Segmental Arterial Mediolysis in Pigs Presenting With Renal Infarcts.

Segmental arterial mediolysis, a rare arteriopathy first reported in humans, is described in the kidneys of 36 pigs slaughtered in an abattoir in Jutland, Denmark. The kidney changes presented themselves macroscopically as one or more cortical wedge-shaped hemorrhagic or pale lesions. The arterial lesions involved the interlobar and arcuate arteries and exhibited injurious and reparative phases of development. Two types of injurious lesions occurred: (1) a tearing separation of the outer media from the adventitia with fibrin, erythrocytes, and edema fluid filling the formed space, causing collapse of the arterial wall, and (2) outer and mid-medial foci showing irregularly bordered cytoplasmic vacuolar change containing membranous and organelle debris or smooth muscle shrinkage with nuclear loss. In the reparative phase, granulation tissue filled and expanded tear sites and zones of arterial medial muscle loss and extended into the adventitia and through the intima into the arterial lumen. Sequelae, including dissecting hematomas and arterial occlusions causing renal infarcts, were found. Although repartitioning agents widely used in animal husbandry in many countries may potentially cause segmental arterial mediolysis, no such link could be identified. The causation of segmental arterial mediolysis in these pigs is currently unknown but is being further investigated.

Myocardial toxicity in a group of greyhounds administered ractopamine.

Ractopamine, a synthetic ß(2)-adrenoceptor agonist, is widely used as a feed additive in the United States to promote a reduction in body fat and enhance muscle growth in cattle, pigs, and turkeys. It has the potential for illegal use in show and racing animals because it may affect performance via its ß-adrenergic agonist properties or anabolic activities. Nine greyhounds were orally administered 1 mg/kg of ractopamine to investigate the ability to detect the drug in urine. Postdosing, 7 of 9 dogs developed cardiac arrhythmias and had elevated troponin levels indicating myocardial damage. One dog necropsied 4 days postdosing had massive myocardial necrosis, mild to focally moderate skeletal muscle necrosis, and widespread segmental arterial mediolysis. A second dog necropsied 17 days postdosing had mild myocardial necrosis and fibrosis. Scattered arteries exhibited segmental medial and perimedial fibromuscular dysplasia. This is the first reported case of arterial, cardiac, and skeletal muscle damage associated with ractopamine.

Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE.

BACKGROUND: Patients with severe persistent asthma who are inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy are a challenging population with significant unmet medical need. We determined the effect of omalizumab on clinically significant asthma exacerbations (requiring systemic corticosteroids) in the first omalizumab study to exclusively enrol patients from this difficult-to-treat patient population. METHODS: Following a run-in phase, patients (12-75 years) inadequately controlled despite therapy with high-dose inhaled corticosteroids (ICS) and long-acting beta(2)-agonists (LABA) with reduced lung function and a recent history of clinically significant exacerbations were randomized to receive omalizumab or placebo for 28 weeks in a double-blind, parallel-group, multicentre study. RESULTS: A total of 419 patients were included in the efficacy analyses. The clinically significant asthma exacerbation rate (primary efficacy variable), adjusted for an observed relevant imbalance in history of clinically significant asthma exacerbations, was 0.68 with omalizumab and 0.91 with placebo (26% reduction) during the 28-week treatment phase (P = 0.042). Without adjustment, a similar magnitude of effect was seen (19% reduction), but this did not reach statistical significance. Omalizumab significantly reduced severe asthma exacerbation rate (0.24 vs 0.48, P = 0.002) and emergency visit rate (0.24 vs 0.43, P = 0.038). Omalizumab significantly improved asthma-related quality of life, morning peak expiratory flow and asthma symptom scores. The incidence of adverse events was similar between treatment groups. CONCLUSIONS: In patients with inadequately controlled severe persistent asthma, despite high-dose ICS and LABA therapy, and often additional therapy, omalizumab significantly reduced the rate of clinically significant asthma exacerbations, severe exacerbations and emergency visits. Omalizumab is effective and should be considered as add-on therapy for patients with inadequately controlled severe persistent asthma who have a significant unmet need despite best available therapy.

