Effect of age and cytoskeletal elements on the indentation-dependent mechanical properties of chondrocytes.

Articular cartilage chondrocytes are responsible for the synthesis, maintenance, and turnover of the extracellular matrix, metabolic processes that contribute to the mechanical properties of these cells. Here, we systematically evaluated the effect of age and cytoskeletal disruptors on the mechanical properties of chondrocytes as a function of deformation. We quantified the indentation-dependent mechanical properties of chondrocytes isolated from neonatal (1-day), adult (5-year) and geriatric (12-year) bovine knees using atomic force microscopy (AFM). We also measured the contribution of the actin and intermediate filaments to the indentation-dependent mechanical properties of chondrocytes. By integrating AFM with confocal fluorescent microscopy, we monitored cytoskeletal and biomechanical deformation in transgenic cells (GFP-vimentin and mCherry-actin) under compression. We found that the elastic modulus of chondrocytes in all age groups decreased with increased indentation (15-2000 nm). The elastic modulus of adult chondrocytes was significantly greater than neonatal cells at indentations greater than 500 nm. Viscoelastic moduli (instantaneous and equilibrium) were comparable in all age groups examined; however, the intrinsic viscosity was lower in geriatric chondrocytes than neonatal. Disrupting the actin or the intermediate filament structures altered the mechanical properties of chondrocytes by decreasing the elastic modulus and viscoelastic properties, resulting in a dramatic loss of indentation-dependent response with treatment. Actin and vimentin cytoskeletal structures were monitored using confocal fluorescent microscopy in transgenic cells treated with disruptors, and both treatments had a profound disruptive effect on the actin filaments. Here we show that disrupting the structure of intermediate filaments indirectly altered the configuration of the actin cytoskeleton. These findings underscore the importance of the cytoskeletal elements in the overall mechanical response of chondrocytes, indicating that intermediate filament integrity is key to the non-linear elastic properties of chondrocytes. This study improves our understanding of the mechanical properties of articular cartilage at the single cell level

Evaluation of renal drug dosing adjustment in chronic kidney disease patients at two university hospitals in Lebanon

Background: Inappropriate medication dosing in patients with chronic kidney disease can cause toxicity or ineffective therapy. Patients are at a high risk of developing related adverse events caused by the altered effect of drugs in conjunction with the use of polypharmacy to treat comorbid conditions. This necessitates adequate renal dosing adjustments. Objective: The current study aims at assessing whether appropriate dosing adjustments were made in hospitalized patients with chronic kidney disease. Methods: A retrospective descriptive study was conducted at two university hospitals in Beirut between January and December 2016. All adult CKD patients with creatinine clearance less than 60 ml/min and receiving at least one medication that require renal dosing adjustment were included. Kidney function was estimated from serum creatinine using Cockcroft-Gault equation, and dose appropriateness was determined by comparing practice with specific guidelines. The rates of renal drug dosing adjustment were investigated, in addition to the influence of possible determinants, such as the severity of renal impairment, reason of hospital admission, and other patient characteristics. Results: 2138 patients admitted in 2016 were screened. 223 adults receiving 578 drug orders that require adjustment were included. Among the 578 orders, 215 (37%) were adjusted adequately, 284 (49%) were adjusted inadequately, and 79 (14%) were not adjusted at all. Beta-blockers were the most inadequately dosed (83.6%) class of medication, whereas lipid-lowering agents had the highest percentage of adequate dosing (65.1%). As per patient, 84.3% of patients appeared to be receiving at least one inappropriate drug dose. Conclusions: Our study confirms that physicians are not prescribing appropriate dosing adjustments in chronic kidney disease inpatients, which may have deleterious effects. This highlights the need for more nephrology consultation and the implementation of physician education programs

Nanocomposite Scaffold for Chondrocyte Growth and Cartilage Tissue Engineering: Effects of Carbon Nanotube Surface Functionalization

