Computational Opioid Prescribing: A Novel Application of Clinical Pharmacokinetics

We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist pre-scribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety

Evaluation of Brain Iron Content Based on Magnetic Resonance Imaging (MRI): Comparison among Phase Value, R2* and Magnitude Signal Intensity

Background and Purpose: Several magnetic resonance imaging (MRI) techniques are being exploited to measure brain iron levels increasingly as iron deposition has been implicated in some neurodegenerative diseases. However, there remains no unified evaluation of these methods as postmortem measurement isn’t commonly available as the reference standard. The purpose of this study was to make a comparison among these methods and try to find a new index of brain iron. Methods: We measured both phase values and R2 * in twenty-four adults, and performed correlation analysis among the two methods and the previously published iron concentrations. We also proposed a new method using magnitude signal intensity and compared it with R2 * and brain iron. Results: We found phase value correlated with R2 * in substantia nigra (r = 20.723, p,0.001) and putamen (r = 20.514, p = 0.010), while no correlations in red nucleus (r = 20.236, p = 0.268) and globus pallidus (r = 20.111, p = 0.605). And the new magnitude method had significant correlations in red nucleus (r = 20.593, p = 0.002), substantia nigra (r = 20.521, p = 0.009), globus pallidus (r = 20.750, p,0.001) and putamen (r = 20.547, p = 0.006) with R2*. A strong inverse correlation was also found between the new magnitude method and previously published iron concentrations in seven brain regions (r = 20.982, P,0.001). Conclusions: Our study indicates that phase value may not be used for assessing the iron content in some brain region

Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism

KIT is a tyrosine kinase receptor expressed by several tumours, which has for specific ligand the stem cell factor (SCF). KIT is the main oncogene in gastrointestinal stromal tumours (GISTs), and gain-of-function KIT mutations are present in 70% of these tumours. The aim of the study was to measure and investigate the mechanisms of KIT activation in 80 KIT-positive GIST patients. KIT activation was quantified by detecting phosphotyrosine residues in Western blotting. SCF production was determined by reverse transcriptase–PCR, ELISA and/or immunohistochemistry. Primary cultures established from three GISTs were also analysed. The results show that KIT activation was detected in all cases, even in absence of KIT mutations. The fraction of activated KIT was not correlated with the mutational status of GISTs. Membrane and soluble isoforms of SCF mRNA were present in all GISTs analysed. Additionally, SCF was also detected in up to 93% of GISTs, and seen to be present within GIST cells. Likewise, the two SCF mRNA isoforms were found to be expressed in GIST-derived primary cultures. Thus, KIT activation in GISTs may in part result from the presence of SCF within the tumours

Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway

The gene and protein expression profiles in myeloproliferative neoplasms (MPNs) may reveal gene and protein markers of a potential clinical relevance in diagnosis, treatment and prediction of response to therapy. Using cDNA microarray analysis of 25,100 unique genes, we studied the gene expression profile of CD34(+) cells and granulocytes obtained from peripheral blood of subjects with essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). The microarray analyses of the CD34(+) cells and granulocytes were performed from 20 de novo MPN subjects: JAK2 positive ET, PV, PMF subjects, and JAK2 negative ET/PMF subjects. The granulocytes for proteomic studies were pooled in 4 groups: PV with JAK2 mutant allele burden above 80%, ET with JAK2 mutation, PMF with JAK2 mutation and ET/PMF with no JAK2 mutation. The number of differentially regulated genes was about two fold larger in CD34(+) cells compared to granulocytes. Thirty-six genes (including RUNX1, TNFRSF19) were persistently highly expressed, while 42 genes (including FOXD4, PDE4A) were underexpressed both in CD34(+) cells and granulocytes. Using proteomic studies, significant up-regulation was observed for MAPK and PI3K/AKT signaling regulators that control myeloid cell apoptosis and proliferation: RAC2, MNDA, S100A8/9, CORO1A, and GNAI2. When the status of the mTOR signaling pathway related genes was analyzed, PI3K/AKT regulators were preferentially up-regulated in CD34(+) cells of MPNs, with down-regulated major components of the protein complex EIF4F. Molecular profiling of CD34(+) cells and granulocytes of MPN determined gene expression patterns beyond their recognized function in disease pathogenesis that included dominant up-regulation of PI3K/AKT signaling

Диагностика и лечение заворота сигмовидной кишки как формы толстокишечной непроходимости

