What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 2. Treatment and prevention.

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE). It provides a summary of key findings from 12 systematic reviews (SRs) that were published or indexed during 2014, and focuses on the treatment and prevention of AE. For an update of SRs on the epidemiology, mechanisms of disease and methodological issues, see Part 1 of this update. Although phototherapy and various systemic medications (including ciclosporin, azathioprine and methotrexate) are commonly used to treat AE, many of these have not been robustly assessed in head-to-head randomized controlled trials. Educational interventions may improve AE severity and quality of life for children and their families. Intake of probiotics prenatally and postnatally may help prevent AE, but there is little evidence to suggest a role in the treatment of AE. Although no benefit was found for allergen avoidance in preventing AE, the use of immunotherapy to treat AE-associated aeroallergen sensitivity requires further evaluation. There is insufficient evidence for Vitamin D supplementation for the treatment of AE This overview of reviews provides a succinct guide for clinicians and patients wishing to remain up to date with the most recent evidence for the treatment and prevention of AE.

What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 1. Epidemiology, risk factors and outcomes.

This review summarizes key findings from nine systematic reviews on atopic eczema (AE) published or first indexed in 2014. It focuses on epidemiology, disease processes and methodological issues. There is reasonable evidence to conclude that high birth weight (> 4000 g) is a risk factor for the development of AE. A lower socioeconomic position is associated with lower prevalence of AE. The effect of exposure to traffic-related air pollution in childhood on the development of AE is uncertain. CD14 polymorphisms do not appear to have an effect in AE. There may be a role for interleukin-18 in AE development. Patients with AE are at decreased risk of brain tumours, but at increased risk of developing attention deficit hyperactivity disorder. Evidence supports the view that normal-appearing skin in AE is in fact structurally abnormal. Lower success rates at inducing remission in AE are associated with increased risk of relapse during long-term follow-up. The Eczema Area Severity Index (EASI) has been agreed as the preferred core instrument to measure clinical signs in future research. There remains a lack of consensus on the definition of an AE flare.

Interaction of Mn with GaAs and InSb: incorporation, surface reconstruction and nano-cluster formation.

The deposition of Mn on to reconstructed InSb and GaAs surfaces, without coincident As or Sb flux, has been studied by reflection high energy electron diffraction, atomic force microscopy and scanning tunnelling microscopy. On both Ga- and As-terminated GaAs(0 0 1), (2 × n) Mn-induced reconstruction domains arise with n = 2 for the most well ordered reconstructions. On the Ga-terminated (4 × 6), the Mn-induced (2 × 2) persists up to around 0.5 ML Mn followed by Mn nano-cluster formation. For deposition on initially ß2(2 × 4)-reconstructed GaAs(0 0 1), the characteristic trench structure of the reconstruction is partially preserved even beyond 1 monolayer Mn coverage. On both the ß2(2 × 4) and c(4 × 4) surfaces, MnAs-like nano-clusters form alongside the reconstruction changes. In contrast, there are no new Mn-induced surface reconstructions on InSb. Instead, the Sb-terminated surfaces of InSb (0 0 1), (1 1 1)A and (1 1 1)B revert to reconstructions characteristic of clean In-rich surfaces after well defined coverages of Mn proportional to the Sb content of the starting reconstruction. These surfaces are decorated with self-assembled MnSb nanoclusters. These results are discussed in terms of basic thermodynamic quantities and the generalized electron counting rule.

New cathepsin d inhibitors with hydroxyethylamine isosteres: preparation and characterization.

The lysosomal aspartyl protease, cathepsin D, has been suggested to play a role in the metastatic potential of several types of cancer. Cathepsin D is secreted by malignant cells, and is believed to be involved in the breakdown of the extracellular matrix. High levels of active cathepsin D have been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. Also cathepsin D has recently been associated with the development of Alzheimer's disease. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. In the present study twenty-eight compounds containing (hydroxyethyl)amine isosteres with cyclic tertiary amines have been synthesized. These compounds show significant activity as cathepsin D inhibitors, many with IC(50) values in the nanomolar range. For example, the compounds that contain hydroxyethylamines where the amine is formed from N-piperazine-2-carboxylic acid methyl ester, 4y-bb, show IC(50) values ranging from 2.5 to 15 nM.

