Autoantibodies against the serotoninergic 5-HT4 receptor and congenital heart block: a reassessment

The specificity of autoantibodies against the serotoninergic 5-HT4 receptor in congenital heart block has led to conflicting observations. In order to clarify the situation, a collaborative effort was undertaken to discover the reasons for these discrepancies and to reassess the importance of such autoantibodies by making use of the Research Registry for Neonatal Lupus. Sera from 128 patients (101 anti-SSA/Ro52 positive mothers among which 74 have children with congenital heart block (CHB), 9 anti-SSA/Ro52 negative patients of which 1 had a child with heart block and 18 healthy donors) were assessed in a single blind test using an ELISA coated with a 5-HT4 receptor-derived peptide. Discrepancies between previous observations in our two groups could be ascribed to small differences in the set up of the assay. Of the 75 sera from mothers of children with CHB, 12 were reactive with the 5-HT4 peptide. Four sera among which three were from 35 Ro52 negative mothers without affected children as well as 2 in the 18 controls were positive. Interestingly, in 1 mother with an isolated child with CHB but who had no detectable anti-SSA/Ro52 antibodies and 1 mother with a child with a structural heart block and no detectable antibodies to any component of SSA/Ro, reactivity with the 5-HT4 receptor was noted. While 5-HT4 receptor autoantibodies do not have the predictive value of anti-Ro52 autoantibodies, the presence of these antibodies in a minor subset of mothers whose children have CHB suggests an additional risk factor which may contribute to the pathogenesis of disease.     

Pulmonary immunity to Pseudomonas aeruginosa in intestinally immunized rats roles of alveolar macrophages, tumor necrosis factor alpha, and interleukin-1 alpha.

The aims of this study were to assess the role played by alveolar macrophages, tumor necrosis factor alpha (TNF-alpha), and interleukin-1 alpha (IL-1 alpha) in pulmonary immunity against Pseudomonas aeruginosa in animals that have been immunized via the gut-associated lymphoid tissue. Following intra-Peyer's patch immunization and subsequent intratracheal challenge with live bacteria, significantly enhanced bacterial clearance from the lungs correlated with an increase in bronchoalveolar neutrophils, increased recruitment and phagocytic activity of alveolar macrophages, and accelerated production of TNF-alpha in the bronchoalveolar space, while levels of IL-1 alpha remained low. Administration of recombinant TNF-alpha in physiological concentrations did not affect the proliferation of P. aeruginosa in vitro, but when given intratracheally to rats at the time of infection, recombinant TNF-alpha significantly increased bacterial clearance from the lungs. In these animals, phagocytic activity of bronchoalveolar neutrophils was enhanced, while the recruitment of alveolar macrophages and neutrophils remained unchanged. In acutely infected nonimmune animals, bronchoalveolar concentrations of soluble IL-1 alpha and TNF-alpha increased until the time of death. Levels of prostaglandin E2 and thromboxane B2 were similar in each experimental group. These results indicate that infection in immune animals enhanced both recruitment and phagocytic activity of alveolar macrophages as well as induced an accelerated production of TNF-alpha. In immune challenged animals, this cytokine enhanced the phagocytic activity of neutrophils and improved bacterial clearance from the lung. Levels of soluble IL-1 alpha and TNF-alpha in nonimmune rats increased consistently following infection until the time of death, thus implicating these cytokines in the pathogenesis of acute P. aeruginosa pneumonia.     

A possible role for lysozyme in determining acute exacerbation in chronic bronchitis.

The aggregation of non-serotypable Haemophilus influenzae (NTHI) by whole saliva from patients with chronic obstructive lung disease (COLD) was investigated. Significant differences were observed between salivary aggregating activity of a control and COLD population (P < 0.001). Saliva from patients less prone to acute exacerbations had a greater capacity to aggregate bacteria compared with saliva from patients with a predilection to infection. The mechanism of saliva-mediated aggregation of NTHI was investigated and shown to be related to lysozyme content. Lysozyme activity in saliva was measured by the turbidimetric technique and results showed that patients with chronic bronchitis had increased levels of salivary lysozyme, with a subpopulation within the non-infection-prone group having greater amounts. A significant difference was observed in salivary lysozyme between controls and non-infection-prone (P < 0.005) and infection-prone (P < 0.05) patients, respectively: the non-infection-prone patients having significantly (P < 0.005) more than the infection-prone patients. There was significant correlation (r = 0.742, P < 0.001) between salivary aggregation of NTHI and lysozyme activity. Chromatographically purified human lysozyme had a similar aggregation profile to that of saliva. There was no difference in serum and saliva lactoferrin concentrations between groups, but there was a significant increase (P < 0.05) in serum lysozyme concentration in the non-infection-prone group. This study suggests that the level of salivary lysozyme derived from macrophages may play an important role in determining resistance or susceptibility to acute bronchitis.     

