Fiber Optic Devices for Endobiliary Photodynamic Therapy

The aim of the study is to optimize the irradiation procedure during endobiliary photodynamic therapy for patients with cholangiocarcinoma. The studies were performed using fiber-optic light delivery tools in various configurations and using different irradiation power levels. Control of photosensitizer accumulation at the site of therapy was also applied. It is shown that the use of fiber-optic light delivery tools with cylindrical diffusers provides more effective and less painful photodynamic therapy. It is shown that after the injection of the photosensitizer, there is an optimal time for the therapy, when the maximum difference in the accumulation of the photosensitizer in the tumor is observed in comparison with the intact tissue.     Keywords: endobiliary photodynamic therapy, fluorescent diagnostics, fiber-optic light delivery tools, cholangiocarcinom

Классификация внутричерепных опухолей на основе оптико-спектрального анализа

The motivation for the present study was the need to develop methods of urgent intraoperative biopsy during surgery for removal of intracranial tumors. Based on the experience of previous joint work of GPI RAS and N.N. Burdenko National Medical Research Center of Neurosurgery to introduce fluorescence spectroscopy methods into clinical practice, an approach combining  various optical-spectral techniques, such as autofluorescence spectroscopy, fluorescence of 5-ALA induced protoporphyrin IX, diffuse reflection of broadband light, which can be used to determine hemoglobin concentration in tissues and their optical density, Raman spectroscopy, which is a spectroscopic method that allows detection of various molecules in tissues by vibrations of individual characteristic molecular bonds. Such a variety of optical and spectral characteristics makes it difficult for the surgeon to analyze them directly during surgery, as it is usually realized in the case of fluorescence methods – tumor tissue can be distinguished from normal with a certain degree of certainty by fluorescence intensity exceeding  a threshold value. In case the number of parameters exceeds a couple of dozens, it is necessary to use machine learning algorithms  to build a intraoperative decision support system for the surgeon. This paper presents research in this direction. Our earlier statistical analysis of the optical-spectral features allowed identifying  statistically significant spectral ranges for analysis of diagnostically  important tissue components. Studies of dimensionality reduction techniques of the optical-spectral feature vector and methods of clustering of the studied samples also allowed us to approach the implementation  of the automatic classification method. Importantly, the classification task can be used in two applications  – to differentiate between different tumors and to differentiate between different parts of the same (center, perifocal zone, normal) tumor. This paper presents the results of our research in the first direction. We investigated the combination of several methods and showed the possibility of differentiating glial and meningeal tumors based on the proposed optical-spectral analysis method.Мотивацией проведения настоящего исследования послужила необходимость развития методов срочной интраоперационной биопсии при проведении операций по поводу удаления внутричерепных опухолей. На основании опыта предыдущей совместной работы ИОФ РАН и НМИЦ нейрохирургии  им. Н.Н. Бурденко по внедрению в клиническую практику методов флуоресцентной спектроскопии был разработан подход, комбинирующий различные оптико-спектральные  методики, такие как спектроскопия  аутофлуоресценции, флуоресценции  5-АЛК индуцированного  протопорфирина  IX, диффузного  отражения  широкополосного излучения,  по которому можно определять концентрацию гемоглобина в тканях и их оптическую  плотность,  спектроскопия  комбинационного  рассеяния, являющаяся методом молекулярной спектроскопии, позволяющим детектировать различные молекулы в тканях за счета колебаний отдельных характерных связей в молекулах. Такое разнообразие оптико-спектральных характеристик  затрудняет их непосредственный анализ хирургом во время операции, как это обычно реализуется в случае флуоресцентных методов – по превышению некоторого порога интенсивности флуоресценции с определенной степенью достоверности можно судить о том, находится ли в зоне исследования нормальная или опухолевая ткань. В случае, если число параметров превышает пару десятков, необходимо использование алгоритмов машинного обучения для построения  системы поддержки принятия  решений хирурга  во время операции. Настоящая работа представляет исследования в этом направлении. Проведенный нами ранее статистический  анализ данных оптико-спектральных характеристик  позволил выделить статистически  значимые спектральные диапазоны для анализа, репрезентирующие  диагностически  важные компоненты тканей. Исследования методов понижения размерности вектора оптико-спектральных признаков  и методов кластеризации исследуемых образцов также позволили приблизиться к реализации метода автоматической классификации. Важно отметить, что задача классификации может быть использована в двух приложениях – для дифференциации различных опухолей и для дифференциации различных частей одной (центр, перифокальная зона, норма) опухоли. В настоящей работе представлены результаты наших исследований в первом направлении. Мы исследовали сочетание нескольких методов и показали возможность дифференциации глиальных и менингеальных опухолей на основании предложенного метода оптико-спектрального анализа

