Simple screening tools predict death and cardiovascular events in patients with rheumatic disease.

OBJECTIVES: Patients with rheumatic disease (RD) have an increased mortality risk compared with the general population, mainly due to cardiovascular disease (CVD). We aimed to identify patients at high risk of CVD and mortality by comparing three screening tools suitable for clinical practice. METHOD: In this prospective, single-centre study, consecutive patients with rheumatoid arthritis (RA), systemic autoimmune disease (SAI), or spondyloarthritides (SpA) including psoriatic arthritis underwent a comprehensive cardiovascular risk assessment. Patients were predefined as being at high risk for cardiovascular events or death if any of the following were present: European Systematic COronary Risk Evaluation (SCORE) ≥ 3%, N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 200 pg/mL, or any pathological electrocardiogram pattern. RESULTS: The patient population (n = 764) comprised 352 patients with RA, 260 with SAI, and 152 with SpA. After a median follow-up of 5.2 years, 6.0% of RD patients had died (7.0%, 7.2%, and 1.4% of patients in the RA, SAI, and SpA subgroups), and 5.0% had experienced a cardiovascular event (5.0%, 6.4%, and 2.8%, respectively). For all RD patients and the RA and SAI subgroups, NT-proBNP ≥ 200 pg/mL and SCORE ≥ 3% identified patients with a 3.5-5-fold increased risk of all-cause death and cardiovascular events. Electrocardiogram pathology was associated with increased mortality risk, but not with cardiovascular events. CONCLUSION: NT-proBNP ≥ 200 pg/mL or SCORE ≥ 3% identifies RA and SAI patients with increased risk of cardiovascular events and death. Both tools are suitable as easy screening tools in daily practice to identify patients at risk for further diagnostics and closer long-term follow-up.

Biodistribution of quantum dots in the kidney after intravenous injection.

The biodistribution of nanoparticles is a major subject of current nanomedical research. To date, however, the exact investigation of nanoparticle fate in the microenvironment of a main excretory organ, the kidney has largely been neglected. In this study, the biodistribution of polyethylene glycol-coated quantum dots (Qdots) with special focus on their interaction with the kidney is investigated. Upon intravenous injection, nanoparticles showed effective blood circulation in mice and significant renal accumulation after two hours. Histological analysis of the kidney revealed that Qdots were strongly associated to the intraglomerular mesangial cells. This preferential deposition of nanoparticles in the kidney mesangium is highly promising, since it could be of utmost value for site-specific treatment of severe kidney diseases like diabetic nephropathy in the future.

The mechanism of protein release from triglyceride microspheres.

The purpose of this study was to reveal factors that have an impact on the protein release kinetics from triglyceride microspheres prepared by spray congealing. We investigated the effect of protein particle size, morphology and distribution on protein release from microspheres by confocal laser scanning microscopy (CLSM)(.) The microspheres were loaded with three types of model particles made of FITC-labeled bovine serum albumin: freeze dried protein, spherical particles obtained by precipitation in the presence of PEG and micronized material. Investigation by light microscopy and laser light diffraction revealed that the freeze dried material consisted mainly of app. 29 µm elongated shaped particles. The precipitated BSA consisted mainly of 9.0 µm diameter spherically shaped particles while the micronized protein prepared by jet milling consisted of 4.9 µm sized rounded particles of high uniformity. Microspheres were embedded into a cold-curing resin and cut with a microtome. Subsequent investigation by CLSM revealed major differences of distribution of the polydisperse protein particles inside the microsphere sections depending on the type of BSA that was used. Particles of micronized and precipitated protein were distributed almost throughout the microsphere cross section. The protein distribution had a marked impact on the release kinetics in phosphate buffer. Large protein particles led to a considerably faster release than small ones. By staining the release medium we demonstrated that in all three cases there was a strong correlation between protein release and buffer intrusion.

[52 year-old patient with severe heart failure due to multiple myeloma]. / 52-jähriger Patient mit schwerer Herzinsuffizienz bei multiplem Myelom.

Cardiac amyloidosis represents a prognostically relevant comorbidity in multiple myeloma. We report the case of a patient in whom severe heart failure symptoms as a consequence of cardiac AL-amyloidosis resolved after tandem high-dose melphalan therapy followed by autologous blood-stem cell transplantation. Partial regression of cardiac amyloid deposits and improvement of cardiac function were objectified.

Methoxy poly(ethylene glycol)--low molecular weight linear polyethylenimine-derived copolymers enable polyplex shielding.

Targeted gene delivery relies on the development of materials that allow for the formation of small neutrally charged particles of sufficient colloidal stability preventing non-specific interactions with cells. In order to identify a copolymer composition that combines adequate plasmid DNA (pDNA) compaction with an efficient charge-shielding effect, we synthesized a series of copolymers by covalent linkage of activated 5 or 20 kDa linear methoxy poly(ethylene glycol) (mPEG) or 10 kDa two-arm-mPEG to non-toxic low molecular weight (2.6 and 4.6 kDa) linear polyethylenimine (lPEI) at different molar ratios (mPEG-lPEI copolymers). All of the copolymers condensed pEGFP-N1 pDNA to form nanoparticles with hydrodynamic diameters between 150 and 420 nm - sizes that were maintained for the entire duration of measurement. PEGylated complexes exhibited a reduced particle stability in comparison to the unmodified lPEI-pDNA polyplexes, determined by gel retardation assays and DNase I experiments. Copolymer-pDNA complexes exhibited a zeta potential between -4 and 6 mV, strongly depending on the dispersion medium applied (0.15M NaCl or 5% glucose supplemented with serum-free cell culture medium). The transfection efficacy, determined in CHO-K1 (between 0.28+/-0.08% and 1.92+/-0.46%) and HeLa (between 1.02+/-0.19% and 3.53+/-0.30%) cells, was significantly reduced compared to lPEI-pDNA particles (between 3.2+/-1.3% and 38.8+/-5.5%). The architecture of the copolymer, the molecular weight of the lPEI residue, and the supplementation of endosomolytic agents (saccharose, chloroquine) all failed to impact the efficacy of gene transfer. Uptake studies, based on Confocal Laser Scanning Microscopy (CLSM) imaging and flow cytometry analysis, suggest that the use of mPEG5/3-lPEI2.6, mPEG10/2-lPEI2.6, and mPEG20-lPEI4.6 lowers unspecific internalization of the corresponding transfection complexes. This provides an ideal basis for the development of transfection vehicles for targeted gene transfer.