IgE antibody to Aspergillus fumigatus recombinant allergens in cystic fibrosis patients with allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) is characterized by a heightened Th2 CD4+ T-cell response to Aspergillus fumigatus (Af) allergens and a hyper-immunoglobulin E (IgE) state compared with cystic fibrosis patients without ABPA. The IgE serologic differentiation of ABPA from atopic CF patients can be difficult. We propose as the reactivity with purified antigens varies qualitatively and quantitatively and that the antibody response is more specific than with crude Af antigen extract, the IgE responses to purified recombinant Af allergens may differentiate ABPA from atopic CF patients. METHODS: Serum IgE reactivity to seven recombinant purified allergens and to a crude extract of Af was measured in 15 ABPA, in 23 Af skin test positive (ST+), and in 19 Af skin test negative (ST-) CF patients. Four of the ABPA CF patients were studied before and after developing ABPA. Nine ABPA patients were studied during flares and remissions of ABPA. RESULTS: Allergic bronchopulmonary aspergillosis patients had significantly increased IgE reactivity to Asp f2, f3, f4, f6, and f16 compared with the Af ST+ and ST- non-ABPA CF patients. In the ABPA patients studied before and after developing ABPA, IgE reactivity also increased to Asp f2, f3, f4, and f6, and to the crude extract. In ABPA CF patients, IgE reactivity to Asp f1, f2, f3, and f6 significantly increased during periods of ABPA flares compared with periods of remission. Analysis of the receiver operating curve demonstrated that IgE reactivity to Asp f3 and f4 gave the best sensitivity and specificity and were better than IgE reactivity to a crude extract of Aspergillus. Furthermore, in ABPA patients studied during periods of remission the IgE reactivity to Asp f3 and f4 remained significantly elevated compared with Af ST+ non-ABPA patients. The IgE responses when considered either to be positive or negative to Asp f3 and f4 significantly differentiated ABPA from Af ST+ and ST- non-ABPA CF patients. In contrast, IgE reactivity was considered positive to the crude extract in 89% of ABPA, 61% of Af ST+, and 0% of Af ST- non-ABPA CF patients. CONCLUSIONS: Immunoglobulin E reactivity to a panel of purified Af allergens, especially to Asp f3 and f4, differentiates ABPA from atopic Af ST+ non-ABPA CF patients. Serial determinations of IgE reactivity to individual purified Aspergillus antigens, especially Asp f3, demonstrates that increases in IgE reactivity may provide improved distinction between stages of flares and remission compared with changes in IgE reactivity to a crude Aspergillus extract.

"Allergic sinusitis" revisited.

BACKGROUND: "Allergic sinusitis" is a frequently used term but there is question about its true existence. OBJECTIVE: To detect the presence of allergic inflammation of the sinuses in five highly symptomatic ragweed sensitive adults. METHOD: Three imaging techniques were utilized: SPECT bone imaging, SPECT Indium111 labeled WBC uptake, and FDG F-18 (PET scanning). RESULTS: We could find no evidence of sinus involvement in association with severe allergic rhinitis. CONCLUSIONS: Employing three different imaging modalities, we were unable to demonstrate inflammation of the sinuses in patients with allergic rhinitis.

Pediatricians' attitudes towards allergy: past and present attitudes of pediatricians towards allergy.

BACKGROUND: In 1971 we published a survey of pediatricians' knowledge, attitudes, and practices relative to the field of allergy. This current survey was conducted to determine how these attitudes and practices have changed over the past 27 years. METHODS: Our survey, consisting of 17 questions, was sent to 250 board certified pediatricians in the St. Louis area. Seven of the questions were similar to those in the 1971 survey, while the other ten were new questions which we thought were pertinent to the field of allergy currently. RESULTS: In 1971, 75% of the pediatricians felt the specialty of allergy had great or moderate importance for the practice of pediatrics compared with 99% in 1998. In 1998, the number of physicians who felt that there was at least some value to skin testing had increased from 1971, although, only 36% felt it had great value. In 1971, 23% of pediatricians performed their own skin tests compared with 3% in 1998. Nine percent indicated that they had never referred a patient to an allergist in 1971, compared with 2% in 1998. Our new questions looked at to whom respondents were more likely to refer patients with: (1) asthma (68% allergy, 27% pulmonary, 4% both), (2) urticaria (53% allergy, 41% dermatology, 2% both), (3) chronic eczema (45% allergy, 50% dermatology, 2% both), and (4) chronic sinusitis (24% allergy, 74% otolaryngology, 2% both). Older physicians placed greater importance on the field of allergy and skin testing and were more likely to refer to an allergist than physicians under the age of 40 years. CONCLUSION: Our results indicate that although there has been significant change in 27 years, allergists must be more aggressive in developing the knowledge, attitudes, and practices of physicians relative to the field of allergy.

Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a disease with uncertain pathology. Studies have suggested a pathogenic role for T(H)2 cells. Previously, we demonstrated, in a small group of patients, that T(H)2 reactivity to a major Aspergillus fumigatus antigen was restricted by HLA-DR2 or HLA-DR5 alleles. OBJECTIVES: We sought to confirm whether susceptibility to ABPA is exclusively associated with HLA-DR locus and to investigate the involvement of HLA-DQ genes in the development of ABPA. METHODS: Genomic DNA was extracted from patients with ABPA, patients without ABPA but with positive A fumigatus skin test responses and asthma or cystic fibrosis, and healthy control subjects. HLA-DR and HLA-DQ genes were detected by using low-resolution typing; high-resolution typing was done only on HLA-DR2- and HLA-DR5-positive individuals by using sequence-specific primers (PCR-SSP). RESULTS: A significantly higher frequency of HLA-DR2 was observed in patients with ABPA versus those without ABPA (corrected P <.01) or healthy control subjects (corrected P <.01). Genotype analysis revealed that susceptibility to ABPA is associated with HLA-DR2 alleles DRB1*1503 and DRB1*1501 and, to a lesser extent, with the HLA-DR5 allele DRB1*1104. The presence of DR4 or DR7 alleles in non-DR2/5 patients with ABPA suggests that these alleles may also be contributing factors in this disease. Another striking observation was the significantly high frequency of HLA-DQ2 in patients without ABPA (67. 4%) compared with patients with ABPA (20.5%) and normal control subjects (37.7%), suggesting that these alleles may confer protection in the population without ABPA. CONCLUSION: These genetic studies suggest that HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility while HLA-DQ2 contributes to resistance and that a combination of these genetic elements determines the outcome of ABPA in patients with cystic fibrosis and asthma.

Endometriosis-associated intestinal tumors: a clinical and pathological study of 6 cases with a review of the literature.

This clinicopathologic study of primary Mullerian tumors of the bowel arising in foci of endometriosis is based on six new cases and an analysis of 17 previously reported cases. Varieties of Mullerian tumors occur in the bowel; the most common types are endometrioid carcinoma, followed by various mixed Mullerian tumors and stromal sarcomas. Seventy-eight percent develop in the rectosigmoid colon, the remaining in the cecum or ileum. Those in the latter area tend to be sarcomas or mixed Mullerian tumors. Certain architectural growth characteristics, derived from precursor endometriosis, are common to most endometriosis-associated intestinal tumors (EAITs). Seventy percent of EAITs occur in the outer bowel wall. Transmural tumors tend to form luminal polyps and assume an hourglass shape. Metachronous or synchronous Mullerian tumors occur in 39% of cases. Seventy percent of women with EAITs are in their mid 30s to early 50s. Common presenting symptoms are abdominal or pelvic pain, melena, and an abdominal or pelvic mass. Documented in 26% of patients is a history of prolonged unopposed estrogen therapy. Only 28.5% of cases die of their tumors, but follow-up is less than 5 years in all but 2 patients.

Results of the National Cooperative Inner-City Asthma Study (NCICAS) environmental intervention to reduce cockroach allergen exposure in inner-city homes.

BACKGROUND: Cockroach allergen is important in asthma. Practical methods to reduce exposure are needed. OBJECTIVE: We sought to evaluate the effectiveness of house cleaning and professional extermination on lowering cockroach antigen levels in inner-city dwellings. METHODS: As part of the National Cooperative Inner-City Asthma Study intervention, 265 of 331 families with asthmatic children who had positive skin test responses to cockroach allergen consented to a professional home extermination with 2 applications of a cockroach insecticide (Abamectin, Avert) combined with directed education on cockroach allergen removal. On a random subset of 48 homes undergoing cockroach extermination in the intervention group, Bla g 1 was measured in settled dust from the kitchen, bedroom, and TV/living room. The first sample was collected 1 week before extermination, with additional samples after the exterminations at approximately 2, 6, and 12 months after the first sample. Self-reported problems with cockroaches were collected at baseline and after 12 months of follow-up in both the intervention and control group. RESULTS: The geometric mean kitchen level of Bla g 1 decreased at 2 months (33.6 U/g) relative to preextermination levels (68.7 U/g, P <.05). The percent of kitchens with over 8 U/g of Bla g 1 followed a similar pattern, but only the decrease from preextermination to 6-month levels was significant (86.8% vs 64.3%, P <.05). By the 12-month visit, the allergen burden had returned to or exceeded baseline levels. Except for an increase in the bedroom at 2 months (8.9 U/g vs 11.1 U/g, P <.05), no other significant change was seen. Only about 50% of the families followed the cleaning instructions; no greater effect was found in these homes. Self-reported problems with cockroaches showed no difference between the intervention and control group after 1 year of follow-up. CONCLUSIONS: Despite a significant, but short-lived, decrease the cockroach allergen burden remained well above levels previously found to be clinically significant.

