RESUMO
Importance: Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available. Objective: To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome. Design, Setting, and Participants: This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin; Children's National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil. Exposures: Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d. Main Outcomes and Measures: Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children's Dermatology Life Quality Index. Adverse effects were monitored throughout treatment. Results: Four patients (mean [SD] age, 7 [6] years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported. Conclusions and Relevance: This study's findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.
Assuntos
Cloridrato de Erlotinib/administração & dosagem , Ceratodermia Palmar e Plantar/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Sirolimo/administração & dosagem , Adolescente , Brasil , Criança , Pré-Escolar , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Imunossupressores/administração & dosagem , Lactente , Ceratodermia Palmar e Plantar/genética , Masculino , Transdução de Sinais/efeitos dos fármacos , Síndrome , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do TratamentoRESUMO
Dengue and influenza-like illness (ILI) are two of the leading causes of viral infection in the world and it is estimated that more than half the world's population is at risk for developing these infections. It is therefore important to develop accurate methods for forecasting dengue and ILI incidences. Since data from multiple sources (such as dengue and ILI case counts, electronic health records and frequency of multiple internet search terms from Google Trends) can improve forecasts, standard time series analysis methods are inadequate to estimate all the parameter values from the limited amount of data available if we use multiple sources. In this paper, we use a computationally efficient implementation of the known variable selection method that we call the Autoregressive Likelihood Ratio (ARLR) method. This method combines sparse representation of time series data, electronic health records data (for ILI) and Google Trends data to forecast dengue and ILI incidences. This sparse representation method uses an algorithm that maximizes an appropriate likelihood ratio at every step. Using numerical experiments, we demonstrate that our method recovers the underlying sparse model much more accurately than the lasso method. We apply our method to dengue case count data from five countries/states: Brazil, Mexico, Singapore, Taiwan, and Thailand and to ILI case count data from the United States. Numerical experiments show that our method outperforms existing time series forecasting methods in forecasting the dengue and ILI case counts. In particular, our method gives a 18 percent forecast error reduction over a leading method that also uses data from multiple sources. It also performs better than other methods in predicting the peak value of the case count and the peak time.
Assuntos
Dengue/epidemiologia , Previsões/métodos , Influenza Humana/epidemiologia , Brasil/epidemiologia , Registros Eletrônicos de Saúde , Humanos , Incidência , Internet/tendências , México/epidemiologia , Modelos Estatísticos , Vigilância da População/métodos , Singapura/epidemiologia , Taiwan/epidemiologia , Tailândia/epidemiologia , Fatores de Tempo , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Custom-fitted skull replacement pieces are often used after a head injury or surgery to replace damaged bone. Chronic brain recordings are beneficial after injury/surgery for monitoring brain health and seizure development. Embedding electrodes directly in these artificial skull replacement pieces would be a novel, low-risk way to perform chronic brain monitoring in these patients. Similarly, embedding electrodes directly in healthy skull would be a viable minimally-invasive option for many other neuroscience and neurotechnology applications requiring chronic brain recordings. NEW METHOD: We demonstrate a preclinical testbed that can be used for refining electrode designs embedded in artificial skull replacement pieces or for embedding directly into the skull itself. Options are explored to increase the surface area of the contacts without increasing recording contact diameter to maximize recording resolution. RESULTS: Embedding electrodes in real or artificial skull allows one to lower electrode impedance without increasing the recording contact diameter by making use of conductive channels that extend into the skull. The higher density of small contacts embedded in the artificial skull in this testbed enables one to optimize electrode spacing for use in real bone. COMPARISON WITH EXISTING METHODS: For brain monitoring applications, skull-embedded electrodes fill a gap between electroencephalograms recorded on the scalp surface and the more invasive epidural or subdural electrode sheets. CONCLUSIONS: Embedding electrodes into the skull or in skull replacement pieces may provide a safe, convenient, minimally-invasive alternative for chronic brain monitoring. The manufacturing methods described here will facilitate further testing of skull-embedded electrodes in animal models.
Assuntos
Traumatismos Craniocerebrais/fisiopatologia , Traumatismos Craniocerebrais/cirurgia , Eletrodos Implantados , Substituição Ossicular/métodos , Crânio/fisiopatologia , Animais , Traumatismos Craniocerebrais/diagnóstico por imagem , Eletroencefalografia , Imageamento Tridimensional , Macaca mulatta , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios XRESUMO
Aim: To find the marginal fit of the porcelain fused to metal crowns by two different margin designs (shoulder and chamfer) and two commercially available base metal alloys. Material and Methods: Tooth preparation of first central incisor for porcelain-fused-to-metal crown with shoulder margin and second incisor for porcelain-fused-to-metal crown with chamfer margin was done. Wax pattern of the same was prepared. Impression of both prepared ivorine incisors was made by light body impression material and poured with pattern resin. Both the patterns were invested and casted with cobalt chromium alloy for making master dies. Two wax patterns of unprepared central incisors were fabricated, one with shoulder margin and another with chamfer margin. These patterns were then cut back to the size of the coping. Four rings were invested. In each ring ten patterns, five with shoulder margin and five with deep chamfer margin were sprued together to ensure that each group would pass through the same investing and casting procedure, followed by ceramic firing and measurement. Results: Marginal fit change or marginal discrepancy (before and after firing) between the groups was highly significant. Conclusions: Veneered crowns exhibited highly significant marginal distortion than non- veneered copings after porcelain firing. Shoulder margin is better in minimizing marginal discrepancy compared to deep chamfer margin. Marginal discrepancy is less when cerabond base metal alloy is used with shoulder margin as compared to commend base metal alloy used for shoulder margin.
