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Biomedical subjects

William C Orr

Publications and source records attributed to William C Orr.

At least 19 recordsLinked to original sources
PubMed2006

Sleep-related autonomic disturbances in symptom subgroups of women with irritable bowel syndrome.

The objective was to investigate whether predominant symptom patterns in women with irritable bowel syndrome (IBS) affect autonomic activity during sleep. Seventy-five women with IBS underwent a polysomnographic sleep study. Twenty-two of the IBS patients were diarrhea-predominant (IBS-D), 33 were constipation-predominant (IBS-C), and 20 patients had alternating symptoms (IBS-A). Autonomic activity was measured by heart rate variability. The IBS-D group had significant vagal withdrawal compared to the IBS-A group during REM and non-REM sleep (P < 0.05). The IBS-D symptom subgroup had significantly (P < 0.05) greater sympathetic dominance during non-REM than IBS-A patients. Lower abdominal pain correlated with sympathetic dominance during sleep in the IBS-D group (r=0.54, P < 0.01). The IBS-D patients were physiologically distinct with regard to autonomic functioning during sleep compared to the alternating patients, but not the constipated patients. Sleep appears to unmask differences in autonomic activity that may distinguish IBS patients.

Adult↗
PubMed2006

Effects of ectopic expression of Drosophila DNA glycosylases dOgg1 and RpS3 in mitochondria.

The main purpose of this study was to determine whether enhancement of repair capacity would attenuate mitochondrial DNA oxidative damage and result in greater cell survival under stressful conditions. The repair of oxidative damage is initiated by DNA glycosylases, which catalyze the excision of oxidized bases, such as 8-hydroxydeoxyguanosine (8-oxodG). Drosophila DNA glycosylases, dOgg1 and RpS3, were ectopically expressed within the mitochondrial matrix in Drosophila S2 cells, causing a severalfold decrease in the levels of 8-oxodG in mitochondrial DNA. Unexpectedly, cells did not show increased resistance to oxidative stress, but instead became more susceptible to treatment with hydrogen peroxide or paraquat. Even in the absence of oxidative challenge, cells expressing RpS3 or dOgg1 in mitochondria exhibited increased apoptosis relative to controls, as determined by flow-cytometric analysis of Annexin V and DNA degradation measured by the Comet assay. Another notable finding was that ectopic expression of either dOgg1 or RpS3 in mitochondria increased cell survival after exposure to the nitric oxide donor SNAP. These results suggest that ectopic expression of one of the constituents of the DNA repair system in mitochondria may cause a perturbation in the base excision repair pathway and lower, rather than enhance, survivability.

Animals↗
PubMed2006

Effects of caloric restriction are species-specific.

This article addresses two questions: (1) 'can caloric restriction (CR) extend the life spans of all species of experimental animals', and (2) 'is CR likely to slow the human aging process and/or extend the human life span?' The answer to the first question is clearly 'no', because CR decreases the life span of the housefly, Musca domestica, and fails to extend the life span of at least one mouse strain. The answer to the second question is unknown, because human CR has not yet been shown either to increase or curtail the human life span. However, recent efforts to develop insect models of CR have been unsuccessful and/or relatively uninformative, so any insights regarding the relationship between CR and human aging are more likely to arise from studies of established, mammalian models of CR.

Aging↗
PubMed2006

Reflux events and sleep: are we vulnerable?

This review addresses the changes in the physiologic responses to esophageal acid contact that occur during sleep. The importance of these changes is addressed as they pertain to the development of esophagitis and other complications of gastroesophageal reflux. Sleep results in physiologic changes that impair esophageal acid clearance, thereby creating a vulnerability to the complications of reflux. These complications are generally considered secondary to prolonged acid mucosal contact. Sleep-related reflux also produces a disruption of sleep, which may result in clinical complaints of sleep disturbance and significant daytime consequences, such as sleepiness and diminished work performance. The significance of these sleep-related findings is addressed as they relate to the diagnosis and treatment of gastroesophageal reflux disease.

Circadian Rhythm↗
PubMed2006

Cardiac autonomic regulation differentiates reflux disease with and without erosive esophagitis.

