Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection

Background: Aiming to answer the broad question “When does mutation occur?” this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection. Methods: A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infected subjects were followed frequently up to 500 days post-seroconversion (p/s). Gag mutations were analyzed by employing single-genome amplification and direct sequencing. Gag mutations were determined in relation to the estimated time of seroconversion. Time of appearance, dominance, and completeness was compared for different types of in vivo Gag mutations. Results: Reverse mutations to the wild type appeared at a median (IQR) of 62 (44;139) days p/s, while escape mutations from the wild type appeared at 234 (169;326) days p/s (p<0.001). Within the subset of mutations that became dominant, reverse and escape mutations appeared at 54 (30;78) days p/s and 104 (47;198) days p/s, respectively (p<0.001). Among the mutations that reached completeness, reverse and escape mutations appeared at 54 (30;78) days p/s and 90 (44;196) days p/s, respectively (p = 0.006). Time of dominance for reverse mutations to and escape mutations from the wild type was 58 (44;105) days p/s and 219 (90;326) days p/s, respectively (p<0.001). Time of completeness for reverse and escape mutations was 152 (100;176) days p/s and 243 (101;370) days p/s, respectively (p = 0.001). Fitting a Cox proportional hazards model with frailties confirmed a significantly earlier time of appearance (hazard ratio (HR): 2.6; 95% CI: 2.3–3.0), dominance (4.8 (3.4–6.8)), and completeness (3.6 (2.3–5.5)) of reverse mutations to the wild type Gag than escape mutations from the wild type. Some complex mutational pathways in Gag included sequential series of reversions and escapes. Conclusions: The study identified the timing of different types of in vivo Gag mutations in primary HIV-1 subtype C infection in relation to the estimated time of seroconversion. Overall, the in vivo reverse mutations to the wild type occurred significantly earlier than escape mutations from the wild type. This shorter time to incidence of reverse mutations remained in the subsets of in vivo Gag mutations that reached dominance or completeness

Single-centre experience of allogeneic haemopoietic stem cell transplant in paediatric patients in Cape Town, South Africa

Background. Allogeneic haemopoietic stem cell transplant (Allo-HSCT) is a specialised and costly intervention, associated with significant morbidity and mortality. It is used to treat a broad range of paediatric conditions. South Africa (SA) is an upper middle-income country with limitations on healthcare spending. The role of paediatric Allo-HSCT in this setting is reviewed.Objectives. To review paediatric patients who underwent Allo-HSCT at the Groote Schuur Hospital/University of Cape Town Private Academic Hospital transplant unit in Cape Town, South Africa, and received post-transplant care at Red Cross War Memorial Children’s Hospital, over the period January 2006 - December 2014 in respect of indications for the transplant, donor sources, conditioning regimens, treatment-related morbidity and overall survival (OS).Methods. A retrospective analysis of patient records was performed and a database was created in Microsoft Access. Descriptive analyses of relevant demographic, clinical and laboratory data were performed. Summary statistics of demographic and clinical parameters were derived with Excel. OS was calculated from the date of transplant to the date of an event (death) or last follow-up using the Kaplan-Meier method in Statistica.Results. A total of 48 children received Allo-HSCT: 24 for haematological malignancies, 20 for non-oncological haematological conditions, 3 for immune disorders and 1 for adrenoleukodystrophy. There were 28 boys (median age 7.5 years) and 20 girls (8.5 years). There were 31 sibling matched peripheral-blood stem cell (PBSC) transplants and 1 maternal haploidentical PBSC transplant. Stem cells were mobilised from bone marrow into peripheral blood by administering granulocyte-colony stimulating factor to donors. PBSCs were harvested by apheresis. Eight patients received 10/10 HLA-matched grafts from unrelated donors. Six were PBSC grafts and 2 were bone marrow grafts. Three of the unrelated PBSC grafts were from SA donors. Eight transplants used umbilical cord blood from international registries. OS for patients with non-oncological disorders was 91.3% (median follow-up 3.9 years), while that for oncology patients was 56.8% (1.9 years). Two of the survivors developed chronic graft-versus-host disease.Conclusions. OS for non-oncological conditions was excellent, while outcomes for oncological disorders were on par with those in high-income settings. Transplantation offers many patients the opportunity for long-term survival and has been shown to be both feasible and rewarding in a less well-resourced environment servicing an economically diverse population

Emission spectra and intrinsic optical bistability in a two-level medium

Scattering of resonant radiation in a dense two-level medium is studied theoretically with account for local field effects and renormalization of the resonance frequency. Intrinsic optical bistability is viewed as switching between different spectral patterns of fluorescent light controlled by the incident field strength. Response spectra are calculated analytically for the entire hysteresis loop of atomic excitation. The equations to describe the non-linear interaction of an atomic ensemble with light are derived from the Bogolubov-Born-Green-Kirkwood-Yvon hierarchy for reduced single particle density matrices of atoms and quantized field modes and their correlation operators. The spectral power of scattered light with separated coherent and incoherent constituents is obtained straightforwardly within the hierarchy. The formula obtained for emission spectra can be used to distinguish between possible mechanisms suggested to produce intrinsic bistability.Comment: 18 pages, 5 figure

Цитокины как индукторы постперфузионной системной воспалительной реакции у кардиохирургических больных с различной продолжительностью коронарной патологии

