Purpose : Several drawbacks of endovascular brachytherapy for the treatment of coronary artery in-stent restenosis may be addressed by high-precision external beam radiotherapy (EBRT). The dosimetric characteristics of both treatment techniques were compared. Methods and Materials : The traversed volume of 10 coronary artery stents during the cardiac cycle was determined by electrocardiographically gated multislice spiral CT in 10 patients. By use of this traversed volume, high-precision EBRT treatment plans were generated for stents in the left circumflex (LCx), left anterior descending (LAD), and right coronary artery (RCA). The maximum dose to the nontargeted major coronary arteries was determined and compared to similar data calculated for endovascular brachytherapy. Results : High-precision EBRT targeted at LCx stents contributed a mean maximum dose (D max ) of 83.5% (range: 71.6–95.3%) and 16.3% to the LAD and RCA, respectively. Targeted LAD stents contributed a mean D max of 39.3% (range: 14.5–94.8%) and 5.2% (range: 0–13.4%) to the LCx and RCA, respectively. Targeted RCA stents contributed a mean D max of 6.2% (range: 0–12.4%) and 5.8% (range: 0–11.5%) to the LCx and LAD, respectively. Endovascular brachytherapy targeted at LCx stents contributed a mean D max of 1.7% (range: 0.7–2.7%) and 1.0% (range: 0.6–1.4%) to the LAD and RCA, respectively. Targeted LAD stents contributed a mean D max of 5.2% (range: 0.5–11.4%) and 0.7% (range: 0.4–1.1%) to the LCx and RCA, respectively; targeted RCA stents contributed a mean D max of 0.3% (range: 0.2–0.5%) and 0.2% (range: 0.1–0.3%) to the LCx and LAD, respectively. Conclusions : Although the doses distributed throughout the heart were higher for high-precision EBRT compared to endovascular brachytherapy, they are expected to be clinically irrelevant when nontargeted major coronary arteries are not closely situated to the targeted vessel segment. These encouraging results warrant further investigation of high-precision EBRT as a potential alternative to endovascular brachytherapy for the treatment of coronary artery in-stent restenosis.
Background/Introduction Functional assessment of coronary artery stenoses plays an important role in guiding the clinical management of patients with ischemic heart disease. Software to compute angiography-derived fractional flow ratio (angio-FFR) have been validated against pressure-wire-derived FFR (PW-FFR) with an area under the receiver operator characteristic curve (AUC) of 0.93-0.97. However, it is unknown whether commercially available angio-FFR software are equally reliable, and to what extent each might over- or under-estimate the true functional severity of a coronary artery lesion. Purpose The aim of this study was to investigate the diagnostic accuracies of five angio-FFR software/methods by an independent core-lab in a prospective cohort of 390 vessels with carefully documented sites of PW instantaneous-wave-free ratio (PW-iFR) and PW-FFR. Methods One "matcher investigator (MI)" colocalized on angiography the sites of PW measurement with angio-FFR measurements and provided the same two optimal angiographic views and frame selection to independent analysts, who were blinded to invasive physiological results and results from other software. Results are anonymized and randomly presented. The AUC of each angio-FFR was compared with 2D-quantative coronary angiography percent diameter stenosis (2D-QCA%DS) using a 2-tailed paired comparison of ROC (DeLong’s method). Results All 5 software/methods yielded a high proportion of analysable vessels (A:100%, B:100%, C:92.1%, D:99.5%, E:92.1%). The AUC’s for predicting an FFR≤0.8 for software A, B, C, D, E, and 2D-QCA%DS were 0.75, 0.74, 0.74, 0.73, 0.73, and 0.65, respectively (Figure A). The AUC for each angio-FFR was significantly greater than that for 2D-QCA%DS. Furthermore, binary logistic regression analyses showed the predictors of false positives and false negative: severity of lesion stenosis, lesion location, microvascular resistance, and intermediate zone of angiography-derived FFR potentially reduce the diagnostic accuracy (Figure B). Conclusions This head-to-head comparison by an independent core-lab demonstrated that the diagnostic accuracy of various angio-FFR software for predicting a PW-FFR≤0.80 was useful, with a higher discrimination compared to 2D-QCA%DS, however it didn’t reach the diagnostic accuracy (AUC≥0.90) previously reported in validation studies of various vendors. The intrinsic clinical value of "angiography-derived FFR" therefore requires confirmation in large clinical trials.Figure AFigure B
In eight extrinsic asthmatic subjects (age range 16-38 years) there was a significant reduction (p less than 0.01) in the severity of bronchoconstriction after a treadmill exercise test performed 30 minutes after nifedipine 20 mg sublingually. The maximum fall in peak expiratory flow after exercise was 36.0 +/- SEM 5.3% compared with a maximum fall of 56.5 +/- 4.1% after matched placebo capsules when given in double-blind randomised manner on separate days. There was no significant resting bronchodilation or change in blood pressure or heart rate after nifedipine. there was a significant rise in venous plasma histamine during exercise with placebo (6.1 +/- 0.8 to 13.5 +/- 3.5 nmol/l, p less than 0.01) but no significant increase with nifedipine (4.6 +/- 0.6 to 4.7 +/- 0.6 nmol/l) suggesting that nifedipine inhibits the release of mast cell mediators. The dose of inhaled histamine which provoked a 20% fall in peak expiratory flow was also significantly higher (p less than 0.05) with nifedipine (1.5 +/- 0.31 mg/ml) compared with placebo (2.7 +/- 0.63 mg/ml), indicating that there is a small inhibitory effect on bronchial smooth muscle contractility. Nifedipine is a potent antagonist of calcium ion influx in smooth muscle and secretory cells, and these studies suggest that it may inhibit release of mast cell mediators and reduce bronchial smooth muscle contractility in asthma.
