Lymphocytes with immunoglobulin E Fc receptors in patients with atopic disorders.

Lymphocytes from normal nonallergic donors and patients with atopic disorders were analyzed for subpopulations bearing Fc receptors for immunoglobulin (Ig)E (Fc(epsilon)) and IgG (Fc(gamma)), surface IgM (sIgM) and IgD (sIgD), and for T cells forming spontaneous rosettes with sheep erythrocytes (E). The patients were divided into three groups according to serum IgE concentrations and systemic corticosteroid treatment. Group I consisted of 12 atopic patients with either normal or moderately increased IgE levels up to 4,000 U/ml. Four patients of group II and three of group III had 10,500-31,000 U/ml and severe atopic dermatitis. Patients of group III, but not I and II, were receiving corticosteroids systemically. The percentage (mean +/-SD) and total number of Fc(epsilon) (+) lymphocytes were 1.2+/-0.5%, 41+/-24/mm(3) in 12 normals; 1.6+/-0.9%, 59+/-43/mm(3) in patients of group I: 7.0+/-2.0%, 187+/-67/mm(3) in group II; and 0.3+/-0.1%, 13+/-5/mm(3) in patients of group III. The increase in group II and decrease in group III of Fc(epsilon) (+) cells were statistically significantly different from the normal persons and patients of group I. In contrast, the patients did not differ significantly from the donors in sIgM(+), sIgD(+), Fc(gamma) (+), and E(+) cell populations. As shown by depletion of sIg(+) cells in four patients with atopic disorders, the great majority of the Fc(epsilon) (+) lymphocytes were B cells. However, two patients with elevated Fc(epsilon) (+) cell numbers had small numbers of mixed E- and Fc(epsilon)-rosetting cells, presumably T cells. Two patients of group II were examined during an acute herpes simplex infection. Both showed an congruent with80% decrease of Fc(epsilon) (+) cells at that time. No apparent correlation between numbers of Fc(epsilon) (+) cells and IgE level existed in patients of group I. Injection of an IgE myeloma protein into two monkeys did not significantly change their percentages of Fc(epsilon) (+) lymphocytes. The data indicate that Fc(epsilon) (+) lymphocytes are increased in patients with markedly elevated serum IgE and severe atopic disease, suggesting that these cells may be involved in the regulation and(or) synthesis of IgE antibody formation.

Ecto-5'-nucleotidase activity in human T cell subsets. Decreased numbers of ecto-5'-nucleotidase positive cells from both OKT4+ and OKT8+ cells in patients with hypogammaglobulinemia.

T lymphocytes from control subjects were separated into subsets using monoclonal antibodies of the OKT series and complement lysis and analyzed for ecto-5'-nucleotidase activity both by quantitative radiochemical assay and a histochemical stain. T cells from 15 control subjects contained 54+/-4% OKT4(+) (helper/inducer) cells and 32+/-3% OKT8(+) (cytotoxic/suppressor) cells. Total T cell ecto-5'-nucleotidase activity was 10.9+/-2.1 nmol/h per 10(6) cells with 25+/-7% positive by histochemical stain. Ecto-5'-nucleotidase activity in OKT4-enriched populations was 5.43+/-1.8 nmol/h per 10(6) cells with 14+/-2% positive by histochemical stain; that in OKT8-enriched populations was 17.1+/-5.9 nmol/h per 10(6) cells with 35+/-8% positive by histochemical stain. Two of four patients with congenital agammaglobulinemia and four of seven patients with common variable immunodeficiency had decreased proportions of OKT4(+) T cells with corresponding increases in the proportions of OKT8(+) T cells (OKT4/OKT8 = 0.60 to 1.0 as compared with 1.7+/-0.2 for control subjects). All four patients with congenital agammaglobulinemia, and three of seven patients with common variable immunodeficiency also had low T cell ecto-5'-nucleotidase activity (<5.5 nmol/h per 10(6) cells). Ecto-5'-nucleotidase activity in OKT4- enriched populations isolated from four patients with low total T cell activity was 2.85+/-0.90 nmol/h per 10(6) cells with 10+/-4% positive by histochemical stain; that in OKT8-enriched populations was 6.82+/-1.7 nmol/h per 10(6) cells with 7.5+/-3% positive by histochemical stain. Thus, the number of ecto-5'-nucleotidase positive cells is decreased, especially in the OKT8(+) subpopulation, and the low total T cell ecto-5'-nucleotidase activity seen in these patients is due to fewer positive cells rather than to substantially less activity per cell. Our data indicate that ecto-5'-nucleotidase activity defines two subpopulations of T lymphocytes (ecto-5'-nucleotidase positive and negative), the proportions of which are markedly altered in many patients with hypogammaglobulinemia. In preliminary studies with seven patients, increased numbers of ecto-5'-nucleotidase negative T cells appeared to correlate with increased suppressor T cell activity toward in vitro immunoglobulin synthesis. Therefore, ecto-5'-nucleotidase may be a useful cell surface marker in the study of imbalances of regulatory T cell subsets in patients with antibody synthesis disorders.

