Instrumentation of Near-term Fetal Sheep for Multivariate Chronic Non-anesthetized Recordings

The chronically instrumented non-anesthetized fetal sheep model is used to study human fetal development in health and disease, because it permits surgical placement and maintenance of catheters and electrodes, repetitive blood sampling, substance injection, recording of bioelectrical activity, and in vivo imaging. We describe the procedures required to establish this model.

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Catecholic amides as potential selective phosphodiesterase 4D inhibitors: Design, synthesis, pharmacological evaluation and structure-activity relationships

Publication date: Available online 24 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Zhong-Zhen Zhou, Bing-Chen Ge, Yu-Fang Chen, Xiu-Dong Shi, Xue-Mei Yang, Jiang-Ping Xu
In this study, a series of catechol-based amides (8a–n) with different amide linkers linking the catecholic moiety to the terminal phenyl ring was designed and synthesized as potent phosphodiesterase (PDE) 4D inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4B1 and PDE4D7 enzymes, and other PDE family members. The results indicated the majority of compounds 8a–n displayed moderate to good inhibitory activities against PDE4CAT. Among these compounds, compound 8j with a short amide linker (–CONHCH2–) displayed comparable PDE4CAT inhibitory activity (IC50 = 410 nM) with rolipram. More interestingly, compound 8g, a potent and selective PDE4D inhibitor (IC50 = 94 nM), exhibited a 10-fold selectivity over the PDE4B subtypes and an over 1000-fold selectivity against other PDE family members. Docking simulations suggested that 8g forms three extra H-bonds with the N–H of residue Asn487 and two water molecules.

Graphical abstract

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Helical peptide–polyamine and –polyether conjugates as synthetic ionophores

Publication date: Available online 24 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Monica Benincasa, Marco Francescon, Massimo Fregonese, Renato Gennaro, Paolo Pengo, Paola Rossi, Paolo Scrimin, Paolo Tecilla
Two new synthetic ionophores in which the hydrophobic portion is represented by a short helical Aib-peptide (Aib = α-amino-isobutyric acid) and the hydrophilic one is a poly-amino (1a) or a polyether (1b) chain have been prepared. The two conjugates show a high ionophoric activity in phospholipid membranes being able to efficiently dissipate a pH gradient and, in the case of 1b, to transport Na⁺ across the membrane. Bioactivity evaluation of the two conjugates shows that 1a has a moderate antimicrobial activity against a broad spectrum of microorganisms and it is able to permeabilize the inner and the outer membrane of E. coli cells.

Graphical abstract

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Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer’s disease

Publication date: Available online 24 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Jeremy E. Chojnacki, Kai Liu, John M. Saathoff, Shijun Zhang
In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.

Graphical abstract

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Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors

Publication date: Available online 24 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Séverine Ravez, Stéphane Arsenlis, Amélie Barczyk, Anthony Dupont, Raphaël Frederick, Stéphanie Hesse, Gilbert Kirsch, Patrick Depreux, Laurence Goossens
Inhibition of receptor tyrosine kinases (RTKs) continued to be a successful approach for the treatment of many types of human cancers and many potent small molecules kinase inhibitors have been discovered the last decade. In the present study, we describe the synthesis of thienopyrimidine derivatives and their pharmacological evaluation against nine kinases (EGFR, PDGFR-ß, c-Kit, c-Met, Src, Raf,VEGFR-1, -2 and -3). Most of the synthesized compounds showed from moderate to potent activities against c-Kit with IC50 values in the nanomolar range. Among them, 4-anilino(urea)thienopyrimidine analogs showed selectivity and potent c-Kit inhibition with IC50 values less than 6 nM. Docking simulation was performed for the most promising compound 9 into the c-Kit active site to determine the potential binding mode. This study reveal that the 4-anilino(urea)thienopyrimidine is an interesting scaffold to design novel potent and selective c-Kit inhibitors which may make promising candidates for cancers where c-Kit receptors are overexpressed.

Graphical abstract

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Does Computer-Assisted Femur First THR Improve Musculoskeletal Loading Conditions?

We have developed a novel, computer-assisted operation method for minimal-invasive total hip replacement (THR) following the concept of "femur first/combined anteversion," which incorporates various aspects of performing a functional optimization of the prosthetic stem and cup position (CAS FF). The purpose of this study is to assess whether the hip joint reaction forces and patient's gait parameters are being improved by CAS FF in relation to conventional THR (CON). We enrolled 60 patients (28 CAS FF/32 CON) and invited them for gait analysis at three time points (preoperatively, postop six months, and postop 12 months). Data retrieved from gait analysis was processed using patient-specific musculoskeletal models. The target parameters were hip reaction force magnitude (hrf), symmetries, and orientation with respect to the cup. Hrf in the CAS FF group were closer to a young healthy normal. Phase-shift symmetry showed an increase in the CAS FF group. Hrf orientation in the CAS FF group was closer to optimum, though no edge or rim-loading occurred in the CON group as well. The CAS FF group showed an improved hrf orientation in an early stage and a trend to an improved long-term outcome.

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Hyaluronan’s Role in Fibrosis: A Pathogenic Factor or a Passive Player?

Fibrosis is a debilitating condition that can lead to impairment of the affected organ's function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor-β (TGF-β) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF-β and whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases.

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Application of Mathematical Modeling for Simulation and Analysis of Hypoplastic Left Heart Syndrome (HLHS) in Pre- and Postsurgery Conditions

This paper is concerned with the mathematical modeling of a severe and common congenital defect called hypoplastic left heart syndrome (HLHS). Surgical approaches are utilized for palliating this heart condition; however, a brain white matter injury called periventricular leukomalacia (PVL) occurs with high prevalence at or around the time of surgery, the exact cause of which is not known presently. Our main goal in this paper is to study the hemodynamic conditions under which HLHS physiology may lead to the occurrence of PVL. A lumped parameter model of the HLHS circulation has been developed integrating diffusion modeling of oxygen and carbon dioxide concentrations in order to study hemodynamic variables such as pressure, flow, and blood gas concentration. Results presented include calculations of blood pressures and flow rates in different parts of the circulation. Simulations also show changes in the ratio of pulmonary to systemic blood flow rates when the sizes of the patent ductus arteriosus and atrial septal defect are varied. These changes lead to unbalanced blood circulations and, when combined with low oxygen and carbon dioxide concentrations in arteries, result in poor oxygen delivery to the brain. We stipulate that PVL occurs as a consequence.