No abstract is provided for this article.
The most used scientific evaluation parameters today are: 1) The impact factor (IF) of scientific journals in which the papers of researchers, and their collaborators, are published and 2) The so-called H-factor which is used to evaluate the work of individual scientists. We explore in detail these particular parameters. Also we briefly discuss alternative forms of assessment in the modern age.
A DPOC constitui um problema de saúde global de importância crescente, com enorme impacto nos custos directos e indirectos em recursos de saúde. Apesar do seu impacto, pouco se sabe ainda sobre os mecanismos celulares, moleculares e genéticos desta doença, e as te-rapêuticas farmacológicas actualmente disponíveis não influenciam a progressão da doença ou a mortalidade. A limitação do débito aéreo avaliada pela redução do volume expiratório máximo no 1.º segundo (FEV1) progride muito lentamente ao longo de várias décadas, condicionando o aparecimento de sintomas em adultos acima dos 40 anos ou já na terceira idade. Desta forma, a prevalência da DPOC é dependente da idade, sugerindo uma relação íntima entre a pato-génese da DPOC e a do envelhecimento. A senescência ou processo de envelhecimento definese como o declínio progressivo da homeostasia que ocorre após estar completa a fase reprodutiva da vida e conduz a um risco aumentado de doença e de morte. Segundo Kirkwood1, o envelhecimento resulta da interacção entre a lesão e a reparação, como resultado da energia produzida pelo indivíduo para manter a integridade orgânica e proteger o ADN da agressão oxidativa. A falência orgânica ou celular na manutenção ou reparação resulta de uma acção integrada entre genes, ambiente e defeitos intrínsecos do organismo. Subjacente ao processo de envelhecimento, existe uma acumulação progressiva de danos a nível molecular. As alterações a nível celular causam reacções inflamatórias, e estas, por sua vez, exacerbam as lesões celulares existentes. Desta forma, os factores inflamatórios e anti-inflamatórios modulam a evolução do envelhe-cimento. As alterações inflamatórias e estruturais associadas ao envelhecimento resultam da falência em eliminar os radicais de oxigénio (ROS), da falência em reparar o ADN lesado e do encurtamento do teló-mero. Os telómeros protegem as extremidades dos cromossomas, mas, quando se encontram expostos a elevados níveis de stress oxidativo, vão-se encurtando progressivamente à medida que as células se dividem. Com o envelhecimento, a perda e encurtamento dos telómeros condicionam o declínio da capacidade para as células se dividirem – senescência replicativa. O stress oxidativo causa lesão do ADN, o que acelera o processo de envelhecimento e aumenta o risco de cancro (exemplo, a senescência da glândula mamária e o risco elevado de cancro da mama). Os gases ambientais, como o fumo do cigarro ou outros poluentes, podem acelerar o envelhecimento do pulmão ou agravar os eventos relacionados com o en-velhecimento pulmonar através de uma resolução defeituosa da inflamação. A redução das moléculas anti-envelhecimento como as histona desacetilases e as sirtuínas, pode igualmente induzir a progressão acelerada para a DPOC. Ainda não é claro como é que o processo de envelhe-cimento está envolvido no declínio da função pulmonar e na inflamação da DPOC. Contudo, o pulmão do idoso e o pulmão do doente com DPOC apresen-tam muitas semelhanças. A lesão provocada pelo fumo do cigarro e outros pneumopoluentes conduz a um declínio mais acelerado da função pulmonar, com falência dos mecanismos de reparação e de manuten-ção. A presença de inflamação nos dois processos (en-velhecimento e DPOC) traduz-se em acumulação de neutrófilos, na activação da NF-kB e na elevação dos níveis plasmáticos de interleucinas IL-6, IL-8 e TNF-α. Também os telómeros das células alveolares tipo II, das células endoteliais e das células mononu-cleares em doentes com enfisema são significativamente mais curtos do que em indivíduos não fumadores da mesma idade. Neste artigo, os autores descrevem ainda estudos recentes sobre os mecanismos de transdução de sinal, como as vias da acetilação das proteínas envolvidas no processo de envelhecimento, identificando assim novas moléculas anti-envelhecimento que poderão constituir abordagens inovadoras na terapêutica da DPOC. Os antioxidantes actualmente disponíveis, como a N-acetilcisteína, não são suficientemente potentes para reduzir o stress oxidativo nos pulmões. Existem vários fármacos em desenvolvimento, como os novos análogos da glutationa e da superoxido dismutase (exemplo, o sulforafano) e novas moléculas antienvelhecimento com maior controlo sobre a resis-tência ao stress oxidativo, a reparação do ADN e a inflamação, como os activadores das sirtuínas (exem-plo, o resveratrol, o activador específico da SIRT1 ou o activador da SIRT6).
The assessment of responses of the respiratory system to new drugs is dependent upon the particular pathology and condition being treated. The lung can be divided into vascular and parenchymal compartments. Pharmacological manipulation of the pulmonary vasculature is discussed elsewhere. Diseases of the parenchyma involve either the conducting airways, as in asthma or chronic obstructive pulmonary disease (COPD), or the alveoli, interstitium and gas-exchanging membranes, as in pulmonary fibrosis. Drug evaluation in respiratory disease therefore depends upon the assessment of responses to therapies manipulating airflow and airway resistance, lung volumes and gas exchange.