What is the efficacy of switching to weekly pegvisomant in acromegaly patients well controlled on combination therapy?

CONTEXT: Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients' comfort, but the efficacy is unknown. OBJECTIVE: To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV. DESIGN: Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly. SUBJECTS AND METHODS: The study included 15 subjects (eight males), with a median age of 58 years (range 35-80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels. RESULTS: After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30-0.84) to 0.83 × ULN (0.30-1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30-80) mg to 80 (50-120) mg. CONCLUSION: Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.

Compliance with national asthma management guidelines and specialty care: a health maintenance organization experience.

BACKGROUND: To improve asthma disease management, the National Asthma Education Program (NAEP) Expert Panel published Guidelines for the Diagnosis and Management of Asthma in 1991. OBJECTIVES: To compare the current status of asthma disease management among patients in a large health maintenance organization with the NAEP guidelines and to identify the factors that may be associated with medical care (eg, emergency department visits and hospital admissions) and adherence to the guidelines. METHODS: Analyses of 1996 survey data from 5580 members with asthma (age range, 14 to 65 years) covered by a major health maintenance organization in California (Health Net). RESULTS: In general, adherence to NAEP guidelines was poor. Seventy-two percent of respondents with severe asthma reported having a steroid inhaler, and of those, only 54% used it daily. Only 26% of respondents reported having a peak flowmeter, and of those, only 16% used it daily. Age (older), duration of asthma (longer), increasing current severity of disease, and treatment by an asthma specialist correlated with daily use of inhaled steroids. Ethnicity (African American and Hispanic) correlated negatively with inhaled steroid use but positively with emergency department visits and hospital admissions for asthma. Increasing age and treatment by an asthma specialist were also identified as common factors significantly related to the daily use of a peak flowmeter and, interestingly, to overuse of beta2-agonist metered-dose inhalers. CONCLUSIONS: Although the NAEP guidelines were published 7 years ago, compliance with the guidelines was low. It was especially poor for use of preventive medication and routine peak-flow measurement. Furthermore, the results showed that asthma specialists provided more thorough care than did primary care physicians in treating patients with asthma. Combining the results of the regression analyses revealed that some of the variation in rates of emergency department visits and hospitalizations among some subpopulations can be explained by the underuse of preventive medication. This study serves the goal of documenting the quality of care and services currently provided to patients with asthma through a large health maintenance organization and provides baseline information that can be used to design and assess effective population-based asthma disease management intervention programs.

Histamine contamination of pokeweed mitogen.

The histamine content of commercial preparations of pokeweed mitogen was measured by amino acid analysis technique, automated fluorometry, and bioassay employing the guinea pig ileum. Ten samples from 5 companies were examined and found to contain between 0.026 micrograms and 167.5 micrograms of histamine per ml of solution. The protein content of 9 of these putative 5 mg samples measured by folin assay and by amino acid analysis varied from 0.56 to 4.4 mg. Their amino acid compositions were similar, except for notable variations in 3 of the 16 residues quantitated.

Reduction of environmental tobacco smoke exposure among asthmatic children: a controlled trial.

STUDY OBJECTIVE: This randomized clinical trial tested a behavioral medicine program designed to reduce asthmatic children's exposure to environmental tobacco smoke (ETS) in the home. DESIGN: Families were randomly assigned to an experimental preventive medicine counseling group, a monitoring control group, or a usual treatment control group. Families were measured six times over 1 year. PARTICIPANTS: Ninety-one families were recruited from four allergy clinics. INTERVENTION: The experimental group received a 6-month series of counseling sessions designed to decrease ETS exposure. This group also monitored smoking, exposure, and children's asthma symptoms. The monitoring group did not receive counseling and the usual treatment control group received outcome measures only. MEASUREMENTS AND RESULTS: Parents reported the daily number of cigarettes children were exposed to during the week preceding interviews. A nicotine air monitor and construct validity analysis confirmed the validity of exposure reports. Exposure to the parent's cigarettes in the home decreased for all groups. The experimental group attained a 79 percent decrease in children's ETS exposure, compared with 42 percent for the monitoring control and 34 percent for the usual treatment control group. Repeated-measures analysis of variance resulted in a significant (F([10,350] = 1.92, p < 0.05) group by time effect. At the final 12-month visit, the experimental/counseling group sustained a 51% decrease in children's exposure to cigarettes in the home from all smokers, while the monitoring control group showed an 18% decrease and the usual treatment control group a 15% decrease from pre-intervention [corrected]. CONCLUSION: A behavioral medicine program was successful in reducing exposure to ETS in the home for these asthmatic children.

