Biomedical subjects

David A Johnson

Publications and source records attributed to David A Johnson.

At least 37 records · Page 2Linked to original sources

PubMed2005

Evaluation of esophageal function/pH in endoscopic therapy for gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) typically requires lifelong medical therapy or surgery for the management of patients with frequent symptoms. The current standard of care is to prescribe medical therapy using proton pump inhibitors. Patients with moderate-to-severe GERD require extended/maintenance therapy. Until recently, the only alternative to this approach was surgical intervention. Endoscopic therapy for GERD has emerged as a second alternative strategy. Primary endpoints for all interventions have aimed at symptomatic control and reduction/discontinuance of medication use. For surgical and endoscopic therapies, however, there are other physiologic endpoints that have attempted to define changes in lower esophageal sphincter pressure and esophageal acid exposure. For patients being evaluated for endoscopic GERD therapy, the author recommends comprehensive esophageal testing and pH testing.

Catheter Ablation↗

PubMed2005

A randomized pilot study of near activities versus non-near activities during patching therapy for amblyopia.

BACKGROUND: To plan a future randomized clinical trial, we conducted a pilot study to determine whether children randomized to near or non-near activities would perform prescribed activities. A secondary aim was to obtain a preliminary estimate of the effect of near versus non-near activities on amblyopic eye visual acuity, when combined with 2 hours of daily patching. METHODS: Sixty-four children, 3 to less than 7 years of age, with anisometropic, strabismic, or combined amblyopia (20/40 to 20/400) were randomly assigned to receive either 2 hours of daily patching with near activities or 2 hours of daily patching without near activities. Parents completed daily calendars for 4 weeks recording the activities performed while patched and received a weekly telephone call in which they were asked to describe the activities performed during the previous 2 hours of patching. Visual acuity was assessed at 4 weeks. RESULTS: The children assigned to near visual activities performed more near activities than those assigned to non-near activities (by calendars, mean 1.6 +/- 0.5 hours versus 0.2 +/- 0.2 hours daily, P < 0.001; by telephone interviews, 1.6 +/- 0.4 hours versus 0.4 +/- 0.5 hours daily, P < 0.001). After 4 weeks of treatment, there was a suggestion of greater improvement in amblyopic eye visual acuity in those assigned to near visual activities (mean 2.6 lines versus 1.6 lines, P = 0.07). The treatment group difference in visual acuity was present for patients with severe amblyopia but not moderate amblyopia. CONCLUSIONS: Children patched and instructed to perform near activities for amblyopia spent more time performing those near activities than children who were instructed to perform non-near activities. Our results suggest that performing near activities while patched may be beneficial in treating amblyopia. Based on our data, a formal randomized amblyopia treatment trial of patching with and without near activities is both feasible and desirable.

Activities of Daily Living↗

PubMed2005

Enteryx implantation for GERD: expanded multicenter trial results and interim postapproval follow-up to 24 months.

BACKGROUND: Enteryx implantation in the esophagus is an alternative therapy for patients with proton pump inhibitor (PPI) dependent GERD. Although this treatment resulted in highly significant improvement at 6 and 12 months, longer follow-up is needed to more fully assess the durability of these positive effects. METHODS: An open-label, international clinical trial was conducted in 144 PPI-dependent patients with GERD with follow-up at 6 and 12 months. In addition, the durability and the safety of the treatment were assessed for 24 months in 64 patients enrolled in a postapproval study. The primary study outcome measure was usage of PPI. Secondary outcomes in the multicenter trial were GERD health-related quality of life (GERD-HRQL) symptom score and esophageal acid exposure. RESULTS: At 12 months, PPI use was reduced > or =50% in 84%: 95% confidence interval (CI) [76%, 90%] and was eliminated in 73%: 95% CI[64%, 81%] of evaluable patients (intent-to-treat analysis 78%: 95% CI[70%, 84%] and 68%: 95% CI[60%, 76%], respectively). A GERD-HRQL < or =11 was attained in 78%: 95% CI[69%, 85%] of evaluable patients. Esophageal acid exposure (total time pH <4) was reduced by 31%: 95% CI[17%, 43%]. At 24 months, a > or =50% or greater reduction in PPI use was achieved in 72%: 95% CI[59%, 82%] and PPI use was eliminated in 67%: 95% CI[54%, 78%] of patients. CONCLUSIONS: This investigation provides evidence for sustained effectiveness and safety of implantation of Enteryx in the esophagus in PPI-dependent patients with GERD.

