Aberrant Structural Brain Connectivity in Adolescents with Attentional Problems Who Were Born Prematurely.

BACKGROUND AND PURPOSE: Differences in structural brain connectivity that underlie inattention have been previously investigated in adolescents with attention deficit/hyperactivity disorder, but not in the context of premature birth, which is often associated with attentional problems. The purpose of this study was to identify the neural correlates of attentional problems in adolescents born prematurely and determine neonatal predictors of those neural correlates and attention problems. MATERIALS AND METHODS: The study included 24 adolescents (12.5 ± 1.8 years of age; 12 girls, 12 boys) who were born prematurely and underwent MR imaging of the brain and cognitive assessment, both shortly after birth and as adolescents. Structural connectivity was assessed at adolescence using diffusion tensor imaging and tractography. RESULTS: Of the 24 subjects, 12 had attention deficits. A set of axonal pathways connecting the frontal, parietal, temporal, and occipital lobes had significantly lower fractional anisotropy in subjects with attentional problems. The temporoparietal connection between the left precuneus and left middle temporal gyrus was the most significantly underconnected interlobar axonal pathway. Low birth weight and ventriculomegaly, but not white matter injury or intraventricular hemorrhage on neonatal MR imaging, predicted temporoparietal hypoconnectivity in adolescence. However, neither birth weight nor other neonatal characteristics were associated with attention deficits directly. CONCLUSIONS: We identified an aberrant structural brain connectivity pattern, involving temporoparietal hypoconnectivity, in prematurely born adolescents with attentional problems. We also identified birth weight as a potential neonatal predictor of the temporoparietal hypoconnectivity. These findings add to our understanding of the neural basis and etiology of inattention in adolescents after premature birth.

The treatment of allergic rhinitis with immunotherapy: a review of 1,000 cases.

We conducted a 10-year retrospective chart review of 1,000 immunotherapy-treated patients to evaluate the efficacy and safety of serial dilution quantitative intradermal testing in the management of allergic rhinitis. Three months after the initiation of immunotherapy, these patients had been assessed to ascertain whether or not they had experienced any overall improvement in their initial symptoms. Also included in this evaluation were determinations of each patient's use of medications as well as the incidence of adverse reactions to treatment and recurrent sinus infections. We found that 860 patients had achieved complete relief of their symptoms and required no other treatment; the remaining 140 patients experienced a partial improvement and continued to use pharmacotherapy to control breakthrough symptoms. During skin testing, only one patient experienced a systemic reaction, which responded to subcutaneous epinephrine. There were no deaths. We conclude that serial dilution quantitative intradermal testing is safe and that quantification of skin reactivity in evaluating and treating allergic rhinitis with immunotherapy is completely effective in the vast majority of patients.

The importance of quantifying skin reactivity in treating allergic rhinitis with immunotherapy.

Therapeutic options for the treatment of allergic rhinitis include environmental modifications to decrease exposure to allergens, pharmacotherapy, and immunotherapy for those patients who do not experience satisfactory relief of their symptoms with medical management. Skin testing is the best established and most sensitive indicator of allergic disease. Several techniques are currently in use to identify pertinent antigens in the treatment of inhalant allergies. We describe the various skin testing techniques that are associated with such inhalant allergies. Quantification of skin reactivity to formulate a successful antigen vial for effective immunotherapy is necessary in the management of allergic disease.

Food pollution.

Food can influence the human body in many ways, both positively and negatively. Several key elements of contemporary food cultivation and production are presented, along with their potential consequences to our health. The history of food cultivation and consumption is contrasted between early hunter-gatherer societies and modern day societies. Natural nutrient-rich foods produced from the soil in early societies have been replaced with artificial supplements and treated with pesticides and herbicides to control plant disease. The evolution of pesticides is chronicled from the synthesis of DDT in 1870 to present day. Several commonly used chemicals are described along with their documented side effects. A number of methods of pest control from ancient to modern day are offered as alternatives to polluting chemicals. Integrated pest management is proposed as a promising, economically feasible method of pest management, reducing pollution and risk to wildlife and human health.

NH2-terminal sequence truncation decreases the stability of bovine rhodanese, minimally perturbs its crystal structure, and enhances interaction with GroEL under native conditions.

The NH2-terminal sequence of rhodanese influences many of its properties, ranging from mitochondrial import to folding. Rhodanese truncated by >9 residues is degraded in Escherichia coli. Mutant enzymes with lesser truncations are recoverable and active, but they show altered active site reactivities (Trevino, R. J., Tsalkova, T., Dramer, G., Hardesty, B., Chirgwin, J. M., and Horowitz, P. M. (1998) J. Biol. Chem. 273, 27841-27847), suggesting that the NH2-terminal sequence stabilizes the overall structure. We tested aspects of the conformations of these shortened species. Intrinsic and probe fluorescence showed that truncation decreased stability and increased hydrophobic exposure, while near UV CD suggested altered tertiary structure. Under native conditions, truncated rhodanese bound to GroEL and was released and reactivated by adding ATP and GroES, suggesting equilibrium between native and non-native conformers. Furthermore, GroEL assisted folding of denatured mutants to the same extent as wild type, although at a reduced rate. X-ray crystallography showed that Delta1-7 crystallized isomorphously with wild type in polyethyleneglycol, and the structure was highly conserved. Thus, the missing NH2-terminal residues that contribute to global stability of the native structure in solution do not significantly alter contacts at the atomic level of the crystallized protein. The two-domain structure of rhodanese was not significantly altered by drastically different crystallization conditions or crystal packing suggesting rigidity of the native rhodanese domains and the stabilization of the interdomain interactions by the crystal environment. The results support a model in which loss of interactions near the rhodanese NH2 terminus does not distort the folded native structure but does facilitate the transition in solution to a molten globule state, which among other things, can interact with molecular chaperones.

Truncations at the NH2 terminus of rhodanese destabilize the enzyme and decrease its heterologous expression.

Rhodanese mutants containing sequential NH2-terminal deletions were constructed to test the distinct contributions of this region of the protein to expression, folding, and stability. The results indicate that the first 11 residues are nonessential for folding to the active conformation, but they are necessary for attaining an active, stable structure when expressed in Escherichia coli. Rhodanese species with up to 9 residues deleted were expressed and purified. Kinetic parameters for the mutants were similar to those of the full-length enzyme. Compared with shorter truncations, mutants missing 7 or 9 residues were (a) increasingly inactivated by urea denaturation, (b) more susceptible to inactivation by dithiothreitol, (c) less able to be reactivated, and (d) less rapidly inactivated by incubation at 37 degreesC. Immunoprecipitation showed that mutants lacking 10-23 NH2-terminal amino acids were expressed as inactive species of the expected size but were rapidly eliminated. Cell-free transcription/translation at 37 degreesC showed mutants deleted through residue 9 were enzymatically active, but they were inactive when deleted further, just as in vivo. However, at 30 degreesC in vitro, both Delta1-10 and Delta1-11 showed considerable activity. Truncations in the NH2 terminus affect the chemical stability of the distantly located active site. Residues Ser-11 through Gly-22, which form the NH2-proximal alpha-helix, contribute to folding to an active conformation, to resisting degradation during heterologous expression, and to chemical stability in vitro.

Air pollution and its effect on the upper respiratory tract and on allergic rhinosinusitis.

The nose is the first organ system encountered by inhaled air and its associated pollutants. Pollutants are deposited during inspiration through the nose. They accumulate on mucus and are absorbed in the nasal mucosa, resulting in a number of deleterious effects on the body. Irritation of the nose and sinus from these pollutants, resulting from direct contact with the nasal mucosa, leads to inflammation, edema, swelling, and blocked sinuses. The result is acute and chronic sinusitis. Absorption of these chemicals into the body produces systemic effects. Their effect on the immune system, although subtle, leads to dramatic changes in the allergic diathesis. The T suppressor cell is the most sensitive cell of the immune system and the first to be affected by exposure to chemical pollutants. Diminution of the suppressor activity and the relative increase in helper activity in turn lead to increased immunoglobulin production and the manifestation of allergy symptoms. The underlying biochemical reaction is caused by the effects of pollutants on the T suppressor cell. Patients with existing allergies become brittle and difficult to treat with the exacerbation of the allergic diathesis. Removal of these chemical pollutants from the body as quickly as possible is essential for effective treatment of this problem. Dietary antioxidants help reduce the oxidizing effect of the pollutants and act as conjugators to remove the pollutants from the body.

Chinese hamster rhodanese cDNA: activity of the expressed protein is not blocked by a C-terminal extension.

We describe a cDNA from Chinese hamster ovary cells which encodes a protein 91 and 96% identical to bovine and rat mitochondrial rhodaneses, respectively. Recombinant protein was expressed from the cDNA in Escherichia coli, purified to homogeneity, and found to have kinetic properties nearly indistinguishable from those of the bovine enzyme, the only cloned rhodanese previously verified by characterization of the recombinant protein. The carboxyl-terminus of the enzyme is characterized by a duplicated tripeptide, which can be proteolytically processed in vivo. We constructed a mutant in which the last 5 amino acids were replaced by 28 residues of unrelated sequence. This protein was expressed, purified, and found to have kinetic constants similar to those of the wild-type enzyme. The functionally verified Chinese hamster rhodanese cDNA encodes a protein of 297 residues and differs from the rat enzyme at 13 positions. None of these substitutions occurs at residues suggested to play essential roles in catalysis or structural stabilization.

Comparison of results of immunotherapy based on skin end-point titration, prick testing, and scratch testing.

Presented is a clinical study comparing the result of immunotherapy based on allergy testing with three different test modalities: skin end-point titration, prick testing, and scratch testing. Thirty patients with allergic rhinitis were randomly assigned to one of the three test groups. Treatment vials were made on test results according to the instructions for each test. For skin end-point titration, each antigen was included at a concentration based on the patient's sensitivity, found with the fivefold dilution testing procedure. For the prick test, treatment vials were based on a two-level test response scale of stronger or lesser positive results. The scratch test yields vials used in one concentration based simply on a positive vs. negative test result. Patients in all three groups were treated at weekly intervals with immunotherapy, progressing in volume until the maximum tolerated dose was achieved. Relief of symptoms was evaluated after 6 months of treatment. Nine of the 10 patients receiving skin end-point titration based immunotherapy had complete relief of symptoms, and one had partial relief. None of the patients in the prick or scratch test groups achieved relief of symptoms after 6 months of treatment. Results dramatically demonstrate the need to base allergy immunotherapy treatment on a test that quantifies the patient's level of sensitivity to each antigen.

The biochemistry of neutralization.

It has been shown that injections of low doses of common environmental antigens or irritants cause a reduced sensitivity during a subsequent exposure to the same antigen and irritant. On the basis of these findings, the following study was performed: 20 allergic patients who manifested allergic symptoms were observed during skin end-point titration testing, which is described in the manuscript. During the testing procedure, 60% of the patients reported a complete relief of symptoms. It is postulated that a cytoprotective dose was given during the testing procedure that caused the symptoms to be relieved. The second part of the study was a double-blind placebo control study in which 40 patients received the end-point dose and 10 patients received placebo. All patients entered the study with allergic symptoms. None of the placebo patients reported any relief of symptoms when given their injection. Of patients who received the active ingredient, 67.5% reported relief of symptoms within 5 to 10 minutes after the subcutaneous administration of the active ingredient. With these findings, it is postulated that this low dose of active ingredient caused the production of prostaglandin E intracellularly, which causes an increase in cyclic AMP and a decrease in cyclic GMP, which results in the resolution of symptoms.

Allergic rhinosinusitis: the total rhinologic disease.

Allergic rhinosinusitis has three forms of therapy: pharmacotherapy, immunotherapy, and surgical therapy. Pharmacotherapeutically, there are six classes of drugs that give symptomatic relief: mucolytics, decongestants, anti-cholinergic agents, antihistamines, mast cell stabilizers, and corticosteroids. All six classes are discussed individually and in detail. For immunotherapeutic therapy of allergic rhinosinusitis, there are four types of skin testing in current use: scratch testing, prick testing, single intradermal testing, and skin end point titration testing. Only the latter is able to quantitate the antigenicity of each antigen, and thus the treatment vial made from only this type of skin testing can adequately treat all antigens to which the patient is sensitive. These differences in testing and vial mixing are explained. The last form of therapy is surgical therapy, which corrects the obstructive phenomenon caused by allergic rhinosinusitis. The procedures described are reduction inferior turbinectomies and endoscopic sinus surgery. It is felt by the authors that the specialist who is uniquely positioned to offer a patient suffering from allergic rhinosinusitis all three forms of therapy is the rhinologist.

Efficacy of alternative tests for delayed-cyclic food hypersensitivity.

With the oral challenge food test (OCFT) used as the standard for delayed-cyclic food hypersensitivity diagnosis, blinded comparison studies were accomplished with 175 in vitro food specific IgE and 180 IgG radioallergosorbent tests, 180 food enzyme-linked immune complex assays, and 155 in vivo Multi-Test prick tests. The study was multi-centered, eight physicians and 37 patients participating. All of the compared tests were shown to be approximately 50% efficient when compared with the OCFT results, and, thus, nonefficacious.

Provocation-neutralization: a two-part study. Part I. The intracutaneous provocative food test: a multi-center comparison study.

This study investigated the clinical usefulness of the intracutaneous provocative-neutralization food test (IPFT). Thirty-seven patients were tested for five identical food allergies by eight physicians in different geographical locations. Throughout the study, comparison was made between the IPFT when interpreted by skin response (IPFT SK) and when interpreted by symptom provocation (IPFT PR). Double-blind IPFT results were compared with those of previously accomplished oral challenge food tests (OCFT). IPFT reliability was determined by a double-blind comparison of the initial IPFT, with two subsequent IPFTs performed 7 days apart. Correlation of the IPFT SK and IPFT PR with the OCFT provided validity coefficients of 0.78 and 0.61 respectively, both significant beyond the 0.01 level of confidence. Reliability of the IPFT SK and IPFT PR was shown to be 0.68 and 0.40, respectively. The IPFT SK was significant beyond the 0.01 level of confidence and the IPFT PR was significant beyond the 0.05 level of confidence.

Provocation-neutralization: a two-part study. Part II. Subcutaneous neutralization therapy: a multi-center study.

Presented is a triple-blind crossover study that investigates the efficacy of subcutaneous neutralization food hypersensitivity therapy. Seven physicians and thirty-three patients from various parts of the country participated. Each patient underwent three 2-week treatment sessions, with 1 week off treatment between each session. During each treatment session, one injection a day was given. The injection consisted of a placebo for one 2-week session, and the active allergen during the other two sessions. The active dose was determined by earlier intracutaneous provocative food testing. The diet during the study period was not varied. Medication-symptom diaries were maintained and treatment result evaluations for both individual complaints and overall results were detailed on a standard form at the end of each treatment session. While the number of foods treated per patient varied from 1 to 13, the majority were treated with 3 to 5 foods. Treatment with the active medication was more efficacious than with placebo. A few patients' symptoms were aggravated with the active medication. This indicates a correct diagnosis, but incorrect treatment dose. In the clinical setting such adverse response should be reversed. Overall, neutralization subcutaneous treatment should be beneficial approximately 75% of the time, and further enhanced by supplemental diet manipulation.

IgG levels after treatment with antigen vials based on the scratch testing, intradermal testing, modified RAST testing.

In this study, there were three groups of patients--each group consisting of four patients. The first group had been skin tested by the scratch method, the second group was skin tested by the end point titration intradermal method, and the third group had been tested for inhalant allergy by the modified RAST technique. All of them had multiple treatment vials made, dependent on the type of testing they had, and the vials all included the ten inhalants that were tested for. All patients had been treated for a year with weekly immunotherapy injections. Specific IgG levels, blocking antibody levels to the ten inhalant allergens, were determined. The results were that the patients who had been scratch tested had the lowest levels of specific IgG blocking antibody--while both intradermal end point titration and modified RAST testing had much higher elevations of blocking IgG antibody, with the RAST having the highest. It is concluded that, since the treatment vials prepared after scratch testing of all the antigens are at the same concentration, there are many antigens that are not given in adequate amounts to cause a good IgG response whereas, by calibrating the concentrations of antigens in the intradermal titration and the modified RAST testing, all the antigens are being injected in sufficient quantities to get a good blocking antibody response.

Immunology of foods.

Investigation of food sensitivity is difficult and often confusing. However, there are multiple articles in the literature which illustrate that food is absorbed from the gastro-intestinal tract in an antigenic fashion and that the entire immune system is stimulated by these antigenic food particles. All four Gell and Coombs varieties of immunologic reactions have been demonstrated as causes of symptoms in patients. Test techniques are available for each of these immunologic reactions, as is treatment for their noxious effects.

Immunologic mechanisms in the production of food sensitivities.

Fifty-five test patients and ten control patients were selected for provocation of symptoms using the oral challenge test. The provoking food was selected with the use of the leukocyte cytotoxic test. The test patients developed adverse symptomatology clinically while the control patients did not. During the phase of symptomatology it was shown that IgE did not change in the blood and, therefore, the Type I, anaphylactic type of reaction, which is IgE dependent, did not participate in symptom production. It was shown that 2 components of the classical pathway of complement C3 and C4 were utilized in the test group and not in the control group. Complement is 1 of the 2 components of the humoral system of the human immune system. C4 is one of the components that is triggered by the classic complement pathway, whose stimulus is IgG and IgM, and not by the other complement pathways. It can therefore be hypothesized that all the components of the circulatory humoral system are participating in this reaction and that Type II, the cytotoxic, and Type III, th immune-complex type of immunologic reaction, are the major contributors in the production of symptoms.