Aim. The changes of blood cytokine profile in patients with ischemic heart disease (IHD) with different development rates and formation of systemic inflammatory response (SIR) after coronary artery bypass grafting by using cardiopulmonary bypass (CPB) are analyzed in this article.Materials and methods. The patients with slowly progressive of IHD (20 patients) and rapidly progressive of IHD (20 patients) were examined. The concentration of interleukine (IL) 1β, IL-1ra, IL-4, IL-6, IL-8 and tumor necrosis factor (TNF) α in blood plasma were evaluated by ELISA at patients with IHD before surgery and at 6 and 24 h after surgery.The results of the study showed that concentration of IL-1β, IL-6, IL-8, TNF-α and IL-1ra in blood plasma increases in patients with IHD of both groups before surgery. The concentration of IL-4 in the blood saved in the normal range before the operation in the case of slow disease progression, but maximum increase in content of proinflammatory (TNF-α, IL-6) and anti-inflammatory (IL-4, IL-1ra) cytokines in the blood and the IL-1ra/IL-1β ratio was detected in a rapidly developing of IHD. It was noticed that after coronary artery bypass grafting in patients with long history case of IHD the content of IL-1β, IL-8, TNF-α, IL-1ra, IL-4 increased with a normalization of the IL-6 concentration in the blood; in patients with a short period of IHD increase of IL-1 concentration and high content of IL-6 are combined with remaining unchanged level of IL1β, IL-8, IL-4 and negative dynamics of the TNF-α concentration in the blood. Thus, the operation in the СРВ in the case of IHD with prolonged course induces the formation of SIR, typical for acute inflammation, and coordinated anti-inflammatory response, and in the case of short period of coronary disease progress this operation causes SIR, characteristic for chronic inflammation, and uncoordinated anti-inflammatory response. Цель исследования – определить характер изменений цитокинового профиля крови при формировании системной воспалительной реакции (СВР) у больных ишемической болезнью сердца (ИБС) с разными темпами развития заболевания после коронарного шунтирования с применением искусственного кровообращения (ИК).Материал и методы. Обследованы больные с медленно прогрессирующей ИБС (20 человек) и быстро прогрессирующей ИБС (20 человек). У больных ИБС до операции и через 6 и 24 ч после оперативного вмешательства оценивали концентрацию цитокинов – интерлейкина (IL)-1β, IL-1ra, IL-4, IL-6, IL-8 и фактора некроза опухоли (TNF) α в плазме крови методом иммуноферментного анализа.Результаты исследования показали, что до операции у больных ИБС обеих групп отмечалось повышение плазменной концентрации IL-1β, IL-6, IL-8, TNF-α и IL-1ra. При этом в случае медленного прогрессирования заболевания концентрация IL-4 в крови сохранялась в пределах нормы, в то время как при быстро развивающейся ИБС обнаруживалось максимально выраженное увеличение содержания провоспалительных (TNF-α, IL-6) и противовоспалительных (IL-4, IL-1rа) цитокинов в крови и соотношения IL-1rа/IL-1β. После коронарного шунтирования у больных ИБС с длительным анамнезом заболевания отмечалось увеличение содержания IL-1β, IL-8, TNF-α, IL-1rа, IL-4 при нормализации концентрации IL-6 в крови; у пациентов с коротким периодом развития ИБС – рост концентрации IL-1rа, высокое содержание IL-6 при сохраняющемся без изменений уровне IL-1β, IL-8, IL-4 и отрицательной динамике концентрации TNF-α в плазме крови.Таким образом, при длительном течении ИБС выполнение операции в условиях ИК вызывает формирование СВР, свойственной острому воспалению, и координированный противовоспалительный ответ, а при коротком периоде коронарной болезни – СВР, характерную для хронического воспаления, и некоординированный противовоспалительный ответ.

Broadening of Plasmonic Resonance Due to Electron Collisions with Nanoparticle Boundary: а Quantum Mechanical Consideration

We present a quantum mechanical approach to calculate broadening of plasmonic resonances in metallic nanostructures due to collisions of electrons with the surface of the structure. The approach is applicable if the characteristic size of the structure is much larger than the de Broglie electron wavelength in the metal. The approach can be used in studies of plasmonic properties of both single nanoparticles and arrays of nanoparticles.Comment: 9 page

К вопросу о дифференциальной диагностике анемического синдрома у беременных

The review is dedicated to the diagnostics of hypochromic microcytic anemia among pregnant women with carbohydrate metabolism disorders by means of existing laboratory algorithm of examination. We give some data on the anemic syndrome in women with diabetes mellitus type 1. These data demonstrate an equal occurrence of anemia of chronic disorder and iron-deficiency anemia in this group of patients. Special attention is paid to the role of hepcidin in iron metabolism as well as to the mechanisms of regulation of hepcidin production under normal and pathological conditions. The review cites researches, which demonstrate the effectiveness of hepcidin measurement for differential diagnostics of anemic syndrome. We also touch upon the problem concerning treatment of anemia of chronic disorder.В обзоре раскрывается проблема дифференциальной диагностики микроцитарных гипохромных анемий у беременных с нарушением углеводного обмена при использовании существующего лабораторного алгоритма обследования. Приводятся данные о неоднородности структуры анемического синдрома у женщин с сахарным диабетом 1-го типа. Особое внимание уделяется описанию роли гепсидина в метаболизме железа и механизмов регуляции его продукции в норме и при патологии. Приводятся ссылки на результаты исследований, подтверждающих целесообразность включения гепсидина в алгоритмы дифференциальной диагностики различных видов анемического синдрома. Затрагивается вопрос терапии анемии хронических заболеваний