Effects of modeling and expectancy of reward on cheating behavior.

The present experiment compared the effects of modeling honest and dishonest responses with the effects of expectancy of reward. Sixty preschool children viewed one of three modeling films prior to their playing a pegboard game: (a) dishonest model receiving positive reinforcement, (b) dishonest model receiving no reinforcement, and (c) honest model receiving positive reinforcement.Ss were also told that a reward was dependent on a high level of performance or that a reward was noncontingent on performance with a bonus reward contingent on performance. An overwhelming majority of children in all groups imitated the model they observed with no significant effect due to expectancy of reward.

A border disease-like syndrome in a southern Ontario sheep flock.

An outbreak of nervous disease and abnormally hairy fleece was observed among newborn lambs in a closed flock of sheep in southern Ontario. The outbreak was investigated and found to closely parallel syndromes described in the British Isles and Australia and variously referred to as border disease, hypomyelinogenesis congenita and hairy shaker syndrome. Clinically affected lambs represented only a portion of the animals affected, considerable losses being caused by reproductive failure in the ewes and suboptimal performance in subclinically affected lambs. Sheep from the affected flock showed a strong serological response to the causative agent of bovine virus diarrhea/mucosal disease. The episode appeared to be chronologically related to the introduction of beef heifers from a sales barn. The paper discusses the results of clinico-epidemiological investigation of the outbreak in the light of current knowledge of border disease-like syndromes.

Modification of social withdrawal through symbolic modeling.

The present experiment was designed to test the efficacy of symbolic modeling as a treatment to enhance social behavior in preschool isolates. Nursery school children who displayed marked social withdrawal were assigned to one of two conditions. One group observed a film depicting increasingly more active social interactions between children with positive consequences ensuing in each scene, while a narrative soundtrack emphasized the appropriate behavior of the models. A control group observed a film that contained no social interaction. Control children displayed no change in withdrawal behavior, whereas those who had the benefit of symbolic modeling increased their level of social interaction to that of non-isolate nursery school children.

Mecp2 deficiency decreases bone formation and reduces bone volume in a rodent model of Rett syndrome.

Rett syndrome (RTT), a neurological disorder characterized by neurological impairment and a high frequency of osteopenia which often manifests early in childhood, most often is caused by inactivating mutations in the X-linked gene encoding a regulator of epigenetic gene expression, methyl CpG binding protein, MeCP2. Clinical data show that, along with neurological defects, females with RTT frequently have marked decreases in bone mineral density (BMD) beyond that expected from disuse atrophy. To investigate the relationship between loss of Mecp2 and reduced BMD, we used a Mecp2 null mouse model, Mecp2 (-/yBIRD), for our histological and biochemical studies. Mecp2 (-/yBIRD) mice have significantly shorter femurs and an overall reduced skeletal size compared to wild-type mice by post-natal day 60 (P60). Histological and histomorphometric studies identified growth plate abnormalities as well as decreased cortical and trabecular bone in P21 and especially in P60 Mecp2 (-/yBIRD) mice. Dynamic histomorphometry revealed decreased mineral apposition rates (MAR) in Mecp2 null femoral trabecular bone as well as in calvarial bone samples. While changes in MAR of cortical bone were not significant, loss of Mecp2 significantly reduced cortical, trabecular and calvarial bone volume compared with age-matched wild-type animals. These differences indicate that Mecp2 deficiency leads to osteoblast dysfunction, which translates into reduced osteoid deposition accounting for the reduced bone volume phenotype. While individual variations were observed in OPG and Rankl concentrations, molar ratios of OPG:Rankl at P21 and P60 were comparable between wild-type and Mecp2 (-/yBIRD) mice and showed a consistent excess of OPG. In tibial sections, TRAP staining demonstrated equivalent osteoclast number per bone surface measurements between wild-type and null animals. Our work with a Mecp2 null mouse model suggests epigenetic regulation of bone in the Mecp2 (-/yBIRD) mice which is associated with decreased osteoblast activity rather than increased osteoclastic bone loss.

