Blood Substitutes in Cardiac Surgery

A safe, inexpensive, noninfectious substitute for red blood cells has long been sought. Despite tremendous advances in blood banking, the logistics of collecting, transporting, and storing human red blood cells contin ues to create infection and shortage problems. The two basic types of blood substitutes currently under devel opment are hemoglobin based and fluorocarbon based. Although they each transport oxygen differently, the basic advantages and limitations are the same. Blood substitute advantages include the unique capacity for room temperature storage, noninfectivity, adequate supply, and low toxicity. Restrictions include limited dosing in the acute period, limited intravascular half-life and, for the fluorocarbons, a requirement for a high PaO2. In addition, there remain questions about the relationship of nitric oxide metabolism to hypertension in hemoglobin solutions. Early clinical and laboratory trials have shown that both types of solutions are effective oxygen-delivery agents, with acceptable side- effect profiles. Clinical trials are currently underway to determine the safety and efficacy of these solutions in patients undergoing cardiopulmonary bypass.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68576/2/10.1177_108925329800200403.pd

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Socioeconomic differences in cancer survival: The Norwegian Women and Cancer Study

<p>Abstract</p> <p>Background</p> <p>Cancer survival has been observed to be poorer in low socioeconomic groups, but the knowledge about the underlying causal factors is limited. The purpose of this study was to examine how cancer survival varies by socioeconomic status (SES) among women in Norway, and to identify factors that explain this variation. SES was measured by years of education and gross household income, respectively.</p> <p>Methods</p> <p>We used data from The Norwegian Women and Cancer Study, a prospective cohort study including 91 814 women who responded to an extensive questionnaire between 1996 and 1998. A total of 3 899 incident cancer cases were diagnosed during follow-up, of whom 1 089 women died, 919 of them from cancer. Cox Proportional Hazards Model was used to calculate relative risks (RR) of mortality and 95% confidence intervals.</p> <p>Results</p> <p>We observed an overall negative socioeconomic gradient in cancer survival, which was most evident in the site specific analyses for survival of ovarian cancer by years of education. For colorectal cancer, mortality increased with years of education, but not with income. After adjustment for household size, marital status, disease stage, and smoking status the SES variation in cancer survival became non-significant. We found that the unequal socioeconomic distribution of smoking status prior to diagnosis contributed considerably to the poorer survival in low SES groups.</p> <p>Conclusion</p> <p>We found an overall negative socioeconomic gradient in cancer survival when SES is measured as years of education or gross household income. Smoking status prior to diagnosis was an important predictive factor for socioeconomic variation in survival.</p

Nef Alleles from All Major HIV-1 Clades Activate Src-Family Kinases and Enhance HIV-1 Replication in an Inhibitor-Sensitive Manner

The HIV-1 accessory factor Nef is essential for high-titer viral replication and AIDS progression. Nef function requires interaction with many host cell proteins, including specific members of the Src kinase family. Here we explored whether Src-family kinase activation is a conserved property of Nef alleles from a wide range of primary HIV-1 isolates and their sensitivity to selective pharmacological inhibitors. Representative Nef proteins from the major HIV-1 subtypes A1, A2, B, C, F1, F2, G, H, J and K strongly activated Hck and Lyn as well as c-Src to a lesser extent, demonstrating for the first time that Src-family kinase activation is a highly conserved property of primary M-group HIV-1 Nef isolates. Recently, we identified 4-amino substituted diphenylfuropyrimidines (DFPs) that selectively inhibit Nef-dependent activation of Src-family kinases as well as HIV replication. To determine whether DFP compounds exhibit broad-spectrum Nef-dependent antiretroviral activity against HIV-1, we first constructed chimeric forms of the HIV-1 strain NL4-3 expressing each of the primary Nef alleles. The infectivity and replication of these Nef chimeras was indistinguishable from that of wild-type virus in two distinct cell lines (U87MG astroglial cells and CEM-T4 lymphoblasts). Importantly, the 4-aminopropanol and 4-aminobutanol derivatives of DFP potently inhibited the replication of all chimeric forms of HIV-1 in both U87MG and CEM-T4 cells in a Nef-dependent manner. The antiretroviral effects of these compounds correlated with inhibition of Nef-dependent activation of endogenous Src-family kinases in the HIV-infected cells. Our results demonstrate that the activation of Hck, Lyn and c-Src by Nef is highly conserved among all major clades of HIV-1 and that selective targeting of this pathway uniformly inhibits HIV-1 replication

