Concomitant anaphylactic sensitization and contact unresponsiveness following the infusion or feeding of picryl chloride to guinea pigs.

Guinea pigs receiving one large dose of picryl chloride by the intravenous or oral routes commonly develop circulating antibody demonstrable by passive cutaneous anaphylaxis or by active anaphylaxis. They often concommittantly become unresponsive to the induction of delayed contact hypersensitivity by intracutaneous injections. Erythrocytes obtained from guinea pigs after infusion or feeding of picryl chloride may be used to sensitize other animals when injected with adjuvant. It is concluded that guinea pigs may be anaphylactically sensitized to simple chemicals by the intravenous and oral routes if a sufficient dose is administered.

HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5. II. Response after ragweed immunotherapy.

After artificial immunization (immunotherapy) with ragweed antigens, specific immunoglobulin G (IgG) antibody (Ab) response to Ra5 was significantly associated with HLA-Dw2 (P less than 0.0001). From a total of 61 treated patients, all 22 Dw2+ subjects made good IgG Ab responses to Ra5 by year 2 of therapy (21 by year 1), even though 8 of them had no detectable IgG Ab and 9 had no detectable IgE Ab before therapy. The prevalence of IgG Ab response among 39 Dw2- subjects was markedly lower; only 11 (28%) responded well after 1-9 yr of therapy. Both by univariate and multivariate statistical analysis, Dw2 was also found to be strongly associated with the quantity of IgG Ab produced. In particular, both the strength and significance of the association between Dw2 and log[IgG Ab] response to Ra5 increased over a 3-yr period of ragweed therapy (P = 10(-9) by year 3). Multiple regression analysis also revealed a weak association with HLA-B13, which became apparent only after year 2 of therapy. Genetic hypotheses for these findings are discussed. In particular, the possibility of a second Ir gene, Ir-Ra5', separate from HLA-Dw2 and possibly located elsewhere in the genome, is considered.

Cutaneous late-phase response to allergen. Mediator release and inflammatory cell infiltration.

To better define the inflammatory infiltrates and kinetics of mediator release during the cutaneous late-phase reaction (LPR), we examined skin biopsies at 8 h, and skin chamber cell counts and mediator release for 12 h after antigen challenge. Compared with the control sites, the antigen-stimulated biopsy sites contained 14 times as many basophils (P less than 0.01) and six times as many eosinophils (P less than 0.001) with one to two fold more mononuclear cells (P less than 0.03) and neutrophils (P less than or equal to 0.01). Similar changes were found in the skin chambers. Although there were neutrophils in the control chamber, they were only twice as numerous in the antigen challenged site (P less than 0.01). Eosinophils were 35-fold (P less than or equal to 0.03) more prevalent in the antigen chamber than the control chamber for hours 8-12 and basophils were noted starting in the eighth hour and were 20-fold (P less than or equal to 0.03) more concentrated in the antigen chamber during the next 4 h. The mononuclear cells were not significantly different between antigen and control blisters. With respect to inflammatory mediators, there was an initial peak of histamine (13.2 +/- 2.9 ng/ml) in the blister fluid at 1 h. The level then fell to approximately 2 ng/ml, followed by a secondary rise starting at the eighth hour and increasing to 9.8 +/- 2.8 ng/ml by the twelfth hour. This secondary increase in histamine correlated significantly (r = 0.81, P less than 0.05) with the observed influx of basophils. PGD2 in the blister fluid rose to 371+/-25 pg/ml during the first 4 h and then slowly decreased to half this level during the last 4 h. Thus, the cutaneous LPR has been shown to manifest a secondary increase in histamine levels and a markedly specific increase in eosinophils and basophils with mediator release apparently being derived from the latter cells.

IgA and IgG anti-ragweed antibodies in nasal secretions. Quantitative measurements of antibodies and correlation with inhibition of histamine release.

