Pharmacovigilance in children : detecting adverse drug reactions in routine electronic healthcare records. A systematic review

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Clinical potential of oligonucleotide-based therapeutics in the respiratory system

The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition.

El color en los códices prehispánicos del México Central: identificación material, cualidad plástica y valor estético

Este artículo investiga algunos de los valores plásticos y estéticos que presidieron la selección y la preparación de las materias colorantes empleadas para iluminar los códices creados por los nahuas del México Central durante el Posclásico Tardío. Estos códices son interesantes porque análisis arqueométricos y exámenes codicológicos recientes han permitido conocer la materialidad de su capa pictórica, así como las características formales y el comportamiento de los colores en estas obras. Uno de los aportes trascendentales de estos estudios ha sido averiguar que la paleta cromática que sirvió para pintar los códices del México Central era principalmente de origen orgánico, lo que contrasta con la naturaleza de los pigmentos detectados en restos de pintura mural y en esculturas creadas por los nahuas que son sobre todo minerales. El objetivo de este artículo es reflexionar sobre las razones de esas diferencias y demostrar que el uso de los colorantes orgánicos en los códices respondía a un fin plástico específico que concordaba con el canon estético imperante en la sociedad náhuatl.

Epigenetic Therapy for the Treatment of Hypertension-Induced Cardiac Hypertrophy and Fibrosis

BACKGROUND: The development of heart failure is associated with changes in the size, shape, and structure of the heart that has a negative impact on cardiac function. These pathological changes involve excessive extracellular matrix deposition within the myocardial interstitium and myocyte hypertrophy. Alterations in fibroblast phenotype and myocyte activity are associated with reprogramming of gene transcriptional profiles that likely requires epigenetic alterations in chromatin structure. The aim of our work was to investigate the potential of a currently licensed anticancer epigenetic modifier as a treatment option for cardiac diseases associated with hypertension-induced cardiac hypertrophy and fibrosis.

METHODS AND RESULTS: The effects of DNA methylation inhibition with 5-azacytidine (5-aza) were examined in a human primary fibroblast cell line and in a spontaneously hypertensive rat (SHR) model. The results from this work allude to novel in vivo antifibrotic and antihypertrophic actions of 5-aza. Administration of the DNA methylation inhibitor significantly improved several echocardiographic parameters associated with hypertrophy and diastolic dysfunction. Myocardial collagen levels and myocyte size were reduced in 5-aza-treated SHRs. These findings are supported by beneficial in vitro effects in cardiac fibroblasts. Collagen I, collagen III, and α-smooth muscle actin were reduced in a human ventricular cardiac fibroblast cell line treated with 5-aza.

CONCLUSION: These findings suggest a role for epigenetic modifications in contributing to the profibrotic and hypertrophic changes evident during disease progression. Therapeutic intervention with 5-aza demonstrated favorable effects highlighting the potential use of this epigenetic modifier as a treatment option for cardiac pathologies associated with hypertrophy and fibrosis.

Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance.

The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution.

Mental Health Pharmacists Views on Shared Decision-Making for Antipsychotics in Serious Mental Illness

A qualitative study to look at the views of pharmacists working in mental health settings in relation to shared decision making, particularly as applied to decisions about the prescription of antipsychotics for those diagnosed with severe and enduring mental illnesses.

Una planta sin clásicos. La berenjena en la farmacología medieval y renacentista

La berenjena (Solanum melongena L.) es una planta solanácea de múltiples variedades, cuyos ancestros salvajes se sitúan en Indochina y el este de África. Su cultivo fue muy temprano en zonas de China e India. Aun así, no se extendió al Occidente antiguo ni apenas se conoció, de ahí su ausencia en los textos clásicos de botánica y farmacología. Fueron los árabes quienes llevaron el cultivo de la planta por el Norte de África y Al-Andalus, de donde pasó ya a Europa. Los primeros testimonios occidentales de la berenjena aparecen en traducciones latinas de textos árabes, para incorporarse luego a la literatura farmacológica medieval y, más tarde ya, a la del Renacimiento, que empezó a tratar de ella por su posible parecido con una especie de mandrágora. Pese a que se le reconocían algunas virtudes medicinales, siempre se la tuvo bajo sospecha por ser de sabor poco agradable, indigesta y causante de algunas afecciones. Solo los botánicos de finales del Renacimiento describirían la planta y sus variedades con criterios más «científicos» y botánicos, ya sin apenas intereses farmacológicos.