Relevance. Intestinal obstruction can occur in all age groups, but most often it occurs at the age of 40–70 years and one of the causes of colonic obstruction may be volvulus of the sigmoid or cecum. Volvulus of the sigmoid colon is most common and reaches 15% of all types of strangulation intestinal obstruction. The mortality rate in sigmoid colon volvulus reaches 14–16%. In cases of necrosis of the sigmoid colon, the mortality can reach 70–78%.Aim of study. To evaluate the results of diagnosis and treatment of patients with sigmoid volvulus.Material and methods. In 2015–2020 at the N.V. Sklifosovsky Research Institute for Emergency Medicine we treated 28 patients with volvulus of the sigmoid colon. Of these, there were 13 women (46.4%) and 15 men (53.6%). The average age of the patients was 69 years. Upon admission to the hospital, patients underwent a clinical examination, basic laboratory and instrumental methods of examination. If volvulus of the sigmoid colon was suspected, colonoscopy, irrigoscopy, computed tomography of the abdominal organs with contrast enhancement, and diagnostic laparoscopy were additionally performed. In the department, patients underwent fluid maintenance, antispasmodic and symptomatic therapy, cleansing enemas. According to the indications, an operative benefit was provided by open and laparoscopic accesses.Results. The sensitivity of the x-ray method was 88%, but the sensitivity of the plain x-ray examination, supplemented with a barium enema (irrigoscopy), was 100%. The sensitivity of the ultrasound method was 57%, however, when supplemented with a Doppler study, the sensitivity increases to 72%. The sensitivity of CT was 100%. The sensitivity of colonoscopy among those studied is 96%. Operations performed in patients with volvulus of the sigmoid colon: endoscopic detorsion in 15 patients (64.3%), video-laparoscopic elimination of volvulus of the sigmoid colon in 3 (10.7%) patients. Midline laparotomy in 17 patients (60.7%). Among patients after endoscopic bowel detorsion, no complications were observed in the early period. After laparotomy and elimination of volvulus of the sigmoid colon, postoperative complications were observed in 3 (17.7%) patients. There were 3 deaths (10.7%).Conclusion. High mortality does not allow us to call the results of treatment satisfactory, and a small number of observations does not allow us to obtain statistically significant results, which requires further case recruitment and data analysis.Актуальность. Кишечная непроходимость может возникать во всех возрастных группах, но наиболее часто она встречается в возрасте 40–70 лет и одной из причин толстокишечной непроходимости может явиться заворот сигмовидной (ЗСК) или слепой кишки. ЗСК является наиболее распространенной формой и достигает 15% от всех видов странгуляционной кишечной непроходимости. Летальность при ЗСК достигает 14–16%. В случаях некроза сигмовидной кишки летальность может достигать 70–78%.Цель. Оценка результатов диагностики и лечения пациентов с ЗСК.Материал и методы. За период 2015–2020 годов в ГБУЗ «НИИ скорой помощи им. Н.В. Склифосовского» пролечены 28 пациентов с ЗСК. Из них было 13 женщин (46,4%) и 15 мужчин (53,6%). Средний возраст пациентов составил 69 лет. При поступлении в стационар пациентам выполняли клинический осмотр, базовые лабораторные и инструментальные методы обследования. При подозрении на ЗСК дополнительно выполняли колоноскопию, ирригоскопию, компьютерную томографию (КТ) органов брюшной полости с контрастным усилением, диагностическую лапароскопию. В отделении пациентам проводили инфузионно-спазмолитическую, симптоматическую терапия, постановку очистительных клизм. По показаниям оказывалось оперативное пособие открытым и лапароскопическим доступами.Результаты. Чувствительность рентгенологического метода составила 88%, однако чувствительность обзорного рентгенологического исследования, дополненная бариевой клизмой (ирригоскопией), составила 100%. Чувствительность ультразвукового метода составила 57%, однако при дополнении к исследованию допплерографии чувствительность повышается до 72%. Чувствительность КТ составила 100%. Чувствительность колоноскопии среди исследуемых — 96%. Выполненные операции у пациентов с ЗСК: эндоскопическая деторсия у 15 пациентов (64,3%), видеолапароскопическое устранение ЗСК — у 3 больных (10,7%). Срединная лапаротомия у 17 пациентов (60,7%). Среди больных после эндоскопической деторсии кишки осложнений в раннем периоде не наблюдалось. После лапаротомии и устранения ЗСК послеоперационные осложнения наблюдались у 3 больных (17,7%). Было 3 смертельных исхода (10,7%).Выводы. Высокая летальность не позволяет назвать результаты лечения удовлетворительными, а небольшое число наблюдений не позволяет получить статистически значимые результаты, что требует дальнейшего набора случаев и анализа данных

Clinical correlates of grey matter pathology in multiple sclerosis

Traditionally, multiple sclerosis has been viewed as a disease predominantly affecting white matter. However, this view has lately been subject to numerous changes, as new evidence of anatomical and histological changes as well as of molecular targets within the grey matter has arisen. This advance was driven mainly by novel imaging techniques, however, these have not yet been implemented in routine clinical practice. The changes in the grey matter are related to physical and cognitive disability seen in individuals with multiple sclerosis. Furthermore, damage to several grey matter structures can be associated with impairment of specific functions. Therefore, we conclude that grey matter damage - global and regional - has the potential to become a marker of disease activity, complementary to the currently used magnetic resonance markers (global brain atrophy and T2 hyperintense lesions). Furthermore, it may improve the prediction of the future disease course and response to therapy in individual patients and may also become a reliable additional surrogate marker of treatment effect

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

ПЕРВЫЙ ОПЫТ УСПЕШНОЙ ТРАНСПЛАНТАЦИИ ТОНКОЙ КИШКИ В ИНСТИТУТЕ СКОРОЙ ПОМОЩИ ИМ. Н.В. СКЛИФОСОВСКОГО

ABSTRACT. The paper describes the first experience of successful small bowel transplantation in the Sklifosovsky Research Institute for Emergency Medicine. It contains a brief review of literature on essential aspects of small bowel transplantation, presents the donor’s case history, specific features of anesthesia, surgical procedure, and postoperative course, including the immunosuppression scheme, diagnosis and treatment of evolved complications. The paper provides in-detail results of morphological control over rejection development, presents the data of ultrasonographic observation of the changes in the transplanted intestine in the course of its adaptation to new requirements, covers the tactics of parenteral and enteral nutrition.РЕЗЮМЕ. Статья посвящена описанию первого опыта успешной трансплантации тонкой кишки (ТТК) в Институте скорой помощи им. Н.В. Склифосовского. Содержит краткий обзор литературы по основным проблемам ТТК, описание истории болезни донора, особенностей проведения наркоза, операции и течения послеоперационного периода, включая тактику иммуносупрессии, диагностики и лечения развившихся осложнений. Подробно описаны результаты морфологического контроля за развитием реакции отторжения, приведены данные УЗ-наблюдения за изменениями трансплантированной кишки по ходу ее адаптации к новым условиям, тактика парентерального и энтерального питания.