Significance of Nano- and Microtopography for Cell-Surface Interactions in Orthopaedic Implants

Cell-surface interactions play a crucial role for biomaterial application in orthopaedics. It is evident that not only the chemical composition of solid substances influence cellular adherence, migration, proliferation and differentiation but also the surface topography of a biomaterial. The progressive application of nanostructured surfaces in medicine has gained increasing interest to improve the cytocompatibility and osteointegration of orthopaedic implants. Therefore, the understanding of cell-surface interactions is of major interest for these substances. In this review, we elucidate the principle mechanisms of nano- and microscale cell-surface interactions in vitro for different cell types onto typical orthopaedic biomaterials such as titanium (Ti), cobalt-chrome-molybdenum (CoCrMo) alloys, stainless steel (SS), as well as synthetic polymers (UHMWPE, XLPE, PEEK, PLLA). In addition, effects of nano- and microscaled particles and their significance in orthopaedics were reviewed. The significance for the cytocompatibility of nanobiomaterials is discussed critically

Spatial evolution of an ion beam created by a geometrically expanding low-pressure argon plasma

The spatial distribution of an ion beam—created at the interface of a small diameter plasma source and much larger diameter diffusion chamber—is studied in a low-pressure inductively coupled plasma using a retarding field energy analyzer. It is found that the ion beam density decays axially and radially in the diffusion chamber following the expansion of the plasma from the source region. The radial distribution of the ion beam indicates that the acceleration region has a convex shape and is located just outside the source exit, giving rise to a hemispherical plasma expansion into the diffusion chamber

Ion beam formation in a low-pressure geometrically expanding argon plasma

Supersonic ion beam formation has been observed in a geometrically expanding low-pressure inductively coupled argon plasma. It is found that the ion beam is only observed below 3mTorr and only when the discharge is operated in inductive mode. The geometrical expansion of the plasma induces density and potential gradients leading to the ion beam formation. The ion beam energy increases with decreasing source tube radius. The results show that ion beam formation can be achieved by geometrical expansion alone and that the ion beam energy depends on the ratio of the cross-sectional area of the source and expansion region

Identification of New Alleles and the Determination of Alleles and Genotypes Frequencies at the CYP2D6 Gene in Emiratis

CYP2D6 belongs to the cytochrome P450 superfamily of enzymes and plays an important role in the metabolism of 20–25% of clinically used drugs including antidepressants. It displays inter-individual and inter-ethnic variability in activity ranging from complete absence to excessive activity which causes adverse drug reactions and toxicity or therapy failure even at normal drug doses. This variability is due to genetic polymorphisms which form poor, intermediate, extensive or ultrarapid metaboliser phenotypes. This study aimed to determine CYP2D6 alleles and their frequencies in the United Arab Emirates (UAE) local population. CYP2D6 alleles and genotypes were determined by direct DNA sequencing in 151 Emiratis with the majority being psychiatric patients on antidepressants. Several new alleles have been identified and in total we identified seventeen alleles and 49 genotypes. CYP2D6*1 (wild type) and CYP2D6*2 alleles (extensive metaboliser phenotype) were found with frequencies of 39.1% and 12.2%, respectively. CYP2D6*41 (intermediate metaboliser) occurred in 15.2%. Homozygous CYP2D6*4 allele (poor metaboliser) was found with a frequency of 2% while homozygous and heterozygous CYP2D6*4 occurred with a frequency of 9%. CYP2D6*2xn, caused by gene duplication (ultrarapid metaboliser) had a frequency of 4.3%. CYP2D6 gene duplication/multiduplication occurred in 16% but only 11.2% who carried more than 2 active functional alleles were considered ultrarapid metabolisers. CYP2D6 gene deletion in one copy occurred in 7.5% of the study group. In conclusion, CYP2D6 gene locus is heterogeneous in the UAE national population and no significant differences have been identified between the psychiatric patients and controls

Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine

Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a `two-way road' - from bench to bedside and backwards from bedside to bench. Copyright (c) 2012 S. Karger AG, Base

Anti-emetic drugs in oncology: pharmacology and individualization by pharmacogenetics

Objective Nausea and vomiting are the most distressful side effects of cytotoxic drugs in cancer patients. Antiemetics are commonly used to reduce these side effects. However, the current antiemetic efficacy is about 70–80% in patients treated with highly-emetogenic cytotoxic drugs. One of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins which play a role in metabolism, transport and receptors related to antiemetic drugs. Aim of this review was to describe the pharmacology and pharmacogenetic concepts of of antiemetics in oncology. Method Pharmacogenetic and pharmacology studies of antiemetics in oncology published between January 1997 and February 2010 were searched in PubMed. Furthermore, related textbooks were also used for exploring the pharmacology of antiemetic drugs. The antiemetic drugs which were searched were the 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs), dopamine antagonists, corticosteroids, benzodiazepines, cannabinoids, antihistamines and neurokinin-1 antagonists. Result The 5-HT3RAs are widely used in highly emetogenic chemotherapy in combination with dexamethasone and a neurokinin-1 antagonist, especially in acute phase. However, the dopamine antagonists and benzodiazepines were found more appropriate for use in breakthrough and anticipatory symptoms or in preventing the delayed phase of chemotherapy induced nausea and vomiting. The use of cannabinoids and antihistamines need further investigation. Only six articles on pharmacogenetics of the 5-HT3RAs in highly emetogenic chemotherapy are published. Specifically, these studies investigated the association of the efficacy of 5-HT3RAs and variants in the multi drug resistance 1 (MDR1) gene, 5-HT3A,B and C receptor genes and CYP2D6 gene. The pharmacogenetic studies of the other antiemetics were not found in this review. Conclusion It is concluded that pharmacogenetic studies with antiemetics are sparse. It is too early to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice: confirmation of early findings is required