OBJECTIVE: Impaired autonomic function has been observed in patients with gastroesophageal reflex disease (GERD), but little is known about autonomic function in patients with non-erosive reflux disease (NERD). The objective of this study was to investigate potential differences in autonomic function by means of heart rate variability in GERD patients with and without erosive esophagitis. MATERIAL AND METHODS: Thirty-five GERD patients and 20 healthy controls participated in the study. Seventeen subjects with NERD and 18 patients with erosive reflux disease (ERD) were identified based on typical reflux symptoms, endoscopic findings, and 24-h esophageal pH. Spectral analysis of heart rate variability was performed to calculate the low-frequency (LF) band, the high-frequency (HF) band, and the LF/HF ratio. RESULTS: No significant differences were found in age, gender, body mass index, or current tobacco use among the reflux patients and controls. The Helicobacter pylori status and severity of reflux symptoms were similar between the two groups. The HF band power was significantly lower in patients with ERD than in NERD patients (p < 0.01) and controls (p < 0.05). LF band power (%) and LF/HF ratio were significantly lower in the NERD patients compared with ERD patients (p < 0.05) and controls (p < 0.05). There was no statistically significant correlation between any heart rate variability parameter and symptom severity score in either the ERD or NERD group. CONCLUSIONS: Patients with ERD and NERD display a similar degree of symptom severity, but the pattern of autonomic function appears to differ between NERD and ERD.

Adult↗
PubMed2006

Part of the series: from dietary antioxidants to regulators in cellular signalling and gene expression. Role of reactive oxygen species and (phyto)oestrogens in the modulation of adaptive response to stress.

There is increasing evidence that reactive oxygen species (ROS) are not only toxic but play an important role in cellular signalling and in the regulation of gene expression. We, here, discuss two examples of improved adaptive response to an altered cellular redox state. First, differences in longevity between males and females may be explained by a higher expression of antioxidant enzymes in females resulting in a lower yield of mitochondrial ROS. Oestrogens are made responsible for these phenomena. Oestradiol induces glutathione peroxidase-1 and MnSOD by processes requiring the cell surface oestrogen receptor (ER) and the activation of pathways usually involved in oxidative stress response. Second, oxygen radicals produced during moderate exercise as performed during training up-regulate the expression of antioxidant enzymes in muscle cells. An increased level of these enzymes might prevent oxidative damage during exhaustive exercise and should, therefore, not be prevented by antioxidants. The relevance of these findings is discussed in the context with observations made in transgenic animals overexpressing MnSOD or catalase.

Aging↗
PubMed2006

Effect of laparoscopic Nissen fundoplication on symptoms and gastric myoelectric activity in gastroesophageal reflux disease.

BACKGROUND: Laparoscopic Nissen fundoplication is an effective treatment for gastroesophageal reflux disease (GERD). The aim of this study was to determine whether laparoscopic fundoplication alters gastric myoelectric activity. Change of digestive symptoms was also assessed. METHODS: Sixteen patients with GERD (2 males, 14 females, mean age: 53 years) undergoing a laparoscopic fundoplication participated. Electrogastrography (EGG) was assessed before and after the subject ingested water until full (water load). Symptoms of upper abdominal discomfort, early satiety, postprandial abdominal distension, nausea, vomiting, and anorexia were recorded. At a 2-month postoperative follow-up, preoperative tests were repeated. RESULTS: The EGG was abnormal in 11 of 16 patients (69%) preoperatively and 6 of 16 patients (38%) postoperatively. The EGG changed from abnormal to normal in 5 of 16 patients (31%). The percentage of power at 3 cpm increased significantly during the fasting state postoperatively (29.9% vs. 21.2%, P < 0.05). There was a significant improvement in epigastric pain (P < 0.001), early satiety (P < 0.01), and postprandial fullness (P < 0.001). CONCLUSIONS: Increased presence of normal 3 cpm activity is the predominant effect of fundoplication on gastric myoelectric activity. Dyspeptic symptoms are also significantly improved postoperatively.

Adult↗
PubMed2005

Therapeutic options in the treatment of nighttime gastroesophageal reflux.

Approximately three quarters of individuals who suffer from gastroesophageal reflux disease (GERD) experience its symptoms at night. Nighttime GERD symptoms disturb sleep and diminish quality of life more so than daytime symptoms. Nighttime gastroesophageal reflux is common in individuals with respiratory disorders such as sleep apnea and asthma, and may affect the severity and the frequency of these disorders. The treatments of choice for nighttime GERD symptoms are proton pump inhibitors (PPIs) due to their efficacy in relieving day- and nighttime GERD symptoms and controlling acid secretion. The onset of action, degree of acid suppression, and duration of effect of PPIs have important implications for the use of these therapies in clinical practice. PPIs that exhibit rapid and prolonged control of acid secretion may be particularly useful for treating nighttime GERD symptoms.

Circadian Rhythm↗
PubMed2005

Mechanisms of gamma-glutamylcysteine ligase regulation.

