The roadmap for the Allergology specialty and allergy care in Europe and adjacent countries. An EAACI position paper.

The high prevalence of allergic diseases warrants for sufficient health care provisions available to patients with allergic diseases. Allergy care should be delivered by well-trained specialists. However, the current status of allergy care is not well documented. For this reason a survey among European and a few non-European countries was launched by the National Allergy Society Committee from the European Academy of Allergy and Clinical Immunology and the Union Européenne des Médecins Spécialistes section and board of Allergology. The survey shows that in the vast majority of countries allergy care services are available. However, a substantial heterogeneity is reported regarding recognition of the full specialty, the number of practicing specialists or subspecialists, and training aspects. Growth but also decline of specialty and subspecialties is reported. In addition, the survey gives insight in strengths, weaknesses, opportunities and threats in this field. It appears that the recognition of the full specialty determines strength as well as weakness. Aging of specialists combined with a decline in the number of trainees form a major threat. Opportunities are seen in creating awareness for allergy, focus on attracting young physicians. The conclusion is that harmonization of allergy services across Europe is needed. Investment in young doctors, creating new opportunities and lobbying for the full specialty is required.

Significant disparities in allergy prevalence and microbiota between the young people in Finnish and Russian Karelia.

BACKGROUND: Atopic allergy has been more common among schoolchildren in Finland, as compared to Russian Karelia. These adjacent regions show one of the most contrasting socio-economical differences in the world. OBJECTIVE: We explored changes in allergy from school age to young adulthood from 2003 to 2010/2012 in these two areas. The skin and nasal microbiota were also compared. METHODS: Randomly selected children from Finnish (n = 98) and Russian Karelia (n = 82) were examined in 2003, when the children were 7-11 years of age, and again in 2010 (Finnish Karelia) and 2012 (Russian Karelia). We analysed self-reported allergy symptoms and sensitization to common allergens by serum sIgE values. The skin (volar forearm) and nasal mucosa microbiota, collected in 2012 (aged 15-20 years), identified from DNA samples, were compared with multivariate methods. RESULTS: Asthma, hay fever, atopic eczema, self-reported rhinitis, as well as atopic sensitization, were threefold to 10-fold more common in Finland, as compared to Russian Karelia. Hay fever and peanut sensitization were almost non-existent in Russia. These patterns remained throughout the 10-year follow-up. Skin microbiota, as well as bacterial and fungal communities in nasal mucosa, was contrastingly different between the populations, best characterized by the diversity and abundance of genus Acinetobacter; more abundant and diverse in Russia. Overall, diversity was significantly higher among Russian subjects (Pskin < 0.0001, Pnasal-bacteria < 0.0001 and Pnasal-fungi < 0.01). Allergic diseases were not associated with microbial diversity in Finnish subjects. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in allergic phenotype, developed in early life, remain between populations. A parallel difference in the composition of skin and nasal microbiota suggests a potential underlying mechanism. Our results also suggest that high abundance and diversity of Acinetobacter might contribute to the low allergy prevalence in Russia. Implications of early-life exposure to Acinetobacter should be further investigated.

Skin Biomes.

The cutaneous microbiome has been investigated broadly in recent years and some traditional perspectives are beginning to change. A diverse microbiome exists on human skin and has a potential to influence pathogenic microbes and modulate the course of skin disorders, e.g. atopic dermatitis. In addition to the known dysfunctions in barrier function of the skin and immunologic disturbances, evidence is rising that frequent skin disorders, e.g. atopic dermatitis, might be connected to a dysbiosis of the microbial community and changes in the skin microbiome. As a future perspective, examining the skin microbiome could be seen as a potential new diagnostic and therapeutic target in inflammatory skin disorders.

Hunt for the origin of allergy - comparing the Finnish and Russian Karelia.