Belgium↗

PubMed2005

Feasibility and safety of string, wireless capsule endoscopy in the diagnosis of Barrett's esophagus.

BACKGROUND: Capsule endoscopy is a major technological advancement in the visualization of the small bowell. Its utility in the evaluation of the esophagus is mainly limited by its rapid and unpredictable transmission, thus limiting the number of pictures of the esophagus, in particular, the distal esophagus. METHODS: Strings were attached to the wireless capsule endoscopy device to allow its controlled movement up and down the esophagus. Microbiologic cultures of the capsule's surface after high-level disinfection were carried out after the procedure. At the time of recording, discomfort associated with the procedure was documented. Patient preference compared with conventional EGD was recorded. An independent endoscopist blinded to the EGD diagnoses assessed the diagnostic accuracy of pictures obtained. OBSERVATIONS: Fifty patients with Barrett's esophagus were enrolled: 28 with short-segment Barrett's and 22 with long-segment Barrett's. The procedure was safe (no strings were disrupted, and no capsule was lost), and it rendered negative microbiologic cultures after high-level disinfection. The mean recording time was 7.9 minutes; all patients with both short- and long-segment Barrett's esophagus were successfully identified. The difficulty/discomfort associated with swallowing the device, throat discomfort, gagging, moving the capsule (up and down and upon retrieval of the capsule) was none or minimal in 74%, 98%, 96%, 94%, and 76%, respectively. A single capsule was used in 24 studies, and the majority of patients (92%) preferred string-capsule endoscopy to EGD. CONCLUSIONS: String-capsule endoscopy was feasible, safe, and highly acceptable, and was preferred by patients and may prove to be more cost effective than screening EGD.

Adult↗

PubMed2005

Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings.

Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency may present with variable neurological manifestations. Radiological features include white matter changes (leukoencephalopathy). Clinical, biochemical, and radiological response to treatment may again be variable. Here we present a 12-year follow-up of two siblings on the same treatment regimen, with contrasting long-term findings. The first patient, a female presenting at 15 years, showed a good clinical response, substantial intellectual gain, and complete reversal of leukoencephalopathy. Her brother presented at 13 years 9 months and showed limited clinical and cognitive improvement with persistence of the leukoencephalopathy. Both siblings showed a partial biochemical response to treatment.

Activities of Daily Living↗

PubMed2005

Recombinant human mast-cell chymase: an improved procedure for expression in Pichia pastoris and purification of the highly active enzyme.

Human mast-cell chymase (EC 3.4.21.39) is a chymotrypsin-like serine protease that is stored in and released from mast-cell granules. This enzyme has been expressed in Pichia pastoris by homologous recombination of the cDNA coding for the mature active chymase into the Pichia genome. Cells producing the highest levels of recombinant human chymase were selected by activity screening and they were grown in a fermentor. Methanol induction resulted in the secretion of active chymase into the Pichia growth media and increasing levels of enzyme were detected in the media for 5 days. Active enzyme was purified from the culture media with a 22% yield of activity by a simple two-step procedure involving hydrophobic-interaction chromatography followed by affinity chromatography on immobilized heparin. The major peak from the heparin column contained a single band of 30.6 kDa on SDS/PAGE. The purified recombinant human chymase was 96% active and the yield was 2.2 mg/l of growth media.

Cell Culture Techniques↗

PubMed2005

Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: a randomized, placebo-controlled trial.

