Radioallergosorbent testing for penicillin allergy in family practice.

OBJECTIVES: To determine (a) the prevalence of patients supposedly allergic to penicillin who have a positive radioallergosorbent test (RAST) result for penicillin G or V and (b) the predictive power of family physicians'' clinical judgement that a patient who is supposedly allergic to penicillin will have a positive RAST result. DESIGN: Prospective multicentre cross-sectional observational study. SETTING: Eleven primary care practices in Newfoundland; 10 were in a rural setting. PATIENTS: Of 110 consecutive adult patients with a supposed allergy to penicillin 97 agreed to participate in the study; 92 underwent RAST. INTERVENTIONS: Patients helped physicians complete a questionnaire and had a venous blood sample taken for the RAST. Physicians examined the clinical history and judged whether the patient was likely to have a positive RAST result. MEAN OUTCOME MEASURES: Rates of positive and negative RAST results for penicillin V and G. RESULTS: Of the 92 patients 8 had a positive RAST result and 84 a negative one. The positive predictive power of a "good" clinical history (e.g., urticaria, swollen eyes, tongue or lips, or an anaphylactic reaction witnessed by a physician) was low (10%); the negative predictive power of a "poor" clinical history (e.g., nausea, vomiting, diarrhea, fever, nonspecific rash or fainting) was 92%. CONCLUSIONS: Less than 10% of primary care patients with a supposed allergy to penicillin will have a positive RAST result. In addition, physicians'' predictions of allergy in such patients are imprecise.     

Place actuelle de la biologie dans l’exploration et le suivi de l’allergie

The allergy disease requires an early diagnosis which, in addition to the management of the disease at its initial stage, will prevent its development towards potentially more severe symptoms. In primary care, screening tests allow to investigate the underlying cause of the symptoms and to confirm or exclude an allergic condition. They were recently completed by a test specially dedicated to the infant, which takes into account the predominance of the food allergens at this age. Specific IgE tests contribute, by the identification of the offending allergens, to implement a specific treatment (more particularly allergen avoidance) and to follow the development of the disease over time. The last scientific and technological advances allow from now on to refine the exploration at the molecular level and the recent development of tests with allergenic components offers new perspectives to the in vitro diagnostic as well as new indications.     

A simplified screening test for the diagnosis of allergy.

The Quidel allergy screen is a relatively rapid (less than 2 hours) multiallergen dipstick method for detecting specific immunoglobin E antibodies in serum. It was developed to answer the need of primary physician nonspecialists in allergy for a convenient in-office screening test for diagnosing allergy. The new test was evaluated against the benchmark diagnostic skin tests and the radioallergosorbent serologic tests for sensitivity, specificity, accuracy, and technical feasibility in an office setting. It was found that while the Quidel allergy screen lacks the specificity of the standard tests, its overall sensitivity, as defined by the percentage of patients with positive skin reactions who also tested positive with the Quidel screen (68%), its ease of use, and its rapidity warrant its consideration as a screening tool for confirming a possible case of allergy.     

Adjuvants--essential components of new generation vaccines

Adjuvants are essential components of vaccines that augment an immunological reaction of organism. New vaccines based on recombinant proteins and DNA, are more save than traditional vaccines but they are less immunogenic. Therefore, there is an urgent need for the development of new, improved vaccine adjuvants. There are two classes of adjuvants: vaccine delivery systems (e.g. emulsions, microparticles, immune-stimulating complexes ISCOMs, liposomes) and immunostimulatory adjuvants (e.g. lipopolysaccharide, monophosphoryl lipid A, CpG DNA, or muramylpeptides). The discovery of more potent and safer adjuvants may allow to development better prophylactic and therapeutic vaccines against chronic infectious (e.g., HSV, HIV, HCV, HBV, HPV, or Helicobacter pylori) and noninfectious diseases as multiple sclerosis, insulin-dependent diabetes, rheumatoid arthritis, allergy and tumors (e.g., melanoma, breast, or colon cancer).     

Direct and indirect estimation of the sex ratio of mutation frequencies in hemophilia A.

