Generation and partial characterization of eosinophil chemotactic activity and neutrophil chemotactic activity during early and late-phase asthmatic response

Asthma has been recognized to consist of hyperresponsive airways and cellular inflammation. Allergen bronchoprovocation (BPC) may define the early (EAR) and late-phase asthmatic response (LAR). The LAR has now been associated with increased nonspecific airway hyperresponsiveness and cellular inflammation consisting of neutrophils and eosinophils. We used BPC to demonstrate EAR and LAR in 12 subjects with seasonal allergic asthma. One normal subject and one subject with asthma who had been treated with allergy immunotherapy were challenged but did not respond. Plasma was sampled at frequent intervals during these aeroallergen challenges and assayed for eosinophil chemotactic activity (ECA) and neutrophil chemotactic activity (NCA). Of the 12 subjects with asthma who were challenged, nine had dual responses (both EAR and LAR), and three subjects demonstrated only an LAR. Those subjects who had dual airway responses had biphasic rises in both ECA (early = 267 +/- 28%; late = 286 +/- 28%) and NCA (early = 279 +/- 24%; late = 215 +/- 15%) in their plasma, whereas those subjects who demonstrated only an LAR had only a late rise in ECA (218 +/- 61%) and NCA (188 +/- 31%). The two individuals who did not respond to aeroallergen challenge demonstrated no change in their plasma chemotactic activity toward either eosinophils or neutrophils. Those individuals with the most severe LAR (greater than or equal to 1,000 mm2) had combined ECA plus NCA peak values of greater than 500%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Minimal residual disease in childhood B-lineage lymphoblastic leukemia. Persistence of leukemic cells during the first 18 months of treatment

BACKGROUND. Whether patients in clinical remission for acute lymphoblastic leukemia (ALL) continue to harbor leukemic cells is not known, because methods of detecting residual malignant cells have not been sufficiently sensitive. This information might be useful for predicting recurrence and determining the duration of therapy. METHODS. Using a sensitive new method--identifying complementarity-determining region III sequences with the polymerase chain reaction--we estimated the number of residual leukemic cells in the bone marrow of eight children with B-lineage lymphoblastic leukemia before and after remission. RESULTS. Induction chemotherapy produced a 3-to-4-log reduction in the number of leukemic cells. In all samples obtained up to 18 months after diagnosis, however, 0.004 to 2.6 percent of bone marrow nucleated cells were residual leukemic cells. Among the four patients studied more than 18 months after diagnosis, three had no detectable leukemic cells in marrow samples. Despite this, one of them, who was no longer receiving therapy, had a central nervous system relapse. In one patient receiving maintenance chemotherapy, there was a 60-fold increase in leukemic cells three months before bone marrow relapse. CONCLUSIONS. The complete disappearance of leukemic cells (or their reduction below our method's threshold of detection, 1 in 100,000 cells) may be necessary to achieve a cure of ALL. The quantification of residual leukemic cells in serial marrow aspirates during therapy may allow the early detection of relapse.     

Double-blind comparison of cetirizine and placebo in the treatment of seasonal rhinitis.

The efficacy and safety of cetirizine were evaluated in 419 patients with seasonal allergic rhinitis. Using a 4-way, double-blind randomization schedule, patients were given a 1-week course of once daily cetirizine (5, 10, or 20 mg) or placebo. Patient and physician efficacy ratings corresponded, indicating superiority of cetirizine to placebo (P less than .05) in reducing symptom severity scores for sneezing, rhinorrhea, ocular pruritus, nasal pruritus, watering of the eyes, and redness of the eyes. All cetirizine doses achieved higher efficacy ratings (72.7%, 79.2%, and 75.7%, respectively) than placebo (52.9%; P less than .05) by the physician's global assessment. Cetirizine was well tolerated, with sedation being the most common adverse experience, increasing in frequency at higher doses. A dose-response relationship was evident for selected symptoms, and the once daily 5-mg dose was found to be an effective minimum dose.     

Failure of misonidazole-sensitized radiotherapy to impact upon outcome among stage III-IV squamous cancers of the head and neck

As part of the RTOG research effort in the treatment of advanced, inoperable squamous cancer of the head and neck region, the hypoxic cell sensitizer, misonidazole, was selected for investigation as an adjuvant to definitive irradiation. Based upon a pilot experience (78-02) showing a 67% complete response rate among 36 AJC Stage III-IV patients receiving full-dose irradiation and 6 weekly p.o. doses of misonidazole, a phase III trial was carried out from '79-'83. Three hundred and six patients were entered, 42% of whom had oropharyngeal primaries and with 78% of all cases representing T3 or T4 (inoperable) lesions. Only 16% of the entire series presented with N0 necks. Fractionation was altered among the misonidazole-receiving patients, in contrast to "standard" 5 treatments per week among "control" patients, such that 2 separate treatments were given on each day of p.o. misonidazole administration (2.0 gm/m2/wk X 6 doses, 2.5 Gy in a.m., 2.1 Gy in p.m.). Total tumor doses were identical among the two treatment arms except that a limitation of 40.0 Gy to spinal cord was specified for sensitized radiotherapy vs. 45.0 Gy for "control" patients. Primary tumor clearance was observed to be 55-60%, with minor variations according to tumor stage and site. The local regional control rate among radiotherapy-alone patients was 26% at 2 years compared to 22% (2 years) within the misonidazole-receiving group. Analysis of survival revealed no advantage to the sensitized patients, with 55 +/- 2% surviving 1 year and 22 +/- 1% living 3 years following treatment in both treatment categories. Distant metastases as first site of failure (12-13%) and the local failure among initial complete responders (46%) showed no advantage to the misonidazole group. Although a misonidazole dosage of 2.0 gm/m2/wk X 6 (12 gm/m2 total) is well tolerated, no clinical benefit was demonstrated in this randomized trial. Other nitroimidazole analogs (e.g. SR-2508) are now being investigated.     