Emerging methods and tools for environmental risk assessment, decision-making, and policy for nanomaterials: summary of NATO Advanced Research Workshop

Nanomaterials and their associated technologies hold promising opportunities for the development of new materials and applications in a wide variety of disciplines, including medicine, environmental remediation, waste treatment, and energy conservation. However, current information regarding the environmental effects and health risks associated with nanomaterials is limited and sometimes contradictory. This article summarizes the conclusions of a 2008 NATO workshop designed to evaluate the wide-scale implications (e.g., benefits, risks, and costs) of the use of nanomaterials on human health and the environment. A unique feature of this workshop was its interdisciplinary nature and focus on the practical needs of policy decision makers. Workshop presentations and discussion panels were structured along four main themes: technology and benefits, human health risk, environmental risk, and policy implications. Four corresponding working groups (WGs) were formed to develop detailed summaries of the state-of-the-science in their respective areas and to discuss emerging gaps and research needs. The WGs identified gaps between the rapid advances in the types and applications of nanomaterials and the slower pace of human health and environmental risk science, along with strategies to reduce the uncertainties associated with calculating these risks

Оптический спектроанализатор с расширенным динамическим диапазоном для фармакокинетических исследований флуоресцирующих препаратов в биотканях

Currently, the most promising method for the study of pharmacokinetics of drugs with fluorescent properties is the spectral-fluorescent method. In this article, we propose an algorithm for expanding the dynamic range of the spectrum analyzer by automatically monitoring the maximum spectral density in the recorded fluorescence spectrum and automatically controlled changes in the accumulation time depending on this value, followed by compensation of the output signal with regard to this change, as well as hardware circuit solutions that allow this algorithm.Testing of LESA-01-"Biospeс" spectrum analyzer, upgraded using the proposed approach, was carried out on photosensitizer dispersions based on tetra-3-phenylthiophthalocyanine hydroxyaluminium of various concentrations (from 0.01 mg/l to 50 mg/l), approximately corresponding to the concentrations realized in the process of studying pharmacokinetics in calibration samples and tissues of experimental animals.The proposed solutions that implement the algorithm for recording fluorescence spectra with automatic change of accumulation time depending on the signal level, ensured a significant expansion of the dynamic range of the spectrum analyzer (up to 3.5 orders of magnitude) and improved accuracy in pharmacokinetic studies.В настоящее время наиболее перспективным методом для исследования фармакокинетики препаратов, обладающих выраженными флуоресцентными свойствами, является спектрально-флуоресцентный метод. В этой статье мы предлагаем алгоритм расширения динамического диапазона спектроанализатора путем автоматического мониторинга максимального значения спектральной плотности в регистрируемом спектре флуоресценции и автоматического контролируемого изменения времени накопления в зависимости от этого значения с последующей компенсацией выходного сигнала с учетом этого изменения, а также схемные решения, позволяющие реализовать этот алгоритм.Тестирование спектроанализатора ЛЭСА-01-«Биоспек», модернизированного с использованием предложенного подхода, проводилось на дисперсиях фотосенсибилизатора на основе тетра-3-фенилтиофталоцианина гидроксиалюминия различной концентрации (от 0,01 мг/л до 50 мг/л), примерно соответствующих концентрациям, реализующихся в процессе исследования фармакокинетики в калибровочных образцах и тканях экспериментальных животных. Предложенные решения, реализующие алгоритм регистрации спектров флуоресценции с автоматическим изменением времени накопления в зависимости от уровня сигнала, обеспечили существенное расширение динамического диапазона спектроанализатора (до 3.5 порядков) и повышение точности при фармакокинетических исследованиях

Аппаратурное и инструментальное обеспечение флюоресцентной диагностики и фотодинамической терапии

The results of hardware and tool development in photodynamic therapy and fluorescence diagnostics performed by the Natural Research Center, A.M. Prokhorov General Physics Institute, Russian Academy of Sciences in collaboration with several research and medical institutes are presented. Physical and technical aspects of the problem are mentioned. We describe schemes and the principle of operation of devices which we use with our medical colleagues in clinical and experimental studies. Some results of clinical use of the developed devices and methods are presented. Представлены результаты аппаратных и инструментальных разработок в области фотодинамической терапии и флюоресцентной диагностики, проведенных Центром естественно-научных исследований Института общей физики им. А.М. Прохорова Российской академии наук совместно с другими исследовательскими и медицинскими институтами. Приведены схемы и описаны принципы работы устройств, используемых в клинических и экспериментальных исследованиях. Представлены некоторые результаты использования разработанных устройств в клинической практике.