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Simulation of Ectopic Pacemakers in the Heart: Multiple Ectopic Beats Generated by Reentry inside Fibrotic Regions

The inclusion of nonconducting media, mimicking cardiac fibrosis, in two models of cardiac tissue produces the formation of ectopic beats. The fraction of nonconducting media in comparison with the fraction of healthy myocytes and the topological distribution of cells determines the probability of ectopic beat generation. First, a detailed subcellular microscopic model that accounts for the microstructure of the cardiac tissue is constructed and employed for the numerical simulation of action potential propagation. Next, an equivalent discrete model is implemented, which permits a faster integration of the equations. This discrete model is a simplified version of the microscopic model that maintains the distribution of connections between cells. Both models produce similar results when describing action potential propagation in homogeneous tissue; however, they slightly differ in the generation of ectopic beats in heterogeneous tissue. Nevertheless, both models present the generation of reentry inside fibrotic tissues. This kind of reentry restricted to microfibrosis regions can result in the formation of ectopic pacemakers, that is, regions that will generate a series of ectopic stimulus at a fast pacing rate. In turn, such activity has been related to trigger fibrillation in the atria and in the ventricles in clinical and animal studies.

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Dental Implants Fatigue as a Possible Failure of Implantologic Treatment: The Importance of Randomness in Fatigue Behaviour

Objective. To show how random variables concern fatigue behaviour by a probabilistic finite element method. Methods. Uncertainties on material properties due to the existence of defects that cause material elastic constant are not the same in the whole dental implant the dimensions of the structural element and load history have a decisive influence on the fatigue process and therefore on the life of a dental implant. In order to measure these uncertainties, we used a method based on Markoff chains, Bogdanoff and Kozin cumulative damage model, and probabilistic finite elements method. Results. The results have been obtained by conventional and probabilistic methods. Mathematical models obtained the same result regarding fatigue life; however, the probabilistic model obtained a greater mean life but with more information because of the cumulative probability function. Conclusions. The present paper introduces an improved procedure to study fatigue behaviour in order to know statistics of the fatigue life (mean and variance) and its probability of failure (fatigue life versus probability of failure).

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Increased Expression of Serglycin in Specific Carcinomas and Aggressive Cancer Cell Lines

In the present pilot study, we examined the presence of serglycin in lung, breast, prostate, and colon cancer and evaluated its expression in cell lines and tissues. We found that serglycin was expressed and constitutively secreted in culture medium in high levels in more aggressive cancer cells. It is worth noticing that aggressive cancer cells that harbor KRAS or EGFR mutations secreted serglycin constitutively in elevated levels. Furthermore, we detected the transcription of an alternative splice variant of serglycin lacking exon 2 in specific cell lines. In a limited number of tissue samples analyzed, serglycin was detected in normal epithelium but was also expressed in higher levels in advanced grade tumors as shown by immunohistochemistry. Serglycin staining was diffuse, granular, and mainly cytoplasmic. In some cancer cells serglycin also exhibited membrane and/or nuclear immunolocalization. Interestingly, the stromal cells of the reactive tumor stroma were positive for serglycin, suggesting an enhanced biosynthesis for this proteoglycan in activated tumor microenvironment. Our study investigated for first time the distribution of serglycin in normal epithelial and cancerous lesions in most common cancer types. The elevated levels of serglycin in aggressive cancer and stromal cells may suggest a key role for serglycin in disease progression.

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Vapotage chez les étudiants à l’université et relation avec le tabagisme

Publication date: Available online 24 October 2015
Source:Revue des Maladies Respiratoires
Author(s): T. Rakotozandry, N. Stenger, C. Burel, L. Penna, M. Ramadour, P. Disdier, D. Charpin
IntroductionOn peut craindre que le vapotage puisse représenter un mode d'entrée dans le tabagisme.Matériel et méthodesCette enquête a concerné 1220 étudiants de l'université d'Aix-Marseille, convoqués durant une période de 6 semaines (mi-février à fin mars). Ces étudiants ont tous répondu à un questionnaire relatif à leurs habitudes tabagiques, au vapotage et à l'influence du vapotage sur le tabagisme. Le questionnaire a été mis à disposition des étudiants durant un mois en salle d'attente avant la visite médicale. Le groupe étudié avait un âge moyen de 19,9ans et était constitué de 56 % de filles.RésultatsL'intégralité des étudiants a répondu au questionnaire. Au total, 13,3 % des étudiants ont répondu avoir déjà vapoté, davantage les garçons (17,5 %) que les filles (10,0 %), à partir d'un âge moyen de 19,2ans. Quarante-six pour cent des étudiants ont déjà fumé du tabac, davantage les filles (55,0 %) que les garçons (45,0 %). Parmi les fumeurs, le vapotage a induit un sevrage tabagique chez 12,6 %, une diminution du tabagisme chez 30,1 %. Vingt pour cent des vapoteurs non-fumeurs ont déclaré s'être mis à fumer du tabac après vapotage.DiscussionLe vapotage est encore beaucoup moins répandu que le fumage du tabac. Il y a un lien fort entre fumage et vapotage. Ce dernier permet dans près de la moitié des cas une diminution ou un arrêt du tabagisme. Le vapotage peut évoluer en tabagisme mais il est difficile de prévoir l'évolution ultérieure de ce dernier. Il pourrait par ailleurs éviter ou retarder le passage au tabagisme.IntroductionThere is concern that e-cigarette use could be a risk factor for subsequent cigarette smoking.MethodsThis survey included a group of 1220 students at Aix-Marseille University who attended a check-up visit and volunteered to participate to the survey. They answered a standardized questionnaire relating to e-cigarette use, smoking habits and the relationship between both habits. Mean age of participants was 19.9 years and 56% of them were female.ResultsAll students invited to the check-up examination attended and agreed to participate in the survey. 13.3% of students answered they had already used e-cigarettes, a higher proportion of boys (17.5%) than girls (10.0%), starting at a mean age equal to 19.2years. Forty-six percent of them had already smoked cigarettes, more girls (55.0%) than boys (45.0%). Among current cigarette smokers, e-cigarette use had induced giving up smoking in 12.6% and a decrease in the number of cigarettes smoked in 30.1%. Twenty percent said they begun to smoke cigarettes after using e-cigarettes.DiscussionE-cigarette use is much less prevalent than smoking conventional tobacco cigarettes. There is a strong link between both. E-cigarette use had allowed a cessation or reduction in tobacco smoking in half of users. E-cigarette users may go on to start tobacco smoking but prospective surveys are needed to know how this will evolve over time. E-cigarette use could also be a means to prevent or postpone cigarette smoking.