DATA DRIVEN APPROACHES TO IDENTIFY DETERMINANTS OF HEART DISEASES AND CANCER RESISTANCE

Cancer and cardio-vascular diseases are the leading causes of death world-wide. Caused by systemic genetic and molecular disruptions in cells, these disorders are the manifestation of profound disturbance of normal cellular homeostasis. People suffering or at high risk for these disorders need early diagnosis and personalized therapeutic intervention. Successful implementation of such clinical measures can significantly improve global health. However, development of effective therapies is hindered by the challenges in identifying genetic and molecular determinants of the onset of diseases; and in cases where therapies already exist, the main challenge is to identify molecular determinants that drive resistance to the therapies. Due to the progress in sequencing technologies, the access to a large genome-wide biological data is now extended far beyond few experimental labs to the global research community. The unprecedented availability of the data has revolutionized the capabilities of computational researchers, enabling them to collaboratively address the long standing problems from many different perspectives. Likewise, this thesis tackles the two main public health related challenges using data driven approaches. Numerous association studies have been proposed to identify genomic variants that determine disease. However, their clinical utility remains limited due to their inability to distinguish causal variants from associated variants. In the presented thesis, we first propose a simple scheme that improves association studies in supervised fashion and has shown its applicability in identifying genomic regulatory variants associated with hypertension. Next, we propose a coupled Bayesian regression approach -- eQTeL, which leverages epigenetic data to estimate regulatory and gene interaction potential, and identifies combinations of regulatory genomic variants that explain the gene expression variance. On human heart data, eQTeL not only explains a significantly greater proportion of expression variance in samples, but also predicts gene expression more accurately than other methods. We demonstrate that eQTeL accurately detects causal regulatory SNPs by simulation, particularly those with small effect sizes. Using various functional data, we show that SNPs detected by eQTeL are enriched for allele-specific protein binding and histone modifications, which potentially disrupt binding of core cardiac transcription factors and are spatially proximal to their target. eQTeL SNPs capture a substantial proportion of genetic determinants of expression variance and we estimate that 58% of these SNPs are putatively causal. The challenge of identifying molecular determinants of cancer resistance so far could only be dealt with labor intensive and costly experimental studies, and in case of experimental drugs such studies are infeasible. Here we take a fundamentally different data driven approach to understand the evolving landscape of emerging resistance. We introduce a novel class of genetic interactions termed synthetic rescues (SR) in cancer, which denotes a functional interaction between two genes where a change in the activity of one vulnerable gene (which may be a target of a cancer drug) is lethal, but subsequently altered activity of its partner rescuer gene restores cell viability. Next we describe a comprehensive computational framework --termed INCISOR-- for identifying SR underlying cancer resistance. Applying INCISOR to mine The Cancer Genome Atlas (TCGA), a large collection of cancer patient data, we identified the first pan-cancer SR networks, composed of interactions common to many cancer types. We experimentally test and validate a subset of these interactions involving the master regulator gene mTOR. We find that rescuer genes become increasingly activated as breast cancer progresses, testifying to pervasive ongoing rescue processes. We show that SRs can be utilized to successfully predict patients' survival and response to the majority of current cancer drugs, and importantly, for predicting the emergence of drug resistance from the initial tumor biopsy. Our analysis suggests a potential new strategy for enhancing the effectiveness of existing cancer therapies by targeting their rescuer genes to counteract resistance. The thesis provides statistical frameworks that can harness ever increasing high throughput genomic data to address challenges in determining the molecular underpinnings of hypertension, cardiovascular disease and cancer resistance. We discover novel molecular mechanistic insights that will advance the progress in early disease prevention and personalized therapeutics. Our analyses sheds light on the fundamental biological understanding of gene regulation and interaction, and opens up exciting avenues of translational applications in risk prediction and therapeutics.