RESUMO
Social unrest is endemic in many societies, and recent news has drawn attention to happenings in Latin America, the Middle East, and Eastern Europe. Civilian populations mobilize, sometimes spontaneously and sometimes in an organized manner, to raise awareness of key issues or to demand changes in governing or other organizational structures. It is of key interest to social scientists and policy makers to forecast civil unrest using indicators observed on media such as Twitter, news, and blogs. We present an event forecasting model using a notion of activity cascades in Twitter (proposed by Gonzalez-Bailon et al., 2011) to predict the occurrence of protests in three countries of Latin America: Brazil, Mexico, and Venezuela. The basic assumption is that the emergence of a suitably detected activity cascade is a precursor or a surrogate to a real protest event that will happen "on the ground." Our model supports the theoretical characterization of large cascades using spectral properties and uses properties of detected cascades to forecast events. Experimental results on many datasets, including the recent June 2013 protests in Brazil, demonstrate the effectiveness of our approach.
Assuntos
Previsões , Modelos Teóricos , Brasil , Humanos , México , VenezuelaRESUMO
BACKGROUND: Hantavirus pulmonary syndrome (HPS) is a life threatening disease transmitted by the rodent Oligoryzomys longicaudatus in Chile. Hantavirus outbreaks are typically small and geographically confined. Several studies have estimated risk based on spatial and temporal distribution of cases in relation to climate and environmental variables, but few have considered climatological modeling of HPS incidence for monitoring and forecasting purposes. METHODOLOGY: Monthly counts of confirmed HPS cases were obtained from the Chilean Ministry of Health for 2001-2012. There were an estimated 667 confirmed HPS cases. The data suggested a seasonal trend, which appeared to correlate with changes in climatological variables such as temperature, precipitation, and humidity. We considered several Auto Regressive Integrated Moving Average (ARIMA) time-series models and regression models with ARIMA errors with one or a combination of these climate variables as covariates. We adopted an information-theoretic approach to model ranking and selection. Data from 2001-2009 were used in fitting and data from January 2010 to December 2012 were used for one-step-ahead predictions. RESULTS: We focused on six models. In a baseline model, future HPS cases were forecasted from previous incidence; the other models included climate variables as covariates. The baseline model had a Corrected Akaike Information Criterion (AICc) of 444.98, and the top ranked model, which included precipitation, had an AICc of 437.62. Although the AICc of the top ranked model only provided a 1.65% improvement to the baseline AICc, the empirical support was 39 times stronger relative to the baseline model. CONCLUSIONS: Instead of choosing a single model, we present a set of candidate models that can be used in modeling and forecasting confirmed HPS cases in Chile. The models can be improved by using data at the regional level and easily extended to other countries with seasonal incidence of HPS.
Assuntos
Clima , Síndrome Pulmonar por Hantavirus/epidemiologia , Chile/epidemiologia , Processos Climáticos , Humanos , Umidade , Modelos Estatísticos , TemperaturaRESUMO
Oxidized low-density lipoprotein (LDL) is a major component in the pathophysiology of atherosclerosis and plays a role in the changes of vascular reactivity observed in this disease. Herein the authors investigate the potential involvement of platelet-activating factor (PAF)-like phospholipid components of oxidized LDL in rabbit aorta reactivity. Aortic rings were precontracted with noradrenaline (0.5 microM) and relaxation was induced by subsequent stimulation with sequential additions of acetylcholine (1 nM to 3 microM). High-performance liquid chromatography (HPLC) fractions (6- and 7-min) obtained from phospholipids extracted from oxidized LDL inhibited relaxation evoked by acetylcholine, but not the relaxation induced by sodium nitroprusside. This effect was not antagonized either by incubation of the fractions with PAF acetylhydrolase or by incubation of the aortic rings with a PAF receptor antagonist. Authentic PAF or C4-PAF, a PAF mimetic previously found in fractions 6 and 7 did not inhibit acetylcholine-induced relaxation. In contrast, lyso-PAF inhibited acetylcholine, but not sodium nitroprusside-induced relaxation. The authors conclude that phospholipids of oxidized LDL impair vascular reactivity to endothelium-dependent agonists. This effect is not due to oxidatively generated proinflammatory PAF mimetics, but rather to a metabolite of these phospholipids, lysoPAF.