Carrier detection tests were carried out in 119 families with hemophilia A by using the data obtained with current DNA techniques (e.g., RFLP analysis and direct identification of mutations), conventional carrier detection tests (e.g., factor VIII:C and von Willebrand factor antigen), and pedigree information. On the basis of this data, we estimated the sex ratio of mutation frequencies with three completely different methods and compared the results. Since the classical indirect method derived from Haldane is substantially influenced by reproductive fitness (f), the sex ratio of mutation frequencies was estimated for both f = .3 and f = .5, resulting in a male:female mutation ratio of 5.37 (95% confidence interval 2.16-13.02) and 3.26 (95% confidence interval 0.97-8.73), respectively. According to the equilibrium-independent indirect method formulated by Rosendaal et al., the male:female ratio was estimated to be 3.4 (95% confidence interval 1.18-8.81). Since current DNA techniques provide information on the grandparental origin of the patient''s X chromosome, we were twice able to estimate directly the male:female mutation ratio as 15:1, by using the quotients of mutation origin (maternal grandfather/maternal grandmother and maternal grandfather/patient''s mother, respectively). Application of the Fisher test shows that the male mutation rate is higher than the female rate (P = 8.55 x 10(-7). Since all three completely different approaches unequivocally showed a higher male than female mutation frequency, this should be considered to be an established fact in calculating the risk in hemophilia A families.     

Nonalimentary tooth use in prehistory: an example from early Holocene in Central Sahara (Uan Muhuggiag,Tadrart Acacus,Libya)

Signs of nonalimentary tooth use were observed on the dentition of an adult male from a single burial excavated in an area close to the Uan Muhuggiag rock shelter (Tadrart Acacus, Libya), dated to more than 7800 uncalibrated years BP, that represents the most ancient human remain found in the Libyan Sahara, and provides a first glimpse of human adaptation in the early Holocene of this region. The wear pattern shows large grooves running across the occlusal surfaces of maxillary and mandibular anterior teeth and premolars. The results of macroscopic and microscopic observation, together with scanning electron microscope (SEM) examination and experimental tests, suggest that the microdamage might be due to repeated friction of vegetal fibers, probably as a consequence of basket making, net production, or mat processing. Further data are needed to allow us to distinguish among plant-oriented activities related to food acquisition (e.g., rope and net processing), food storage (e.g., basket making), or domestic handicraft (e.g., mat processing), whose implications may generate different interpretations of sexual division of labor.     

THE USE OF DNA DIVERGENCE TO HELP DETERMINE THE CORRELATES OF EVOLUTION OF MORPHOLOGICAL CHARACTERS

Even though, from Darwin onwards, interisland evolution has been a cornerstone of evolutionary theory it has not been possible to determine to what extent this geographic variation reflects the phylogeny (e.g., pattern of island colonization) or ecogenetic adaptation to different ecological conditions on each island. Using the morphology of western Canary Island lacertids (Gallotia galloti) as an example, a procedure is explored that gives a preliminary answer to this problem when there are a limited number of islands. The phylogenetic component (represented by patristic distances derived from 1005 mitochondrial DNA [mtDNA] base pairs) can be separated from two potential ecogenetic factors (environmental richness and climate) by partial Mantel tests. This reveals that, although these components interact, some characters are correlated primarily to biodiversity/paucity (e.g., size), others are correlated to wet and lush environments (e.g., dorsal pattern), and others are correlated primarily to the phylogeny (e.g., sexual leg markings). The former two correlations may be due to ecogenetic adaptation to current ecological conditions, wheras the latter reflects historical processes.     

Formation of pollen-induced allergy in guinea pigs after specific immunotherapy with a bacterial allergen

The investigation was aimed at elucidating the process of the development of allergy to exoallergens (e.g., to linear-leaf wormwood pollen) in the body after desensitization by specific immunotherapy (SIT) with heterologous (staphylococcal) allergen. The study revealed that in staphylococcal allergy the subsequent development of pollen sensitization occurred with greater intensity, and SIT was found to exert no influence on this process. For the first time pollen allergy was found to produce an unfavorable effect on the quality and effectiveness of SIT with heterologous staphylococcal allergen, this effect consisting in the acceleration and intensification of the process leading to the recovery of sensitization to staphylococci. The importance of measures for limiting contacts with heterologous allergens and their elimination during SIT is emphasized.     