Impacts of climate change on plant diseases – opinions and trends

There has been a remarkable scientific output on the topic of how climate change is likely to affect plant diseases in the coming decades. This review addresses the need for review of this burgeoning literature by summarizing opinions of previous reviews and trends in recent studies on the impacts of climate change on plant health. Sudden Oak Death is used as an introductory case study: Californian forests could become even more susceptible to this emerging plant disease, if spring precipitations will be accompanied by warmer temperatures, although climate shifts may also affect the current synchronicity between host cambium activity and pathogen colonization rate. A summary of observed and predicted climate changes, as well as of direct effects of climate change on pathosystems, is provided. Prediction and management of climate change effects on plant health are complicated by indirect effects and the interactions with global change drivers. Uncertainty in models of plant disease development under climate change calls for a diversity of management strategies, from more participatory approaches to interdisciplinary science. Involvement of stakeholders and scientists from outside plant pathology shows the importance of trade-offs, for example in the land-sharing vs. sparing debate. Further research is needed on climate change and plant health in mountain, boreal, Mediterranean and tropical regions, with multiple climate change factors and scenarios (including our responses to it, e.g. the assisted migration of plants), in relation to endophytes, viruses and mycorrhiza, using long-term and large-scale datasets and considering various plant disease control methods

HIF-1 and SKN-1 Coordinate the Transcriptional Response to Hydrogen Sulfide in Caenorhabditis elegans

Hydrogen sulfide (H2S) has dramatic physiological effects on animals that are associated with improved survival. C. elegans grown in H2S are long-lived and thermotolerant. To identify mechanisms by which adaptation to H2S effects physiological functions, we have measured transcriptional responses to H2S exposure. Using microarray analysis we observe rapid changes in the abundance of specific mRNAs. The number and magnitude of transcriptional changes increased with the duration of H2S exposure. Functional annotation suggests that genes associated with protein homeostasis are upregulated upon prolonged exposure to H2S. Previous work has shown that the hypoxia-inducible transcription factor, HIF-1, is required for survival in H2S. In fact, we show that hif-1 is required for most, if not all, early transcriptional changes in H2S. Moreover, our data demonstrate that SKN-1, the C. elegans homologue of NRF2, also contributes to H2S-dependent changes in transcription. We show that these results are functionally important, as skn-1 is essential to survive exposure to H2S. Our results suggest a model in which HIF-1 and SKN-1 coordinate a broad transcriptional response to H2S that culminates in a global reorganization of protein homeostasis networks

Розрахунок та проектування окремого фундаменту будівлі на природній ґрунтовій основі. Методичні рекомендації до виконання практичних завдань та курсового проекту з дисципліни «Механіка ґрунтів, основи і фундаменти» сту- дентами напрямів підготовки 6.060101 Будівництво та 6.050301 Гірництво

Подано методичні рекомендації до виконання практичних завдань та кур- сового проекту з дисципліни «Механіка ґрунтів, основи і фундаменти» для сту- дентів напрямів підготовки 6.060101 Будівництво та 6.050301 Гірництво. Розглянуто порядок проектування фундаменту будівлі мілкого закладан- ня на природній ґрунтовій основі. Методичні рекомендації передбачають виконання курсового проекту «Розрахунок та проектування окремого фундаменту будівлі на природній ґрун- товій основі» як із викладачем, так і під час самостійної роботи. Можна використовувати також у підготовці курсового та дипломного про- ектування

HIV-1 Nef Protein Structures Associated with Brain Infection and Dementia Pathogenesis

