Autoimmunity, immunodeficiency and mucosal infections: chronic intestinal inflammation as a sensitive indicator of immunoregulatory defects in response to normal luminal microflora

Despite the fact that target antigens and the genetic basis of several autoimmune diseases are now better understood, the initial events leading to a loss of tolerance towards self-components remain unknown. One of the most attractive explanations for autoimmune phenomena involves various infections as possible natural events capable of initiating the process in genetically predisposed individuals. The most accepted explanation of how infection causes autoimmunity is based on the concept of "molecular mimicry" (similarity between the epitopes of an autoantigen and the epitopes in the environmental antigen). Infectious stimuli may also participate in the development of autoimmunity by inducing an increased expression of stress proteins (hsp), chaperones and transplantation antigens, which leads to abnormal processing and presentation of self antigens. Superantigens are considered to be one of the most effective bacterial components to induce inflammatory reactions and to take part in the development and course of autoimmune mechanisms. It has long been known that defects in the host defense mechanism render the individual susceptible to infections caused by certain microorganisms. Impaired exclusion of microbial antigens can lead to chronic immunological activation which can affect the tolerance to self components. Defects in certain components of the immune system are associated with a higher risk of a development of autoimmune disease. The use of animal models for the studies of human diseases with immunological pathogenesis has provided new insights into the influence of immunoregulatory factors and the lymphocyte subsets involved in the development of disease. One of the most striking conclusion arising from work with genetically engineered immunodeficient mouse models is the existence of a high level of redundancy of the components of the immune system. However, when genes encoding molecules involved in T cell immunoregulatory functions are deleted, spontaneous chronic inflammation of the gut mucosa (similar to human inflammatory bowel disease) develops. Surprisingly, when such immunocompromised animals were placed into germfree environment, intestinal inflammation did not develop. Impairment of the mucosal immune response to the normal bacterial flora has been proposed to play a crucial role in the pathogenesis of chronic intestinal inflammation. The use of immunodeficient models colonized with defined microflora for the analysis of immune reactivity will shed light on the mode of action of different immunologically important molecules responsible for the delicate balance between luminal commensals, nonspecific and specific components of the mucosal immune system.     

Carbohydrate chromatography: towards yoctomole sensitivity

Ward atmosphere was assessed with the help of the Ward Atmosphere Scale (WAS) by patients, nurses and physicians on 8 admission units before and after the introduction of the partial open door system. On average, on 45% of the days on which the units could have been potentially open, they were indeed at least temporarily open. Several significant changes in the WAS scores, mostly in desirable direction, were registered. However, close relationship with the partial opening of the units could be substantiated only with regard to the scale "praxis orientation"; still a positive result. No unequivocal relationships could be demonstrated between the introduction of the partial open door system and the changes in the frequency of "special events".     

Robust skeletonization using the discrete λ-medial axis

Medial axes and skeletons are notoriously sensitive to contour irregularities. This lack of stability is a serious problem for applications in e.g. shape analysis and recognition. In 2005, Chazal and Lieutier introduced the λ-medial axis as a new concept for computing the medial axis of a shape subject to single parameter filtering. The λ-medial axis is stable under small shape perturbations, as proved by these authors. In this article, a discrete λ-medial axis (DLMA) is introduced and compared with the recently introduced integer medial axis (GIMA). We show that DLMA provides measurably better results than GIMA, with regard to stability and sensibility to rotations. We give efficient algorithms to compute the DLMA, and we also introduce a variant of the DLMA which may be computed in linear-time.     

The dielectric formalism for3He-4He mixtures

The microscopic theory of³He-⁴He mixtures with a Bose condensate is formulated in terms of the dielectric formalism. By expressing all correlation functions in terms of proper, irreducible contributions, one sets the stage for approximate calculations that will be consistent with various exact sum rules and Ward identities, just as in the case of pure⁴He. The present analysis includes a symmetry-breaking term that allows us to deal with the continuity equations properly, and is valid at finite temperature. As a specific application, we express the normal fluid density _N in terms of the static⁴He current-current correlation function. We also give the first formal proof that in the presence of a moving condensate, the³He atoms make no direct contribution to the superfluid flow.     

