The statistics of string/M theory vacua

We discuss systematic approaches to the classification of string/M theory vacua, and physical questions this might help us resolve. To this end, we initiate the study of ensembles of effective Lagrangians, which can be used to precisely study the predictive power of string theory, and in simple examples can lead to universality results. Using these ideas, we outline an approach to estimating the number of vacua of string/M theory which can realize the Standard Model.Comment: harvmac, 72pp (v4: fixed error in discussion of quiver ensembles

The relationships between exposure dose and response in induction and elicitation of contact hypersensitivity in humans

Like all physiological systems, the human immune system exhibits dose-response relationships in its reactions. The strength of sensitization is related to the potency of the immunogen and the dose that reaches the immune system. In skin, as sensitizing dose per unit area (mug cm(-2)) is increased on a log scale, there is a sigmoid dose-response curve for subsequent reactivity. Similarly, the response to elicitation shows a classical sigmoid response to increasing challenge dose, with the dose per unit area again being the determinant. There is a clear inverse correlation between the strength of sensitization and the subsequent dose of antigen to which an individual will respond. This is reflected in the different challenge systems used to diagnose the existence of allergic contact sensitization to a given allergen. The occluded patch test aims to use the highest concentration possible to detect the weakest degrees of allergy, whereas the repeated open application test uses much lower concentrations similar to those encountered in real life, applied repeatedly but without occlusion, to assess clinical relevance. Many authors have attempted to use the lowest concentrations to which rare, highly sensitized individuals can react to define the concentrations which might be free of risk in terms of inducing allergic sensitization. However, it is clear that the dose-response relationships for induction of sensitivity by repeated low-dose exposures must be carefully defined in future studies. This article reviews the dose-response relationships of human contact sensitization

Contact sensitisation and allergic contact dermatitis: Immunobiological mechanisms

The dose–response relationships of the human immune system can be defined using the induction and elicitation of lymphocyte mediated allergic reactions to experimental contact sensitisers such as dinitrochlorobenzene (DNCB). Five groups of healthy volunteers received a sensitising dose of DNCB applied to a 3 cm diameter circle on the volar forearm. Doses applied were 62.5 µg, 125 µg, 250 µg, 500 µg and 1000 µg. Four weeks later a concentration series of 3.125 µg, 6.25 µg, 12.5 µg and 25 µg was applied to the upper inner arm on 1 cm paper discs which were removed after 6 h. Forty-eight hours later the responses were scored clinically and thickness measured with callipers. The proportion of people reacting to the challenge doses showed a sigmoid log-dose–response curve, 100% reacting to 500 µg. The responses to challenge also showed a log-dose–response. As sensitising dose increased so more people were sensitised to a proportionately greater degree. These dose–response relationships reflect the effects of increasing the concentration of sensitiser on a fixed area. The effect was examined of keeping the concentration per sq cm constant but of varying the total area. When 35.4 µg/cm2, which sensitised 80% of people when applied to a circle 3 cm diameter (area 7.1 cm2), was applied on a 1.5 cm diameter circle or 4.5 cm diameter, there were no differences in the proportions sensitised or their degree of reactivity. This was clearly on the plateau for the sensitising effect. However, when the same concentration per cm2 was applied on a 3 mm diameter area much weaker sensitisation was obtained. This shows the concentration of sensitiser per unit area is the critical determinant of whether sensitisation occurs, whereas the total dose may be varied over a wide range, but if the concentration per unit area is constant there is no effect on sensitising potency. In other words few Langerhans cells presenting many antigen molecules per cell is a much more potent sensitising stimulus than the same number of molecules presented by many Langerhans cells, each presenting few molecules. These observations clearly have important implications across the whole field of risk assessment for induction of contact sensitivity

Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea

The 'old favourites' used for treatment of inflammatory diseases, and hence, the original immunomodulators, include the glucocorticoids, azathioprine, methotrexate and hydroxyurea. Glucocorticoids are still one of the most effective anti-inflammatory agents because they work on several different intracellular processes and hence, block many components that contribute to inflammatory and immune responses. They bind to intracellular glucocorticoid receptors which transport them into the nucleus. Here the receptor/steroid complex may bind to many genes that interact with transcription factors including NF?B and AP-1, to inhibit their activation, thereby preventing activation of many genes encoding immune effector and pro-inflammatory cytokines. Also, protein kinases involved in intracellular signalling, are directly activated resulting in phosphorylation of various targets of which Annexin (AXA)-1 is critical in inhibiting biosynthesis of both purines and DNA. This results in reduced proliferation of B and T lymphocytes, reduced immune effector mechanisms and reduced recruitment of mononuclear cells including monocytes into sites of immune inflammation. Methotrexate also blocks DNA synthesis and hence cellular proliferation but also induces release of adenosine. This inhibits chemotaxis of polymorph neutrophils and release of critical cytokines such as TNF-? and Interleukins 6 and 8. Hydroxyurea also inhibits DNA synthesis with inhibitory effects on proliferation of lymphocytes and possibly kerationcytes.Even though many new agents with much greater selectivity are coming through into clinical use, this group of old agents still have an absolutely central position in the therapeutic armamentarium. Their value lies in the fact that they are not 'clean' drugs with narrow effects but they inhibit a wide range of mechanisms involved in immune and inflammatory processes

Effect of house dust mite avoidance measures in children with atopic dermatitis

Background House dust mite allergens are associated with atopic dermatitis (AD). Objectives The aim of our study was to verify if house dust mite allergen avoidance measures can improve the clinical manifestations of AD in children. Methods Forty-one children (mean age 3·9 years) affected by AD associated with high total and/or specific IgE serum levels ('extrinsic' AD) were recruited. Clinical evaluation was performed utilizing the Severity Scoring of AD (SCORAD) index; dust was sampled from the children's beds and tested using an enzyme-linked immunosorbent assay. The study was planned in two parts. In the first part, a placebo-controlled trial of 2 months duration, mite allergen avoidance measures (encasing mattresses and pillows; a weekly hot wash of bedding; frequent vacuum cleaning of living room and bedroom; soft toys and carpets regularly cleaned or removed; no pets allowed) were recommended to group A patients, but not to group B. In the second part of the study, environmental avoidance measures were recommended to initial control group B patients also. One year after the start of the study the amounts of mite allergen in the home and clinical score of AD were measured in both groups. Results At the end of the first part of the study, significant decreases in major allergens of Dermatophagoides pteronyssinus (Der p1) and D. farinae (Der f1) load (from 393 to 94 ng m2) and concentration (from 1·84 to 0·73 µg g1 of dust) in children's beds were observed in treatment group A. At the same time, in this group the mean SCORAD index improved significantly (from 33 to 26; P = 0·022). After 12 months, when all patients had used allergen avoidance measures, Der p1 + Der f1 load, concentration and clinical score had improved, reaching similar values in both groups. Conclusions Simple mite allergen avoidance measures should be recommended to families with children affected by extrinsic AD in order to control the clinical manifestations and prevent mite sensitization