The difference between regional rates of HIV-associated dementia (HAD) in patients infected with different subtypes of HIV suggests that genetic determinants exist within HIV that influence the ability of the virus to replicate in the central nervous system (in Uganda, Africa, subtype D HAD rate is 89%, while subtype A HAD rate is 24%). HIV-1 nef is a multifunctional protein with known toxic effects in the brain compartment. The goal of the current study was to identify if specific three-dimensional nef structures may be linked to patients who developed HAD. HIV-1 nef structures were computationally derived for consensus brain and non-brain sequences from a panel of patients infected with subtype B who died due to varied disease pathologies and consensus subtype A and subtype D sequences from Uganda. Site directed mutation analysis identified signatures in brain structures that appear to change binding potentials and could affect folding conformations of brain-associated structures. Despite the large sequence variation between HIV subtypes, structural alignments confirmed that viral structures derived from patients with HAD were more similar to subtype D structures than to structures derived from patient sequences without HAD. Furthermore, structures derived from brain sequences of patients with HAD were more similar to subtype D structures than they were to their own non-brain structures. The potential finding of a brain-specific nef structure indicates that HAD may result from genetic alterations that alter the folding or binding potential of the protein

Sequence- and Interactome-Based Prediction of Viral Protein Hotspots Targeting Host Proteins: A Case Study for HIV Nef

Virus proteins alter protein pathways of the host toward the synthesis of viral particles by breaking and making edges via binding to host proteins. In this study, we developed a computational approach to predict viral sequence hotspots for binding to host proteins based on sequences of viral and host proteins and literature-curated virus-host protein interactome data. We use a motif discovery algorithm repeatedly on collections of sequences of viral proteins and immediate binding partners of their host targets and choose only those motifs that are conserved on viral sequences and highly statistically enriched among binding partners of virus protein targeted host proteins. Our results match experimental data on binding sites of Nef to host proteins such as MAPK1, VAV1, LCK, HCK, HLA-A, CD4, FYN, and GNB2L1 with high statistical significance but is a poor predictor of Nef binding sites on highly flexible, hoop-like regions. Predicted hotspots recapture CD8 cell epitopes of HIV Nef highlighting their importance in modulating virus-host interactions. Host proteins potentially targeted or outcompeted by Nef appear crowding the T cell receptor, natural killer cell mediated cytotoxicity, and neurotrophin signaling pathways. Scanning of HIV Nef motifs on multiple alignments of hepatitis C protein NS5A produces results consistent with literature, indicating the potential value of the hotspot discovery in advancing our understanding of virus-host crosstalk

Polypharmacy among anabolic-androgenic steroid users: A descriptive metasynthesis

Background: As far as we are aware, no previous systematic review and synthesis of the qualitative/descriptive literature on polypharmacy in anabolic-androgenic steroid(s) (AAS) users has been published. Method: We systematically reviewed and synthesized qualitative/descriptive literature gathered from searches in electronic databases and by inspecting reference lists of relevant literature to investigate AAS users' polypharmacy. We adhered to the recommendations of the UK Economic and Social Research Council's qualitative research synthesis manual and the PRISMA guidelines. Results: A total of 50 studies published between 1985 and 2014 were included in the analysis. Studies originated from 10 countries although most originated from United States (n = 22), followed by Sweden (n = 7), England only (n = 5), and the United Kingdom (n = 4). It was evident that prior to their debut, AAS users often used other licit and illicit substances. The main ancillary/supplementary substances used were alcohol, and cannabis/cannabinoids followed by cocaine, growth hormone, and human chorionic gonadotropin (hCG), amphetamine/meth, clenbuterol, ephedra/ephedrine, insulin, and thyroxine. Other popular substance classes were analgesics/opioids, dietary/nutritional supplements, and diuretics. Our classification of the various substances used by AAS users resulted in 13 main groups. These non-AAS substances were used mainly to enhance the effects of AAS, combat the side effects of AAS, and for recreational or relaxation purposes, as well as sexual enhancement. Conclusions: Our findings corroborate previous suggestions of associations between AAS use and the use of other licit and illicit substances. Efforts must be intensified to combat the debilitating effects of AAS-associated polypharmacy