The goal of this study was to assess the long-term biocompatibility of single-wall carbon nanotubes (SWNTs) for tissue engineering of articular cartilage. We hypothesized that SWNT nanocomposite scaffolds in cartilage tissue engineering can provide an improved molecular-sized substrate for stimulation of chondrocyte growth, as well as structural reinforcement of the scaffold\u27s mechanical properties. The effect of SWNT surface functionalization (-COOH or -PEG) on chondrocyte viability and biochemical matrix deposition was examined in two-dimensional cultures, in three-dimensional (3D) pellet cultures, and in a 3D nanocomposite scaffold consisting of hydrogels + SWNTs. Outcome measures included cell viability, histological and SEM evaluation, GAG biochemical content, compressive and tensile biomechanical properties, and gene expression quantification, including extracellular matrix (ECM) markers aggrecan (Agc), collagen-1 (Col1a1), collagen-2 (Col2a1), collagen-10 (Col10a1), surface adhesion proteins fibronectin (Fn), CD44 antigen (CD44), and tumor marker (Tp53). Our findings indicate that chondrocytes tolerate functionalized SWNTs well, with minimal toxicity of cells in 3D culture systems (pellet and nanocomposite constructs). Both SWNT-PEG and SWNT-COOH groups increased the GAG content in nanocomposites relative to control. The compressive biomechanical properties of cell-laden SWNT-COOH nanocomposites were significantly elevated relative to control. Increases in the tensile modulus and ultimate stress were observed, indicative of a tensile reinforcement of the nanocomposite scaffolds. Surface coating of SWNTs with -COOH also resulted in increased Col2a1 and Fn gene expression throughout the culture in nanocomposite constructs, indicative of increased chondrocyte metabolic activity. In contrast, surface coating of SWNTs with a neutral -PEG moiety had no significant effect on Col2a1 or Fn gene expression, suggesting that the charged nature of the -COOH surface functionalization may promote ECM expression in this culture system. The results of this study indicate that SWNTs exhibit a unique potential for cartilage tissue engineering, where functionalization with bioactive molecules may provide an improved substrate for stimulation of cellular growth and repair

Public Health Entrepreneurship: A Novel Path for Training Future Public Health Professionals

Background: As schools of public health adapt to the new Council on Public Health (CEPH) competencies there is increased relevance in training public health professionals in public health entrepreneurship. Public health entrepreneurship provides an alternate process to traditional academic approaches focusing on translating public health knowledge into effective, sustainable, and scalable solutions.Objective: This study reports student perceptions of public health entrepreneurship and training needs for successfully equipping future public health professionals.Methods: Focus groups were conducted in April 2018 with graduate public health students in pilot entrepreneurship courses at two U.S.-based CEPH-accredited schools of public health.Results: Participating students (n = 29) were mainly pursing MPH degrees (62%) within Health Management and Policy (38%) or Health Promotion/Global Health (31%) departments. Most students (52%) were between 21 and 30 years old. For 71% of students this was their first academic course with a focus on entrepreneurial thinking. Four themes emerged regarding public health entrepreneurship and training needs for becoming a successful public health professional of the future. Students confirmed a place for public health entrepreneurship in the emerging educational paradigm because it is action-oriented, skills-driven, and fosters innovation through inter-professional collaboration and cross-pollination of knowledge and skills between professional disciplines.Conclusions: The competencies required for public health entrepreneurship are in alignment with CEPH competencies and are well-received by the next generation of public health professionals as an adjunct but nascent approach to stimulate public health innovation

Exact relations between damage spreading and thermodynamic functions for the N-color Ashkin-Teller model

Exact results are derived relating quantities computable by the so-called damage spreading method and thermodynamic functions for the N-color Ashkin-Teller model. The results are valid for any ergodic dynamics. Since we restrict our analysis to the ferromagnetic case the results are also valid for any translational invariant lattice. The derived relations should be used in order to determine numerically the N-color Ashkin-Teller critical exponents with better accuracy and less computational efforts than standard Monte Carlo simulations.Comment: 6 pages, to be published in JSTAT (Journal of Statistical Mechanics: Theory and Experiment). The results of a computer simulation were included for N=3 as an example on how to use the analytical relations derived in the paper as a guide to obtain the critical temperature and critical exponent