OBJECTIVES: Sleep disturbances are common in patients with gastroesophageal reflux disease (GERD). This study examined the effects of esomeprazole on nighttime heartburn, GERD-related sleep disturbances, sleep quality, work productivity, and regular activities. METHODS: This multicenter, randomized, double-blind, placebo-controlled trial included adults with GERD-associated sleep disturbances and moderate-to-severe nighttime heartburn (recorded by patient diary during screening). Patients received oral esomeprazole 40 mg (n = 220) or 20 mg (n = 226) or placebo (n = 229) once daily for 4 wk. The primary outcome was relief of nighttime heartburn. Secondary outcomes included resolution of sleep disturbances, sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI) questionnaire, and work productivity measured by the Work Productivity and Activity Impairment Questionnaire. RESULTS: Nighttime heartburn was relieved in 53.1% (111/209), 50.5% (111/220), and 12.7% (28/221) of patients who received esomeprazole 40 mg, esomeprazole 20 mg, and placebo, respectively. Differences (95% CI) versus placebo were 40.5% (32.4%, 48.5%) and 37.8% (29.9%, 45.7%) and were highly significant (p < 0.0001). GERD-related sleep disturbances resolved in significantly more (p < 0.0001) patients who received esomeprazole 40 (73.7%) or 20 mg (73.2%) than in those who received placebo (41.2%). Both esomeprazole groups had greater PSQI global score changes from baseline (p < 0.0001 vs placebo) and more (p < 0.0001 vs placebo) work hours saved per week per patient compared with baseline (esomeprazole 40 mg, 11.6 h; esomeprazole 20 mg, 12.3 h; placebo, 6.2 h). CONCLUSIONS: Esomeprazole reduced nighttime heartburn and GERD-related sleep disturbances and improved sleep quality and work productivity.

Administration, Oral↗

PubMed2005

Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge.

A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.

Animals↗

PubMed2005

Enteryx for gastroesophageal reflux disease.

The Enteryx procedure is an endoscopic injectable treatment for the management of gastroesophageal reflux disease symptoms. Enteryx was approved by the US Food and Drug Administration in April 2003 for patients who respond to, and require daily pharmacologic therapy with proton-pump inhibitors. Although gastroesophageal reflux disease is rarely life threatening, symptoms are often chronic and disabling. Therefore, safe and cost-effective alternative treatments for chronic gastroesophageal reflux disease are sought by patients, physicians and payers. Multicenter clinical trials have demonstrated that the Enteryx procedure safely and effectively eliminates, or significantly reduces, proton-pump inhibitor use in approximately 84% of patients at 1 year, and 72% of patients at 2 years.

Clinical Trials as Topic↗

PubMed2005

Gastroesophageal reflux disease and sleep disorders: a wake-up call for physicians and their patients.

Sleep's implications to the physiology and pathogenesis of a number of diseases have been ignored until recently. With the evolution of studies conducted in sleep laboratories, the relationship between various gastrointestinal diseases, in particular gastroesophageal reflux disease (GERD), and sleep disorders is being recognized. This article discusses the personal and societal impact of GERD-related sleep disorders, including quality of life issues and work and leisure impairment. A review of intervention studies indicates that GERD-related sleep disorders respond effectively to acid-suppressive medical therapy. Clinicians are advised to take a proactive stance in evaluating patients with GERD for unrecognized sleep disorders and ascertaining whether patients with sleep disorders have GERD symptoms as well.

Anti-Ulcer Agents↗

PubMed2004

Nanosecond dynamics of acetylcholinesterase near the active center gorge.

To delineate the role of peptide backbone flexibility and rapid molecular motion in acetylcholinesterase catalysis and inhibitor association, we investigated the decay of fluorescence anisotropy at three sites of fluorescein conjugation to cysteine-substitution mutants of the enzyme. One cysteine was placed in a loop at the peripheral site near the rim of the active center gorge (H287C); a second was in a helical region outside of the active center gorge (T249C); a third was at the tip of a small, flexible omega loop well separated from the gorge (A262C). Mutation and fluorophore conjugation did not appreciably alter catalytic or inhibitor binding parameters of the enzyme. The results show that each site examined was associated with a high degree of segmental motion; however, the A262C and H287C sites were significantly more flexible than the T249C site. Association of the active center inhibitor, tacrine, and the peripheral site peptide inhibitor, fasciculin, had no effect on the anisotropy decay of fluorophores at positions 249 and 262. Fasciculin, but not tacrine, on the other hand, dramatically altered the decay profile of the fluorophore at the 287 position, in a manner consistent with fasciculin reducing the segmental motion of the peptide chain in this local region. The results suggest that the motions of residues near the active center gorge and across from the Cys(69)-Cys(96) omega loop are uncoupled and that ligand binding at the active center or the peripheral site does not influence acetylcholinesterase conformational dynamics globally, but induces primarily domain localized decreases in flexibility proximal to the bound ligand.

