con circuitos multiples: propiedades electrofisiológicas y fulguración de todas las vías accesorias en dos casos.

We report two patients (male, 35 and female, 28 years old) with recurrent and refractory tachycardias referred for an electrophysiological study. EKG showed left lateral accessory pathway in both, two tachycardias with identical morphology but with different frequency and activation sequence were detected. One was orthodromic with anterograde conduction by the His-Purkinje budle and retrograde by the accessory pathway and the other with slow nodal anterograde conduction. The accessory pathway was first fulgurated with radiofrequency at the third attempt. Posteriorly, a nodal reentry tachycardia was induced in the first patient and in the second, a double nodal pathway was confirmed. In both, the slow pathway was modified using Jackman's technique, after three and four attempts respectively. After these applications, the induction of tachycardia with programmed atrial or ventricular stimulation, with or without isoproterenol, was not possible. It is concluded that radiofrequency fulguration is a reasonable therapeutic alternative for patients with multiple circuit tachycardias.