Total secretory IgA and specific anti-antigen E (AgE) antibodies (ab) in the IgA and IgG classes were measured in concentrated nasal washings from ragweed allergic and normal individuals by antigen binding or anti-alpha-radioimmunoassays. Virtually all the allergic patients had significant IgA (45/49) and IgG (46/49) ab to AgE in their nasal washings. By contrast, washings from most normal persons contained no measurable IgA (13/15) ab or IgG (13/15) ab to AgE. The total IgA levels in allergic washings were not significantly different from those in normal washings and they were used to standardize the ab measurements. Parenteral immunotherapy with ragweed extract increased specific nasal IgA ab from 10.6 +/- 2.7 (SEM) to 39.0 +/- 8.7 ng AgE bound/mg IgA and IgG ab from 17.2 +/- 2.6 to 65.1 +/- 7.4 ng AgE bound/mg IgA (P less than 0.001 for both classes). The ratio of IgA:IgG ab was not affected by therapy, and for treated patients, there was no correlation (rs + 0.32, P greater than 0.1) between nasal IgG ab and serum IgG ab. These results suggest that at least part of the nasal IgG ab is produced locally. Blocking activity in the nasal washings was measured by inhibition of histamine release and was found to correlate directly (rs + 0.85, P less than 0.001) with binding activity for AgE. Some washings from normal persons caused slight inhibition of histamine release but others caused enhancement. Nasal washings were fractionated by passage over Sephadex G-200. Inhibition of histamine release by dilutions of the IgA-rich and IgG-rich fractions correlated well with binding activity in these fractions. None of these results support the hypothesis that allergic individuals are deficient in secretory IgA or secretory ab responses. These results, however, are in keeping with the theory that hay fever occurs in a high-responder population which is genetically able to respond to low doses of inhalant antigens.

Influx of kininogens into nasal secretions after antigen challenge of allergic individuals.

We have recently demonstrated that kinins are generated in vivo after nasal challenge with antigen of allergic, but not nonallergic, individuals. The present study was undertaken as a first step in determining the mechanism(s) of kinin formation during the allergic reaction and was directed towards establishing the availability and origin of kininogens in nasal secretions. Allergic individuals (n = 6) and nonallergic controls (n = 5) were challenged with antigen; and by using specific radioimmunoassays, nasal washes, obtained before and after challenge, were assayed for high molecular weight kininogen (HMWK), total kininogen (TK), albumin, and kinins. Dramatic increases in HMWK (1,730 +/- 510 ng/ml), TK (3,810 +/- 1035 ng/ml), kinin (9.46 +/- 1.75 ng/ml), and albumin (0.85 +/- 0.2 mg/ml) were observed after challenge of allergic individuals which correlated (P less than 0.001) with increases in histamine and N-alpha-tosyl-L-arginine methyl esterase activity and with the onset of clinical symptoms. For nonallergic individuals, levels of kininogens, albumin, and all mediators after antigen challenge were not different from base line. Linear regression analysis revealed excellent correlations (P less than 0.001 in each case) between increases in HMWK, TK, kinin, and albumin during antigen titration experiments and between the time courses of appearance and disappearance of HMWK, TK, kinin, and albumin after antigen challenge. Gel filtration revealed no evidence of degradation products of kininogens in nasal washes. For each allergic individual the ratio of HMWK/TK in postchallenge nasal washes was similar to the ratio of these two proteins in the same individual's plasma. These data suggest that, during the allergic reaction, there is an increase in vascular permeability and a transudation of kininogens from plasma into nasal secretions, where they can provide substrate for kinin-forming enzymes.

IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy.

Specific IgE anti-ragweed antibodies (IgEAR) were measured over two years in two groups of highly sensitive patients treated (immunized) with either ragweed extract or placebo and in a third group of placebo-treated, relatively insensitive patients. The IgEAR on the patients' basophils were assessed by ragweed antigen E (AgE)-induced histamine release; blocking (IgG) antibodies were measured by their ability to inhibit AgE induced histamine release. These data were evaluated against the clinical severity of ragweed hay fever in each patient. WE FOUND THAT: (a) In placebo treated patients IgEAR usually declined gradually prior to the ragweed season and were boosted by environmental exposure to ragweed pollen. (b) In immunized patients the IgEAR rose at the beginning of treatment, but fell as immunotherapy proceeded; by the end of the second year the levels had decreased in 18/19 patients. (c) The increase in blocking antibody during immunotherapy correlated significantly (P < 0.05) with the decrease in serum IgEAR. (d) Judged by their sensitivity to AgE induced histamine release, IgEAR on basophils correlated significantly with IgEAR in the serum of untreated patients (P < 0.01). (e) The highly sensitive placebo treated patients' symptom scores were significantly correlated with their IgEAR in serum (P < 0.01) and with the sensitivity of their basophils to AgE-induced histamine release (P < 0.01). Neither correlation was observed in the relatively insensitive patients. (f) In the treated group the IgEAR measurements predicted neither the degree of their illness nor their clinical improvement We conclude tha IgE antibody measurements may be useful in the assessment of the severity of reaginic allergy in highly sensitive patients. Its use in modestly sensitive patients requires patients requires further study, as does the inverse association between IgE and IgG antiragweed antibodies.

Kinins are generated in vivo following nasal airway challenge of allergic individuals with allergen.

Using a recently developed model of nasal challenge, we have obtained data that clearly demonstrate, for the first time, kinin generation during a local allergic reaction in vivo. Allergic individuals (n = 8) and matched nonallergic controls (n = 8) were challenged intranasally with the appropriate antigen and nasal washes were taken before and after challenge. Washes were assayed for kinin, histamine, and [3H]-N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity. Increased kinin generation was found by radioimmunoassay (RIA) in the nasal washes of all the allergics (5,560 +/- 1,670 pg/ml) but in none of the controls (38 +/- 16 pg/ml). The presence of kinin was highly correlated with that of histamine and TAME-esterase activity and with the onset of clinical symptoms (P less than 0.001). Serial dilutions of nasal washes produced RIA displacement curves that paralleled the standard curve, and recovery of standard kinins that were added to nasal washes was 100 +/- 4% (n = 14). Kinin recovery was identical in both allergics and controls and did not vary significantly with antigen challenge. The immunoreactive kinin in nasal washes was stable to boiling and not precipitated by ethanol, but completely destroyed by carboxypeptidase B. It was evenly distributed between the sol and gel phases of nasal washes. High performance liquid chromatography analysis of the immunoreactive kinin in nasal washes showed it to be a mixture of lysylbradykinin and bradykinin. We conclude that kinins are produced during local allergic reactions in the nose and may contribute to the symptomatology of the allergic response.

Effect of short-term systemic glucocorticoid treatment on human nasal mediator release after antigen challenge.

The effect of systemic glucocorticoid treatment on early- and late-phase nasal allergic reactions after allergen challenge was determined in a double-blind, cross-over study in 13 allergic individuals. The subjects were pretreated for 2 d before challenge with 60 mg prednisone per day or a matching placebo. A previously described model using repeated nasal lavages for measuring mediator release in vivo was utilized. Symptom scores obtained repeatedly before, during, and after the challenge and the number and timing of sneezes were recorded. The mediators measured were histamine. N-alpha-p-tosyl-L-arginine methyl ester (TAME)-esterase activity, kinins, PGD2, and LTC4/D4. Albumin was also measured as a marker of plasma transudation. Blood samples were taken for determination of total number of white blood cells, differential count, and total blood histamine content. No effect of steroid therapy was found on the appearance of symptoms or any of the mediators, except a reduction in kinins, in the early phase of the allergic reaction. However, in the late phase, the prednisone reduced the number of sneezes (P less than 0.01), as well as the level of histamine (P less than 0.05), TAME-esterase activity (P less than 0.05), kinins (P less than 0.05), and albumin (P less than 0.05). Only low levels of leukotrienes were found in the late phase, but the quantities of these mediators seemed to be decreased by the glucocorticoid treatment (P = 0.06). PGD2 did not increase during the LPR and thus was not affected by glucocorticosteroids. The immediate response to a second challenge 11 h after the first was also evaluated. Whereas the appearance of mediators was enhanced over the initial response to the same challenge dose in placebo-treated subjects, this enhancement was abrogated after prednisone treatment. As this dose of drug is known to be clinically effective in treating hay fever, the present study confirms the earlier findings of others that short-term systemic glucocorticoid treatment inhibits the late phase but not the immediate phase of antigen challenge. Furthermore, secondary enhancement of immediate responses is inhibited. This study shows that glucocorticoids inhibit the generation or release of inflammatory mediators during the late reaction and the physiologic response.

Nasal challenge with cold, dry air results in release of inflammatory mediators. Possible mast cell involvement.

The purpose of our study was to assess the effect of cold, dry air (CDA) on the nasal mucosa of selected individuals in relation to the release of inflammatory mediators associated with mast cells. 12 subjects with a history of nasal symptoms of rhinorrhea and congestion upon cold or dry environmental exposure were challenged by nasal breathing of CDA and warm, moist air (WMA). Each subject was tested on two occasions with the order of the challenges reversed. Symptom scores were recorded, and the levels of histamine, prostaglandin (PG) D2, kinins, and [3H]-N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity in nasal lavage fluids were measured. CDA caused a significant increase in mediator levels and in symptom scores as compared to baseline or to WMA. No significant increase in symptom scores or mediators was noted after WMA challenge, with the exception of a marginal increase in kinins. The response to CDA was similar, regardless of challenge order. Changes in mediators correlated with one another, and symptom scores correlated significantly with the levels of histamine, kinins, and PGD2. Five subjects without a history of nasal symptoms on cold air exposure had no change in mediators or symptom scores after CDA or WMA challenge. We conclude that CDA causes the release of inflammatory mediators possibly associated with mast cells and speculate that such a mechanism may be involved in the bronchospasm induced by CDA in asthmatics.

Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy.

Challenge of the nasal mucosa of allergic subjects with specific allergen induces not only the expected sneezing and rhinorrhea, but also the appearance in nasal secretions of mediators commonly associated with activation of mast cells or basophils: histamine, leukotrienes, prostaglandin D2 (PGD2), kinins, and TAME ([3H]-N-alpha-tosyl-L-arginine methyl ester)-esterase. To determine whether specific immunotherapy alters mediator release in vivo, nasal pollen challenge was used to compare 27 untreated highly sensitive ragweed (RW)-allergic subjects with 12 similarly sensitive patients receiving long-term immunotherapy (3-5 yr) with RW extract (median dose, 6 micrograms RW antigen E). The two groups were equally sensitive based on skin tests and basophil histamine release. The immunized group had a diminished response as demonstrated by (a) the treated group required higher pollen doses to excite sneezing or mediator release; (b) significantly fewer subjects in the treated group released mediators at any dose (TAME-esterase [P = 0.005], PGD2 [P = 0.04]), and (c) the treated group released 3-5-fold less mediator (TAME-esterase [P = 0.01], and histamine [P = 0.02]).

Modern concepts of immunotherapy.

Although common allergies have been considered as immediate IgE antibody mediated responses, attention is now turning to inflammatory responses that appear to be initiated by T-cell responses to peptides from allergens presented in combination with HLA class II molecules. Although classic immunotherapy with allergen extracts has been found to downregulate these T-cell responses, more efficient and safe methods are being sought.

The influence of prosthesis size and design on exercise dynamics after aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: Residual gradient following aortic valve replacement (AVR) may adversely affect clinical outcome. The size and design of the valve may influence these characteristics. The study aim was to determine the influence of prosthesis physical size and leaflet design on hemodynamic performance after mechanical AVR. METHODS: After AVR, two patient groups with a range of valve sizes were studied. Group 1 patients (n=19) each received a monoleaflet valve; group 2 patients (n=18) each received a bileaflet valve. Transthoracic echocardiography was performed at rest and after graded bicycle ergometry to assess prosthetic valve parameters, including mean and peak transvalvular gradient and effective orifice area (EOA). RESULTS: Transprosthetic gradients (mean and peak) measured at rest, maximum exercise and 3-min recovery were related to indexed geometric orifice area (IGOA) by an exponential decay function, with no significant advantage for either valve design. However, in valve sizes < or =25 mm the bileaflet valves demonstrated lower gradients, both at rest and under exercise conditions (mean gradient during exercise, bileaflet versus monoleaflet 19.9 +/- 7.2 mmHg versus 25.6 +/- 6.3 mmHg, p = 0.01). Similarly, EOAs were larger in the bileaflet group when equivalent GOAs < or =2.5 cm2 were compared (EOA: bileaflet versus monoleaflet 1.51 +/- 0.33 cm2 versus 1.14 +/- 0.26 cm2, p = 0.018). The total work performed correlated with prosthesis diameter (r2 = 0.81, p = 0.037) and was not influenced by valve design. CONCLUSION: The hemodynamic performance of mechanical aortic valves, including transprosthetic gradient and maximum exercise work performed, related principally to the prosthesis physical size. However, within the smaller valve sizes, the bileaflet design appeared to offer hemodynamic advantages.

Secretagogue-induced changes in system A amino acid transport in the rat exocrine pancreas: stimulation of 2-methylaminoisobutyric acid efflux by carbachol.

Secretagogue-induced changes in exocrine pancreatic amino acid transport are poorly understood. In this study uptake of the specific non-metabolized System A amino acid analogue 2-methylaminoisobutyric acid (2-MeAIB) was measured in the isolated perfused rat pancreas during 60 min loading with D-[3H]mannitol (extracellular tracer) and 2-[14C]MeAIB. Tracer 2-MeAIB reached a maximal uptake of 37 +/- 4% (n = 4) after 3 min of loading and gradually decreased to a steady-state uptake of 13 +/- 1%. Infusion of carbachol (3.10(-7) M) during the tracer loading period abolished net tracer 2-MeAIB uptake, and reperfusion in the absence of carbachol restored net uptake to the prestimulus value. Less than 41% of the arterial 2-[14C]MeAIB or D-[3H]mannitol activity appeared in the basal pancreatic secretion. Carbachol evoked a 4.8-fold increase in pancreatic juice flow and appeared to reduce the activity of both tracers in the exocrine secretion. During washout of the pancreas with an isotope-free medium 2-[14C]MeAIB cleared from a rapidly exchanging pool with a time constant (tau 1) of 1.4 +/- 0.3 min (n = 4) and a more slowly exchanging pool with a time constant (tau 2) of 20.7 +/- 1.1 min. Carbachol accelerated efflux of 2-[14C]MeAIB from the epithelium but had no effect on the slow phase of D-[3H]mannitol washout. Our findings suggest that activation of cholinergic receptors modifies Na+-dependent System A amino acid transport in the basolateral membrane of the exocrine pancreatic epithelium.

Regulatory effects of insulin and experimental diabetes on neutral amino acid transport in the perfused rat exocrine pancreas. Kinetics of unidirectional L-serine influx and efflux at the basolateral plasma membrane.

Relatively little is known about the hormonal regulation of amino acid transport in the normal and diabetic exocrine pancreas. In this study unidirectional influx and tracer efflux of L-serine at the basolateral interface of the rat pancreatic epithelium was investigated in the perfused exocrine pancreas using a rapid (less than 30 s) paired-tracer dilution technique. In the non-diabetic pancreas L-serine influx was saturable and stimulated by perfusion with exogenous bovine insulin (100 microU/ml). Transport of L-serine and methylaminoisobutyric acid was markedly elevated in pancreata isolated from streptozotocin diabetic rats and insulin partially reversed the stimulation of L-serine transport induced by experimental diabetes. These results suggest that insulin and diabetes modulate the epithelial transport activity for small neutral amino acids in the intact exocrine pancreas.

Transport characteristics of system A in the rat exocrine pancreatic epithelium analyzed using the specific non-metabolized amino acid analogue alpha-methylaminoisobutyric acid.

The selectivity and kinetics of system A amino acid transport in the rat exocrine pancreatic epithelium were characterized using the specific analogue alpha-methylaminoisobutyric acid. Unidirectional influx of alpha-methylaminoisobutyric acid was measured in isolated perfused pancreata by rapid dual tracer dilution. In cross-inhibition experiments DL-methylalanine, L-serine, L-cysteine, glycine, L-phenylalanine and L-glutamine were effective inhibitors of influx, whereas L-glutamate and L-lysine were less effective. In the presence of sodium alpha-methylaminoisobutyric acid influx was saturable with an apparent Kt = 1.7 +/- 0.2 mM and Vmax = 0.49 +/- 0.03 mumol/min per g (mean +/- S.E., n = 6). Influx of alpha-methylaminoisobutyric acid at 50 microM and 100 microM concentrations was significantly inhibited as the perfusate sodium concentration was gradually decreased from 156 mM to 26 mM by isoosmolar choline replacement. Estimated Kt values for sodium at these two methylaminoisobutyric acid concentrations approximated 200 mM. System A activity in the basolateral membrane of the exocrine pancreatic epithelium exhibits a high transport affinity, a wide tolerance for different amino acids and a dependency upon the extracellular sodium concentration.

Theophylline reduces the response to nasal challenge with antigen.

A nasal challenge model of allergic rhinitis was used to determine if pretreatment with oral theophylline reduces histamine release in vivo. Ten subjects were entered into a double-blind, cross-over trial. The results showed that both the physiologic response (sneezing) (p = 0.02) and the amount of mediators (histamine, kinins, toluene sulfonyl arginine methyl ester esterase activity) (p less than 0.01 for all) released into nasal secretions were significantly reduced after one week of pretreatment with theophylline. At the time of challenge, the serum concentrations of theophylline were between 8 and 22 micrograms/ml. It is speculated that the ability of theophylline to block the clinical response to antigen challenge and to decrease the release of mast cell mediators contributes to its clinical efficacy in the treatment of asthma.

Mediator release during nasal provocation. A model to investigate the pathophysiology of rhinitis.

The pathogenesis of rhinitis was investigated using a model of nasal provocation with different types of stimuli. Allergic subjects had an immediate response to antigenic challenge with symptoms of rhinitis highly correlated with increments in the concentrations of histamine, prostaglandin D2, kinins and kininogens, leukotrienes, and toluene sulfonyl arginine methyl ester esterase activity in their nasal secretions. This reaction was abated by a tricyclic antihistamine also capable of inhibiting mediator release from human mast cells in vitro and, in some subjects, by disodium cromoglycate. In a number of patients, symptoms reappeared three to 12 hours after nasal provocation. This late reaction also involves release of all of the aforementioned mediators except for prostaglandin D2, and preliminary data suggest that it can be inhibited by oral or topical steroids. Cold, dry air can induce rhinitis with mast cell mediator release from selected subjects. The pathogenesis of this reaction is unclear, but there are indications that osmolarity changes are responsible for mast cell activation. Thus, mast cells can be induced to release mediators and cause nasal symptoms by both immunologic and physical mechanisms, which may account for the pathophysiology of several types of rhinitis.