The MicroRNA pathway plays a regulatory role in stem cell division.

One of the key characteristics of stem cells is their capacity for self-renewal for long periods of time. In this respect, stem cells are similar to cancer cells, which also have the ability to escape cell cycle stop signals. Therefore, a critical question in stem cell and cancer biology is how cell division is regulated in these cell types. In this review, we summarize recent progress and describe future challenges to understanding the role the microRNA pathway plays in regulating mechanisms controlling stem cell division.

Stem cell division is regulated by the microRNA pathway.

One of the key characteristics of stem cells is their capacity to divide for long periods of time in an environment where most of the cells are quiescent. Therefore, a critical question in stem cell biology is how stem cells escape cell division stop signals. Here, we report the necessity of the microRNA (miRNA) pathway for proper control of germline stem cell (GSC) division in Drosophila melanogaster. Analysis of GSCs mutant for dicer-1 (dcr-1), the double-stranded RNaseIII essential for miRNA biogenesis, revealed a marked reduction in the rate of germline cyst production. These dcr-1 mutant GSCs exhibit normal identity but are defective in cell cycle control. On the basis of cell cycle markers and genetic interactions, we conclude that dcr-1 mutant GSCs are delayed in the G1 to S transition, which is dependent on the cyclin-dependent kinase inhibitor Dacapo, suggesting that miRNAs are required for stem cells to bypass the normal G1/S checkpoint. Hence, the miRNA pathway might be part of a mechanism that makes stem cells insensitive to environmental signals that normally stop the cell cycle at the G1/S transition.

Dipeptide seryl-histidine and related oligopeptides cleave DNA, protein, and a carboxyl ester.

The amino acids histidine (His) and serine (Ser), or amino acids similar to Ser, function together as key catalytic amino acids in the active sites of such diverse enzymes as the serine- and thiol-proteases, lipases, and esterases. Ser and His are also conserved in the intein-extein junctions of the phylogenetically widespread self-splicing proteins and at the N- and C-termini of the homing endonucleases spliced from them. Here we show that the dipeptide seryl-histidine (Ser-His) and related oligopeptides can themselves cleave DNA, protein, and the ester p-nitrophenyl acetate (p-NPA) over wide ranges of pH and temperature. Denaturing polyacrylamide gel electrophoresis (PAGE) of 5'-end labeled DNA samples incubated with Ser-His reveals a pattern of two bands per nucleotide position, consistent with the generation of both 3'-hydroxyl and 3'-phosphate DNA cleavage fragments, as would be expected of phosphodiester hydrolysis by Ser-His. To the best of our knowledge, Ser-His is the shortest peptide ever reported to show cleavage activity with multiple categories of natural substrates. The amenability of the dipeptide to variation through addition of amino acid residues, either internally or to the C-terminus while retaining its multiple cleavage activities, combined with its reactivity over wide ranges of pH and temperature, demonstrates the evolutionary capacity of the Ser/His dyad and evokes many questions about possible roles it may have played in molecular evolution and its potential role as a core for selection of oligopeptides with enhanced cleavage activities and target specificity.

Rapamycin and FK506 differentially inhibit mast cell cytokine production and cytokine-induced proliferation and act as reciprocal antagonists.

We have previously demonstrated that cyclosporine (CSA) and FK506 are able to selectively inhibit cytokine production by murine mast cell lines at concentrations comparable to those observed with thymus-derived lymphocytes (T cells). The selectivity of these effects were demonstrated by the failure of CSA and FK506 to inhibit cytokine-induced mast cell proliferation at equivalent or higher concentrations. In this report, we examined the ability of rapamycin (RAP) to inhibit cytokine production and cytokine-induced proliferation by a factor-dependent murine mast cell line and compared its activity to that of the structurally related macrolide FK506. The mast cell clone, MC/9, was stimulated to produce cytokines with phorbol myristate acetate plus the calcium ionophore A23187, or to proliferate in response to exogenous cytokines such as interleukin-3 and interleukin-4, produced by the helper T cell clone D10.G4. RAP did not inhibit cytokine production by MC/9, even at concentrations greater than 1000 nM. FK506 and CSA inhibited cytokine production with IC50 of 0.8 and 16.2 nM, respectively. In contrast to its lack of effect on cytokine production, RAP potently inhibited cytokine-induced proliferation of MC/9 cells with an IC50 of 1.9 nM. Because RAP and FK506 are structurally related and yet have divergent biological effects, we examined the ability of RAP to antagonize inhibitory effects of FK506 on mast cell cytokine production and the ability of FK506 to antagonize inhibitory effects of RAP on cytokine-induced mast cell proliferation. The addition of RAP in molar excess reversed inhibition of mast cell cytokine production mediated by FK506, but not that of CSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine and FK506 inhibition of murine mast cell cytokine production.

