Effect of phthiocerol dimycocerosate deficiency on the transcriptional response of human macrophages to Mycobacterium tuberculosis.

The control of mycobacterial infections is dependent on the finely tuned synergism between the innate and adaptive immune responses. The macrophage is the major host cell for Mycobacterium tuberculosis and the degree of virulence of mycobacteria may influence the initial macrophage response to infection. The cell wall molecule, phthiocerol dimycocerosate (DIM), is an important virulence factor that influences the early growth of M. tuberculosis in the lungs. To explore the basis for this effect we have compared the early gene response of human THP-1 macrophages to infection with virulent M. tuberculosis and the DIM-deficient DeltafadD26 M. tuberculosis strain using microarrays. Detailed analysis revealed a common core of macrophage genes, which were rapidly induced following infection with both strains, and deficiency of DIM had no significant effect on this initial macrophage transcriptional responses. In addition to chemokines and pro-inflammatory cytokines, the early response genes included components of the Toll-like receptor signalling, antigen presentation and apoptotic pathways, interferon response genes, cell surface receptors and their ligands, including TNF-related apoptosis inducing ligand (TRAIL) and CD40, and other novel genes. Therefore, although fadD26 deficiency is responsible for the early attenuation of the growth of M. tuberculosis in vivo, this effect is not associated with differences in the initial macrophage transcriptional response.

Upregulation of the esophago-UES relaxation response: a possible pathophysiological mechanism in suspected reflux laryngitis.

BACKGROUND: Inappropriate or excessive, non-swallow related, reflexive relaxation of the upper esophageal sphincter (UES) in response to esophageal distension may be the principal mechanism permitting retrograde trans-sphincteric flow during acid regurgitation. The neural pathways mediating reflexive UES relaxation in the human have received little attention. Patients with laryngitis demonstrate an increased acid reflux in the proximal esophagus. Such events, combined with an increased tendency for UES relaxation, might precipitate regurgitation into the pharynx. The aim was to determine whether the esophago-UES relaxation reflex induced by rapid esophageal distension is upregulated in patients with posterior laryngitis. METHODS: In 21 healthy volunteers and 14 patients with posterior laryngitis, UES responses to rapid air insufflation were examined. UES responses were monitored with perfused manometry catheter with a oval sleeve sensor. KEY RESULTS: The probability of triggering UES relaxation in response to the rapid esophageal air distension, for all volumes of insufflation, was higher in laryngitis (45%) than in health (17%). The minimum distension volume required to elicit an UES relaxation response was significantly lower in laryngitis patients when compared with controls. Patients who demonstrated a laryngoscopic response to a trial of omeprazole, were less likely to generate a distension-induced UES contractile response (5%) than patients who did not respond (23%). CONCLUSIONS & INFERENCES: The threshold for esophageal distension-induced UES relaxation is reduced in patients with laryngitis when compared with controls. This finding supports the hypothesis that in this population, a hypersensitive belch-like response may be one contributory mechanism of regurgitation when triggered by an abrupt spontaneous gastro-esophageal reflux event.

Predictors of outcome in an open label, therapeutic trial of high-dose omeprazole in laryngitis.

BACKGROUND: Gastroesophageal reflux is implicated in some cases of laryngitis. There are no established predictors of response to acid suppression therapy in suspected reflux laryngitis. AIM: In a population with laryngitis, the aim is to determine whether (a) omeprazole 20 mg tds (3 months) improves symptoms and laryngitis, and (b) the outcome in response to potent acid suppression can be predicted by esophageal and/or pharyngeal parameters during ambulatory pH monitoring or by other pretreatment variables. METHODS: From the 70 consecutive patients with laryngitis screened, 20 patients met the inclusion criteria (dysphonia >3 months; laryngoscopically demonstrated laryngitis); and 50 patients were excluded because of one or more criteria indicating alternative causes for laryngeal injury. The primary outcome measure was improvement of at least one level in a 4-point laryngitis grading at 3 months. Twenty-four-hour dual, pharyngo-esophageal pH monitoring was performed at baseline. Secondary outcomes (symptom questionnaire; computerized voice analysis) were measured at baseline, and at 6 and 12 wk. RESULTS: Response rates at 6 and 12 wk were 47% and 63%, respectively. GERD symptoms (heartburn (p= 0.03) and regurgitation (p= 0.0001)) improved. However, neither baseline GERD symptoms nor endoscopic findings predicted laryngoscopic or symptomatic response. Neither baseline laryngitis grade (p= 0.46) nor esophageal acid exposure on pH testing (p= 0.3) predicted outcome. Four of 20 patients demonstrated pharyngeal regurgitation on pH testing, all four of whom responded to potent acid suppression (p= 0.2). Computerized voice measures were not predictive of outcome, although fundamental frequency (Fo) was inversely related to baseline laryngoscopic grade. CONCLUSION: In a carefully defined population of patients with laryngitis (a) 63% have a laryngoscopic response to 3 months of potent acid suppression without significant improvement in laryngeal symptoms; (b) neither voice measures, esophageal acid exposure time, symptoms nor severity of laryngitis predict outcome; and (c) although numbers were small, all patients with a positive pharyngeal pH study responded to therapy and pharyngeal pH-metry may prove useful; (4) available evidence supports an empiric trial of high-dose proton pump inhibitors (PPI), for at least 12 wk, as the initial diagnostic step for suspected reflux laryngitis.

Oropharyngeal scintigraphy: a reliable technique for the quantitative evaluation of oral-pharyngeal swallowing.

A valid and reliable technique to quantify the efficiency of the oral-pharyngeal phase of swallowing is needed to measure objectively the severity of dysphagia and longitudinal changes in swallowing in response to intervention. The objective of this study was to develop and validate a scintigraphic technique to quantify the efficiency of bolus clearance during the oral-pharyngeal swallow and assess its diagnostic accuracy. To accomplish this, postswallow oral and pharyngeal counts of residual for technetium-labeled 5- and 10-ml water boluses and regional transit times were measured in 3 separate healthy control groups and in a group of patients with proven oral-pharyngeal dysphagia. Repeat measures were obtained in one group of aged (> 55yr) controls to establish test-retest reliability. Scintigraphic transit measures were validated by comparison with radiographic temporal measures. Scintigraphic measures in those with proven dysphagia were compared with radiographic classification of oral vs. pharyngeal dysfunction to establish their diagnostic accuracy. We found that oral ( p = 0.04), but not pharyngeal, isotope clearance is swallowed bolus-dependently. Scintigraphic transit times do not differ from times derived radiographically. All scintigraphic measures have extremely good test-retest reliability. The mean difference between test and retest for oral residual was -1% (95% CI -3%-1%) and for pharyngeal residual it was -2% (95% CI -5%-1%). Scintigraphic transit times have very poor diagnostic accuracy for regional dysfunction. Abnormal oral and pharyngeal residuals have positive predictive values of 100% and 92%, respectively, for regional dysfunction. We conclude that oral-pharyngeal scintigraphic clearance is highly reliable, bolus volume-dependent, and has a high predictive value for regional dysfunction. It may prove useful in assessment of dysphagia severity and longitudinal change.