Acetylcholinesterase↗

PubMed2004

Effects of raloxifene and estradiol on hippocampal acetylcholine release and spatial learning in the rat.

The effects of raloxifene on acquisition of a delayed matching to position (DMP) T-maze task and on hippocampal acetylcholine release were evaluated and compared with estradiol, to determine whether raloxifene has estrogenic effects on cognitive performance and hippocampal cholinergic activity. Ovariectomized rats received continuous treatment with raloxifene (one of two doses), estradiol, or vehicle for 30 days, followed by behavioral training, and then in vivo microdialysis assessment of basal and potassium-stimulated acetylcholine release. The data show that estradiol significantly enhanced DMP acquisition, whereas raloxifene did not. In contrast, both estradiol and the higher dose of raloxifene significantly increased potassium-stimulated acetylcholine release in the hippocampus. These data suggest that, despite increasing evidence for estrogenic effects of raloxifene in brain, raloxifene does not mimic the effects of estrogen on cognitive performance as assessed by acquisition of a simple spatial memory task in ovariectomized rats.

Acetylcholine↗

PubMed2004

Elevated vasoactive intestinal peptide concentrations in patients with irritable bowel syndrome.

The aim was to assess the roles of gut hormones and immune dysfunction in irritable bowel. In Study I, rectal mucosal samples examined blindly showed no histological evidence of inflammation in 16 irritable bowel patients compared to 17 healthy controls. The proinflammatory mediators interleukin-1beta and prostaglandin E2 also failed to show evidence of inflammation. Vasoactive intestinal peptide was elevated in irritable bowel (P = 0.01), but substance P, calcitonin gene-related peptide, and somatostatin levels were similar to control values. In Study II, 30 irritable bowel patients had elevated (P = 0.002) plasma concentrations of vasoactive intestinal peptide compared to 30 controls, and peptide levels were unrelated to whether the patient's predominant bowel habit was constipation, diarrhea, or both in alternation. In conclusion, no evidence of inflammation was detected in irritable bowel patients, but elevated vasoactive intestinal peptide concentrations were observed in both studies and might represent a potential diagnostic tool for irritable bowel syndrome.

Adult↗

PubMed2004

Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastroesophageal reflux disease.

BACKGROUND & AIMS: Gastroesophageal reflux disease is common in adults of all ages, but its complications are more frequent in elderly patients. Although heartburn is the most common symptom of reflux disease, it is unclear whether the severity of heartburn reliably indicates the severity of erosive esophagitis. We therefore assessed the relationship between age, severe heartburn symptoms, and severe erosive esophagitis. METHODS: This post hoc analysis of baseline data on the severity of both heartburn and erosive esophagitis pooled data from 5 prospective, randomized, controlled clinical trials that assessed the effect of proton pump inhibitors on healing of erosive esophagitis and symptom resolution. The clinical trials were conducted in 683 private and academic offices and hospital-based gastroenterology practices and involved 11,945 patients aged 18 years and older with gastroesophageal reflux disease and erosive esophagitis. RESULTS: A progressive increase in the prevalence of severe erosive esophagitis was observed with each decade of age, ranging from 12% in patients aged <21 years to 37% in patients aged >70 years. Among patients with severe esophagitis, severe heartburn was less frequent in the older age groups: ranging from 82% of patients aged <21 years to 34% of those aged >70 years. Each of these associations was statistically significant (P < 0.001). CONCLUSIONS: Although the prevalence of severe erosive esophagitis increases with age, the severity of heartburn is an unreliable indicator of the severity of erosive disease. More aggressive investigation and treatment may be necessary for elderly patients, regardless of the reported severity of heartburn.

Adult↗

PubMed2004

Endpoints for the assessment of response to gastroesophageal reflux disease therapy--what are the appropriate measures of "success"?

