Oral tolerance, food allergy, and immunotherapy: implications for future treatment

The lumen of the gastrointestinal tract is exposed daily to an array of dietary proteins. The vast majority of proteins are tolerated through suppression of cellular or humoral responses, a process known as oral tolerance. However, in approximately 6% of children and 4% of adults in the United States, tolerance to a given dietary antigen either is not established or breaks down, resulting in food hypersensitivity. Although food allergies can result in sudden and life-threatening symptoms, their prevalence is remarkably low considering the complexities of the gut-associated mucosal system. Suppression involves signaling by an array of nonprofessional antigen-presenting cells, dendritic cells, and regulatory T cells, as well as lymphocyte anergy or deletion. Several factors, including antigen properties, route of exposure, and genetics and age of the host, contribute to the development of oral tolerance. Although the current standard of care for patients with food allergies is based on avoidance of the trigger, increased understanding of the mechanisms involved in tolerance has shifted focus of treatment and prevention toward inducing tolerance. Data from early-phase clinical trials suggest both sublingual and oral immunotherapy are effective in reducing sensitivity to allergens. In this article we review the mechanisms of tolerance, discuss aberrations in oral tolerance, and provide information on novel prevention and treatment paradigms for food allergy.     

Sozialschicht, Lebenszufriedenheit und Gesundheitseinsch?tzung. Ergebnisse einer repr?sentativen Untersuchung der deutschen Bev?lkerung

Der Zusammenhang zwischen einem erhöhten Morbiditäts- und Mortalitätsrisiko und der sozialen Schicht- bzw. Klassenzugehörigkeit ist in den letzten Jahren an einer grossen Zahl von Studien, auch im internationalen Bereich, bestätigt worden. Ungeklärt ist dabei die Frage, wie die objektive gesellschaftliche Situation zu individuellen Krankheitsprozessen führt. Zur Klärung dieser Frage wurde in einer repräsentativen Untersuchung der deutschen Bevölkerung die Lebenszufriedenheit, Aspekte der Persönlichkeit, subjektive Körperbeschwerden und Einstellungen zur aktuellen Gesundheit an 2948 Personen erfragt. Bei fast allen Skalen der eingesetzten Instrumente fanden sich deutliche Schichtgradienten. Die Personen der unteren Sozialschicht zeigen eine geringere Lebenszufriedenheit, deutliche Unterschiede in der Persönlichkeit, mehr Körperbeschwerden, einen schlechteren Gesundheitszustand und sie waren der Überzeugung, selbst wenig für ihre Gesundheit tun zu können. Diese Selbsteinschätzungen weisen auf Prozesse hin, die vor der Manifestation einer körperlichen Erkrankung stehen. Sie können als Ausdruck für die psychische Auseinandersetzung der Personen mit ihrer sozialen Situation gewertet werden. Es wird dafür plädiert, im Rahmen der Analyse sozialer Ungleichheit und Krankheit neben soziologischen Theorien auch sozialpsychologische und stresstheoretische Theorien einzubeziehen. Sie leisten einen wesentlichen Beitrag zur Klärung der Schnittstelle zwischen Schichtungslagen bzw. Lebensbedingungen, Distresserfahrung, verfügbaren Bewältigungs-ressourcen und den individuellen Prozessen der Krankheitsentstehung.     

Effects of skin temperature on lesion size in fractional photothermolysis

BACKGROUND AND OBJECTIVES: Fractional photothermolysis is a new concept in cutaneous re-modeling whereby laser-induced microscopic zones of thermal injury (MTZ-Microscopic Treatment Zones) are surrounded by normal, viable tissue. This unique thermal damage pattern allows re-epithelialization in less than 24 hours. To increase patient comfort level during the procedure of fractional photothermolysis, simultaneous skin cooling has been proposed and is now extensively used. The purpose of this in vitro study was to examine the influence of skin temperature on the diameter of the epidermal microthermal zone and the extent of thermal injury per unit area. The determination of the changes in these parameters that are due to skin temperature will allow the better control and understanding of fractional photothermolysis at different skin temperatures. MATERIALS AND METHODS: Fractional photothermolysis was performed with a 1,550 nm fiber laser (Fraxel SR Laser) with 10 mJ per pulse on full-thickness cadaver skin. The skin samples were brought prior to exposure to temperatures that ranged from 0 to 45 degrees C. The epidermis of the skin samples was separated by dispase treatment, stained for thermal damage by NBTC stain, and lesion diameter was assessed by a blinded investigator. RESULTS: The average MTZ diameter exhibits a positive, linear relationship with skin temperature (R(2) = 0.904, P < 0.0001). As the skin temperature increases from 0 to 45 degrees C. The MTZ diameter increases from 93 to 147 microm (58%), and the MTZ area from 6,870 to 17,050 microm(2) (148%). CONCLUSION: The skin temperature affects the size of epidermal MTZs during fractional photothermolysis and is an important variable factor. The use of simultaneous skin cooling increases patient comfort; however, as it also decreases MTZ size, it may interfere with treatment efficacy. The control of skin temperature is necessary to provide a consistent outcome and to be able to compare treatments.     

Reversible inactivations of rat medial prefrontal cortex impair the ability to wait for a stimulus

In simple reaction time tasks, lesions of rat dorsomedial prefrontal cortex impair the ability to wait for trigger stimuli and result in increased premature responding. This effect could be due to impairments in attending to trigger stimuli, estimating the timing of trigger stimuli, or inhibitory control of the motor response. Here, we examined these issues by reversibly inactivating dorsomedial prefrontal cortex during simple reaction time tasks with variable or fixed foreperiods. There were three consistent effects of dorsomedial prefrontal cortex inactivation: 1) increased premature responding, 2) increased variability in the timing of premature responses, and 3) speeded response latencies, especially on trials with short foreperiods in tasks with variable foreperiods. We observed these effects independent of differences in foreperiod duration, foreperiod variability, and stimulus probabilities. Therefore, dorsomedial prefrontal cortex appears not to be involved in attending to the trigger stimulus or in time estimation. Instead, we suggest that dorsomedial prefrontal cortex is critical for inhibiting responses before the maximum foreperiod duration, i.e. the "deadline" [Ollman RT, Billington MJ (1972) The deadline model for simple reaction times. Cognit Psychol 3:311-336], after which the rat should respond even if the trigger stimulus has not occurred.     

Imaging the spread of reversible brain inactivations using fluorescent muscimol

Muscimol is a GABA_A-agonist that causes rapid and reversible suppression of neurophysiological activity. Interpretations of the effects of muscimol infusions into the brain have been limited because of uncertainty about spread of the drug around the injection site. To solve this problem, the present study explored the use of a fluorophore-conjugated muscimol molecule (FCM). Whole-cell recordings from horizontal brain slices demonstrated that bath-applied FCM acts like muscimol in reversibly suppressing excitatory synaptic transmission. Two types of in vivo experiments demonstrated that the behavioral effects of FCM infusion are similar to the behavioral effects of muscimol infusion. FCM infusion into the rat amygdala before fear conditioning impaired both cued and contextual freezing, which were tested 24 or 48 h later. Normal fear conditioning occurred when these same rats were subsequently given phosphate-buffered saline infusions. FCM infusion into the dorsomedial prefrontal cortex impaired accuracy during a delayed-response task. Histological analysis showed that the region of fluorescence was restricted to 0.5–1 mm from the injection site. Myelinated fiber tracts acted as diffusional barriers, thereby shaping the overall spread of fluorescence. The results suggest that FCM is indeed useful for exploring the function of small brain regions.