Simplified assessment of fine aerosol distribution in human airways.

We characterized homogeneity of bronchopulmonary distribution of a 0.9% saline aerosol with a mass median aerodynamic diameter (MMAD) of 1.12 micron (sigma g = 2.04) labeled with [99mTc]sulfur colloid in nine normal subjects and nine patients with asthma. Aerosol distribution was quantified from frequency distribution histograms generated from Anger camera scans. Skew (a measure of histogram asymmetry) and kurtosis (a measure of histogram range) were significantly elevated (p less than 0.05) in the asthma patients with 0.68 +/- 0.30 and 2.62 +/- 0.81, respectively, compared with 0.39 +/- 0.12 and 1.89 +/- 0.18, respectively, in the normal subjects. Skew and kurtosis were significantly correlated with baseline forced expiratory volume in 1 sec (FEV1, an index of airway obstruction) with rs = -0.4799 (p less than 0.05) and -0.5929 (p less than 0.01), respectively. Skew and kurtosis were also significantly correlated with mucociliary clearance after approximately 90 min (an index of large, central airway deposition) with rs = 0.6801 and 0.6373, respectively (p less than 0.01). This simplified method of analysis does not require additional study days or procedures and facilitates the detection of airflow obstruction in asthma.

Fasting, refeeding and diabetes modulate free amino acid concentrations in the rat exocrine pancreas: role of transstimulation in amino acid efflux.

The effects of fasting, refeeding, and streptozotocin-induced experimental diabetes on free amino acid concentrations in the rat exocrine pancreas were investigated. Extracts of pancreatic tissue and plasma were analyzed using high-performance liquid chromatography (HPLC). Pancreatic and plasma concentrations of alanine were reduced in animals fasted for 24 to 72 h. Pancreatic concentrations of leucine, arginine, and glutamine were increased after fasting for 48 h, and concentrations of all essential amino acids plus the nonessential amino acids glycine, serine, taurine, and glutamine were elevated after fasting for 72 h. Refeeding 72 h fasted animals for 3 h or 24 h had a negligible effect on the plasma amino acid concentrations, but markedly lowered the concentration of essential amino acids within the pancreatic tissue. Diabetes lowered the total plasma amino acid concentration from 4.9 mM to 3.1 mM but increased the total pancreatic tissue amino acid level from 16.4 mM to 18.3 mM. Efflux of intracellular amino acids into the circulation of the isolated perfused pancreas was assessed under basal conditions and in response to a vascular amino acid challenge using HPLC. L-serine transstimulated efflux of a large number of amino acids, whereas cellular efflux was only minimally affected by L-phenylalanine. Fasting and diabetes-induced increases in essential amino acid concentrations within the pancreas may reflect decreased protein synthesis, accelerated protein catabolism, or a change in membrane transport. Altered intracellular amino acid levels may directly regulate exchange diffusion of intracellular for extracellular amino acid(s).

The effect of cetirizine on early allergic response.

A double blind, placebo-controlled, cross-over study was performed to determine the effect of cetirizine, an H1 antihistamine, on the immediate nasal allergic response. Ten persons underwent nasal challenge with antigen after premedication with 20 mg of cetirizine or placebo QD for 2 days. The response was monitored by counting the number of sneezes and by measuring the levels of histamine, prostaglandin D2, leukotriene C4, albumin, and TAME-esterase activity in recovered nasal lavages. The results showed a significant reduction in sneezing and in the amounts of recovered albumin, TAME-esterase activity, and leukotriene C4 but no reduction in the amounts of recovered histamine and prostaglandin D2. These results suggest that cetirizine does not inhibit mast cell activation but inhibits the consequences of the released histamine on H1 receptors: sneezing and increased vascular permeability. The results further suggest that mast cell release of histamine is the direct result of antigen stimulation, as opposed to reflex activation, and that other cells in addition to mast cells generate leukotrienes during the early allergic response.