Activation of airway cl- secretion in human subjects by adenosine

We investigated cystic fibrosis (CF) transmembrane conductance regulator (CFTR) regulation by A2 adenosine (Ado) receptors and beta2 adrenergic receptors in CFTR-corrected CFBE41o- airway cells and human subjects. CFBE41o- cells stimulated with Ado (10 microM), isoproterenol (Iso, 10 microM), or Ado + Iso (10 microM each) elevated cyclic AMP (cAMP) above control conditions (P < 0.001), with the Iso conditions increasing cAMP approximately 10-fold above that produced by Ado alone (P < 0.001). All agonist conditions had similar effects on short circuit current at 10 and 25 microM, with no further currents produced by subsequent stimulation with forskolin (20 microM). CFTR dependence was demonstrated by glybenclamide block of agonist-stimulated currents. Nasal potential difference studies in normal (n = 50) subjects demonstrated that Ado (10 microM) and Ado + Iso (10 microM each) produced more polarization compared with Iso (10 microM Ado increase = 44%, 10 microM Ado + Iso increase = 52%, P < 0.05 for each condition compared with Iso alone). Studies completed in patients with CF (n = 10, "severe" genotypes) confirmed that Ado-stimulated polarization was CFTR-dependent. Together, these results indicate that Ado is a potent Cl- secretagogue in vivo, with relatively small effects on cAMP levels despite strong effects on CFTR-dependent short circuit current and nasal Cl- transport. These findings support growing evidence indicating a role for Ado regulation of CFTR-dependent Cl- secretion in vivo.     

Enhanced clearance of Candida albicans from the oral cavities of mice following oral administration of Lactobacillus acidophilus

Orally administered live Lactobacillus acidophilus was assessed for its capacity to enhance clearance from the oral cavity of DBA/2 mice shown previously to be 'infection prone'. L. acidophilus fed to DBA/2 mice significantly shortened the duration of colonization of the oral cavity compared to controls. Enhanced clearance of Candida albicans correlated with both early mRNA gene expression for interleukin (IL)-4 and interferon (IFN)-gamma and expression of their secreted products in cultures of cervical lymph nodes stimulated with Candida antigen. In addition rapid clearance correlated with higher levels of IFN-gamma and nitric oxide in saliva. Delayed clearance, less pronounced levels of the cytokine response, saliva IFN-gamma and nitric oxide, and later mRNA expression for IL-4 and IFN-gamma relative to feeding with the L. acidophilus isolate were noted in mice fed a different Lactobacillus isolate (L. fermentum). These observations indicate significant variations in individual isolates to activate the common mucosal system.     

Specific immune response in the respiratory tract after administration of an oral polyvalent bacterial vaccine.

An oral killed polyvalent bacterial vaccine was assessed in a double-blind trial involving healthy volunteers. Three courses of oral vaccine were given over a 2-month period; each course contained 10(10) Haemophilus influenzae and 7 X 10(9) Staphylococcus aureus organisms. Immunity was assessed by monitoring antibody in saliva and serum over a 3-month period. No evidence of a nonspecific effect on immune parameters (immunoglobulin levels and Escherichia coli antibody) was detected in saliva or serum. An increase in H. influenzae antibody in saliva was detected in 55% of subjects receiving the vaccine compared with 6.7% of the placebo group. Antibody was associated with immunoglobulin A (IgA), IgG, and IgM, but the greatest increases over preimmunization levels were detected in the IgA class. No increase in serum antibody levels was detected. Subjects with higher preimmunization levels of salivary antibody to H. influenzae were less likely to respond to the oral bacterial vaccine. No increase in S. aureus antibody was detected in saliva or serum.     

Bronchitis symptoms in young teenagers who actively or passively smoke cigarettes

This study was undertaken to examine the prevalence of bronchitis (cough with phlegm) symptoms in teenagers who either smoked cigarettes on a regular basis (active smokers) or were non-smokers but who are exposed to passive smoking (passive smokers) in the home. The study was undertaken in 1995 and repeated in 1998. The 1995 study was a cross sectional questionnaire survey of smoking habits in secondary school children aged 13-14 years and was undertaken as part of the ISAAC questionnaire survey. Thirty representative and randomly selected schools from throughout the Republic of Ireland took part in the study. In the 1995 study, 3066 students completed a questionnaire on their current smoking habits and symptoms of cough and phlegm. We found that 634 (20.7%) of these young teenagers actively smoked cigarettes with significantly more females smoking than males with 23.3% of girls compared to 17.6% boys (p = 0.0001). We found that 46.3% of non-smoking children were exposed to smoking in the home (passive smokers) with parental smoking accounting for most of the passive smoking. Bronchitis symptoms were more commonly reported in active smokers compared to non-smokers with an odds ratio of 3.02 (95% CI 2.34-3.88) (p < 0.0001) or in passive smokers compared to those not exposed to smoking with odds ratio of 1.82 (95% CI 1.32-2.52) (p < 0.0001). The 1998 study showed similar results for smoking habits, passive smoking and prevalence of bronchitis symptoms as with the 1995 study. These results document that increased bronchitis symptoms occur in teenagers exposed to active or passive smoking.     

A geometric method of calculating tendo Achillis lengthening

Twenty-six open "Z-type" tendo Achillis lengthenings were performed on 20 children with equinus contractures secondary to spastic cerebral palsy. The patients' average age was 8.6 years (range 4.0-17.5 years). A preoperative calculation of the amount of lengthening needed to accomplish a satisfactory correction of equinus was used before all procedures in the hope of avoiding iatrogenic overlengthening. This calculation was done with simple clinical measurements on the foot and ankle and is based on elementary lever arm and geometric principles. After an average follow-up of 3.1 years (range 6 months to 7 years), there were no instances of overlengthening, nor was there residual equinus.