The ability of cyclosporine (CSA) and FK506 to inhibit cytokine production by factor-dependent murine mast cell lines was investigated. The mast cell clone, MC/9, and two mast cell lines, MCIII and MCVI, were stimulated to produce cytokines with phorbol myristate acetate plus the calcium ionophore A23187. The production of cytokines by stimulated mast cells cultured in the presence or absence of drug was monitored by bioassay of culture supernatants for induction of proliferation by factor-dependent cell lines and inhibition of these responses by neutralizing monoclonal antibodies. Both CSA and FK506 inhibited mast cell cytokine production at concentrations comparable to those observed with T cells. However, the degree of inhibition of cytokine production varied among the mast cell lines as well as between different cytokines produced by a given mast cell line. For example, CSA completely inhibited interleukin-2 (IL-2), IL-3, IL-4 and granulocyte-macrophage colony stimulating factor secretion by all three lines, with the exception that IL-2/IL-4 production by MCIII was partially resistant to inhibition by CSA. Similarly, FK506 completely inhibited cytokine production by MC/9, partially inhibited cytokine production by MCIII and had differential effects on IL-3/granulocyte-macrophage colony-stimulating factor and IL-2/IL-4 production by MCVI. Consistent with their ability to selectively inhibit cytokine gene transcription in T cells, neither CSA nor FK506 inhibited factor-dependent proliferation by these mast cell lines. In view of the putative role of cytokines in inflammation and late phase asthmatic reactions, these observations may be of particular significance in development of methods of pharmacologic intervention.

An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT.

A new tetrazolium salt XTT, sodium 3'-[1-[(phenylamino)-carbonyl]-3,4-tetrazolium]-bis(4-methoxy-6- nitro)benzene-sulfonic acid hydrate, was evaluated for use in a colorimetric assay for cell viability and proliferation by normal activated T cells and several cytokine dependent cell lines. Cleavage of XTT by dehydrogenase enzymes of metabolically active cells yields a highly colored formazan product which is water soluble. This feature obviates the need for formazan crystal solubilization prior to absorbance measurements, as required when using other tetrazolium salts such as MTT. Bioreduction of XTT by all the murine cells examined was not particularly efficient, but could be potentiated by addition of electron coupling agents such as phenazine methosulfate (PMS) or menadione (MEN). Optimal concentrations of PMS or MEN were determined for the metabolism of XTT by the T cell lines HT-2 and 11.6, NFS-60 a myeloid leukemia, MC/9 a mast cell line and mitogen activated splenic T cells. When used in combination with PMS, each of these cells generated higher formazan absorbance values with XTT than were observed with MTT. Thus the use of XTT in colorimetric proliferation assays offer significant advantages over MTT, resulting from reduced assay time and sample handling, while offering equivalent sensitivity.

Patterns of lymphokine production by primary antigen-specific/MHC restricted murine helper T cell clones.