The principal objective of this study was to investigate the mechanisms regulating the activity of gamma-glutamylcysteine ligase (GCL; EC 6.3.2.2), the rate limiting enzyme in glutathione biosynthesis. Two phylogenetically divergent species, mouse and the fruitfly, Drosophila melanogaster were used to test the hypothesis that reversible protein phosphorylation and pyridine dinucleotide phosphate dependent allostery regulate GCL activity. GCL was almost completely inhibited under phosphorylating conditions, involving preincubations with MgATP and endogenous protein kinases. Maximal GCL inhibitions of 94%, 77%, 85%, 87%, 83%, 95% and 89% occurred, respectively, in mouse cerebellum, hippocampus, brainstem, striatum, cortex and heart, and Drosophila. These changes in GCL activity were detected using saturating levels of substrates, suggesting that V(max) was dramatically affected, whereas K(m) values showed no differences. In vitro activation of GCL, presumably due to dephosphorylation, was blocked by inhibitors of protein phosphatases, suggesting that GCL exists in vivo as a mixture of phosphorylated and dephosphorylated forms. The reversibility of the dephosphorylation-dependent activation was indicated by the time-dependent inactivation of the in vitro activated Drosophila GCL, by preincubation with MgATP. NADPH increased maximal GCL activity by up to 93%, whereas several other nucleotide analogues did not, thereby demonstrating specificity. Kinetic analysis using Hanes-Woolf replots of initial velocity data suggested that the NADPH-dependent stimulation of GCL activity is brought about by a change in the maximal activity, V(max), rather than changes in substrate affinity. Results of this study suggest that mechanisms of modulation of eukaryotic GCL enzymes may include specific binding of ligands such as pyridine dinucleotide phosphates and reversible protein phosphorylation.

Adenosine Triphosphate↗
PubMed2005

Enhanced catabolism of mitochondrial superoxide/hydrogen peroxide and aging in transgenic Drosophila.

The generation of superoxide anion radicals (O2*-) and hydrogen peroxide (H2O2) during mitochondrial respiration has been widely postulated to be causally linked to the aging process. The hypothesis that a specific enhancement of mitochondrial O2*-/H2O2 catabolism would delay age-associated physiological changes and extend the lifespan was tested by simultaneous overexpression of MnSOD (manganese superoxide dismutase) and catalase, ectopically targeted to the mitochondrial matrix of transgenic Drosophila melanogaster. The increased activities of these antioxidative enzymes resulted in a decrease of mitochondrial H2O2 release and enhancement of free methionine content. The MnSOD/mitochondrial catalase transgenic flies displayed an enhanced resistance to experimental oxidative stress, induced by dietary H2O2 administration or by exposure to 100% ambient oxygen. However, the lifespan of the flies was decreased, by up to 43%, and this effect coincided with (i) an overall decrease in physical fitness, as measured by the speed of walking, and (ii) an age-related decrease in mitochondrial state 3 (ADP-stimulated) respiration. These findings support the notion that mitochondrial O2*-/H2O2 production at physiological levels is essential for normal biological processes leading to the attainment of a normal lifespan.

Aging↗
PubMed2005

Overexpression of glutamate-cysteine ligase extends life span in Drosophila melanogaster.

The hypothesis that overexpression of glutamate-cysteine ligase (GCL), which catalyzes the rate-limiting reaction in de novo glutathione biosynthesis, could extend life span was tested in the fruit fly, Drosophila melanogaster. The GAL4-UAS binary transgenic system was used to generate flies overexpressing either the catalytic (GCLc) or modulatory (GCLm) subunit of this enzyme, in a global or neuronally targeted pattern. The GCL protein content of the central nervous system was elevated dramatically in the presence of either global or neuronal drivers. GCL activity was increased in the whole body or in heads, respectively, of GCLc transgenic flies containing global or neuronal drivers. The glutathione content of fly homogenates was increased by overexpression of GCLc or GCLm, particularly in flies overexpressing either subunit globally, or in the heads of GCLc flies possessing neuronal drivers. Neuronal overexpression of GCLc in a long-lived background extended mean and maximum life spans up to 50%, without affecting the rate of oxygen consumption by the flies. In contrast, global overexpression of GCLm extended the mean life span only up to 24%. These results demonstrate that enhancement of the glutathione biosynthetic capability, particularly in neuronal tissues, can extend the life span of flies, and thus support the oxidative stress hypothesis of aging.

Animals↗
PubMed2005

Age-associated decline in mitochondrial respiration and electron transport in Drosophila melanogaster.

The principal objective of the present study was to identify specific alterations in mitochondrial respiratory functions during the aging process. Respiration rates and the activities of electron transport chain complexes were measured at various ages in mitochondria isolated from thoraces of the fruit fly, Drosophila melanogaster, which consist primarily of flight muscles. The rates of state 3 respiration (ADP-stimulated), RCRs (respiratory control ratios) and uncoupled respiration rates decreased significantly as a function of age, using either NAD+- or FAD-linked substrates; however, there were no differences in state 4 respiration (ADP-depleted) rates. There was also a significant age-related decline in the activity of cytochrome c oxidase (complex IV), but not of the other mitochondrial oxidoreductases examined. Exposure of mitochondria isolated from young flies to low doses of KCN or NaAz (sodium azide), complex IV inhibitors, decreased cytochrome c oxidase activity and increased the production of H2O2. Collectively, these results support the hypothesis that impairment of mitochondrial respiration may be a causal factor in the aging process, and that such impairment may result from and contribute to increased H2O2 production in vivo.