Adverse reactions to foods

Allergic reactions to foods represent a prominent, actual and increasing problem in clinical medicine. Symptoms of food allergy comprise skin reactions (urticaria, angioedema, eczema) respiratory (bronchoconstriction, rhinitis), gastrointestinal (cramping, diarrhea) and cardiovascular symptoms with the maximal manifestation of anaphylactic shock. They can be elicited by minute amounts of allergens. The diagnosis of food allergy is done by history, skin test, in vitro allergy diagnosis and — if necessary — oral provocation tests, if possible placebo-controlled. Avoidance of respective allergens for the allergic patient, however, is often complicated or impossible due to deficits in declaration regulations in many countries. Increasing numbers of cases including fatalities, due to inadvertent intake of food allergens are reported. It is therefore necessary to improve declaration laws and develop methods for allergen detection in foods. Allergens can be detected by serological methods (enzyme immunoassays, in vitro basophil histamine release or in vivo skin test procedures in sensitized individuals). The problem of diagnosis of food allergy is further complicated by cross-reactivity between allergens in foods and aeroallergens (pollen, animal epithelia, latex etc.). Elicitors of pseudo-allergic reactions with similar clinical symptomatology comprise low-molecular-mass chemicals (preservatives, colorings, flavor substances etc.). For some of them (e.g. sulfites) detection assays are available. In some patients classic allergic contact eczema can be elicited systemically after oral intake of low-molecular-mass contact allergens such as nickel sulfate or flavorings such as vanillin in foods. The role of xenobiotic components in foods (e.g. pesticides) is not known at the moment. In order to improve the situation of the food allergic patient, research programs to elucidate the pathophysiology and improve allergen detection strategies have to be implemented together with reinforced declaration regulations on a quantitative basis.     

Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations.

OBJECTIVE--To investigate clinical features of acute allergic reactions to peanuts and other nuts. DESIGN--Analysis of data from consecutive patients seen by one doctor over one year in an allergy clinic at a regional referral centre. SUBJECTS--62 patients aged 11 months to 53 years seen between October 1993 and September 1994. MAIN OUTCOME MEASURES--Type and severity of allergic reactions, age at onset of symptoms, type of nut causing allergy, results of skin prick tests, and incidence of other allergic diseases and associated allergies. RESULTS--Peanuts were the commonest cause of allergy (47) followed by Brazil nut (18), almond (14), and hazelnut (13). Onset of allergic symptoms occurred by the age of 2 years in 33/60 and by the age of 7 in 55/60. Peanuts accounted for all allergies in children sensitised in the first year of life and for 82% (27/33) of allergies in children sensitised by the third year of life. Multiple allergies appeared progressively with age. The commonest symptom was facial angioedema, and the major feature accounting for life threatening reactions was laryngeal oedema. Hypotension was uncommon. Of 55 patients, 53 were atopic--that is, had positive skin results of tests to common inhaled allergens--and all 53 had other allergic disorders (asthma, rhinitis, eczema) due to several inhaled allergens and other foods. CONCLUSIONS--Sensitisation, mainly to peanuts, is occurring in very young children, and multiple peanut/nut allergies appear progressively. Peanut and nut allergy is becoming common and can cause life threatening reactions. The main danger is laryngeal oedema. Young atopic children should avoid peanuts and nuts to prevent the development of this allergy.     

Expression of MAL, an integral protein component of the machinery for raft-mediated pical transport, in human epithelia.

