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Adherence describes how a patient follows a medical regime recommended by a healthcare provider. Poor treatment adherence represents a complex and challenging problem of international healthcare systems, as it has a substantial impact on clinical outcomes and patient safety and constitutes an important financial burden. Since it is one of the most common causes of treatment failure, it is extremely important for physicians to reliably distinguish between non-adherence and non-response. This systematic review aims to summarize the current literature on treatment adherence in dermatology, focusing on chronic inflammatory skin diseases such as psoriasis, atopic dermatitis and acne. A systematic literature search was performed using the PubMed Database, including articles from 2008 to 2018. Low treatment adherence is a multidimensional phenomenon defined by the interplay of numerous factors and should under no circumstances be considered as the patient's fault alone. Factors influencing treatment adherence in dermatology include patient characteristics and beliefs, treatment efficacy and duration, administration routes, disease chronicity and the disease itself. Moreover, the quality of the physician-patient relationship including physician-time available for the patient plays an important role. Understanding patients' adherence patterns and the main drivers of non-adherence creates opportunities to improve adherence in the future. Strategies to increase treatment adherence range from reminder programs to simplifying prescriptions or educational interventions. Absolute adherence to treatment may not be realistically achievable, but efforts need to be made to raise awareness in order to maximize adherence as far as possible.

Der monoklonale Antikorper Dupilumab (Dupixent® ) ist seit September 2017 in der EU als neue systemische Therapie bei mittelschwerem bis schwerem atopischem Ekzem zugelassen. Eine Unterdruckung der IL-4- und IL-13-Signalwege durch die Anwendung von Dupilumab fuhrt zu einer Verbesserung objektiver und subjektiver Komponenten der Erkrankung. Die Blockade der IL-4Rα-Untereinheit fuhrt zu einer Reduktion der Th2-vermittelten Entzundung und zu einer Verbesserung der Hautbarriere. Die Nebenwirkungsrate unter Dupilumab ist gering. Allerdings entwickelten bis zu 28 % der Patienten unter Behandlung mit Dupilumab (gegenuber bis zu 11 % unter Placebo) eine bilaterale, milde bis moderate Konjunktivitis mit Rotung, Brennen und Fremdkorpergefuhl der Augen. Mit topischen Steroiden und topischen Calcineurininhibitoren stehen verschiedene Therapieoptionen der Dupilumab-assoziierten Konjunktivitis zur Verfugung. Dieser Artikel berichtet uber die klinische Prasentation sowie die medikamentosen und nichtmedikamentosen Therapieoptionen der klinisch hochrelevanten Dupilumab-assoziierten Konjunktivitis.

Background Cartilage shortage is a major problem in facial reconstructive surgery. Prior studies have shown that decellularized porcine nasal septal cartilage (DPNC) seeded with primary human nasal chondrocytes enabled cartilage regeneration and showed potential as a replacement material for nasal cartilage. Since adipose tissue-derived stem cells (ASCs) are easily accessible and almost abundantly available, they appear to be a promising alternative to limited chondrocytes making the combination of DPNC and ASCs a feasible approach towards clinical translation. Thus, this study was intended to investigate the interactions between ASCs and DPNC in an in vitro model. Methods DPNCs were seeded and 3D-cultured with primary human ASCs that were priorly characterized with trilineage differentiation and flow cytometry. Cell vitality and proliferation were evaluated by Live-Dead, alamarBlue, and PicoGreen assays. Chondrogenic differentiation was examined by DMMB assay and cryosectioning-based histology. Cell invasion within DPNC was visualized and quantified by fluorescent histology (DAPI, Phalloidin). Results ASCs showed good adherence to DPNC and Live-Dead assay proved their viability over 2 weeks. AlamarBlueassay showed an increase in metabolic activity compared to 2D cultures, and PicoGreen assay demonstrated an increase of cell number within DPNC over time. Biochemical assays and histology added evidence of chondrogenic differentiation of 3D-cultured ASCs under the influence of chondrogenic induction medium. Fluorescent image analysis showed a significant increase of cell-occupied areas of scaffolds over time (P Conclusions DPNC scaffolds provided a suitable environment for ASCs that allowed good cell vitality, high proliferation, and chondrogenic differentiation. Thus, the use of ASCs and DPNC yields a promising alternative to the use of primary human chondrocytes. For facial cartilage tissue engineering, we regard ASCs as an attractive alternative to human nasal chondrocytes due to their better accessibility and availability. Further research will be necessary to determine long-term effects and in vivo outcomes of ASCs and DPNC in cartilage regeneration of the face.

The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin (Tnmd) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of Tnmd. Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. Tnmd knockout (Tnmd − / −) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, Tnmd and chondromodulin I (Chm1, the only homologous gene to Tnmd) double knockout (Tnmd − / − Chm1 − / −) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of Tnmd in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration., Cartoon highlighting the hallmarks of Tnmd−/− intervertebral disc (IVD) phenotype. Tnmd−/− mice exhibited more rapid progression of age‐related IVD degeneration. These signs include lower disc height index, smaller collagen fibrils with lower compressive stiffness in the outer annulus fibrosus, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis and macrophage infiltration in outer annulus fibrous, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus.

Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell���based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome���based pathway analysis of in vitro���expanded human bone marrow���derived mesenchymal stem cell (hBM���MSCs), supplemented with cellular assays focusing on DNA double���strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination (HR), cell cycle control, and chromosomal replication. Assays for the recognition (�����H2AX + 53BP1 foci) and repair (pBRCA1 + �����H2AX foci) of X���ray���induced DNA DSBs in hBM���MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by HR (e.g., Rad51, Rad54, BRCA1) show a 2.3��� to fourfold reduction of their mRNA expression by qRT���PCR. We conclude that the in vitro expansion of hMSCs can lead to aging���related impairment of the recognition and repair of DNA breaks., publishedVersion

Bone tissue engineering (BTE) utilizing biomaterial scaffolds and human mesenchymal stem cells (hMSCs) is a promising approach for the treatment of bone defects. The quality of engineered tissue is crucially affected by numerous parameters including cell density and the oxygen supply. In this study, a novel oxygen-imaging sensor was introduced to monitor the oxygen distribution in three dimensional (3D) scaffolds in order to analyze a new cell-seeding strategy. Immortalized hMSCs, pre-cultured in a monolayer for 30-40% or 70-80% confluence, were used to seed demineralized bone matrix (DBM) scaffolds. Real-time measurements of oxygen consumption in vitro were simultaneously performed by the novel planar sensor and a conventional needle-type sensor over 24h. Recorded oxygen maps of the novel planar sensor revealed that scaffolds, seeded with hMSCs harvested at lower densities (30-40% confluence), exhibited rapid exponential oxygen consumption profile. In contrast, harvesting cells at higher densities (70-80% confluence) resulted in a very slow, almost linear, oxygen decrease due to gradual achieving the stationary growth phase. In conclusion, it could be shown that not only the seeding density on a scaffold, but also the cell density at the time point of harvest is of major importance for BTE. The new cell seeding strategy of harvested MSCs at low density during its log phase could be a useful strategy for an early in vivo implantation of cell-seeded scaffolds after a shorter in vitro culture period. Furthermore, the novel oxygen imaging sensor enables a continuous, two-dimensional, quick and convenient to handle oxygen mapping for the development and optimization of tissue engineered scaffolds. Biotechnol. Bioeng. 2017;114: 894-902. (c) 2016 Wiley Periodicals, Inc.

Long-bone growth by endochondral ossification is cooperatively accomplished by chondrocyte proliferation, hypertrophic differentiation, and appropriate secretion of collagens, glycoproteins, and proteoglycans into the extracellular matrix (ECM). Before folding and entering the secretory pathway, ECM macromolecules in general are subject to extensive posttranslational modification, orchestrated by chaperone complexes in the endoplasmic reticulum (ER). ERp57 is a member of the protein disulfide isomerase (PDI) family and facilitates correct folding of newly synthesized glycoproteins by rearrangement of native disulfide bonds. Here, we show that ERp57-dependent PDI activity is essential for postnatal skeletal growth, especially during the pubertal growth spurt characterized by intensive matrix deposition. Loss of ERp57 in growth plates of cartilage-specific ERp57 knockout mice (ERp57 KO) results in ER stress, unfolded protein response (UPR), reduced proliferation, and accelerated apoptotic cell death of chondrocytes. Together this results in a delay of long-bone growth with the following characteristics: (1) enlarged growth plates; (2) expanded hypertrophic zones; (3) retarded osteoclast recruitment; (4) delayed remodeling of the proteoglycan-rich matrix; and (5) reduced numbers of bone trabeculae. All the growth plate and bone abnormalities, however, become attenuated after the pubertal growth spurt, when protein synthesis is decelerated and, hence, ERp57 function is less essential.

Integrins are cell surface receptors that connect extracellular matrix (ECM) components to the actin cytoskeleton and transmit chemical and mechanical signals into the cells through adhesion complexes. Integrin-activated downstream pathways have been implicated in the regulation of various cellular functions, including proliferation, survival, migration, and differentiation. Integrin-based attachment to the matrix plays a central role in development, tissue morphogenesis, adult tissue homeostasis, remodeling and repair, and disturbance of the ECM-integrin-cytoskeleton signaling axis often results in diseases and tissue dysfunction. Increasing amount of in vitro and in vivo evidences suggest that integrins are pivotal for proper development, function, and regeneration of skeletal tissues. In this paper, we will summarize and discuss the role of integrins in skeletogenesis and their influence on the physiology and pathophysiology of cartilage, bone, and tendon. Birth Defects Research (Part C) 102:13–36, 2014. © 2014 Wiley Periodicals, Inc.