Aging↗
PubMed2005

Comparison of esophageal motility in patients with solid dysphagia and mixed dysphagia.

It is unclear whether there is any difference in esophageal motor abnormalities between patients complaining of dysphagia for solids or both solids and liquids. The aim of this study was to determine any difference in the manometric findings between patients with dysphagia for solids and those with mixed dysphagia. Manometric tracings were performed in 200 consecutive patients (66 M, 134 F; mean age = 51 years) with nonobstructive dysphagia. Ambulatory pH studies were performed in all patients. Subjects were divided into two groups: patients with solid dysphagia (n = 94, 33 M, 61 F; mean age = 51 years) and those with mixed dysphagia (n = 106, 33 M, 73 F; mean age = 51 years). A normal motility study was the most frequent finding. Achalasia occurred more frequently in patients with mixed dysphagia than in those with solid dysphagia (12% vs. 3%, p < 0.01). Gastroesophageal reflux disease (GERD) was observed in 59% of patients with solid dysphagia compared with 29% of patients with mixed dysphagia (p < 0.02). The most common esophageal motility abnormality is nonspecific esophageal motility disorders. This study has shown that abnormal esophageal motility occurs slightly more in mixed dysphagia than solid dysphagia. The clinical utility of a symptomatic differentiation of patients with solid or mixed dysphagia appears to be limited.

Adult↗
PubMed2005

Sleep and the gastrointestinal tract.

In this review, an integration of GI functioning is attempted with regard to its relationship to sleep, how this interaction may lead to complaints of sleep disorders, and the pathogenesis of some GI disorders. Data are presented to support the notion that sleep-related GER is an important factor not only in the development of esophagitis but also in the respiratory complications of GER. Although sensory functioning is altered markedly during sleep with regard to most standard sensory functions (eg, auditory), there seems to be an enhancement of some visceral sensation during sleep that seems to protect the tracheobronchial tree from aspiration of gastric contents reflux during sleep. Patients who have functional bowel disorders reveal an increase in sleep complaints compared with normal volunteers. The actual mechanisms of these disturbances remain somewhat obscure and studies do not demonstrate any consistent abnormalities in sleep patterns of these patients. Some studies show that autonomic functioning during sleep, particularly REM sleep, can distinguish patients who have IBS. Thus, the continued study of sleep and GI functioning promises to create a new dimension in the understanding of the pathophysiology of a variety of GI disorders.

Colon↗
PubMed2005

Night-time gastro-oesophageal reflux disease: prevalence, hazards, and management.

Patients who complain of symptoms of gastro-oesophageal reflux disease (GORD) that occur at night require special attention. Night-time GORD can profoundly impair quality of life by causing pain, disturbing sleep, and interfering with next-day mental and physical functioning. Sleep impairs oesophageal acid clearance resulting in a prolongation of acid mucosal contact, and nocturnal reflux portends a greater risk of erosive oesophagitis and other significant complications of gastro-oesophageal reflux. Lifestyle changes such as elevating the head of the bed and adjusting the sleeping position can relieve night-time heartburn, and instituting some dietary changes along with occasional use of histamine H2 blockers can also be helpful. Relief of night-time reflux and its attendant symptoms usually requires a medication with acid-suppressing properties that extend into the sleeping interval. In most instances, more powerful acid suppression in the form of proton-pump inhibitors will be required. Clinical studies have shown that 40 mg esomeprazole provides better control of night-time GORD symptoms than 20 mg omeprazole or 30 mg lansoprazole. Furthermore, 40 mg pantoprazole offers even faster relief than 40 mg esomeprazole for night-time GORD symptoms. Of the several proton-pump inhibitors available on the market, esomeprazole and pantoprazole appear to have some advantages, which have been documented in recent studies. Esomeprazole has been shown to be more effective than lansoprazole in relieving GORD symptoms, and esomeprazole and pantoprazole appear to be equally effective in resolving GORD symptoms in a comparative study. Pantoprazole has pharmacokinetic properties that document a longer half-life compared with the other proton-pump inhibitors, and pantoprazole has the slowest inhibition recovery rate. These properties lend credence to pantoprazole as an effective treatment for associated symptoms of night-time reflux.

2-Pyridinylmethylsulfinylbenzimidazoles↗
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↗