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Functional and Phenotypic Plasticity of CD4+ T Cell Subsets

The remarkable plasticity of CD4+ T cells allows individuals to respond to environmental stimuli in a context-dependent manner. A balance of CD4+ T cell subsets is critical to mount responses against pathogen challenges to prevent inappropriate activation, to maintain tolerance, and to participate in antitumor immune responses. Specification of subsets is a process beginning in intrathymic development and continuing within the circulation. It is highly flexible to adapt to differences in nutrient availability and the tissue microenvironment. CD4+ T cell subsets have significant cross talk, with the ability to "dedifferentiate" given appropriate environmental signals. This ability is dependent on the metabolic status of the cell, with mTOR acting as the rheostat. Autoimmune and antitumor immune responses are regulated by the balance between regulatory T cells and Th17 cells. When a homeostatic balance of subsets is not maintained, immunopathology can result. CD4+ T cells carry complex roles within tumor microenvironments, with context-dependent immune responses influenced by oncogenic drivers and the presence of inflammation. Here, we examine the signals involved in CD4+ T cell specification towards each subset, interconnectedness of cytokine networks, impact of mTOR signaling, and cellular metabolism in lineage specification and provide a supplement describing techniques to study these processes.

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Recent Advances on Pathophysiology, Diagnostic and Therapeutic Insights in Cardiac Dysfunction Induced by Antineoplastic Drugs

Along with the improvement of survival after cancer, cardiotoxicity due to antineoplastic treatments has emerged as a clinically relevant problem. Potential cardiovascular toxicities due to anticancer agents include QT prolongation and arrhythmias, myocardial ischemia and infarction, hypertension and/or thromboembolism, left ventricular (LV) dysfunction, and heart failure (HF). The latter is variable in severity, may be reversible or irreversible, and can occur soon after or as a delayed consequence of anticancer treatments. In the last decade recent advances have emerged in clinical and pathophysiological aspects of LV dysfunction induced by the most widely used anticancer drugs. In particular, early, sensitive markers of cardiac dysfunction that can predict this form of cardiomyopathy before ejection fraction (EF) is reduced are becoming increasingly important, along with novel therapeutic and cardioprotective strategies, in the attempt of protecting cardiooncologic patients from the development of congestive heart failure.

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In Vivo Targeted Magnetic Resonance Imaging of Endogenous Neural Stem Cells in the Adult Rodent Brain

Neural stem cells in the adult mammalian brain have a significant level of neurogenesis plasticity. In vivo monitoring of adult endogenous NSCs would be of great benefit to the understanding of the neurogenesis plasticity under normal and pathological conditions. Here we show the feasibility of in vivo targeted MR imaging of endogenous NSCs in adult mouse brain by intraventricular delivery of monoclonal anti-CD15 antibody conjugated superparamagnetic iron oxide nanoparticles. After intraventricular administration of these nanoparticles, the subpopulation of NSCs in the anterior subventricular zone and the beginning of the rostral migratory stream could be in situ labeled and were in vivo visualized with 7.0-T MR imaging during a period from 1 day to 7 days after the injection. Histology confirmed that the injected targeted nanoparticles were specifically bound to CD15 positive cells and their surrounding extracellular matrix. Our results suggest that in vivo targeted MR imaging of endogenous neural stem cells in adult rodent brain could be achieved by using anti-CD15-SPIONs as the molecular probe; and this targeting imaging strategy has the advantage of a rapid in vivo monitoring of the subpopulation of endogenous NSCs in adult brains.

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Revisiting the Posttherapeutic Cure Criterion in Chagas Disease: Time for New Methods, More Questions, Doubts, and Polemics or Time to Change Old Concepts?

One of the most relevant issues beyond the effectiveness of etiological treatment of Chagas disease is the lack of consensual/feasible tools to identify and certify the definitive parasitological cure. Several methods of distinct natures (parasitological, serological, and molecular) have been continuously proposed and novel perspectives are currently under investigation. Although the simultaneous use of distinct tests may offer better contributions and advances, it also leads to controversies of interpretation, with lack of mutual consent of cure criterion amongst researchers and physicians. In fact, when distinct host compartments (blood/tissues) are evaluated and explored, novel questions may arise due to the nature and sensitivity limit of each test. This short analytical review intends to present a chronological and critical overview and discuss the state-of-the-art distinct devices available for posttherapeutic cure assessment in Chagas disease, their contributions, meanings, and interpretation, aiming to point out the major gaps and propose novel insight for future perspectives of posttherapeutic management of Chagas disease patients.

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Species Composition and Diversity of Malaria Vector Breeding Habitats in Trincomalee District of Sri Lanka

Introduction. Mosquito larval ecology is important in determining larval densities and species assemblage. This in turn influences malaria transmission in an area. Therefore, understanding larval habitat ecology is important in designing malaria control programs. Method. Larval surveys were conducted in 20 localities under five sentinel sites (Padavisiripura, Gomarankadawala, Thoppur, Mollipothana, and Ichchallampaththu) in Trincomalee District, Eastern Province of Sri Lanka, between June 2010 and July 2013. The relationship between seven abiotic variables (temperature, pH, conductivity, Total Dissolved Solid (TDS), turbidity, Dissolved Oxygen (DO), and salinity) was measured. Results. A total of 21,347 anophelines were recorded representing 15 species. Anopheles subpictus 24.72% (5,278/21,347) was the predominant species, followed by 24.67% (5,267/21,347) of An. nigerrimus and 14.56% (3,109/21,347) of An. peditaeniatus. A total of 9,430 breeding habitats under twenty-one categories were identified. An. culcicifacies was noted to be highest from built wells (20.5%) with high salinity (1102.3 ± 81.8 mg/L), followed by waste water collections (20.2%) having low DO levels (2.85 ± 0.03 mg/L) and high TDS (1,654 ± 140 mg/L). Conclusion. This study opens an avenue to explore new breeding habitats of malaria vectors in the country and reemphasizes the requirement of conducting entomological surveillance to detect potential transmission of malaria in Sri Lanka under the current malaria elimination programme.

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Organotypic Cultures of Intervertebral Disc Cells: Responses to Growth Factors and Signaling Pathways Involved

Intervertebral disc (IVD) degeneration is strongly associated with low back pain, a major cause of disability worldwide. An in-depth understanding of IVD cell physiology is required for the design of novel regenerative therapies. Accordingly, aim of this work was the study of IVD cell responses to mitogenic growth factors in a three-dimensional (3D) organotypic milieu, comprising characteristic molecules of IVD's extracellular matrix. In particular, annulus fibrosus (AF) cells were cultured inside collagen type-I gels, while nucleus pulposus (NP) cells in chondroitin sulfate A (CSA) supplemented collagen gels, and the effects of Platelet-Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF), and Insulin-Like Growth Factor-I (IGF-I) were assessed. All three growth factors stimulated DNA synthesis in both AF and NP 3D cell cultures, with potencies similar to those observed previously in monolayers. CSA supplementation inhibited basal DNA synthesis rates, without affecting the response to growth factors. ERK and Akt were found to be phosphorylated following growth factor stimulation. Blockade of these two signaling pathways using pharmacologic inhibitors significantly, though not completely, inhibited growth factor-induced DNA synthesis. The proposed culture systems may prove useful for further in vitro studies aiming at future interventions for IVD regeneration.

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Effects of Fourteen-Day Bed Rest on Trunk Stabilizing Functions in Aging Adults

Bed rest has been shown to have detrimental effects on structural and functional characteristics of the trunk muscles, possibly affecting trunk and spinal stability. This is especially important in populations such as aging adults with often altered trunk stabilizing functions. This study examined the effects of a fourteen-day bed rest on anticipatory postural adjustments and postural reflex responses of the abdominal wall and back muscles in sixteen adult men. Postural activation of trunk muscles was measured using voluntary quick arm movement and sudden arm loading paradigm. Measurements were conducted prior to the bed rest, immediately after, and fourteen days after the bed rest. Immediately after the bed rest, latencies of anticipatory postural adjustments showed significant shortening, especially for the obliquus internus and externus muscles. After a fourteen-day recuperation period, anticipatory postural adjustments reached a near to complete recovery. On the contrary, reactive response latencies increased from pre-bed-rest to both post-bed-rest measurement sessions. Results indicate an important effect of bed rest on stabilizing functions of the trunk muscles in elderly adults. Moreover, there proved to be a significant deterioration of postural reactive responses that outlasted the 14-day post-bed-rest rehabilitation.

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The Impact of a Vestibular-Stimulating Exercise Regime on Postural Stability in People with Visual Impairment

The aim of the study was to assess the impact of a vestibular-stimulating exercise regime on postural stability in individuals with visual impairment. The study group consisted of 70 people, including 28 persons (15 female and 13 male) with visual impairment and 42 (21 female and 21 male) without visual impairment. Each individual in the group with visual impairment was medically qualified for a 3-month training program. The research methodology included medical examination, anthropometric tests, and stabilometry tests on a Biodex Balance System SD (BBS). The tests were conducted twice: once before the start of training and again after 3 months of rehabilitation. The group with visual impairment showed significantly worse postural stability results than the control group for most of the stability parameters evaluated (OSI, APSI, and MLSI). Differences were noted between the groups with and without visual impairment for dynamic tests in women and for static tests in men. After training, the two groups showed roughly similar results for the stabilometry test with eyes closed. We conclude that exercises stimulating the vestibular system with head and body movements should be recommended for individuals with visual impairments to achieve better balance retention.

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Effects of Surface Modification and Bulk Geometry on the Biotribological Behavior of Cross-Linked Polyethylene: Wear Testing and Finite Element Analysis

The wear and creep deformation resistances of polymeric orthopedic bearing materials are both important for extending their longevity. In this study, we evaluated the wear and creep deformation resistances, including backside damage, of different polyethylene (PE) materials, namely, conventional PE, cross-linked PE (CLPE), and poly(2-methacryloyloxyethyl phosphorylcholine)- (PMPC-) grafted CLPE, through wear tests and finite element analysis. The gravimetric and volumetric degrees of wear of disks (3 or 6 mm in thickness) of these materials against a cobalt-chromium-molybdenum alloy pin were examined using a multidirectional pin-on-disk tester. Cross-linking and PMPC grafting decreased the gravimetric wear of the PE disks significantly. The volumetric wear at the bearing surface and the volumetric penetration in the backside of the 3-mm thick PE disk were higher than those of the 6-mm thick PE disk, regardless of the bearing material. The geometrical changes induced in the PE disks consisted of creep, because the calculated internal von Mises stress at the bearing side of all disks and that at the backside of the 3-mm thick disks exceeded their actual yield strengths. A highly hydrated bearing surface layer, formed by PMPC grafting, and a cross-linking-strengthened substrate of adequate thickness are essential for increasing the wear and creep deformation resistances.

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Vitamin A Impairs the Reprogramming of Tregs into IL-17-Producing Cells during Intestinal Inflammation

Maintaining the identity of Foxp3+ regulatory T cells (Tregs) is critical for controlling immune responses in the gut, where an imbalance between Tregs and T effector cells has been linked to inflammatory bowel disease. Accumulating evidence suggests that Tregs can convert into Th17 cells and acquire an inflammatory phenotype. In this study, we used an adoptive transfer model of Ag-specific T cells to study the contribution of different factors to the reprogramming of in vitro-generated Treg cells (iTreg) into IL-17-producing cells in a mouse model of gut inflammation in vivo. Our results show that intestinal inflammation induces the reprogramming of iTreg cells into IL-17-producing cells and that vitamin A restrains reprogramming in the gut. We also demonstrate that the presence of IL-2 during the in vitro generation of iTreg cells confers resistance to Th17 conversion but that IL-2 and retinoic acid (RA) cooperate to maintain Foxp3 expression following stimulation under Th17-polarizing conditions. Additionally, although IL-2 and RA differentially regulate the expression of different Treg cell suppressive markers, Treg cells generated under different polarizing conditions present similar suppressive capacity.