Parameter and model uncertainty in a life-table model for fine particles (PM2.5): a statistical modeling study

<p>Abstract</p> <p>Background</p> <p>The estimation of health impacts involves often uncertain input variables and assumptions which have to be incorporated into the model structure. These uncertainties may have significant effects on the results obtained with model, and, thus, on decision making. Fine particles (PM_2.5) are believed to cause major health impacts, and, consequently, uncertainties in their health impact assessment have clear relevance to policy-making. We studied the effects of various uncertain input variables by building a life-table model for fine particles.</p> <p>Methods</p> <p>Life-expectancy of the Helsinki metropolitan area population and the change in life-expectancy due to fine particle exposures were predicted using a life-table model. A number of parameter and model uncertainties were estimated. Sensitivity analysis for input variables was performed by calculating rank-order correlations between input and output variables. The studied model uncertainties were (i) plausibility of mortality outcomes and (ii) lag, and parameter uncertainties (iii) exposure-response coefficients for different mortality outcomes, and (iv) exposure estimates for different age groups. The monetary value of the years-of-life-lost and the relative importance of the uncertainties related to monetary valuation were predicted to compare the relative importance of the monetary valuation on the health effect uncertainties.</p> <p>Results</p> <p>The magnitude of the health effects costs depended mostly on discount rate, exposure-response coefficient, and plausibility of the cardiopulmonary mortality. Other mortality outcomes (lung cancer, other non-accidental and infant mortality) and lag had only minor impact on the output. The results highlight the importance of the uncertainties associated with cardiopulmonary mortality in the fine particle impact assessment when compared with other uncertainties.</p> <p>Conclusion</p> <p>When estimating life-expectancy, the estimates used for cardiopulmonary exposure-response coefficient, discount rate, and plausibility require careful assessment, while complicated lag estimates can be omitted without this having any major effect on the results.</p

A trio of gamma-ray burst supernovae: GRB 120729A, GRB 130215A/SN 2013ez, and GRB 130831A/SN 2013fu

We present optical and near-infrared (NIR) photometry for three gamma-ray burst supernovae (GRB-SNe): GRB 120729A, GRB 130215A/SN 2013ez, and GRB 130831A/SN 2013fu. For GRB 130215A/SN 2013ez, we also present optical spectroscopy at t − t0 = 16.1 d, which covers rest-frame 3000–6250 Å. Based on Fe ii λ5169 and Si ii λ6355, our spectrum indicates an unusually low expansion velocity of ~4000–6350 km s-1, the lowest ever measured for a GRB-SN. Additionally, we determined the brightness and shape of each accompanying SN relative to a template supernova (SN 1998bw), which were used to estimate the amount of nickel produced via nucleosynthesis during each explosion. We find that our derived nickel masses are typical of other GRB-SNe, and greater than those of SNe Ibc that are not associated with GRBs. For GRB 130831A/SN 2013fu, we used our well-sampled R-band light curve (LC) to estimate the amount of ejecta mass and the kinetic energy of the SN, finding that these too are similar to other GRB-SNe. For GRB 130215A, we took advantage of contemporaneous optical/NIR observations to construct an optical/NIR bolometric LC of the afterglow. We fit the bolometric LC with the millisecond magnetar model of Zhang & Mészáros (2001, ApJ, 552, L35), which considers dipole radiation as a source of energy injection to the forward shock powering the optical/NIR afterglow. Using this model we derive an initial spin period of P = 12 ms and a magnetic field of B = 1.1 × 1015 G, which are commensurate with those found for proposed magnetar central engines of other long-duration GRBs

ИССЛЕДОВАНИЕ ФОТОСЕНСИБИЛИЗАТОРА ДЛЯ АНТИБАКТЕРИАЛЬНОЙ ФОТОДИНАМИЧЕСКОЙ ТЕРАПИИ НА ОСНОВЕ ЦИКЛОДЕКСТРИНОВОЙ КОМПОЗИЦИИ МЕТИЛОВОГО ЭФИРА 133-N-(N-МЕТИЛНИКОТИНИЛ) БАКТЕРИОПУРПУРИНИМИДА