The MAL protein is the only integral membrane protein identified as being an essential component of the machinery necessary for apical transport in the canine MDCK cell line, a paradigm of polarized epithelial cells. To characterize the range of human epithelia that use MAL-mediated pathways of transport, we performed an immunohistochemical survey of normal tissues using a monoclonal antibody (MAb) specific for the MAL protein. For comparison, different types of carcinoma were also analyzed. MAL, with a characteristic strong supranuclear granular distribution, was detected in specific types of normal epithelial cells throughout the respiratory system, the gastrointestinal and genitourinary tracts, and in exocrine and endocrine glands. Absorptive cells (e.g., enterocytes), and many different types of specialized secretory cells, either organized in discrete clusters (e.g., endocrine cells in the pancreas), gathered together in an endocrine gland (e.g., thyroid), interspersed with other cells in glands (e.g., parietal cells), or dispersed singly among other cells (e.g., type 2 pneumocytes) were positive for MAL. We also analyzed a series of epithelial renal and thyroid tumors and found alterations dependent on the particular histological type of tumor. These results open potential applications of the anti-MAL antibody for the characterization of neoplastic tissue.     

Exponential distance statistics to detect the effects of population subdivision.

Statistical tests are needed to determine whether spatial structure has had a significant effect on the genetic differentiation of subpopulations. Here we introduce a new family of statistics based on a sum of an exponential function of the distances between individuals, which can be used with any genetic distance (e.g., nucleotide differences, number of nonshared alleles, or separation on a phylogenetic tree). The power of the tests to detect genetic differentiation in Wright-Fisher island models and stepping stone models was calculated for various sample sizes, rates of migration and mutation, and definitions of spatial neighborhoods. We found that our new test was in some cases more powerful than the Ks* statistic of Hudson et al. (Mol. Biol. Evol. 9, 138-151, 1992), but in all cases was slightly less powerful than both a traditional chi2 test without lumping of rare haplotypes and the S(nn) test of Hudson (Genetics 155, 2011-2014, 2000). However, when we applied our new tests to three data sets, we found in some cases highly significant results that were missed by the other tests.     

On the value of knowing a z* ion for what it is

Computer simulation of database searches of electron transfer dissociation (ETD) spectra using both "bottom up" and "top down" approaches was performed to evaluate the utility of knowing a priori which product ions contain the C-terminus (i.e., the z* ions). In this work, knowledge of the identities of the z* ions was used to exclude putative identifications that are based solely on the mass matching of undifferentiated product ions derived from an experiment with those derived from in silico fragmentation. The benefit from knowing which ions are z* ions was found to be heavily dependent on the quality of the ETD spectra, in terms of sequence coverage afforded by the product ions, the amount of noise in the spectra (i.e., extraneous peaks that do not directly reflect primary structure), and mass measurement accuracy. Under conditions in which the likelihood for misidentifications are high without a priori knowledge of ion types (e.g., b-, y-, c-, or z-ions), a knowledge of which product ions are z* ions allows discrimination against false-positive identifications. Relatively little benefit from knowing which ions are z* ions was noted when product spectra reflected relatively high sequence coverage and when a low fraction of the products ions were due to extraneous peaks (i.e., spectra with relatively little noise). In all cases, specificity is higher with higher mass measurement accuracy with the consequent reduction in benefit from knowledge of which ions are z* ions.     

Immunoglobulin E mediated food allergy.Modelling and application of diagnostic and predictive tests for existing and novel foods

It is known that some foods cause an allergenic response in certain individuals. Clinical and immunological tests are available for the diagnosis of food allergy and identification of food allergens. However, there are no valid tests for the prediction of the allergenic potential of foods not normally recognized as allergenic. Such foods include: food products developed from foods which may not be recognizable as allergenic in their modified forms; foods produced using novel processes (novel foods), for example genetically modified foods; and foods not normally consumed but that are being used increasingly as alternatives to more traditional foods. Both the risks associated with food allergy and the fact that foods such as the ones described above will become available to the consumer, highlight the need for methods to screen for potential food allergens. This review provides a general overview of food allergy including mechanism, development and prevalence, but focuses on and discusses: 1) the possible risks (with specific reference to food allergy) associated with new and novel foods; and 2) the development/use of food allergy models (in vivo and in vitro) to assess the allergenic potential of new and novel foods.     