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High LIN28A Expressing Ovarian Cancer Cells Secrete Exosomes That Induce Invasion and Migration in HEK293 Cells

Epithelial ovarian cancer is the most aggressive and deadly form of ovarian cancer and is the most lethal gynecological malignancy worldwide; therefore, efforts to elucidate the molecular factors that lead to epithelial ovarian cancer are essential to better understand this disease. Recent studies reveal that tumor cells release cell-secreted vesicles called exosomes and these exosomes can transfer RNAs and miRNAs to distant sites, leading to cell transformation and tumor development. The RNA-binding protein LIN28 is a known marker of stem cells and when expressed in cancer, it is associated with poor tumor outcome. We hypothesized that high LIN28 expressing ovarian cancer cells secrete exosomes that can be taken up by nontumor cells and cause changes in gene expression and cell behavior associated with tumor development. IGROV1 cells were found to contain high LIN28A and secrete exosomes that were taken up by HEK293 cells. Moreover, exposure to these IGROV1 secreted exosomes led to significant increases in genes involved in Epithelial-to-Mesenchymal Transition (EMT), induced HEK293 cell invasion and migration. These changes were not observed with exosomes secreted by OV420 cells, which contain no detectable amounts of LIN28A or LIN28B. No evidence was found of LIN28A transfer from IGROV1 exosomes to HEK293 cells.

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Simulating Cardiac Electrophysiology Using Unstructured All-Hexahedra Spectral Elements

We discuss the application of the spectral element method to the monodomain and bidomain equations describing propagation of cardiac action potential. Models of cardiac electrophysiology consist of a system of partial differential equations coupled with a system of ordinary differential equations representing cell membrane dynamics. The solution of these equations requires solving multiple length scales due to the ratio of advection to diffusion that varies among the different equations. High order approximation of spectral elements provides greater flexibility in resolving multiple length scales. Furthermore, spectral elements are extremely efficient to model propagation phenomena on complex shapes using fewer degrees of freedom than its finite element equivalent (for the same level of accuracy). We illustrate a fully unstructured all-hexahedra approach implementation of the method and we apply it to the solution of full 3D monodomain and bidomain test cases. We discuss some key elements of the proposed approach on some selected benchmarks and on an anatomically based whole heart human computational model.

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An Overview of the Mechanical Integrity of Dental Implants

With the growing use of dental implants, the incidence of implants' failures grows. Late treatment complications, after reaching full osseointegration and functionality, include mechanical failures, such as fracture of the implant and its components. Those complications are deemed severe in dentistry, albeit being usually considered as rare, and therefore seldom addressed in the clinical literature. The introduction of dental implants into clinical practice fostered a wealth of research on their biological aspects. By contrast, mechanical strength and reliability issues were seldom investigated in the open literature, so that most of the information to date remains essentially with the manufacturers. Over the years, implants have gone through major changes regarding the material, the design, and the surface characteristics aimed at improving osseointegration. Did those changes improve the implants' mechanical performance? This review article surveys the state-of-the-art literature about implants' mechanical reliability, identifying the known causes for fracture, while outlining the current knowledge-gaps. Recent results on various aspects of the mechanical integrity and failure of implants are presented and discussed next. The paper ends by a general discussion and suggestions for future research, outlining the importance of mechanical considerations for the improvement of their future performance.

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T Helper Subsets, Peripheral Plasticity, and the Acute Phase Protein, α1-Antitrypsin

The traditional model of T helper differentiation describes the naïve T cell as choosing one of several subsets upon stimulation and an added reciprocal inhibition aimed at maintaining the chosen subset. However, to date, evidence is mounting to support the presence of subset plasticity. This is, presumably, aimed at fine-tuning adaptive immune responses according to local signals. Reprograming of cell phenotype is made possible by changes in activation of master transcription factors, employing epigenetic modifications that preserve a flexible mode, permitting a shift between activation and silencing of genes. The acute phase response represents an example of peripheral changes that are critical in modulating T cell responses. α1-antitrypsin (AAT) belongs to the acute phase responses and has recently surfaced as a tolerogenic agent in the context of adaptive immune responses. Nonetheless, AAT does not inhibit T cell responses, nor does it shutdown inflammation per se; rather, it appears that AAT targets non-T cell immunocytes towards changing the cytokine environment of T cells, thus promoting a regulatory T cell profile. The present review focuses on this intriguing two-way communication between innate and adaptive entities, a crosstalk that holds important implications on potential therapies for a multitude of immune disorders.

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Effects of Exercise on Spinal Deformities and Quality of Life in Patients with Adolescent Idiopathic Scoliosis

Objectives. This systematic review was conducted to examine the effects of exercise on spinal deformities and quality of life in patients with adolescent idiopathic scoliosis (AIS). Data Sources. Electronic databases, including PubMed, CINAHL, Embase, Scopus, Cochrane Register of Controlled Trials, PEDro, and Web of Science, were searched for research articles published from the earliest available dates up to May 31, 2015, using the key words "exercise," "postural correction," "posture," "postural curve," "Cobb's angle," "quality of life," and "spinal deformities," combined with the Medical Subject Heading "scoliosis." Study Selection. This systematic review was restricted to randomized and nonrandomized controlled trials on AIS published in English language. The quality of selected studies was assessed by the PEDro scale, the Cochrane Collaboration's tool, and the Grading of Recommendations Assessment, Development, and Evaluation System (GRADE). Data Extraction. Descriptive data were collected from each study. The outcome measures of interest were Cobb angle, trunk rotation, thoracic kyphosis, lumbar kyphosis, vertebral rotation, and quality of life. Data Synthesis. A total of 30 studies were assessed for eligibility. Six of the 9 selected studies reached high methodological quality on the PEDro scale. Meta-analysis revealed moderate-quality evidence that exercise interventions reduce the Cobb angle, angle of trunk rotation, thoracic kyphosis, and lumbar lordosis and low-quality evidence that exercise interventions reduce average lateral deviation. Meta-analysis revealed moderate-quality evidence that exercise interventions improve the quality of life. Conclusions. A supervised exercise program was superior to controls in reducing spinal deformities and improving the quality of life in patients with AIS.

