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Biomedical subjects

William C Orr

Publications and source records attributed to William C Orr.

At least 37 records · Page 2Linked to original sources
PubMed2004

Effect of caloric restriction on life span of the housefly, Musca domestica.

Caloric restriction (CR) has been found to extend the life spans of a wide variety of species, transcending phylogenetic boundaries. The objective of this study was to test the generality of this phenomenon, using the male housefly as an insect model in which food intake can be quantified precisely. Sucrose was found to promote a longer life span than diets additionally containing proteins and lipids. Flies were fed sucrose or a more complex diet ad libitum (AL), or in amounts ranging from 50% to 100% of the average amount consumed by young flies. CR shortened rather than prolonged the life span of houseflies, particularly flies fed sucrose only. The rate of oxygen consumption was not affected by caloric restriction or by the exclusion of proteins and lipids from the diet, and the reproductive activity of male flies remained unchanged by sucrose feeding. Thus, it is unlikely that the life-shortening effects of CR can be explained either in terms of an adaptive response in metabolic rate or use of a suboptimal food source. Results of this study contradict the widely held view that CR has a life-extending effect in all species.

Aging↗
PubMed2004

Free aminothiols, glutathione redox state and protein mixed disulphides in aging Drosophila melanogaster.

The main purpose of the present study was to test the hypothesis that the aging process is associated with a pro-oxidizing shift in the cellular redox state. The amounts of the redox-sensitive free aminothiols (glutathione, cysteine, Cys-Gly and methionine) and protein mixed disulphides were measured at different ages and ambient temperatures in Drosophila melanogaster. GSH/GSSG ratios decreased significantly with increasing age of the flies, due to an increase in GSSG content. Concentrations of Cys-Gly increased and methionine decreased with age. The amounts of protein mixed disulphides, measured as protein-cysteinyl, protein-Cys-Gly and protein-glutathionyl mixed disulphides, increased as a function of age. The pattern of changes in free aminothiol content, glutathione-redox state and protein mixed disulphides varied in proportion to the ambient temperature, which is inversely related to the life expectancy of the flies. Collectively, these results support the idea that the pro-oxidizing shift in the glutathione-redox state, the decrease in methionine content and increase in abundance of protein mixed disulphides are associated with the life expectancy of flies, and are indicative of enhanced oxidative stress during aging.

Aging↗
PubMed2004

Profiling Cu,Zn-superoxide dismutase expression in Drosophila melanogaster--a critical regulatory role for intron/exon sequence within the coding domain.

Cu,Zn-superoxide dismutase (SOD1) represents along with catalase the first coordinated line of defense against ROS and is found in all aerobic organisms. The dissection of the regulatory controls that drive the expression of SOD1 may provide further insight into the functional significance of this enzyme. The aim of this study was to elucidate temporal and spatial patterns of SOD1 expression, as well as to identify gene domains that govern its expression. Immunostaining analysis was used to delineate marked tissue and stage-specific expression patterns during the course of development and aging. By and large, there were no significant alterations in SOD1 mRNA and protein levels in response to the stress that accompanies aging, nor in response to different environmental insults, such as heat and hyperoxia. Expression of SOD1 seems to be largely determined by intrinsic factors. By histochemical analysis of transgenics carrying various sod1-reporter gene fusions, it was also possible to identify sequence domains, governing SOD1 expression. In particular a 1140 base pair region, composed of the single sod1 intron along with exon 2, was found to be essential for permitting spatial and temporal expression patterns that approximate normal endogenous expression.

Aging↗
PubMed2004

Transfer function analysis of heart rate variability in response to water intake: correlation with gastric myoelectrical activity.