In this study we examined a panel of CD4+ antigen specific/MHC restricted T cell clones for their ability to secrete IL-2, IL-4, and IFN-gamma upon stimulation with con A, three lymphokines which are diagnostic for the TH1 and TH2 subtypes of helper T cells. Eight of the twelve clones we analyzed did not fit the classical TH1/TH2 patterns of lymphokine secretion. Seven of these clones secreted both IL-2 and IL-4 and two of these also produced IFN-gamma. The remaining non-classical clone secreted IL-4 and IFN-gamma but not IL-2. Data from the subcloning of the IL-2/IL-4/IFN-gamma triple producers were not consistent with the parental lines being a mixture of TH1 and TH2 cells. The IL-2/IL-4 double producers (IFN-gamma negative) cannot be explained by the parental lines being a mixture of the TH1 and TH2 subtypes. Nevertheless, these double producers were subcloned and the results provided convincing evidence that clones which secrete both IL-2 and IL-4 do exist. Lymphokine loss variants involving IL-2, IL-4 or IFN-gamma were observed among subclones derived from the double and triple producers as well as in several parental lines maintained in continuous culture. We also observed the appearance of inducible IFN-gamma production in some subclones derived from parental clones where production of IFN-gamma was not detectable. The phenotypes of these variants failed to indicate an obvious trend toward the TH1 and TH2 subtypes. Thus, our results suggest that more heterogeneity in the population of CD4+ helper T cells exists than can be explained by the TH1 and TH2 subtypes of these cells.

Mupirocin: a topical antibiotic with a unique structure and mechanism of action.

The chemistry, mechanism of action, antimicrobial activity, pharmacokinetics, clinical efficacy, adverse effects, dosage, and administration of mupirocin are reviewed. Mupirocin, formerly termed pseudomonic acid A, is a topical antibiotic under investigation for the treatment of impetigo and other superficial primary and secondary skin infections. Mupirocin (Bactroban, Beecham Laboratories) is currently formulated as a 2% ointment in a water-miscible polyethylene glycol base. The drug is a unique antimicrobial agent because of its structure and mechanism of action. Mupirocin apparently exerts its antimicrobial activity by reversibly inhibiting isoleucyl-transfer RNA, thereby inhibiting bacterial protein and RNA synthesis. Mupirocin has excellent in vitro activity against staphylococci and most streptococci but less activity against other gram-positive and gram-negative bacteria. The drug will only be used topically because of its rapid and extensive systemic metabolism. Several controlled clinical trials documented that mupirocin was significantly better than the polyethylene glycol vehicle alone or ampicillin and as effective as cloxacillin, dicloxacillin, or erythromycin in producing clinical and bacteriological cures in patients with impetigo and wound infections caused by gram-positive pathogens. Limited studies suggest that mupirocin may also have a role in eradicating nasal carriage of staphylococci. Reported adverse effects are local and may be related to the polyethylene glycol vehicle base. Mupirocin should be useful for treating patients with impetigo and wound infections caused by Staphylococcus aureus. However, additional controlled, comparative clinical studies are needed to identify the role of mupirocin in treating other primary and secondary skin infections and for eliminating nasal carriage of staphylococci.

Beta adrenoceptor modulation of the generation of murine cytotoxic T lymphocytes in vitro.

The effects of stimulating beta adrenoceptors on lymphocytes during the generation of cell-mediated immunity were examined. In an in vitro system for the generation of murine cell-mediated cytotoxicity, addition of isoproterenol (10(-7) M), epinephrine (10(-6) M) or norepinephrine (10(-4) M) enhanced the number of lytic units generated compared to control cultures. This increase was blocked by dl-propranolol (5 X 10(-6) M). I-Propranolol (10(-11) to 10(-7) M) blocked the isoproterenol-induced increase in lytic units per culture, but d-propranolol (10(-11) to 10(-7) M) did not. Terbutaline (10(-5) M), a relatively selective beta-2 agonist, similarly augmented the generation of cell-mediated cytotoxicity, with the increase again blocked by propranolol. Butoxamine (5 X 10(-6) M), a beta-2 antagonist, but not atenolol (5 X 10(-6) M), a beta-1 antagonist, blocked the epinephrine-induced increase in cell-mediated cytotoxicity. Addition of phentolamine (5 X 10(-6) M) had no effect on the epinephrine-induced increase in lytic units per culture. However, in the presence of phentolamine, norepinephrine increased lytic units per culture to a greater degree than that seen with norepinephrine alone, suggesting a balance between positive beta effects and inhibitory alpha effects upon simultaneous alpha and beta stimulation. These data provide further evidence for an immunoenhancing role of beta receptor stimulation during the generation of immune responses.