Biosynthesis and mode of action of ribosomally synthesized and post-translationally modified antimicrobial peptides

One of the greatest sources of biologically active compounds is natural products. Often these compounds serve as platforms for the design and development of novel drugs and therapeutics. The overwhelming amount of genomic information acquired in recent years has revealed that ribosomally synthesized and post-translationally modified natural products are much more widespread than originally anticipated. Identified in nearly all forms of life, these natural products display incredible structural diversity and possess a wide range of biological functions that include antimicrobial, antiviral, anti-inflammatory, antitumor, and antiallodynic activities. The unique pathways taken to biosynthesize these compounds offer exciting opportunities for the bioengineering of these complex molecules. The studies described herein focus on both the mode of action and biosynthesis of antimicrobial peptides. In Chapter 2, it is demonstrated that haloduracin, a recently discovered two-peptide lantibiotic, possesses nanomolar antimicrobial activity against a panel of bacteria strains. The potency of haloduracin rivals that of nisin, an economically and therapeutically relevant lantibiotic, which can be attributed to a similar dual mode of action. Moreover, it was demonstrated that this lantibiotic of alkaliphile origin has better stability at physiological pH than nisin. The molecular target of haloduracin was identified as the cell wall peptidoglycan precursor lipid II. Through the in vitro biosynthesis of haloduracin, several analogues of Halα were prepared and evaluated for their ability to inhibit peptidoglycan biosynthesis as well as bacterial cell growth. In an effort to overcome the limitations of in vitro biosynthesis strategies, a novel strategy was developed resulting in a constitutively active lantibiotic synthetase enzyme. This methodology, described in Chapter 3, enabled the production of fully-modified lacticin 481 products with proteinogenic and non-proteinogenic amino acid substitutions. A number of lacticin 481 analogues were prepared and their antimicrobial activity and ability to bind lipid II was assessed. Moreover, site-directed mutagenesis of the constitutively active synthetase resulted in a kinase-like enzyme with the ability to phosphorylate a number of peptide substrates. The hunt for a lantibiotic synthetase enzyme responsible for installing the presumed dehydro amino acids and a thioether ring in the natural product sublancin, led to the identification and characterization of a unique post-translational modification. The studies described in Chapter 4, demonstrate that sublancin is not a lantibiotic, but rather an unusual S-linked glycopeptide. Its structure was revised based on extensive chemical, biochemical, and spectroscopic characterization. In addition to structural investigation, bioinformatic analysis of the sublancin gene cluster led to the identification of an S-glycosyltransferase predicted to be responsible for the post-translational modification of the sublancin precursor peptide. The unprecedented glycosyltransferase was reconstituted in vitro and demonstrated remarkable substrate promiscuity for both the NDP-sugar co-substrate as well as the precursor peptide itself. An in vitro method was developed for the production of sublancin and analogues which were subsequently evaluated in bioactivity assays. Finally, a number of putative biosynthetic gene clusters were identified that appear to harbor the necessary genes for production of an S-glycopeptide. An additional S-glycosyltransferase with more favorable intrinsic properties including better expression, stability, and solubility was reconstituted in vitro and demonstrated robust catalytic abilities.

Modeling and analysis of thermoelectric energy conversion efficiency in nanostructures.