Opioids accelerate fetal rat lung maturation in vitro.

Infants born to heroin- and cocaine-addicted mothers have been reported to have a lower incidence of respiratory distress syndrome (RDS) compared with nonaddicted infants. However, it is not known whether these are direct drug-mediated effects or secondary phenomena. We therefore investigated the effect of opioids and cocaine on fetal rat lung maturation in vitro. Using 18- to 20-d fetal rat lung explants and 20-d fetal type II cells, we measured the effect of varying concentrations (1 x 10(-8) to 1 x 10(-3) M) of heroin, morphine, methadone, and the nonopioid cocaine on the rate of choline incorporation into phosphatidylcholine (PC) and disaturated PC. We also analyzed the morphology of 19-d explants after exposure to opioids. Significant increases in rate of choline incorporation were noted in 19- and 20-d explants using 1 x 10(-3) M heroin, 1 x 10(-3) M morphine, and 1 x 10(-4) M methadone (P < 0. 005). No acceleratory effect was seen with cocaine. Morphologic analysis of the three opioid-treated groups revealed a significant (192 to 251%) increase in type II pneumocytes and lamellar bodies per alveolar lining cell (P < 0.01). Choline incorporation into PC by type II cells was also significantly increased by opioids (P < 0. 01); lactate dehydrogenase release and cell viability were not affected by opioid treatment. These data indicate that high-dose opioids have an acceleratory effect on biochemical and morphologic parameters of fetal lung maturation in vitro. The lack of in vitro acceleration with cocaine suggests that any cocaine-related reduction in the incidence of RDS is a secondary effect.

Occupational rhinitis.

BACKGROUND: Occupational rhinitis is a common but generally unappreciated entity. It frequently exists with asthma but may present alone. While not as dramatic a presentation as bronchial asthma, it nevertheless results in significant discomfort and work inefficiency. The history and physical examination are the most important components to the workup of the patient. The frequent occurrence of an isolated late phase nasal response may make the correct diagnosis confusing. A site visit to the specific work area may give helpful insights to the patient's exposure. Greater objectivity to the diagnosis can be obtained through the rapidly developing technique of rhinomanometry. CONCLUSION: The management of occupational rhinitis should include not simply pharmacotherapy but also environmental control measures. Through these means, patients may be spared the distress and discomfort of occupational rhinitis.

Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma.

BACKGROUND: It is important to understand the relationship between environmental allergen exposure dose and the risk of atopic individuals becoming sensitized to that allergen if we are to change the risk of sensitization and morbidity from allergic disease. OBJECTIVE: The objective of these studies was to determine whether there was a dose response between current exposure to mite, cockroach, and cat allergen in inner-city children and to determine the prevalence of sensitization to these allergens. METHODS: A sample of 500 children was selected from the 1528 children enrolled in the National Cooperative Inner City Asthma Study. Children were selected who had a sample of home dust and valid skin test responses performed with a MultiTest skin test device. The samples of home dust were collected from the floor and furniture in the kitchen, bedroom, and television/living room and were assayed for Der p 1, Der f 1, Bla g 1, and Fel d 1 allergens. RESULTS: Each allergen level correlated significantly between rooms in individual homes. Mite (Der p 1 and Der f 1) and cat (Fel d 1) allergen levels were frequently below the detection limit of the assay. Cockroach allergen (Bla g 1) concentrations in the child's bedroom were related to the prevalence of positive skin test responses to cockroach allergen extract among the children, with an odds ratio for sensitization of 1.45 (1.11-1.92). Positive skin test responses to cockroach allergen were seen in 15% of children exposed to bedroom dust with a Bla g 1 concentration below the level of detection compared with a rate of 32% in bedrooms with Bla g 1 levels of 1 to 2 U/g and 40% to 44% among those in rooms with 4 U/g or greater. The relationship between exposure and positive skin test responses was clearly stronger among atopic children with a greater number of positive skin test responses. CONCLUSIONS: Despite widespread exposure to household allergens, the strongest relationship between exposure and sensitization was seen in the bedroom. The dose response between exposure to cockroach allergen and sensitization suggested that exposure to low doses of allergen, 2 U/g or less, was a risk factor and that the risk plateaus above 4 U/g. Atopy modified the relationship of exposure to sensitization.