The Finnish and Russian Karelia are adjacent areas in northern Europe, socio-economically distinct but geoclimatically similar. The Karelia Allergy Study was commenced in 1998 to characterize the allergy profiles in the two areas. Allergy prevalence had increased in Finland since the early 1960s, but the situation in Russia was unknown. The key finding was that allergic symptoms and diseases were systematically more common in Finnish children and adults than in their Russian counterparts. For example, in the early 2000s, hay fever in school children was almost non-existent in Russian Karelia, and only 2% were sensitized to birch pollen compared with 27% in Finnish Karelia. Adult birth cohorts showed that among those born in the 1940s, the sensitization to pollens and pets was at the same low level in both countries, but among younger generation born in the late 1970s, the difference was already manifold. Seropositivity to some pathogens, microbial content in house dust and drinking water seemed to confer allergy protection in Russia. In subsequent studies, it became apparent that on the Finnish side, healthy children had a more biodiverse living environment as well as greater diversity of certain bacterial classes on their skin than atopic children. Abundance of skin commensals, especially Acinetobacter (gammaproteobacteria), associated with anti-inflammatory gene expression in blood leucocytes. In vivo experiments with the mouse model demonstrated that intradermally applied Acinetobacter protected against atopic sensitization and lung inflammation. These observations support the notion that the epidemic of allergy and asthma results from reduced exposure to natural environments with rich microbiota, changed diet and sedentary lifestyle. Genetic studies have confirmed strong influence of lifestyle and environment. With our results from the Karelia study, a 10-year National Allergy Programme was started in 2008 to combat the epidemic in Finland.

Green areas around homes reduce atopic sensitization in children.

BACKGROUND: Western lifestyle is associated with high prevalence of allergy, asthma and other chronic inflammatory disorders. To explain this association, we tested the 'biodiversity hypothesis', which posits that reduced contact of children with environmental biodiversity, including environmental microbiota in natural habitats, has adverse consequences on the assembly of human commensal microbiota and its contribution to immune tolerance. METHODS: We analysed four study cohorts from Finland and Estonia (n = 1044) comprising children and adolescents aged 0.5-20 years. The prevalence of atopic sensitization was assessed by measuring serum IgE specific to inhalant allergens. We calculated the proportion of five land-use types--forest, agricultural land, built areas, wetlands and water bodies--in the landscape around the homes using the CORINE2006 classification. RESULTS: The cover of forest and agricultural land within 2-5 km from the home was inversely and significantly associated with atopic sensitization. This relationship was observed for children 6 years of age and older. Land-use pattern explained 20% of the variation in the relative abundance of Proteobacteria on the skin of healthy individuals, supporting the hypothesis of a strong environmental effect on the commensal microbiota. CONCLUSIONS: The amount of green environment (forest and agricultural land) around homes was inversely associated with the risk of atopic sensitization in children. The results indicate that early-life exposure to green environments is especially important. The environmental effect may be mediated via the effect of environmental microbiota on the commensal microbiota influencing immunotolerance.

In search of the visual pigment template.

Absorbance spectra were recorded by microspectrophotometry from 39 different rod and cone types representing amphibians. reptiles, and fishes, with A1- or A2-based visual pigments and lambdamax ranging from 357 to 620 nm. The purpose was to investigate accuracy limits of putative universal templates for visual pigment absorbance spectra, and if possible to amend the templates to overcome the limitations. It was found that (1) the absorbance spectrum of frog rhodopsin extract very precisely parallels that of rod outer segments from the same individual, with only a slight hypsochromic shift in lambdamax, hence templates based on extracts are valid for absorbance in situ: (2) a template based on the bovine rhodopsin extract data of Partridge and De Grip (1991) describes the absorbance of amphibian rod outer segments excellently, contrary to recent electrophysiological results; (3) the lambdamax/lambda invariance of spectral shape fails for A1 pigments with small lambdamax and for A2 pigments with large lambdamax, but the deviations are systematic and can be readily incorporated into, for example, the Lamb (1995) template. We thus propose modified templates for the main "alpha-band" of A1 and A2 pigments and show that these describe both absorbance and spectral sensitivities of photoreceptors over the whole range of lambdamax. Subtraction of the alpha-band from the full absorbance spectrum leaves a "beta-band" described by a lambdamax-dependent Gaussian. We conclude that the idea of universal templates (one for A1- and one for A2-based visual pigments) remains valid and useful at the present level of accuracy of data on photoreceptor absorbance and sensitivity. The sum of our expressions for the alpha- and beta-band gives a good description for visual pigment spectra with lambdamax > 350 nm.

Measurement of thermal contribution to photoreceptor sensitivity.