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Fabrication and characterization of hybrid ferromagnetic-organic heterostructures for spintronics application

Recent research in the field of organic spintronics highlighted the peculiar spin-dependent properties of the interface formed by an organic semiconductor (OSC) chemisorbed over a 3d ferromagnetic metal, also known as spinterface. The hybridization between the molecular and metallic orbitals, typically π orbitals of the molecule and the d orbitals of the ferromagnet, give rise to spin dependent properties that were not expected by considering the single components of interfaces, as for example the appearance of a magnetic moment on non-magnetic molecules or changes in the magnetic behavior of the ferromagnet. From a technological viewpoint these aspects provide novel engineering schemes for spin memory and for spintronics devices, featuring unexpected interfacial magnetoresistance, spin-filtering effects and even modulated magnetic anisotropy. Applications of these concepts to devices require nevertheless to transfer the spinterface effects from an ideal interface to room temperature operating thin films. In this view, my work presents for the first time how spinterface effects can be obtained even at room temperature on polycrystalline ferromagnetic Co thin films interfaced with organic molecules. The considered molecules were commercial and widely used in the field of organic electronics: Fullerene (C60), Gallium Quinoline (Gaq3) and Sexithiophene (T6). An increase of coercivity, up to 100% at room temperature, has been obtained on the Co ultra-thin films by the deposition of an organic molecule. This effect is accompanied by a change of in-plane anisotropy that is molecule-dependent. Moreover the Spinterface effect is not limited to the interfacial layer, but it extends throughout the whole thickness of the ferromagnetic layer, posing new questions on the nature of the 3d metal-molecule interaction.

Maus-tratos infantis: um resgate da história e das políticas de proteção

O estudo apresenta uma revisão bibliográfica, cujo objetivo foi conhecer e divulgar a evolução histórica da violência contra a criança, bem como as políticas desenvolvidas na atenção à violência contra menores, além de discutir a importância da prevenção e da atuação dos profissionais de saúde. A pesquisa bibliográfica foi realizada na base de dados MEDLINE, LILACS e SciELO, selecionando-se os estudos com os descritores: Violência, Agressão, Maus-Tratos, Síndrome da Criança Maltratada, Pediatria, não se fazendo restrição aos idiomas espanhol, inglês e francês. A literatura mostra a importância de ações preventivas e a necessidade de discussões e reflexões entre os diferentes setores que possam culminar em políticas e estratégias preventivas, diagnósticas e terapêuticas, além da relevância de incluir o tema na formação dos profissionais de saúde para que possam contribuir para o diagnóstico, tratamento e profilaxia do abuso infantil, rompendo as cadeias de determinação e fatalidade.

Perfil de prescrições e uso de antibióticos em infecções comunitárias

INTRODUÇÃO: O objetivo deste estudo foi conhecer os padrões de utilização de antibióticos no município de Sorocaba, avaliando o diagnóstico referido, a terapêutica empregada e sua utilização. MÉTODOS: Utilizou-se um instrumento de avaliação aplicado por 12 meses em usuários de antibióticos. Foram coletados dados de 403 usuários e referiram-se à: informações sociodemográficas e de saúde, diagnóstico e terapêutica. RESULTADOS: Encontrou-se grande utilização e a maior utilização prévia na faixa etária de 0-10 anos (p<0,05). As infecções com envolvimento pulmonar foram as mais citadas (p<0,05) e as penicilinas, os fármacos mais utilizados, presentes em 45,1% das prescrições. Tempo médio de terapêutica (8,9 dias) esteve abaixo do preconizado para otites. Em sinusites, 22% das prescrições não orientaram para o uso recomendado (10 dias). CONCLUSÕES: A inexistência e não utilização de protocolos terapêuticos têm resultado em grande diferença nos padrões de prescrição, levando a insucesso terapêutico e recidiva de infecções - situações frequentemente encontradas neste estudo.