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Cognitive Interventions in Older Persons: Do They Change the Functioning of the Brain?

Background. Cognitive interventions for older persons that may diminish the burden of cognitive problems and could delay conversion to dementia are of great importance. The underlying mechanisms of such interventions might be psychological compensation and neuronal plasticity. This review provides an overview of the literature concerning the evidence that cognitive interventions cause brain activation changes, even in damaged neural systems. Method. A systematic search of the literature was conducted in several international databases, Medline, Embase, Cinahl, Cochrane, and Psychinfo. The methodological quality was assessed according to the guidelines of the Dutch Institute for Health Care Improvement (CBO). Results. Nineteen relevant articles were included with varied methodological quality. All studies were conducted in diverse populations from healthy elderly to patients with dementia and show changes in brain activation after intervention. Conclusions. The results thus far show that cognitive interventions cause changes in brain activation patterns. The exact interpretation of these neurobiological changes remains unclear. More study is needed to understand the extent to which cognitive interventions are effective to delay conversion to dementia. Future studies should more explicitly try to relate clinically significant improvement to changes in brain activation. Long-term follow-up data are necessary to evaluate the stability of the effects.

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Characterization of Electrograms from Multipolar Diagnostic Catheters during Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia in USA with more than 2.3 million people affected annually. Catheter ablation procedure is a method for treatment of AF, which involves 3D electroanatomic mapping of the patient's left atrium (LA) by maneuvering a conventional multipolar diagnostic catheter (MPDC) along the LA endocardial surface after which pulmonary vein (PV) isolation is performed, thus eliminating the AF triggers originating from the PVs. However, it remains unclear how to effectively utilize the information provided by the MPDC to locate the AF-sustaining sites, known as sustained rotor-like activities (RotAs). In this study, we use computer modeling to investigate the variations in the characteristics of the MPDC electrograms, namely, total conduction delay (TCD) and average cycle length (CL), as the MPDC moves towards a RotA source. Subsequently, a study with a human subject was performed in order to verify the predictions of the simulation study. The conclusions from this study may be used to iteratively direct an MPDC towards RotA sources thus allowing the RotAs to be localized for customized and improved AF ablation.

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A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs

Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carriers, and various approaches used for the delivery. The present review article aims to assess the utility of cyclodextrin-based carriers like liposomes, niosomes, nanoparticles, micelles, millirods, and siRNA for delivery of antineoplastic agents. These systems based on cyclodextrin complexation and nanotechnology will camouflage the undesirable properties of drug and lead to synergistic or additive effect. Cyclodextrin-based nanotechnology seems to provide better therapeutic effect and sustain long life of healthy and recovered cells. Still, considerable study on delivery system and administration routes of cyclodextrin-based carriers is necessary with respect to their pharmacokinetics and toxicology to substantiate their safety and efficiency. In future, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents.

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Hexosamine-Induced TGF-β Signaling and Osteogenic Differentiation of Dental Pulp Stem Cells Are Dependent on N-Acetylglucosaminyltransferase V

Glycans of cell surface glycoproteins are involved in the regulation of cell migration, growth, and differentiation. N-acetyl-glucosaminyltransferase V (GnT-V) transfers N-acetyl-d-glucosamine to form β1,6-branched N-glycans, thus playing a crucial role in the biosynthesis of glycoproteins. This study reveals the distinct expression of GnT-V in STRO-1 and CD-146 double-positive dental pulp stem cells (DPSCs). Furthermore, we investigated three types of hexosamines and their N-acetyl derivatives for possible effects on the osteogenic differentiation potential of DPSCs. Our results showed that exogenous d-glucosamine (GlcN), N-acetyl-d-glucosamine (GlcNAc), d-mannosamine (ManN), and acetyl-d-mannosamine (ManNAc) promoted DPSCs' early osteogenic differentiation in the absence of osteogenic supplements, but d-galactosamine (GalN) or N-acetyl-galactosamine (GalNAc) did not. Effects include the increased level of TGF-β receptor type I, activation of TGF-β signaling, and increased mRNA expression of osteogenic differentiation marker genes. The hexosamine-treated DPSCs showed an increased mineralized matrix deposition in the presence of osteogenic supplements. Moreover, the level of TGF-β receptor type I and early osteogenic differentiation were abolished in the DPSCs transfected with siRNA for GnT-V knockdown. These results suggest that GnT-V plays a critical role in the hexosamine-induced activation of TGF-β signaling and subsequent osteogenic differentiation of DPSCs.

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Tinnitus and Headache

Background. Tinnitus and headache are frequent disorders. Here, we aimed to investigate whether the occurrence of headache among tinnitus patients is purely coincidental or whether tinnitus and headache are pathophysiologically linked. We investigated a large sample of patients with tinnitus and headache to estimate prevalence rates of different headache forms, to determine the relationship between tinnitus laterality and headache laterality, and to explore the relationship between tinnitus and headache over time. Method. Patients who presented at a tertiary referral center because of tinnitus and reported comorbid headache were asked to complete validated questionnaires to determine the prevalence of migraine and tension-type headache and to assess tinnitus severity. In addition, several questions about the relationship between headache and tinnitus were asked. Results. Datasets of 193 patients with tinnitus and headache were analysed. 44.6% suffered from migraine, 13% from tension-type headache, and 5.7% from both. Headache laterality was significantly related to tinnitus laterality and in the majority of patients fluctuations in symptom severity of tinnitus and headache were interrelated. Conclusion. These findings suggest a significant relationship between tinnitus and headache laterality and symptom interaction over time and argue against a purely coincidental cooccurrence of tinnitus and headache. Both disorders may be linked by common pathophysiological mechanisms.