Therapeutic efficacy for gastroesophageal reflux disease (GERD) has been justified by a variety of different endpoints. Across the surgical, endoscopic, and pharmacologic treatment interventions, an attempt has been made to justify the success of the effect by objective and subjective means. This has included objective measures of esophageal sphincter pressure, intraesophageal acid exposure, and endoscopic esophagitis. More subjective measures have included symptom response as determined by questionnaires, severity scales, physician assessment, and quality-of-life impact. Despite the innumerable studies reporting various treatment interventions for GERD, overall there is a general lack of a standardized methodology to allow comparison of the relative success achieved among various methodologies. Furthermore, there is a striking lack of use of validated instruments to accurately assess treatment effect in many of these studies. This review focuses on the questions that should be raised by clinicians in their evidence-based evaluation of the outcomes achieved in these GERD intervention trials.

Endoscopy, Gastrointestinal↗

PubMed2004

Gastroesophageal reflux disease in the elderly--a prevalent and severe disease.

Gastroesophageal reflux disease (GERD) is a prevalent problem that has particular implications for physicians treating geriatric patients. In elderly patients, there are multiple physiologic changes that occur and influence both the manifestations and severity of GERD. Elderly patients typically have less severe symptoms of GERD, yet they have more severe esophagitis compared to the younger patient population. Physicians treating elderly patients with GERD need to recognize that these patients require more potent and sustained acid inhibition to effectively and consistently achieve optimal clinical outcomes.

Aged↗

PubMed2003

Structure-activity relationship of synthetic toll-like receptor 4 agonists.

Important questions remain regarding the impact of variations in the structure of the lipid A portion of lipopolysaccharide on activation of cells via the Toll-like receptor 4 complex. We have studied a series of synthetic lipid A mimetic compounds known as aminoalkyl glucosaminide phosphates in which the length of the secondary acyl chain has been systematically varied. Using transcriptional profiling of human monocytes and responses of Toll-like receptor 4 complex cell transfectants, we demonstrate a clear dependence of length on secondary acyl chain on Toll-like receptor 4 activation. Compounds with secondary acyl chains less than eight carbons in length have dramatically reduced activity, and substitutions of the left-sided secondary acyl chain had the most important effect on the Toll-like receptor 4 agonist activity of these molecules. The structure-function relationships of these compounds assessed via the induction of chemokines and cytokines following in vivo administration closely mirrored those seen with cell-based studies. This novel set of synthetic lipid A mimetics will be useful for Toll-like receptor 4-based investigations and may have clinical utility as stand-alone immunomodulators.

Adjuvants, Immunologic↗

PubMed2003

Nanosecond dynamics of the mouse acetylcholinesterase cys69-cys96 omega loop.

The paradox of high substrate turnover occurring within the confines of a deep, narrow gorge through which acetylcholine must traverse to reach the catalytic site of acetylcholinesterase has suggested the existence of transient gorge enlargements that would enhance substrate accessibility. To establish a foundation for the experimental study of transient fluctuations in structure, site-directed labeling in conjunction with time-resolved fluorescence anisotropy were utilized to assess the possible involvement of the omega loop (Omega loop), a segment that forms the outer wall of the gorge. Specifically, the flexibility of three residues (L76C, E81C, and E84C) in the Cys69-Cys96 Omega loop and one residue (Y124C) across the gorge from the Omega loop were studied in the absence and presence of two inhibitors of different size, fasciculin and huperzine. Additionally, to validate the approach molecular dynamics was employed to simulate anisotropy decay of the side chains. The results show that the Omega loop residues are significantly more mobile than the non-loop residue facing the interior of the gorge. Moreover, fasciculin, which binds at the mouth of the gorge, well removed from the active site, decreases the mobility of 5-((((2-acetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid reporter groups attached to L76C and Y124C but increases the mobility of the reporter groups attached to E81C and E84C. Huperzine, which binds at the base of active-site gorge, has no effect on the mobility of reporter groups attached to L76C and Y124C but increases the mobility of the reporter groups attached to E81C and E84C. Besides showing that fluctuations of the Omega loop residues are not tightly coupled, the results indicate that residues in the Omega loop exhibit distinctive conformational fluctuations and therefore are likely to contribute to transient gorge enlargements in the non-liganded enzyme.

Acetylcholinesterase↗