The penicillin-binding protein (PBP) 1b of Escherichia coli catalyses the assembly of lipid-transported N-acetyl glucosaminyl-beta-1, 4-N-acetylmuramoyl-L-alanyl-gamma-D-glutamyl-(L)-meso-diaminopimelyl+ ++- (L)-D-alanyl-D-alanine disaccharide pentapeptide units into polymeric peptidoglycan. These units are phosphodiester linked, at C1 of muramic acid, to a C55 undecaprenyl carrier. PBP1b has been purified in the form of His tag (M46-N844) PBP1bgamma. This derivative provides the host cell in which it is produced with a functional wall peptidoglycan. His tag (M46-N844) PBP1bgamma possesses an amino-terminal hydrophobic segment, which serves as transmembrane spanner of the native PBP. This segment is linked, via an congruent with 100-amino-acid insert, to a D198-G435 glycosyl transferase module that possesses the five motifs characteristic of the PBPs of class A. In in vitro assays, the glycosyl transferase of the PBP catalyses the synthesis of linear glycan chains from the lipid carrier with an efficiency of congruent with 39 000 M-1 s-1. Glu-233, of motif 1, is central to the catalysed reaction. It is proposed that the Glu-233 gamma-COOH donates its proton to the oxygen atom of the scissile phosphoester bond of the lipid carrier, leading to the formation of an oxocarbonium cation, which then undergoes attack by the 4-OH group of a nucleophile N-acetylglucosamine. Asp-234 of motif 1 or Glu-290 of motif 3 could be involved in the stabilization of the oxocarbonium cation and the activation of the 4-OH group of the N-acetylglucosamine. In turn, Tyr-310 of motif 4 is an important component of the amino acid sequence-folding information. The glycosyl transferase module of PBP1b, the lysozymes and the lytic transglycosylase Slt70 have much the same catalytic machinery. They might be members of the same superfamily. The glycosyl transferase module is linked, via a short junction site, to the amino end of a Q447-N844 acyl transferase module, which possesses the catalytic centre-defining motifs of the penicilloyl serine transferases superfamily. In in vitro assays with the lipid precursor and in the presence of penicillin at concentrations sufficient to derivatize the active-site serine 510 of the acyl transferase, the rate of glycan chain synthesis is unmodified, showing that the functioning of the glycosyl transferase is acyl transferase independent. In the absence of penicillin, the products of the Ser-510-assisted double-proton shuttle are glycan strands substituted by cross-linked tetrapeptide-pentapeptide and tetrapeptide-tetrapeptide dimers and uncross-linked pentapeptide and tetrapeptide monomers. The acyl transferase of the PBP also catalyses aminolysis and hydrolysis of properly structured thiolesters, but it lacks activity on D-alanyl-D-alanine-terminated peptides. This substrate specificity suggests that carbonyl donor activity requires the attachment of the pentapeptides to the glycan chains made by the glycosyl transferase, and it implies that one and the same PBP molecule catalyses transglycosylation and peptide cross-linking in a sequential manner. Attempts to produce truncated forms of the PBP lead to the conclusion that the multimodular polypeptide chain behaves as an integrated folding entity during PBP1b biogenesis.

A vinylogous cephalosporine bearing a dihydroxythiophene moiety as a potential catechol surrogate has been synthesised ( I-e Download : Download high-res image (58KB) Download : Download full-size image Figure 1 . -β). Even if the anti staphylococcus spectrum displayed by this compound is of interest, its activity against Pseudomonas species, expected for such a structure, remains disappointing.

As part of an effort to discover novel antibacterial agents, a new and efficient synthesis was established in order to provide a large amount of UDP-N-acetylmuramic acid (UDP-MurNAc).

The O -β- d -ribofuranosyl nucleoside I is the minimal structural entity of liposidomycins maintaining enzyme inhibitory activity. Modifications performed on both the primary amine and the uracil moieties clearly demonstrate their major contribution to the inhibition of the bacterial translocase (MraY).

O-beta-D-ribofuranosyl nucleoside I is the minimal structural entity of liposidomycins that maintains enzyme inhibitory activity on MraY. A set of compounds with hydroxyl patterns different from I has been synthesized. The presence of a hydroxyl group in the 3" position is essential for the activity. The 3'-deoxy derivative (IV), however, shows a 5-fold improved potency.

The synthesis and inhibitory activity against MraY of a series of simplified analogues of liposidomycins are described. These compounds were mainly obtained by performing parallel synthesis in the 6′-position of a scaffold that gathers key features found necessary for the binding to MraY. Thus, inhibitory activity was improved from 5300 to 140 nM. This improvement was correlated with the length and lipophilicity of substituents, but was found to be independent of the nature of the chemical bond generated. In addition, some of these inhibitors presented encouraging antibacterial activities.

Enantioselective synthesis of the isocephem synthon 2 has been carried out by assembling 3 building blocks. Cycloaddition of phthalimido acetyl chloride with a chiral imine gave the β-lactam nucleus in 80% diastereoisomeric excess (d.e.). The elaboration of the thiazine ring was carried out using a highly functionalised epoxy ester 12 and P2I4 mediated water elimination.