Prognostic relevance of postirradiation lymphocyte reactivity in breast cancer patients

The prognostic relevance of phytohemagglutinin (PHA) and purified protein derivative (PPD) lymphocyte reactivity at diagnosis and after radiotherapy was evaluated in breast cancer patients. The patients were followed up to 13 years and the prognostic value expressed as ratios between observed number of deaths and "estimated" number of deaths under the null hypothesis. There was no significant association between the initial PHA and PPD reactivity and the survival of the patients. On the other hand, mortality up to 8 years after radiotherapy was significantly higher for patients with low PHA and PPD reactivity at completion of treatment. Furthermore, patients who had higher than average PPD reactivity 6 to 10 months after radiotherapy, seemed to have a higher survival rate. The prognostic relevance of postirradiation lymphocyte reactivity was only to some extent explained by clinical stage.     

Effect of the air hammer on the hands of stonecutters. The limestone quarries of Bedford, Indiana, revisited.

In the limestone quarries of Indiana, USA, pneumatic percussive hammers replaced the mallet and hammer around 1900. By 1917 the air hammer was being used exclusively for periods of eight to ten hours a shift. In 1918 Alice Hamilton investigated an unusual "disease" in these stonecutters of Bedford, Indiana, who complained of "attacks of numbness and blanching of the fingers coming on suddenly under the influence of cold and then disappearing." The prevalence of vibration induced white finger (VWF) found in this population of 38 stonecutters was 89%, with decreased light touch, pain, and temperature appreciation in advanced cases. In 1978 a VWF research team revisited these limestone quarries. During the 60 year interval the stonecutting industry had contracted from 4000 workers in 40 quarries in 1918 to 3-400 in 10 quarries in 1978, with only 50 employees remaining in the Bedford area. In a population of 30 stonecutters the prevalence of VWF in 1978 was 80%, with similar sensory loss in light touch, pain, and temperature appreciation. Between 1918 and 1978 no change had taken place in the design of the air hammers used for stonecutting. Vibration levels of 4859 metres/s2 on the chisel, and 2010 metres/s2 on the barrel were measured over a frequency range 6.3 to 1000 Hz. The fundamental frequency was 75 Hz. These measured vibration levels are outside the ISO/DIS/5349 (1979) recommended limits for human exposure to vibration transmitted to the hand. The VWF data presented in this paper, and those originally reported by Hamilton in 1918, call for an immediate redesign of stonecutting pneumatic hammers in order to remove one cause of Raynaud's phenomenon of occupational origin.     

Synthesis, corticotropin-releasing factor receptor binding affinity, and pharmacokinetic properties of triazolo-, imidazo-, and pyrrolopyrimidines and -pyridines

The synthesis and CRF receptor binding affinities of several new series of N-aryltriazolo- and -imidazopyrimidines and -pyridines are described. These cyclized systems were prepared from appropriately substituted diaminopyrimidines or -pyridines by nitrous acid, orthoester, or acyl halide treatment. Variations of amino (ether) pendants and aromatic substituents have defined the structure-activity relationships of these series and resulted in the identification of a variety of high-affinity agents (Ki's < 10 nM). On the basis of this property and lipophilicity differences, six of these compounds (4d,i,n,x, 8k, 9a) were initially chosen for rat pharmacokinetic (PK) studies. Good oral bioavailability, high plasma levels, and duration of four of these compounds (4d,i,n,x) prompted further PK studies in the dog following both iv and oral routes of administration. Results from this work indicated 4i,x had properties we believe necessary for a potential therapeutic agent, and 4i1 has been selected for further pharmacological studies that will be reported in due course.     

Treatment of periocular capillary hemangiomas.

PURPOSE: To report the results of a survey of the members of the American Association of Pediatric Ophthalmology and Strabismus (AAPOS) regarding the treatment of periocular capillary hemangiomas. METHODS: A survey was delivered to the 600 members of AAPOS. Surveys were returned via facsimile. Results were collected in a computerized spreadsheet and then tabulated and analyzed. RESULTS: Of the 600 AAPOS members, 225 responded to the survey. The results showed that intralesional steroid injection is the most commonly used treatment modality for periorbital capillary hemangiomas. Oral steroids and excision were also commonly used in the treatment of these lesions. CONCLUSIONS: Further controlled studies are needed to determine which treatment modality offers the most benefit and least risk. More standardization based on these studies is necessary to improve treatment of periocular capillary hemangiomas.     

What do pediatric primary care providers think are important research questions? A perspective from PROS providers.

OBJECTIVE: To describe what pediatric primary care providers involved in the Pediatric Research in Office Settings (PROS) research network think are important yet inadequately addressed questions in pediatric primary care research. METHODS: A total of 1785 pediatric primary care providers in the PROS network were asked what they thought were important yet inadequately addressed areas of primary care research. We used a single, open-ended question in a mail survey. Written answers to this question were analyzed by qualitative methods to determine the main themes of interest to pediatric primary care providers. RESULTS: Overall survey response rate was 48.7%; the open-ended question yielded 1109 individual answers. Six lines of inquiry were identified as being important to these providers: (1) effective counseling techniques to use in anticipatory guidance; (2) strategies to prevent and treat obesity; (3) the effectiveness of well-child care; (4) ongoing management of patients with attention-deficit/hyperactivity disorder; (5) the role of the primary care provider in caring for children with mental health needs; and (6) optimal organization of office practices. CONCLUSIONS: The translation of research into practice may be improved by a better understanding of the needs and interests of those who see pediatric patients in the primary care setting.