Does inhaled pollen enter the sinus cavities?

BACKGROUND: While there is evidence of an increased incidence of sinusitis in patients with allergic rhinitis, it is unclear whether an allergic process occurs in the sinus tissues per se. OBJECTIVE: The purpose of this study was to determine whether inhaled pollen reaches the sinus mucosa. METHODS: Tc99m labeled ragweed pollen was inhaled by five non-atopic adults. Imaging studies of the sinuses were performed with a tomographic rotating gamma camera. To determine the sensitivity of the technique, the nose and the maxillary sinuses of cadaver heads were painted with varying amounts of Tc99m and then similarly scanned. RESULTS: Scans of the cadaver heads showed clear resolution between the nasal cavity and the maxillary sinus. It was determined that 20 microci was the smallest amount of Tc99m that could be resolved to be in the sinuses. Scans of subjects showed intense activity in the nasal cavity but none in the paranasal sinuses despite the delivery of a supraphysiologic dose of Tc99m ragweed pollen. CONCLUSION: Inhaled ragweed pollen does not appear to enter the paranasal sinuses. It is unlikely that an inhaled antigen-IgE antibody reaction occurs in the sinus mucosa.

Continuous intrapulmonary distension with perfluorocarbon accelerates neonatal (but not adult) lung growth.

BACKGROUND/PURPOSE: We have previously demonstrated that experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia associated with congenital diaphragmatic hernia. The purpose of this study was to determine if lung growth could be similarly accelerated postnatally by continuous liquid-based intrapulmonary distension. METHODS: Ten neonatal lambs were divided into two experimental groups. Five neonatal animals underwent a right thoracotomy with isolation of the anterior superior segment of the right upper lobe. A pressure monitoring catheter was introduced and perfluorocarbon (PFC) was instilled into the segment. Animals were subjected to a 21-day distention period with continuous maintenance of 7 to 10 mm Hg intrabronchial pressure. Five other neonatal animals used as age- and weight-matched controls were killed immediately after distension with PFC to 7 to 10 mm Hg. To evaluate the effect of age on postnatal growth, identical procedures were performed on seven mature sheep. Four adult animals underwent a 21-day distension with PFC, and three animals were killed immediately after PFC distension. RESULTS: Neonatal animals who underwent distension showed a significant acceleration of lung growth based on right upper lobe volume to body weight ratio (P = .0019), total alveolar number (P = .003), and total alveolar surface area (P = .006), when compared with controls. Alveolar growth was attributed to an increased alveolar number rather than increased alveolar size based on a normal histological appearance, normal airspace fraction (P = NS), and normal alveolar numerical density (P = NS). In contrast, no significant differences in lung growth or maturation indices were present in adult animals. CONCLUSIONS: From this preliminary data we conclude: (1) Liquid-based airway distension does accelerate postnatal lung growth, (2) lung architecture remains normal during this period of accelerated growth, (3) adult sheep do not respond to liquid-based airway distension with lung growth, and (4) prolonged exposure to intrapulmonary PFC appears to be safe. We speculate that stretch is the stimulus for lung growth because there are no known growth factors present in PFC.

Adrenal insufficiency in an adult on inhaled corticosteroids; recovery of adrenal function with inhaled nedocromil sodium.

BACKGROUND: Whereas oral corticosteroids and high-dose inhaled corticosteroids may be associated with suppression of the hypothalamic-pituitary-adrenal axis, medium-dose inhaled corticosteroids have not been reported to be associated with clinically significant adrenal insufficiency in the adult. OBJECTIVE: A case study of adrenal responsiveness after prolonged medium-dose inhaled corticosteroids and after replacement of steroid therapy by inhaled nedocromil sodium is described. METHODS: Standard 250-microg dose ACTH (cosyntropin) stimulation tests were followed after replacement of inhaled triamcinolone acetonide therapy by nedocromil sodium. RESULTS: A 55-year-old woman who had been on inhaled triamcinolone acetonide, 1600 microg/day for 12 years, presented with symptoms of adrenal hypofunction upon inhaled corticosteroid taper. An ACTH stimulation test confirmed adrenal insufficiency. She was switched to inhaled nedocromil sodium with improvement in her clinical syndrome and normalization of her ACTH stimulation test. CONCLUSION: Withdrawal from prolonged use of inhaled medium-dose corticosteroids may be associated with clinically significant adrenal insufficiency in adults. Steroid sparing agents may be considered for those on long-term inhaled corticosteroid therapy.