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The Effect of Risk Factors on the Levels of Chemical Elements in the Tibial Plateau of Patients with Osteoarthritis following Knee Surgery

The aim of this study was to evaluate the aforementioned chemical elements in tibial plateau samples obtained during knee arthroplasty. The gender-specific analysis of chemical element levels in the bone samples revealed that there were statistically significant differences in the concentration of Pb and Se/Pb ratio. The contents of elements in the tibial plateau in the patients with osteoarthritis (OA) can be arranged in the following descending order: F− > K > Zn > Fe > Sr > Pb > Mn > Se > Cd > THg. We observed statistical significant effects of environmental factors including smoking, seafood diet, and geographical distribution on the levels of the elements in tibial bone. Significant positive correlation coefficients were found for the relationships K-Cd, Zn-Sr, Zn-F−, THg-Pb, Pb-Cd, Se-Se/Pb, Se-Se/Cd, Se/Pb-Se/Cd, Pb-Cd/Ca, Cd-Cd/Ca, and F−-F−/Ca1000. Significant negative correlations were found for the relationships THg-Se/Pb, Pb-Se/Pb, Cd-Se/Pb, K-Se/Cd, Pb-Se/Cd, Cd-Se/Cd, THg-Se/THg, Pb-Se/THg, Se-Pb/Cd, Zn-Cd/Ca, and Se/Cd-Cd/Ca. The results reported here may provide a basis for establishing reference values for the tibial plateau in patients with OA who had undergone knee replacement surgery. The concentrations of elements in the bone with OA were determined by age, presence of implants, smoking, fish and seafood diet, and sport activity.

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Image-Based Structural Modeling of the Cardiac Purkinje Network

The Purkinje network is a specialized conduction system within the heart that ensures the proper activation of the ventricles to produce effective contraction. Its role during ventricular arrhythmias is less clear, but some experimental studies have suggested that the Purkinje network may significantly affect the genesis and maintenance of ventricular arrhythmias. Despite its importance, few structural models of the Purkinje network have been developed, primarily because current physical limitations prevent examination of the intact Purkinje network. In previous modeling efforts Purkinje-like structures have been developed through either automated or hand-drawn procedures, but these networks have been created according to general principles rather than based on real networks. To allow for greater realism in Purkinje structural models, we present a method for creating three-dimensional Purkinje networks based directly on imaging data. Our approach uses Purkinje network structures extracted from photographs of dissected ventricles and projects these flat networks onto realistic endocardial surfaces. Using this method, we create models for the combined ventricle-Purkinje system that can fully activate the ventricles through a stimulus delivered to the Purkinje network and can produce simulated activation sequences that match experimental observations. The combined models have the potential to help elucidate Purkinje network contributions during ventricular arrhythmias.

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The Association between Cerebral White Matter Lesions and Plasma Omega-3 to Omega-6 Polyunsaturated Fatty Acids Ratio to Cognitive Impairment Development

Objective. Cerebral white matter hyperintensity (WMH) with magnetic resonance imaging (MRI) has a potential for predicting cognitive impairment. Serum polyunsaturated fatty acid (PUFA) levels are important for evaluating the extent of atherosclerosis. We investigated whether abnormal PUFA levels affected WMH grading and cognitive function in patients without significant cognitive impairment. Methods. Atherosclerotic risk factors, the internal carotid artery (ICA) plaque, and serum ratios of eicosapentaenoic to arachidonic acids (EPA/AA) and docosahexaenoic to arachidonic acids (DHA/AA) were assessed in 286 patients. The relationship among these risk factors, WMH, and cognitive function was evaluated using WMH grading and the Mini-Mental State Examination (MMSE). Results. The development of WMH was associated with aging, hypertension, ICA plaques, and a low serum EPA/AA ratio (

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Epidemiology of rubella and congenital rubella syndrome in Japan before 1989

Publication date: Available online 21 October 2015
Source:Vaccine
Author(s): Kohji Ueda
Epidemiological studies of rubella and congenital rubella syndrome (CRS) in Japan have been conducted since the first nationwide rubella epidemic of 1965–1969 and subsequent epidemics of 1975–1977, 1982, 1987–1988, and 1992–1993. Rubella was non-endemic in Japan before the 1975–1977 epidemic, and endemic thereafter. Japan started a selective rubella vaccination program for junior high school girls in 1977, and universal rubella vaccination of children of both sexes in 1989. No nationwide rubella epidemics have occurred since 1994.Only three children with CRS were reported in Japan before 1964; however, many children with CRS were identified in 1965 when a rubella epidemic struck Okinawa, which has many the United States military bases. After the 1965–1969 and 1975–1977 rubella epidemics on the Japanese mainland, small numbers of children with CRS were identified (hospital survey). These findings led to the hypothesis that, compared to U.S. rubella virus strains, Japanese strains of rubella virus are less teratogenic. This hypothesis strongly affected the development of rubella vaccines in Japan. However, retrospective seroepidemiological studies attributed the CRS in many children in Okinawa to the high rate of rubella infection in pregnant women. According to the survey conducted at special schools for the deaf, 83, 232, 77, and 167 children were born with CRS on the Japanese mainland respectively after the 1965–1969, 1975–1977, 1982, and 1987–1988 nationwide rubella epidemics, suggesting that the incidence of CRS in Japan is in fact comparable to that in the U.S. and Europe.Rubella epidemics in children have been effectively prevented since 1994. However, a rubella outbreak among adult males and CRS occurred between 2012 and 2014.



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A cytomegalovirus DNA vaccine induces antibodies that block viral entry into fibroblasts and epithelial cells

Publication date: Available online 24 October 2015
Source:Vaccine
Author(s): Michael A. McVoy, Ronzo Lee, Frances M. Saccoccio, Jukka Hartikka, Larry R. Smith, Rohit Mahajan, Jian Ben Wang, Xiaohong Cui, Stuart P. Adler
A vaccine to prevent congenital cytomegalovirus (CMV) infections is a national priority. Investigational vaccines have targeted the viral glycoprotein B (gB) as an inducer of neutralizing antibodies and phosphoprotein 65 (pp65) as an inducer of cytotoxic T cells. Antibodies to gB neutralize CMV entry into all cell types but their potency is low compared to antibodies that block epithelial cell entry through targeting the pentameric complex (gH/gL/UL128/UL130/UL131). Hence, more potent overall neutralizing responses may result from a vaccine that combines gB with pentameric complex-derived antigens. To assess the ability of pentameric complex subunits to generate epithelial entry neutralizing antibodies, DNA vaccines encoding UL128, UL130, and/or UL131 were formulated with Vaxfectin^®, an adjuvant that enhances antibody responses to DNA vaccines. Mice were immunized with individual DNA vaccines or with pair-wise or trivalent combinations. Only the UL130 vaccine induced epithelial entry neutralizing antibodies and no synergy was observed from bi- or trivalent combinations. In rabbits the UL130 vaccine again induced epithelial entry neutralizing antibodies while UL128 or UL131 vaccines did not. To evaluate compatibility of the UL130 vaccine with DNA vaccines encoding gB or pp65, mono-, bi-, or trivalent combinations were evaluated. Fibroblast and epithelial entry neutralizing titers did not differ between rabbits immunized with gB alone vs. gB/UL130, gB/pp65, or gB/UL130/pp65 combinations, indicating a lack of antagonism from coadministration of DNA vaccines. Importantly, gB-induced epithelial entry neutralizing titers were substantially higher than activities induced by UL130, and both fibroblast and epithelial entry neutralizing titers induced by gB alone as well as gB/pp65 or gB/UL130/pp65 combinations were comparable to those observed in sera from humans with naturally-acquired CMV infections. These findings support further development of Vaxfectin^®-formulated gB-expressing DNA vaccine for prevention of congenital CMV infections.



