Treatment of metastatic hormone‐sensitive prostate cancer

Men with metastatic prostate cancer have a significantly reduced median five-year survival compared with that associated with the cancer overall. Clinical trials are exploring the most effective treatment strategies for metastatic hormone-sensitive prostate cancer to intervene before transformation to castration-resistant prostate cancers when options are limited

Always Better Control-Vital Essential Desirable analysis of the drugs used in health centres of Ahmedabad district

Background: The basic principle of inventory control is Always Better Control (ABC) based on cost criteria and Vital Essential Desirable (VED) on criticality. Inequity in drug prioritization and expenses directly affects the health of the community. Study design: Based on ABC-VED matrix, inventory analysis was done. Study area: Community health centre (CHC) - Singarva, two primary health centres (PHC) - Kanbha and Sanathal and two urban health centre (UHC) - Amraiwadi and Sabarmati. Study period: December 2012 to December 2013.Methods: The drugs were first categorized by ABC method and then by VED method. On coupling the two techniques, ABC-VED matrix was made and drugs were classified in to Category I (AV + BV +CV + AE + AD), Category II (BE + CE + BD) and Category III (CD).Results: According to VED analysis large amount of money was spent on D category that is; 35% of annual drug expenditure (ADE) from CHC, 7.6% and 23.4% from both the PHC respectively, 20.1% and 24.7% from both the UHCs. On considering the ABC-VED matrix analysis the ADE spent on Class III was 6.6% among CHC, 1.2% and 1.5% among PHC, 2.6% and 7.2% among the UHC.Conclusion: The ADE used among the ABC-VED Class III should be avoided and the ADE on Class II drugs should be controlled and used judiciously

A retrieval analysis of the Precice intramedullary limb lengthening system

OBJECTIVES: The Precice nail is the latest intramedullary lengthening nail with excellent early outcomes. Implant complications have led to modification of the nail design. The aim of this study was to perform a retrieval study of Precice nails following lower-limb lengthening and to assess macroscopical and microscopical changes to the implants and evaluate differences following design modification, with the aim of identifying potential surgical, implant, and patient risk factors. METHODS: A total of 15 nails were retrieved from 13 patients following lower-limb lengthening. Macroscopical and microscopical surface damage to the nails were identified. Further analysis included radiology and micro-CT prior to sectioning. The internal mechanism was then analyzed with scanning electron microscopy and energy dispersive x-ray spectroscopy to identify corrosion. RESULTS: Seven male and three female patients underwent 12 femoral lengthenings. Three female patients underwent tibial lengthening. All patients obtained the desired length with no implant failure. Surface degradation was noted on the telescopic part of every nail design, less on the latest implants. Microscopical analysis confirmed fretting and pitting corrosion. Following sectioning, black debris was noted in all implants. The early designs were found to have fractured actuator pins and the pin and bearings showed evidence of corrosive debris. The latest designs showed evidence of biological deposits suggestive of fluid ingress within the nail but no corrosion. CONCLUSION: This study confirms less internal corrosion following modification, but evidence of titanium debris remains. We recommend no change to current clinical practice. However, potential reuse of the Precice nail, for secondary limb lengthening in the same patient, should be undertaken with caution

Moving from advocacy to activism? The fourth WHO global forum on human resources for health and implications for dentistry

As we debate shaping the future oral health workforce within the UK, to meet the needs of current and future populations, it is helpful to take an international perspective on this very important issue. Globally, there is a strong recognition that human resources for health (HRH) are fundamentally important to deliver effective care, accessible to all people. This paper reviews the outcome of the fourth global forum held by the World Health Organisation (WHO) in Dublin which highlighted the urgency for action. The main objectives of the forum were to advance the implementation of (i) the WHO Global Strategy on HRH 2030 and (ii) the United Nations High-Level Commission's Health Employment and Economic Growth recommendations. From an oral health perspective, the global burden of oral disease remains huge with untreated dental caries, periodontal disease and tooth loss ranking among the most prevalent conditions worldwide. Major considerations are how dental education, practice delivery and/or oral health systems as a whole could and should innovate to accommodate the growing needs of the population. As dental professionals, it also becomes necessary for us to engage and play a proactive role in this change process. Due to growing differences between population needs and available services, it is necessary for oral health personnel to work more closely with the broader health workforce so as to identify solutions that are in the best interests of the patients and populations at large.M. Balasubramanian, L. Davda, S. D. Short, and J. E. Gallaghe

Enhanced presentation of MHC class Ia, Ib and class II-restricted peptides encapsulated in biodegradable nanoparticles: a promising strategy for tumor immunotherapy

<p>Abstract</p> <p>Background</p> <p>Many peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation. Therefore, the development of suitable and efficient vaccine carrier systems remains a major challenge.</p> <p>Methods</p> <p>To address this issue, we have engineered polylactic-co-glycolic acid (PLGA) nanoparticles incorporating: (i) two MHC class I-restricted clinically-relevant peptides, (ii) a MHC class II-binding peptide, and (iii) a non-classical MHC class I-binding peptide. We formulated the nanoparticles utilizing a double emulsion-solvent evaporation technique and characterized their surface morphology, size, zeta potential and peptide content. We also loaded human and murine dendritic cells (DC) with the peptide-containing nanoparticles and determined their ability to present the encapsulated peptide antigens and to induce tumor-specific cytotoxic T lymphocytes (CTL) <it>in vitro</it>.</p> <p>Results</p> <p>We confirmed that the nanoparticles are not toxic to either mouse or human dendritic cells, and do not have any effect on the DC maturation. We also demonstrated a significantly enhanced presentation of the encapsulated peptides upon internalization of the nanoparticles by DC, and confirmed that the improved peptide presentation is actually associated with more efficient generation of peptide-specific CTL and T helper cell responses.</p> <p>Conclusion</p> <p>Encapsulating antigens in PLGA nanoparticles offers unique advantages such as higher efficiency of antigen loading, prolonged presentation of the antigens, prevention of peptide degradation, specific targeting of antigens to antigen presenting cells, improved shelf life of the antigens, and easy scale up for pharmaceutical production. Therefore, these findings are highly significant to the development of synthetic vaccines, and the induction of CTL for adoptive immunotherapy.</p

Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity

Nanoparticles for Applications in Cellular Imaging

In the following review we discuss several types of nanoparticles (such as TiO2, quantum dots, and gold nanoparticles) and their impact on the ability to image biological components in fixed cells. The review also discusses factors influencing nanoparticle imaging and uptake in live cells in vitro. Due to their unique size-dependent properties nanoparticles offer numerous advantages over traditional dyes and proteins. For example, the photostability, narrow emission peak, and ability to rationally modify both the size and surface chemistry of Quantum Dots allow for simultaneous analyses of multiple targets within the same cell. On the other hand, the surface characteristics of nanometer sized TiO2allow efficient conjugation to nucleic acids which enables their retention in specific subcellular compartments. We discuss cellular uptake mechanisms for the internalization of nanoparticles and studies showing the influence of nanoparticle size and charge and the cell type targeted on nanoparticle uptake. The predominant nanoparticle uptake mechanisms include clathrin-dependent mechanisms, macropinocytosis, and phagocytosis