Human oogenesis in organ culture

The authors compared the extent of development of the germ cells of the human fetus ovaries developing in the organ culture and of control ovaries obtained of fetuses of "equivalent" age. The capacity to enter the meiosis prophase under conditions of the organ culture was expressed by the germ cells of fetuses of 8-9 week of gestation, and older; only individual oocytes reached the leptotene stage in the explants of the ovaries of 7-8 week fetuses. The oocytes at the leptotene, zygotene and pachitene stage appeared in the culture at the same periods as in the organism. However, the percentage of cells of these stages in the explant was as a rule lower than in control ovaries. In case of pulse administration of thymidine-3H into the culture labeled oocytes at the zygotene stage appeared in 4, and at the pachitene stage - in 14 days.     

Structural interaction of natural and synthetic inhibitors with the venom metalloproteinase, atrolysin C (form d)

The structure of the metalloproteinase and hemorrhagic toxin atrolysin C form d (EC 3.4.24.42), from the venom of the western diamondback rattlesnake Crotalus atrox, has been determined to atomic resolution by x-ray crystallographic methods. This study illuminates the nature of inhibitor binding with natural (< Glu-Asn-Trp, where < Glu is pyroglutamic acid) and synthetic (SCH 47890) ligands. The primary specificity pocket is exceptionally deep; the nature of inhibitor and productive substrate binding is discussed. Insights gained from the study of these complexes facilitate the design of potential drugs to treat diseases where matrix metalloproteinases have been implicated, e.g., arthritis and tumor metastasis.     

Homogeneous cooling of hard ellipsoids

We study the homogeneous cooling of hard, smooth ellipsoids in three dimensions using event driven numerical simulation. The elongation of the particle has a strong effect on the cooling behavior. Weakly elongated ellipsoids display two distinct cooling regimes. For small times, the translational and rotational energy decay at a different rates. Once their ratio reaches a time-independent value (different from equipartition), the overall temperature of the system decays like t ^?2, as predicted by Haff??s law. For more elongated ellipsoids the translational and rotational temperatures rapidly reach a constant ratio near unity. The cooling behavior in the homogeneous state can be predicted from Haff??s law and the equilibrium collision rate.     

Exploring inattention and distraction in the SafetyNet Accident Causation Database

Distraction and inattention are considered to be very important and prevalent factors in the causation of road accidents. There have been many recent research studies which have attempted to understand the circumstances under which a driver becomes distracted or inattentive and how distraction/inattention can be prevented. Both factors are thought to have become more important in recent times partly due to the evolution of in-vehicle information and communication technology. This study describes a methodology that was developed to understand when factors such as distraction and inattention may have been contributors to crashes and also describes some of the consequences of distraction and inattention in terms of subsequent driver actions.     

Effects of pramipexole on contraversive rotation and functional motor impairments in 1-methyl-4-phenyl1,2,3, 6-tetrahydropyridine-induced chronic hemiparkinsonian monkeys

Rotational and functional motor behavioral changes were studied in five MPTP lesioned chronic hemiparkinsonian Macaca nemestrina monkeys after i.m. pramipexole, a predominant D2 subfamily agonist. Pramipexole induced contraversive rotations in a dose-dependent manner with an optimal dose of 56 microg/kg for approximately 2 to 4 hr after injection. Three different rating scales were used to determine drug-induced functional improvement. They included a monkey parkinsonism rating scale, volitional responses to fruit presentations, and number of hand movements that appeared volitional. A dose of 56 microg/kg of pramipexole produced functional improvements on hand disability, and on a parkinsonian rating scale for monkeys in a dose-dependent manner from 32 to 100 microg/kg. These doses produced an increase in significant hand movements in the affected (contralateral) as well as in the normal (ipsilateral) hand to the side of the brain lesion compared with 5% dextrose in water vehicle control. With a dose of 100 microg/kg, the therapeutic effects of pramipexole on hand movements were less than with 56 microg/kg, due to side effects such as scratching.