Clinical utility of diagnostic markers for malignant pleural mesothelioma

Malignant mesothelioma has a very dismal prognosis with very few patients surviving one year after diagnosis. Early multimodal treatment, however, is expected to improve the outcome. Today, there is a strong need to have disease markers which could be used for screening, diagnosing, and/or monitoring tumour response to treatment. Old markers such as hyaluronic acid, various cytokeratin fragments (CYFRA 21.1, TPA) and other cancer antigens (CA 15.3, CA 125 or CA 19.9 or CEA) are not sensitive or specific enough and cannot be used in practice. More recently new molecules, such as soluble mesothelin and osteopontin, have been proposed for diagnostic purposes. Soluble mesothelin has a good specificity but has a suboptimal sensitivity being negative in all sarcomatoid and in up to one half of epithelioid mesothelioma. On the contrary osteopontin has an inadequate specificity. Combining different markers together does not lead to an improvement in diagnostic accuracy. Neither marker can be used for screening purposes, the main limitation being the very low incidence of the disease in the at-risk, asbestos exposed population. Mesothelin is also a promising marker for monitoring response to treatment but published data is still insufficient to make recommendations. There is still a strong need for research is this area both in order to discover new markers as well as to correct the positioning of each existing molecule (alone or in combination) is the evaluation of the patients with a mesothelioma

A Baker\u27s Dozen of Top Antimicrobial Stewardship Intervention Publications in 2017

With an increasing number of antimicrobial stewardship-related articles published each year, attempting to stay current is challenging. The Southeastern Research Group Endeavor (SERGE-45) identified antimicrobial stewardship-related peer-reviewed literature that detailed an actionable intervention for 2017. The top 13 publications were selected using a modified Delphi technique. These manuscripts were reviewed to highlight the actionable intervention used by antimicrobial stewardship programs to provide key stewardship literature for training and teaching and identify potential intervention opportunities within their institutions

Assessment of Antimicrobial Pharmacokinetics Curricula Across Schools and Colleges of Pharmacy in the United States

Introduction Advances in technology and understanding of pharmacokinetic/pharmacodynamic relationships have prompted guideline updates and advances in precision dosing, but the role of clinical pharmacokinetics (PK) in pharmacy education remains inconsistent. Previous surveys of pharmacy school PK curricula revealed large variations in content, integration, and teaching tools but did not focus on antimicrobials or details of andragogy used. Objective Identify how antimicrobial PK is taught in pharmacy curricula across the United States, as well as instructor perceptions of current practices. Methods An online survey was distributed to 118 pharmacy programs across the United States in 2018. This 30-minute questionnaire covered curriculum content, teaching strategies, assessment modalities, and perceptions. Results Completed surveys were received from 53 programs (45% response rate) via relevant course coordinators. Among 35 traditional progressive curriculum programs (TPC), antimicrobial PK was taught in basic science (33, 94%), clinical PK (15, 43%), pharmacology (8, 23%), therapeutics (28, 80%), and skills lab courses (21, 65%). Among 18 integrated block curriculum programs (IBC), it was taught in foundations/principles (17, 94%), organ systems (12, 67%), and skills lab courses (9, 50%). On average, TPC programs had more courses with antimicrobial PK than IBC programs. Vancomycin and aminoglycosides were the most common antimicrobials taught (100%), while didactic lecturing was the predominant andragogy. Multiple choice was the primary assessment modality, being frequently used in 64% of TPC and 68% of IBC courses, respectively. Among respondents, 72% believed more time was needed to teach PK and 53% believed students were adequately prepared at the start of APPEs. Conclusion Antimicrobial PK instruction remains highly inconsistent in U.S. pharmacy schools and colleges. IBC programs may provide less opportunity for antimicrobial PK instruction, which conflicts with the desire for more instruction time. As clinical applications of antimicrobial PK change and expand, it is crucial that pharmacy education prioritizes PK education appropriately

Statistical mechanics of RNA folding: a lattice approach

We propose a lattice model for RNA based on a self-interacting two-tolerant trail. Self-avoidance and elements of tertiary structure are taken into account. We investigate a simple version of the model in which the native state of RNA consists of just one hairpin. Using exact arguments and Monte Carlo simulations we determine the phase diagram for this case. We show that the denaturation transition is first order and can either occur directly or through an intermediate molten phase.Comment: 8 pages, 9 figure