We utilized transfer function analysis of heart rate variability (HRV) and respiration to investigate the effect of water intake on gastric myoelectrical activity and its relationship to vagal activity. The electrogastrography (EGG) and HRV were recorded simultaneously before and after drinking 500 ml of water in 10 healthy subjects. We observed good linearity between lung volumes and HRV signals at a ventilatory rate between 0.2 and 0.4 Hz before and after water intake. The EGG power of 3 cycles/min increased remarkably after the water intake. We found that there was a significant increase in the magnitude of the respiration-HRV transfer function after water intake (P < 0.05). The EGG 3 cycles/min power was positively correlated with the transfer magnitude throughout the study (r = 0.54, P = 0.01). These results confirm that transfer function analysis of HRV sensitively identifies subtle changes in the respiratory sinus arrhythmia that occurs with water intake. The present findings suggest that transfer function analysis of HRV and respiration after water intake can be used to evaluate vagal nervous activity in the human gut.

Adult↗
PubMed2004

Profiling catalase gene expression in Drosophila melanogaster during development and aging.

Catalase represents one of the key antioxidant enzymes (AOE) in the metabolism of oxygen free radicals. A comprehensive analysis was brought to bear on establishing catalase gene expression profiles during development and aging, with the underlying objective being to identify potential regulatory factors. Expression of the catalase gene exhibits substantial variations during development and aging in a stage- and tissue-specific manner. At the temporal level, previous observations of the coincidence of ecdysteroid pulses with peaks in catalase expression during developmental stages were largely corroborated. In adults, a small but significant decline in catalase expression was noted in adults as a function of age. Spatially, it was ascertained that catalase expression is mostly confined to tissues related to intermediary metabolism, digestive and adipose systems as well as oenocytes. By combining histochemical analysis of reporter gene expression with immunostaining of the endogenous product, it was possible to identify putative positive and negative regulatory elements that control catalase expression. Finally, when adult flies were subjected to various environmental insults, such as heat, paraquat, hyperoxia and H(2)O(2), no significant responses were observed, suggesting that catalase gene expression is largely governed by intrinsic genetic programs.

Aging↗
PubMed2004

Nightly variability of sleep-disordered breathing measured over 3 nights.

OBJECTIVE: To examine the nightly variability of sleep-disordered breathing (SDB) as measured by the apnea-hypopnea index (AHI). STUDY DESIGN AND SETTING: Retrospective comparison of 3 sequential nights of testing performed in the home in 1091 patients who were referred for diagnostic testing of SDB. RESULTS: The Pearson and Intraclass correlation coefficients ranged between 0.88 and 0.90 for each pair of nights. Based on night 1, approximately 90% of patients were classified consistently with "AHI-high" (the highest AHI measured across the 3 nights) using an AHI threshold of 5. However, 10% were misclassified on night 1 relative to the highest AHI level. CONCLUSION AND SIGNIFICANCE: These findings suggest that (1) 1 night of diagnostic testing for SDB is not sufficient to diagnosis SDB in approximately 1 of every 10 cases, and (2) there is little, if any, significant nightly change in SDB in the home environment. EBM RATING: D.

Adolescent↗
PubMed2004

Modulation of sleep quality and autonomic functioning by symptoms of depression in women with irritable bowel syndrome.

The objective of this study was to determine how depressive symptoms affect autonomic activity during sleep, objective and subjective sleep, and gastrointestinal symptom severity in women with irritable bowel syndrome (IBS). Seventy women who met the Rome II criteria for IBS and 21 healthy volunteers participated. All participants were recruited from the surrounding community. IBS patients were stratified into two groups based on their Beck Depression Inventory II score and 44 IBS patients with depressive symptoms (IBS+DS) were compared to 26 IBS patients without depressive symptoms (IBS-DS). Autonomic activity was measured by heart rate variability (HRV) analysis. Fifteen-minute segments were selected from a baseline presleep period, stage 2, slow-wave sleep, and rapid-eye movement sleep for heart rate variability spectral analysis. Subjective sleep quality was assessed by the Pittsburg Sleep Quality Index (PSQI) and gastrointestinal symptom severity was assessed by an 18-item questionnaire. The IBS+DS group reported significantly (P < 0.01) more sleep complaints, measured by the PSQI, than the IBS-DS group and healthy controls. The IBS+DS group took significantly (P < 0.05) longer to enter their first rapid-eye movement period than healthy controls. The IBS+DS group reported significantly (P = 0.01) increased gastrointestinal symptom severity compared to the IBS-DS group. There were no significant group differences in autonomic activity during the baseline presleep period or sleep stages. The results demonstrated that IBS patients with significant depressive symptoms had increased gastrointestinal symptom severity, increased sleep complaints, and alterations in sleep architecture compared to healthy controls and IBS patients without significant depressive symptoms.

