Modification of the Antibiotic, Colistin, with Dextrin Causes Enhanced Cytotoxicity and Triggers Apoptosis in Myeloid Leukemia.

Introduction: Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different 'subtypes' in combination with current chemotherapies. We have previously developed dextrin-colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity.

Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury .

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant Gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected/inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells .

LipoParticles: a lipid membrane coating onto polymer particles to enhance the internalization in osteoblast cells.

LipoParticles, core-shell assemblies consisting of a polymer core coated by a lipid membrane, are promising carriers for drug delivery applications with intracellular targets. This is of great interest since it is actually challenging to treat infections involving intracellular bacteria such as bone and joint infections where the bacteria are hidden in osteoblast cells. The present work reports for the first time to the best of our knowledge the proof of enhanced internalization of particles in osteoblast cells thanks to a lipid coating of particles (= LipoParticles).

Alginate oligosaccharides enhance diffusion and activity of colistin in a mucin-rich environment.

In a number of chronic respiratory diseases e.g. cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), the production of viscous mucin reduces pulmonary function and represents an effective barrier to diffusion of inhaled therapies e.

A physicochemical assessment of the thermal stability of dextrin-colistin conjugates.

Attachment of polysaccharide carriers is increasingly being used to achieve precision delivery and improved effectiveness of protein and peptide drugs. Although it is clear that their clinical effectiveness relies on the purity and integrity of the conjugate in storage, as well as following administration, instability of polysaccharide-based conjugates can reduce the protective efficacy of the polymer, which may adversely affect the bioactive's potency. As a model, these studies used dextrin-colistin conjugates, with varying degrees of polymer modification (1, 2.

Optimization of a Solid-Phase Extraction Procedure for the Analysis of Drug-Loaded Lipid Nanoparticles and its Application to the Determination of Leakage and Release Profiles.

To understand and predict the efficacy and toxicity of nanoparticle-based drugs in vivo, the free and entrapped forms of the drug have to be determined using suitable characterization methods. Herein, a solid-phase extraction (SPE) method combined with high-performance liquid chromatography (HPLC) measurements were used to separately quantify free and entrapped cyclosporine A (CsA) in 50 and 120 nm-sized lipid nanoparticles (NPs). Combined with colloidal stability measurements, HPLC quantification of the free and entrapped drug, separated using SPE, was used to monitor the stability of the nanotherapeutics under storage or physiological conditions.

Quantification of Surface GalNAc Ligands Decorating Nanostructured Lipid Carriers by UPLC-ELSD.

Nanoparticles have been extensively studied for drug delivery and targeting to specific organs. The functionalization of the nanoparticle surface by site-specific ligands (antibodies, peptides, saccharides) can ensure efficient recognition and binding with relevant biological targets. One of the main challenges in the development of these decorated nanocarriers is the accurate quantification of the amount of ligands on the nanoparticle surface.

Polymer Masked-Unmasked Protein Therapy: Identification of the Active Species after Amylase Activation of Dextrin-Colistin Conjugates.

Polymer masked-unmasked protein therapy (PUMPT) uses conjugation of a biodegradable polymer, such as dextrin, hyaluronic acid, or poly(l-glutamic acid), to mask a protein or peptide's activity; subsequent locally triggered degradation of the polymer at the target site regenerates bioactivity in a controllable fashion. Although the concept of PUMPT is well established, the relationship between protein unmasking and reinstatement of bioactivity is unclear. Here, we used dextrin-colistin conjugates to study the relationship between the molecular structure (degree of unmasking) and biological activity.

Development and validation of a novel UPLC-ELSD method for the assessment of lipid composition of nanomedicine formulation.

Lipid nanocarriers incorporating glycerides, polyethylene glycol (PEG)-stearates and phospholipids have attracted great attention for in vivo diagnostic, in vivo imaging, activated or non-activated targeted drug delivery. For quality control purposes, the development of appropriate methods for the quantification of their lipid components is needed. In the present study, we developed an analytical method for lipid quantification in formulated nanoparticles.

Assessment of major salivary gland size in primary Sjögren's syndrome: Comparison between clinical examination and ultrasonography.

Objective: Parotidomegaly is a criterion of the EULAR Primary Sjögren Syndrome Disease Activity Index (ESSDAI). The cut-off value was set at 3 cm in length for the parotid gland, 2 cm for the submandibular glands. However, clinical appreciation of salivary glands size remains hazardous.

Mycobacterium tuberculosis prosthetic joint infections: A case series and literature review.

Objectives: We aimed to characterize diagnosis, management, and outcome of Mycobacterium tuberculosis prosthetic joint infections (PJI).

Methods: Cases of M. tuberculosis PJI documented in 7 referral French centers were retrospectively reviewed.

Development and validation of an HPLC-fluorescence method for the quantification of IR780-oleyl dye in lipid nanoparticles.

