Classification of the effectiveness of combination treatments

According to FDA regulations, a combination drug is not efficacious unless each component contributes to the claimed effects. For a univariate endpoint, this implies that the combination at specific doses must be superior to each of its components at the same doses. More demanding is the property of synergy, in which the effect of the combination must be superior to the effect expected based on those of its components. If it is equal to those effects, it is additive, and if it is inferior, it is antagonistic. We give regions in the combination dose plane where these concepts are well defined. If the effect of the combination is greater than the greatest effect achievable by any of its components it is therapeutically synergistic. A combination can be antagonistic, yet its components can still contribute to the claimed effects. If it is additive, synergistic or therapeutically synergistic, its components must contribute to the claimed effects. We relate these concepts and provide designs and sequential procedures for determining whether a combination is therapeutically synergistic, synergistic, additive, antagonistic and contributing or antagonistic and non-contributing.     

Dieulafoy lesion as a cause of massive gastrointestinal bleeding

The Dieulafoy lesion, also referred to as exulceratio simplex, caliber-persistent artery anomaly, or cirsoid aneurysm, is a relatively rare, yet possibly fatal cause of gastrointestinal bleeding. Recent journal articles suggest that this pathological entity is not as uncommon as once thought. Advances in endoscopic technique and esophagogastroduodenoscopy (EGD) have greatly assisted in earlier diagnosis and added options to the treatment regimen for this lesion. The relationship of this anomaly to possible exsanguination makes it essential that both medical and surgical endoscopists be knowledgeable of the anatomy, diagnosis, and management of this pathology. Several therapeutic approaches to Dieulafoy's lesion are available and are described.     

HoxA is a transcriptional regulator for expression of the hup structural genes in free-living Bradyrhizobium japonicum

A chromosomally integrated Bradyrhizobium japonicum hoxA mutant is unable to oxidize hydrogen in free-living conditions. Derepressing conditions that induce hydrogenase activity in free-living, wild-type B. japonicum cells cannot induce expression of the hydrogenase structural genes in the hoxA mutant. The DNA-binding capacity of HoxA at the hup promoter region was studied by means of gel retardation. Both heterotrophically growing cells and cells induced to express hydrogenase activity contain a protein that specifically binds to the hup promoter region. Crude protein extracts isolated from a B. japonicum hoxA mutant do not contain this binding compound. The HoxA protein was overexpressed in E. coli and isolated in the form of a maltose-binding protein (MBP)-HoxA fusion. The MBP-HoxA hybrid protein specifically bound to a 50 bp region of the hupSL promoter known to be important for regulation of hupSL expression.     

Expression of recombinant antigens in Escherichia coli: application on immunochemical studies of Schistosoma mansoni tegumental antigens

Sm15 and Sm13 are recognized by antibodies from mice protectively vaccinated with tegumental membranes, suggesting a potential role in protective immunity. In order to raise antibodies for immunochemical investigations, the genes for these antigens were expressed in pGEX and pMal vectors so that comparisons could be made among different expression systems and different genes. The fusion proteins corresponding to several parts of the gene for the precursor of Sm15 failed in producing antibodies recognizing the parasite counterpart. On the other hand, antibodies raised against Sm13 MBP-fusion proteins recognized the 13 kDa tegumental protein. Thus the peculiarities of the gene of interest are important and the choice of the expression system must sometimes be decided on an empirical basis.     

Antiserum against Escherichia coli J5 contains antibodies reactive with outer membrane proteins of heterologous gram-negative bacteria

The binding of IgG in antiserum to Escherichia coli J5 to the surface of Enterobacteriaceae and to cell wall fragments released from serum-exposed bacteria was studied in a search for potentially protective epitopes other than lipopolysaccharide (LPS). IgG titers to multiple heterologous gram-negative smooth bacteria increased following incubation of the bacteria in serum and decreased following absorption with serum-exposed heterologous bacteria. IgG eluted from absorbing bacteria bound to at least three conserved bacterial outer membrane proteins (OMPs), but not LPS, as assessed by immunoblotting. The same OMPs were present in LPS-containing macromolecular cell wall fragments released by incubation of heterologous gram-negative bacteria in human serum. Part of the protection offered by J5 antiserum could be from binding of IgG to conserved OMPs at the bacterial surface or to OMPs in cell-wall fragments released from dying bacteria.     

Inhibiting and deactivating effects of water on the selective catalytic reduction of nitric oxide with ammonia over MnOx/Al2O3

The effect of water on the selective catalytic reduction (SCR) of nitric oxide with ammonia over alumina supported with 2–15 wt.-% manganese oxide was investigated in the temperature range 385–600 K, with the emphasis on the low side of this temperature window. Studies on the effect of 1–5 vol.-% water vapour on the SCR reaction rate and selectivity were combined with TPD experiments to reveal the influence of water on the adsorption of the single SCR reactants. It turned out that the activity decrease due to water addition can be divided into a reversible inhibition and an irreversible deactivation. Inhibition is caused by molecular adsorption of water. TPD studies showed that water can adsorb competitively with both ammonia and nitric oxide. Additional kinetic experiments revealed that adsorbed ammonia is present in excess on the catalyst surface, even in the presence of water. Reduced nitric oxide adsorption is responsible for the observed reversible decrease in the reaction rate; the fractional reaction order changes from 0.79 in the absence of water to 1.07 in its presence. Deactivation is probably due to the dissociative adsorption of water, resulting in the formation of additional surface hydroxyls. As the amount of surface hydroxyls formed is limited to a saturation level, the deactivating effect on the catalyst is limited too. The additional hydroxyls condense and desorb in the temperature range 525–775 K, resulting in a lower degree of deactivation at higher temperature. A high temperature treatment at 775 K results in a complete regeneration. The amount of surface hydroxyls formed per unit surface area decreases at increasing MnO_x-loading. The selectivity to the production of nitrogen is enhanced significantly by the presence of gas phase water.     

