Initial Semantics for Strengthened Signatures

We give a new general definition of arity, yielding the companion notions of signature and associated syntax. This setting is modular in the sense requested by Ghani and Uustalu: merging two extensions of syntax corresponds to building an amalgamated sum. These signatures are too general in the sense that we are not able to prove the existence of an associated syntax in this general context. So we have to select arities and signatures for which there exists the desired initial monad. For this, we follow a track opened by Matthes and Uustalu: we introduce a notion of strengthened arity and prove that the corresponding signatures have initial semantics (i.e. associated syntax). Our strengthened arities admit colimits, which allows the treatment of the \lambda-calculus with explicit substitution.Comment: In Proceedings FICS 2012, arXiv:1202.317

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Parental stress before, during, and after pediatric stem cell transplantation: a review article

Goals of work: Pediatric stem cell transplantation (SCT) is a stressful treatment for children with relapsed or high-risk malignancies, immune deficiencies and certain blood diseases. Parents of children undergoing SCT can experience ongoing stress related to the SCT period. The aim of this article was to present a literature review of articles on parental distress and adaptation before, during, and after SCT and to identify risk and protective factors. Materials and methods: The review was conducted systematically by using PubMed, Web of Science, PsychInfo, and Picarta databases. Eighteen articles met our inclusion criteria: publishing date between January 1, 1990 and January 1, 2009; studies concerning parents of children undergoing SCT; studies examining the psychological adjustment and/or stress reactions of parents as primary outcomes and studies available in English. Main results: Highest levels of parental stress are reported in the period preceding SCT and during the acute phase. Stress levels decrease steadily after discharge in most parents. However, in a subgroup of parents, stress levels still remain elevated post-SCT. Parents most at risk in the longer term display highest levels of stress during the acute phase of the SCT. Conclusions: Psychosocial assessment before SCT, during the acute phase and in the longer term, is necessary to identify parents in need for support and follow-up care

Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents

GermlineGATA2 mutations cause cellular deficiencieswith high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOGMDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72%of adolescents withmonosomy 7).Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced diseasemust guide decision-making toward timely HSCT

Treatment of Community-Acquired Pneumonia in Immunocompromised Adults:A Consensus Statement Regarding Initial Strategies

Background Community-acquired pneumonia (CAP) guidelines have improved the treatment and outcomes of patients with CAP, primarily by standardization of initial empirical therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no consensus regarding the initial treatment of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the treatment of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiologic workup, general principles of empirical therapy, and empirical therapy for specific pathogens. Interpretation This document offers general suggestions for the initial treatment of the immunocompromised patient who arrives at the hospital with pneumonia

Rapid and mobile determination of alcoholic strength in wine, beer and spirits using a flow-through infrared sensor

<p>Abstract</p> <p>Background</p> <p>Ever since Gay-Lussac's time, the alcoholic strength by volume (% vol) has been determined by using densimetric measurements. The typical reference procedure involves distillation followed by pycnometry, which is comparably labour-intensive and therefore expensive. At present, infrared (IR) spectroscopy in combination with multivariate regression is widely applied as a screening procedure, which allows one to determine alcoholic strength in less than 2 min without any sample preparation. The disadvantage is the relatively large investment for Fourier transform (FT) IR or near-IR instruments, and the need for matrix-dependent calibration. In this study, we apply a much simpler device consisting of a patented multiple-beam infrared sensor in combination with a flow-through cell for automated alcohol analysis, which is available in a portable version that allows for on-site measurements.</p> <p>Results</p> <p>During method validation, the precision of the infrared sensor was found to be equal to or better than densimetric or FTIR methods. For example, the average repeatability, as determined in 6 different wine samples, was 0.05% vol and the relative standard deviation was below 0.2%. Accuracy was ensured by analyzing 260 different alcoholic beverages in comparison to densimetric or FTIR results. The correlation was linear over the entire range from alcohol-free beers up to high-proof spirits, and the results were in substantial agreement (R = 0.99981, p < 0.0001, RMSE = 0.279% vol). The applicability of the device was further proven for the analysis of wines during fermentation, and for the determination of unrecorded alcohol (i.e. non-commercial or illicit products).</p> <p>Conclusions</p> <p>The flow-through infrared device is much easier to handle than typical reference procedures, while time-consuming sample preparation steps such as distillation are not necessary. Therefore, the alcoholic strength can be economically and quickly controlled (requiring less than 60 s per sample). The device also gives the opportunity for mobile on-site control in the context of labelling control of wine, beer and spirits, the process monitoring of fermentations, or the evaluation of unrecorded alcohols.</p