The Effects of Commercially Available Preservative-Free FDA-Approved Triamcinolone (Triesence (R)) on Retinal Cells in Culture

Purpose: To evaluate the effects of Triesence (R) (TRI), a new preservative-free triamcinolone approved by the U. S. Food and Drug Administration (FDA) for intraocular use, on human retina pigment epithelial (ARPE-19) and rat neurosensory (R28) cells in culture. Methods: ARPE-19 and R28 cell cultures were treated 24 h with 1,000, 500, 200, or 100 mu g/mL of crystalline (cTRI) or 1,000, 500, or 200 mu g/mL of solubilized (sTRI). TRI was solubilized by centrifuging the drug, discarding the supernatant containing the vehicle and then resuspending the drug pellet in an equivalent amount of Dimethyl sulfoxide to achieve the same concentration as the commercial preparation. Percentage of cell viability (CV) was evaluated by a trypan blue dye-exclusion assay. The mitochondrial membrane potential (Delta Psi m) was analyzed with the JC-1 assay. The caspase-3/7 activity was measured by a fluorochrome assay. Results: In the ARPE-19 cultures, the cTRI caused a decrease in CV at 1,000 mg/mL (13.03 +/- 6.51; P < 0.001), 500 mu g/mL (28.87 +/- 9.3; P < 0.001), 200 mu g/mL (54.93 +/- 5.61; P < 0.001), and 100 mu g/mL (82.53 +/- 0.65; P < 0.005) compared with the untreated controls (96.98 +/- 0.16). In R28 cultures, the cTRI treatment also reduced CV values significantly (P < 0.001) for the 1,000 mu g/mL (22.73 +/- 2.44), 500 mu g/mL (34.63 +/- 1.91), 200 mu g/mL (58.70 +/- 1.39), and 100 mu g/m (75.33 +/- 2.47) compared with the untreated controls (86.08 +/- 3.54). Once the TRI was solubilized (sTRI), the CV and Delta Psi m remained similar to the untreated controls for both ARPE-19 and R28 cells. The sTRI treatment with 1,000, 500, and 200 mu g/mL increased in caspase-3/7 activity in ARPE-19 cells (P < 0.01) and in R28 cells (P < 0.05) compared with dimethyl sulfoxide equivalent controls. Conclusion: The crystalline form of TRI (cTRI) can cause a significant decrease in CV to cultured retinal cells. Once the TRI is solubilized (sTRI), at the same concentrations, the cells remain viable with no decrease in CV or Delta Psi m. The sTRI can, however, increase caspase-3/7 activity, thus suggesting some degree of apoptosis.

Toxicity of High-Dose Intravitreal Adalimumab (Humira) in the Rabbit

Purpose: To evaluate the ocular toxicity of escalating doses of intravitreous adalimumab (Humira (R)) in the rabbit eye. Methods: Thirty New Zealand albino rabbits received intravitreous injections of 0.5mg (6 eyes), 1.0mg (6 eyes), 2.5mg (6 eyes), 5mg (6 eyes), and 10mg (6 eyes) adalimumab. Slit lamp biomicroscopy and fundoscopy were carried out at baseline, day 7, and day 14 after intravitreous injection, whereas electroretinography (ERG) was carried out at baseline and day 14. Animals were euthanized on day 14, and histopathological examination of the eyes was performed. Results: Slit lamp biomicroscopy and fundoscopy were normal in all eyes receiving doses up to 5mg. In the 10mg group, 3 of 6 eyes showed mild anterior chamber inflammatory reaction on day 7. Similarly, scotopic and photopic a- and b-wave ERG amplitudes at baseline and day 14 were similar in all groups up to 5mg, but there was a significant decrease in the photopic-wave ERG response in the 10mg group (P = 0.046). Finally, histopathology demonstrated no differences among eyes receiving balanced salt solution, 0.5, 1.0, 2.5, 5.0, or 10mg of adalimumab. Conclusions: Intravitreous adalimumab exhibited no associated ocular short-term toxicity in rabbit eyes up to the 5mg dose. In the 10mg group mild clinical findings and ERG amplitude reduction could reflect early toxicity.