Assuntos
Aorta/fisiologia , Células Endoteliais/metabolismo , Lipoproteínas LDL/metabolismo , Músculo Liso Vascular/metabolismo , Fosfolipídeos/metabolismo , Vasodilatação/fisiologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/farmacologia , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Lipoproteínas LDL/química , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Técnicas de Cultura de Órgãos , Fosfolipídeos/farmacologia , Fator de Ativação de Plaquetas/análogos & derivados , Fator de Ativação de Plaquetas/metabolismo , Fator de Ativação de Plaquetas/farmacologia , Glicoproteínas da Membrana de Plaquetas/antagonistas & inibidores , Glicoproteínas da Membrana de Plaquetas/metabolismo , Coelhos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Oxidized low density lipoprotein (LDL) has an important proinflammatory role in atherogenesis. In this study, we investigated the ability of oxidized LDL (oxLDL) and its phospholipid components to induce lipid body formation in leukocytes. Incubation of mouse peritoneal macrophages with oxidized, but not with native LDL led to lipid body formation within 1 h. This was blocked by platelet-activating factor (PAF) receptor antagonists or by preincubation of oxLDL with rPAF acetylhydrolase. HPLC fractions of phospholipids purified from oxLDL induced calcium flux in neutrophils as well as lipid body formation in macrophages. Injection of the bioactive phospholipid fractions or butanoyl and butenoyl PAF, a phospholipid previously shown to be present in oxLDL, into the pleural cavity of mice induced lipid body formation in leukocytes recovered after 3 h. The 5-lipoxygenase and cyclooxygenase-2 colocalized within lipid bodies formed after stimulation with oxLDL, bioactive phospholipid fractions, or butanoyl and butenoyl PAF. Lipid body formation was inhibited by 5-lipoxygenase antagonists, but not by cyclooxygenase-2 inhibitors. Azelaoyl-phosphatidylcholine, a peroxisome proliferator-activated receptor-gamma agonist in oxLDL phospholipid fractions, induced formation of lipid bodies at late time points (6 h) and synergized with suboptimal concentrations of oxLDL. We conclude that lipid body formation is an important proinflammatory effect of oxLDL and that PAF-like phospholipids and peroxisome proliferator-activated receptor-gamma agonists generated during LDL oxidation are important mediators in this phenomenon.
Assuntos
Corpos de Inclusão/metabolismo , Leucócitos/metabolismo , Lipoproteínas LDL/metabolismo , Peroxissomos/metabolismo , Fator de Ativação de Plaquetas/fisiologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/agonistas , Fatores de Transcrição/fisiologia , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Araquidonato 5-Lipoxigenase/fisiologia , Ciclo-Oxigenase 2 , Sinergismo Farmacológico , Feminino , Humanos , Isoenzimas/metabolismo , Leucócitos/fisiologia , Lipoproteínas LDL/administração & dosagem , Lipoproteínas LDL/farmacologia , Macrófagos Peritoneais/metabolismo , Masculino , Proteínas de Membrana , Camundongos , Oxirredução , Peroxissomos/enzimologia , Peroxissomos/fisiologia , Fosfolipídeos/metabolismo , Fator de Ativação de Plaquetas/administração & dosagem , Fator de Ativação de Plaquetas/metabolismo , Cavidade Pleural/citologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Cavidade Torácica , Fatores de Transcrição/metabolismoRESUMO
Oxidized low-density lipoprotein (LDL) contains inflammatory agents, including oxidatively fragmented phospholipids that activate the platelet-activating factor (PAF) receptor, but in vivo events caused by these pathologically generated agents are not well defined. Injection of PAF-like lipids derived from oxidized LDL, or C(4)-PAF that is a major PAF-like lipid in these particles, into the pleural cavity of mice resulted in rapid monocyte, neutrophil, and eosinophil accumulation. Increased numbers of intracellular lipid bodies in these cells show they were in an inflammatory environment. Leukocyte recruitment was abolished by a PAF receptor antagonist, as expected. PAF-like lipids induced 5-lipoxygenase expression in leukocytes, mRNA expression for monocyte chemoattractant protein-1 (MCP-1) and other chemokines, synthesis of MCP-1, and leukotriene B(4). The 5-lipoxygenase inhibitor zileuton impaired neutrophil influx, while MCP-1 had a more global role, as determined with MCP-1(-/-) mice. The lack of MCP-1 abrogated leukocyte accumulation and lipid body formation both in vivo and in vitro and chemokine transcription in vivo, and reduced in vivo leukotriene B(4) production. Thus, PAF-like phospholipids in oxidized LDL induce an inflammatory infiltrate through the PAF receptor, chemokine transcription, lipid body formation, and 5-lipoxygenase expression in leukocytes. MCP-1 has a key role in this inflammatory response, and 5-lipoxygenase products are essential for neutrophil recruitment into the inflamed pleural cavity.