Polymers and nanoparticles: intelligent tools for intracellular targeting?

In recent years, a new generation of drugs has entered the pharmaceutical market. Some are more potent, but some are also more toxic and thus, therapeutical efficacy may be hindered, and severe side effects may be observed, unless they are delivered to their assigned place of effect. Those targets are not only certain cell types, moreover, in cancer therapy for example, some drugs even have to be targeted to a specific cell organelle. Those targets in eukaryotic cells include among others endo- and lysosomes, mitochondria, the so-called power plants of the cells, and the biggest compartment with almost all the genetic information, the nucleus. In this review, we describe how the drugs can be directed to specific subcellular organelles and focus especially on synthetic polymers and nanoparticles as their carriers. Furthermore, we portray the progress that has been accomplished in recent years in the field of designing the carriers for efficient delivery into these target structures. Yet, we do not fail to mention the obstacles that still exist and are preventing polymeric and nanoparticular drug carrier systems from their broad application in humans.

Quantum dots - nano-sized probes for the exploration of cellular and intracellular targeting.

Nanoparticles emerged as promising tool in drug targeting, since, after appropriate modification, they are able to deliver their payload to specific sites, like tissues, cells, or even certain cellular organelles. In this context, the delivery of nanoparticles from the circulation into the target cells represents a crucial step. Here, model drug delivery systems such as quantum dots are ideal candidates to elucidate this process in more detail, since they provide outstanding features like a small and uniform size, unique optical properties for most sensitive detection and modifiable surfaces. Recent progress in the surface chemistry of quantum dots expanded their use in biological applications, reduced their cytotoxicity and rendered quantum dots a powerful tool for the investigation of distinct cellular processes, like uptake, receptor trafficking and intracellular delivery. In this review, we will not only describe the ideal attributes of QDs for biological applications and imaging but also their distinct specific and non-specific pathways into the cells as well as their intracellular fate.

Polyethylenimine-based non-viral gene delivery systems.

Gene therapy has become a promising strategy for the treatment of many inheritable or acquired diseases that are currently considered incurable. Non-viral vectors have attracted great interest, as they are simple to prepare, rather stable, easy to modify and relatively safe, compared to viral vectors. Unfortunately, they also suffer from a lower transfection efficiency, requiring additional effort for their optimization. The cationic polymer polyethylenimine (PEI) has been widely used for non-viral transfection in vitro and in vivo and has an advantage over other polycations in that it combines strong DNA compaction capacity with an intrinsic endosomolytic activity. Here, we give some insight into strategies developed for PEI-based non-viral vectors to overcome intracellular obstacles, including the improvement of methods for polyplex preparation and the incorporation of endosomolytic agents or nuclear localization signals. In recent years, PEI-based non-viral vectors have been locally or systemically delivered, mostly to target gene delivery to tumor tissue, the lung or liver. This requires strategies to efficiently shield transfection polyplexes against non-specific interaction with blood components, extracellular matrix and untargeted cells and the attachment of targeting moieties, which allow for the directed gene delivery to the desired cell or tissue. In this context, materials, facilitating the design of novel PEI-based non-viral vectors are described.

Biomimetic polymers in pharmaceutical and biomedical sciences.

This review describes recent developments in the emerging field of biomimetic polymeric biomaterials, which signal to cells via biologically active entities. The described biological effects are, in contrast to many other known interactions, receptor mediated and therefore very specific for certain cell types. As an introduction into this field, first some biological principles are illustrated such as cell attachment, cytokine signaling and endocytosis, which are some of the mechanisms used to control cells with biomimetic polymers. The next topics are then the basic design rules for the creation of biomimetic materials. Here, the major emphasis is on polymers that are assembled in separate building blocks, meaning that the biologically active entity is attached to the polymer in a separate chemical reaction. In that respect, first individual chemical standard reactions that may be used for this step are briefly reviewed. In the following chapter, the emphasis is on polymer types that have been used for the development of several biomimetic materials. There is, thereby, a delineation made between materials that are processed to devices exceeding cellular dimensions and materials predominantly used for the assembly of nanostructures. Finally, we give a few current examples for applications in which biomimetic polymers have been applied to achieve a better biomaterial performance.

The use of programmed materials in the analysis of academic contingencies.

Programmed handwriting materials were used to examine the effects of different reinforcement contingencies on the academic performance of six public school kindergarten children. The children's responses to these materials provided an educationally relevant dependent variable for the analysis of factors that affected the accuracy of their responses and the attainment of criterion performances. Variations in the complexity of most academic materials, which confound the analysis of contingencies, were eliminated by the programmed sequence so that the differential effects of three reinforcement conditions were observed. The three conditions were: baseline without tokens, tokens contingent on correct writing responses, and noncontingent tokens. It was consistently observed that the children were more accurate when their correct responses produced tokens, and that noncontingent tokens reduced accuracy below baseline levels.