Interaction of β-Sheet Folds with a Gold Surface

The adsorption of proteins on inorganic surfaces is of fundamental biological importance. Further, biomedical and nanotechnological applications increasingly use interfaces between inorganic material and polypeptides. Yet, the underlying adsorption mechanism of polypeptides on surfaces is not well understood and experimentally difficult to analyze. Therefore, we investigate here the interactions of polypeptides with a gold(111) surface using computational molecular dynamics (MD) simulations with a polarizable gold model in explicit water. Our focus in this paper is the investigation of the interaction of polypeptides with β-sheet folds. First, we concentrate on a β-sheet forming model peptide. Second, we investigate the interactions of two domains with high β-sheet content of the biologically important extracellular matrix protein fibronectin (FN). We find that adsorption occurs in a stepwise mechanism both for the model peptide and the protein. The positively charged amino acid Arg facilitates the initial contact formation between protein and gold surface. Our results suggest that an effective gold-binding surface patch is overall uncharged, but contains Arg for contact initiation. The polypeptides do not unfold on the gold surface within the simulation time. However, for the two FN domains, the relative domain-domain orientation changes. The observation of a very fast and strong adsorption indicates that in a biological matrix, no bare gold surfaces will be present. Hence, the bioactivity of gold surfaces (like bare gold nanoparticles) will critically depend on the history of particle administration and the proteins present during initial contact between gold and biological material. Further, gold particles may act as seeds for protein aggregation. Structural re-organization and protein aggregation are potentially of immunological importance

Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: Indications and management recommendations from an international expert panel

Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management. \ua9 2014 by the Ferrata Storti Foundation

Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex

The 5′-cap structure is a distinct feature of eukaryotic mRNAs, and eukaryotic viruses generally modify the 5′-end of viral RNAs to mimic cellular mRNA structure, which is important for RNA stability, protein translation and viral immune escape. SARS coronavirus (SARS-CoV) encodes two S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTase) which sequentially methylate the RNA cap at guanosine-N7 and ribose 2′-O positions, catalyzed by nsp14 N7-MTase and nsp16 2′-O-MTase, respectively. A unique feature for SARS-CoV is that nsp16 requires non-structural protein nsp10 as a stimulatory factor to execute its MTase activity. Here we report the biochemical characterization of SARS-CoV 2′-O-MTase and the crystal structure of nsp16/nsp10 complex bound with methyl donor SAM. We found that SARS-CoV nsp16 MTase methylated m7GpppA-RNA but not m7GpppG-RNA, which is in contrast with nsp14 MTase that functions in a sequence-independent manner. We demonstrated that nsp10 is required for nsp16 to bind both m7GpppA-RNA substrate and SAM cofactor. Structural analysis revealed that nsp16 possesses the canonical scaffold of MTase and associates with nsp10 at 1∶1 ratio. The structure of the nsp16/nsp10 interaction interface shows that nsp10 may stabilize the SAM-binding pocket and extend the substrate RNA-binding groove of nsp16, consistent with the findings in biochemical assays. These results suggest that nsp16/nsp10 interface may represent a better drug target than the viral MTase active site for developing highly specific anti-coronavirus drugs