Adverse Drug Reactions in Hospital In-Patients: A Prospective Analysis of 3695 Patient-Episodes

Adverse drug reactions (ADRs) are a major cause of hospital admissions, but recent data on the incidence and clinical characteristics of ADRs which occur following hospital admission, are lacking. Patients admitted to twelve wards over a six-month period in 2005 were assessed for ADRs throughout their admission. Suspected ADRs were recorded and analysed for causality, severity and avoidability and whether they increased the length of stay. Multivariable analysis was undertaken to identify the risk factors for ADRs. The 5% significance level was used when assessing factors for inclusion in multivariable models. Out of the 3695 patient episodes assessed for ADRs, 545 (14.7%, 95% CI 13.6–15.9%) experienced one or more ADRs. Half of ADRs were definitely or possibly avoidable. The patients experiencing ADRs were more likely to be older, female, taking a larger number of medicines, and had a longer length of stay than those without ADRs. However, the only significant predictor of ADRs, from the multivariable analysis of a representative sample of patients, was the number of medicines taken by the patient with each additional medication multiplying the hazard of an ADR episode by 1.14 (95% CI 1.09, 1.20). ADRs directly increased length of stay in 147 (26.8%) patients. The drugs most frequently associated with ADRs were diuretics, opioid analgesics, and anticoagulants. In conclusion, approximately one in seven hospital in-patients experience an ADR, which is a significant cause of morbidity, increasing the length of stay of patients by an average of 0.25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10?77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14?nM) compared with high (>35?nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS

Aptamer-based field-effect biosensor for tenofovir detection

During medical treatment it is critical to maintain the circulatory concentration of drugs within their therapeutic range. A novel biosensor is presented in this work to address the lack of a reliable point-of-care drug monitoring system in the market. The biosensor incorporates high selectivity and sensitivity by integrating aptamers as the recognition element and field-effect transistors as the signal transducer. The drug tenofovir was used as a model small molecule. The biointerface of the sensor is a binary self-assembled monolayer of specific thiolated aptamer and 6-mercapto-1-hexanol (MCH), whose ratio was optimized by electrochemical impedance spectroscopy measurements to enhance the sensitivity towards the specific target. Surface plasmon resonance, performed under different buffer conditions, shows optimum specific and little non-specific binding in phosphate buffered saline. The dose-response behavior of the field-effect biosensor presents a linear range between 1 nM and 100 nM of tenofovir and a limit of detection of 1.2 nM. Two non-specific drugs and one non-specific aptamer, tested as stringent control candidates, caused negligible responses. The applications were successfully extended to the detection of the drug in human serum. As demonstrated by impedance measurements, the aptamer-based sensors can be used for real-time drug monitoring

Extracellular signal-regulated kinase 1/2-mediated phosphorylation of p300 enhances myosin heavy chain I/β gene expression via acetylation of nuclear factor of activated T cells c1

The nuclear factor of activated T-cells (NFAT) c1 has been shown to be essential for Ca2+-dependent upregulation of myosin heavy chain (MyHC) I/β expression during skeletal muscle fiber type transformation. Here, we report activation of extracellular signal-regulated kinase (ERK) 1/2 in Ca2+-ionophore-treated C2C12 myotubes and electrostimulated soleus muscle. Activated ERK1/2 enhanced NFATc1-dependent upregulation of a −2.4 kb MyHCI/β promoter construct without affecting subcellular localization of endogenous NFATc1. Instead, ERK1/2-augmented phosphorylation of transcriptional coactivator p300, promoted its recruitment to NFATc1 and increased NFATc1–DNA binding to a NFAT site of the MyHCI/β promoter. In line, inhibition of ERK1/2 signaling abolished the effects of p300. Comparison between wild-type p300 and an acetyltransferase-deficient mutant (p300DY) indicated increased NFATc1–DNA binding as a consequence of p300-mediated acetylation of NFATc1. Activation of the MyHCI/β promoter by p300 depends on two conserved acetylation sites in NFATc1, which affect DNA binding and transcriptional stimulation. NFATc1 acetylation occurred in Ca2+-ionophore treated C2C12 myotubes or electrostimulated soleus. Finally, endogenous MyHCI/β gene expression in C2C12 myotubes was strongly inhibited by p300DY and a mutant deficient in ERK phosphorylation sites. In conclusion, ERK1/2-mediated phosphorylation of p300 is crucial for enhancing NFATc1 transactivation function by acetylation, which is essential for Ca2+-induced MyHCI/β expression