A reversed-phase (RP) high-performance liquid chromatography (HPLC) method for the content determination of IR780-oleyl (IRO) dye in lipid nanoparticles was developed and validated. Chromatographic separation was performed on a RP C18 column with a gradient program of water and acetonitrile both with 0.1% (v/v) TFA, at a flow rate of 1.

Diagnostic impact of routine Lyme serology in recent-onset arthritis: results from the ESPOIR cohort.

Objectives: Lyme disease may be considered by rheumatologists in patients with recent-onset arthritis, even in the absence of suggestive symptoms. The aim of this study was to determine the diagnostic impact of routine Lyme serology in a French cohort of patients with recent-onset arthritis affecting at least 2 joints.

Methods: We performed an ancillary study of a French prospective multicentre cohort established to monitor clinical, biological and radiographic data in patients with inflammatory arthritis in at least 2 joints, lasting for 6 weeks to 6 months.

Comparison of ACR 1987 and ACR/EULAR 2010 criteria for predicting a 10-year diagnosis of rheumatoid arthritis.

Objective: To compare the diagnostic accuracy of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) and 1987 ACR criteria for rheumatoid arthritis (RA) in a cohort of patients with recent-onset arthritis followed-up for 10 years.

Methods: One hundred and sixty-four patients with recent-onset arthritis of less than 1 year's duration were included prospectively between 1995 and 1997. The diagnosis of RA was defined as having a diagnosis of RA made by the office-based rheumatologist 10 years after enrolment.

Is routine viral screening useful in patients with recent-onset polyarthritis of a duration of at least 6 weeks? Results from a nationwide longitudinal prospective cohort study.

Objective: To study the contribution of routine viral screening tests in patients with early rheumatoid arthritis (RA) or a potential for progressing to RA.

Methods: Eight hundred thirteen patients with swelling of at least 2 joints for at least 6 weeks and a symptom duration of less than 6 months in the ESPOIR cohort were screened for parvovirus B19 (IgG and IgM anti-parvovirus B19 antibodies), hepatitis B virus (HBV; hepatitis B surface antigen), hepatitis C virus (HCV; anti-HCV antibodies), and human immunodeficiency virus (HIV; anti-HIV-1 and -2 antibodies).

Results: Parvovirus B19 testing was performed in 806 patients and showed longstanding immunity in 574 (71.

Diagnostic accuracy of ACR/EULAR 2010 criteria for rheumatoid arthritis in a 2-year cohort.

Objective: To evaluate the diagnostic accuracy of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) and 1987 ACR criteria for rheumatoid arthritis (RA), and the respective role of the algorithm and scoring of the ACR/EULAR.

Methods: In total, 270 patients with recent-onset arthritis of < 1 year duration were included prospectively between 1995 and 1997 and followed for 2 years. RA was defined as the combination, at completion of followup, of RA diagnosed by an office-based rheumatologist and treatment with a disease-modifying antirheumatic drug or glucocorticoid.

Value of ultrasonography for detecting ligament damage in athletes with chronic ankle instability compared to computed arthrotomography.

Ankle sprains may be followed by chronic pain and/or instability, which may induce substantial disability, most notably in athletes. Chronic ankle instability promotes the development of cartilage lesions in athletes. Therefore, accurate evaluation of the ankle ligaments is crucial to the optimal management of chronic ankle instability after a sprain.

[Pays de la Loire Pneumococcus Observatory: antimicrobial resistance of Streptococcus pneumoniae in 2007].

Objectives: Between 1st January and 31st December 2007, 331 Streptococcus pneumoniae strains were collected from 20 participating laboratories in the Pneumococcus Network Pays de la Loire county to assess their susceptibility to antibiotics and to evaluate serogroups of strains.

Method: The coordinating centre performed MICs of penicillin G, amoxicillin and cefotaxime by the reference agar dilution method. Results were interpreted according to CA-SFM breakpoints.

[Coexistence of hepatocellular carcinoma and hepatic metastasis: advantages of positron emission tomography for liver tumors].

We report the case of a cirrhotic patient with a hepatocellular carcinoma and a synchronous hepatic metastasis of a colorectal cancer, both visualized on a positron emission tomography (PET) and a CT scanner. We repeat the need for the arterial phase on CT scanner when a possibility of cirrhosis exists, even in the follow-up of a colorectal cancer. We detail the usual pattern of HCC and the present efficacy of the PET in the diagnosis of HCC.

Panton-Valentine leukocidin-producing Staphylococcus aureus infections: report of 4 French cases.

We report 4 cases of community-acquired infections due to Staphylococcus aureus producing Panton-Valentin leukocidin (SA-PVL) with uncommon multivisceral localizations. These cases highlight the need to screen for PVL in patients with serious staphylococcal infections. All patients were cured.

[Pulmonary malacoplakia caused by Rhodococcus equi in AIDS: a case report].

We describe the observation of a right upper lobe consolidation with cavitation produced by Rhodococcus equi in a patient suffering from AIDS. The inefficacy of a prolonged antimicrobial therapy adapted against R. equi led to a right upper lobectomy.