Adult↗
PubMed2004

Autonomic responses to heartburn induced by esophageal acid infusion.

BACKGROUND AND AIM: Studies have shown that altered visceral perception and lower pain thresholds in patients with symptomatic gastroesophageal reflux disease (GERD) and non-cardiac chest pain. Autonomic changes associated with the perception of heartburn in patients with GERD are poorly understood. METHODS: A total of 12 GERD patients (six male, six female; mean age 37.2 +/- 2.7 years) and 12 controls (five male, seven female; mean age 32.8 +/- 2.2 years) were studied. The study protocol included a 20-min water infusion (6 mL/min), and 20-min acid infusion (0.1 N HCl, 6 mL/min). Spectral analysis of heart-rate variability (HRV) was used to assess autonomic functioning. The measured HRV indices included the power in the low-frequency (LF) band (0.04-0.15 Hz) reflecting sympathetic tone, and power in the high-frequency (HF) band (0.15-0.5 Hz) reflecting vagal tone, and the LF/HF ratio as an indicator of sympathovagal balance. RESULTS: The GERD group experienced more heartburn than controls with acid infusion. Between-group comparisons showed no significant changes in LF band power in any period. The HF band power was significantly lower in GERD patients during all infusion periods. The LF/HF ratio was significantly larger in GERD patients. CONCLUSIONS: The perception of heartburn induced by esophageal acid infusion is associated with a simultaneous increase in sympathetic modulation in patients with GERD. The autonomic responses with esophageal acid infusion are significantly different between healthy subjects and GERD patients.

Adult↗
PubMed2004

Sleep and gastroesophageal reflux disease: a wake-up call.

The medical community has mostly ignored the relationship between sleep and gastroesophageal reflux (GER), although recent studies have begun to explore the connection and suggest possible treatments. These studies have found that the relationship is reciprocal; reflux influences sleep and sleep influences reflux. It has been found that nighttime GER can result in a number of complications, and more generally, lower the quality of life for its sufferers, establishing sleep-related GER as a more intolerable form of GER. Though some lifestyle modifications may help reduce the risk of nighttime reflux, the use of a proton pump inhibitor may be a valuable tool in the management of both heartburn and nighttime GER.

Gastroesophageal Reflux↗
PubMed2003

Sleep and gastroesophageal reflux: what are the risks?

To understand the phenomenon of sleep-related gastroesophageal reflux, it is necessary to understand how sleep alters basic physiologic mechanisms. Several mechanisms are depressed during sleep, which may lead to prolonged acid contact times. These mechanisms include the warning signal of heartburn, the frequency of swallowing, and the suppression of salivary secretion. Several investigations have shown that esophageal acid clearance is significantly prolonged during sleep, compared with the waking state; this is true even when sleeping subjects are compared with awake subjects in the supine position. Studies have also demonstrated an enhanced risk of pulmonary aspiration of gastric contents associated with depressed consciousness, likely related to the depression of upper airway protective mechanisms such as cough and swallowing. Available data also support the theory that certain endogenous response mechanisms involving the central nervous system that protect against the potentially damaging consequences of prolonged acid mucosal contact are invoked during sleep.

Deglutition↗
PubMed2003

Effects of overexpression of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster.