The birth of immunology. III. The fate of the phagocytosis theory.

During the period of 1895-1910, immunology was preoccupied with defining the cellular (Elie Metchnikoff's phagocytosis theory) as opposed to the humoral basis of bactericidal defense. Although initial discovery of immunopathologic phenomena had been made (e.g., relating to transplantation, autoimmunity, allergy), focus on microbicidal therapy and diagnosis of infectious diseases remained the major stimuli of inquiry. The debate concerning the relative roles of phagocytes, complement, amboceptors (sensibilizing factors, antibody, antitoxins), various lysins (e.g., bacteriolysins, spermatolysins, hemolysins), agglutinins, stimulines, and then Almoth Wright's opsonins reflects the ambiguity of a scientific language being created in an era still struggling with a poorly defined experimental system, for the language, both its vocabulary (newly studied phenomena) and grammar (operational mechanisms) was yet to be codified. The joint award of the Nobel Prize to Metchnikoff and Paul Ehrlich in 1908 for their respective contributions to the "theory of immunity" appeared to proclaim a consensus, but the secret Nobel Committee reports that evaluated Metchnikoff's contributions reveal only a grudging acceptance of his position, and the award was clearly made on the basis of an apparent complementarity between the theoretical views of the humoralists and those elements of the phagocytosis theory that fit the then current discussion of immunity. In this regard, opsonins played an especially important role as both an experimental and conceptual bridge between the competing schools. What was no longer under consideration (and in fact never was explicitly debated) concerned the intellectual foundation of Metchnikoff's original concept of immunity as those activities that defined organismal identity, (developed from Metchnikoff's research in developmental biology) and which regarded host defense mechanisms as only subordinate to this primary function. Immunology in the first half of the 20th century pursued issues pertinent to chemically characterizing immune specificity and only later returned to the Metchnikovian question of how the immune identity was established. This latter venture has achieved molecular sophistication, but even such a formulation may be an inadequate answer to the Metchnikovian postulate. The theoretical discussion between cellularists and humoralists continues in new guises, for the essential debate remains unresolved.     

Chemical Display of Pyrimidine Bases Flipped Out by Modification-Dependent Restriction Endonucleases of MspJI and PvuRts1I Families

The epigenetic DNA modifications 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in eukaryotes are recognized either in the context of double-stranded DNA (e.g., by the methyl-CpG binding domain of MeCP2), or in the flipped-out state (e.g., by the SRA domain of UHRF1). The SRA-like domains and the base-flipping mechanism for 5(h)mC recognition are also shared by the recently discovered prokaryotic modification-dependent endonucleases of the MspJI and PvuRts1I families. Since the mechanism of modified cytosine recognition by many potential eukaryotic and prokaryotic 5(h)mC “readers” is still unknown, a fast solution based method for the detection of extrahelical 5(h)mC would be very useful. In the present study we tested base-flipping by MspJI- and PvuRts1I-like restriction enzymes using several solution-based methods, including fluorescence measurements of the cytosine analog pyrrolocytosine and chemical modification of extrahelical pyrimidines with chloroacetaldehyde and KMnO₄. We find that only KMnO₄ proved an efficient probe for the positive display of flipped out pyrimidines, albeit the method required either non-physiological pH (4.3) or a substitution of the target cytosine with thymine. Our results imply that DNA recognition mechanism of 5(h)mC binding proteins should be tested using a combination of all available methods, as the lack of a positive signal in some assays does not exclude the base flipping mechanism.     