Activation of a visual pigment molecule to initiate phototransduction requires a minimum energy, Ea, that need not be wholly derived from a photon, but may be supplemented by heat. Theory predicts that absorbance at very long wavelengths declines with the fraction of molecules that have a sufficient complement of thermal energy, and that Ea is inversely related to the wavelength of maximum absorbance (lambda(max)) of the pigment. Consistent with the first of these predictions, warming increases relative visual sensitivity to long wavelengths. Here we measure this effect in amphibian photoreceptors with different pigments to estimate Ea (refs 2, 5-7) and test experimentally the predictions of an inverse relation between Ea and lambda(max). For rods and 'red' cones in the adult frog retina, we find no significant difference in Ea between the two pigments involved, although their lambda(max) values are very different. We also determined Ea for the rhodopsin in toad retinal rods--spectrally similar to frog rhodopsin but differing in amino-acid sequence--and found that it was significantly higher. In addition, we estimated Ea for two pigments whose lambda(max) difference was due only to a chromophore difference (A1 and A2 pigment, in adult and larval frog cones). Here Ea for A2 was lower than for A1. Our results refute the idea of a necessary relation between lambda(max) and Ea, but show that the A1 --> A2 chromophore substitution decreases Ea.

Rhodopsins from three frog and toad species: sequences and functional comparisons.

The frequency of thermal 'dark events' in the membrane current of rhodopsin rods of the bullfrog, Rana catesbeiana, is considerably lower than observed in rods of two toad species, even though all three rhodopsins have approximately the same absorbance characteristics. In order to map amino acid substitutions possibly associated with thermal stability in the genus Rana, the cDNA's coding for the rhodopsins of Bufo bufo, B. marinus and R. temporaria were sequenced and the conceptually translated protein sequences aligned to the previously sequenced rhodopsins of R. catesbeiana, R. pipiens and Xenopus laevis. Across the six anuran species studied, there are sixteen non-conserved substitutions and six changes that include gain or loss of a hydroxyl group. Serine or threonine at position 220 is unique to the three Rana species, phenylalanine at position 270 is unique to all three Ranas and to X. laevis, and phenylalanine at position 274 is unique to both species of the genus Bufo. This investigation produces a list of substitutions that are candidates for future studies of thermal stability. In addition, a number of amino acids are identified that apparently do not influence absorbance characteristics, at least not cumulatively.

Rod pigment and rod noise in the European toad Bufo bufo.

Behavioural experiments and ganglion cell recordings indicate that the visual sensitivity of dark-adapted toads is limited by the occurrence of spontaneous isomerization-like noise events in the rods. The frequency of these "false photons" has previously been studied (with micropipette recording) in the toad species Bufo marinus, while the behavioural thresholds were determined using Bufo bufo toads. Thus, it was necessary to check that the noise event frequency is roughly the same in these two species. Here we show that it is, in both species, close to 0.02 events per second and rod (at 22 degrees C). Using microspectrophotometry we further show that the absorption spectra of these two rhodopsins are very similar, peaking around 503.3 and 501.8 nm for B. marinus and B. bufo, respectively.

The effect of background luminance on visual responses to strong flashes: perceived brightness and the early rise of photoreceptor responses.

The threshold intensity for large-long incremental stimuli rises proportionally to adapting background luminance IB (Weber adaptation), but the intensity required to evoke a criterion high-brightness sensation rises much less steeply. We propose that this difference originates in the very first stage of visual processing, in the phototransduction and adaptation properties of the retinal photoreceptor cells. A physiological model previously found to account for visual latency and brightness as functions of stimulus intensity in the dark-adapted state [Donner, K. (1989). Visual Neuroscience, 3, 39-51] is extended to cover different states of adaptation. It is assumed that the neural coding of high intensities is based on the rate of rise (quasi-derivative) of the photoreceptor response just after it reaches a small threshold amplitude. The shallow background adaptation functions for high-brightness criteria emerge as a consequence of the relative constancy of the leading edge of large responses under backgrounds, a phenomenon that can be formally described by compensating changes in photoreceptor sensitivity and time scale. We first test the model on supra-threshold responses in the frog retina, where the discharge rate of ganglion cells (a possible neural code for brightness) and the primary rod hyperpolarizations can be recorded under identical conditions. The two are related as predicted over at least 3 log units of background intensity. We then show that published data on the background adaptation of human foveal high brightness judgments conform to the same model, assuming that human cones accelerate as IB-b with b = 0.14-0.15.