The overexpression of antioxidative enzymes such as CuZn-superoxide dismutase (SOD), Mn-SOD, and catalase has previously been reported to extend life span in transgenic flies (Drosophila melanogaster). The purpose of this study was to determine whether life-extending effects persist if the recipient control strains of flies are relatively long-lived. Accordingly, the life spans of large numbers of replicate control and overexpressor lines were determined in two long-lived genetic backgrounds involving a combined total of >90,000 flies. Significant increases in the activities of both CuZn-SOD and catalase had no beneficial effect on survivorship in relatively long-lived y w mutant flies and were associated with slightly decreased life spans in wild type flies of the Oregon-R strain. The introduction of additional transgenes encoding Mn-SOD or thioredoxin reductase in the same genetic background also failed to cause life span extension. In conjunction with data from earlier studies, the results show that increasing the activities of these major antioxidative enzymes above wild type levels does not decrease the rate of aging in long-lived strains of Drosophila, although there may be some effect in relatively short-lived strains.

Aging↗
PubMed2003

Thioredoxin peroxidases can foster cytoprotection or cell death in response to different stressors: over- and under-expression of thioredoxin peroxidase in Drosophila cells.

Recently, we identified a set of five genes constituting the peroxiredoxin gene family in Drosophila melanogaster [Radyuk, Klichko, Spinola, Sohal and Orr (2001) Free Radical Biol. Med. 31, 1090-1100]. This set includes two abundant thioredoxin peroxidase (TPx) species, namely Drosophila peroxiredoxin DPx-4783, a cytosolic TPx and DPx-5037, a mitochondrial TPx. Overexpression of either one of them in Drosophila S2 cells conferred increased resistance to toxicity induced by hydrogen peroxide, paraquat or cadmium. To understand further the functional roles of these enzymes in vivo, we report in the present study the effects of decreased expression, using RNA interference, on the response of S2 cells to different stressors. When either of the TPxs was blocked, cells became relatively more susceptible to oxidative stress caused by exposure to hydrogen peroxide or paraquat, but were unaffected when challenged with copper and heat stress. In contrast, TPx overexpressing cells were more susceptible to copper and heat stress when compared with control cells and exhibited DNA fragmentation. Furthermore, when cells were supplemented with N -acetyl-L-cysteine together with copper, there was a clear negative effect on cell survival, which was exacerbated by TPx overexpression. Manipulations in the levels of TPxs demonstrated that, under different stress conditions, these enzymes might have both beneficial and detrimental effects on Drosophila cell viability.

Acetylcysteine↗
PubMed2003

Ectopic expression of catalase in Drosophila mitochondria increases stress resistance but not longevity.

The goal of this study was to test the hypothesis that the rate of mitochondrial oxidant production governs the aging process of the fruit fly, Drosophila melanogaster. Catalase, an antioxidative enzyme expressed in the cytosol and peroxisomes of Drosophila, was targetted ectopically to the mitochondrial matrix by fusion of a leader peptide derived from ornithine aminotransferase with its N-terminus. The presence of the transgene encoding this fusion protein was associated with moderate (35 +/- 13%) increases in total catalase activity in most lines, and measurable levels of catalase activity in the mitochondria (30-140 U/mg protein). There was no impact on the life span of the flies at 25 degrees C, even in an exceptional line with a 149% increase in total catalase activity, and there was a small decrease in longevity at 29 degrees C. There were no compensatory changes in the rate of metabolism or physical activity, or in the levels of other major antioxidants, suggesting that the aging process was largely unaffected. Resistance to exogenous hydrogen peroxide, paraquat, and cold stress was enhanced, but there was no appreciable effect on resistance to hyperoxia. The results demonstrate the importance of mitochondrial antioxidant levels in the resistance to oxidative stress at the organismal level, and illustrate that different effects on aging and stress resistance may ensue from a single treatment. The main inferences drawn are that: (i) levels of stress resistance may neither be a cause nor a reliable indicator of the rate of aging, and (ii) bolstering antioxidant levels in Drosophila may not delay or slow down the aging process.