Benzodiazepine dependence--a treatment perspective and an advocacy for control.

This clinical data is presented to emphasize the clinical seriousness of benzodiazepine dependence, its relationship to other addictive diseases, the complicated and protracted nature of its withdrawal syndrome, the various clinical reasons for prescribing benzodiazepines, and the need for physicians in all medical specialties to be alert to the possibility of chemical dependence in their patient population. Those of us prescribing benzodiazepines should have a clinical knowledge of addictive diseases and not complicate the disease process by prescribing benzodiazepines when they are clearly contraindicated.

Interleukin-2 inhibits the interleukin-4-induced human IgE and IgG4 secretion in vivo.

The effect of interleukin-2 (IL-2) on IL-4-induced IgE and IgG4 secretion by B cells in peripheral blood mononuclear cell (PBMC) preparations from non-atopic healthy humans and atopic dermatitis patients was investigated. PBMC were cultured at an optimal concentration of recombinant IL-4 with or without addition of IL-2 for 10 days. Native and recombinant IL-2 inhibited the IL-4-induced IgE and IgG4 secretion in a dose-dependent manner by cells from both normal and atopic donors. Rabbit antibodies to IL-2 or to the monoclonal anti-IL-2 receptor antibody anti-TAC reversed the IL-2 effect. Culturing cells with IL-4 and IL-2 for 1 or 2 days only slightly suppressed the IgE and IgG4 secretion whereas addition of IL-2 to IL-4 containing cultures on day 4 or 5 inhibited the IgE and IgG4 secretion more effectively. This is in contrast to interferon-gamma (IFN-gamma) which inhibited the IL-4 induced IgE and IgG4 secretion when added for the first 24 or 48 h but had no effect when added on days 4 or 5. The data demonstrate that both IL-2 and IFN-gamma act as antagonists in the IL-4-induced IgE and IgG4 secretion by human B cells; while IL-2 appears to inhibit relatively late in culture, IFN-gamma has an early inhibitory effect, suggesting that the two lymphokines inhibit the IL-4 effect by different mechanisms.

Interleukin-4 induced IgE and IgG4 secretion by B cells from atopic dermatitis patients.

Peripheral blood mononuclear cells from 8 normals and 8 patients with atopic dermatitis (AD) were cultured with recombinant interleukin-4 (IL-4) and the IgE and IgG subclass levels in the culture supernatants measured by radioimmunoassays. IL-4 induced IgE and IgG4 secretion by B cells from both normals and AD patients whereas it has no consistent effect on IgG1, IgG2 and IgG3 secretion. The IL-4 dose response was similar for IgE and IgG4 secretion by cells from both normals and AD patients. On the average, the patients' cells secreted more IgE and less IgG4 than the cells from normals, but because of a large variation, the differences were not significant. However, the ratio of IgG4:IgE secretion was significantly greater for normals than AD patients (mean +/- SEM 7.1 +/- 1.6:1 vs. 1.5 +/- 0.4:1; p less than 0.01). The data demonstrate that IL-4 induces IgE and IgG4 secretion by B cells from both normals and AD patients and suggest that the IL-4 induced switch from IgM to IgG4 or IgE secretion may proceed preferentially to IgE in AD patients as compared to normals.

Asthma and diving.

BACKGROUND: Approximately 10 to 15 million Americans are scuba divers. The prevalence of scuba diving and asthma makes it likely some asthmatics will be interested in scuba diving and some scuba divers will have asthma. Conditions present during scuba diving may provoke airway obstruction in asthmatic patients. Further, asthmatic patients may, in theory, face a greater than normal risk of pulmonary barotrauma from lung overdistension on ascent through the water column. OBJECTIVE: The purpose of this paper is to review the theoretical issues underlying the prohibition against scuba diving for asthmatic patients as advanced by most major diving organizations in the United States and critically examine the relevant accident data. METHODS: All reports that dealt with asthma and diving, and all available American accident data including both fatal and nonfatal accidents were reviewed. RESULTS: Actuarial data on the risk of scuba accidents attributable to asthma do not define several important variables likely to affect accident risk during scuba diving. Despite these limitations, careful review indicates the risks of serious morbidity or mortality during scuba diving appears to be inconsequentially elevated in subjects whose asthma was not characterized. CONCLUSIONS: Additional data are needed to define accurately risks of diving in subjects with different forms of asthma, however, the available data suggest asthmatic patients with normal airway function at rest, and with little airway reactivity in response to exercise or cold air inhalation, have a risk of pulmonary barotrauma similar to that of normal subjects.