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Analyse coût-efficacité de l’introduction du vaccin contre le virus du papillome humain au Honduras

Publication date: Available online 24 October 2015
Source:Vaccine
Author(s): Ida Molina Berenice, Lourdes Otilia Mendoza, Odalys García, Iris Díaz, Jacqueline Figueroa, Rosa María Duarte, Gabriel Perdomo, Ana Gabriela Félix Garcia, Cara Bess Janusz
Contextele cancer du col de l'utérus constitue la principale cause des décès dus au cancer au Honduras. Puisqu'il existe un vaccin pouvant prévenir le virus du papillome humain (VPH), l'agent responsable du cancer du col de l'utérus, le secrétaire à la Santé du Honduras a entrepris une analyse coût-efficacité portant sur l'introduction du vaccin contre le VPH afin de soutenir le processus national de prise de décision.Méthodesune équipe nationale multidisciplinaire a effectué cette analyse à l'aide du modèle CERVIVAC, élaboré par la London School of Hygiene and Tropical Medicine en collaboration avec l'Initiative ProVac de l'Organisation panaméricaine de la Santé. On a évalué les coûts cumulatifs et les bénéfices pour la santé de l'introduction du vaccin contre le VPH sur toute la durée de vie d'une cohorte unique de fillettes de 11 ans. Nous avons émis l'hypothèse d'une série de trois doses avec couverture vaccinale de 95 % chez cette cohorte; la vaccination serait réalisée à la fois en milieu scolaire et en établissement de santé. Afin d'estimer le nombre de cas et de décès relatifs au cancer du col de l'utérus à l'échelle nationale, nous avons eu recours aux projections démographiques des Nations unies et aux estimations GLOBOCAN fondées sur les données des registres du Salvador, du Guatemala et du Nicaragua. Sur la base d'estimations de l'Organisation mondiale de la Santé (OMS) et de la Division de la coopération intensifiée avec les pays (ICO), nous sommes partis du principe que 70 % des cancers du col de l'utérus seraient dus aux types de vaccin VPH16 et VPH18. Nous avons utilisé un prix de 13,45 USD par dose de vaccin et des données provenant de la documentation scientifique pour estimer l'efficacité de celui-ci. Nous nous sommes servis d'informations nationales pour estimer l'utilisation et les coûts des services de santé relativement au traitement contre le cancer du col de l'utérus. Tous les coûts et tous les bénéfices pour la santé ont été actualisés à 3 %.Résultatssi on vaccinait complètement 86 906 fillettes de 11 ans, 2 250 cas de cancer du col de l'utérus (chiffre non actualisé) et 1 336 décès (chiffre non actualisé) seraient évités sur toute la durée de vie de la cohorte. Après une actualisation à 3 % par année des bénéfices futurs pour la santé, le nombre de cas et de décès équivalents évités était de 421 et 170. On estime que la vaccination contre le VPH coûte environ 5 millions USD par cohorte vaccinée, mais cette somme serait compensée par des coûts évités d'environ 1 million USD que le gouvernement aurait dû payer pour le traitement du cancer du col de l'utérus. En outre, 4 349 années de vie ajustées sur l'incapacité (DALY) actualisées pourraient être évitées, à un coût de 926 USD par DALY évitée, ce qui fait de la vaccination contre le VPH au Honduras une intervention très efficace au regard des coûts.Analysele coût net de la vaccination contre le VPH par DALY évitée est inférieur au seuil fixé par l'OMS en matière de rapport coût-efficacité. Toutefois, puisqu'il en coûte environ 5 millions USD par cohorte vaccinée, les conséquences budgétaires de l'introduction du vaccin contre le VPH pour ce pays sont un élément important à prendre en considération dans le cadre de cette analyse.Conclusionslorsque l'on compare les coûts et les bénéfices de l'introduction du vaccin contre le VPH au Honduras, cette intervention s'avère clairement d'un très bon rapport coût-efficacité et réduirait considérablement la maladie due au cancer du col de l'utérus. Pour ces raisons, le pays a tout intérêt à étudier les possibilités de financement qui pourraient appuyer l'introduction du vaccin.



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Neptunism and Transformism: Robert Jameson and other Evolutionary Theorists in Early Nineteenth-Century Scotland

Abstract

This paper sheds new light on the prevalence of evolutionary ideas in Scotland in the early nineteenth century and establish what connections existed between the espousal of evolutionary theories and adherence to the directional history of the earth proposed by Abraham Gottlob Werner and his Scottish disciples. A possible connection between Wernerian geology and theories of the transmutation of species in Edinburgh in the period when Charles Darwin was a medical student in the city was suggested in an important 1991 paper by James Secord. This study aims to deepen our knowledge of this important episode in the history of evolutionary ideas and explore the relationship between these geological and evolutionary discourses. To do this it focuses on the circle of natural historians around Robert Jameson, Wernerian geologist and professor of natural history at the University of Edinburgh from 1804 to 1854. From the evidence gathered here there emerges a clear confirmation that the Wernerian model of geohistory facilitated the acceptance of evolutionary explanations of the history of life in early nineteenth-century Scotland. As Edinburgh was at this time the most important center of medical education in the English-speaking world, this almost certainly influenced the reception and development of evolutionary ideas in the decades that followed.

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