Animals↗
PubMed2003

Does overexpression of Cu,Zn-SOD extend life span in Drosophila melanogaster?

The argument is presented here that, while there exists considerable correlative evidence supporting the oxidative stress hypothesis of aging, key experiments to test this hypothesis using Drosophila transgenics overexpressing Cu,Zn-SOD fall short in providing validation. In particular, significant life span extensions tend to be observed when the backgrounds of the control flies are relatively short-lived, suggesting that bolstering antioxidative defenses is only effective in compromised genetic backgrounds. Other shortcomings of the transgenic approaches adopted to date will be summarized.

Animals↗
PubMed2003

Sleep issues in gastroesophageal reflux disease: beyond simple heartburn control.

There is a burgeoning interest in the relationship between sleep-related gastroesophageal reflux (GER) and the development of esophageal and extra esophageal complications. The physiological changes associated with sleep, such as suspension of the regulation of body temperature, may influence nocturnal GER and esophageal acid clearance. Data indicate that sleep induces considerable risk of prolonged acid mucosal contact and facilitates the occurrence of proximal migration of acid, thereby increasing the probability of pulmonary aspiration. Nocturnal GER can lead to the development of esophagitis and other extra esophageal complications, such as exacerbation of asthmatic symptoms.

Antacids↗
PubMed2002

Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila.

A subset of patients suffering from familial amyotrophic lateral sclerosis (FALS) exhibit point mutations in the gene encoding Cu-Zn superoxide dismutase [superoxide:superoxide oxidoreductase, EC (SOD)]. The human wild-type and five FALS Sod mutant transgenes were introduced into the fruit fly, Drosophila melanogaster, in a Cu-Zn Sod null background. Sod null flies had dramatically decreased life span, glutathione and methionine content, fertility, locomotor activity, and resistance to hyperoxic stress, compared with wild-type controls. All of these phenotypic manifestations were rescued fully by a single human wild-type allele, expressing 5-10% of wild-type SOD activity. Full recovery of wild-type life span was also observed when human mutant and wild-type alleles were placed together in the fly Sod null background. The FALS Sod mutations alone caused a recessive phenotype, usually involving low or undetectable levels of SOD activity, in which: (i) full restoration of the wild-type phenotype was observed among young adults, and (ii) older adults exhibited a sudden increase in oxidative stress, accompanied by physiological impairment of abrupt onset, and followed by premature death. Thus, the minimal SOD activity associated with the FALS Sod mutations appears to determine longevity, not by chronically increasing oxidative stress, but by limiting the time in which a viable redox environment can be maintained. However, the dominant gain of function by mutant SOD, which occurs in human patients and in the transgenic mouse model of FALS, is not observed in Drosophila.

Aging↗
PubMed2002

Mechanisms of aging: an appraisal of the oxidative stress hypothesis.

The main purpose of this article is to provide a critical overview of the currently available evidence bearing on the validity of the oxidative stress hypothesis of aging, which postulates that senescence-associated attenuations in physiological functions are caused by molecular oxidative damage. Several lines of correlative evidence support the predictions of the hypothesis, e.g., macromolecular oxidative damage increases with age and tends to be associated with life expectancy of organisms. Nevertheless, a direct link between oxidative stress and aging has not as yet been established. Single gene mutations have been reported to extend the life spans of lower organisms, such as nematodes and insects; however, such prolongations of chronological clock time survival are usually associated with decreases in the rate of metabolism and reproductive output without affecting the metabolic potential, i.e., the total amount of energy consumed during life. Studies on genetic manipulations of the aging process have often been conducted on relatively short-lived strains that are physiologically weak, whereby life-span extensions can not be unambiguously assigned to a slowing effect on the rate of aging. It is concluded that although there is considerable evidence implicating oxidative stress in the aging process, additional evidence is needed to clearly define the nature of the involvement.

Aging↗