Aportación al diagnóstico y cirugía de la cavidad nasal

Tras una revisión de las técnicas empleadas actualmente en el diagnóstico y tratamiento de los procesos patológicos de la cavidad nasal en perros y gatos se describe una técnica nueva en medicina veterinaria, similar a la utilizada con frecuencia en medicina humana, para el abordaje de la cavidad nasal a través del surco gingivolabial superior. Esta vía permite la aplicación más cómoda y más profunda de los métodos diagnósticos habituales y de la cirugía curativa o paliativa esperada en la mayoría de los casos.Having made a whole review of the techniques used at present in the diagnostic and treatment of the pathological processes of the nasal cavity in dogs and cats, it 's described a new technique in veterinary surgery, which is like the one used frequently in human medicine, to the approach to the nasal cavity through the upper gingioobuccal sulcus. This way allows a more comfortable and deep application of the current diagnostical methods and the wanted palliative or curatiue surgery in most of the cases

Analysis of a short tail type in farmed Atlantic salmon (Salmo salar)

The short tail phenotype represents one of the main causes for downgrading of farmed Atlantic salmon (Salmo salar) at slaughterhouses. Prevalence of short tail is variable and the aetiology is suspected to be multi-factorial. Risk factors have been identified but descriptions of the aetiology and the pathology of the condition are still rare. In the current study, a radiological and histological analysis of short tails has been performed, examining six normal and six downgraded individuals from a slaughterhouse in southern Norway. In the short tail phenotype, vertebral bodies were shifted and bent at the contact zone of adjacent vertebral bodies. Changes either affected the entire spine or were located at the medial caudal-spine. While the internal bone structure of the vertebrae was similar in deformed and non-deformed animals, a lack of intervertebral space apparently caused a shortening of the vertebral column and corresponded to an elevated condition factor in deformed individuals. Histological analysis revealed different degrees of proliferation of cartilaginous tissues, which replaced the intervertebral notochord tissue. The displacement of adjacent vertebral bodies and the development of cartilage in between vertebral bodies suggest mechanical forces as a possible cause for the observed deformations, since mechanically-induced overload and a subsequent direct contact of bones are factors that can stimulate heterotopic cartilage development and pseudoarthrosi

Compressed vertebrae in Atlantic salmon <i>Salmo salar</i>: evidence for metaplastic chondrogenesis as a skeletogenic response late in ontogeny

Anterior/posterior (a/p) compression of the vertebral column, referred to as 'short tails', is a recurring event in farmed Atlantic salmon. Like other skeletal deformities, the problem usually becomes evident in a late life phase, too late for preventive measures, making it difficult to understand the aetiology of the disease. We use structural, radiological, histological, and mineral analyses to study 'short tail' adult salmon and to demonstrate that the study of adult fish can provide important insights into earlier developmental processes. 'Short tails' display a/p compressed vertebrae throughout the spine, except for the first post-cranial vertebrae. The vertebral number is unaltered, but the intervertebral space is reduced and the vertebrae are shorter. Compressed vertebrae are characterized by an unchanged central part, altered vertebral end plates (straight instead of funnel-shaped), an atypical inward bending of the vertebral edges, and structural alterations in the intervertebral tissue. The spongiosa is unaffected. The growth zones of adjacent vertebrae fuse and blend towards the intervertebral space into chondrogenic tissue. This tissue produces different types of cartilage, replacing the notochord. The correspondence in location of intervertebral cartilage and deformed vertebral end plates, and the clearly delimited, unaltered, central vertebral parts suggest that the a/p compression of vertebral bodies is a late developmental disorder that may be related to a metaplastic shift of osteogenic tissue into chondrogenic tissue in the vertebral growth zone. Given the lack of evidence for infections, metabolic disorders and/or genetic disorders, we propose that an altered mechanical load could have caused the transformation of the bone growth zones and the concomitant replacement of the intervertebral (notochord) tissue by cartilaginous tissues in the 'short tails' studied here. This hypothesis is supported by the role that notochord cells are known to play in spine development and in maintaining the structure of the intervertebral disk

A primary phosphorus-deficient skeletal phenotype in juvenile Atlantic salmon Salmo salar : the uncoupling of bone formation and mineralization

To understand the effect of low dietary phosphorus (P) intake on the vertebral column of Atlantic salmon Salmo salar, a primary P deficiency was induced in post-smolts. The dietary P provision was reduced by 50% for a period of 10 weeks under controlled conditions. The animal's skeleton was subsequently analysed by radiology, histological examination, histochemical detection of minerals in bones and scales and chemical mineral analysis. This is the first account of how a primary P deficiency affects the skeleton in S. salar at the cellular and at the micro-anatomical level. Animals that received the P-deficient diet displayed known signs of P deficiency including reduced growth and soft, pliable opercula. Bone and scale mineral content decreased by c. 50%. On radiographs, vertebral bodies appear small, undersized and with enlarged intervertebral spaces. Contrary to the X-ray-based diagnosis, the histological examination revealed that vertebral bodies had a regular size and regular internal bone structures; intervertebral spaces were not enlarged. Bone matrix formation was continuous and uninterrupted, albeit without traces of mineralization. Likewise, scale growth continues with regular annuli formation, but new scale matrix remains without minerals. The 10 week long experiment generated a homogeneous osteomalacia of vertebral bodies without apparent induction of skeletal malformations. The experiment shows that bone formation and bone mineralization are, to a large degree, independent processes in the fish examined. Therefore, a deficit in mineralization must not be the only cause of the alterations of the vertebral bone structure observed in farmed S. salar. It is discussed how the observed uncoupling of bone formation and mineralization helps to better diagnose, understand and prevent P deficiency-related malformations in farmed S. salar

Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut)

Catalan healthcare; Decision-making; Multi-criteria decision analysis; Orphan drugsSanitat catalana; Presa de decisions; Anàlisi de decisions multicriteri; Medicaments orfesSanidad catalana; Toma de decisiones; Análisis de decisiones multicriteria; Medicamentos huérfanosBACKGROUND: Orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut. METHODS: The assessment and decision-making process for orphan drugs in the Programa d'Harmonització Farmacoterapeutica (PHF) of CatSalut was prioritized to test the implementation of the reflective MCDA both a qualitative and quantitatively. A staged approach was used with the following main steps: selection and structuration of quantitative criteria (Core Model) and qualitative criteria (Contextual Tool), framework scoring and assessment of three orphan drug case studies. This proof-of-concept would grant a continued refinement of the methodology and, if and when validated, its potential integration to other therapeutic areas of the PHF. RESULTS: The final framework was composed by 10 quantitative criteria (Core Model) and 4 qualitative criteria (Contextual Tool) according to the PHF goals being the most important criteria "disease severity", "unmet need", "comparative effectiveness" and "comparative safety /tolerability". The matrix developed for the case studies served as a guide for the selection of the essential information that the decision-makers were expected to include in a framework. The reflective discussion was considered the most relevant phase of the approach to support inputs for health decision-making processes reflecting both drug value and place in therapy. CONCLUSIONS: The study showed that reflective MCDA methodology could be implemented to complement the decision-making process in CatSalut, as an aid to determine the clinical added value for orphan medicines. MCDA provided transparency and a structured discussion during the committee meetings, thus increasing transparency and predictability of the relevant items supporting the agreements adopted on orphan drugs access

Linking in vitro lipolysis and microsomal metabolism for the quantitative prediction of oral bioavailability of BCS II drugs administered in lipidic formulations

Lipidic formulations (LFs) are increasingly utilized for the delivery of drugs that belong to class II of the Biopharmaceutics Classification System (BCS). The current work proposes, for the first time, the combination of in vitro lipolysis and microsomal metabolism studies for the quantitative prediction of human oral bioavailability of BCS II drugs administered in LFs. Marinol® and Neoral® were selected as model LFs and their observed oral bioavailabilities (Fobserved) obtained from published clinical studies in humans. Two separate lipolysis buffers, differing in the level of surfactant concentrations, were used for digestion of the LFs. The predicted fraction absorbed (Fabs) was calculated by measuring the drug concentration in the micellar phase after completion of the lipolysis process. To determine first-pass metabolism (Fg∙Fh), drug depletion studies with human microsomes were performed. Clearance values were determined by applying the “in vitro half-life approach”. The estimated Fabs and Fg∙Fh values were combined for the calculation of the predicted oral bioavailability (Fpredicted). Results showed that there was a strong correlation between Fobserved and Fpredicted values only when Fabs was calculated using a buffer with surfactant concentrations closer to physiological conditions. The general accuracy of the predicted values suggests that the novel in vitro lipolysis/metabolism approach could quantitatively predict the oral bioavailability of lipophilic drugs administered in LFs

Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients

Background: Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug's distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds' molecular descriptors and the compounds' tissue:plasma partition coefficients (Kt:p) - often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds' molecular descriptors but also (a subset of) their predicted Kt:p values. Results: Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied. Conclusions: Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models. Figure not available: see fulltext. © 2015 Freitas et al.; licensee Springer

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug–cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug–cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug–cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.Pfizer Inc.Institute for Collaborative BiotechnologiesMIT Center for Cell Decision ProcessesNational Institute of Mental Health (U.S.) (grant P50-GM68762)National Institute of Mental Health (U.S.) (grant T32-GM008334)Massachusetts Institute of Technology. Biotechnology Process Engineering CenterMassachusetts Institute of Technology. Center for Environmental Health SciencesNational Institute of Mental Health (U.S.) (grant U19ES011399)Whitaker Foundatio

What are the most efficacious treatment regimens for isoniazid-resistant tuberculosis?:A systematic review and network meta-analysis

INTRODUCTION: Consensus on the best treatment regimens for patients with isoniazid-resistant TB is limited; global treatment guidelines differ. We undertook a systematic review and meta-analysis using mixed-treatment comparisons methodology to provide an up-to-date summary of randomised controlled trials (RCTs) and relative regimen efficacy. METHODS: Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Extracted data were inputted into fixed-effects and random-effects models. ORs for all possible network comparisons and hierarchical rankings for different regimens were obtained. RESULTS: 12 604 records were retrieved and 118 remained postextraction, representing 59 studies-27 standalone and 32 with multiple papers. In comparison to a baseline category that included the WHO-recommended regimen for countries with high levels of isoniazid resistance (rifampicin-containing regimens using fewer than three effective drugs at 4 months, in which rifampicin was protected by another effective drug at 6 months, and rifampicin was taken for 6 months), extending the duration of rifampicin and increasing the number of effective drugs at 4 months lowered the odds of unfavourable outcomes (treatment failure or the lack of microbiological cure; relapse post-treatment; death due to TB) in a fixed-effects model (OR 0.31 (95% credible interval 0.12-0.81)). In a random-effects model all estimates crossed the null. CONCLUSIONS: Our systematic review and network meta-analysis highlight a regimen category that may be more efficacious than the WHO population level recommendation, and identify knowledge gaps where data are sparse. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014015025