Using indices to differentiate dimensions of knowledge regarding modes of HIV transmission in the U.S. population, 1987-1989

Spores of Bacillus subtilis NCTC 8236 were treated with glutaraldehyde, Lugol's iodine, polyvinylpyrrolidone-iodine (PVP-I), sodium hypochlorite or sodium dichloroisocyanurate (NaDCC). After exposure survivors were enumerated on nutrient agar containing potential revival agents (subtilisin, lysozyme, calcium dipicolinate, calcium lactate). Of these, only calcium lactate had any significant enhancing effect and then only with iodine-treated spores. Calcium lactate (9 mmol l-1) in nutrient broth enhanced the rate and extent of germination of iodine-treated spores but not of spores previously subjected to glutaraldehyde, hypochlorite or NaDCC.     

High-resolution HLA typing for the DQB1 gene by sequence-based typing

BACKGROUND: Monocytic tissue factor (TF), initiating the extrinsic blood coagulation pathway, is often upregulated under septic or inflammatory conditions. The complex activating mechanism remains largely unclear and no effective strategy has been firmly established. In this study, we used a model monocytic cell line (human leukemic THP-1 promonocytes) to address (1) the nature of TF activation in response to bacterial endotoxin and (2) the application of anti-inflammatory cytokines in relieving monocytic hypercoagulation. RESULTS: TF in THP-1 cells was substantially activated by exposure to bacterial endotoxin (LPS; 5 micrograms/ml) for 6 h. Human recombinant IL-4 (500 ng/ml) and IL-10 (500 ng/ml) inhibited TF activation induced by LPS. To determine if these cytokines depressed LPS recognition resulting in such inhibition, we employed an anti-CD14 mAb (UCHM-1; Sigma Chemical) to address the role of CD14 in LPS transmembrane signaling. LPS-induced TF activation was depressed by 35% upon inclusion of the anti-CD14 mAb (1:10 dilution). This antibody alone mimicked TF activation which accounted for 35% of the LPS-induced TF activation, suggesting the activating role of CD14 ligation. In addition, the anti-CD14 mAb elicited the production of nitric oxide (NO) which was found to be independent of TF activation. NO production could serve as an independent index for monitoring LPS recognition. IL-4 depressed the anti-CD14 mAb-induced TF activation as well as NO elicitation, indicating the blockade of CD14 ligation. In contrast, IL-10 showed differential inhibitory activities. TF activation induced by either LPS or anti-CD14 mAb was inhibited by IL-10 which did not show any inhibition on NO elicitation under these conditions. In a separate approach, neither IL-4 nor IL-10 inhibited phorbol ester-induced NO elicitation. More direct evidence came from an epifluorescent demonstration showing that IL-4 blocked binding of FITC-conjugated LPS and anti-CD14 mAb to THP-1 cells. CONCLUSIONS: Taken together, the results suggest that LPS action in relation to TF activation consists of CD14-independent and -dependent signaling including CD14 ligation. We also showed that anti-inflammatory cytokines (IL-4 and -10) significantly depressed TF activation. IL-4 antagonized CD14-dependent LPS recognition leading to the depression in TF activation.     

Subspace-based signal analysis using singular value decomposition

A unified approach is presented to the related problems of recovering signal parameters from noisy observations and identifying linear system model parameters from observed input/output signals, both using singular value decomposition (SVD) techniques. Both known and new SVD-based identification methods are classified in a subspace-oriented scheme. The SVD of a matrix constructed from the observed signal data provides the key step in a robust discrimination between desired signals and disturbing signals in terms of signal and noise subspaces. The methods that are presented are distinguished by the way in which the subspaces are determined and how the signal or system model parameters are extracted from these subspaces. Typical examples, such as the direction-of-arrival problem and system identification from input/output measurements, are elaborated upon, and some extensions to time-varying systems are given     

Nanocell logic gates for molecular computing

Molecular electronics seeks to build electrical devices to implement computation - logic and memory - using individual or small collections of molecules. These devices have the potential to reduce device size and fabrication costs, by several orders of magnitude, relative to conventional CMOS. However, the construction of a practical molecular computer will require the molecular switches and their related interconnect technologies to behave as large-scale diverse logic, with input/output wires scaled to molecular dimensions. It is unclear whether it is necessary or even. possible to control the precise regular placement and interconnection of these diminutive molecular systems. This paper describes genetic algorithm-based simulations of molecular device structures in a nanocell where placement and connectivity of the internal molecular switches are not specifically directed and the internal topology is generally disordered. With some simplifying assumptions, these results show that it is possible to use easily fabricated nanocells as logic devices by setting the internal molecular switch states after the topological molecular assembly is complete. Simulated logic devices include an inverter, a NAND gate, an XOR gate and a 1-bit adder. Issues of defect and fault tolerance are addressed.