Cationic bacteriochlorins are promising as antibacterial photosensitizers (PS) for antibacterial photodynamic therapy. Current work is devoted to the study of properties of new nanostructured cationic photosensitizer based on cyclodextrin dispersion of bacteriochlorine derivative – 133-N-(N-methylnicotinyl)-bacteriopurpurinimide methyl ester, for optimization of dispersion composition and selection of time interval between administration of the PS and photodynamic ttherapy of infected septic wounds. Specifics of absorption and fluorescence of PS in dependence of its concentration and proportions of components in dispersion was assessed. Pharmacokinetics and biodistribution of PS were studies in vivo in organs and tissues of intact mice and septic wounds infected with P. аeruginosa or S. aureus. The preliminary studies have shown high efficiency of antimicrobial photodynamic therapy of septic wounds with cyclodextrin dispersion of 133-N-(N-methylnicotinyl)-bacteriopurpurinimide methyl ester. Results of study of absorption and spectral and fluorescence properties of its drug formulation depending on its composition allowed to recommend the use of weight ratio 133-N-(N-methylnicotinyl)bacteriopurpurinimide methyl ester : cyclodextrin about 1:200 and addition of 0,1% Tween 80 to reduce aggregation. The study showed that 133-N-(N-methylnicotinyl)-bacteriopurpurinimide methyl ester was rapidly cleared from mouse blood circulation: more than 70% – for 2 h, 95% – for 1 day, more than 99% – for 6 days. About 98% was cleared from skin and muscles for 6 days. The long-term (up to 24 h) persistence of PS were observed in liver and kidneys, however more than 99% was cleared for 6 days. Thus, it may be supposed that elimination of PS form mice body is through kidneys and liver. After 24 h partial PS aggregation in tissues, particularly in skin and muscles, was observed. Thus, it may be supposed that the reduce of fluorescence intensity after 24 hand later was associated not only with its elimination from body but with its aggregation. Spectral and fluorescence studies showed that 133-N-(Nmethylnicotinyl)-bacteriopurpurinimide methyl ester selectively accumulated in septic wounds, fluorescence contrast was in the range of 3–4. The highest values of concentration and selectivity of its accumulation were achieved at 1.5–3 h after intravenous injection. The irradiation 2 h after injection provided high efficacy of the therapy of septic wounds.Катионные бактериохлорины перспективны как антимикробные фотосенсибилизаторы для антибактериальной фотодинамической терапии. Настоящая работа посвящена изучению свойств нового наноструктурированного катионного фотосенсибилизатора на основе циклодекстриновой дисперсии производного бактериохлорина – метилового эфира 133-N-(N-метилникотинил)бактериопурпуринимида (КБХ), с целью оптимизации состава дисперсии и выбора интервала времени от введения фотосенсибилизатора до проведения фотодинамической терапии инфицированных гнойных ран. Оценены особенности поглощения и флуоресценции фотосенсибилизатора в зависимости от его концентрации и соотношения между компонентами дисперсии. Изучена фармакокинетика и биораспределение фотосенсибилизатора в органах и тканях интактных мышей и гнойных ранах, инфицированных P. аeruginosa или S. aureus. Предварительные исследования показали высокую эффективность антимикробной фотодинамической терапии инфицированных гнойных ран с циклодекстрированной дисперсией КБХ. Проведенные исследования поглощения и спектрально-флуоресцентных свойств его лекарственной формы в зависимости от ее состава позволили рекомендовать использование массового отношения КБХ : циклодекстрин около 1:200 и введение для уменьшения агрегации 0,1% Твин-80. Установлено, что КБХ быстро выводится из кровотока мыши: более 70% – за 2 ч, 95% – за 1 сут , более 99% – за 6 сут. Из кожи и мышц около 98% выводится за 6 сут. Фотосенсибилизатор накапливается и удерживается до 24 ч в печени и почках. Это позволяет предположить, что элиминирование фотосенсибилизатора из организма мышей происходит через почки и печень. Обнаружено, что в тканях, в частности, в коже и мышцах, через 24 ч наблюдается частичная агрегация фотосенсибилизатора. Это позволяет предположить, что уменьшение интенсивности его флуоресценции через 24 и более часа связано не только с его элиминацией из организма, но и с агрегацией. Спектрально-флуоресцентное исследования показали, что КБХ селективно накапливается в инфицированных ранах, флуоресцентная контрастность лежит в пределах 3–4. Наиболее высокие значения концентрации и селективности его накопления в инфицированных ранах были достигнуты через 1,5–3 ч после внутривенного введения. Облучение через 2 ч после введения обеспечило высокую эффективность терапии инфицированных гнойных ран

Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case fora causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding