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Cadmium, zinc and lead concentrations in soils and plants near a smelter at Avonmouth are reported for samples collected in May 1979 and in May 1980. The total metal soil concentrations fall as distance from the smelter increases and decrease rapidly with depth for cadmium and zinc. The concentrations of these two metals are highly correlated at all depths. Near the smelter, where the carbon content and pH values of the soils are lowest, almost all the cadmium, as measured by EDTA extraction, is available. Concentration of metals in plants also decrease with distance from the smelter, with concentrations being lower in samples collected in 1980. This is possibly due to a seasonal variation in biomass, producing a dilution effect. We conclude that uptake of cadmium and that of zinc by grass species have different relationships to the carbon content of the soil.

SUMMARY Blood samples were collected by jugular puncture, initially and at four times during one grazing season, from steers grazing Midland bermudagrass pastures (1) not fertilized with nitrogen (N), or fertilized in three equal installments with either (2) 112, (3) 224, or (4) 448 kg N/ha/year or grazing (5) common bermudagrass (112 kg N/ha/year) and (6) orchardgrassladino clover pastures. The blood plasma was analyzed for urea nitrogen (PUN). Each increment in N fertilization of Midland resulted in an increase in PUN levels of steers grazing these pastures. The data were reduced to polynomials describing the regression of crude protein (CP) and in vitro digestible dry matter (IVDDM) content of consumed forage and average daily gain (ADG) on PUN. PUN levels estimated from a regression equation which are necessary to sustain gains of .5 kg/day were 15, 10, 15, 25, 15 and 8 rag/100 ml for treatments 1 through 6, respectively. Animals grazing all pastures consumed enough CP to attain or exceed these levels at the beginning of the grazing season. However, PUN levels of the steers grazing the bermudagrass treatments fell below these levels 48, 75, 75, 48 and 48 days after the beginning of the grazing season, respectively. Animals grazing orchardgrassladino maintained a high enough PUN level throughout the grazing season to sustain an ADG of .5 kg/head/day.

A variety of ingenious methods have been devised to challenge and incite episodes of acute allergic rhinitis in susceptible individuals. These methods teach us much about basic mechanisms involved in the disease. There is some danger in using them for efficacy trials because antihistamines are only partially effective treatment for hay fever and the challenge administered could easily overcome the degree of protection. Additional studies may lead to a better understanding of the factors involved in challenges and hence, their usefulness in clinical testing. The out-patient trial design is successful in demonstrating efficacy in 40 to 60 per cent of trials. The field trial is 70 to 90 percent accurate in its findings. The clinical design of antihistamine trials has improved remarkably in the past 10 years. Because of the nature of the disadvantages discussed throughout this report, I would doubt that further improvements in design will occur in future years unless a substitute is found for subjective evaluations.

Summary As part of a study of the effectiveness of beclomethasone dipropionate in perennial rhinitis five immunologically related parameters were measured. These included skin tests, total IgE, specific IgE, nasal and peripheral blood eosinophil counts. In addition, nasal biopsies were obtained in twenty out of sixty patients. It was apparent that patients with perennial rhinitis formed a heterogeneous group who could be divided into three groups based on the extent of immunological abnormality detected. Group 1 consisted of twenty patients who displayed no abnormality in any of the five parameters studied. Group 2 consisted of twenty-six patients in whom specific IgE was not detected but who had varying degrees of abnormal findings in the other laboratory parameters. The remaining fourteen patients formed a third group in whom specific IgE was detected in addition to abnormalities in other parameters. In general, patients with detectable specific IgE had a higher frequency of abnormal parameters, including abnormal histology of their nasal biopsy, than patients in whom no specific IgE was detected. The heterogeneous nature of perennial rhinitis is discussed. Despite the heterogeneous nature of the total patient group, the majority of patients (80%) treated with beclomethasone dipropionate improved compared to 20% improved in the placebo group. There was no difference in the drug effect between the three groups of patients.

The low frequency antigen Orriss (Or) was found on the erythrocytes of a healthy blood donor. A subsequent family investigation showed Or to segregate independently of the Rh, Colton and Kidd blood group systems; however, it appeared to be inherited with the Ms gene complex. Studies carried out demonstrated that sialoglycoproteins (SGPs) extracted from Or+ erythrocytes specifically neutralize anti-Or and that all Or+ individuals tested carry an M antigen which is more resistant to trypsin treatment than the M antigen of Or- erythrocytes. These results lead to the conclusion that the Or antigen is found on a variant alpha-SGP and its presence renders this molecule more resistant to trypsin than normal.

Azelastine, a novel antiallergic medication, was compared with chlorpheniramine maleate and placebo for efficacy and safety in the treatment of spring allergic rhinitis in a multicenter, double-blind, multiple-dose, parallel-groups study. One hundred fifty-five subjects participated. Subjects ranged in age from 18 to 60 years of age and had at least a 2-year history of spring allergic rhinitis, confirmed by positive skin test to spring aeroallergens. Medications were given four times daily; the azelastine groups received 0.5, 1.0, or 2.0 mg in the morning and evening with placebo in the early and late afternoon; the chlorpheniramine group received 4.0 mg four times daily. Daily subject symptom cards were completed during a screening period to assess pretreatment symptoms and during a 4-week treatment period while subjects received study medications. Individual symptoms, total symptoms, and major symptoms were compared to determine efficacy of medication. Elicited, volunteered, and observed adverse experiences were recorded for each subject and compared among groups. Vital signs, body weights, serum chemistry values, complete blood cell counts, urine studies, and electrocardiograms were obtained for each subject and compared among groups. Symptoms relief in the group receiving the highest concentration of azelastine (2.0 mg twice daily) was statistically greater than in the placebo group during all weeks of the study. Lower doses of azelastine were statistically more effective than placebo only during portions of the first 3 weeks of the study. In contrast, although the chlorpheniramine group did have fewer symptoms than the placebo group during the study, the difference never reached statistical significance during any week of the study. There were no serious side effects in any of the treatment groups. Drowsiness and altered taste perception were increased significantly over placebo only in the high-dose azelastine group. Azelastine appears to be a safe, efficacious medication for seasonal allergic rhinitis.

Two in vitro systems of measuring total IgE and specific IgE antibodies were compared using serum of patients suspected of having allergic rhinitis due to inhalation of grass pollen. One in vitro system was the Phadebas PRIST and RAST. The accuracy of these tests has been well defined and they were used as the standard. The Acti*Tip Allerg*E and Allerg*ENS system is a new technique utilizing a similar solid-phase immunologic methodology with an enzyme-based detection system. It has some advantages primarily related to the mechanics of performing the test and marked reduction in time for obtaining results. The correlation between the Phadebas and Acti*Tip systems was highly significant for measuring total IgE and specific IgE antibodies for grasses in serum.

Antihistamine therapy reduces hay fever symptoms 50–60% within 5 hours after the first dose. Treatment for 9 days maintains but does not reduce symptoms further. Patients treated with placebo for 8 days and then treated with chlorpheniramine obtained as much relief by the 5th hour after treatment as those treated with chlorpheniramine for 9 days. Increasing the dose of any antihistamine we tested over that necessary for maximal relief produces no greater benefit. Antihistamine treatment doses currently recommended may be greater than necessary for most patients. Antihistamines do not reduce nasal congestion and are not decongestants.

Oxymetazoline (Afrin) and pseudoephedrine (Sudafed) were compared by rhinomanometric measurements using nasal airflow, a parameter of nasal airway patency, and therefore airway congestion. Oxymetazoline had a more rapid onset and duration of action, greater improvement in airway patency, and longer action than pseudoephedrine, the best of the oral decongestants. The decongestive effect was more reliable for oxymetazoline with 28 of 29 subjects experiencing some degree of decongestion compared to 21 of 30 for pseudoephedrine. Utilizing a combination of oral and topical decongestants may result in the most logical regimen for treatment of nasal congestion. Oxymetazoline is the drug of choice for night time decongestion.

Injections of aqueous ragweed extract are generally not thought to be capable of sensitizing ragweed-negative skin reactors. A review of our passive transfer recipients showed that of 22 recipients challenged with aqueous ragweed extract on more than two occasions, 3 developed positive ragweed skin tests. One of these recipients became sensitized and lost the sensitivity in time only to become sensitized again when challenged on one occasion.

Acute episodes of allergic rhinitis were produced in the laboratory with quantitated challenges of ragweed pollen. Nasal congestion caused by ragweed inhalation was measured objectively as often as every two minutes during an episode of hay fever. Challenges given one hour daily on four successive days decreased the nasal threshold for allergic rhinitis more than fivefold. This effect is called "priming of the end organ." The priming effect was readily reversed by stopping challenges for several days. It was shown that environmental exposure during the ragweed pollinating season also primed ragweed-sensitive individuals. Reversibility of the priming effect required weeks after seasonal pollen exposure had ceased. In four subjects challenged during the season, the pollen dose which caused an acute episode of allergic rhinitis varied according to skin-sensitizing antibody titer; the higher the titer, the greater the susceptibility. In six ragweed-sensitive subjects tested, neither hay fever symptoms nor nasal congestion followed placebo challenges.

It having been shown in previous articles1 that the antigens of many bacteria and cells consist of pure fats, it seemed advisable to inquire whether a spore-bearing organism such as B. anthracis would yield a similar antigen. For this purpose there was selected a laboratory strain of anthrax bacillus, and a strain sent me from the Hygienic Laboratory at Washington. These strains were pure, the one a meager, the other an abundant, spore producer, and were easily raised in virulence for guinea-pigs and rabbits. While the method of isolation of fatty antigens has been given before, it will be briefly summarized.

The titers of skin sensitizing antibody of the sera of untreated hay fever patients differ significantly from those of the sera of persons who react to intracutaneous tests with ragweed pollen extract but who do not have clinical hay fever.

Eosinophilia of some degree is associated with many allergic conditions, but the function of the eosinophil in these conditions is not known. This report describes a morphological change, vacuoles in the eosinophil, previously unrecognized in human beings in vivo. Vacuolizaton of the eosinophil occurred more frequently in symptomatic asthmatic patients. It was also found in other allergic conditions such as allergic rhinitis and serum sickness. In a large control population of hospitalized patients, vacuolization of eosinophils was often found associated with those illnesses in which tissue damage played an important role, such as myocardial infarction. In a control group of student nurses, vacuolization of eosinophils was observed only in those patients who had active allergic disease. In a group of healthy nonallergic subjects such eosinophils were rarely seen. The meaning of vacuolization was not established. One hypothesis suggested by the findings is that vacuoles repesent phagocytized foreign protein. In allergic individuals, the protein could be either antigen-antibody complexes or antigen.

1. 1. The severity of hay fever varied according to the titer of skin-sensitizing antibody, the group of patients showing the highest titers of antibody reporting the most symptoms and those with the lowest titers the fewest symptoms. 2. 2. Clinical symptoms were more directly related to the titers of skin-sensitizing antibody than to the type of injection therapy administered. 3. 3. Sex of the patient is not a determinant in the severity of hay fever symptoms.

Summary The skin-sensitizing and hemagglutinating antibody titers of most ragweed hay fever patients rise after an injection of emulsified ragweed extract reaching a peak at 3 to 6 weeks and showing a gradual decline by the end of 12 weeks. The least sensitive group of patients who received the highest dosage (10,000 PNU) showed no significant changes in skin-sensitizing antibody titer, but did respond with increased hemagglutinating and blocking antibody titers. All groups of patients showed a rise in blocking antibody after treatment reaching a peak at approximately 6 weeks. The group that received 10,000 PNU remained essentially unchanged from the 6th to 12th weeks whereas those that received 1000, 2500, or 5000 PNU showed a decrease in titer. Patients who received two injections of emulsified ragweed extract showed further increases of all antibody titers after the second injection.

The “priming effect” has been defined as an increase in reactivity of the nasal membrane following repeated exposures to pollen. Priming is reversible in days to weeks, depending on the degree of exposure to antigen. Additional characteristics of the priming effect were determined by administering ragweed pollen to only one nostril. Such challenges caused unilateral allergic rhinitis. When unilateral challenges were repeated daily they eventually caused priming or a hyperreactivity of the challenged nostril only; the resistance of the contralateral nostril was unchanged. These findings suggest that the priming effect is related to a local change in the challenged tissue rather than a systemic change. After one nostril was primed by repeated daily exposures to ragweed pollen, sorrel pollen—an antigen to which the patient had a positive skin test but which did not provoke symptoms during normal environmental exposure—was administered on the same day to both the primed and unprimed nostrils. Severe rhinitis occurred in the primed nostril during minimal exposure to this antigen; no symptoms occurred in the unprimed nostril despite a tenfold increase in the pollen dose. Evidence is presented indicating little or no cross-reactivity between ragweed and sorrel. These findings suggest that priming is nonspecific.

Skin-sensitizing antibody in low titer was present in the lacrimal secretion of 2 out of 7 atopic individuals whose sera showed a high skin-sensitizing antibody titer. Blocking antibody to ragweed was not found in the lacrimal secretion of one treated patient who had an elevated serum blocking antibody titer. Serum protein components found in tears were albumin and beta-2A globulin.

Skin-sensitizing antibody was not found in cord serum when it was detectable in the corresponding maternal serum except in one case. In this case, the cord serum contained all classes of the immunoglobulins and an admixture of maternal and fetal blood was suspected. Six maternal sera which contained skin-sensitizing antibody showed significant binding of I 131 -labeled ragweed pollen fraction (I*RW-IV 2 ), and four of the corresponding cord sera in which skin-sensitizing antibody could not be detected also bound significant amounts of I*RW-IV 2 . In a small series of maternal-cord sets tested, all maternal sera contained IgG, IgA, and IgM, whereas cord sera always contained IgG, occasionally IgM, and in one case previously mentioned, IgA. The results suggest that significant binding of I*RW-IV 2 was associated with a factor other than skin-sensitizing antibody in the cord sera, although this interference should be limited by the known detecting ability of the techniques used.

Titers of SSA decreased in 10 of 21 previously untreated patients with hay fever after treatment with injections of aqueous extract for 13 to 48 months. Quantity of antigen injected did not appear to influence the change in titer. Patients with the highest titers before treatment changed least after therapy. All patients with the lowest pretreatment titers showed significant declines in titer after treatment. Fifteen subjects did not receive injections of extract. Titers did not change in 12 and increased in 3 during a period of 2 to 3 years. Titers of SSA were determined in 2 other groups of patients. In one group, treated with aqueous extracts for many years, titers did not change during one additional year of therapy. The average of this group's first titers was low and suggested that previous therapy had caused a decrease in titer during early years of treatment. Forty other patients received repository injections of extract for 3 consecutive years. No difference existed between the average titers of pre- and postreatment sera. Titers of 5 patients in this group increased significantly. Results suggest that aqueous injection therapy frequently causes a decrease in SSA, "hyposensitization." One hypothesis to explain hyposensitization is that injected antigen suppresses antibody synthesis. Hyposensitization may be analagous to partial immune tolerance.

Summary Sera of treated hay fever patients, which contained blocking antibody in high titers (800 PNU or more), induced PCA in the skin of guinea pigs. There was a similar but less definite relation between high titers of hemagglutinating antibody and induction of PCA. Titers of skin sensitizing (Prausnitz-Kuestner) antibody have no relation to the activity of sera in PCA. Activity of the sera of treated hay fever patients in producing PCA was not affected by heating for 4 hr at 56°C or storage for 2 years at 4°C.

1.1. The intracutaneous skin test tends to vary directly with the skin-sensitizing antibody titer. However, individual variations are so great that titer cannot be determined from the skin test. 2.2. The doses of aqueous ragweed extract tolerated by patients vary inversely with the skin-sensitizing antibody titer. 3.3. Development of blocking antibody increases the tolerance for injected extracts. 4.4. Patients with high titers of skin-sensitizing antibody are more likely to have constitutional reactions to emulsions of ragweed pollen extract even with lower doses of antigen. The titer of skin-sensitizing antibody is a helpful guide in determining the dose of emulsified pollen extract to be used. 5.5. Prolonged treatment with injections of aqueous ragweed extract is accompanied by a decrease in the titer of skin-sensitizing antibody. This decrease is greatest between the first and fifth year of treatment but continues up to 20 years. Comparative studies of untreated patients and of patients who, after 1 or 2 years of treatment, were untreated for an average of 9 years suggest that this decrease in titer of skin-sensitizing antibody results directly from the treatment and not from the increasing age of the patient or duration of hay fever.

It is noted that sera of 5 of 11 patients who have been treated with 5,000 or 10,000 PNU of ragweed extract in mineral oil emulsions contained an anaphylactic type of antibody (or antibodies) capable of inducing passive cutaneous anaphylaxis in guinea pig skin.

Terfenadine is the first of a new class of non-sedating H1 antihistamines. It differs from chlorpheniramine in its lower anticholinergic activity in rabbit salivation tests. In animal model distribution studies, the drug is not found in the brain. In most clinical studies sedation attributed to terfenadine was on the order of that observed with placebo. Clinical trials of efficacy show that at best terfenadine is slightly less effective than or as effective as chlorpheniramine.

Nasal tissues can be affected by a greater variety of stimuli than is generally considered, stimuli which can produce many different diseases. The manner in which the nose can respond symptomatically and physically is limited so that symptoms and findings in different diseases frequently overlap and the conditions may be difficult to diagnose. An understanding of nasal diseases is only in its infancy. This report outlines some of these diseases and speculates about the presence of others. Classification of nasal disease is presented based on the suspected presence or absence of an immunological mechanism.

A method has been developed to equalize as many of the variables as possible in a clinical trial to assess the response to medication in allergic rhinitis. This method was used to study the effectiveness of azatadine maleate and pseudoephedrine sulfate alone and in combination. Azatadine effectively relieved symptoms of hay fever but did not reduce nasal congestion to a significant degree. Pseudoephedrine relieved nasal congestion but did not reduce symptoms. The combination of azatadine and pseudoephedrine relieved both symptoms and congestion.

In a double-blind study, a timed-release tablet containing carbinoxamine maleate 8 mg and pseudoephedrine hydrochloride 120 mg was compared with placebo for the treatment of signs and symptoms of nasal allergy. Ninety-four adults with rhinitis caused by grass or ragweed allergy were paired according to severity of symptoms and nasal congestion, then assigned randomly to drug or placebo. After baseline measurements were taken, three doses of drug or placebo were given at 12-hour intervals. The active drug was significantly better than placebo in relieving the following symptoms: nasal congestion, nose blowing, sneezing, nasal pruritus, rhinorrhea, ophthalmic pruritus, and sniffles. Improvement over baseline in mean total nasal air flow also was greater in subjects given active drug. The incidence of nonspecific symptoms, including possible drug side effects, was similar between groups. We conclude that the timed-release tablet is safe and effective therapy for the treatment of signs and symptoms of nasal allergy.

Azelastine is capable of interfering with a wide variety of mediators of airway hyperreactivity and provides significant protection and bronchodilation in allergic hay fever and allergic asthma, respectively. Clinical studies have shown that azelastine produces clinically significant bronchodilation of long duration in moderate to severe reversible lower airway disease. In addition, azelastine has been shown to have an effect on the upper airways by effective symptom relief in patients with seasonal allergic rhinitis; furthermore, azelastine affords protection against exercise and allergen provocation.

A multicentered trial compared the effects of the non-sedating antihistamine, loratadine, 5 mg plus pseudoephedrine 120 mg with a placebo on the signs and symptoms of the common cold. One hundred forty-two (142) subjects were treated with the loratadine/pseudoephedrine combination and 141 subjects were treated with placebo twice daily for five days. Evaluations by both subjects and physicians suggest that this antihistamine/decongestant combination is superior to placebo in relieving symptoms of the common cold. Specific differences were found in symptoms including nasal congestion, sneezing, postnasal drainage, and nasal discharge. Differences between groups for the following side effects were found: dry mouth (9% for the combination vs 2% for placebo), insomnia (6% vs 3%), and nervousness (4% vs 2%). There were no differences between groups for the frequency of drowsiness.

Pseudoephedrine and triprolidine, administered every 6 hours as a combination, made separate and distinct contributions to the treatment of allergic rhinitis. Furthermore, the combination was perceived by the patients as being clinically superior to either of its components or placebo.

A solid-phase enzyme immunoassay for allergen-specific IgE antibodies in serum is descirbed. In this technique these antibodies are allowed to bind to the allergen previously adsorbed to the wells of polystyrene microtiter plates. After a washing step the tubes are incubated with rabbit antihuman IgE labelled with horseradish peroxidase. Following a second washing step, the enzyme bound to the tubes is assayed spectrophotometrically using O-phenylene diamine as the substrate. The standard curves obtained with this method and with the RAST technique are illustrated. For the assay of serum antiragweed IgE antibodies, concordance between the results obtained with the RAST test and this immunoperoxidase assay was observed in 85 or 95 (90%) patients with symptoms of ragweed hayfever. The coefficients of variation ranged from 4.4% (2SD +/- .010) TO 14% (2SD +/- .008). The advantages of using peroxidase as the enzymatic marker for the assay of allergen-specific IgE are discussed.

An indirect immunoperoxidase technique was used to study the content and distribution of IgE in formaldehyde solution-fixed, paraffin-embedded adenoid and nasal tissues of atopic and nonatopic persons. Adenoid tissue from 15 patients, and nasal tissue from five patients with symptoms of inhalant allergies and augmented serum levels of total and allergen-specific IgE were examined with this method. Adenoid tissues from five patients without allergic symptoms were studied for comparison. A rich content of IgE, largely within the cytoplasm of the plasma cells, was observed in tissues of atopic subjects. The sections from nonallergic persons contained few weakly staining IgE-positive cells. These observations provide anatomic support for the role of IgE in hypersensitivity reaction of immediate type. This immunoperoxidase technique, circumventing the principal shortcomings of the immunofluorescence procedures, affords a highly sensitive and practical approach to cellular and tissue localization of IgE.

Airflow through the nose is a complex function since the nose is a tortuous series of channels. Mathematicians can only guess at formulas which would explain the intricacies of the nasal passages and flow of air through them. For practical purposes a "black box technique" may be used in which input and output are measured at either end of the black box (the nose). A very useful and accurate measure of nasal patency is obtained from these measurements. Rhinometry has been limited in research environment but is now feasible for clinical practice. With the advent of simpler techniques and improved instruments any physician can be trained to do rhinometry.

This report describes an instrument which measures the effective cross-sectional area of the nasal airway. The patient breathes into a mask which extends from the upper lip to the forehead and across the cheeks laterally. Two openings in the mask system permit air to flow: one is the nasal airway (N a ) and the other an opening to the atmosphere (M a ), which can be varied. Pharyngeal pressure (P p ) and mask pressure (M p ) are recorded continuously during normal respiration. N a can be calculated in square millimeters by the empirical formula Na=2.5 (Ma) (Mp)Pp. This device offers a number of advantages over previously described instruments. The nose itself is not physically touched. All variables, such as pressures and the opening from the mask to the atmosphere, can be measured with existing equipment. An airway measurement can be made with each inspiration, and patients can be followed for prolonged periods without discomfort. The patient's effort in breathing need not be constant nor must it be strenuous, permitting measurements in the physiologic range.