Categorical perception of orientation in monkeys

Structural and functional substrates of orientation processing in monkeys have been clarified. However, orientation perception in monkeys has not been fully studied. In this study, the cognitive mechanism that controls monkeys' perception of orientation was evaluated. After the monkeys were trained to discriminate between a cardinal and an oblique orientation (e.g., 0 degrees and 30 degrees), their perceptual mechanisms underlying orientation discrimination were tested by using six orientations, ranging from 0 degrees to 150 degrees, including ones used in the discrimination training. Generalization tests showed that the monkeys who were trained with cardinal orientations (e.g., 0 degrees) as positive stimuli generalized their responses to the other cardinal orientation (e.g., 90 degrees). Similarly, the monkeys who were trained with oblique orientations (e.g., 30 degrees) as positive stimuli generalized their responses to all other oblique orientations (e.g., 60 degrees, 120 degrees, and 150 degrees). These findings indicated that the monkeys abstracted the quality of the cardinal/oblique category from the physical features of orientation stimuli although they were not trained to do so. Such an abstraction also suggested a discrepancy between a continuously and orderly arranged cortical map and a discontinuously categorized perception of orientation. The present findings provide insight into the learning-correlated plasticity of cortical orientation preference.     

Random-effects ordination: describing and predicting multivariate correlations and co-occurrences

Ecology is inherently multivariate, but high-dimensional data are difficult to understand. Dimension reduction with ordination analysis helps with both data exploration and clarification of the meaning of inferences (e.g., randomization tests, variation partitioning) about a statistical population. Most such inferences are asymmetric, in that variables are classified as either response or explanatory (e.g., factors, predictors). But this asymmetric approach has limitations (e.g., abiotic variables may not entirely explain correlations between interacting species). We study symmetric population-level inferences by modeling correlations and co-occurrences, using these models for out-of-sample prediction. Such modeling requires a novel treatment of ordination axes as random effects, because fixed effects only allow within-sample predictions. We advocate an iterative methodology for random-effects ordination: (1) fit a set of candidate models differing in complexity (e.g., number of axes); (2) use information criteria to choose among models; (3) compare model predictions with data; (4) explore dimension-reduced graphs (e.g., biplots); (5) repeat 1–4 if model performance is poor. We describe and illustrate random-effects ordination models (with software) for two types of data: multivariate-normal (e.g., log morphometric data) and presence–absence community data. A large simulation experiment with multivariate-normal data demonstrates good performance of (1) a small-sample-corrected information criterion and (2) factor analysis relative to principal component analysis. Predictive comparisons of multiple alternative models is a powerful form of scientific reasoning: we have shown that unconstrained ordination can be based on such reasoning.     

Allergy screening using a microcomputer.

Data are presented to show that a microcomputer can be programmed to: (1) analyse a standard allergy questionnaire, (2) reliably predict the ranked order probabilities with which IgE antibody tests will produce positive results, (3) store the IgE test results, and (4) print a comprehensive report that summarises and integrates the clinical and laboratory data. Consequently, the practitioner who refers a blood sample and a questionnaire completed by the patient to a centre where both can be analysed will obtain enough practical information to decide whether to treat or refer that patient to a specialist. The microcomputer is therefore potentially of great value in any preliminary allergy investigation.     

Mechanism and epidemiology of laboratory animal allergy

Laboratory animal allergy (LAA) is a form of occupational allergic disease. The development of laboratory animal allergy is due to the presence of IgE antibodies directed against animal proteins. The process of sensitization (development of IgE antibodies) is a complex process which involves interaction of antigen presenting cells and lymphocytes of the Th-2 cell type. These cells generate a host of cytokines and other factors which lead to immediate hypersensitivity reactions and other factors which lead to immediate hypersensitivity reactions and the generation of allergic inflammation. Typical symptoms of laboratory animal allergy include nasal symptoms, such as sneezing, watery discharge, and congestion. Skin rashes are also common. Asthma, which produces symptoms of cough, wheezing, and shortness of breath, may affect 20-38% of workers who are sensitized to laboratory animal allergens. Rarely a generalized, life-threatening allergic reaction (anaphylaxis) may occur. The estimated prevalence of laboratory animal allergy is variable depending on the method used for diagnosis, but nonetheless may affect up to 46% of exposed workers. The presence of pre-existing allergies to non-work place allergens (e.g., dust mite, pollens, molds), exposure to laboratory animal allergens, and possibly tobacco smoking are risk factors for the development of laboratory animal allergy. Progress in the understanding of the mechanism and epidemiology of laboratory animal allergy will lead to improved methods for its prevention.